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Unpredictable neonatal stress enhances adult anxiety and alters amygdala gene expression related to serotonin and GABA.

ABSTRACT: Anxiety-related disorders are among the most common psychiatric illnesses, thought to have both genetic and environmental causes. Early-life trauma, such as abuse from a caregiver, can be predictable or unpredictable, each resulting in increased prevalence and severity of a unique set of disorders. In this study, we examined the influence of early unpredictable trauma on both the behavioral expression of adult anxiety and gene expression within the amygdala. Neonatal rats were exposed to unpaired odor-shock conditioning for 5 days, which produces deficits in adult behavior and amygdala dysfunction. In adulthood, we used the Light/Dark box test to measure anxiety-related behaviors, measuring the latency to enter the lit area and quantified urination and defecation. The amygdala was then dissected and a microarray analysis was performed to examine changes in gene expression. Animals that had received early unpredictable trauma displayed significantly longer latencies to enter the lit area and more defecation and urination. The microarray analysis revealed over-represented genes related to learning and memory, synaptic transmission and trans-membrane transport. Gene ontology and pathway analysis identified highly represented disease states related to anxiety phenotypes, including social anxiety, obsessive-compulsive disorders, post-traumatic stress disorder and bipolar disorder. Addiction-related genes were also overrepresented in this analysis. Unpredictable shock during early development increased anxiety-like behaviors in adulthood with concomitant changes in genes related to neurotransmission, resulting in gene expression patterns similar to anxiety-related psychiatric disorders.

SUBMITTER: Sarro EC

PROVIDER: S-EPMC4050971 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Unpredictable neonatal stress enhances adult anxiety and alters amygdala gene expression related to serotonin and GABA.

Sarro E C EC Sullivan R M RM Barr G G

Neuroscience 20131113

Anxiety-related disorders are among the most common psychiatric illnesses, thought to have both genetic and environmental causes. Early-life trauma, such as abuse from a caregiver, can be predictable or unpredictable, each resulting in increased prevalence and severity of a unique set of disorders. In this study, we examined the influence of early unpredictable trauma on both the behavioral expression of adult anxiety and gene expression within the amygdala. Neonatal rats were exposed to unpaire ...[more]

PMID: 24240029

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Project description:The serotonin transporter (SERT) gene, especially the short allele of the human serotonin transporter linked polymorphic region (5-HTTLPR), has been associated with the development of stress-related neuropsychiatric disorders. In line, exposure to early life stress in SERT knockout animals contributes to anxiety- and depression-like behavior. However, there is a lack of investigation of how early-life exposure to beneficial stimuli, such as tactile stimulation (TS), affects later life behavior in these animals. In this study, we investigated the effect of TS on social, anxiety, and anhedonic behavior in heterozygous SERT knockouts rats and wild-type controls and its impact on gene expression in the basolateral amygdala. Heterozygous SERT+/- rats were submitted to TS during postnatal days 8-14, for 10 min per day. In adulthood, rats were assessed for social and affective behavior. Besides, brain-derived neurotrophic factor (Bdnf) gene expression and its isoforms, components of glutamatergic and GABAergic systems as well as glucocorticoid-responsive genes were measured in the basolateral amygdala. We found that exposure to neonatal TS improved social and affective behavior in SERT+/- animals compared to naïve SERT+/- animals and was normalized to the level of naïve SERT+/+ animals. At the molecular level, we observed that TS per se affected Bdnf, the glucocorticoid-responsive genes Nr4a1, Gadd45β, the co-chaperone Fkbp5 as well as glutamatergic and GABAergic gene expression markers including the enzyme Gad67, the vesicular GABA transporter, and the vesicular glutamate transporter genes. Our results suggest that exposure of SERT+/- rats to neonatal TS can normalize their phenotype in adulthood and that TS per se alters the expression of plasticity and stress-related genes in the basolateral amygdala. These findings demonstrate the potential effect of a supportive stimulus in SERT rodents, which are more susceptible to develop psychiatric disorders.

Project description:The bed nucleus of the stria terminalis (BNST) plays a critical role in regulating the behavioral response to stress. Stressors that activate the BNST also activate serotonergic (5-HT) systems. Hence, maladaptive changes of 5-HT receptor expression may contribute to stress-induced anxiety disorders. The BNST contains three neuronal types, Type I-III neurons. However, little is known about 5-HT receptor subtypes mRNA expression in these neurons, or whether it can be modulated by stress. Whole-cell patch clamp recording from Type I-III neurons was used in conjunction with single cell reverse transcriptase polymerase chain reaction (RT-PCR) to characterize 5-HT receptor mRNA expression, and examine the effects of stress on this expression. We report that Type I neurons expressed mRNA transcripts predominantly for 5-HT(1A) and 5-HT(7) receptors. Type II neurons expressed transcripts for every 5-HT receptor except the 5-HT(2C) receptor. Type II neurons were divided into three sub-populations: Type IIA in which transcripts for 5-HT(3) and 5-HT(7) receptors predominate, Type IIB that mainly express 5-HT(1B) and 5-HT(4) receptor transcripts, and Type IIC in which transcripts for 5-HT(1A) and 5-HT(2A) receptors predominate. Type III neurons were also subdivided into two sub-populations; one that predominantly expressed transcripts for 5-HT(1A), 5-HT(1B) and 5-HT(2A) receptors, and another that mainly expressed transcripts for 5-HT(2C) receptor. Unpredictable shock stress (USS) caused a long-lasting increase in anxiety-like behavior, and a concomitant decrease in 5-HT(1A) transcript expression in Type I-III neurons, as well as an up-regulation of a transcriptional repressor of 5-HT(1A) gene expression, deformed epidermal autoregulatory factor 1 (Deaf-1). Significantly USS decreased 5-HT(1A) protein level, and increased the level of Deaf-1. USS also increased 5-HT(1B) transcript expression in Type III neurons, as well as 5-HT(7) expression in Type I and II neurons. These data suggest that cell type-specific disruption of 5-HT receptor expression in BNST(ALG) neurons may contribute to stress-induced anxiety disorders.

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Unpredictable neonatal stress enhances adult anxiety and alters amygdala gene expression related to serotonin and GABA.

Publications

Unpredictable neonatal stress enhances adult anxiety and alters amygdala gene expression related to serotonin and GABA.

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