Abnormal response to chronic social defeat stress and fear extinction in a mouse model of Lynx2-based cholinergic dysregulation

Kristin Anderson ¹ Peter Rogu ² Talulla Belle Palumbo ³ Julie M. Miwa ^3*

• ¹ College of Science, University of Galway, Galway, County Galway, Ireland
• ² New York Institute of Technology, Old Westbury, New York, United States
• ³ Department of Biological Sciences, College of Arts and Sciences, Lehigh University, Bethlehem, United States

Nicotinic receptor signaling is critical for an individual to react appropriately and adaptably to salient stimuli while navigating a complex environment. The cholinergic neurotransmitter system drives attention to salient stimuli, such as stressors, and aids in orchestrating the proper neural and behavioral response. Fine-tuned regulation of the cholinergic system has been linked to appropriate stress responses and subsequent mood regulation while dysregulation has been implicated in mood disorders. Among the multiple layers of regulation are cholinergic protein modulators. Here, we use validated models of experiential-based affective disorders to investigate differences in responses to stress in a genetic mouse model of cholinergic dysregulation based on the loss of protein modulator.The nicotinic receptor modulatory protein, Lynx2/Lypd1 provides negative cholinergic regulation within the amygdala, medial prefrontal cortex, and other brain regions. We discovered here that mice null for the Lynx2 gene, Lynx2 knockout mice demonstrate an inability to extinguish learned fear during a fear extinction test. We also observed, under an increased stress load following exposure to chronic social defeat stress paradigm, there was a unified resilience/approach phenotype in Lynx2KO mice, as opposed to the wild-type cohort which was split between resilience/approach and susceptible/avoidant phenotypes. Furthermore, we provide evidence for the functional role of α7 nicotinic receptor subtypes by phenotypic rescue with MLA or crossing with an α7 null mutant mouse (e.g. Lynx2/α7 double KO mice).We demonstrate a direct physical interaction between Lynx2 and α7 nAChR by co-immunoprecipitation of complexes from mouse BLA extracts. The genetic predisposition to heightened basal anxiety-like behavior and altered cholinergic signaling impairs individual behavior responses stressors. Together, these data indicate that the effects of social stress can be influenced by baseline genetic factors involved in anxiety regulation. Here, we show that Lynx2KO mice display a robust lack of fear extinction, but contrary to our prediction, the Lynx2KO mice switched from a socially avoidant phenotype (which could be considered susceptible) before defeat to a social approach/resilient phenotype after defeat. These abnormal displays, both in the initial response and long-term perturbations to stressors may underlie the likelihood of developing a disorder and provide potential screening tools to identify high-risk individuals