Francisco T. Gallo
Cynthia Katche
Juan F. Morici
Jorge H. Medina
Noelia V. Weisstaub- 1Instituto de Fisiología y Biofísica Bernardo Houssay, Departamento de Fisiología, Facultad de Medicina, Universidad de Buenos Aires (UBA), Buenos Aires, Argentina
- 2Instituto de Biología Celular y Neurociencias (IBCN) Dr. Eduardo de Robertis, Facultad de Medicina, CONICET, Universidad de Buenos Aires (UBA), Buenos Aires, Argentina
- 3Departamento de Fisiología, Facultad de Medicina, Universidad de Buenos (UBA), Buenos Aires, Argentina
Many psychiatric disorders, despite their specific characteristics, share deficits in the cognitive domain including executive functions, emotional control and memory. However, memory deficits have been in many cases undervalued compared with other characteristics. The expression of Immediate Early Genes (IEGs) such as, c-fos, Egr1 and arc are selectively and promptly upregulated in learning and memory among neuronal subpopulations in regions associated with these processes. Changes in expression in these genes have been observed in recognition, working and fear related memories across the brain. Despite the enormous amount of data supporting changes in their expression during learning and memory and the importance of those cognitive processes in psychiatric conditions, there are very few studies analyzing the direct implication of the IEGs in mental illnesses. In this review, we discuss the role of some of the most relevant IEGs in relation with memory processes affected in psychiatric conditions.
Introduction
The diagnoses of psychiatric disorders are based on a cluster of specific symptoms. The genetic, clinical and neuroimaging evidence suggests that they share important features including common affected functions (Bearden and Freimer, 2006). Dysregulation of some mnemonic processes and the mechanisms of neuroplasticity could contribute to prevalent neuropsychiatric diseases. Many psychiatric disorders, despite their specific characteristics, share deficits in the cognitive domain including executive functions, emotional control and memory (Pittenger, 2013). Even though memory deficits have been in many cases undervalued compared with other characteristics, they can be considered as an endophenotype across many psychiatric disorders (Kéri and Janka, 2004; Gur et al., 2007; Henry et al., 2012). Of the many types, episodic and fear memories are two main categories commonly affected in different psychiatric disorders (Dickerson and Eichenbaum, 2010). Episodic memory deficits have been reported in schizophrenia, autism, bipolar disorder, obsessive-compulsive disorder, panic disorder and major depression (Muller and Roberts, 2005; Exner et al., 2009; Brezis, 2015; Czepielewski et al., 2015; Herold et al., 2015; Oertel-Knöchel et al., 2015; Ragland et al., 2015; Vrabie et al., 2015; Meconi et al., 2016; Solomon et al., 2016; Whitton et al., 2016; Green et al., 2017). Fear memories can be linked to anxiety and particularly to post-traumatic stress disorder (PTSD; Parsons and Ressler, 2013; Briscione et al., 2014).
For decades, Immediate Early Genes (IEGs) were used as an indirect marker to measure neuronal activity and, although many of them are routinely measured in thousands of labs around the world, their role in many biological processes is still unknown. The IEGs most commonly used to map neuronal activity, c-fos and Egr1, have had their expression time-course systematically studied (for mRNA and protein expression dynamics; Mello and Ribeiro, 1998; Bisler et al., 2002; Zangenehpour and Chaudhuri, 2002). They encode transcription factors that influence neuronal physiology by regulating the expression of downstream target genes, normally referred to as late-response genes (Curran and Morgan, 1987; Curran and Franza, 1988; Herdegen and Leah, 1998; O’Donovan et al., 1999; Tischmeyer and Grimm, 1999; Pinaud, 2004; Pinaud et al., 2005). Both c-Fos and Egr1 interact with an array of other transcription factors (Herdegen and Leah, 1998; Knapska and Kaczmarek, 2004). Besides, other IEGs encode proteins that directly influence cellular function, as in the case of arc (reviewed in Lanahan and Worley, 1998).
The expression of, c-fos, Egr1 and arc are related in literature to learning and memory. Changes in their expression observed in a limited number of cells in regions associated with learning and memory lead to widespread use as readout of plastic changes subserving long-term memory formation and maintenance in specific neuronal populations (Rosen et al., 1998; Guzowski et al., 1999; Ramírez-Amaya et al., 2005; Minatohara et al., 2016). In this review, we focus on the role of, c-Fos, Egr1 and Arc since they have been associated to different memory processes, becoming good candidates as markers or effectors of these processes usually affected in psychiatric conditions.
Memory and Psychiatric Disorders
Memory is a complex process through which the information acquired during learning is stored. Memory processes can be studied by their stages (acquisition, consolidation, and retrieval), duration (short-term and long-term) and to the type of information that it is stored (explicit and implicit), which are reviewed somewhere else (Eysenck, 1988; Abel and Lattal, 2001; Kandel et al., 2014; Squire and Dede, 2015). We now have significant knowledge and consensus regarding the phases of the memory process as well as some of the key structures, signaling pathways and genes involved in many different types of memories. Though it is still a matter of debate “where” and “how” memories are stored, memories are “stored” as spatiotemporal representations within a given neuronal network (Davis et al., 2006). Then, a particular memory might produce an identifiable pattern due to expression of a specific set of activity dependent genes.
Memory consolidation is a process that is proposed to occur at the same synapses involved in the encoding of the information (Dudai, 2002). It includes the activation of transcription factors, protein synthesis, and post-translational modification that lead to plastic changes that make the memory trace stable (Lamprecht and LeDoux, 2004; Morris, 2006; Alberini, 2009; Ruediger et al., 2011). During retrieval, memory reactivation can trigger two quite different processes, extinction or reconsolidation. The reactivated memory trace becomes labile and is susceptible to being modified or disrupted in the process called reconsolidation. If there is a reinforcement of the original trace during retrieval, the reconsolidation—a protein synthesis-dependent process—re-stabilizes the original memory trace (Lee, 2008). On the contrary, after repeated reactivations in the absence of the appropriate reinforcement, memory extinction is triggered, leading to the loss in memory expression. This process is also protein-synthesis dependent and evidence shows that a new memory trace is formed, replacing the original one without erasing it (Quirk and Mueller, 2008). Then, it emerges that from the clinical point of view, it is important to understand the underlying mechanisms of these phenomena in order to develop new tools as novel treatment in Psychiatry (Monfils et al., 2009; Schiller et al., 2010).
In psychiatric disorders, episodic, working and fear memories are the most commonly affected types of memories, making them relevant to be studied in animal models (Dickerson and Eichenbaum, 2010; Parsons and Ressler, 2013; Briscione et al., 2014; Oertel-Knöchel et al., 2015; Meconi et al., 2016; Whitton et al., 2016; Martinussen et al., 2005; Rasetti and Weinberger, 2011). Episodic memories encode series of events that occur at a particular place and a specific time. Despite that episodic memories bear a strong anthropocentric character, it is now accepted that some characteristics of episodic memory, like recognition, are found in different species, allowing the study of their mechanisms and substrates in different models (Binder et al., 2015; Morici et al., 2015).
Working memory is the ability to maintain current representations of goal relevant knowledge. It is an executive component that is distributed across the frontal lobe together with sensory cortices of various modalities which interact through attentional processes (Postle, 2006; Carruthers, 2013). Over the years, working memory tasks were developed to allowed the study of working memory, its processes and neural substrates in different animal models (Carruthers, 2013; Dudchenko et al., 2013).
Although the expression of fear in animals might not have its exact correlate in humans, fear memories have been extensively studied in animal models to identify the neurobiological basis underlying memory processes (LeDoux, 2014; Izquierdo et al., 2016). Historically, the most common tasks used to study fear memories have been fear conditioning and inhibitory avoidance tasks. Both behavioral approaches are associative learning tasks, were an “unconditioned stimulus” (context or cue) is linked to an aversive “conditioned stimulus” (shock) resulting in a “conditioned response” (freezing or place avoidance). These kinds of tasks allowed the study of the molecular mechanisms and brain structures involved in the processing of fear memories.
Immediate Early Genes in Learning and Memory
IEGs represent a class of genes that respond rapidly and transiently to a variety of cellular stimuli (Hughes and Dragunow, 1995; Kaczmarek and Chaudhuri, 1997; Herdegen and Leah, 1998; Pinaud et al., 2005; Terleph and Tremere, 2006; Bahrami and Drabløs, 2016). There are more than 100 genes classified as IEGs (Sheng and Greenberg, 1990; Minatohara et al., 2016), although only a small subgroup was found in neurons (Sheng et al., 1995). Since the discovery of the regulation of IEGs in the brain by neural activity, there has been an extensive research using IEGs as neural activity markers in studies of behavior and cognition. However, there is some controversy regarding the physiological role that these genes might have. Over the years, different hypotheses were put forward. For example, some groups assigned IEGs a role in homeostatic maintenance or replenishment, while others found in IEG’s expression a role for the maintenance of activity dependent plastic changes (for review Dragunow, 1996). Another hypothesis suggested that they might be involved in mechanisms of information integration (Kaczmarek, 2000). Independently of the role that these genes have at a cellular level, it is clear that their expression is affected by neuronal activity and they are used as neuronal activity markers. In particular, some studies have reported changes in IEG expression associated with learning and memory processes and in connection with psychiatric disorders. In the next subsections we will discuss three of the most common IEGs studied in relation with memory processes and psychiatric disorders.
Molecular Mechanisms of c-Fos
c-Fos was one of the first transcription factors whose induction was shown to be activity-dependent (Morgan and Curran, 1988; Sagar et al., 1988). In neurons, c-fos expression appears to be stimulated by cAMP and Ca2+ through the activation of the CREB/CRE complex. The c-fos gene codes for the Fos protein that dimerizes with transcription factors of the Jun family to build up the transcription factor AP-1 (Chiu et al., 1988; Pennypacker, 1995).
c-Fos and Memory
c-fos is a clear example of an IEG whose increased expression is routinely used as an indicator for neuronal activation. For instance, it has been shown that c-fos expression following behavioral training specifically correlates with learning (Maleeva et al., 1989, 1990; Kaczmarek and Nikołajew, 1990; Tischmeyer et al., 1990), performance (Sakai and Yamamoto, 1997; Radulovic et al., 1998; Bertaina-Anglade et al., 2000; Vann et al., 2000a,b) and with cellular ensembles that are activated following memory retrieval (Maviel et al., 2004; Kubik et al., 2007; Lopez et al., 2012; Bravo-Rivera et al., 2015), supporting its role as activity marker.
Interestingly, changes in c-Fos expression were observed mainly during the first sessions of multiple-session training protocols, indicating an adaptive response (Maleeva et al., 1989, 1990; Kaczmarek and Nikołajew, 1990; Nikolaev et al., 1992a,b; Hess et al., 1995a,b, 1997; Gall et al., 1998; Lukasiuk et al., 1999; Anokhin et al., 2000; Bertaina-Anglade et al., 2000).
Genetic manipulations of the c-fos gene were performed during the first genetic engineering Era. One of the first approaches aimed to analyze the function of c-Fos in memory was done using whole-body knockout mice. With this model they were found deficits in complex but not in simple behavioral tasks, indicating that c-fos is not necessary for all types of learning tasks and memories. It is important to point out that these animals showed many developmental malformations which might affect the interpretation of the behavioral studies (Paylor et al., 1994).
Using the cre/loxP system Fleischmann et al. (2003) developed a central-nervous-system-selective knock out mouse. This model had normal locomotion and emotional related responses but was impaired in hippocampus-dependent spatial and associative learning tasks, such as Morris water maze and contextual fear memory. The mutant mice displayed a reduction of synaptic plasticity mechanisms in hippocampal CA3-CA1 synapses. These specific deficit were consistent with cued and spatial tasks in which an increase in hippocampal c-Fos expression was observed (Guzowski et al., 2001a) and also with experiments done with c-fos antisense oligonucleotide (ASO) in rats in which the infusion of the ASO produce deficits in spatial long-term memory (Guzowski, 2002; Kemp et al., 2013).
Fear memory paradigms were also able to produce changes in c-Fos expression in different structures: using an inhibitory avoidance task (Bekinschtein et al., 2010; Katche et al., 2010; Katche and Medina, 2017). It was shown that fear memory persistence required c-Fos expression and that blockade of c-Fos expression by infusion of c-fos ASO into the dorsal CA1 region of the hippocampus or retrosplenial cortex produces deficits in the consolidation and persistence of this type of memory (Katche et al., 2010, 2013; Katche and Medina, 2017). Similarly, the infusion of c-fos ASO in the prefrontal cortex affected long-term cued fear memory (Morris and Frey, 1999).
The results described here concerning c-Fos expression and function in learning and memory still do not answer the question of the biological role of c-Fos within the brain. Then, is c-Fos expression a response to the activity of neurons within a memory circuit? Or, does it play a role in maintenance of cellular homeostasis? An important obstacle in solving these questions is that the role of c-Fos in synaptic plasticity is still unclear. c-Fos is part of a complex, the AP-1, whose target genes downstream have yet to be fully characterized. Independently of the mechanism operating after c-Fos activation, it is clear that understanding its role at the cellular level is more complex than for other IEGs, such as narp, homer1a and arc, that are known to encode proteins that have a direct effect on the synapses (Chowdhury et al., 2006; Chang et al., 2010; Roloff et al., 2010; Lu et al., 2013). Still, it is important to increase our knowledge of the role of c-Fos at the cellular level to be able to address if it is really a marker of specific neuronal engrams associated with specific memory episodes.
More recently, the c-fos promoter was combined with optical sensitive proteins to mark and manipulate a particular subset of cells involved in contextual learning. With this technique, Cowansage et al. (2014) found that c-Fos-expressing neurons in retrosplenial cortex are involved in the acquisition of contextual memories and that the reactivation of this particular set of cells can control behavioral response. Using a similar approach Liu et al. (2012) attempted to test the existence of memory engrams with a strategy of optogenetic and temporary control of cellular activation. Their results lead to two important conclusions. First, they provide evidence that IEGs, combined with optogenetics, can tag neurons that are activated during memory encoding for later manipulation. Second that artificial light-reactivation of these memory engrams is sufficient for behavioral memory recall for contextual fear conditioning. These results support the role of c-Fos in learning and memory while, at the same time demonstrate the power that this type of approach have to understand memory processing in more detail. If it is combined with other genetic models, it can become an extraordinary tool for better understanding the functional link between IEG, memory (Semon, 1904; Morris, 1999; Martin and Morris, 2002; Gerber et al., 2004; Josselyn, 2010) and psychiatric disorders (Chowdhury et al., 2006; Chang et al., 2010; Roloff et al., 2010; Lu et al., 2013).
