The central amygdala (CeA) is a key nodal brain structure that integrates autonomic, arousal, and sensory information to initiate fear and anxiety responses to appropriate salient stimuli. Amygdalar activity links environmental stress to the development of psychopathological states in susceptible individuals, and dysregulation of amygdala function has been demonstrated in numerous affective disorders including major depression, and anxiety disorders such as posttraumatic stress disorder. Thus, understanding the cellular and synaptic organization of the amygdala, and the mechanisms regulating information processing in this region could provide important insights into the mechanisms regulating fear and anxiety generation and stress response physiology. Moreover, understanding the synaptic adaptations induced by stress exposure could reveal novel mechanisms contributing to the development of stress-related neuropsychiatric disorders. Here we aim to elucidate the synaptic organization of the CeA using optogenetic projection-targeting approaches in order to uncover synaptic and functional anatomical mechanisms by which different excitatory inputs to the CeA could exert differential control of anxiety states via cell type-specific targeting. We will determine the role of endogenous cannabinoid signaling in the cell-type- and afferent-specific modulation of excitatory drive to the CeA. Lastly, we will test th hypothesis that cell-type specific adaptations in endogenous cannabinoid signaling counteract stress-induced synaptic remodeling associated with anxiety states. These studies will provide an unprecedented understanding of the synaptic organization of the CeA and elucidate endogenous cannabinoid signaling mechanisms regulating glutamatergic drive to CeA neurons in an afferent and cell type-specific manner. These studies could also reveal novel synaptic adaptations in endocannabinoid signaling that could serve a homeostatic function aimed at normalizing stress-induced anxiety states. Understanding the synaptic and molecular mechanisms regulating CeA function could ultimately advance our understanding of the pathophysiological mechanisms subserving mood and anxiety disorders in humans.

Public Health Relevance

The amygdala plays a critical role in translating stressful experiences into affective pathology in susceptible individuals;therefore, understanding the biological mechanisms regulating information processing in the amygdala could provide insight into the neural mechanisms regulating mood and anxiety and ultimately the pathophysiology of affective disorders. We will investigate how different forms of information, arising from distinct brain regions, enter the amygdala to selectively excite different populations of neurons. These studies may ultimately provide a deeper understanding of the neurobiological mechanisms contributing anxiety disorders and the mechanisms by which environmental stress interacts with biology to promote psychopathology.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Exploratory/Developmental Grants (R21)
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Molecular Neuropharmacology and Signaling Study Section (MNPS)
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Nadler, Laurie S
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Vanderbilt University Medical Center
Schools of Medicine
United States
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