We welcome you to our Frontiers Research Topic on Neural Circuits: Korea. This Research Topic highlights some of the exciting work being done on brain circuitry within the dynamic neuroscience community of South Korea. As you will see, work featured in this issue spans the range from fine-scale mapping of microcircuitry up to cognitive functions such as memory. In addition to some fine examples of biological applications, there are also some contributions on emerging connectomics technology. We hope that you will be impressed by the range and quality of the science represented in this sampler of circuit work in Korea.

Lee Kong Chian School of Medicine, Nanyang Technological University

Frontiers in Neural Circuits

Neural Circuits: Korea

Here we characterize several new lines of transgenic mice useful for optogenetic analysis of brain circuit function. These mice express optogenetic probes, such as enhanced halorhodopsin or several different versions of channelrhodopsins, behind various neuron-specific promoters. These mice permit photoinhibition or photostimulation both in vitro and in vivo. Our results also reveal the important influence of fluorescent tags on optogenetic probe expression and function in transgenic mice.

Here we characterize several new lines of transgenic mice useful for optogenetic analysis of brain circuit function. These mice express optogenetic probes, such as enhanced halorhodopsin or several different versions of channelrhodopsins, behind various neuron-specific promoters. These mice permit photoinhibition or photostimulation both in vitro and in vivo. Our results also reveal the important influence of fluorescent tags on optogenetic probe expression and function in transgenic mice.

Next-generation transgenic mice for optogenetic analysis of neural circuits

Specific behavioral patterns are expressed by complex combinations of muscle coordination. Tremors are simple behavioral patterns and are the focus of studies investigating motor coordination mechanisms in the brain. T-type Ca2+ channels mediate intrinsic neuronal oscillations and rhythmic burst spiking, and facilitate the generation of tremor rhythms in motor circuits. Despite substantial evidence that T-type Ca2+ channels mediate pathological tremors, their roles in physiological motor coordination and behavior remain unknown. Here, we review recent progress in understanding the roles that T-type Ca2+ channels play under pathological conditions, and discuss the potential relevance of these channels in mediating physiological motor coordination.

Specific behavioral patterns are expressed by complex combinations of muscle coordination. Tremors are simple behavioral patterns and are the focus of studies investigating motor coordination mechanisms in the brain. T-type Ca2+ channels mediate intrinsic neuronal oscillations and rhythmic burst spiking, and facilitate the generation of tremor rhythms in motor circuits. Despite substantial evidence that T-type Ca2+ channels mediate pathological tremors, their roles in physiological motor coordination and behavior remain unknown. Here, we review recent progress in understanding the roles that T-type Ca2+ channels play under pathological conditions, and discuss the potential relevance of these channels in mediating physiological motor coordination.

The potential roles of T-type Ca2+ channels in motor coordination

Dopamine (DA) regulates emotional and motivational behavior through the mesolimbic dopaminergic pathway. Changes in DA mesolimbic neurotransmission have been found to modify behavioral responses to various environmental stimuli associated with reward behaviors. Psychostimulants, drugs of abuse, and natural reward such as food can cause substantial synaptic modifications to the mesolimbic DA system. Recent studies using optogenetics and DREADDs, together with neuron-specific or circuit-specific genetic manipulations have improved our understanding of DA signaling in the reward circuit, and provided a means to identify the neural substrates of complex behaviors such as drug addiction and eating disorders. This review focuses on the role of the DA system in drug addiction and food motivation, with an overview of the role of D1 and D2 receptors in the control of reward-associated behaviors.

Dopamine (DA) regulates emotional and motivational behavior through the mesolimbic dopaminergic pathway. Changes in DA mesolimbic neurotransmission have been found to modify behavioral responses to various environmental stimuli associated with reward behaviors. Psychostimulants, drugs of abuse, and natural reward such as food can cause substantial synaptic modifications to the mesolimbic DA system. Recent studies using optogenetics and DREADDs, together with neuron-specific or circuit-specific genetic manipulations have improved our understanding of DA signaling in the reward circuit, and provided a means to identify the neural substrates of complex behaviors such as drug addiction and eating disorders. This review focuses on the role of the DA system in drug addiction and food motivation, with an overview of the role of D1 and D2 receptors in the control of reward-associated behaviors.