Molecular Mechanisms of Egr1
Egr1, also known as Zif-268, NGFI-A, Krox 24 or ZENK (Milbrandt, 1987; Lemaire et al., 1988), is a member of the zinc finger family of transcription factors. Its expression can be induced by a variety of signals that includes injury, stress, differentiation factors, as well as extracellular signals like peptides, neurotransmitters and growth factors (Herdegen and Leah, 1998; O’Donovan et al., 1999; Davis et al., 2003; Clements and Wainwright, 2010). Compared to c-fos, Egr1 has a distinct pattern of expression in the brain (Milbrandt, 1987; Herdegen et al., 1990; Mack et al., 1990; Waters et al., 1990) and mediates the expression of a number of late-response genes involved in different neuronal processes from growth control to plastic changes (Sukhatme et al., 1988; Williams et al., 2000; Bozon et al., 2003; Maddox et al., 2011). Egr1 has a relatively high expression maintained by normal ongoing neuronal activity (Worley et al., 1991; Beckmann et al., 1997; Herdegen and Leah, 1998) in the hippocampus (Hughes et al., 1992; Cullinan et al., 1995; Okuno et al., 1995; Desjardins et al., 1997), including the dentate gyrus (Cole et al., 1989; Wisden et al., 1990), as well as other brain regions (Herdegen et al., 1990, 1995; Cullinan et al., 1995; Okuno et al., 1995).
Egr1 and Memory
The first approach to study Egr1 expression and its relation with behavior employed two-way avoidance training (Nikolaev et al., 1992b). In this study it was shown, for the first time, an increased level of Egr1 mRNA in the hippocampus after one training session (Nikolaev et al., 1992a). In general, most studies use fear conditioning paradigms. With fear conditioning, Egr1 is rapidly induced by behavioral training in the amygdala (Rosen et al., 1998; Kwon et al., 2012), the hippocampus (Nikolaev et al., 1992a; Miyashita et al., 1998; Guzowski et al., 2001b) and the retrosplenial cortex (Pothuizen et al., 2009). Nonetheless, inconsistent results were also found: Hall et al. (2000) reported non-specific expression of this IEG. Similarly Weitemier and Ryabinin (2004) showed a lack of Egr1 expression in the septum, amygdala, hippocampus and the anterior cingulate cortex when studying fear conditioning in C57BL/6J mice.
Despite these discrepancies, it is accepted that Egr1 has an important role in learning and memory. Deletion of Egr1 produces impairment across a broad number of behavioral tasks related to different brain regions. Typically, Egr1 mutant mice displayed intact short-term memory in several types of tasks; however, long-term memory was drastically impaired in tasks such as social transmission of food preference, taste aversion memory, spatial memory, object recognition memory and object-place recognition memory (Jones et al., 2001; Bozon et al., 2003; Davis et al., 2010). Interestingly, studies using ASOs to partially knock down Egr1 in specific structures showed that the knockdown of Egr1 in the hippocampus does not impair contextual fear conditioning (Lee et al., 2004) but impairs inhibitory avoidance memory persistence (Katche et al., 2012) as well as recognition memory (Zalcman et al., 2015). Egr1 knockdown in the amygdala impairs both contextual (Malkani et al., 2004) and cued-fear memory formation (Maddox et al., 2011) suggesting that the deficits observed in the knockout might be attributed to its role in specific structures or circuits. Egr1 knockout mice were also shown to be impaired in the consolidation and reconsolidation of contextual fear memory, while heterozygous mice showed impairment only in the reconsolidation (Besnard et al., 2013). This difference supported the hypothesis that memory reconsolidation is not mechanistically a repetition of consolidation. Consistent with the phenotype observed in knockout mice, overexpression of Egr1 improved spatial memory, but not memory for the objects, during a recognition memory task (Penke et al., 2014) and enhanced aversive memories’ resistance to extinction (Baumgärtel et al., 2008). On the other side, failure to induce Egr1 allowed spontaneous recovery of fear memory after extinction (Herry and Mons, 2004).
Historically, a number of studies supported the view that proposed that Egr1 expression is sensitive to information gained after the exposure to novelty or learning associated environments (Tischmeyer and Grimm, 1999; Bozon et al., 2002; Guzowski, 2002; Davis et al., 2003, 2006; Knapska and Kaczmarek, 2004). This idea came from the increments in the expression of Egr1 mRNA or protein after different learning paradigms. Some examples are cited above, others are: brightness discrimination (Grimm and Tischmeyer, 1997), visual paired associate learning in monkeys (Okuno and Miyashita, 1996; Tokuyama et al., 2002), birds song learning (Mello et al., 1992; Jarvis et al., 1995; Bolhuis et al., 2000), learning and retrieval of contextual and cue fear memory (Frankland et al., 2004; Weitemier and Ryabinin, 2004) and spatial learning (Guzowski et al., 2001b). Mechanistically, a role of Egr1 in learning and memory is supported partially by its modulation of plastic changes including spine and synapse remodeling as well as growth of new synaptic connections (Lamprecht and LeDoux, 2004; Miniaci et al., 2008; Lai et al., 2012).
These studies support a role of Egr1 in processes of learning and memory formation and they do determine a necessity of Egr1 for these neural and cognitive functions. But what is the specific role of Egr1 in plasticity or memory processes? It is a highly regulated transcription factor with many identified target genes and probably many more still unknown. Unlike c-Fos, there is a multitude of genes related to vesicular transport and neurotransmitter release, clathrin-dependent, or actin, which are commonly observed as direct Egr1 targets (Koldamova et al., 2014; Duclot and Kabbaj, 2015, 2017b), supporting its role in synaptic plasticity and, through this mechanism, in learning and memory. Then, alterations in the normal expression of Egr1, or in its protein function, could affect the encoding of information in the engram and, therefore, affect higher orders of organization.
Molecular Mechanisms of Arc
The activity-regulated cytoskeletal (Arc) protein also known as Arg3.1, is one of the most characterized molecules involved in the consolidation of different types of memories. In contrast to c-fos or egr1, this gene is known to code for a synaptic protein. Arc is one of the effectors of the BDNF, glutamatergic, dopaminergic and serotonin signaling (Chowdhury et al., 2006; Granado et al., 2008; Karabeg et al., 2013; Leal et al., 2014; Panja and Bramham, 2014; Pastuzyn and Keefe, 2014; Managò et al., 2016; Mastwal et al., 2016). arc expression is under regulation of Egr1 (Li et al., 2005). It is well characterized that the arc mRNA is transported to the dendrites (Fujimoto et al., 2004; Steward et al., 2015) and is usually used as marker for neural activity (Chowdhury et al., 2006; Shepherd et al., 2006; Li et al., 2015; Ivashkina et al., 2016). In this sense, the post-synaptic dendrites are enriched with arc mRNA in contrast to the absence at the pre-synaptic axons (Moga et al., 2004; Dynes and Steward, 2012; #6010; Steward et al., 2015). Arc is involved in the generation of new synapses and the maintenance of old ones required for some plasticity mechanisms such as long-term potentiation (LTP) and long-term depression (LTD; Korb and Finkbeiner, 2011; Minatohara et al., 2016). Besides, arc encodes a growth factor that associates with F-actin (Lyford et al., 1995). These features led to postulate that Arc is involved in experience-dependent dendritic reconfiguration (Pinaud et al., 2001; Steward and Worley, 2001; Pinaud, 2004).
Arc gene has specific sequences normally found in retroviruses such as HIV (Campillos et al., 2006). Recent evidence was found of a plausible novel molecular mechanism by which genetic information could be transferred between neurons. It was shown that Arc protein forms a virus-like particle that can enclose RNA and be transferred through the synapse (Pastuzyn et al., 2018). Interestingly it was also proven in Drosophila (Ashley et al., 2018). Though the mechanism is not entirely new, considering there have been studies suggesting these pathways and their potential role in synaptic plasticity before Budnik et al. (2016); Zappulli et al. (2016) this was the first time that Arc was proven to form these particles and enclose RNA. Further research is needed on this mechanism to understand how it can be linked with synaptic plasticity.
Arc and Memory
Up-regulation of arc in the Morris water maze was observed in cortical and para-hippocampal regions during memory spatial retention and after fear conditioning training, triggered by context exploration (Lonergan et al., 2010; Barry et al., 2016). Gusev and Gubin (2010) found differences in arc expression with memory durability; select segments in the prefrontal, retrosplenial, somatosensory and motor cortex showed similar robust increases in arc expression in recent and remote spatial memories. In another work, the study on the expression of arc yielded its requirement for the consolidation of long-term memory, but not for learning or short-term memory (Plath et al., 2006). Kubik et al. (2012) showed that the inactivation of dorsal CA1 was sufficient to impair the spatial performance in the Morris water maze task and this was also followed by a reduction of the expression of arc in the retrosplenial cortex. The requirement of Arc expression for long-term plasticity and memory consolidation was shown by infusing arc ASO into the dorsal hippocampus, the lateral amygdala or the anterior cingulate cortex (Guzowski et al., 2000; Ploski et al., 2008; Holloway and McIntyre, 2011; Nakayama et al., 2015). Arc also facilitates the consolidation of weak memories, and has been reported to play a role in behavioral tagging in the hippocampus (Moncada and Viola, 2007; Ballarini et al., 2009; Wang et al., 2010; Moncada et al., 2011; Martínez et al., 2012).
A genetic KO for arc expression generates deficits in the consolidation of different types of long-term memories (spatial, fear and episodic-like) together with changes in long-term plasticity (Plath et al., 2006; Peebles et al., 2010; Yamada et al., 2011). In addition, a significant correlation between arc mRNA expression and behavioral performance was found during spatial reversal task suggesting a role in cognitive flexibility (Guzowski et al., 2001b). The same group, Guzowski et al. (2006) showed that both the activity and the arc dynamic expression of CA1 neurons depend on the recent behavioral history of the animal: when the animals were exposed repeatedly to the same context, arc expression in the CA1 region was decreased. A recent study showed that the infusion of arc ASO into the perirhinal cortex in an object-pattern-separation task affects the consolidation of overlapping object memories (Miranda and Bekinschtein, 2018).
In summary, of the three genes reviewed here, a large and robust body of evidence suggests that arc and Egr1, although to a different extent, influence the dynamics of large networks associated with learning and memory, indicating that they have a more specific role than c-fos.
Psychiatric Disorders: Memory Deficits and IEGs
Going from genes to neuropsychiatric disorders has proven to be a hard task, partly because psychiatric disorders have polygenic origin with increasing levels of complexity. Each gene will have an effect at a cellular level but it will also interact with other genes with its own regulation.
Another relevant issue is the environmental factor. It is well established that complex interactions between genes and the environment are involved in multiple aspects of neuropsychiatric disorders. It can determine the vulnerability to a particular disorder and even the response to therapeutic intervention. Then, it seems crucial to achieve a better comprehension of the reaction of individuals to environmental stimuli in a particular genetic context. This level of analysis exceeds the scope of this review. Here we will approach how IEGs can intervene with fundamental neurobiological mechanisms of behavior, bearing in mind that in the central nervous system neuronal plasticity and neurotransmission are among the main processes of interactions between genes and the environment. In particular, IEGs are critical components of these interactions for they provide the molecular framework for a rapid and dynamic response to neuronal activity, opening the possibility of a lasting and sustained adaptation by regulating the expression of a wide range of genes.
The defining characteristics of the IEGs, i.e., activation within the range of minutes and independent expression of protein synthesis, give us a very strong guideline that they are a necessary mechanism of action that will, in turn, allow encoding and storing of memories. Then, deciphering the functions of IEG can provide relevant information on how these mechanisms fail in pathological conditions and thus provide new insights into the molecular mechanisms that are responsible for symptoms associated with neuropsychiatric disorders.
IEGs in Major Depression Disorder
Major depressive disorder (MDD) is a mood disorder with prominent disturbances in cognitive functions such as certain types of memory, executive function, and attention (Jaeger et al., 2006; Mcintyre et al., 2013). MDD patients have reduced hippocampal and prefrontal cortex volumes. These alterations are mainly due to a clear-cut reduction in the neuropil and neurons in both regions have less complex dendritic trees (Saylam et al., 2006; Arnone et al., 2012). Animal models of depression have also shown a reduction in the volume of some regions of the prefrontal cortex and hippocampal formation (Hains et al., 2009; Czeh et al., 2016) with decreases in the length and complexity of dendrites and reduced number of dendritic spines.
One IEG that participates in synaptic transmission and dendritic plasticity is arc. Given that it has been shown that the expression of arc in the hippocampus and prefrontal cortex in animal models of depression change in a similar way to the alterations found in post-mortem tissues of MDD patients (Lee et al., 2012), it was postulated as a candidate target for intervening to ameliorate cognitive deficits in MDD. Interestingly, chronic stress reduces arc expression in medial prefrontal cortex and increases it in the amygdala (Ons et al., 2010), mirroring what is observed in MDD patients (Lee et al., 2012). Interestingly, chronic—but not acute—treatments with antidepressants restore arc expression in the hippocampus and prefrontal cortex (Pei et al., 2003; Molteni et al., 2008, 2010) supporting its involvement in psychiatric disorders.
Another IEG associated to MDD is Egr1. Covington et al. (2010) found a decreased expression of Egr1 in the medial prefrontal cortex in depressed patients refractory to treatment and it was also observed in non-medicated subject. It should be noticed that this region has consistently been reported to be affected in depressed patients and in animal models of depression (Krishnan and Nestler, 2008; Koenigs and Grafman, 2009; Duclot and Kabbaj, 2017a,b; Lefaucheur et al., 2017). Based on these and other studies, a direct link between Egr1 in the mPFC and the depressive phenotype had begun to be analyzed as a possible marker to predict the effectiveness of antidepressants (Morinobu et al., 1995, 1997; Bjartmar et al., 2000; Duclot and Kabbaj, 2017a,b).
Repeated exposure to stressful experiences is one of the main risk factors for the development of stress-related mood disorders like anxiety and depression (Kessler and Wang, 2008). Depending on the nature, duration, and intensity of the stress, changes in the expression of Egr1 may vary across the entire central nervous system (Knapska and Kaczmarek, 2004). In addition, Egr1 is a critical factor in encoding the behavioral enduring effects of stress in the hippocampus. Moreover, stress-related fear memory is associated with an increased expression of Egr1 and the fear related response is blocked by knocking down Egr1 expression (Revest et al., 2005, 2010; Saunderson et al., 2016).
In line with this clinical observations, it was found that chronic stress provoked in rodents a decreased expression of Egr1 in the medial prefrontal cortex (Covington et al., 2010) and hippocampus (Xu et al., 2015), and an increase of Egr1 expression in the lateral amygdala (Monsey et al., 2014). In addition, using social isolation in rodents, another animal model of depression, it was observed a marked reduction in Egr1 mRNA levels in the hypothalamus, the hippocampus, and the medial prefrontal cortex (Matsumoto et al., 2012; Hodges et al., 2014; Okada et al., 2014). This can be paralleled to the general idea that stress-related depressive disorders are associated with a down-regulated activity in the prefrontal cortex and the hippocampus, and an up-regulation of neuronal activity in the amygdala.
A new player in the neurobiology of depression is another member of the FOS family, ΔFosB. In marked contrast to what happens with the other members of the family, this transcriptional regulator is not rapidly activated by environmental stimuli. Instead, its activation is delayed and accumulates to repeated stimulation (chronic stress) mainly in nucleus accumbens neurons (Perrotti et al., 2004; Nestler, 2008). In addition, chronic administration of antidepressants, like fluoxetine and ketamine, induce ΔFosB in nucleus accumbens (Vialou et al., 2010; Donahue et al., 2014), a brain region associated to reward and motivation. Nestlers group has established that increased expression of ΔFosB within accumbal D1-type medium spiny neurons promotes stress resilience, and mediates antidepressant-like responses (Nestler, 2015). In addition, ΔFosB overexpression in nucleus accumbens promotes several rewarding behaviors, including sucrose drinking, consumption of high-fat food, and sexual activity. Despite its role in nucleus accumbens associated behaviors, since depression is a complex disorder affecting many brain regions, it will be important to study ΔFosB role in other brain structures in which its expression is induced by chronic antidepressant administration (Vialou et al., 2014).
