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Developmental underpinnings of differences in rodent novelty-seeking and emotional reactivity

ABSTRACT: Innate differences in human temperament strongly influence how individuals cope with stress and predispose for specific types of psychopathology. The present study examines the developing brain in an animal model of temperamental differences to understand how altered neurodevelopment may engender differences in emotional reactivity that are stable throughout the animal’s life. We utilize selectively-bred High Responder (bHR) and Low Responder (bLR) rats that exhibit dramatic emotional behavior differences, with bHRs exhibiting exaggerated novelty-exploration, aggression, impulsivity and drug self-administration, and bLRs showing marked behavioral inhibition, exaggerated anxiety- and depressive-like behavior. Using Affymetrix microarrays, we assessed bLR/bHR gene expression in the developing brain on postnatal days (P)7, 14, and 21, focusing on the hippocampus and nucleus accumbens, two regions related to emotionality and known to differ in adult bLR/bHR rats. We found dramatic bLR/bHR gene expression differences in the P7 and P14 hippocampus, with minimal differences in the nucleus accumbens. Some of the most profound differences involved genes critical for neurodevelopment and synaptogenesis. Stereological studies evaluated hippocampal structure in developing bHR/bLR pups, revealing enhanced hippocampal volume and cell proliferation in bLR animals. Finally, behavioral studies showed that the bHR/bLR behavioral phenotypes emerge very early in life, with exploratory differences apparent at P16 and anxiety differences present by P25. Together these data point to specific brain regions and critical periods when the bHR/bLR phenotypes begin to diverge, which may eventually allow us to test possible therapeutic interventions to normalize extreme phenotypes (e.g. the anxiety-prone nature of bLRs or drug addiction proclivity of bHRs).

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE29552 | GEO | 2011/12/31

SECONDARY ACCESSION(S): PRJNA141317

REPOSITORIES: GEO

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Project description:Innate differences in human temperament strongly influence how individuals cope with stress and predispose for specific types of psychopathology. The present study examines the developing brain in an animal model of temperamental differences to understand how altered neurodevelopment may engender differences in emotional reactivity that are stable throughout the animal’s life. We utilize selectively-bred High Responder (bHR) and Low Responder (bLR) rats that exhibit dramatic emotional behavior differences, with bHRs exhibiting exaggerated novelty-exploration, aggression, impulsivity and drug self-administration, and bLRs showing marked behavioral inhibition, exaggerated anxiety- and depressive-like behavior. Using Affymetrix microarrays, we assessed bLR/bHR gene expression in the developing brain on postnatal days (P)7, 14, and 21, focusing on the hippocampus and nucleus accumbens, two regions related to emotionality and known to differ in adult bLR/bHR rats. We found dramatic bLR/bHR gene expression differences in the P7 and P14 hippocampus, with minimal differences in the nucleus accumbens. Some of the most profound differences involved genes critical for neurodevelopment and synaptogenesis. Stereological studies evaluated hippocampal structure in developing bHR/bLR pups, revealing enhanced hippocampal volume and cell proliferation in bLR animals. Finally, behavioral studies showed that the bHR/bLR behavioral phenotypes emerge very early in life, with exploratory differences apparent at P16 and anxiety differences present by P25. Together these data point to specific brain regions and critical periods when the bHR/bLR phenotypes begin to diverge, which may eventually allow us to test possible therapeutic interventions to normalize extreme phenotypes (e.g. the anxiety-prone nature of bLRs or drug addiction proclivity of bHRs). 2x2x3 factorial design with N=6 per group. Factors as follows: 1) Two selectively bred strains of rats (derived from an original Sprague Dawley population) termed High Responders (HR) and Low Responders (LR), 2) Two brain regions, Hippocampus (HPC) and Nucleus Accumbens (N.Acc), 3) Three developmental timepoints, specifically postnatal days 7 (P7), 14 (P14) and 21 (P21).

