Endocannabinoid control of the insular-bed nucleus of the stria terminalis circuit regulates negative affective behavior associated with alcohol abstinence.

Autor: Centanni SW; Vanderbilt Center for Addiction Research, Vanderbilt University School of Medicine, Nashville, TN, USA.; Department of Molecular Physiology & Biophysics, Vanderbilt University School of Medicine, Nashville, TN, USA.; Vanderbilt Brain Institute, Vanderbilt University School of Medicine, Nashville, TN, USA.; Vanderbilt J.F. Kennedy Center for Research on Human Development, Vanderbilt University School of Medicine, Nashville, TN, USA., Morris BD; Vanderbilt Center for Addiction Research, Vanderbilt University School of Medicine, Nashville, TN, USA., Luchsinger JR; Vanderbilt Center for Addiction Research, Vanderbilt University School of Medicine, Nashville, TN, USA.; Vanderbilt Brain Institute, Vanderbilt University School of Medicine, Nashville, TN, USA.; Vanderbilt J.F. Kennedy Center for Research on Human Development, Vanderbilt University School of Medicine, Nashville, TN, USA., Bedse G; Vanderbilt Center for Addiction Research, Vanderbilt University School of Medicine, Nashville, TN, USA.; Vanderbilt Brain Institute, Vanderbilt University School of Medicine, Nashville, TN, USA.; Vanderbilt J.F. Kennedy Center for Research on Human Development, Vanderbilt University School of Medicine, Nashville, TN, USA.; Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, TN, USA., Fetterly TL; Vanderbilt Center for Addiction Research, Vanderbilt University School of Medicine, Nashville, TN, USA.; Vanderbilt Brain Institute, Vanderbilt University School of Medicine, Nashville, TN, USA.; Vanderbilt J.F. Kennedy Center for Research on Human Development, Vanderbilt University School of Medicine, Nashville, TN, USA.; Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, USA., Patel S; Vanderbilt Center for Addiction Research, Vanderbilt University School of Medicine, Nashville, TN, USA.; Department of Molecular Physiology & Biophysics, Vanderbilt University School of Medicine, Nashville, TN, USA.; Vanderbilt Brain Institute, Vanderbilt University School of Medicine, Nashville, TN, USA.; Vanderbilt J.F. Kennedy Center for Research on Human Development, Vanderbilt University School of Medicine, Nashville, TN, USA.; Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, TN, USA., Winder DG; Vanderbilt Center for Addiction Research, Vanderbilt University School of Medicine, Nashville, TN, USA. danny.winder@vanderbilt.edu.; Department of Molecular Physiology & Biophysics, Vanderbilt University School of Medicine, Nashville, TN, USA. danny.winder@vanderbilt.edu.; Vanderbilt Brain Institute, Vanderbilt University School of Medicine, Nashville, TN, USA. danny.winder@vanderbilt.edu.; Vanderbilt J.F. Kennedy Center for Research on Human Development, Vanderbilt University School of Medicine, Nashville, TN, USA. danny.winder@vanderbilt.edu.; Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, TN, USA. danny.winder@vanderbilt.edu.
Jazyk: angličtina
Zdroj: Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology [Neuropsychopharmacology] 2019 Feb; Vol. 44 (3), pp. 526-537. Date of Electronic Publication: 2018 Nov 02.
DOI: 10.1038/s41386-018-0257-8
Abstrakt: Negative affect is a core symptom domain associated with an array of neurological and psychiatric disorders and is only partially targeted by current therapies, highlighting the need for better, more targeted treatment options. This study focuses on negative affective symptoms associated with prolonged alcohol abstinence, one of the leading causes of relapse. Using a mouse model of chronic alcohol consumption followed by forced abstinence (CDFA), prolonged alcohol abstinence increased c-fos expression and spontaneous glutamatergic neurotransmission in the dorsal bed nucleus of the stria terminalis (dBNST), a region heavily implicated in negative affect in both humans and rodents. Further, pharmacologically enhancing endogenous cannabinoids (eCB) with JZL184 prevents abstinence-induced increases in dBNST neuronal activity, underscoring the therapeutic potential of drugs targeting the brain's eCB system. Next, we used a channelrhodopsin-assisted mapping strategy to identify excitatory inputs to the dBNST that could contribute to CDFA-induced negative affect. We identified the insular cortex (insula), a region involved in regulating interoception, as a dense, functional, eCB-sensitive input to the dBNST. Using a chemogenetic strategy to locally mimic eCB signaling, we demonstrate that the insula strongly influences the CDFA behavioral phenotype and dBNST neuronal activity. Lastly, we used an anterograde strategy for transynaptic targeting of Cre expression in combination with a G q -DREADD to selectively recruit dBNST neurons receiving insula projections. Chemogenetic recruitment of these neurons mimicked behavioral and c-fos responses observed in CDFA. Collectively, this study supports a role for the insula-BNST neural circuit in negative affective disturbances and highlights the therapeutic potential of the eCB system for treating negative affective disorders.
Databáze: MEDLINE
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