Fear-Related Disorders and the Involvement of IEGs
Most anxiety disorders are associated with a strong environmental component (fear) and a physiological defect in response to that component. Anxiety disorders include simple phobia, social phobia—which involves fear and avoidance of social situations—, and panic disorder; they all share abnormal fear responses associated with different environmental stimuli but also differ in important and specific symptoms. For example, PTSD is a chronic neuropsychiatric disorder that results from a very strong traumatic event and it is characterized by intrusive and persistence fear related memories. The etiology of PTSD remains largely unknown but different neurobiological systems have been identified as participants in the disorder (Parsons and Ressler, 2013).
The first opportunity to apply treatments designed to modify the formation and persistence of fear memories is around the aversive experience, mainly through pharmacological manipulations (Monfils et al., 2009; Quirk and Milad, 2010; Quirk et al., 2010). Modulation of opioid systems has been proven to be effective in PTSD (Holbrook et al., 2010). However, other pharmacological manipulation yielded mixed results (Maren and Chang, 2006; Myers et al., 2006; Parsons and Ressler, 2013). A new strategy was developed to attenuate fear-related memories by manipulating memory reconsolidation and extinction processes. Immediate or delayed extinction procedures induce a reduction in those aversive memories that are context-dependent and short-lived (Hermans et al., 2006; Woods and Bouton, 2008) suggesting that its efficacy as a treatment depends on how old the memory is (Milekic and Alberini, 2002; Suzuki et al., 2004). A novel behavioral design that involves a mixed reconsolidation-extinction procedure has proved to be a better strategy (Monfils et al., 2009; Chan et al., 2010; Schiller et al., 2010).
Few studies have analyzed the role of IEG in PTSD related animal models, though they reported interesting results. Changes in arc expression was observed along the septo-temporal axis of the hippocampus of PTSD susceptible rats (Nalloor et al., 2014), suggesting that it might exist a basal difference among susceptible population. arc expression in the hippocampus is also involved in the perpetuation of fear related memories (Nakayama et al., 2015) while changes in the amygdala appeared to be related to the response to uncontrollable stress (Machida et al., 2018). Then, the IEGs analyzed here directly or indirectly play a role in these processes, so that a better understanding of the molecular mechanisms underlying memory processing, including the role of specific IEGs, may be essential to obtain new targets and strategies as treatments for fear-related disorders.
IEG in Schizophrenia
Schizophrenia is characterized by profound cognitive deficits that are not alleviated by currently available medications. Many of these cognitive deficits involve dysfunction of the newly evolved, dorsolateral prefrontal cortex. The brains of patients with schizophrenia show atrophy in the dendrites of the pyramidal cells, particularly from dorsolateral prefrontal cortex (Weinberger et al., 1986; Bonilha et al., 2008; Konopaske et al., 2014).
It has been shown that Egr1 expression is decreased in the dorsolateral prefrontal cortex of schizophrenic patients. This down-regulation correlates with the levels of gad1 mRNA, which is also down-regulated in schizophrenia (Yamada et al., 2007; Pérez-Santiago et al., 2012; Kimoto et al., 2014). Antipsychotics administration, in contrast, up-regulates Egr1 and related IEGs in frontal and striatal regions (de Bartolomeis et al., 2015a).
Searching for biological markers of schizophrenia in peripheral tissues, it was found that whole blood samples of patients suffering this disease have an increased expression of Egr1 (Kurian et al., 2011; Cattane et al., 2015). Besides, Egr1 and other IEGs are also associated with response to antipsychotic drugs (MacGibbon et al., 1994; Robbins et al., 2008; Bruins Slot et al., 2009; Wheeler et al., 2014; de Bartolomeis et al., 2015b; Duclot and Kabbaj, 2017b).
Changes in c-fos expression have been reported in schizophrenia related animal models. Acute treatment with the NMDA antagonist MK-801 produced deficits in novel object recognition, conditioned test aversion and a moderate increase in locomotion. Interestingly, animals treated with this drug showed increased levels of c-Fos expression in cortical regions associated with cognitive processing (Vishnoi et al., 2015). Subchronic, but not acute, treatment with PCP, another NMDA antagonist, produces deficits in working memory tasks and evokes a particular pattern of c-fos expression (Castañé et al., 2015) suggesting that there are plastic changes related to the behavioral output. Interestingly, c-fos expression in the mPFC does not correlate with glutamic acid decarboxylase 67 expression as does Egr1 (Kimoto et al., 2014). CamKII is a Serine/Threonine protein that plays a key role in neural plasticity. α-CamkII heterozygous and knock out mice have working memory deficits. This behavioral deficits correlate with decrease c-Fos expression in key areas associated with working memory like mPFC and hippocampus (Matsuo et al., 2009). This changes in c-Fos expression appears to be task specific since the same α-CamkII +/– mice showed normal c-Fos expression pattern in the mPFC after fear conditioning training (Frankland et al., 2004). An interesting and new target is matrix metalloproteinase 9 (MMP-9), an enzyme activated outside the cell by proteolytic cleavage that degrades extracellular matrix. It has been implicated in synaptic plasticity and is under c-fos regulation (Michaluk and Kaczmarek, 2007; Michaluk et al., 2007; Huntley, 2012). Aberrant levels of MMP-9 has been observed in different psychiatric disorders, including schizophrenia and importantly, blood levels of MMP-9 or gene responsiveness to antipsychotics has been related to this disorder (Lepeta and Kaczmarek, 2015; Vafadari et al., 2016).
The interaction between Arc and dopamine appears to be bidirectional. Using a genetic model in which arc was deleted in the whole brain, Managò et al. (2016) found a dysregulation in the dopaminergic system with reduced dopamine levels in the cortex and increased levels in the striatum. Arc deletion induced these changes that are characteristic of a schizophrenia-related model. Consistent with this finding, the authors also found deficits in multiple domains correlated with cognitive, positive and negative associated symptoms of schizophrenia and identified a complex interaction between Arc, dopaminergic system and schizophrenia (Managò et al., 2016; Managò and Papaleo, 2017).
Psychiatric Related Drugs and IEGs
IEGs have not only been associated directly with particular psychiatric disorders but they have also been used as markers of the specific action of different psychiatric drugs that are related. Haloperidol, a typical antipsychotic drug induces changes in c-fos and Egr1 expression in the striatum and nucleus accumbens (MacGibbon et al., 1994). Olanzapine, in acute doses show increased c-fos expression in the medial prefrontal cortex (Robertson and Fibiger, 1996; Ohashi et al., 2000), and the locus coeruleus (Ohashi et al., 2000; Dawe et al., 2001), while a chronic treatment showed a downregulation of Egr1 and an upregulation of FOS-like expression in the same structures (Verma et al., 2006). These results, together with other studies (Nguyen et al., 1992), suggest those antipsychotics do affect in some way IEG expression, however, they do not do it in a concerted fashion. It would be interesting to address if the IEGs’ expression pattern correlates with antipsychotics’ activity.
Antidepressants’ activity has also been analyzed in relation to their effect on IEG expression. Acute administration of fluoxetine, imipramine, LiCl, or mirtazapine produced changes in IEG expression in different regions. There were changes found for c-fos in the anterior insular cortex, the septum and the amygdala using different antidepressants. In the case of Egr1 a consistent change was found only in the amygdala (Slattery et al., 2005). Chronic antidepressants can restore the up-regulation of c-fos in the frontal cortex following an acute stress experience (Beck and Fibiger, 1995a,b). Furthermore, chronic administration of fluoxetine and vortioxetine decreased Arc and c-Fos, but not Egr1 in the frontal cortex, hippocampus and amygdala of rodents (Waller et al., 2017).
Although these studies show changes in the expression of IEGs in apparent response to different drugs, they are correlational studies and do not address any role of these proteins in their mechanism of action. Despite this caveat, even these studies provide important information regarding circuits involved in learning and memory that can be affected in psychiatric disorders.
Conclusion
Although the prolific use of IEGs in neuroscience, our understanding of their role in neurobiological processes remains insufficient. This is due at least to the large number of IEGs that are currently under study, but also because of the difficulty in fully comprehending their roles and their downstream effectors. Independently of this, IEGs are used as markers of synaptic activity and as that, are useful. Even more, when combined with modern techniques, like optogenetic or chemogenetics (Reijmers et al., 2007; Garner et al., 2012; Liu et al., 2012; Cowansage et al., 2014) IEGs can become powerful tools to identify activity-dependent cell populations. However, important gaps in the study of IEGs exist. As we mentioned above we still do not know much regarding the cellular effectors of these genes specifically in the Central Nervous System. Likewise, their role in memory processes requires further investigation. The lack of information regarding this particular point is surprising, especially if we consider that tools to address it have been around for decades (e.g., use of antisense or inducible genetic manipulations). A better understanding of these points becomes particularly relevant considering their role in psychiatric conditions. Understanding neuropsychiatric disorders is principally challenging since their etiology and pathophysiology are mostly unknown. Nonetheless, by focusing on the study of endophenotypes (Bearden and Freimer, 2006) together with the use of animal models (Krishnan et al., 2008; Nestler and Hyman, 2010; Anderzhanova et al., 2017), our understanding of these disorders has considerably improved in the last decade. Analyzing the role of IEGs in specific endophenotypes or animal models of psychiatric disorders could shed light on both the genetic and molecular basis of these diseases. Together with a better understanding of their biological roles, the manipulation of these genes in animal models could provide a robust model for the discovery of new pharmacological targets. In this review, we aimed to resume the literature looking at the intersection between psychiatric disorders, IEG and memory. Interestingly, we found that most of these studies were correlational; with surprisingly few studies analyzing a causal role of IEGs in psychiatric disorders. It is clear now that IEGs are much more than simple activation markers and they deserve to be analyzed as possible key participants in psychiatric conditions. Genetic manipulations that allow the temporal and spatial control of expression of these genes are powerful tools to analyze the role that IEGs have in memory and other cognitive domains in psychiatric animal models. We consider that, until now, the intersection between psychiatric models, cognition and IEG function did not receive the attention that it deserves. The manipulation of IEG expression as a means of intervention on the onset and progression of psychiatric conditions could generate new targets in the development of their treatments, targets that nowadays are completely unnoticed.
Author Contributions
FTG, CK, JFM, JHM and NVW conceived the content, wrote and organized the manuscript.
Funding
This work was supported by grants from the National Agency of Scientific and Technological Promotion of Argentina (Agencia Nacional de Promoción Científica y Tecnológica, ANPCyT, Argentina) PICT2015-2344 (NVW), PICT2015-1552 (CK), PICT2013-0335 (JHM).
Conflict of Interest Statement
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Acknowledgments
We would like to thank Dr. Cecilia Martinez for her suggestions and critical reading of the manuscript.
References
Abel, T., and Lattal, K. M. (2001). Molecular mechanisms of memory acquisition, consolidation and retrieval. Curr. Opin. Neurobiol. 11, 180–187. doi: 10.1016/s0959-4388(00)00194-x
Alberini, C. M. (2009). Transcription factors in long-term memory and synaptic plasticity. Physiol. Rev. 89, 121–145. doi: 10.1152/physrev.00017.2008
Anderzhanova, E., Kirmeier, T., and Wotjak, C. T. (2017). Animal models in psychiatric research: the RDoC system as a new framework for endophenotype-oriented translational neuroscience. Neurobiol. Stress 7, 47–56. doi: 10.1016/j.ynstr.2017.03.003
Anokhin, K. V., Riabinin, A. E., and Sudakov, K. V. (2000). The expression of the c-fos gene in the brain of mice in the dynamic acquisition of defensive behavioral habits. Zh. Vyssh. Nerv. Deiat. Im. I P Pavlova 50, 92–94.
