Impact of individual differences in glucocorticoid adaptation to stress on behavior, neurophysiology and metabolism

The stress system is a key modulator of homeostasis and allows organisms to adapt to environmental changes. Proper survival is dependent on the appropriate stress response, for example initiating food (energy) intake or provoking physical reaction. However, long-term activity of the stress system is related to cardiovascular diseases, metabolic syndromes as well as accelerated aging and cognitive impairments. In order to assess the impacts of stress regulation on cardiac, metabolic and aging health processes, we used lines of rats selected for their differential glucocorticoid responsiveness to stress during juvenile period, in the different experiments presented here. The three lines of rats showed low, intermediate or high response to stress and elicited differences in biobehavioral phenotypes. Cardiovascular diseases are highly exacerbated by stress exposure and autonomic imbalance. Reduced vagal modulation has been related to a lower stress flexibility and deleterious effects on cardiac health. In a first study, we investigated the autonomic nervous system modulation of heart rate in the three lines of rats (differing in their responsiveness to stress). Electrocardiographic recordings were performed at rest and following autonomic pharmacological manipulations. Rats with intermediate reactivity to stress had a higher resting parasympathetic (vagal) modulation and a reduced heart rate compared to rats with low or high stress responses. Furthermore, pharmacological treatments showed that the sympathetic regulation of the heart was not impaired in rats with low and high responsiveness to stress. Stress can affect social interactions and, in return, social interactions can be the cause of critical stress. Furthermore, since the stress system is related to key metabolic mediators, we investigated in a second study, the general metabolism of rats from the three lines. Moreover, we paired rats from the different lines together, in mixed-line dyads, and we evaluated the differences in social interactions and the long-term effects of mixed-line pairing on metabolism. We used indirect calorimetry and mitochondrial respirometry to measure energy expenditure and mitochondrial function. We observed that the selection for differences in glucocorticoid responsiveness induced constitutive differences in energy expenditure and fuel use. Moreover, we showed that the biobehavioral phenotypes affected the social interactions between the different lines. Finally, long-term mixed-line pairing affected global and central metabolism of the rats, with rats from the low and intermediate responsive lines being more susceptible to changes. In a final experiment, we studied the interaction of two risk factors for cognitive decline, the secretion of corticosterone and aging. Indeed, dysfunctions of the stress system contribute and facilitate aging and increased glucocorticoids induce cognitive alterations. We assessed anxiety, stress responsiveness, coping-style and cognitive functions in a Morris water-maze at early-aging. Results indicated that the phenotype of the lines were stable throughout life and that learning, swimming strategies and reversal ability were different between the lines. Overall, we showed that this model is suitable to study the systems related to stress regulation. Future research may use this animal model in order to investigate further the relationship between opposite stress regulation and health

The link between aberrant hypothalamic-pituitary-adrenal axis activity during development and the emergence of aggression-Animal studies

Aggressive behavior is not uniform, including proactive and reactive forms of aggression. Aberrant functioning of the hypothalamic-pituitary-adrenal (HPA) axis is frequently associated with abnormal aggression. Here, we review the rodent literature in order to assess whether developmental abnormalities in the HPA axis can be causally linked with the emergence of abnormal aggression. We examine studies that involve genetic models and life challenges (e.g., early life stress, drug exposure) that course with developmental alterations in the HPA axis. Although the lack of systematic studies hinders development of an integrated model, existing evidence supports a U-shaped function regarding differences in HPA axis functioning during development and the emergence of aggressive phenotypes. Thus, developmentally low or high HPA axis reactivity are typically found to be aligned with the emergence of aggressive phenotypes; however, existing information is insufficient to causally link divergent HPA axis aberration with specific types of aggression. Progress in this field is needed to support interventions in children aimed at ameliorating social dysfunctions associated with aberrations in HPA axis functio

Constitutive differences in glucocorticoid responsiveness are related to divergent spatial information processing abilities

The stress response facilitates survival through adaptation and is intimately related to cognitive processes. The Morris water maze task probes spatial learning and memory in rodents and glucocorticoids (i.e. corticosterone (CORT) in rats) have been suggested to elicit a facilitating action on memory formation. Moreover, the early aging period (around 16-18 months of age) is susceptible to stress- and glucocorticoid-mediated acceleration of cognitive decline. In this study, we tested three lines of rats selectively bred according to their individual differences in CORT responsiveness to repeated stress exposure during juvenility. We investigated whether endogenous differences in glucocorticoid responses influenced spatial learning, long-term memory, and reversal learning abilities in a Morris water maze task at early aging. Additionally, we assessed the quality of the different swimming strategies of the rats. Our results indicate that rats with differential CORT responsiveness exhibit similar spatial learning abilities but different long-term memory retention and reversal learning. Specifically, the high CORT responding line had a better long-term spatial memory, while the low CORT responding line was impaired for both long-term retention and reversal learning. Our modeling analysis of performance strategies revealed further important line-related differences. Therefore, our findings support the view that individuals with high CORT responsiveness would form stronger long-term memories to navigate in stressful environments. Conversely, individuals with low CORT responsiveness would be impaired at different phases of spatial learning and memory. LAY SUMMARY Rats selected for different glucocorticoid responses to stress show differences in spatial learning and cognition. While the high responding animals have a better long-term spatial memory retention, the low responding rats have an inferior spatial memory and impaired reversal learning abilities

