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Altered expression of somatostatin signaling molecules and clock genes in the hippocampus of subjects with substance use disorder - PubMed

  • ️Sat Jan 01 2022

Altered expression of somatostatin signaling molecules and clock genes in the hippocampus of subjects with substance use disorder

Jake Valeri et al. Front Neurosci. 2022.

Abstract

Substance use disorders are a debilitating group of psychiatric disorders with a high degree of comorbidity with major depressive disorder. Sleep and circadian rhythm disturbances are commonly reported in people with substance use disorder and major depression and associated with increased risk of relapse. Hippocampal somatostatin signaling is involved in encoding and consolidation of contextual memories which contribute to relapse in substance use disorder. Somatostatin and clock genes also have been implicated in depression, suggesting that these molecules may represent key converging pathways involved in contextual memory processing in substance use and major depression. We used hippocampal tissue from a cohort of subjects with substance use disorder (n = 20), subjects with major depression (n = 20), subjects with comorbid substance use disorder and major depression (n = 24) and psychiatrically normal control subjects (n = 20) to test the hypothesis that expression of genes involved in somatostatin signaling and clock genes is altered in subjects with substance use disorder. We identified decreased expression of somatostatin in subjects with substance use disorder and in subjects with major depression. We also observed increased somatostatin receptor 2 expression in subjects with substance use disorder with alcohol in the blood at death and decreased expression in subjects with major depression. Expression of the clock genes Arntl, Nr1d1, Per2 and Cry2 was increased in subjects with substance use disorder. Arntl and Nr1d1 expression in comparison was decreased in subjects with major depression. We observed decreased expression of Gsk3β in subjects with substance use disorder. Subjects with comorbid substance use disorder and major depression displayed minimal changes across all outcome measures. Furthermore, we observed a significant increase in history of sleep disturbances in subjects with substance use disorder. Our findings represent the first evidence for altered somatostatin and clock gene expression in the hippocampus of subjects with substance use disorder and subjects with major depression. Altered expression of these molecules may impact memory consolidation and contribute to relapse risk.

Keywords: circadian; hippocampus; sleep; somatostatin; substance use disorder.

Copyright © 2022 Valeri, O’Donovan, Wang, Sinclair, Bollavarapu, Gisabella, Platt, Stockmeier and Pantazopoulos.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1

History of sleep disturbances in subjects with SUD and subjects with MDD. Sleep quality ratings representing presence or absence of history of sleep disturbances were obtained from medical records and family interviews of each donor. Sleep quality was characterized as normal sleep, decreased sleep, or increased sleep. Chi-square analysis revealed a significant effect of diagnosis group (Controls, MDD or SUD and SUD with MDD) on sleep quality. Subjects with MDD and subjects with MDD/SUD had higher prevalence of decreased sleep as well as a smaller group of subjects with increased sleep.

FIGURE 2
FIGURE 2

Altered SST signaling in the hippocampus of subjects with SUD and subjects with MDD. Scatterplots depicting normalized mRNA expression for Sst in each diagnosis group (A). Green circles represent subjects with alcohol in the blood at death. SST mRNA expression was significantly greater in subjects with SUD compared to control subjects, (p < 0.0007, *adjusted for effects of alcohol in the blood at death and pH). Subjects with alcohol in the blood at death had significantly greater Sst mRNA expression than subjects without alcohol in the blood (B). Subjects with MDD/SUD had no significant difference in Sst mRNA expression when compared to control subjects (adjusted for significant effects of age and suicide). A significant decrease in Sst mRNA expression was detected in subjects with MDD (p < 0.04, **adjusted for effects of age, duration of illness, and PMI). No significant differences in Sstr2 mRNA expression were detected in subjects with SUD compared to control subjects when adjusted for effect of alcohol in the blood at death (C). Subjects with alcohol in the blood at death had significantly greater expression of SSTR2 mRNA (D). Subjects with MDD had significantly lower Sstr2 mRNA expression compared to control subjects (p < 0.02, ***adjusted for effects of smoking history and ZT time). Subjects with MDD also displayed lower Sstr2 mRNA expression in comparison to subjects with SUD or subjects with MDD/SUD (C). Significance values are derived from stepwise linear regression models. Scatterplots show the mean (histogram) and 95% confidence intervals (black lines).

FIGURE 3
FIGURE 3

ARNTL expression is differentially altered in the hippocampus of subjects with SUD and subjects with MDD. (A) Arntl mRNA expression was significantly greater in subjects with SUD compared to control subjects (p < 0.03, *adjusted for significant effects of ZT time and interaction of ZT time with diagnosis). A significant decrease in Arntl mRNA expression was observed in subjects with MDD only compared to control subjects (p < 0.02, **adjusted for significant effects of ZT time, duration of illness, and age). Subjects with MDD also displayed lower Arntl expression compared to subjects with SUD (p < 0.001, ***adjusted for significant effects of ZT time and duration of MDD). Subjects with MDD who died by suicide had significantly less ARrntl mRNA expression than subjects with MDD who died from other causes (B). Subjects with MDD/SUD with opioids in the blood at death had a non-significant trend toward increased Arntl expression (C) compared to significantly less Arntl expression in subjects with ethanol in the blood at death (D). Significance values are derived from stepwise linear regression models. Scatterplots show the mean (histogram) and 95% confidence intervals (black lines).

