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Convergent abnormalities in striatal gene networks in human cocaine use disorder and mouse cocaine administration models.

ABSTRACT: Cocaine use disorder (CUD) is an intractable syndrome, and rising overdose death rates represent a substantial public health crisis that exacts tremendous personal and financial costs on patients and society. Sharp increases in cocaine use drive the urgent need for better mechanistic insight into this chronic relapsing brain disorder that currently lacks effective treatment options. To investigate the transcriptomic changes involved, we conducted RNA sequencing on two striatal brain regions that are heavily implicated in CUD, the nucleus accumbens and caudate nucleus, from men suffering from CUD and matched controls. Weighted gene coexpression analyses identified CUD-specific gene networks enriched in ionotropic receptors and linked to lowered neuroinflammation, contrasting the proinflammatory responses found in opioid use disorder. Integration of comprehensive transcriptomic datasets from mouse cocaine self-administration models revealed evolutionarily conserved gene networks in CUD that implicate especially D1 medium spiny neurons as drivers of cocaine-induced plasticity.

SUBMITTER: Mews P

PROVIDER: S-EPMC9916993 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Convergent abnormalities in striatal gene networks in human cocaine use disorder and mouse cocaine administration models.

Mews Philipp P Cunningham Ashley M AM Scarpa Joseph J Ramakrishnan Aarthi A Hicks Emily M EM Bolnick Sarah S Garamszegi Susanna S Shen Li L Mash Deborah C DC Nestler Eric J EJ

Science advances 20230210 6

Cocaine use disorder (CUD) is an intractable syndrome, and rising overdose death rates represent a substantial public health crisis that exacts tremendous personal and financial costs on patients and society. Sharp increases in cocaine use drive the urgent need for better mechanistic insight into this chronic relapsing brain disorder that currently lacks effective treatment options. To investigate the transcriptomic changes involved, we conducted RNA sequencing on two striatal brain regions that ...[more]

PMID: 36763659

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Project description:Animal models of drug use have investigated possible mechanisms governing human substance use traits for over 100 years. Most cross-species research on drug use/addiction examines behavioral overlap, but studies assessing neuromolecular (e.g. RNA) correspondence are lacking. Our study utilized transcriptome-wide data from the hippocampus and ventral tegmental area (VTA)/midbrain from a total of 35 human males with cocaine use disorder/controls and 49 male C57BL/6J cocaine/saline administering/exposed mice. We hypothesized differential expressed genes and systems of co-expressed genes (gene networks) would show appreciable overlap across mouse cocaine self-administration and human cocaine use disorder. We found modest, but significant relationships between differentially expressed genes associated with cocaine self-administration (short access) and cocaine use disorder within reward circuitry. Differentially expressed genes underlying models of acute cocaine exposure (cocaine), context re-exposure and cocaine + context re-exposure were not consistently associated with human CUD across brain regions. Investigating systems of co-expressed genes, we found several validated gene networks with weak to moderate conservation between cocaine/saline self-administering mice and disordered cocaine users/controls. The most conserved hippocampal and VTA gene networks demonstrated substantial overlap (2029 common genes) and included both novel and previously implicated targets for cocaine use/addiction. Lastly, we conducted (expression-based) phenome-wide association studies of the nine common hub genes across conserved gene networks. Common hub genes were associated with dopamine/serotonin function, cocaine self-administration and other relevant mouse traits. Overall, our study pinpointed and characterized conserved brain-related RNA patterns across mouse cocaine self-administration and human cocaine use disorder. We offer recommendations for future research and add to the dialogue surrounding pre-clinical animal research for human disease.

