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Front. Cell. Neurosci. | doi: 10.3389/fncel.2019.00158

Predisposition to alcohol drinking and alcohol consumption alter expression of calcitonin gene-related peptide, neuropeptide Y, and microglia in bed nucleus of stria terminalis in a subnucleus-specific manner

  • 1Italian National Research Council (CNR), Italy
  • 2University of Milan, Italy
  • 3Department of Biomedical Sciences, University of Cagliari, Italy
  • 4Max-Planck-Institut für Molekulare Zellbiologie und Genetik, Germany
  • 5Neuroscience Institute C.N.R, Italy

Excessive alcohol consumption is often linked to anxiety states and has a major relay center in the anterior part of bed nucleus of stria terminalis (BNST). We analyzed the impact of (i) genetic predisposition to high alcohol preference and consumption, and (ii) alcohol intake on anterior BNST, namely anterolateral (AL), anteromedial (AM), and anteroventral (lateral + medial subdivisions: AVl, AVm) subnuclei. We used two rat lines selectively bred for low- and high- alcohol preference and consumption, named Sardinian alcohol-non preferring (sNP) and -preferring (sP), respectively, the latter showing also inherent anxiety-related behaviors. We analyzed the modulation of calcitonin gene-related peptide (CGRP; exerting anxiogenic effects in BNST), neuropeptide Y (NPY; exerting mainly anxiolytic effects), and microglia activation (neuroinflammation marker, thought to increase anxiety).
CGRP-immunofluorescent fibers/terminals did not differ between alcohol-naive sP and sNP rats. Fiber/terminal NPY-immunofluorescent intensity was lower in BNST-AM and BNST-AVm of alcohol-naive sP rats. Activation of microglia (revealed by morphological analysis) was decreased in BNST-AM and increased in BNST-AVm of alcohol-naive sP rats.
Prolonged (30 consecutive days), voluntary alcohol intake under the homecage 2-bottle “alcohol vs water” regimen strongly increased CGRP intensity in BNST of sP rats in a subnucleus-specific manner: in BNST-AL, BNST-AVm, and BNST-AM. CGRP area sum, however, decreased in BNST-AM, without changes in other subnuclei. Alcohol consumption increased NPY expression, in a subnucleus-specific manner, in BNST-AL, BNST-AVl, and BNST-AVm. Alcohol consumption increased many size/shape parameters in microglial cells, indicative of microglia de-activation. Finally, microglia density was increased in ventral anterior BNST (BNST-AVl, BNST-AVm) by alcohol consumption.
In conclusion, genetic predisposition of sP rats to high alcohol intake could be in part mediated by anterior BNST subnuclei showing lower NPY expression and differential microglia activation. Alcohol intake in sP rats produced complex subnucleus-specific changes in BNST, affecting CGRP/NPY expression and microglia and leading to hypothesize that these changes might contribute to the anxiolytic effects of voluntarily consumed alcohol repeatedly observed in sP rats.

Keywords: BNST, Bed Nucleus of the Stria Terminalis, CGRP (calcitonin gene-related peptide), NPY (neuropeptide Y), Microglia, Alcohol consumption, anterior subnuclei, Sardinian alcohol-preferring rats, Sardinian alcohol-non preferring rats

Received: 29 Dec 2018; Accepted: 08 Apr 2019.

Edited by:

Laura Cancedda, Istituto Italiano di Tecnologia, Italy

Reviewed by:

Carlos C. Crestani, Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista Júlio de Mesquita Filho, Brazil
Shovan Naskar, National Institute of Mental Health (NIMH), United States  

Copyright: © 2019 Rossetti, Zambusi, Maccioni, Sau, Provini, Castelli, Gonciarz, Colombo and Morara. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Stefano Morara, Neuroscience Institute C.N.R, Milano, Italy,