Project description:The strong pattern of comorbidity amongst psychiatric disorders is believed to be generated by a spectrum of latent liability, arising from a complex interplay of genetic risk and environmental factors, such as stress and childhood adversity. At one end of this spectrum are internalizing disorders, which are associated with neuroticism, anxiety, and depression. At the other end of the spectrum are externalizing disorders, which are associated with risk-taking and novelty-seeking, as seen in mania, substance abuse, and impulse-control disorders. We model the genetic contributions underlying both extremes of this spectrum by selectively breeding rats that react differently to a novel environment. “Bred high responder” (bHR) rats are highly exploratory with a disinhibited, novelty-seeking temperament, including hyperactivity, aggression, and drug-seeking. “Bred low responder” (bLR) rats are highly-inhibited, exhibiting reduced locomotor activity and anxious and depressive-like behavior. These behavioral propensities are robust and stable, beginning early in development similar to temperament in humans. This dataset was part of a larger RNA-Sequencing study examining gene expression in the bHR/bLR hippocampus, a region critical for emotional regulation. The original study compared repeated injections of either antidepressant medication (fluoxetine or desipramine) or vehicle (VEH=1:1 saline and water) solution in bHR and bLR rats (14 days of intraperitoneal injections - P78-P92, 1 per day) under either standard laboratory housing conditions or chronic variable stress. This upload includes only the data from the control subjects: generation F43 adult male bHR VEH rats and bLR VEH rats housed in standard conditions (n=5/group). Prior to sacrifice, at age P92, the rats underwent social interaction testing after 15 minutes of exposure to an anxiogenic environment (the elevated plus maze). The results from the social interaction testing are provided here along with the gene expression data.

Project description:Stress is a major influence on mental health status; the ways that individuals respond to or copes with stressors determine whether they are negatively affected in the future. Stress responses are established by an interplay between genetics, environment, and life experiences. Psychosocial stress is particularly impactful during adolescence, a critical period for the development of mood disorders. In this study we compared two established, selectively-bred Sprague Dawley rat lines, the “internalizing” bred Low Responder (bLR) line versus the “externalizing” bred High Responder (bHR) line, to investigate how genetic temperament and adolescent environment impact future responses to social interactions and psychosocial stress, and how these determinants of stress response interact. Animals were exposed to social and environmental enrichment in adolescence prior to experiencing social defeat and were then assessed for social interaction and anxiety-like behavior. Adolescent enrichment caused bLR rats to display less social avoidance, more social interaction, less submission during defeat, and resilience to the prolonged effects of social stress on corticosterone, while enrichment caused bHR animals to show greater aggression during defeat and during a neutral social encounter, and decreased anxiety-like behavior. To gain insight into the development of social resilience in the anxious phenotype bLRs, RNA-seq was conducted on the hippocampus and nucleus accumbens, two brain regions that mediate stress regulation and social behavior. Gene sets previously associated with stress, social behavior, aggression and exploratory activity were enriched with differential expression in both regions, with a particularly large effect on gene sets that regulate social behaviors. These findings provide further evidence that adolescent enrichment can serve as an inoculating experience against future stressors. The ability to induce social resilience in a usually anxious line of animals by manipulating their environment has translational implications, as it underscores the feasibility of intervention strategies targeted at genetically vulnerable adolescent populations.

Project description:Adolescence is a critical period in cognitive and emotional development, characterized by high levels of social interaction and increases in risk-taking behavior including binge drinking. Adolescent exposure to social stress and binge ethanol have individually been associated with the development of social, emotional, and cognitive deficits, as well as increased risk for alcohol use disorder. Disruption of cortical development by early life social stress and/or binge drinking may partly underlie these enduring emotional, cognitive, and behavioral effects. The study goal is to implement a novel neighbor housing environment to identify the effects of adolescent neighbor housing and/or binge ethanol drinking on (1) a battery of emotional and cognitive tasks (2) adult ethanol drinking behavior, and (3) the nucleus accumbens and prefrontal cortex transcriptome. Adolescent male and female C57BL/6J mice were single or neighbor housed with or without access to intermittent ethanol. One cohort underwent behavioral testing during adulthood to determine social preference, expression of anxiety-like behavior, cognitive performance, and patterns of ethanol intake. The second cohort was sacrificed in late adolescence and brain tissue was used for transcriptomics analysis. As adults, single housed mice displayed decreased social interaction, deficits in the novel object recognition task, and increased anxiety-like behavior, relative to neighbor-housed mice. There was no effect of housing condition on adolescent or adult ethanol consumption. Adolescent ethanol exposure did not alter adult ethanol intake. Transcriptomics analysis revealed that adolescent housing condition and ethanol exposure resulted in differential expression of genes related to synaptic plasticity in the nucleus accumbens and genes related to methylation, the extracellular matrix and inflammation in the prefrontal cortex. The behavioral results indicate that social interaction during adolescence via the neighbor housing model may protect against emotional, social, and cognitive deficits. In addition, the transcriptomics results suggest that these behavioral alterations may be mediated in part by dysregulation of transcription in the frontal cortex or the nucleus accumbens

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Developmental underpinnings of differences in rodent novelty-seeking and emotional reactivity

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