Genetic Liability for Internalizing Versus Externalizing Behavior Manifests in the Developing and Adult Hippocampus: Insight From a Meta-analysis of Transcriptional Profiling Studies in a Selectively Bred Rat Model

Abstract

Background: For over 16 years, we have selectively bred rats to show either high or low levels of exploratory activity within a novel environment. These "bred High Responder" (bHR) and "bred Low Responder" (bLR) rats serve as a model for temperamental extremes, exhibiting large differences in many internalizing and externalizing behaviors relevant to mood and substance abuse disorders. Methods:Our study elucidated persistent differences in gene expression related to bHR/bLR phenotype across development and adulthood in the hippocampus, a region critical for emotional regulation. We meta-analyzed eight transcriptional profiling datasets (microarray, RNA-Seq) spanning 43 generations of selective breeding (adult: n=46, P7: n=22, P14: n=49, P21: n=21; all male). We cross-referenced these results with exome sequencing performed on our colony to pinpoint candidates likely to mediate the effect of selective breeding on behavioral phenotype.Results: Genetic and transcriptional profiling results converged to implicate two genes with previous associations with metabolism and mood: Thyrotropin releasing hormone receptor and Uncoupling protein 2. Our results also highlighted bHR/bLR functional differences in the hippocampus, including a network essential for neurodevelopmental programming, proliferation, and differentiation, containing hub genes Bone morphogenetic protein 4 and Marker of proliferation ki-67. Finally, we observed differential expression related to microglial activation, which is important for synaptic pruning, including two genes within implicated chromosomal regions: Complement C1q A chain and Milk fat globule-EGF factor 8. Conclusion:These candidate genes and functional pathways have the capability to direct bHR/bLR rats along divergent developmental trajectories and promote a widely different reactivity to the environment..

Differences in microglia morphological profiles reflect divergent emotional temperaments: insights from a selective breeding model

“…Our first goal was to confirm and extend findings from our recent bHR/bLR meta-analysis showing differential expression of microglial signaling genes in hippocampus [ 25 ]. qPCR measured expression levels of multiple genes within the classical complement cascade, including cascade components C1q and C3 , and the receptor molecule cd11b (Fig.…”

“…In multiple laboratory assays, bLRs display increased anxiety- and depressive-like behaviors and reduced social exploration and proactive coping [ 3 ]. Several lines of evidence from our lab implicate the hippocampus as a critical brain region underlying bHR/bLR phenotypes [ 14 , 20 , 23 , 24 ], and a recent meta-analysis of transcriptional studies spanning multiple generations identified broadly divergent gene expression patterns within hippocampus [ 25 ]. Interestingly, microglia-related pathways emerged as one of the main functional candidates from this analysis, with bLR hippocampus exhibiting elevated expression of several key genes related to microglial activation and signaling [ 25 ].…”

“…Taken together, these studies suggest that microglia play a role in the pathophysiology of affective disorders, yet critical questions remain regarding how individual differences in microglia relate to underlying temperament. Given that our transcriptional profiling data indicated elevated microglial gene expression in naïve bLRs [ 25 ], we hypothesized that bLR phenotype may be due, at least in part, to a steady-state of microglia over-activation. To address this question, we administered minocycline and characterized its impact on the phenotypic behaviors of our bred lines.…”

Effects of Voluntary Running Wheel Exercise-Induced Extracellular Vesicles on Anxiety

“…Trhr encodes the receptor for thyrotropin-releasing hormone (TRH); TRH-R1 knockout mice exhibited increased anxiety- and depressive-like behaviors (Zeng et al, 2007 ). Low levels of exploratory activity in novel environment rats which are highly inhibited and anxious, depressive-like behavior expressed low Trhr level in dentate gyrus where neural proliferation within the hippocampus (Birt et al, 2021 ).…”

Data_Sheet_1.xlsx

“…Trhr encodes the receptor for thyrotropin-releasing hormone (TRH); TRH-R1 knockout mice exhibited increased anxietyand depressive-like behaviors (Zeng et al, 2007). Low levels of exploratory activity in novel environment rats which are highly inhibited and anxious, depressive-like behavior expressed low Trhr level in dentate gyrus where neural proliferation within the hippocampus (Birt et al, 2021).…”