Dysregulation of prefrontal circuits is thought to underlie aberrant emotional processing contributing to the persistent vulnerability to alcohol misuse in abstinence. Corticotropin-releasing factor (CRF) and its cognate type-1 receptor (CRF1) form a prominent brain stress system that has been impli- cated in anxiety and alcohol use disorder (AUD). We hypothesized that withdrawal from chronic alco- hol exposure uniquely impacts CRF1-expressing neurons in the medial prefrontal cortex (mPFCCRF1+) leading to the development of AUD-related behaviors (e.g. anxiety and escalated alco- hol drinking) contributing to relapse. In support of this hypothesis, we found that mPFCCRF1+ neurons comprise a unique population of prelimbic layer 2/3 glutamatergic neurons that regulate anxiety-like behavior. Withdrawal from chronic alcohol exposure induces distinct neuroadaptations in mPFCCRF1+ neurons compared to neighboring neurons including decreased excitability and gluta- matergic signaling, indicating the unique sensitivity of mPFCCRF1+ neurons to withdrawal. This dys- regulated glutamate transmission is driven in part by the basolateral amygdala (BLA), which directly innervate mPFCCRF1+ neurons. Notably, chemogenetic activation of mPFCCRF1+ neurons during abstinence abolishes escalated alcohol intake induced by chronic alcohol exposure, but not baseline alcohol drinking. This points to a role of the mPFCCRF1+ population in regulating relapse-like alcohol drinking and is consistent with the observed decrease in excitability of this population in withdrawal potentially driving drinking. Indeed, cell type specific transcriptomic analysis revealed that withdrawal fundamentally alters the neurobiology of mPFCCRF1+ neurons, leading to increased expression of the neuroimmune mediator colony-stimulating factor 1 (CSF1). Selective CSF1 overexpression in mPFCCRF1+ neurons is sufficient to decrease postsynaptic glutamate transmission specifically in mPFCCRF1+ neurons, providing mechanistic insight into the observed synaptic adaptations in gluta- matergic transmission induced by withdrawal in mPFCCRF1+ neurons. In addition, CSF1 overexpres- sion in mPFCCRF1+ neurons exacerbates anxiety-like behavior, suggesting that mPFCCRF1+ CSF1 signaling mimics behavioral adaptations observed during abstinence from chronic alcohol and may be a novel target for therapeutic intervention. Taken together, these findings highlight mPFC CRF1- expressing neurons as a critical site of enduring neuroadaptations underlying aberrant emotional processing and alcohol drinking in withdrawal contributing to the persistent vulnerability to alcohol misuse and the chronic nature of AUD.

PREFRONTAL CRF1-EXPRESSING NEURONS UNDERGO ENDURING ADAPTATIONS UNDERLYING ABERRANT EMOTIONAL PROCESSING AND ALCOHOL DRINKING IN ABSTINENCE / RR Patel, SA Wolfe, V Borgonetti, S D'Ambrosia, M Bajo, A Domissy, S Head, C Contet, RD Mayfield, AJ Roberts, M Roberto. - In: ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH. - ISSN 0145-6008. - STAMPA. - (2021), pp. 90-91. ((Intervento presentato al convegno 44th Annual Speaker & Poster Abstracts of the Research Society on Alcoholism jointly with the International Society for Biomedical Research on Alcoholism, June 2021.

PREFRONTAL CRF1-EXPRESSING NEURONS UNDERGO ENDURING ADAPTATIONS UNDERLYING ABERRANT EMOTIONAL PROCESSING AND ALCOHOL DRINKING IN ABSTINENCE

V Borgonetti;
2021

Abstract

Dysregulation of prefrontal circuits is thought to underlie aberrant emotional processing contributing to the persistent vulnerability to alcohol misuse in abstinence. Corticotropin-releasing factor (CRF) and its cognate type-1 receptor (CRF1) form a prominent brain stress system that has been impli- cated in anxiety and alcohol use disorder (AUD). We hypothesized that withdrawal from chronic alco- hol exposure uniquely impacts CRF1-expressing neurons in the medial prefrontal cortex (mPFCCRF1+) leading to the development of AUD-related behaviors (e.g. anxiety and escalated alco- hol drinking) contributing to relapse. In support of this hypothesis, we found that mPFCCRF1+ neurons comprise a unique population of prelimbic layer 2/3 glutamatergic neurons that regulate anxiety-like behavior. Withdrawal from chronic alcohol exposure induces distinct neuroadaptations in mPFCCRF1+ neurons compared to neighboring neurons including decreased excitability and gluta- matergic signaling, indicating the unique sensitivity of mPFCCRF1+ neurons to withdrawal. This dys- regulated glutamate transmission is driven in part by the basolateral amygdala (BLA), which directly innervate mPFCCRF1+ neurons. Notably, chemogenetic activation of mPFCCRF1+ neurons during abstinence abolishes escalated alcohol intake induced by chronic alcohol exposure, but not baseline alcohol drinking. This points to a role of the mPFCCRF1+ population in regulating relapse-like alcohol drinking and is consistent with the observed decrease in excitability of this population in withdrawal potentially driving drinking. Indeed, cell type specific transcriptomic analysis revealed that withdrawal fundamentally alters the neurobiology of mPFCCRF1+ neurons, leading to increased expression of the neuroimmune mediator colony-stimulating factor 1 (CSF1). Selective CSF1 overexpression in mPFCCRF1+ neurons is sufficient to decrease postsynaptic glutamate transmission specifically in mPFCCRF1+ neurons, providing mechanistic insight into the observed synaptic adaptations in gluta- matergic transmission induced by withdrawal in mPFCCRF1+ neurons. In addition, CSF1 overexpres- sion in mPFCCRF1+ neurons exacerbates anxiety-like behavior, suggesting that mPFCCRF1+ CSF1 signaling mimics behavioral adaptations observed during abstinence from chronic alcohol and may be a novel target for therapeutic intervention. Taken together, these findings highlight mPFC CRF1- expressing neurons as a critical site of enduring neuroadaptations underlying aberrant emotional processing and alcohol drinking in withdrawal contributing to the persistent vulnerability to alcohol misuse and the chronic nature of AUD.
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44th Annual Speaker & Poster Abstracts of the Research Society on Alcoholism jointly with the International Society for Biomedical Research on Alcoholism, June 2021
RR Patel, SA Wolfe, V Borgonetti, S D'Ambrosia, M Bajo, A Domissy, S Head, C Contet, RD Mayfield, AJ Roberts, M Roberto
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2158/1281444
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