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Research Articles, Systems/Circuits

Chronic Ethanol Exposure Modulates Periaqueductal Gray to Extended Amygdala Dopamine Circuit

Dipanwita Pati, Anthony M. Downs, Zoe A. McElligott and Thomas L. Kash
Journal of Neuroscience 1 February 2023, 43 (5) 709-721; DOI: https://doi.org/10.1523/JNEUROSCI.1219-22.2022
Dipanwita Pati
1Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599
2Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, North Carolina 2751
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Anthony M. Downs
1Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599
2Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, North Carolina 2751
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Zoe A. McElligott
1Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599
2Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, North Carolina 2751
3Department of Psychiatry, University of North Carolina School of Medicine, Chapel Hill, North Carolina 2751
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Thomas L. Kash
1Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599
2Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, North Carolina 2751
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Abstract

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/DRDA neurons in tyrosine hydroxylase-expressing transgenic adult male mice. Using ex vivo electrophysiology, we found hyperexcitability of vlPAG/DRDA neurons in CIE-treated mice. Further, using optogenetic approaches to target vlPAG/DRDA 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/DRDA-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.

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The Journal of Neuroscience: 43 (5)
Journal of Neuroscience
Vol. 43, Issue 5
1 Feb 2023
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Chronic Ethanol Exposure Modulates Periaqueductal Gray to Extended Amygdala Dopamine Circuit
Dipanwita Pati, Anthony M. Downs, Zoe A. McElligott, Thomas L. Kash
Journal of Neuroscience 1 February 2023, 43 (5) 709-721; DOI: 10.1523/JNEUROSCI.1219-22.2022

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Chronic Ethanol Exposure Modulates Periaqueductal Gray to Extended Amygdala Dopamine Circuit
Dipanwita Pati, Anthony M. Downs, Zoe A. McElligott, Thomas L. Kash
Journal of Neuroscience 1 February 2023, 43 (5) 709-721; DOI: 10.1523/JNEUROSCI.1219-22.2022
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