Forced swim test induces divergent global transcriptomic alterations in the hippocampus of high versus low novelty-seeker rats

Abstract

BackgroundMany neuropsychiatric disorders, including stress-related mood disorders, are complex multi-parametric syndromes. Susceptibility to stress and depression is individually different. The best animal model of individual differences that can be used to study the neurobiology of affect regards spontaneous reactions to novelty. Experimentally, when naive rats are exposed to the stress of a novel environment, they display a highly variable exploratory activity and are classified as high or low responders (HR or LR, respectively). Importantly, HR and LR rats do not seem to exhibit a substantial differentiation in relation to their ‘depressive-like’ status in the forced swim test (FST), a widely used animal model of ‘behavioral despair’. In the present study, we investigated whether FST exposure would be accompanied by phenotype-dependent differences in hippocampal gene expression in HR and LR rats.ResultsHR and LR rats present a distinct behavioral pattern in the pre-test session but develop comparable depressive-like status in the second FST session. At 24 h following the second FST session, HR and LR rats (stressed and unstressed controls) were sacrificed and hippocampal samples were independently analyzed on whole rat genome Illumina arrays. Functional analysis into pathways and networks was performed using Ingenuity Pathway Analysis (IPA) software. Notably, hippocampal gene expression signatures between HR and LR rats were markedly divergent, despite their comparable depressive-like status in the FST. These molecular differences are reflected in both the extent of transcriptional remodeling (number of significantly changed genes) and the types of molecular pathways affected following FST exposure. A markedly higher number of genes (i.e., 2.28-fold) were statistically significantly changed following FST in LR rats, as compared to their HR counterparts. Notably, genes associated with neurogenesis and synaptic plasticity were induced in the hippocampus of LR rats in response to FST, whereas in HR rats, FST induced pathways directly or indirectly associated with induction of apoptotic mechanisms.ConclusionsThe markedly divergent gene expression signatures exposed herein support the notion that the hippocampus of HR and LR rats undergoes distinct transcriptional remodeling in response to the same stress regimen, thus yielding a different FST-related ‘endophenotype’, despite the seemingly similar depressive-like phenotype.

Anti-Apoptotic Protein Bcl-xL Expression in the Midbrain Raphe Region Is Sensitive to Stress and Glucocorticoids

“…The up-regulation occurred together with the activation of anti-apoptotic protein expression. Interestingly, in addition to the midbrain raphe nuclei, the main serotonergic region of the brain [ 7 , 63 ], similar interrelation between the enzyme gene expression and cell-viability processes were found in the hippocampus [ 64 ]. In this study, using a whole transcriptome analysis, it was found that rats with low responsiveness to stress of a novel environment had increased hippocampal expression of tph2 as well as of genes related to neuroprotection at 24 h following the second forced swim exposure.…”

Sex-Specific Diurnal Immobility Induced by Forced Swim Test in Wild Type and Clock Gene Deficient Mice

“…FST is now widely used both in basic research and in pharmaceutical screens for potential antidepressant treatments due to its high predictive validity [ 12 ]. In addition, “behavioral despair” just as increased immobility and decreased swimming or climbing in FST is, by some, considered an indication of “depressive-like” symptomatology [ 13 ]. To investigate the roles of core clock genes in the rhythm of response to FST, we characterized the circadian patterns of immobility behavior in wild type, Clock Δ19 , Per1 ( Per1 Brdm1 ) and Per2 ( Per2 Brdm1 ) mutant mice at 4 h intervals.…”

Exposure to Prenatal Stress Is Associated With an Excitatory/Inhibitory Imbalance in Rat Prefrontal Cortex and Amygdala and an Increased Risk for Emotional Dysregulation

“…In addition, choosing another behavioral readout for exploring the depressive-like dimension, such as the traditional forced swim test (FST), could have unmasked differences between control and PNS animals. While on the one hand this may be true, on the other hand, the FST could have masked the molecular alterations that we found at baseline, as it is known that exposure to a session of forced swim potently activates players and circuits that are otherwise silenced under resting conditions (Reed et al, 2012;Warden et al, 2012;Pitychoutis et al, 2014).…”