Arnone, D., McIntosh, A. M., Ebmeier, K. P., Munafò, M. R., and Anderson, I. M. (2012). Magnetic resonance imaging studies in unipolar depression: systematic review and meta-regression analyses. Eur. Neuropsychopharmacol. 22, 1–16. doi: 10.1016/j.euroneuro.2011.05.003
Ashley, J., Cordy, B., Lucia, D., Fradkin, L. G., Budnik, V., and Thomson, T. (2018). Retrovirus-like Gag protein Arc1 binds RNA and traffics across synaptic boutons. Cell 172, 262–274.e11. doi: 10.1016/j.cell.2017.12.022
Bahrami, S., and Drabløs, F. (2016). Gene regulation in the immediate-early response process. Adv. Biol. Regul. 62, 37–49. doi: 10.1016/j.jbior.2016.05.001
Ballarini, F., Moncada, D., Martinez, M. C., Alen, N., and Viola, H. (2009). Behavioral tagging is a general mechanism of long-term memory formation. Proc. Natl. Acad. Sci. U S A 106, 14599–14604. doi: 10.1073/pnas.0907078106
Barry, D. N., Coogan, A. N., and Commins, S. (2016). The time course of systems consolidation of spatial memory from recent to remote retention: a comparison of the Immediate Early Genes Zif268, c-Fos and Arc. Neurobiol. Learn. Mem. 128, 46–55. doi: 10.1016/j.nlm.2015.12.010
Baumgärtel, K., Genoux, D., Welzl, H., Tweedie-Cullen, R. Y., Koshibu, K., Livingstone-Zatchej, M., et al. (2008). Control of the establishment of aversive memory by calcineurin and Zif268. Nat. Neurosci. 11, 572–578. doi: 10.1038/nn.2113
Bearden, C. E., and Freimer, N. B. (2006). Endophenotypes for psychiatric disorders: ready for primetime? Trends Genet. 22, 306–313. doi: 10.1016/j.tig.2006.04.004
Beck, C. H., and Fibiger, H. C. (1995a). Conditioned fear-induced changes in behavior and in the expression of the immediate early gene c-fos: with and without diazepam pretreatment. J. Neurosci. 15, 709–720. doi: 10.1523/jneurosci.15-01-00709.1995
Beck, C. H., and Fibiger, H. C. (1995b). Chronic desipramine alters stress-induced behaviors and regional expression of the immediate early gene, c-fos. Pharmacol. Biochem. Behav. 51, 331–338. doi: 10.1016/0091-3057(94)00391-u
Beckmann, A. M., Davidson, M. S., Goodenough, S., and Wilce, P. A. (1997). Differential expression of Egr1-like DNA-binding activities in the naive rat brain and after excitatory stimulation. J. Neurochem. 69, 2227–2237. doi: 10.1046/j.1471-4159.1997.69062227.x
Bekinschtein, P., Katche, C., Slipczuk, L., Gonzalez, C., Dorman, G., Cammarota, M., et al. (2010). Persistence of long-term memory storage: new insights into its molecular signatures in the hippocampus and related structures. Neurotox. Res. 18, 377–385. doi: 10.1007/s12640-010-9155-5
Bertaina-Anglade, V., Tramu, G., and Destrade, C. (2000). Differential learning-stage dependent patterns of c-Fos protein expression in brain regions during the acquisition and memory consolidation of an operant task in mice. Eur. J. Neurosci. 12, 3803–3812. doi: 10.1046/j.1460-9568.2000.00258.x
Besnard, A., Caboche, J., and Laroche, S. (2013). Recall and reconsolidation of contextual fear memory: differential control by ERK and Zif268 expression dosage. PLoS One 8:e72006. doi: 10.1371/journal.pone.0072006
Binder, S., Dere, E., and Zlomuzica, A. (2015). A critical appraisal of the what-where-when episodic-like memory test in rodents: achievements, caveats and future directions. Prog. Neurobiol. 130, 71–85. doi: 10.1016/j.pneurobio.2015.04.002
Bisler, S., Schleicher, A., Gass, P., Stehle, J. H., Zilles, K., and Staiger, J. F. (2002). Expression of c-Fos, ICER, Krox-24 and JunB in the whisker-to-barrel pathway of rats: time course of induction upon whisker stimulation by tactile exploration of an enriched environment. J. Chem. Neuroanat. 23, 187–198. doi: 10.1016/s0891-0618(01)00155-7
Bjartmar, L., Johansson, I. M., Marcusson, J., Ross, S. B., Seckl, J. R., and Olsson, T. (2000). Selective effects on NGFI-A, MR, GR and NGFI-B hippocampal mRNA expression after chronic treatment with different subclasses of antidepressants in the rat. Psychopharmacology 151, 7–12. doi: 10.1007/s002130000468
Bolhuis, J. J., Zijlstra, G. G., den Boer-Visser, A. M., and Van Der Zee, E. A. (2000). Localized neuronal activation in the zebra finch brain is related to the strength of song learning. Proc. Natl. Acad. Sci. U S A 97, 2282–2285. doi: 10.1073/pnas.030539097
Bonilha, L., Molnar, C., Horner, M. D., Anderson, B., Forster, L., George, M. S., et al. (2008). Neurocognitive deficits and prefrontal cortical atrophy in patients with schizophrenia. Schizophr. Res. 101, 142–151. doi: 10.1016/j.schres.2007.11.023
Bozon, B., Davis, S., and Laroche, S. (2002). Regulated transcription of the immediate-early gene Zif268: mechanisms and gene dosage-dependent function in synaptic plasticity and memory formation. Hippocampus 12, 570–577. doi: 10.1002/hipo.10100
Bozon, B., Davis, S., and Laroche, S. (2003). A requirement for the immediate early gene zif268 in reconsolidation of recognition memory after retrieval. Neuron 40, 695–701. doi: 10.1016/s0896-6273(03)00674-3
Bravo-Rivera, C., Roman-Ortiz, C., Montesinos-Cartagena, M., and Quirk, G. J. (2015). Persistent active avoidance correlates with activity in prelimbic cortex and ventral striatum. Front. Behav. Neurosci. 9:184. doi: 10.3389/fnbeh.2015.00184
Brezis, R. S. (2015). Memory integration in the autobiographical narratives of individuals with autism. Front. Hum. Neurosci. 9:76. doi: 10.3389/fnhum.2015.00076
Briscione, M. A., Jovanovic, T., and Norrholm, S. D. (2014). Conditioned fear associated phenotypes as robust, translational indices of trauma-, stressor-, and anxiety-related behaviors. Front. Psychiatry 5:88. doi: 10.3389/fpsyt.2014.00088
Bruins Slot, L. A., Lestienne, F., Grevoz-Barret, C., Newman-Tancredi, A., and Cussac, D. (2009). F15063, a potential antipsychotic with dopamine D2/D3 receptor antagonist and 5-HT1A receptor agonist properties: influence on immediate-early gene expression in rat prefrontal cortex and striatum. Eur. J. Pharmacol. 620, 27–35. doi: 10.1016/j.ejphar.2009.08.019
Budnik, V., Ruiz-Cañada, C., and Wendler, F. (2016). Extracellular vesicles round off communication in the nervous system. Nat. Rev. Neurosci. 17, 160–172. doi: 10.1038/nrn.2015.29
Campillos, M., Doerks, T., Shah, P. K., and Bork, P. (2006). Computational characterization of multiple Gag-like human proteins. Trends Genet. 22, 585–589. doi: 10.1016/j.tig.2006.09.006
Carruthers, P. (2013). Evolution of working memory. Proc. Natl. Acad. Sci. U S A 110, 10371–10378. doi: 10.1073/pnas.1301195110
Castañé, A., Santana, N., and Artigas, F. (2015). PCP-based mice models of schizophrenia: differential behavioral, neurochemical and cellular effects of acute and subchronic treatments. Psychopharmacology 232, 4085–4097. doi: 10.1007/s00213-015-3946-6
Cattane, N., Minelli, A., Milanesi, E., Maj, C., Bignotti, S., Bortolomasi, M., et al. (2015). Altered gene expression in schizophrenia: findings from transcriptional signatures in fibroblasts and blood. PLoS One 10:e0116686. doi: 10.1371/journal.pone.0116686
Chan, W. Y., Leung, H. T., Westbrook, R. F., and McNally, G. P. (2010). Effects of recent exposure to a conditioned stimulus on extinction of Pavlovian fear conditioning. Learn. Mem. 17, 512–521. doi: 10.1101/lm.1912510
Chang, M. C., Park, J. M., Pelkey, K. A., Grabenstatter, H. L., Xu, D., Linden, D. J., et al. (2010). Narp regulates homeostatic scaling of excitatory synapses on parvalbumin-expressing interneurons. Nat. Neurosci. 13, 1090–1097. doi: 10.1038/nn.2621
Chiu, R., Boyle, W. J., Meek, J., Smeal, T., Hunter, T., and Karin, M. (1988). The c-Fos protein interacts with c-Jun/AP-1 to stimulate transcription of AP-1 responsive genes. Cell 54, 541–552. doi: 10.1016/0092-8674(88)90076-1
Chowdhury, S., Shepherd, J. D., Okuno, H., Lyford, G., Petralia, R. S., Plath, N., et al. (2006). Arc/Arg3.1 interacts with the endocytic machinery to regulate AMPA receptor trafficking. Neuron 52, 445–459. doi: 10.1016/j.neuron.2006.08.033
Clements, K. M., and Wainwright, P. E. (2010). Swim stress increases hippocampal Zif268 expression in the spontaneously hypertensive rat. Brain Res. Bull. 82, 259–263. doi: 10.1016/j.brainresbull.2010.05.002
Cole, A. J., Saffen, D. W., Baraban, J. M., and Worley, P. F. (1989). Rapid increase of an immediate early gene messenger RNA in hippocampal neurons by synaptic NMDA receptor activation. Nature 340, 474–476. doi: 10.1038/340474a0
Covington, H. E. III., Lobo, M. K., Maze, I., Vialou, V., Hyman, J. M., Zaman, S., et al. (2010). Antidepressant effect of optogenetic stimulation of the medial prefrontal cortex. J. Neurosci. 30, 16082–16090. doi: 10.1523/JNEUROSCI.1731-10.2010
Cowansage, K. K., Shuman, T., Dillingham, B. C., Chang, A., Golshani, P., and Mayford, M. (2014). Direct reactivation of a coherent neocortical memory of context. Neuron 84, 432–441. doi: 10.1016/j.neuron.2014.09.022
Cullinan, W. E., Herman, J. P., Battaglia, D. F., Akil, H., and Watson, S. J. (1995). Pattern and time course of immediate early gene expression in rat brain following acute stress. Neuroscience 64, 477–505. doi: 10.1016/0306-4522(94)00355-9
Curran, T., and Franza, B. R. Jr. (1988). Fos and Jun: the AP-1 connection. Cell 55, 395–397. doi: 10.1016/0092-8674(88)90024-4
Curran, T., and Morgan, J. I. (1987). Memories of fos. Bioessays 7, 255–258. doi: 10.1002/bies.950070606
Czeh, B., Fuchs, E., Wiborg, O., and Simon, M. (2016). Animal models of major depression and their clinical implications. Prog. Neuropsychopharmacol. Biol. Psychiatry 64, 293–310. doi: 10.1016/j.pnpbp.2015.04.004
Czepielewski, L. S., Massuda, R., Goi, P., Sulzbach-Vianna, M., Reckziegel, R., Costanzi, M., et al. (2015). Verbal episodic memory along the course of schizophrenia and bipolar disorder: a new perspective. Eur. Neuropsychopharmacol. 25, 169–175. doi: 10.1016/j.euroneuro.2014.09.006
Davis, S., Bozon, B., and Laroche, S. (2003). How necessary is the activation of the immediate early gene zif268 in synaptic plasticity and learning? Behav. Brain Res. 142, 17–30. doi: 10.1016/s0166-4328(02)00421-7
Davis, S., Libbey, M., and Laroche, S. (2006). “Neuronal dysfunction and cognitive impairment resulting from inactivation of the egr-family transcription factor zif268,” in Immediate Early Genes in Sensory Processing, Cognitive Performance and Neurological Disorders, eds R. Pinaud and L. A. Tremere (Boston, MA: Springer), 177–195.
Davis, S., Renaudineau, S., Poirier, R., Poucet, B., Save, E., and Laroche, S. (2010). The formation and stability of recognition memory: what happens upon recall? Front. Behav. Neurosci. 4:177. doi: 10.3389/fnbeh.2010.00177
Dawe, G. S., Huff, K. D., Vandergriff, J. L., Sharp, T., O’neill, M. J., and Rasmussen, K. (2001). Olanzapine activates the rat locus coeruleus: in vivo electrophysiology and c-Fos immunoreactivity. Biol. Psychiatry 50, 510–520. doi: 10.1016/s0006-3223(01)01171-4
de Bartolomeis, A., Iasevoli, F., Marmo, F., Buonaguro, E. F., Eramo, A., Rossi, R., et al. (2015a). Progressive recruitment of cortical and striatal regions by inducible postsynaptic density transcripts after increasing doses of antipsychotics with different receptor profiles: insights for psychosis treatment. Eur. Neuropsychopharmacol. 25, 566–582. doi: 10.1016/j.euroneuro.2015.01.003
de Bartolomeis, A., Tomasetti, C., and Iasevoli, F. (2015b). Update on the mechanism of action of aripiprazole: translational insights into antipsychotic strategies beyond dopamine receptor antagonism. CNS Drugs 29, 773–799. doi: 10.1007/s40263-015-0278-3
Desjardins, S., Mayo, W., Vallée, M., Hancock, D., Le Moal, M., Simon, H., et al. (1997). Effect of aging on the basal expression of c-Fos, c-Jun and Egr1 proteins in the hippocampus. Neurobiol. Aging 18, 37–44. doi: 10.1016/s0197-4580(96)00206-0
Dickerson, B. C., and Eichenbaum, H. (2010). The episodic memory system: neurocircuitry and disorders. Neuropsychopharmacology 35, 86–104. doi: 10.1038/npp.2009.126
Donahue, R. J., Muschamp, J. W., Russo, S. J., Nestler, E. J., and Carlezon, W. A. Jr. (2014). Effects of striatal ΔFosB overexpression and ketamine on social defeat stress-induced anhedonia in mice. Biol. Psychiatry 76, 550–558. doi: 10.1016/j.biopsych.2013.12.014
Dragunow, M. (1996). A role for immediate-early transcription factors in learning and memory. Behav. Genet. 26, 293–299. doi: 10.1007/bf02359385
Duclot, F., and Kabbaj, M. (2015). The estrous cycle surpasses sex differences in regulating the transcriptome in the rat medial prefrontal cortex and reveals an underlying role of early growth response 1. Genome Biol. 16:256. doi: 10.1186/s13059-015-0815-x
