Exposure to chronic stress is a leading pre-disposing factor for several neuropsychiatric disorders as it often leads to maladaptive responses. The response to stressful events is heterogeneous, underpinning a wide spectrum of distinct changes amongst stress-exposed individuals'. Several factors can underlie a different perception to stressors and the setting of distinct coping strategies that will lead to individual differences on the susceptibility/resistance to stress. Beyond the factors related to the stressor itself, such as intensity, duration or predictability, there are factors intrinsic to the individuals that are relevant to shape the stress response, such as age, sex and genetics. In this review, we examine the contribution of such intrinsic factors to the modulation of the stress response based on experimental rodent models of response to stress and discuss to what extent that knowledge can be potentially translated to humans.

Alterations in hormone levels during aging impact on cognition and mood. Serum concentration levels of testosterone (TT), estradiol (E2), follicle-stimulating hormone (FSH), luteinizing hormone (LH), dehydroepiandrosterone sulfate (DHEAS) and prolactin (PRL) were assessed in 120 community-dwellers (51+ years of age, males and females), in a cross-sectional approach. Performance clusters based on executive functioning (GENEXEC), memory (MEM), mood and well-being were obtained. In males, higher PRL levels associated with worse cognitive performance, lower well-being, and higher scores in depression scales, and lower E2 with poorer cognition and higher depressive mood. DHEAS positively associated with GENEXEC and MEM. Nutritional status significantly associated with PRL (positively) and with DHEAS (negatively). Findings indicate that besides the more exhaustively studied E2 and TT, variations in the levels of sex-related hormones such as PRL, FSH, LH and DHEAS are of interest for the mental health aging profile particularly in men.

Exposure to chronic stress leads to an array of anatomical, functional, and metabolic changes in the brain that play a key role in triggering psychiatric disorders such as depression. The hippocampus is particularly well known as a target of maladaptive responses to stress. To capture stress-induced changes in metabolic and functional connectivity in the hippocampus, stress-resistant (low-responders) or -susceptible (high-responders) rats exposed to a chronic unpredictable stress paradigm (categorized according to their hormonal and behavioral responses) were assessed by multimodal neuroimaging; the latter was achieved by using localized¹H MR spectroscopy and resting-state functional MRI (fMRI) at 11,7T data from stressed (n= 25) but also control (n= 15) male Wistar rats.Susceptible animals displayed increased GABA–glutamine (+19%) and glutamate–glutamine (+17%) ratios and decreased levels of macromolecules (−11%); these changes were positively correlated with plasma corticosterone levels. In addition, the neurotransmitter levels showed differential associations with functional connectivity between the hippocampus and the amygdala, the piriform cortex and thalamus between stress-resistant and -susceptible animals. Our observations are consistent with previously reported stress-induced metabolomic changes that suggest overall neurotransmitter dysfunction in the hippocampus. Their association with the fMRI data in this study reveals how local adjustments in neurochemistry relate to changes in the neurocircuitry of the hippocampus, with implications for its stress-associated dysfunctions.SIGNIFICANCE STATEMENTChronic stress disrupts brain homeostasis, which may increase the vulnerability of susceptible individuals to neuropsychiatric disorders such as depression. Characterization of the differences between stress-resistant and -susceptible individuals on the basis of noninvasive imaging tools, such as magnetic resonance spectroscopy (MRS) and magnetic resonance imaging (MRI), contributes to improved understanding of the mechanisms underpinning individual differences in vulnerability and can facilitate the design of new diagnostic and intervention strategies. Using a combined functional MRI/MRS approach, our results demonstrate that susceptible- and non-susceptible subjects show differential alterations in hippocampal GABA and glutamate metabolism that, in turn, associate with changes in functional connectivity.