Dopamine Signaling in reward-related behaviors

The neural circuit consisting of mediodorsal nucleus (MDN) of thalamus and prefrontal cortex (PFC) has been implicated in working memory. In order to investigate whether and how the rodent MDN processes working memory-related signals, we recorded activity of single neurons from the MDN in rats performing a delayed spatial alternation task. The MDN conveyed significant neural signals for the animal's previously chosen goal (retrospective information) in the early delay period, but the signals deteriorated gradually over time so that they became weak toward the end of the delay period. Neural signals for the animal's upcoming goal choice (prospective information) were even weaker than those for the previously chosen goal. These results are in contrast to the finding in monkeys that both MDN and PFC persistently maintain task-related neural signals throughout delay period. Our results do not support sustained MDN-PFC interactions as a general mechanism for mediating working memory across different behavioral tasks and/or animal species.

The neural circuit consisting of mediodorsal nucleus (MDN) of thalamus and prefrontal cortex (PFC) has been implicated in working memory. In order to investigate whether and how the rodent MDN processes working memory-related signals, we recorded activity of single neurons from the MDN in rats performing a delayed spatial alternation task. The MDN conveyed significant neural signals for the animal&apos;s previously chosen goal (retrospective information) in the early delay period, but the signals deteriorated gradually over time so that they became weak toward the end of the delay period. Neural signals for the animal&apos;s upcoming goal choice (prospective information) were even weaker than those for the previously chosen goal. These results are in contrast to the finding in monkeys that both MDN and PFC persistently maintain task-related neural signals throughout delay period. Our results do not support sustained MDN-PFC interactions as a general mechanism for mediating working memory across different behavioral tasks and/or animal species.

Neural activity in mediodorsal nucleus of thalamus in rats performing a working memory task

The amygdala is important for emotional memory, including learned fear. A number of studies for amygdala neural circuits that underlie fear conditioning have elucidated specific cellular and molecular mechanisms of emotional memory. Recent technical advances such as optogenetic approaches have not only confirmed the importance of excitatory circuits in fear conditioning, but have also shed new light for a direct role of inhibitory circuits in both the acquisition and extinction of fear memory in addition to their role in fine tuning of excitatory neural circuitry. As a result, the circuits in amygdala could be drawn more elaborately, and it led us to understand how fear or extinction memories are formed in the detailed circuit level, and various neuromodulators affect these circuit activities, inducing subtle behavioral changes.

The amygdala is important for emotional memory, including learned fear. A number of studies for amygdala neural circuits that underlie fear conditioning have elucidated specific cellular and molecular mechanisms of emotional memory. Recent technical advances such as optogenetic approaches have not only confirmed the importance of excitatory circuits in fear conditioning, but have also shed new light for a direct role of inhibitory circuits in both the acquisition and extinction of fear memory in addition to their role in fine tuning of excitatory neural circuitry. As a result, the circuits in amygdala could be drawn more elaborately, and it led us to understand how fear or extinction memories are formed in the detailed circuit level, and various neuromodulators affect these circuit activities, inducing subtle behavioral changes.

Inhibitory networks of the amygdala for emotional memory

Animals including humans engage in goal-directed behavior flexibly in response to items and their background, which is called contextual behavior in this review. Although the concept of context has long been studied, there are differences among researchers in defining and experimenting with the concept. The current review aims to provide a categorical framework within which not only the neural mechanisms of contextual information processing but also the contextual behavior can be studied in more concrete ways. For this purpose, we categorize contextual behavior into three subcategories as follows by considering the types of interactions among context, item, and response: contextual response selection, contextual item selection, and contextual item–response selection. Contextual response selection refers to the animal emitting different types of responses to the same item depending on the context in the background. Contextual item selection occurs when there are multiple items that need to be chosen in a contextual manner. Finally, when multiple items and multiple contexts are involved, contextual item–response selection takes place whereby the animal either chooses an item or inhibits such a response depending on item–context paired association. The literature suggests that the rhinal cortical regions and the hippocampal formation play key roles in mnemonically categorizing and recognizing contextual representations and the associated items. In addition, it appears that the fronto-striatal cortical loops in connection with the contextual information-processing areas critically control the flexible deployment of adaptive action sets and motor responses for maximizing goals. We suggest that contextual information processing should be investigated in experimental settings where contextual stimuli and resulting behaviors are clearly defined and measurable, considering the dynamic top-down and bottom-up interactions among the neural systems for contextual behavior.