FIGURE 4
FIGURE 4

Altered expression of NR1D1 and GSK3β in the hippocampus of subjects with SUD. (A) Significantly greater Nr1d1 mRNA expression was observed in subjects with SUD compared to control subjects (p < 0.02, *adjusted for significant effect of cocaine in the blood at death). Subjects with SUD with cocaine in the blood at death had significantly less Nr1d1 mRNA expression (B). Subjects with MDD/SUD had significantly lower Nr1d1 expression compared to control subjects (p < 0.03; **adjusted for significant effects of ZT time, duration of MDD, sex, opioids in the blood at death, smoking, and cocaine in the blood at death). Subjects with MDD/SUD with opioids in the blood at death had significantly higher Nr1d1 expression than subjects (C). Subjects with MDD only had no significant difference in Nr1d1 expression when compared to control subjects (A). Subjects with MDD only had significantly lower expression compared to subjects with SUD (p < 0.05, ***adjusted for significant effect of cocaine in the blood at death). Scatterplots depicting normalized mRNA expression for Gsk3β (D). Gsk3β mRNA expression was significantly decreased in subjects with SUD (p < 0.002; ^adjusted for significant effects of ZT time, interaction of ZT time and diagnosis, PMI, ethanol in the blood at death (E), and opioids in the blood at death) (F). Significance values are derived from stepwise linear regression models. Scatterplots show the mean (histogram) and 95% confidence intervals (black lines). ^^Adjusted for effects of duration of alcohol use disorder and suicide.

FIGURE 5
FIGURE 5

Altered Per2 and Cry2 expression in the hippocampus of subjects with SUD. (A) ANCOVA analysis detected increased Per2 mRNA expression in subjects with SUD (p < 0.001; **adjusted for effects of ZT time, calcium channel blockers, and rating of lifetime alcohol exposure). Subjects with comorbid MDD/SUD also displayed significantly increased Per2 expression (p < 0.008; ^adjusted for effects of ZT time, history of sleep disturbances, calcium channel blockers, and amount of antipsychotics in the last month of life) (A). No differences in Per2 expression were detected in subjects with MDD. (B) Increased Cry2 expression was also detected in subjects with SUD (p < 0.03; *adjusted for effects of ZT time, interaction of ZT time with diagnosis, and duration of alcohol use disorder). No differences in Per2 expression were detected in subjects with MDD/SUD or subjects with MDD. Significance values are derived from stepwise linear regression models. Scatterplots show the mean (histogram) and 95% confidence intervals (black lines).

FIGURE 6
FIGURE 6

Diurnal rhythms of SST Signaling and ARNTL gene expression. Diurnal gene expression rhythms for Sst signaling genes and Arntl demonstrating enhanced rhythms in subjects with SUD. Expression level values in the scatterplots are indicated on the y axis with each dot representing an individual subject and the x axis representing ZT time of death values. The colored lines represent the fit sinusoidal curve for each marker in each diagnosis group. R2 values and corresponding p-values represent significance of fit for diurnal expression rhythms. Significant rhythms were observed in control subjects for Sstr2 and ARNTL expression, and enhanced rhythm and altered phase was detected for Sstr2 in subjects with SUD while Arntl rhythms were lost in subjects with SUD and MDD/SUD. Phase and amplitude estimates and p-values are indicated on each scatterplot for outcome measures with significant R2 values.

FIGURE 7
FIGURE 7

Diurnal clock gene expression rhythms. Diurnal gene expression rhythms for clock genes in the human hippocampus. Expression level values in the scatterplots are indicated on the y axis with each dot representing an individual subject and the x axis representing ZT time of death values. The colored lines represent the fit sinusoidal curve for each marker in each diagnosis group. R2 values and corresponding p-values represent significance of fit for diurnal expression rhythms. Significant diurnal expression rhythm was observed for Gsk3β in control subjects. Enhanced rhythms were observed in subjects with SUD for Gsk3β and Nr1d1 gene expression and for Nr1d1 in subjects with MDD/SUD. Phase and amplitude estimates and p-values are indicated on each scatterplot for outcome measures with significant R2 values.

FIGURE 8
FIGURE 8

Hypothetical model of molecular clock and SST signaling in SUD. (A) The core molecular circadian clock depicting the dimerization of Arntl and Clock genes which promotes the expression of several “clock-controlled genes” which may potentially include Sst and the Sstr2. (B) A summary of findings of diagnosis group differences in gene expression. (C) A hypothetical model showing altered clock gene rhythms in subjects with SUD and MDD/SUD, with amplified and shifted diurnal rhythms in SUD compared to dampened rhythms in the MDD/SUD group.

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