Limbic circuitry activation in ethanol withdrawal is regulated by a chromosome 1 locus

Abstract

Physiological dependence and associated withdrawal episodes are thought to constitute a motivational force sustaining alcohol use/abuse and contributing to relapse in alcoholics. Although no animal model exactly duplicates alcoholism, models for specific factors, including the withdrawal syndrome, are useful for identifying potential genetic and neural determinants of liability in humans. We previously identified highly significant quantitative trait loci (QTLs) with large effects on predisposition to withdrawal after chronic and acute alcohol exposure in mice and mapped these loci to the same region of chromosome 1 (Alcdp1 and Alcw1, respectively). The present studies utilize a novel Alcdp1/Alcw1 congenic model (in which an interval spanning Alcdp1 and Alcw1 from the C57BL/6J donor strain [build GRCm38 150.3–174.6 Mb] has been introgressed onto a uniform inbred DBA/2J genetic background) known to demonstrate significantly less severe chronic and acute withdrawal compared to appropriate background strain animals. Here, using c-Fos induction as a high-resolution marker of neuronal activation, we report that male Alcdp1/Alcw1 congenic animals demonstrate significantly less alcohol withdrawal-associated neural activation compared to appropriate background strain animals in the prelimbic and cingulate cortices of the prefrontal cortex as well as discrete regions of the extended amygdala (i.e., basolateral) and extended basal ganglia (i.e., dorsolateral striatum, and caudal substantia nigra pars reticulata). These studies are the first to begin to elucidate circuitry by which this confirmed addiction-relevant QTL could influence behavior. This circuitry overlaps limbic circuitry involved in stress, providing additional mechanistic information. Alcdp1/Alcw1 maps to a region syntenic with human chromosome 1q, where multiple studies find significant associations with risk for alcoholism.

Distinct Roles for Two Chromosome 1 Loci in Ethanol Withdrawal, Consumption, and Conditioned Place Preference

“…Our data using c-Fos induction as a high-resolution marker of neuronal activation show that mice congenic for a region spanning Alcw1 1 and Alcw1 2 demonstrate significantly ( p < 0.05) less alcohol withdrawal associated activation than background strain mice in the prelimbic cortex, basolateral amygdala, nucleus accumbens shell, dorsolateral striatum, and caudal substantia nigra pars reticulata (Buck et al, 2017 ). These data elucidate circuitry by which Alcw1 1 and/or Alcw1 2 influence alcohol withdrawal behaviors.…”

“…Ndufs2 is significantly DE in reciprocal congenic vs. respective background strains (Walter et al, 2017 ). Its mRNA content is regulated by ethanol in the amygdala (Most et al, 2015 ), which is a region implicated in Alcw1 actions (Buck et al, 2017 ). In our genetic models, Ndufs2 also contains a single coding region nonsynonymous SNP that is predicted to be functionally relevant (Denmark and Buck, 2008 ).…”

From Phenomes to Genes: Phenotype-based Strategies in Rodents for Research on the Neurobiological and Genetic Bases of Psychiatric-relevant Traits

“…Ctnnd2 was also validated in knockout and transgenic mice [ 13 , 14 ], as well as in a human psychiatric sample [ 15 ]. Another example is the Mpdz gene, which was identified as a QTG for alcohol dependence in mice after several QTL studies [ 16 - 18 ].…”