Duclot, F., and Kabbaj, M. (2017a). Comparative transcriptomic analysis of the effects of antidepressant drugs in stress-susceptible mice. Biol. Psychiatry 81, 278–279. doi: 10.1016/j.biopsych.2016.10.022
Duclot, F., and Kabbaj, M. (2017b). The role of early growth response 1 (egr1) in brain plasticity and neuropsychiatric disorders. Front. Behav. Neurosci. 11:35. doi: 10.3389/fnbeh.2017.00035
Dudai, Y. (2002). Molecular bases of long-term memories: a question of persistence. Curr. Opin. Neurobiol. 12, 211–216. doi: 10.1016/s0959-4388(02)00305-7
Dudchenko, P. A., Talpos, J., Young, J., and Baxter, M. G. (2013). Animal models of working memory: a review of tasks that might be used in screening drug treatments for the memory impairments found in schizophrenia. Neurosci. Biobehav. Rev. 37, 2111–2124. doi: 10.1016/j.neubiorev.2012.03.003
Dynes, J. L., and Steward, O. (2012). Arc mRNA docks precisely at the base of individual dendritic spines indicating the existence of a specialized microdomain for synapse-specific mRNA translation. J. Comp. Neurol. 520, 3105–3119. doi: 10.1002/cne.23073
Exner, C., Kohl, A., Zaudig, M., Langs, G., Lincoln, T. M., and Rief, W. (2009). Metacognition and episodic memory in obsessive-compulsive disorder. J. Anxiety Disord. 23, 624–631. doi: 10.1016/j.janxdis.2009.01.010
Eysenck, M. W. (1988). Models of memory: information processing. Psychopharmacol. Ser. 6, 3–11. doi: 10.1007/978-3-642-73288-1_1
Fleischmann, A., Hvalby, O., Jensen, V., Strekalova, T., Zacher, C., Layer, L. E., et al. (2003). Impaired long-term memory and NR2A-type NMDA receptor-dependent synaptic plasticity in mice lacking c-Fos in the CNS. J. Neurosci. 23, 9116–9122. doi: 10.1523/jneurosci.23-27-09116.2003
Frankland, P. W., Bontempi, B., Talton, L. E., Kaczmarek, L., and Silva, A. J. (2004). The involvement of the anterior cingulate cortex in remote contextual fear memory. Science 304, 881–883. doi: 10.1126/science.1094804
Fujimoto, T., Tanaka, H., Kumamaru, E., Okamura, K., and Miki, N. (2004). Arc interacts with microtubules/microtubule-associated protein 2 and attenuates microtubule-associated protein 2 immunoreactivity in the dendrites. J. Neurosci. Res. 76, 51–63. doi: 10.1002/jnr.20056
Gall, C. M., Hess, U. S., and Lynch, G. (1998). Mapping brain networks engaged by, and changed by, learning. Neurobiol. Learn. Mem. 70, 14–36. doi: 10.1006/nlme.1998.3835
Garner, A. R., Rowland, D. C., Hwang, S. Y., Baumgaertel, K., Roth, B. L., Kentros, C., et al. (2012). Generation of a synthetic memory trace. Science 335, 1513–1516. doi: 10.1126/science.1214985
Gerber, B., Tanimoto, H., and Heisenberg, M. (2004). An engram found? Evaluating the evidence from fruit flies. Curr. Opin. Neurobiol. 14, 737–744. doi: 10.1016/j.conb.2004.10.014
Granado, N., Ortiz, O., Suárez, L. M., Martin, E. D., Ceña, V., Solís, J. M., et al. (2008). D1 but not D5 dopamine receptors are critical for LTP, spatial learning, and LTP-Induced arc and zif268 expression in the hippocampus. Cereb. Cortex 18, 1–12. doi: 10.1093/cercor/bhm026
Green, A. E., Fitzgerald, P. B., Johnston, P. J., Nathan, P. J., Kulkarni, J., and Croft, R. J. (2017). Evidence for a differential contribution of early perceptual and late cognitive processes during encoding to episodic memory impairment in schizophrenia. World J. Biol. Psychiatry 18, 369–381. doi: 10.1080/15622975.2016.1208839
Grimm, R., and Tischmeyer, W. (1997). Complex patterns of immediate early gene induction in rat brain following brightness discrimination training and pseudotraining. Behav. Brain Res. 84, 109–116. doi: 10.1016/s0166-4328(97)83330-x
Gur, R. E., Calkins, M. E., Gur, R. C., Horan, W. P., Nuechterlein, K. H., Seidman, L. J., et al. (2007). The consortium on the genetics of schizophrenia: neurocognitive endophenotypes. Schizophr. Bull. 33, 49–68. doi: 10.1093/schbul/sbl055
Gusev, P. A., and Gubin, A. N. (2010). Arc/Arg3.1 mRNA global expression patterns elicited by memory recall in cerebral cortex differ for remote versus recent spatial memories. Front. Integr. Neurosci. 4:15. doi: 10.3389/fnint.2010.00015
Guzowski, J. F. (2002). Insights into immediate-early gene function in hippocampal memory consolidation using antisense oligonucleotide and fluorescent imaging approaches. Hippocampus 12, 86–104. doi: 10.1002/hipo.10010
Guzowski, J. F., Lyford, G. L., Stevenson, G. D., Houston, F. P., Mcgaugh, J. L., Worley, P. F., et al. (2000). Inhibition of activity-dependent arc protein expression in the rat hippocampus impairs the maintenance of long-term potentiation and the consolidation of long-term memory. J. Neurosci. 20, 3993–4001. doi: 10.1523/jneurosci.20-11-03993.2000
Guzowski, J. F., McNaughton, B. L., Barnes, C. A., and Worley, P. F. (1999). Environment-specific expression of the immediate-early gene Arc in hippocampal neuronal ensembles. Nat. Neurosci. 2, 1120–1124. doi: 10.1038/16046
Guzowski, J. F., McNaughton, B. L., Barnes, C. A., and Worley, P. F. (2001a). Imaging neural activity with temporal and cellular resolution using FISH. Curr. Opin. Neurobiol. 11, 579–584. doi: 10.1016/s0959-4388(00)00252-x
Guzowski, J. F., Setlow, B., Wagner, E. K., and McGaugh, J. L. (2001b). Experience-dependent gene expression in the rat hippocampus after spatial learning: a comparison of the immediate-early genes Arc, c-fos, and zif268. J. Neurosci. 21, 5089–5098. doi: 10.1523/jneurosci.21-14-05089.2001
Guzowski, J. F., Miyashita, T., Chawla, M. K., Sanderson, J., Maes, L. I., Houston, F. P., et al. (2006). Recent behavioral history modifies coupling between cell activity and Arc gene transcription in hippocampal CA1 neurons. Proc. Natl. Acad. Sci. U S A 103, 1077–1082. doi: 10.1073/pnas.0505519103
Hains, A. B., Vu, M. A., Maciejewski, P. K., Van Dyck, C. H., Gottron, M., and Arnsten, A. F. (2009). Inhibition of protein kinase C signaling protects prefrontal cortex dendritic spines and cognition from the effects of chronic stress. Proc. Natl. Acad. Sci. U S A 106, 17957–17962. doi: 10.1073/pnas.0908563106
Hall, J., Thomas, K. L., and Everitt, B. J. (2000). Rapid and selective induction of BDNF expression in the hippocampus during contextual learning. Nat. Neurosci. 3, 533–535. doi: 10.1038/75698
Henry, J. D., Rendell, P. G., Rogers, P., Altgassen, M., and Kliegel, M. (2012). Prospective memory in schizophrenia and schizotypy. Cogn. Neuropsychiatry 17, 133–150. doi: 10.1080/13546805.2011.581536
Herdegen, T., Kovary, K., Buhl, A., Bravo, R., Zimmermann, M., and Gass, P. (1995). Basal expression of the inducible transcription factors c-Jun, JunB, JunD, c-Fos, FosB, and Krox-24 in the adult rat brain. J. Comp. Neurol. 354, 39–56. doi: 10.1002/cne.903540105
Herdegen, T., and Leah, J. D. (1998). Inducible and constitutive transcription factors in the mammalian nervous system: control of gene expression by Jun, Fos and Krox and CREB/ATF proteins. Brain Res. Brain Res. Rev. 28, 370–490. doi: 10.1016/s0165-0173(98)00018-6
Herdegen, T., Walker, T., Leah, J. D., Bravo, R., and Zimmermann, M. (1990). The KROX-24 protein, a new transcription regulating factor: expression in the rat central nervous system following afferent somatosensory stimulation. Neurosci. Lett. 120, 21–24. doi: 10.1016/0304-3940(90)90158-6
Hermans, D., Craske, M. G., Mineka, S., and Lovibond, P. F. (2006). Extinction in human fear conditioning. Biol. Psychiatry 60, 361–368. doi: 10.1016/j.biopsych.2005.10.006
Herold, C. J., Lässer, M. M., Schmid, L. A., Seidl, U., Kong, L., Fellhauer, I., et al. (2015). Neuropsychology, autobiographical memory, and hippocampal volume in “younger” and “older” patients with chronic schizophrenia. Front. Psychiatry 6:53. doi: 10.3389/fpsyt.2015.00053
Herry, C., and Mons, N. (2004). Resistance to extinction is associated with impaired immediate early gene induction in medial prefrontal cortex and amygdala. Eur. J. Neurosci. 20, 781–790. doi: 10.1111/j.1460-9568.2004.03542.x
Hess, U. S., Gall, C. M., Granger, R., and Lynch, G. (1997). Differential patterns of c-fos mRNA expression in amygdala during successive stages of odor discrimination learning. Learn. Mem. 4, 262–283. doi: 10.1101/lm.4.3.262
Hess, U. S., Lynch, G., and Gall, C. M. (1995a). Changes in c-fos mRNA expression in rat brain during odor discrimination learning: differential involvement of hippocampal subfields CA1 and CA3. J. Neurosci. 15, 4786–4795. doi: 10.1523/jneurosci.15-07-04786.1995
Hess, U. S., Lynch, G., and Gall, C. M. (1995b). Regional patterns of c-fos mRNA expression in rat hippocampus following exploration of a novel environment versus performance of a well-learned discrimination. J. Neurosci. 15, 7796–7809. doi: 10.1523/jneurosci.15-12-07796.1995
Hodges, T. E., Green, M. R., Simone, J. J., and McCormick, C. M. (2014). Effects of social context on endocrine function and Zif268 expression in response to an acute stressor in adolescent and adult rats. Int. J. Dev. Neurosci. 35, 25–34. doi: 10.1016/j.ijdevneu.2014.03.001
Holbrook, T. L., Galarneau, M. R., Dye, J. L., Quinn, K., and Dougherty, A. L. (2010). Morphine use after combat injury in Iraq and post-traumatic stress disorder. N. Engl. J. Med. 362, 110–117. doi: 10.1056/NEJMoa0903326
Holloway, C. M., and McIntyre, C. K. (2011). Post-training disruption of Arc protein expression in the anterior cingulate cortex impairs long-term memory for inhibitory avoidance training. Neurobiol. Learn. Mem. 95, 425–432. doi: 10.1016/j.nlm.2011.02.002
Hughes, P., and Dragunow, M. (1995). Induction of immediate-early genes and the control of neurotransmitter-regulated gene expression within the nervous system. Pharmacol. Rev. 47, 133–178.
Hughes, P., Lawlor, P., and Dragunow, M. (1992). Basal expression of Fos, Fos-related, Jun, and Krox 24 proteins in rat hippocampus. Brain Res. Mol. Brain Res. 13, 355–357. doi: 10.1016/0169-328x(92)90219-2
Huntley, G. W. (2012). Synaptic circuit remodelling by matrix metalloproteinases in health and disease. Nat. Rev. Neurosci. 13, 743–757. doi: 10.1038/nrn3320
Ivashkina, O. I., Toropova, K. A., Ivanova, A. A., Chekhov, S. A., and Anokhin, K. V. (2016). Waves of c-Fos and arc proteins expression in neuronal populations of the hippocampus in response to a single episode of new experience. Bull. Exp. Biol. Med. 160, 729–732. doi: 10.1007/s10517-016-3296-3
Izquierdo, I., Furini, C. R., and Myskiw, J. C. (2016). Fear memory. Physiol. Rev. 96, 695–750. doi: 10.1152/physrev.00018.2015
Jaeger, J., Berns, S., Uzelac, S., and Davis-Conway, S. (2006). Neurocognitive deficits and disability in major depressive disorder. Psychiatry Res. 145, 39–48. doi: 10.1016/j.psychres.2005.11.011
Jarvis, E. D., Mello, C. V., and Nottebohm, F. (1995). Associative learning and stimulus novelty influence the song-induced expression of an immediate early gene in the canary forebrain. Learn. Mem. 2, 62–80. doi: 10.1101/lm.2.2.62
Jones, M. W., Errington, M. L., French, P. J., Fine, A., Bliss, T. V., Garel, S., et al. (2001). A requirement for the immediate early gene Zif268 in the expression of late LTP and long-term memories. Nat. Neurosci. 4, 289–296. doi: 10.1038/85138
Josselyn, S. A. (2010). Continuing the search for the engram: examining the mechanism of fear memories. J. Psychiatry Neurosci. 35, 221–228. doi: 10.1503/jpn.100015
Kaczmarek, L., and Chaudhuri, A. (1997). Sensory regulation of immediate-early gene expression in mammalian visual cortex: implications for functional mapping and neural plasticity. Brain Res. Brain Res. Rev. 23, 237–256. doi: 10.1016/s0165-0173(97)00005-2
Kaczmarek, L., and Nikołajew, E. (1990). c-fos protooncogene expression and neuronal plasticity. Acta Neurobiol. Exp. 50, 173–179.
Kandel, E. R., Dudai, Y., and Mayford, M. R. (2014). The molecular and systems biology of memory. Cell 157, 163–186. doi: 10.1016/j.cell.2014.03.001
Karabeg, M. M., Grauthoff, S., Kollert, S. Y., Weidner, M., Heiming, R. S., Jansen, F., et al. (2013). 5-HTT deficiency affects neuroplasticity and increases stress sensitivity resulting in altered spatial learning performance in the Morris water maze but not in the Barnes maze. PLoS One 8:e78238. doi: 10.1371/journal.pone.0078238
Katche, C., Bekinschtein, P., Slipczuk, L., Goldin, A., Izquierdo, I. A., Cammarota, M., et al. (2010). Delayed wave of c-Fos expression in the dorsal hippocampus involved specifically in persistence of long-term memory storage. Proc. Natl. Acad. Sci. U S A 107, 349–354. doi: 10.1073/pnas.0912931107
