Mechanisms of male-specific amygdala-dependent deficits in approach and avoidance behaviors

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Project Summary/Abstract Neurodevelopmental disorders currently affect 1 in 6 children but males are disproportionately affected. The cause of this robust sex difference is not known. Neurodevelopmental disorders involve disruptions in approach and avoidance behaviors, which rely heavily on amygdala function. Our transgenic mice missing one copy of the cell-adhesion molecule gene, PCDH10, exhibit male-specific behavioral and amygdalar impairments, including social approach and threat conditioning deficits, decreased connectivity between the lateral and basal nuclei of the amygdala, decreased NMDAR expression in the basolateral amygdala (BLA), and increased filopodial spine density in the BLA; impairments in behavior, structure, and function that are relevant to neurodevelopmental disorders. With this experimental system, we will study the mechanisms of male-specific deficits in approach and avoidance behaviors and the mechanisms underlying behavioral rescue on behavioral, cellular, molecular, and circuit levels. We will manipulate neonatal levels of testosterone and measure social approach, threat conditioning, NMDAR expression, synaptic properties, and calcium activity in excitatory BLA cells in vivo, using Western blots, whole-cell patch-clamp electrophysiology, and fiber photometry. We will also study the effects of d-cycloserine, shown to rescue social approach, on ex vivo and in vivo BLA activity. We will study main effects of sex, genotype, and treatment to help uncover mechanisms that underlie the male preponderance of neurodevelopmental disorders in order to develop novel treatment strategies.