Nuclear transcriptional changes in hypothalamus of Pomc enhancer knockout mice after excessive alcohol drinking

Abstract

Persistent alterations of proopiomelanocortin (Pomc) and mu‐opioid receptor (Oprm1) activity and stress responses after alcohol are critically involved in vulnerability to alcohol dependency. Gene transcriptional regulation altered by alcohol may play important roles. Mice with genome‐wide deletion of neuronal Pomc enhancer1 (nPE1−/−), had hypothalamic‐specific partial reductions of beta‐endorphin and displayed lower alcohol consumption, compared to wildtype littermates (nPE1+/+). We used RNA‐Seq to measure steady‐state nuclear mRNA transcripts of opioid and stress genes in hypothalamus of nPE1+/+ and nPE1−/− mice after 1‐day acute withdrawal from chronic excessive alcohol drinking or after water. nPE1−/− had lower basal Pomc and Pdyn (prodynorphin) levels compared to nPE1+/+, coupled with increased basal Oprm1 and Oprk1 (kappa‐opioid receptor) levels, and low alcohol drinking increased Pomc and Pdyn to the basal levels of nPE1+/+ in the water group, without significant effects on Oprm1 and Oprk1. In nPE1+/+, excessive alcohol intake increased Pomc and Oprm1, with no effect on Pdyn or Oprk1. For stress genes, nPE1−/− had lowered basal Oxt (oxytocin) and Avp (arginine vasopressin) that were restored by low alcohol intake to basal levels of nPE1+/+. In nPE1+/+, excessive alcohol intake decreased Oxt and Avpi1 (AVP‐induced protein1). Functionally examining the effect of pharmacological blockade of mu‐opioid receptor, we found that naltrexone reduced excessive alcohol intake in nPE1+/+, but not nPE1−/−. Our results provide evidence relevant to the transcriptional profiling of the critical genes in mouse hypothalamus: enhanced opioid and reduced stress gene transcripts after acute withdrawal from excessive alcohol may contribute to altered reward and stress responses.

Unraveling epigenomic signatures and effectiveness of electroconvulsive therapy in treatment-resistant depression patients: a prospective longitudinal study

“…In regional analyses between the two time points, we found no significant DMRs, although some genes known to be associated with inflammatory and immune processes ( MIR637 , RUNX3 , AVPI1 , MCF2L , FOXK2 , POU6F1 ) were noted. Moreover, FAM124B is related to anorexia nervosa [ 29 ], and AVPI1 is associated with alcohol dependence [ 26 ]. In the regional analyses including clinical symptoms variation as a covariate, we identified several significant DMRs annotated in notable genes.…”

GPCR and Alcohol-Related Behaviors in Genetically Modified Mice

“…In another study, voluntary consumption was reduced in β-endorphin knockout mice with a stronger reduction in female mice [47]. Recently, a mouse line with a genome-wide deletion of neuronal Pomc enhancer 1 was generated [127]. This deletion reduces specifically βendorphin levels in the hypothalamus and decreases significantly alcohol consumption in two alcohol drinking paradigms: drinking in the dark and intermittent access [127].…”

“…Conditional MOR deletion in GABAergic forebrain neurons using a Dlx5/6-Cre driver line (Cre expressed in GABAergic neurons [125] crossed with floxed Oprm1 mice) diminished voluntary alcohol drinking and alcohol rewarding properties [126]. Endogenous peptides binding to MORs such as β-endorphin and his precursor proopiomelanocortin (POMC) have also been implicated in alcohol use and abuse disorders [121,127,128]. Specifically, β-endorphin heterozygote knockout mice showed an increased voluntary alcohol consumption in a two-bottle choice paradigm [46].…”

“…Recently, a mouse line with a genome-wide deletion of neuronal Pomc enhancer 1 was generated [127]. This deletion reduces specifically βendorphin levels in the hypothalamus and decreases significantly alcohol consumption in two alcohol drinking paradigms: drinking in the dark and intermittent access [127]. Together, these studies revealed a contribution of βendorphin in alcohol consumption.…”

Effect of Short-Term Restraint Stress on the Hypothalamic Transcriptome Profiles of Rats with Inherited Stress-Induced Arterial Hypertension (ISIAH) and Normotensive Wistar Albino Glaxo (WAG) Rats

“…Researchers often choose the hypothalamus to analyze transcriptomic changes after exposure to various stressors: heat stress for 24 h [ 9 ] or for 14 days [ 10 , 11 ], social conflict (within 20 days) [ 12 ], alcohol consumption [ 13 ], short-term starvation [ 14 ], and repeated homotypic stress [ 15 ]. The hypothalamic transcriptome has also been investigated when studying the molecular mechanisms of blood pressure regulation.…”