The role of corticotropin releasing factor (CRF) within the extended amygdala in binge ethanol drinking

Alcohol use disorder (AUD) costs the United States over $200 billion annually. Of that cost, binge drinking accounts for 75%, making it a public health crisis. It is well known that the behavioral consequences of binge drinking are mediated by long-term alterations in brain stress circuits residing within the extended amygdala. CRF, a neuropeptide involved in the modulation of binge drinking, is expressed by neurons within the extended amygdala comprising the central amygdala (CeA) and the bed nucleus of the stria terminals (BNST). Dissecting the contribution of CeA and BNST CRF in binge ethanol drinking has been challenging because both nuclei contain non-CRF neurons. To overcome this obstacle, the Sparta Lab uses gene-targeted strategies in mice to specifically identify and manipulate CeA and BNST CRF neurons to determine their causal role in binge ethanol drinking. Combining optogenetics with in vivo electrophysiology, we identified and recorded from CeA CRF neurons in mice during a repeated binge ethanol drinking task. We found that CeA CRF neurons were more active than CeA non-CRF cells during our binge ethanol drinking paradigm, an effect not seen during sucrose and water consumption. We also observed that CeA CRF neurons displayed a heterogenous spectrum of responses to a lick of ethanol. Interestingly, one group of CeA CRF neurons, that were active immediately before a lick of ethanol, exhibited higher activity during a binge ethanol drinking session as well as enhanced tonic and phasic electrical activity over repeated binge ethanol drinking sessions. Thus, binge ethanol consumption may “hijack or plastically alter the intrinsic excitability of selective CeA CRF neurons. Ongoing studies will examine the projection targets of these selective CeA CRF neurons.

This project is funded by a NIH/NIAAA grant through 2024

Cortico-limbic pathways and substance use disorder (SUD)

Individuals suffering from SUD often experience relapse events that are attributed to drug craving. Insular cortex (IC) function is implicated in processing drug-predictive cues and is thought to be a critical substrate for drug craving, but the downstream neural circuit effectors of the IC that mediate reward processing are poorly understood. By using slice electrophysiology we found that the IC sends a glutamatergic projection to ventral BNST neurons in mice. We also found that the IC-vBNST pathway enhances reward-related behavior through optogenetic techniques. Conversely, optogenetic silencing of this pathway was aversive and resulted in anxiety-like behavior. These data provide a potential mechanism by which the IC processes exteroceptive triggers that are predictive of reward. Ongoing studies will examine the role of this pathway in attributing saliency to cues associated with drug and alcohol intake.