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Forebrain gene expression predicts deficits in sensorimotor gating after isolation rearing in male rats.

ABSTRACT: Compared to socially housed (SH) rats, adult isolation-reared (IR) rats exhibit phenotypes relevant to schizophrenia (SZ), including reduced prepulse inhibition (PPI) of startle. PPI is normally regulated by the medial prefrontal cortex (mPFC) and nucleus accumbens (NAC). We assessed PPI, auditory-evoked local field potentials (LFPs) and expression of seven PPI- and SZ-related genes in the mPFC and NAC, in IR and SH rats. Buffalo (BUF) rats were raised in same-sex groups of 2-3 (SH) or in isolation (IR). PPI was measured early (d53) and later in adulthood (d74); LFPs were measured approximately on d66. Brains were processed for RT-PCR measures of mPFC and NAC expression of Comt, Erbb4, Grid2, Ncam1, Slc1a2, Nrg1 and Reln. Male IR rats exhibited PPI deficits, most pronounced at d53; male and female IR rats had significantly elevated startle magnitude on both test days. Gene expression levels were not significantly altered by IR. PPI levels (d53) were positively correlated with mPFC expression of several genes, and negatively correlated with NAC expression of several genes, in male IR but not SH rats. Late (P90) LFP amplitudes correlated significantly with expression levels of 6/7 mPFC genes in male rats, independent of rearing. After IR that disrupts early adult PPI in male BUF rats, expression levels of PPI- and SZ-associated genes in the mPFC correlate positively with PPI, and levels in the NAC correlate negatively with PPI. These results support the model that specific gene-behavior relationships moderate the impact of early-life experience on SZ-linked behavioral and neurophysiological markers.

SUBMITTER: Swerdlow NR

PROVIDER: S-EPMC3897308 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Forebrain gene expression predicts deficits in sensorimotor gating after isolation rearing in male rats.

Swerdlow Neal R NR Light Gregory A GA Trim Ryan S RS Breier Michelle R MR Hines Samantha R SR Powell Susan B SB

Behavioural brain research 20130925

Compared to socially housed (SH) rats, adult isolation-reared (IR) rats exhibit phenotypes relevant to schizophrenia (SZ), including reduced prepulse inhibition (PPI) of startle. PPI is normally regulated by the medial prefrontal cortex (mPFC) and nucleus accumbens (NAC). We assessed PPI, auditory-evoked local field potentials (LFPs) and expression of seven PPI- and SZ-related genes in the mPFC and NAC, in IR and SH rats. Buffalo (BUF) rats were raised in same-sex groups of 2-3 (SH) or in isolat ...[more]

PMID: 24076151

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Project description:BackgroundEvidence from anatomical, pharmacological, and genetic studies supports a role for the neuropeptide melanin concentrating hormone system in modulating emotional and cognitive functions. Genome-wide association studies revealed a potential association between the melanin concentrating hormone receptor (MCHR1) gene locus and schizophrenia, and the largest genome-wide association study conducted to date shows a credible genome-wide association.MethodsWe analyzed MCHR1 and pro-melanin concentrating hormone RNA-Seq expression in the prefrontal cortex in schizophrenia patients and healthy controls. Disruptions in the melanin concentrating hormone system were modeled in the mouse brain by germline deletion of MCHR1 and by conditional ablation of melanin concentrating hormone expressing neurons using a Cre-inducible diphtheria toxin system.ResultsMCHR1 expression is decreased in the prefrontal cortex of schizophrenia samples (false discovery rate (FDR) P < .05, CommonMind and PsychEncode combined datasets, n = 901) while pro-melanin concentrating hormone is below the detection threshold. MCHR1 expression decreased with aging (P = 6.6E-57) in human dorsolateral prefrontal cortex. The deletion of MCHR1 was found to lead to behavioral abnormalities mimicking schizophrenia-like phenotypes: hyperactivity, increased stereotypic and repetitive behavior, social impairment, impaired sensorimotor gating, and disrupted cognitive functions. Conditional ablation of pro-melanin concentrating hormone neurons increased repetitive behavior and produced a deficit in sensorimotor gating.ConclusionsOur study indicates that early disruption of the melanin concentrating hormone system interferes with neurodevelopmental processes, which may contribute to the pathogenesis of schizophrenia. Further neurobiological research on the developmental timing and circuits that are affected by melanin concentrating hormone may lead to a therapeutic target for early prevention of schizophrenia.

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Forebrain gene expression predicts deficits in sensorimotor gating after isolation rearing in male rats.

Publications

Forebrain gene expression predicts deficits in sensorimotor gating after isolation rearing in male rats.

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