Chronic ethanol exposure differentially alters neuronal function in the medial prefrontal cortex and dentate gyrus

Avchalumov, Yosef; Oliver, Robert J. Lemke; Trenet, Wulfran; Osorno, Rocio Erandi Heyer; Sibley, Britta D.; Purohit, Dvijen C.; Contet, Candice; Roberto, Marisa; Woodward, John J.; Mandyam, Chitra D.

doi:10.1016/j.neuropharm.2020.108438

Cited by 19 publications

(16 citation statements)

References 100 publications

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“…In contrast, mPFC CRF1− displayed increases in excitability and glutamate transmission following dependence and withdrawal. This finding is consistent with previous work showing an increase in mPFC neuronal excitability following chronic intermittent ethanol exposure [ 59 , 60 ], which may contribute to CIE-induced cognitive deficits [ 60 – 63 ]. This highlights the selective sensitivity of mPFC CRF1+ to withdrawal and its potential in uniquely contributing to AUD-related behaviors.…”

Section: Discussionsupporting

confidence: 93%

Ethanol withdrawal-induced adaptations in prefrontal corticotropin releasing factor receptor 1-expressing neurons regulate anxiety and conditioned rewarding effects of ethanol

et al. 2022

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Prefrontal circuits are thought to underlie aberrant emotion contributing to relapse in abstinence; however, the discrete cell-types and mechanisms remain largely unknown. Corticotropin-releasing factor and its cognate type-1 receptor, a prominent brain stress system, is implicated in anxiety and alcohol use disorder (AUD). Here, we tested the hypothesis that medial prefrontal cortex CRF1-expressing (mPFCCRF1+) neurons comprise a distinct population that exhibits neuroadaptations following withdrawal from chronic ethanol underlying AUD-related behavior. We found that mPFCCRF1+ neurons comprise a glutamatergic population with distinct electrophysiological properties and regulate anxiety and conditioned rewarding effects of ethanol. Notably, mPFCCRF1+ neurons undergo unique neuroadaptations compared to neighboring neurons including a remarkable decrease in excitability and glutamatergic signaling selectively in withdrawal, which is driven in part by the basolateral amygdala. To gain mechanistic insight into these electrophysiological adaptations, we sequenced the transcriptome of mPFCCRF1+ neurons and found that withdrawal leads to an increase in colony-stimulating factor 1 (CSF1) in this population. We found that selective overexpression of CSF1 in mPFCCRF1+ neurons is sufficient to decrease glutamate transmission, heighten anxiety, and abolish ethanol reinforcement, providing mechanistic insight into the observed mPFCCRF1+ synaptic adaptations in withdrawal that drive these behavioral phenotypes. Together, these findings highlight mPFCCRF1+ neurons as a critical site of enduring adaptations that may contribute to the persistent vulnerability to ethanol misuse in abstinence, and CSF1 as a novel target for therapeutic intervention for withdrawal-related negative affect.

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Section: Discussionsupporting

confidence: 93%

Ethanol withdrawal-induced adaptations in prefrontal corticotropin releasing factor receptor 1-expressing neurons regulate anxiety and conditioned rewarding effects of ethanol

et al. 2022

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“… 87 Chronic ethanol exposure modifies neuronal function in the hippocampus, medial prefrontal cortex and dentate gyrus. 1 This neuronal activity would tend to impair socialization as confirmed by our findings that there was a decrease in social interaction (time spent sniffing novel juvenile mice) by chronic ethanol-treated animals. Flavonoids have been reported to ameliorate cognitive function in humans, 88 and the outcome of treatment chronically with ethanol plus 6-MOF partially reversed ethanol impaired socialization behavior in our study.…”

Section: Discussionsupporting

confidence: 65%

“…Such outcomes have been coupled not only with shrinkage in brain volume but may also be detrimental to hippocampal and prefrontal cortical function. 1 In addition, chronic alcohol exposure followed by abstinence, is injurious to grey matter by way of microstructural disruption of myelin and dysfunction in the prefrontal cortex instigating impaired retrieval and recall of fear memories. 2 Studies have shown that chronic alcohol consumption modifies cholinergic and monoamine neurotransmission inducing a negative affective state, although in this respect, adaptation to hippocampal neuronal excitability is subject to a gender difference.…”

Section: Introductionmentioning

confidence: 99%

6-Methoxyflavone and Donepezil Behavioral Plus Neurochemical Correlates in Reversing Chronic Ethanol and Withdrawal Induced Cognitive Impairment

Arif¹,

Rauf²,

Rehman³

et al. 2022

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“…Although considerable mechanistic research has been done on the acute cellular effects of ethanol, including effects on the fast time scales of ion channel activity and synaptic transmission [102][103][104][105][106][107] , as well as the chronic long-term circuit neuroadaptations 36,[108][109][110] Significance testing with one-way Kruskal-Wallis test.…”

Section: Discussionmentioning

confidence: 99%

Voluntary alcohol consumption disrupts coupling of prefrontal cortical activity to arousal

Sipe

Nguyen

et al. 2021

Preprint

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Alcohol use disorder (AUD) exacts a major personal, societal, and economic toll. Top-down control from the prefrontal cortex (PFC), a critical hub for decision making, executive, and other cognitive functions, is key for the regulation of alcohol consumption. Arousal exerts profound effects on cortical processing, allowing it to potentially modulate PFC functions relevant for alcohol consumption and AUD. Despite this, it is unclear whether and how arousal-mediated modulation of PFC circuits relates to voluntary alcohol drinking behaviors. Two-photon microscopy is ideally suited for dissecting the neural circuit mechanisms underlying the effect of alcohol on intact circuits in behaving animals. We addressed a major limitation of this technology by developing a novel behavioral paradigm for voluntary drinking in head-fixed mice. We recorded responses of layer 2/3 excitatory neurons in the anterior cingulate cortex (ACC) subdivision of the PFC as mice voluntarily consumed ethanol, along with video recording of the pupil to track momentary fluctuations in arousal. Ethanol consumption bidirectionally modified the activity of subsets of ACC neurons, both at slow (minutes) and fast (sub-second) time scales. Remarkably, we found that the coupling of arousal to ACC activity before drinking was associated with subsequent ethanol engagement behavior. In turn, ethanol consumption modulated neuronal-arousal coupling. Together, our results suggest neuronal-arousal coupling as a key biomarker for alcohol drinking and lays the groundwork for future studies to dissect the therapeutic potential of this process for AUD and other substance use disorders.

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Chronic ethanol exposure differentially alters neuronal function in the medial prefrontal cortex and dentate gyrus

Cited by 19 publications

References 100 publications

Ethanol withdrawal-induced adaptations in prefrontal corticotropin releasing factor receptor 1-expressing neurons regulate anxiety and conditioned rewarding effects of ethanol

Ethanol withdrawal-induced adaptations in prefrontal corticotropin releasing factor receptor 1-expressing neurons regulate anxiety and conditioned rewarding effects of ethanol

6-Methoxyflavone and Donepezil Behavioral Plus Neurochemical Correlates in Reversing Chronic Ethanol and Withdrawal Induced Cognitive Impairment

Voluntary alcohol consumption disrupts coupling of prefrontal cortical activity to arousal

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