Katche, C., Dorman, G., Gonzalez, C., Kramar, C. P., Slipczuk, L., Rossato, J. I., et al. (2013). On the role of retrosplenial cortex in long-lasting memory storage. Hippocampus 23, 295–302. doi: 10.1002/hipo.22092
Katche, C., Goldin, A., Gonzalez, C., Bekinschtein, P., and Medina, J. H. (2012). Maintenance of long-term memory storage is dependent on late posttraining Egr1 expression. Neurobiol. Learn. Mem. 98, 220–227. doi: 10.1016/j.nlm.2012.08.001
Katche, C., and Medina, J. H. (2017). Requirement of an early activation of BDNF/c-Fos cascade in the retrosplenial cortex for the persistence of a long-lasting aversive memory. Cereb. Cortex 27, 1060–1067. doi: 10.1093/cercor/bhv284
Kemp, A., Tischmeyer, W., and Manahan-Vaughan, D. (2013). Learning-facilitated long-term depression requires activation of the immediate early gene, c-fos, and is transcription dependent. Behav. Brain Res. 254, 83–91. doi: 10.1016/j.bbr.2013.04.036
Kéri, S., and Janka, Z. (2004). Critical evaluation of cognitive dysfunctions as endophenotypes of schizophrenia. Acta Psychiatr. Scand. 110, 83–91. doi: 10.1111/j.1600-0047.2004.00359.x
Kessler, R. C., and Wang, P. S. (2008). The descriptive epidemiology of commonly occurring mental disorders in the United States. Annu. Rev. Public Health 29, 115–129. doi: 10.1146/annurev.publhealth.29.020907.090847
Kimoto, S., Bazmi, H. H., and Lewis, D. A. (2014). Lower expression of glutamic acid decarboxylase 67 in the prefrontal cortex in schizophrenia: contribution of altered regulation by Zif268. Am. J. Psychiatry 171, 969–978. doi: 10.1176/appi.ajp.2014.14010004
Knapska, E., and Kaczmarek, L. (2004). A gene for neuronal plasticity in the mammalian brain: Zif268/Egr1/NGFI-A/Krox-24/TIS8/ZENK? Prog. Neurobiol. 74, 183–211. doi: 10.1016/j.pneurobio.2004.05.007
Koenigs, M., and Grafman, J. (2009). The functional neuroanatomy of depression: distinct roles for ventromedial and dorsolateral prefrontal cortex. Behav. Brain Res. 201, 239–243. doi: 10.1016/j.bbr.2009.03.004
Koldamova, R., Schug, J., Lefterova, M., Cronican, A. A., Fitz, N. F., Davenport, F. A., et al. (2014). Genome-wide approaches reveal EGR1-controlled regulatory networks associated with neurodegeneration. Neurobiol. Dis. 63, 107–114. doi: 10.1016/j.nbd.2013.11.005
Konopaske, G. T., Lange, N., Coyle, J. T., and Benes, F. M. (2014). Prefrontal cortical dendritic spine pathology in schizophrenia and bipolar disorder. JAMA Psychiatry 71, 1323–1331. doi: 10.1001/jamapsychiatry.2014.1582
Korb, E., and Finkbeiner, S. (2011). Arc in synaptic plasticity: from gene to behavior. Trends Neurosci. 34, 591–598. doi: 10.1016/j.tins.2011.08.007
Krishnan, V., Berton, O., and Nestler, E. (2008). The use of animal models in psychiatric research and treatment. Am. J. Psychiatry 165:1109. doi: 10.1176/appi.ajp.2008.08071076
Krishnan, V., and Nestler, E. J. (2008). The molecular neurobiology of depression. Nature 455, 894–902. doi: 10.1038/nature07455
Kubik, S., Miyashita, T., and Guzowski, J. F. (2007). Using immediate-early genes to map hippocampal subregional functions. Learn. Mem. 14, 758–770. doi: 10.1101/lm.698107
Kubik, S., Miyashita, T., Kubik-Zahorodna, A., and Guzowski, J. F. (2012). Loss of activity-dependent Arc gene expression in the retrosplenial cortex after hippocampal inactivation: interaction in a higher-order memory circuit. Neurobiol. Learn. Mem. 97, 124–131. doi: 10.1016/j.nlm.2011.10.004
Kurian, S. M., Le-Niculescu, H., Patel, S. D., Bertram, D., Davis, J., Dike, C., et al. (2011). Identification of blood biomarkers for psychosis using convergent functional genomics. Mol. Psychiatry 16, 37–58. doi: 10.1038/mp.2009.117
Kwon, J.-T., Jhang, J., Kim, H.-S., Lee, S., and Han, J.-H. (2012). Brain region-specific activity patterns after recent or remote memory retrieval of auditory conditioned fear. Learn. Mem. 19, 487–494. doi: 10.1101/lm.025502.112
Lai, C. S., Franke, T. F., and Gan, W. B. (2012). Opposite effects of fear conditioning and extinction on dendritic spine remodelling. Nature 483, 87–91. doi: 10.1038/nature10792
Lamprecht, R., and LeDoux, J. (2004). Structural plasticity and memory. Nat. Rev. Neurosci. 5, 45–54. doi: 10.1038/nrn1301
Lanahan, A., and Worley, P. (1998). Immediate-early genes and synaptic function. Neurobiol. Learn. Mem. 70, 37–43. doi: 10.1006/nlme.1998.3836
Leal, G., Comprido, D., and Duarte, C. B. (2014). BDNF-induced local protein synthesis and synaptic plasticity. Neuropharmacology 76, 639–656. doi: 10.1016/j.neuropharm.2013.04.005
LeDoux, J. E. (2014). Coming to terms with fear. Proc. Natl. Acad. Sci. U S A 111, 2871–2878. doi: 10.1073/pnas.1400335111
Lee, J. L. (2008). Memory reconsolidation mediates the strengthening of memories by additional learning. Nat. Neurosci. 11, 1264–1266. doi: 10.1038/nn.2205
Lee, J. L., Everitt, B. J., and Thomas, K. L. (2004). Independent cellular processes for hippocampal memory consolidation and reconsolidation. Science 304, 839–843. doi: 10.1126/science.1095760
Lee, R. S., Hermens, D. F., Porter, M. A., and Redoblado-Hodge, M. A. (2012). A meta-analysis of cognitive deficits in first-episode Major Depressive Disorder. J. Affect. Disord. 140, 113–124. doi: 10.1016/j.jad.2011.10.023
Lefaucheur, J. P., Antal, A., Ayache, S. S., Benninger, D. H., Brunelin, J., Cogiamanian, F., et al. (2017). Evidence-based guidelines on the therapeutic use of transcranial direct current stimulation (tDCS). Clin. Neurophysiol. 128, 56–92. doi: 10.1016/j.clinph.2016.10.087
Lemaire, P., Revelant, O., Bravo, R., and Charnay, P. (1988). Two mouse genes encoding potential transcription factors with identical DNA-binding domains are activated by growth factors in cultured cells. Proc. Natl. Acad. Sci. U S A 85, 4691–4695. doi: 10.1073/pnas.85.13.4691
Lepeta, K., and Kaczmarek, L. (2015). Matrix metalloproteinase-9 as a novel player in synaptic plasticity and schizophrenia. Schizophr. Bull. 41, 1003–1009. doi: 10.1093/schbul/sbv036
Li, L., Carter, J., Gao, X., Whitehead, J., and Tourtellotte, W. G. (2005). The neuroplasticity-associated arc gene is a direct transcriptional target of early growth response (Egr) transcription factors. Mol. Cell. Biol. 25, 10286–10300. doi: 10.1128/mcb.25.23.10286-10300.2005
Li, Y., Pehrson, A. L., Waller, J. A., Dale, E., Sanchez, C., and Gulinello, M. (2015). A critical evaluation of the activity-regulated cytoskeleton-associated protein (Arc/Arg3.1)’s putative role in regulating dendritic plasticity, cognitive processes and mood in animal models of depression. Front. Neurosci. 9:279. doi: 10.3389/fnins.2015.00279
Liu, X., Ramirez, S., Pang, P. T., Puryear, C. B., Govindarajan, A., Deisseroth, K., et al. (2012). Optogenetic stimulation of a hippocampal engram activates fear memory recall. Nature 484, 381–385. doi: 10.1038/nature11028
Lonergan, M. E., Gafford, G. M., Jarome, T. J., and Helmstetter, F. J. (2010). Time-dependent expression of Arc and zif268 after acquisition of fear conditioning. Neural Plast. 2010:139891. doi: 10.1155/2010/139891
Lopez, J., Herbeaux, K., Cosquer, B., Engeln, M., Muller, C., Lazarus, C., et al. (2012). Context-dependent modulation of hippocampal and cortical recruitment during remote spatial memory retrieval. Hippocampus 22, 827–841. doi: 10.1002/hipo.20943
Lu, B., Nagappan, G., Guan, X., Nathan, P. J., and Wren, P. (2013). BDNF-based synaptic repair as a disease-modifying strategy for neurodegenerative diseases. Nat. Rev. Neurosci. 14, 401–416. doi: 10.1038/nrn3505
Lukasiuk, K., Savonenko, A., Nikolaev, E., Rydz, M., and Kaczmarek, L. (1999). Defensive conditioning-related increase in AP-1 transcription factor in the rat cortex. Mol. Brain Res. 67, 64–73. doi: 10.1016/s0169-328x(99)00045-5
Lyford, G. L., Yamagata, K., Kaufmann, W. E., Barnes, C. A., Sanders, L. K., Copeland, N. G., et al. (1995). Arc, a growth factor and activity-regulated gene, encodes a novel cytoskeleton-associated protein that is enriched in neuronal dendrites. Neuron 14, 433–445. doi: 10.1016/0896-6273(95)90299-6
MacGibbon, G. A., Lawlor, P. A., Bravo, R., and Dragunow, M. (1994). Clozapine and haloperidol produce a differential pattern of immediate early gene expression in rat caudate-putamen, nucleus accumbens, lateral septum and islands of Calleja. Mol. Brain Res. 23, 21–32. doi: 10.1016/0169-328x(94)90207-0
Machida, M., Lonart, G., and Sanford, L. D. (2018). Effects of stressor controllability on transcriptional levels of c-fos, Arc, and brain-derived neurotrophic factor in mouse amygdala and medial prefrontal cortex. Neuroreport 29, 112–117. doi: 10.1097/WNR.0000000000000919
Mack, K., Day, M., Milbrandt, J., and Gottlieb, D. I. (1990). Localization of the NGFI-A protein in the rat brain. Mol. Brain Res. 8, 177–180. doi: 10.1016/0169-328x(90)90062-i
Maddox, S. A., Monsey, M. S., and Schafe, G. E. (2011). Early growth response gene 1 (Egr1) is required for new and reactivated fear memories in the lateral amygdala. Learn. Mem. 18, 24–38. doi: 10.1101/lm.1980211
Maleeva, N. E., Bikbulatova, L. S., Ivolgina, G. L., Anokhin, K. V., Limborskaia, S. A., and Kruglikov, R. I. (1990). Activation of the c-fos proto-oncogene in different structures of the rat brain during training and pseudoconditioning. Dokl. Akad. Nauk SSSR 314, 762–764.
Maleeva, N. E., Ivolgina, G. L., Anokhin, K. V., and Limborskaia, S. A. (1989). Analysis of the expression of the c-fos proto-oncogene in the rat cerebral cortex during learning. Genetika 25, 1119–1121. doi: 10.1016/0304-3940(89)90381-9
Malkani, S., Wallace, K. J., Donley, M. P., and Rosen, J. B. (2004). An Egr1 (zif268) antisense oligodeoxynucleotide infused into the amygdala disrupts fear conditioning. Learn. Mem. 11, 617–624. doi: 10.1101/lm.73104
Managò, F., and Papaleo, F. (2017). Schizophrenia: what’s arc got to do with it? Front. Behav. Neurosci. 11:181. doi: 10.3389/fnbeh.2017.00181
Managò, F., Mereu, M., Mastwal, S., Mastrogiacomo, R., Scheggia, D., Emanuele, M., et al. (2016). Genetic disruption of Arc/Arg3.1 in mice causes alterations in Dopamine and neurobehavioral phenotypes related to schizophrenia. Cell Rep. 16, 2116–2128. doi: 10.1016/j.celrep.2016.07.044
Maren, S., and Chang, C. H. (2006). Recent fear is resistant to extinction. Proc. Natl. Acad. Sci. U S A 103, 18020–18025. doi: 10.1073/pnas.0608398103
Martin, S. J., and Morris, R. G. (2002). New life in an old idea: the synaptic plasticity and memory hypothesis revisited. Hippocampus 12, 609–636. doi: 10.1002/hipo.10107
Martínez, M. C., Alen, N., Ballarini, F., Moncada, D., and Viola, H. (2012). Memory traces compete under regimes of limited Arc protein synthesis: implications for memory interference. Neurobiol. Learn. Mem. 98, 165–173. doi: 10.1016/j.nlm.2012.05.007
Martinussen, R., Hayden, J., Hogg-Johnson, S., and Tannock, R. (2005). A meta-analysis of working memory impairments in children with attention-deficit/hyperactivity disorder. J. Am. Acad. Child Adolesc. Psychiatry 44, 377–384. doi: 10.1097/01.chi.0000153228.72591.73
Mastwal, S., Cao, V., and Wang, K. H. (2016). Genetic feedback regulation of frontal cortical neuronal ensembles through activity-dependent arc expression and dopaminergic input. Front. Neural Circuits 10:100. doi: 10.3389/fncir.2016.00100
Matsumoto, K., Ono, K., Ouchi, H., Tsushima, R., and Murakami, Y. (2012). Social isolation stress down-regulates cortical early growth response 1 (Egr1) expression in mice. Neurosci. Res. 73, 257–262. doi: 10.1016/j.neures.2012.04.004
Matsuo, N., Yamasaki, N., Ohira, K., Takao, K., Toyama, K., Eguchi, M., et al. (2009). Neural activity changes underlying the working memory deficit in α-CaMKII heterozygous knockout mice. Front. Behav. Neurosci. 3:20. doi: 10.3389/neuro.08.020.2009
Maviel, T., Durkin, T. P., Menzaghi, F., and Bontempi, B. (2004). Sites of neocortical reorganization critical for remote spatial memory. Science 305, 96–99. doi: 10.1126/science.1098180
Mcintyre, R. S., Cha, D. S., Soczynska, J. K., Woldeyohannes, H. O., Gallaugher, L. A., Kudlow, P., et al. (2013). Cognitive deficits and functional outcomes in major depressive disorder: determinants, substrates and treatment interventions. Depress Anxiety 30, 515–527. doi: 10.1002/da.22063
Meconi, F., Anderl-Straub, S., Raum, H., Landgrebe, M., Langguth, B., Bäuml, K. T., et al. (2016). Aberrant prefrontal β oscillations predict episodic memory encoding deficits in schizophrenia. Neuroimage Clin. 12, 499–505. doi: 10.1016/j.nicl.2016.08.017
Mello, C. V., and Ribeiro, S. (1998). ZENK protein regulation by song in the brain of songbirds. J. Comp. Neurol. 393, 426–438. doi: 10.1002/(sici)1096-9861(19980420)393:4<426::aid-cne3>3.0.co;2-2