Animals including humans engage in goal-directed behavior flexibly in response to items and their background, which is called contextual behavior in this review. Although the concept of context has long been studied, there are differences among researchers in defining and experimenting with the concept. The current review aims to provide a categorical framework within which not only the neural mechanisms of contextual information processing but also the contextual behavior can be studied in more concrete ways. For this purpose, we categorize contextual behavior into three subcategories as follows by considering the types of interactions among context, item, and response: contextual response selection, contextual item selection, and contextual item–response selection. Contextual response selection refers to the animal emitting different types of responses to the same item depending on the context in the background. Contextual item selection occurs when there are multiple items that need to be chosen in a contextual manner. Finally, when multiple items and multiple contexts are involved, contextual item–response selection takes place whereby the animal either chooses an item or inhibits such a response depending on item–context paired association. The literature suggests that the rhinal cortical regions and the hippocampal formation play key roles in mnemonically categorizing and recognizing contextual representations and the associated items. In addition, it appears that the fronto-striatal cortical loops in connection with the contextual information-processing areas critically control the flexible deployment of adaptive action sets and motor responses for maximizing goals. We suggest that contextual information processing should be investigated in experimental settings where contextual stimuli and resulting behaviors are clearly defined and measurable, considering the dynamic top-down and bottom-up interactions among the neural systems for contextual behavior.

Contextual behavior and neural circuits

Despite considerable progress over the past several decades, our understanding of the mechanisms underlying memory encoding, storage, and expression in a complex neural network are far from complete. In particular, how some neurons rather than others are selectively engaged to encode memory remains largely unknown. Using virus-mediated gene delivery into a small subset of neurons in a given network, molecular imaging of neuronal activity, pharmacological perturbation of specific neurons' activity and animal behavior assays, recent studies have begun to provide insight into molecular and cellular mechanisms responsible for the selection of neurons for inclusion into a memory trace. Here, we focus on a review of recent findings supporting the hypothesis that the level of the transcription factor CREB (cAMP/Ca2+-response element binding protein) is a key factor governing which neurons are recruited to a given memory trace. These recent findings open a new perspective on memory trace at the neural circuit level and also raise many important questions. Future studies employing more advanced neurobiological techniques for targeting defined populations of neurons and manipulating their activity in time and space in a complex neural network will give answers to these newly emerging questions and extend our understanding of the neurobiological basis of the memory trace.

Despite considerable progress over the past several decades, our understanding of the mechanisms underlying memory encoding, storage, and expression in a complex neural network are far from complete. In particular, how some neurons rather than others are selectively engaged to encode memory remains largely unknown. Using virus-mediated gene delivery into a small subset of neurons in a given network, molecular imaging of neuronal activity, pharmacological perturbation of specific neurons' activity and animal behavior assays, recent studies have begun to provide insight into molecular and cellular mechanisms responsible for the selection of neurons for inclusion into a memory trace. Here, we focus on a review of recent findings supporting the hypothesis that the level of the transcription factor CREB (cAMP/Ca2+-response element binding protein) is a key factor governing which neurons are recruited to a given memory trace. These recent findings open a new perspective on memory trace at the neural circuit level and also raise many important questions. Future studies employing more advanced neurobiological techniques for targeting defined populations of neurons and manipulating their activity in time and space in a complex neural network will give answers to these newly emerging questions and extend our understanding of the neurobiological basis of the memory trace.