Altered metabolic activity in the developing brain of rats predisposed to high versus low depression-like behavior

Abstract

Individual differences in human temperament can increase risk for psychiatric disorders like depression and anxiety. Our laboratory utilized a rat model of temperamental differences to assess neurodevelopmental factors underlying emotional behavior differences. Rats selectively bred for low novelty exploration (Low Responders, LR) display high levels of anxiety- and depression-like behavior compared to High Novelty Responder (HR) rats. Using transcriptome profiling, the present study uncovered vast gene expression differences in the early postnatal HR versus LR limbic brain, including changes in genes involved in cellular metabolism. These data led us to hypothesize that rats prone to high (versus low) anxiety/depression-like behavior exhibit distinct patterns of brain metabolism during the first weeks of life, which may reflect disparate patterns of synaptogenesis and brain circuit development. Thus, in a second experiment we examined activity of Cytochrome C Oxidase (COX), an enzyme responsible for ATP production and a correlate of metabolic activity, to explore functional energetic differences in HR/LR early postnatal brain. We found that HR rats display higher COX activity in the amygdala and specific hippocampal subregions compared to LRs during the first 2 weeks of life. Correlational analysis examining COX levels across several brain regions and multiple early postnatal time points suggested desynchronization in the developmental timeline of the limbic HR versus LR brain during the first two postnatal weeks. These early divergent COX activity levels may reflect altered circuitry or synaptic activity in the early postnatal HR/LR brain, which could contribute to the emergence of their distinct behavioral phenotypes.

Genetic predisposition to high anxiety- and depression-like behavior coincides with diminished DNA methylation in the adult rat amygdala

“…A pivotal question now is: are DNA methylation differences present in adulthood and, if so, what roles do they play in shaping the HR/LR phenotypes? Moreover, although prior work indicates that hippocampal differences contribute to the disparate HR/LR behavioral phenotypes [35,40–43], our recent data point to differences in the amygdala as well [36, 44]. The amygdala is well known for its roles in regulating novelty detection, emotion, and fear responses [45, 46], and clinical and basic animal studies alike indicate that individual differences in temperament correspond to distinct structure and function of the amygdala [47–52].…”

“…Based on the dramatic HR/LR transcriptome differences in the early postnatal amygdala and hippocampus [35, 44], we sought to determine whether these alterations exist into adulthood. We therefore performed a transcriptome profiling study in the adult HR and LR amygdala.…”

“…Because epigenetic mechanisms (such as DNA methylation) simultaneously regulate myriad genes, a perturbation of a regulatory system such as DNA methylation could induce many gene expression changes and downstream biobehavioral effects. Recent work in our laboratory identified DNA methylation differences as well as widespread transcriptome differences in the limbic brains of LR/HR rats during early postnatal development [38, 39, 44]. We hypothesized that these differences would also occur in adulthood and that HR/LR DNA methylation differences represent a molecular mechanism that drives their disparate emotional behavior phenotypes.…”

“…Given our previous observations of disparate gene expression and DNA methylation patterns in the early postnatal HR versus LR amygdala [38, 39, 44], we hypothesized that these differences would also occur during adulthood. To test this, we first performed a transcriptome profiling experiment in the amygdala of adult HR versus LR rats.…”

Differential stress induced c-Fos expression and identification of region-specific miRNA-mRNA networks in the dorsal raphe and amygdala of high-responder/low-responder rats

“…Adult male HR/LR rats were obtained from the 4 th –6 th generations of our in-house colony [48]. Rats were pair-housed in a 12:12 light-dark cycle in a temperature- and humidity-controlled environment with food and water available ad libitum .…”