Mello, C. V., Vicario, D. S., and Clayton, D. F. (1992). Song presentation induces gene expression in the songbird forebrain. Proc. Natl. Acad. Sci. U S A 89, 6818–6822. doi: 10.1073/pnas.89.15.6818
Michaluk, P., and Kaczmarek, L. (2007). Matrix metalloproteinase-9 in glutamate-dependent adult brain function and dysfunction. Cell Death Differ. 14, 1255–1258. doi: 10.1038/sj.cdd.4402141
Michaluk, P., Kolodziej, L., Mioduszewska, B., Wilczynski, G. M., Dzwonek, J., Jaworski, J., et al. (2007). β-dystroglycan as a target for MMP-9, in response to enhanced neuronal activity. J. Biol. Chem. 282, 16036–16041. doi: 10.1074/jbc.M700641200
Milbrandt, J. (1987). A nerve growth factor-induced gene encodes a possible transcriptional regulatory factor. Science 238, 797–799. doi: 10.1126/science.3672127
Milekic, M. H., and Alberini, C. M. (2002). Temporally graded requirement for protein synthesis following memory reactivation. Neuron 36, 521–525. doi: 10.1016/s0896-6273(02)00976-5
Minatohara, K., Akiyoshi, M., and Okuno, H. (2016). Role of immediate-early genes in synaptic plasticity and neuronal ensembles underlying the memory trace. Front. Mol. Neurosci. 8:78. doi: 10.3389/fnmol.2015.00078
Miniaci, M. C., Kim, J. H., Puthanveettil, S. V., Si, K., Zhu, H., Kandel, E. R., et al. (2008). Sustained CPEB-dependent local protein synthesis is required to stabilize synaptic growth for persistence of long-term facilitation in Aplysia. Neuron 59, 1024–1036. doi: 10.1016/j.neuron.2008.07.036
Miranda, M., and Bekinschtein, P. (2018). Plasticity mechanisms of memory consolidation and reconsolidation in the perirhinal cortex. Neuroscience 370, 46–61. doi: 10.1016/j.neuroscience.2017.06.002
Miyashita, Y., Kameyama, M., Hasegawa, I., and Fukushima, T. (1998). Consolidation of visual associative long-term memory in the temporal cortex of primates. Neurobiol. Learn. Mem. 70, 197–211. doi: 10.1006/nlme.1998.3848
Moga, D. E., Calhoun, M. E., Chowdhury, A., Worley, P., Morrison, J. H., and Shapiro, M. L. (2004). Activity-regulated cytoskeletal-associated protein is localized to recently activated excitatory synapses. Neuroscience 125, 7–11. doi: 10.1016/j.neuroscience.2004.02.004
Molteni, R., Calabrese, F., Chourbaji, S., Brandwein, C., Racagni, G., Gass, P., et al. (2010). Depression-prone mice with reduced glucocorticoid receptor expression display an altered stress-dependent regulation of brain-derived neurotrophic factor and activity-regulated cytoskeleton-associated protein. J. Psychopharmacol. 24, 595–603. doi: 10.1177/0269881108099815
Molteni, R., Calabrese, F., Mancini, M., Racagni, G., and Riva, M. A. (2008). Basal and stress-induced modulation of activity-regulated cytoskeletal associated protein (Arc) in the rat brain following duloxetine treatment. Psychopharmacology 201, 285–292. doi: 10.1007/s00213-008-1276-7
Moncada, D., Ballarini, F., Martinez, M. C., Frey, J. U., and Viola, H. (2011). Identification of transmitter systems and learning tag molecules involved in behavioral tagging during memory formation. Proc. Natl. Acad. Sci. U S A 108, 12931–12936. doi: 10.1073/pnas.1104495108
Moncada, D., and Viola, H. (2007). Induction of long-term memory by exposure to novelty requires protein synthesis: evidence for a behavioral tagging. J. Neurosci. 27, 7476–7481. doi: 10.1523/jneurosci.1083-07.2007
Monfils, M. H., Cowansage, K. K., Klann, E., and LeDoux, J. E. (2009). Extinction-reconsolidation boundaries: key to persistent attenuation of fear memories. Science 324, 951–955. doi: 10.1126/science.1167975
Monsey, M. S., Boyle, L. M., Zhang, M. L., Nguyen, C. P., Kronman, H. G., Ota, K. T., et al. (2014). Chronic corticosterone exposure persistently elevates the expression of memory-related genes in the lateral amygdala and enhances the consolidation of a Pavlovian fear memory. PLoS One 9:e91530. doi: 10.1371/journal.pone.0091530
Morgan, J. I., and Curran, T. (1988). Calcium as a modulator of the immediate-early gene cascade in neurons. Cell Calcium 9, 303–311. doi: 10.1016/0143-4160(88)90011-5
Morici, J. F., Bekinschtein, P., and Weisstaub, N. V. (2015). Medial prefrontal cortex role in recognition memory in rodents. Behav. Brain Res. 292, 241–251. doi: 10.1016/j.bbr.2015.06.030
Morinobu, S., Nibuya, M., and Duman, R. S. (1995). Chronic antidepressant treatment down-regulates the induction of c-fos mRNA in response to acute stress in rat frontal cortex. Neuropsychopharmacology 12, 221–228. doi: 10.1038/sj.npp.1380254
Morinobu, S., Strausbaugh, H., Terwilliger, R., and Duman, R. S. (1997). Regulation of c-Fos and NGF1-A by antidepressant treatments. Synapse 25, 313–320. doi: 10.1002/(sici)1098-2396(199704)25:4<313::aid-syn1>3.3.co;2-j
Morris, R. G. (1999). D.O. Hebb: The Organization of Behavior, Wiley: New York; 1949. Brain Res. Bull. 50:437. doi: 10.1016/s0361-9230(99)00182-3
Morris, R. G. (2006). Elements of a neurobiological theory of hippocampal function: the role of synaptic plasticity, synaptic tagging and schemas. Eur. J. Neurosci. 23, 2829–2846. doi: 10.1111/j.1460-9568.2006.04888.x
Morris, R. G., and Frey, U. (1999). Tagging the hebb synapse: reply. Trends Neurosci. 22:256. doi: 10.1016/s0166-2236(99)01413-7
Muller, J., and Roberts, J. E. (2005). Memory and attention in Obsessive-Compulsive Disorder: a review. J. Anxiety Disord. 19, 1–28. doi: 10.1002/0470861657.ch1
Myers, K. M., Ressler, K. J., and Davis, M. (2006). Different mechanisms of fear extinction dependent on length of time since fear acquisition. Learn. Mem. 13, 216–223. doi: 10.1101/lm.119806
Nakayama, D., Iwata, H., Teshirogi, C., Ikegaya, Y., Matsuki, N., and Nomura, H. (2015). Long-delayed expression of the immediate early gene Arc/Arg3.1 refines neuronal circuits to perpetuate fear memory. J. Neurosci. 35, 819–830. doi: 10.1523/JNEUROSCI.2525-14.2015
Nalloor, R., Bunting, K. M., and Vazdarjanova, A. (2014). Altered hippocampal function before emotional trauma in rats susceptible to PTSD-like behaviors. Neurobiol. Learn. Mem. 112, 158–167. doi: 10.1016/j.nlm.2014.02.006
Nestler, E. J. (2008). Review. Transcriptional mechanisms of addiction: role of DeltaFosB. Philos. Trans. R. Soc. Lond. B Biol. Sci. 363, 3245–3255. doi: 10.1098/rstb.2008.0067
Nestler, E. J. (2015). FosB: a transcriptional regulator of stress and antidepressant responses. Eur. J. Pharmacol. 753, 66–72. doi: 10.1016/j.ejphar.2014.10.034
Nestler, E. J., and Hyman, S. E. (2010). Animal models of neuropsychiatric disorders. Nat. Neurosci. 13, 1161–1169. doi: 10.1038/nn.2647
Nguyen, T. V., Kosofsky, B. E., Birnbaum, R., Cohen, B. M., and Hyman, S. E. (1992). Differential expression of c-fos and zif268 in rat striatum after haloperidol, clozapine, and amphetamine. Proc. Natl. Acad. Sci. U S A 89, 4270–4274. doi: 10.1073/pnas.89.10.4270
Nikolaev, E., Kaminska, B., Tischmeyer, W., Matthies, H., and Kaczmarek, L. (1992a). Induction of expression of genes encoding transcription factors in the rat brain elicited by behavioral training. Brain Res. Bull. 28, 479–484. doi: 10.1016/0361-9230(92)90050-8
Nikolaev, E., Werka, T., and Kaczmarek, L. (1992b). C-fos protooncogene expression in rat brain after long-term training of two-way active avoidance reaction. Behav. Brain Res. 48, 91–94. doi: 10.1016/s0166-4328(05)80143-3
O’Donovan, K. J., Tourtellotte, W. G., Millbrandt, J., and Baraban, J. M. (1999). The EGR family of transcription-regulatory factors: progress at the interface of molecular and systems neuroscience. Trends Neurosci. 22, 167–173. doi: 10.1016/s0166-2236(98)01343-5
Oertel-Knöchel, V., Reinke, B., Matura, S., Prvulovic, D., Linden, D. E., and van de Ven, V. (2015). Functional connectivity pattern during rest within the episodic memory network in association with episodic memory performance in bipolar disorder. Psychiatry Res. 231, 141–150. doi: 10.1016/j.pscychresns.2014.11.014
Ohashi, K., Hamamura, T., Lee, Y., Fujiwara, Y., Suzuki, H., and Kuroda, S. (2000). Clozapine- and olanzapine-induced Fos expression in the rat medial prefrontal cortex is mediated by β-adrenoceptors. Neuropsychopharmacology 23, 162–169. doi: 10.1016/s0893-133x(00)00105-6
Okada, R., Matsumoto, K., Tsushima, R., Fujiwara, H., and Tsuneyama, K. (2014). Social isolation stress-induced fear memory deficit is mediated by down-regulated neuro-signaling system and Egr1 expression in the brain. Neurochem. Res. 39, 875–882. doi: 10.1007/s11064-014-1283-5
Okuno, H., and Miyashita, Y. (1996). Expression of the transcription factor Zif268 in the temporal cortex of monkeys during visual paired associate learning. Eur. J. Neurosci. 8, 2118–2128. doi: 10.1111/j.1460-9568.1996.tb00733.x
Okuno, H., Saffen, D. W., and Miyashita, Y. (1995). Subdivision-specific expression of ZIF268 in the hippocampal formation of the macaque monkey. Neuroscience 66, 829–845. doi: 10.1016/0306-4522(94)00619-g
Ons, S., Rotllant, D., Marín-Blasco, I. J., and Armario, A. (2010). Immediate-early gene response to repeated immobilization: Fos protein and arc mRNA levels appear to be less sensitive than c-fos mRNA to adaptation. Eur. J. Neurosci. 31, 2043–2052. doi: 10.1111/j.1460-9568.2010.07242.x
Panja, D., and Bramham, C. R. (2014). BDNF mechanisms in late LTP formation: a synthesis and breakdown. Neuropharmacology 76, 664–676. doi: 10.1016/j.neuropharm.2013.06.024
Parsons, R. G., and Ressler, K. J. (2013). Implications of memory modulation for post-traumatic stress and fear disorders. Nat. Neurosci. 16, 146–153. doi: 10.1038/nn.3296
Pastuzyn, E. D., Day, C. E., Kearns, R. B., Kyrke-Smith, M., Taibi, A. V., McCormick, J., et al. (2018). The neuronal gene arc encodes a repurposed retrotransposon gag protein that mediates intercellular RNA transfer. Cell 172, 275.e18–288.e18. doi: 10.1016/j.cell.2017.12.024
Pastuzyn, E. D., and Keefe, K. A. (2014). Changes in neural circuitry regulating response-reversal learning and Arc-mediated consolidation of learning in rats with methamphetamine-induced partial monoamine loss. Neuropsychopharmacology 39, 963–972. doi: 10.1038/npp.2013.296
Paylor, R., Johnson, R. S., Papaioannou, V., Spiegelman, B. M., and Wehner, J. M. (1994). Behavioral assessment of c-fos mutant mice. Brain Res. 651, 275–282. doi: 10.1016/0006-8993(94)90707-2
Peebles, C. L., Yoo, J., Thwin, M. T., Palop, J. J., Noebels, J. L., and Finkbeiner, S. (2010). Arc regulates spine morphology and maintains network stability in vivo. Proc. Natl. Acad. Sci. U S A 107, 18173–18178. doi: 10.1073/pnas.1006546107
Pei, Q., Zetterström, T. S., Sprakes, M., Tordera, R., and Sharp, T. (2003). Antidepressant drug treatment induces Arc gene expression in the rat brain. Neuroscience 121, 975–982. doi: 10.1016/s0306-4522(03)00504-9
Penke, Z., Morice, E., Veyrac, A., Gros, A., Chagneau, C., Leblanc, P., et al. (2014). Zif268/Egr1 gain of function facilitates hippocampal synaptic plasticity and long-term spatial recognition memory. Philos. Trans. R. Soc. Lond. B Biol. Sci. 369:20130159. doi: 10.1098/rstb.2013.0159
Pennypacker, K. R. (1995). AP-1 transcription factor complexes in CNS disorders and development. J. Fla. Med. Assoc. 82, 551–554.
Pérez-Santiago, J., Diez-Alarcia, R., Callado, L. F., Zhang, J. X., Chana, G., White, C. H., et al. (2012). A combined analysis of microarray gene expression studies of the human prefrontal cortex identifies genes implicated in schizophrenia. J. Psychiatr. Res. 46, 1464–1474. doi: 10.1016/j.jpsychires.2012.08.005
Perrotti, L. I., Hadeishi, Y., Ulery, P. G., Barrot, M., Monteggia, L., Duman, R. S., et al. (2004). Induction of deltaFosB in reward-related brain structures after chronic stress. J. Neurosci. 24, 10594–10602. doi: 10.1523/JNEUROSCI.2542-04.2004
Pinaud, R., Tremere, L. A., and De Weerd, P. (2005). Critical Calcium-Regulated Biochemical and Gene Expression Programs Involved in Experience-Dependent Plasticity. Boston, MA: Springers.
Pinaud, R. (2004). Experience-dependent immediate early gene expression in the adult central nervous system: evidence from enriched-environment studies. Int. J. Neurosci. 114, 321–333. doi: 10.1080/00207450490264142
Pinaud, R., Penner, M. R., Robertson, H. A., and Currie, R. W. (2001). Upregulation of the immediate early gene arc in the brains of rats exposed to environmental enrichment: implications for molecular plasticity. Mol. Brain Res. 91, 50–56. doi: 10.1016/s0169-328x(01)00121-8
Pittenger, C. (2013). Disorders of memory and plasticity in psychiatric disease. Dialogues Clin. Neurosci. 15, 455–463.