The impact of C-Tactile Low threshold mechanoreceptors on affective touch and social interactions in mice.

Affective touch is necessary for proper neurodevelopment and sociability. However, it is still unclear how the neurons innervating the skin detect affective and social behaviours. To clarify this matter, we targeted a specific population of somatosensory neurons in mice, named C-low threshold mechanoreceptors (C-LTMRs), that appears particularly well suited physiologically and anatomically to perceive affective and social touch but whose contribution to these processes has not yet been resolved. Our observations revealed that C-LTMRs functional deficiency from birth induced social isolation and reduced tactile interactions in adults. Conversely, transient increase in C-LTMRs excitability in adults using chemogenetics was rewarding, temporally promoted touch seeking behaviours and thus had pro-social effects on group dynamics. This work provides the first empirical evidence that specific peripheral inputs alone can drive complex social behaviour, demonstrating the existence of a specialised neuronal circuit originating from the skin wired to promote interaction with other individuals

Low vagal tone in two rat models of psychopathology involving high or low corticosterone stress responses

The two stress-responsive physiological systems, autonomic nervous system (ANS) and hypothalamus-pituitary-adrenal (HPA) axis exert complementary and interrelated actions in the organism. Individuals that suffer stress-related psychopathologies frequently present simultaneous alterations –i.e., either low or high- responsiveness– in both systems. However, there is scarce evidence establishing whether a priori alterations in these systems –i.e., independent of previous stress exposure– may predispose to the development of psychopathologies possibly due to the lack of animal models simultaneously involving aberrant HPA and SNS responses. In this study, we describe two animal models selectively bred according to their differential (either high, ‘High’ or low, ‘Low’) glucocorticoid responsiveness to stress, in comparison to a third line of rats that displays intermediate (‘Inter’) glucocorticoid responses. The two extreme lines may be considered distinct models of psychopathology; the High line representing a model of constitutive mood alterations while the Low line a model of vulnerability to develop stress-induced psychopathologies. We recorded the electrocardiogram in rats from the three lines and quantified heart rate variability and vagal tone indexes during rest and stress challenges. Rats from both High and Low lines displayed higher heart rate and lower basal vagal tone than the Inter group, both at resting and following stress exposure. Specific pharmacological manipulations probing the relative contribution of sympathetic and parasympathetic components on HR modulation confirmed a relative lower vagal tone in High and Low lines and discarded differences in the sympathetic regulation of heart rate between the lines. Therefore, the two genetically-selected High and Low glucocorticoid rat lines emerge as two valuable preclinical models of psychopathology involving two key risk factors for psychiatric and cardiovascular disorders, namely dysregulations in the HPA axis and cardiac vagal functioning

Experience and activity-dependent control of glucocorticoid receptors during the stress response in large-scale brain networks

International audienceThe diversity of actions of the glucocorticoid stress hormones among individuals and within organs, tissues and cells is shaped by age, gender, genetics, metabolism, and the quantity of exposure. However, such factors cannot explain the heterogeneity of responses in the brain within cells of the same lineage, or similar tissue environment, or in the same individual. Here, we argue that the stress response is continuously updated by synchronized neural activity on large-scale brain networks. This occurs at the molecular, cellular and behavioral levels by crosstalk communication between activity-dependent and glucocorticoid signaling pathways, which updates the diversity of responses based on prior experience. Such a Bayesian process determines adaptation to the demands of the body and external world. We propose a framework for understanding how the diversity of glucocorticoid actions throughout brain networks is essential for supporting optimal health, while its disruption may contribute to the pathophysiology of stress-related disorders, such as major depression, and resistance to therapeutic treatments

Low empathy-like behaviour in male mice associates with impaired sociability, emotional memory, physiological stress reactivity and variations in neurobiological regulations.