Project description:Background: Individual differences in gray-matter morphometry in the limbic system and frontal cortex have been linked to clinical features of cocaine use disorder (CUD). Self-administration paradigms can provide more direct measurements of the relationship between the regulation of cocaine use and gray-matter morphometry when compared to self-report assessments.Objectives: Our goal was to investigate associations with self-administration behavior in subcortical and cortical brain regions. We hypothesized the number of cocaine infusions self-administered would be correlated with gray-matter volumes (GMVs) in the striatum, amygdala, and hippocampus. Due to scarcity in human studies, we did not hypothesize subcortical directionality. In the frontal cortex, we hypothesized thickness would be negatively correlated with self-administered cocaine.Methods: We conducted an analysis of cocaine self-administration and structural MRI data from 33 (nFemales = 10) individuals with moderate-to-severe CUD. Self-administration lasted 60-minutes and cocaine (8, 16, or 32 mg/70 kg) was delivered on an FR1 schedule (5-minute lockout). Subcortical and cortical regression analyses were performed that included combined bilateral regions and age, experimental variables and use history as confounders.Results: Self-administered cocaine infusions were positively associated with caudal GMV (b = 0.18, p = 0.030) and negatively with putamenal GMV (b = -0.10, p = 0.041). In the cortical model, infusions were positively associated with insular thickness (b = 0.39, p = 0.008) and women appeared to self-administer cocaine more frequently (b = 0.23, p = 0.019).Conclusions: Brain morphometry features in the striatum and insula may contribute to cocaine consumption in CUD. These differences in morphometry may reflect consequences of prolonged use, predisposed vulnerability, or other possibilities.Clinical Trial Numbers: NCT01978431; NCT03471182.

Project description:Autism spectrum disorder (ASD) and congenital heart disease (CHD) are linked on a functional and genetic level. Most work has investigated CHD-related neurodevelopmental abnormalities. Cardiac abnormalities in ASD have been less studied. We investigated the prevalence of cardiac comorbidities relative to ASD genetic contributors. Using high frequency ultrasound imaging, we screened 9 ASD-related genetic mouse models (Arid1b(+/-) , Chd8(+/-) , 16p11.2 (deletion), Sgsh(+/-) , Sgsh(-/-) , Shank3 Δexon 4-9(+/-) , Shank3 Δexon 4-9(-/-) , Fmr1(-/-) , Vps13b(+/-) ), and pooled wild-type littermates (WTs). We measured heart rate (HR), aorta diameter (AoD), thickness and thickening of the left-ventricular (LV) anterior and posterior walls, LV chamber diameter, fractional shortening, stroke volume and cardiac output, mitral inflow Peak E and A velocity ratio, ascending aorta velocity time integral (VTI). Mutant groups presented small-scale alterations in cardiac structure and function compared to WTs (LV anterior wall thickness and thickening, chamber diameter and fractional shortening, HR). A greater number of significant differences was observed among mutant groups than between mutant groups and WTs. Mutant groups differed primarily in structural measures (LV chamber diameter and anterior wall thickness, HR, AoD). The mutant groups with most differences to WTs were 16p11.2 (deletion), Fmr1(-/-) , Arid1b(+/-) . The mutant groups with most differences from other mutant groups were 16p11.2 (deletion), Sgsh(+/-) , Fmr1(-/-) . Our results recapitulate the associated clinical findings. The characteristic ASD heterogeneity was recapitulated in the cardiac phenotype. The type of abnormal measures (morphological, functional) can highlight common underlying mechanisms. Clinically, knowledge of cardiac abnormalities in ASD can be essential as even non-lethal abnormalities impact normal development. LAY SUMMARY: Autism spectrum disorder (ASD) and congenital heart disease (CHD) are linked functionally and genetically. ASD cardiac phenotyping is limited. We assessed the cardiac phenotype of 9 ASD-related mouse models. We found subtle heterogenous cardiac abnormalities compared to controls, with more differences within ASD than between ASD and controls, mirroring clinical findings. Clinically, knowing the cardiac abnormalities in ASD is vital as even non-lethal cardiac abnormalities can impact development.

Dataset Information

Convergent abnormalities in striatal gene networks in human cocaine use disorder and mouse cocaine administration models.

Publications

Convergent abnormalities in striatal gene networks in human cocaine use disorder and mouse cocaine administration models.

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