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 remains unclear how the neurons innervating the skin detect affective and social behaviors. The C low-threshold mechanoreceptors (C-LTMRs), a specific population of somatosensory neurons in mice, appear particularly well suited, physiologically and anatomically, to perceive affective and social touch. However, their contribution to sociability has not been resolved yet. Our observations revealed that C-LTMR functional deficiency induced social isolation and reduced tactile interactions in adulthood. Conversely, transient increase in C-LTMR excitability in adults, using chemogenetics, was rewarding, promoted touch-seeking behaviors, and had prosocial influences on group dynamics. This work provides the first empirical evidence that specific peripheral inputs alone can drive complex social behaviors. It demonstrates the existence of a specialized neuronal circuit, originating in the skin, wired to promote interactions with other individuals.

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

The 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.

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.

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.

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 function.

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.

Urolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents.

The biological effects of urolithins remain poorly characterized, despite wide-spread human exposure via the dietary consumption of their metabolic precursors, the ellagitannins, which are found in the pomegranate fruit, as well as in nuts and berries. We identified urolithin A (UA) as a first-in-class natural compound that induces mitophagy both in vitro and in vivo following oral consumption. In C. elegans, UA prevented the accumulation of dysfunctional mitochondria with age and extended lifespan. Likewise, UA prolonged normal activity during aging in C. elegans, including mobility and pharyngeal pumping, while maintaining mitochondrial respiratory capacity. These effects translated to rodents, where UA improved exercise capacity in two different mouse models of age-related decline of muscle function, as well as in young rats. Our findings highlight the health benefits of urolithin A and its potential application in strategies to improve mitochondrial and muscle function.

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 socially-enriched environment(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 gland and body weights as well as on behavior in rats housed under SEE or standard, non-enriched environment (NEE), conditions. We found that SEEs reduced the anxiogenic effects of stress. Moreover, SEEs improved the performance in 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 SEEs, adrenal gland weights were increased while total body weights were decreased in SEE rats, suggesting that SEEs 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.