Deficits in empathy have been proposed to constitute a hallmark of several psychiatric disturbances like conduct disorder, antisocial and narcissistic personality disorders. Limited sensitivity to punishment, shallow or deficient affect and reduced physiological reactivity to environmental stressors have been often reported to co-occur with limited empathy and contribute to the onset of antisocial phenotypes. Empathy in its simplest form (i.e. emotional contagion) is addressed in preclinical models through the evaluation of the social transmission of emotional states: mice exposed to a painful stimulus display a higher response if in the presence of a familiar individual experiencing a higher degree of discomfort, than in isolation. In the present study, we investigated whether a reduction of emotional contagion can be considered a predictor of reduced sociality, sensitivity to punishment and physiological stress reactivity. To this aim, we first evaluated emotional contagion in a group of Balb/cJ mice and then discretised their values in four quartiles. The upper (i.e. Emotional Contagion Prone, ECP) and the lower (i.e. Emotional Contagion Resistant, ECR) quartiles constituted the experimental groups. Our results indicate that mice in the lower quartile are characterized by reduced sociability, impaired memory of negative events and dampened hypothalamic-pituitary-adrenocortical reactivity to external stressors. Furthermore, in the absence of changes in oxytocin receptor density, we show that these mice exhibit elevated concentrations of oxytocin and vasopressin and reduced density of BDNF receptors in behaviourally-relevant brain areas. Thus, not only do present results translate to the preclinical investigation of psychiatric disturbances, but also they can contribute to the study of emotional contagion in terms of its adaptive significance

The effects of extrinsic stress on somatic markers and behavior are dependent on animal housing conditions

Properties of the environment play an important role in animal wellbeing and may modulate the effects of external threats. Whereas stressors can affect emotion and impair cognition, environmental enrichment may prevent the occurrence of such negative sequelae. Animals exposed to semi-natural group-housing experience a complex environment; whereas environmental enrichment might protect against stressors, a social and environmental enrichment (SEE) could entail aggressive inter-male encounters with additive stress effects. In the present study, we investigated the effects of exposure to external stressors, footshocks and forced swimming, on adrenal- and bodyweight as well as on behavior in rats housed under SEE or standard, non-enriched environment (NEE), conditions. We found that SEE reduced the anxiogenic effects of stress. Moreover, SEE improved the performance of an operant task and prevented the increase in impulsive behavior produced by external stressors on NEE animals. Whereas these findings are indicative of stress-buffering effects of SEE, adrenal weights were increased while total body weights were decreased in SEE rats, suggesting that SEE may simultaneously exacerbate physiological measurements of stress. Finally, in the SEE, total aggressive behaviors and body wounds were paradoxically reduced in animals that received external stressors in comparison to non-stressed controls. The consequences of the external stressors applied here are not uniform, varying according to the housing condition and the outcome considered

Theoretical rationale behind the selection of BALB/cJ mice as study subjects.

<p>Based on literature data indicating that BALB/cJ mice exhibit very low levels of social behaviour and on the hypothetical association between social behaviour and emotional contagion, we selected the upper and lower quartiles of BALB/cJ mice as our study population. The full line indicates the theoretical distribution of emotional contagion in a heterogeneous population of different mouse strains; the dashed line represents the theoretical distribution of BALB/cJ mice and the shaded rectangles represent our study population characterised by emotional contagion resistant (ECR; left rectangle) and prone (ECP; right rectangle) populations. Importantly whilst emotional contagion resistant theoretically represent an extreme population, emotional contagion prone subjects shall locate around the average of the general population.</p

Behavioural results and plasma corticosterone profile following restraint stress.

<p><b>(a) Identification of subgroups based on time spent in paw-licking behaviour.</b> Paw-licking behaviour (s) scored in the emotional contagion test by mice belonging to the lower (25%), intermediate (50%) and upper quartiles (25%). The former and the latter constituted, respectively, the emotional contagion resistant (ECR) and the emotional contagion prone (ECP) subgroups. Mice whose values were comprised in the two intermediate quartiles (25% below and 25% above the median) were excluded from further analyses. <b>(b) Social behaviour.</b> Affiliative behaviours scored in the resident-intruder test by mice belonging to ECR and ECP subgroups. Data are expressed as seconds out of 10-min testing. * p < 0.05, ECR vs ECP. <b>(c) Plasma corticosterone profile.</b> Plasma corticosterone concentrations before a 25-min restraint stress (t0), immediately after (t25) and 35, 95 and 155 minutes later (t60, t120, t180). <b>(inset)</b> Comparison for the area under the curve (AUC) response, as a measure of corticosterone release in response to restraint stress, between mice belonging to ECR and ECP subgroups. * p < 0.05, ECR vs ECP. <b>(d) Emotional memory in the cued fear-conditioning test.</b> Comparison of time spent in freezing (in the cued fear-conditioning test) between subjects belonging to ECR and ECP subgroups. Data are expressed as seconds out of 10-min testing. * p < 0.05, ECR vs ECP.</p