My lab research on unraveling neural circuits that are disrupted in complex brain disorders such as alcohol dependence, depression, and Alzheimer's disease

Serotonin (5-hydroxytryptamine; 5-HT) neurons project widely throughout the brain and serve a diverse array of physiological functions including mood regulation, sleep, feeding behavior, reward processing and aversive learning. We are ultimately interested in 5-HT circuits that drive compulsive alcohol and drug seeking behavior, which involves a shift in hedonic homeostasis as well as an increase in brain stress systems that promote anxiety and dysphoria. Currently, we are utilizing optogenetic and chemogenetic tools to dissect out anatomically- and neurochemically-defined populations of 5-HT neurons in the DRN that promote negative affective states during alcohol withdrawal, which in drives compulsive alcohol drinking. We are also investigating the role of 5-HT inputs to the nucleus accumbens (NAcc) in the hedonic shift that drives escalations of alcohol drinking after chronic intermittent alcohol. It is generally thought that serotonin can inhibit phasic dopamine release in the NAcc, but the precise neural mechanisms involved have yet to be delineated. Data from our lab suggests that 5-HT acting at 5-HT2C receptors activate a population of neurons in the NAcc that express dynorphin, an opioid peptide that has been previously linked to anxiety and depression. Dynorphin binds to receptors known as kappa opioid receptors (KORs), which are Gi-coupled GPCRs that are present on dopamine releasing axons in the nucleus accumbens and can inhibit the release of dopamine and other neurotransmitters. We are currently investigating whether chronic alcohol enhances 5-HT2C receptor signaling in these dynorphin-expressing neurons, and whether this enhanced dynorphin/KOR signaling in the NAcc can lead to deficits in reward processing during alcohol withdrawal.

Department/Program Affiliations:
Neuroscience and Pharmacology