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.
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.
|Robinson, Stacey L; Alexander, Nancy J; Bluett, Rebecca J et al. (2016) Acute and chronic ethanol exposure differentially regulate CB1 receptor function at glutamatergic synapses in the rat basolateral amygdala. Neuropharmacology 108:474-84|
|BÃ¡ldi, Rita; Ghosh, Dipanwita; Grueter, Brad A et al. (2016) Electrophysiological Measurement of Cannabinoid-Mediated Synaptic Modulation in Acute Mouse Brain Slices. Curr Protoc Neurosci 75:6.29.1-6.29.19|
|Gray, J Megan; Wilson, Christopher D; Lee, Tiffany T Y et al. (2016) Sustained glucocorticoid exposure recruits cortico-limbic CRH signaling to modulate endocannabinoid function. Psychoneuroendocrinology 66:151-8|
|Morena, Maria; Patel, Sachin; Bains, Jaideep S et al. (2016) Neurobiological Interactions Between Stress and the Endocannabinoid System. Neuropsychopharmacology 41:80-102|
|Brown, J A; Ramikie, T S; Schmidt, M J et al. (2015) Inhibition of parvalbumin-expressing interneurons results in complex behavioral changes. Mol Psychiatry 20:1499-507|
|Bukalo, Olena; Pinard, Courtney R; Silverstein, Shana et al. (2015) Prefrontal inputs to the amygdala instruct fear extinction memory formation. Sci Adv 1:|
|Gray, J Megan; Vecchiarelli, Haley A; Morena, Maria et al. (2015) Corticotropin-releasing hormone drives anandamide hydrolysis in the amygdala to promote anxiety. J Neurosci 35:3879-92|
|Shonesy, Brian C; Winder, Danny G; Patel, Sachin et al. (2015) The initiation of synaptic 2-AG mobilization requires both an increased supply of diacylglycerol precursor and increased postsynaptic calcium. Neuropharmacology 91:57-62|