Arousal-induced noradrenergic signaling modulates cortical astrocyte-neuron circuits during ethanol consumption

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My career goal is to lead an independent research program studying astrocyte-neuron dynamics, arousal, and alcohol use disorder (AUD). I have benefitted from experimental training in numerous techniques including two-photon microscopy, neurophysiology, circuit anatomy, and behavior. During the mentored phase of this grant (K99), I will continue to work closely with my co-mentors, Drs. Mriganka Sur and Elena Vazey. Mriganka is an expert in cortical information processing, neuron- astrocyte circuits, and optical techniques. Elena Vazey is an expert in noradrenergic signaling, stress, alcohol-related behaviors, and chemogenetics. In addition, I will receive advice from my mentoring team consisting of Drs. Kerry Ressler, Heather Richardson, and Thomas Kash. Their combined expertise ranges across stress pathophysiology, alcohol-related processing, limbic and reward circuits, neuromodulation, and anxiety behaviors. The additional training from my mentoring team will equip me with the conceptual and technical acumen to become a significant contributor to the fields of alcohol behavior and stress. This training will be done within the Brain and Cognitive Sciences department at MIT, which provides both a vibrant intellectual research community and expansive research infrastructure support. During my postdoctoral fellowship, I developed novel methods of simultaneously imaging astrocyte-neuron networks to study astrocyte roles in information processing. This work led me to study how astrocytes affect neuromodulation of cortical circuits by norepinephrine (NE). I have found an intriguing astrocyte-neuron calcium signature that reflects a shift in cortical processing during periods of high arousal. Furthermore, the drugs that are currently being tested in arousal disorders and AUD block these signatures, suggesting that astrocyte-neuron interactions may provide crucial insight into the pathophysiology of stress and AUD. My immediate goals are to understand how these events relate to arousal and alcohol drinking behavior, and to determine the relationship with abnormal NE release. (Aim 1) I will study the astrocyte-neuron processing in the prefrontal cortex (PFC) while mice actively drink alcohol on using in vivo two-photon imaging. (Aim 2) I will determine the role of NE in affecting astrocyte-neuron physiology through pharmacological and chemogenetic manipulations of NE release. (Aim 3) Finally, during R00 phase, I will manipulate astrocyte-specific mechanisms to determine the role of astrocytes in arousal-mediated alcohol consumption. These experiments will clarify how astrocyte-neuron dysregulation in the PFC is related to NE release and AUD.