Plath, N., Ohana, O., Dammermann, B., Errington, M. L., Schmitz, D., Gross, C., et al. (2006). Arc/Arg3.1 is essential for the consolidation of synaptic plasticity and memories. Neuron 52, 437–444. doi: 10.1016/j.neuron.2006.08.024
Ploski, J. E., Pierre, V. J., Smucny, J., Park, K., Monsey, M. S., Overeem, K. A., et al. (2008). The activity-regulated cytoskeletal-associated protein (Arc/Arg3.1) is required for memory consolidation of pavlovian fear conditioning in the lateral amygdala. J. Neurosci. 28, 12383–12395. doi: 10.1523/JNEUROSCI.1662-08.2008
Postle, B. R. (2006). Working memory as an emergent property of the mind and brain. Neuroscience 139, 23–38. doi: 10.1016/j.neuroscience.2005.06.005
Pothuizen, H. H., Davies, M., Albasser, M. M., Aggleton, J. P., and Vann, S. D. (2009). Granular and dysgranular retrosplenial cortices provide qualitatively different contributions to spatial working memory: evidence from immediate-early gene imaging in rats. Eur. J. Neurosci. 30, 877–888. doi: 10.1111/j.1460-9568.2009.06881.x
Quirk, G. J., and Milad, M. R. (2010). Neuroscience: editing out fear. Nature 463, 36–37. doi: 10.1038/463036a
Quirk, G. J., and Mueller, D. (2008). Neural mechanisms of extinction learning and retrieval. Neuropsychopharmacology 33, 56–72. doi: 10.1038/sj.npp.1301555
Quirk, G. J., Pare, D., Richardson, R., Herry, C., Monfils, M. H., Schiller, D., et al. (2010). Erasing fear memories with extinction training. J. Neurosci. 30, 14993–14997. doi: 10.1523/JNEUROSCI.4268-10.2010
Radulovic, J., Kammermeier, J., and Spiess, J. (1998). Relationship between fos production and classical fear conditioning: effects of novelty, latent inhibition, and unconditioned stimulus preexposure. J. Neurosci. 18, 7452–7461. doi: 10.1523/JNEUROSCI.18-18-07452.1998
Ragland, J. D., Ranganath, C., Harms, M. P., Barch, D. M., Gold, J. M., Layher, E., et al. (2015). Functional and neuroanatomic specificity of episodic memory dysfunction in schizophrenia: a functional magnetic resonance imaging study of the relational and item-specific encoding task. JAMA Psychiatry 72, 909–916. doi: 10.1001/jamapsychiatry.2015.0276
Ramírez-Amaya, V., Vazdarjanova, A., Mikhael, D., Rosi, S., Worley, P. F., and Barnes, C. A. (2005). Spatial exploration-induced Arc mRNA and protein expression: evidence for selective, network-specific reactivation. J. Neurosci. 25, 1761–1768. doi: 10.1523/JNEUROSCI.4342-04.2005
Rasetti, R., and Weinberger, D. R. (2011). Intermediate phenotypes in psychiatric disorders. Curr. Opin. Genet. Dev. 21, 340–348. doi: 10.1016/j.gde.2011.02.003
Reijmers, L. G., Perkins, B. L., Matsuo, N., and Mayford, M. (2007). Localization of a stable neural correlate of associative memory. Science 317, 1230–1233. doi: 10.1126/science.1143839
Revest, J. M., Di Blasi, F., Kitchener, P., Rougé-Pont, F., Desmedt, A., Turiault, M., et al. (2005). The MAPK pathway and Egr1 mediate stress-related behavioral effects of glucocorticoids. Nat. Neurosci. 8, 664–672. doi: 10.1038/nn0605-835b
Revest, J. M., Kaouane, N., Mondin, M., Le Roux, A., Rouge-Pont, F., Vallee, M., et al. (2010). The enhancement of stress-related memory by glucocorticoids depends on synapsin-Ia/Ib. Mol. Psychiatry 15, 1140–1151. doi: 10.1038/mp.2010.40
Robbins, M. J., Critchlow, H. M., Lloyd, A., Cilia, J., Clarke, J. D., Bond, B., et al. (2008). Differential expression of IEG mRNA in rat brain following acute treatment with clozapine or haloperidol: a semi-quantitative RT-PCR study. J. Psychopharmacol. 22, 536–542. doi: 10.1177/0269881107081521
Robertson, G. S., and Fibiger, H. C. (1996). Effects of olanzapine on regional C-Fos expression in rat forebrain. Neuropsychopharmacology 14, 105–110. doi: 10.1016/0893-133x(95)00196-k
Roloff, A. M., Anderson, G. R., Martemyanov, K. A., and Thayer, S. A. (2010). Homer 1a gates the induction mechanism for endocannabinoid-mediated synaptic plasticity. J. Neurosci. 30, 3072–3081. doi: 10.1523/JNEUROSCI.4603-09.2010
Rosen, J. B., Fanselow, M. S., Young, S. L., Sitcoske, M., and Maren, S. (1998). Immediate-early gene expression in the amygdala following footshock stress and contextual fear conditioning. Brain Res. 796, 132–142. doi: 10.1016/s0006-8993(98)00294-7
Ruediger, S., Vittori, C., Bednarek, E., Genoud, C., Strata, P., Sacchetti, B., et al. (2011). Learning-related feedforward inhibitory connectivity growth required for memory precision. Nature 473, 514–518. doi: 10.1038/nature09946
Sagar, S. M., Sharp, F. R., and Curran, T. (1988). Expression of c-fos protein in brain: metabolic mapping at the cellular level. Science 240, 1328–1331. doi: 10.1126/science.3131879
Sakai, N., and Yamamoto, T. (1997). Conditioned taste aversion and c-fos expression in the rat brainstem after administration of various USs. Neuroreport 8, 2215–2220. doi: 10.1097/00001756-199707070-00025
Saunderson, E. A., Spiers, H., Mifsud, K. R., Gutierrez-Mecinas, M., Trollope, A. F., Shaikh, A., et al. (2016). Stress-induced gene expression and behavior are controlled by DNA methylation and methyl donor availability in the dentate gyrus. Proc. Natl. Acad. Sci. U S A 113, 4830–4835. doi: 10.1073/pnas.1524857113
Saylam, C., Ucerler, H., Kitis, O., Ozand, E., and Gönül, A. S. (2006). Reduced hippocampal volume in drug-free depressed patients. Surg. Radiol. Anat. 28, 82–87. doi: 10.1007/s00276-005-0050-3
Schiller, D., Monfils, M. H., Raio, C. M., Johnson, D. C., Ledoux, J. E., and Phelps, E. A. (2010). Preventing the return of fear in humans using reconsolidation update mechanisms. Nature 463, 49–53. doi: 10.1038/nature08637
Sheng, M., and Greenberg, M. E. (1990). The regulation and function of c-fos and other immediate early genes in the nervous system. Neuron 4, 477–485. doi: 10.1016/0896-6273(90)90106-p
Sheng, H. Z., Lin, P. X., and Nelson, P. G. (1995). Combinatorial expression of immediate early genes in single neurons. Mol. Brain Res. 30, 196–202. doi: 10.1016/0169-328x(94)00291-l
Shepherd, J. D., Rumbaugh, G., Wu, J., Chowdhury, S., Plath, N., Kuhl, D., et al. (2006). Arc/Arg3.1 mediates homeostatic synaptic scaling of AMPA receptors. Neuron 52, 475–484. doi: 10.1016/j.neuron.2006.08.034
Slattery, D. A., Morrow, J. A., Hudson, A. L., Hill, D. R., Nutt, D. J., and Henry, B. (2005). Comparison of alterations in c-fos and Egr1 (zif268) expression throughout the rat brain following acute administration of different classes of antidepressant compounds. Neuropsychopharmacology 30, 1278–1287. doi: 10.1038/sj.npp.1300717
Solomon, M., McCauley, J. B., Iosif, A. M., Carter, C. S., and Ragland, J. D. (2016). Cognitive control and episodic memory in adolescents with autism spectrum disorders. Neuropsychologia 89, 31–41. doi: 10.1016/j.neuropsychologia.2016.05.013
Squire, L. R., and Dede, A. J. (2015). Conscious and unconscious memory systems. Cold Spring Harb. Perspect. Biol. 7:a021667. doi: 10.1101/cshperspect.a021667
Steward, O., Farris, S., Pirbhoy, P. S., Darnell, J., and Van Driesche, S. J. (2015). Localization and local translation of Arc/Arg3.1 mRNA at synapses: some observations and paradoxes. Front. Mol. Neurosci. 7:101. doi: 10.3389/fnmol.2014.00101
Steward, O., and Worley, P. F. (2001). A cellular mechanism for targeting newly synthesized mRNAs to synaptic sites on dendrites. Proc. Natl. Acad. Sci. U S A 98, 7062–7068. doi: 10.1073/pnas.131146398
Sukhatme, V. P., Cao, X. M., Chang, L. C., Tsai-Morris, C. H., Stamenkovich, D., Ferreira, P. C., et al. (1988). A zinc finger-encoding gene coregulated with c-fos during growth and differentiation and after cellular depolarization. Cell 53, 37–43. doi: 10.1016/0092-8674(88)90485-0
Suzuki, A., Josselyn, S. A., Frankland, P. W., Masushige, S., Silva, A. J., and Kida, S. (2004). Memory reconsolidation and extinction have distinct temporal and biochemical signatures. J. Neurosci. 24, 4787–4795. doi: 10.1523/JNEUROSCI.5491-03.2004
Terleph, T. A., and Tremere, L. A. (2006). “The use of immediate early genes as mapping tools for neuronal activation: concepts and methods,” in Immediate Early Genes in Sensory Processing, Cognitive Performance and Neurological Disorders, eds R. Pinaud and L. A. Tremere (Boston, MA: Springer), 1–10.
Tischmeyer, W., and Grimm, R. (1999). Activation of immediate early genes and memory formation. Cell. Mol. Life Sci. 55, 564–574. doi: 10.1007/s000180050315
Tischmeyer, W., Kaczmarek, L., Strauss, M., Jork, R., and Matthies, H. (1990). Accumulation of c-fos mRNA in rat hippocampus during acquisition of a brightness discrimination. Behav. Neural Biol. 54, 165–171. doi: 10.1016/0163-1047(90)91366-j
Tokuyama, W., Okuno, H., Hashimoto, T., Li, Y. X., and Miyashita, Y. (2002). Selective zif268 mRNA induction in the perirhinal cortex of macaque monkeys during formation of visual pair-association memory. J. Neurochem. 81, 60–70. doi: 10.1046/j.1471-4159.2002.00790.x
Vafadari, B., Salamian, A., and Kaczmarek, L. (2016). MMP-9 in translation: from molecule to brain physiology, pathology, and therapy. J. Neurochem. 139, 91–114. doi: 10.1111/jnc.13415
Vann, S. D., Brown, M. W., and Aggleton, J. P. (2000a). Fos expression in the rostral thalamic nuclei and associated cortical regions in response to different spatial memory tests. Neuroscience 101, 983–991. doi: 10.1016/s0306-4522(00)00288-8
Vann, S. D., Brown, M. W., Erichsen, J. T., and Aggleton, J. P. (2000b). Fos imaging reveals differential patterns of hippocampal and parahippocampal subfield activation in rats in response to different spatial memory tests. J. Neurosci. 20, 2711–2718. doi: 10.1523/JNEUROSCI.20-07-02711.2000
Verma, V., Rasmussen, K., and Dawe, G. S. (2006). Effects of short-term and chronic olanzapine treatment on immediate early gene protein and tyrosine hydroxylase immunoreactivity in the rat locus coeruleus and medial prefrontal cortex. Neuroscience 143, 573–585. doi: 10.1016/j.neuroscience.2006.08.010
Vialou, V., Bagot, R. C., Cahill, M. E., Ferguson, D., Robison, A. J., Dietz, D. M., et al. (2014). Prefrontal cortical circuit for depression- and anxiety-related behaviors mediated by cholecystokinin: role of DeltaFosB. J. Neurosci. 34, 3878–3887. doi: 10.1523/JNEUROSCI.1787-13.2014
Vialou, V., Robison, A. J., Laplant, Q. C., Covington, H. E. III., Dietz, D. M., Ohnishi, Y. N., et al. (2010). DeltaFosB in brain reward circuits mediates resilience to stress and antidepressant responses. Nat. Neurosci. 13, 745–752. doi: 10.1038/nn.2551
Vishnoi, S., Raisuddin, S., and Parvez, S. (2015). Modulatory effects of an NMDAR partial agonist in MK-801-induced memory impairment. Neuroscience 311, 22–33. doi: 10.1016/j.neuroscience.2015.10.008
Vrabie, M., Marinescu, V., Talasman, A., Tăutu, O., Drima, E., and Micluţia, I. (2015). Cognitive impairment in manic bipolar patients: important, understated, significant aspects. Ann. Gen. Psychiatry 14:41. doi: 10.1186/s12991-015-0080-0
Waller, J. A., Tamm, J. A., Abdourahman, A., Pehrson, A. L., Li, Y., Cajina, M., et al. (2017). Chronic vortioxetine treatment in rodents modulates gene expression of neurodevelopmental and plasticity markers. Eur. Neuropsychopharmacol. 27, 192–203. doi: 10.1016/j.euroneuro.2016.11.014
Wang, S. H., Redondo, R. L., and Morris, R. G. (2010). Relevance of synaptic tagging and capture to the persistence of long-term potentiation and everyday spatial memory. Proc. Natl. Acad. Sci. U S A 107, 19537–19542. doi: 10.1073/pnas.1008638107
Waters, C. M., Hancock, D. C., and Evan, G. I. (1990). Identification and characterisation of the Egr1 gene product as an inducible, short-lived, nuclear phosphoprotein. Oncogene 5, 669–674.
Weinberger, D. R., Berman, K. F., and Zec, R. F. (1986). Physiologic dysfunction of dorsolateral prefrontal cortex in schizophrenia. I. Regional cerebral blood flow evidence. Arch. Gen. Psychiatry 43, 114–124. doi: 10.1001/archpsyc.1986.01800020020004
Weitemier, A. Z., and Ryabinin, A. E. (2004). Subregion-specific differences in hippocampal activity between Delay and Trace fear conditioning: an immunohistochemical analysis. Brain Res. 995, 55–65. doi: 10.1016/j.brainres.2003.09.054
Wheeler, A. L., Creed, M. C., Voineskos, A. N., and Nobrega, J. N. (2014). Changes in brain functional connectivity after chronic haloperidol in rats: a network analysis. Int. J. Neuropsychopharmacol. 17, 1129–1138. doi: 10.1017/s1461145714000042
Whitton, L., Cosgrove, D., Clarkson, C., Harold, D., Kendall, K., Richards, A., et al. (2016). Cognitive analysis of schizophrenia risk genes that function as epigenetic regulators of gene expression. Am. J. Med. Genet. B Neuropsychiatr. Genet. 171, 1170–1179. doi: 10.1002/ajmg.b.32503
Williams, J. M., Beckmann, A. M., Mason-Parker, S. E., Abraham, W. C., Wilce, P. A., and Tate, W. P. (2000). Sequential increase in Egr1 and AP-1 DNA binding activity in the dentate gyrus following the induction of long-term potentiation. Mol. Brain Res. 77, 258–266. doi: 10.1016/s0169-328x(00)00061-9
Wisden, W., Errington, M. L., Williams, S., Dunnett, S. B., Waters, C., Hitchcock, D., et al. (1990). Differential expression of immediate early genes in the hippocampus and spinal cord. Neuron 4, 603–614. doi: 10.1016/0896-6273(90)90118-y
Woods, A. M., and Bouton, M. E. (2008). Immediate extinction causes a less durable loss of performance than delayed extinction following either fear or appetitive conditioning. Learn. Mem. 15, 909–920. doi: 10.1101/lm.1078508
Worley, P. F., Christy, B. A., Nakabeppu, Y., Bhat, R. V., Cole, A. J., and Baraban, J. M. (1991). Constitutive expression of zif268 in neocortex is regulated by synaptic activity. Proc. Natl. Acad. Sci. U S A 88, 5106–5110. doi: 10.1073/pnas.88.12.5106
Xu, Y., Pan, J., Sun, J., Ding, L., Ruan, L., Reed, M., et al. (2015). Inhibition of phosphodiesterase 2 reverses impaired cognition and neuronal remodeling caused by chronic stress. Neurobiol. Aging 36, 955–970. doi: 10.1016/j.neurobiolaging.2014.08.028
Yamada, K., Gerber, D. J., Iwayama, Y., Ohnishi, T., Ohba, H., Toyota, T., et al. (2007). Genetic analysis of the calcineurin pathway identifies members of the EGR gene family, specifically EGR3, as potential susceptibility candidates in schizophrenia. Proc. Natl. Acad. Sci. U S A 104, 2815–2820. doi: 10.1073/pnas.0610765104
Yamada, K., Homma, C., Tanemura, K., Ikeda, T., Itohara, S., and Nagaoka, Y. (2011). Analyses of fear memory in Arc/Arg3.1-deficient mice: intact short-term memory and impaired long-term and remote memory. World J. Neurosci. 1, 1–8. doi: 10.4236/wjns.2011.11001
Zalcman, G., Federman, N., de la Fuente, V., and Romano, A. (2015). Nuclear factor kappa B-dependent Zif268 expression in hippocampus is required for recognition memory in mice. Neurobiol. Learn. Mem. 119, 10–17. doi: 10.1016/j.nlm.2014.12.013
Zangenehpour, S., and Chaudhuri, A. (2002). Differential induction and decay curves of c-fos and zif268 revealed through dual activity maps. Mol. Brain Res. 109, 221–225. doi: 10.1016/s0169-328x(02)00556-9
Keywords: Egr1, c-Fos, Arc, fear memory, episodic memory, rodents, psychiatric disorders
Citation: Gallo FT, Katche C, Morici JF, Medina JH and Weisstaub NV (2018) Immediate Early Genes, Memory and Psychiatric Disorders: Focus on c-Fos, Egr1 and Arc. Front. Behav. Neurosci. 12:79. doi: 10.3389/fnbeh.2018.00079
Received: 07 September 2017; Accepted: 10 April 2018;
Published: 25 April 2018.
Edited by:
Amelia Gallitano, University of Arizona, United StatesReviewed by:
Francesco Papaleo, Fondazione Istituto Italiano di Technologia, ItalyAndrea De Bartolomeis, University of Naples Federico II, Italy
Copyright © 2018 Gallo, Katche, Morici, Medina and Weisstaub. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Noelia V. Weisstaub, noelia.weisstaub@gmail.com; nweisstaub@favaloro.edu.ar
† These authors have contributed equally to this work.
‡ Present address: Francisco T. Gallo, Instituto de Neurociencia Cognitiva y Translacional, Universidad Favaloro, INECO, CONICET, Buenos Aires, Argentina
Juan F. Morici, Instituto de Neurociencia Cognitiva y Translacional, Universidad Favaloro, INECO, CONICET, Buenos Aires, Argentina
Noelia V. Weisstaub, Instituto de Neurociencia Cognitiva y Translacional, Universidad Favaloro, INECO, CONICET, Buenos Aires, Argentina