| First Author | Pati D | Year | 2023 |
| Journal | J Neurosci | Volume | 43 |
| Issue | 5 | Pages | 709-721 |
| PubMed ID | 36526372 | Mgi Jnum | J:348302 |
| Mgi Id | MGI:7640274 | Doi | 10.1523/JNEUROSCI.1219-22.2022 |
| Citation | Pati D, et al. (2023) Chronic Ethanol Exposure Modulates Periaqueductal Gray to Extended Amygdala Dopamine Circuit. J Neurosci 43(5):709-721 |
| abstractText | The bed nucleus of the stria terminalis (BNST) is a component of the extended amygdala that regulates motivated behavior and affective states and plays an integral role in the development of alcohol-use disorder (AUD). The dorsal subdivision of the BNST (dBNST) receives dense dopaminergic input from the ventrolateral periaqueductal gray (vlPAG)/dorsal raphe (DR). To date, no studies have examined the effects of chronic alcohol on this circuit. Here, we used chronic intermittent ethanol exposure (CIE), a well-established rodent model of AUD, to functionally interrogate the vlPAG/DR-BNST dopamine (DA) circuit during acute withdrawal. We selectively targeted vlPAG/DR(DA) neurons in tyrosine hydroxylase-expressing transgenic adult male mice. Using ex vivo electrophysiology, we found hyperexcitability of vlPAG/DR(DA) neurons in CIE-treated mice. Further, using optogenetic approaches to target vlPAG/DR(DA) terminals in the dBNST, we revealed a CIE-mediated shift in the vlPAG/DR-driven excitatory-inhibitory (E/I) ratio to a hyperexcitable state in dBNST. Additionally, to quantify the effect of CIE on endogenous DA signaling, we coupled optogenetics with fast-scan cyclic voltammetry to measure pathway-specific DA release in dBNST. CIE-treated mice had significantly reduced signal half-life, suggestive of faster clearance of DA signaling. CIE treatment also altered the ratio of vlPAG/DR(DA)-driven cellular inhibition and excitation of a subset of dBNST neurons. Overall, our findings suggest a dysregulation of vlPAG/DR to BNST dopamine circuit, which may contribute to pathophysiological phenotypes associated with AUD.SIGNIFICANCE STATEMENT The dorsal bed nucleus of the stria terminalis (dBNST) is highly implicated in the pathophysiology of alcohol-use disorder and receives dopaminergic inputs from ventrolateral periaqueductal gray/dorsal raphe regions (vlPAG/DR). The present study highlights the plasticity within the vlPAG/DR to dBNST dopamine (DA) circuit during acute withdrawal from chronic ethanol exposure. More specifically, our data reveal that chronic ethanol strengthens vlPAG/DR-dBNST glutamatergic transmission while altering both DA transmission and dopamine-mediated cellular inhibition of dBNST neurons. The net result is a shift toward a hyperexcitable state in dBNST activity. Together, our findings suggest chronic ethanol may promote withdrawal-related plasticity by dysregulating the vlPAG/DR-dBNST DA circuit. |
