With aging, incidence of severe stress‐related diseases increases. However, mechanisms, underlying individual vulnerability to stress and age‐related diseases are not clear. The goal of this review is to analyze finding from the recent literature on age‐related characteristics of the hypothalamic‐pituitary‐adrenal (HPA) axis associated with stress reactivity in animals that show behavioral signs of anxiety and depression under mild stress, and in human patients with anxiety disorders and depression with emphasis on the impact of the circadian rhythm and the negative feedback (...) mechanisms involved in the stress response. One can conclude that HPA axis reaction to psycho‐emotional stress, at least acute stress, increases in the aged individuals with anxiety and depression behavior. Elevated stress reactivity is associated with disruption of the circadian rhythm and the mineralocorticoid receptor‐mediated glucocorticoid negative feedback. The disordered function of the HPA axis in individuals with anxiety and depression behavior can contribute to aging‐related pathology. (shrink)

Background: Hypothalamic-pituitary-adrenal (HPA) system activation is adaptive in response to stress, and HPA dysregulation occurs in stress-related psychopathology. It is important to understand the mechanisms that modulate HPA output, yet few studies have addressed the neural circuitry associated with HPA regulation in primates and humans. Using high-resolution F-18-fluorodeoxyglucose positron emission tomography (FDG-PET) in rhesus monkeys, we assessed the relation between individual differences in brain activity and HPA function across multiple contexts that varied in stressfulness.

We recently described a novel form of stress‐associated bidirectional plasticity at GABA synapses onto hypothalamic parvocellular neuroendocrine cells (PNCs), the apex of the hypothalamus‐pituitary‐adrenal axis. This plasticity may contribute to neuroendocrine adaptation. However, this GABA synapse plasticity likely does not translate into a simple more and less of inhibition because the ionic driving force for Cl−, the primary charge carrier for GABAA receptors, is dynamic. Specifically, stress impairs a Cl− extrusion mechanism in PNCs. This not only renders the steady‐state GABA (...) response less hyperpolarizing but also makes PNCs susceptible to the activity‐dependent accumulation of Cl−. Accordingly, GABA synapse plasticity impacts both the robustness of GABA voltage response and dynamic Cl− loading, imposing nonlinear influences on PNC excitability during circuit activities. This theoretical consideration predicts roles for GABA transmission far more versatile than canonical inhibition. We propose potential impacts of GABA synapse plasticity on the experience‐dependent fine‐tuning of neuroendocrine stress responses. (shrink)

Human skin produces numerous neurohormones and neuropeptides. Recent evidence has shown that the neuroendocrine regulation of human skin biology also extends to keratins, the major structural components of epithelial cells. For example, thyrotropin‐releasing hormone, thyrotropin, opioids, prolactin, and cannabinoid receptor 1‐ligands profoundly modulate human keratin gene and protein expression in human epidermis and/or hair follicle epithelium in situ. Since selected keratins are now understood to exert important regulatory functions beyond mechanical stability, we argue that neuroendocrine pathways of keratin regulation are (...) important for maintaining skin and hair follicle homeostasis. This invites innovative neuroendocrine therapeutic interventions for skin disorders characterized by abnormal keratin expression, ranging from psoriasis to genodermatoses, and for promoting skin wound healing and hair growth. This strategy can be probed in simple, but instructive and readily available human skin and hair follicle organ culture assays as ideal models for exploring this new neuroendocrine frontier in translational epithelial biology. (shrink)

Human development has become particularly complex during the evolution. In this complexity, adolescence is an extremely important developmental stage. Adolescence is characterized by biological and social changes that create the prerequisites to psychopathological problems, including both substance and non-substance addictive behaviors. Central to the dynamics of the biological changes during adolescence are the synergy between sexual and neurophysiological development, which activates the motivational/emotional systems of Dominance/Submission. The latter are characterized by the interaction between the sexual hormones, the dopaminergic system and (...) the stress axis (HPA). The maturation of these motivational/emotional systems requires the integration with the phylogenetically more recent Attachment/CARE Systems, which primarily have governed the subject’s relationships until puberty. The integration of these systems is particularly complex in the human species, due to the evolution of the process of competition related to sexual selection: from a simple fight between two individuals (of the same genus and species) to a struggle for the acquisition of a position in rank and the competition between groups. The latter is an important evolutionary acquisition and believed to be the variable that has most contributed to enhancing the capacity for cooperation in the human species. The interaction between competition and cooperation, and between competition and attachment, characterizes the entire human relational and emotional structure and the unending work of integration to which the BrainMind is involved. The beginning of the integration of the aforementioned motivational/emotional systems is currently identified in the prepubertal period, during the juvenile stage, with the development of the Adrenarche—the so-called Adrenal Puberty. This latter stage is characterized by a low rate of release of androgens, the hormones released by the adrenal cortex, which activate the same behaviors as those observed in the PLAY system. The Adrenarche and the PLAY system are biological and functional prerequisites of adolescence, a period devoted to learning the difficult task of integrating the phylogenetically ancient Dominance/Submission Systems with the newer Attachment/CARE Systems. These systems accompany very different adaptive goals which can easily give rise to mutual conflict and can in turn make the balance of the BrainMind precarious and vulnerable to mental suffering. (shrink)

Patients suffering from chronic obstructive pulmonary diseases, frequently exhibit expiratory airflow limitation. We propose a mathematical model describing the mechanical behavior of the ventilated respiratory system. This model has to simulate applied positive end-expiratory pressure effects during expiration, a process used by clinicians to improve airflow. The proposed model consists of a nonlinear two-compartment system. One of the compartments represents the collapsible airways and mimics its dynamic compression, the other represents the lung and chest wall compartment. For all clinical conditions (...) tested, the mathematical model simulates the removal of expiratory airflow limitation at PEEP lower than 70–80% of intrinsic end-expiratory pressure, i.e. the end-expiratory alveolar pressure without PEEP. It also shows the presence of an optimal PEEP. The optimal PEEP contributes to decrease PAet from 7.4 ± 0.9 to 5.4 ± 0.9 hPa. This simplistic mathematical model gives a plausible explanation of the expiratory airflow limitation removal with PEEP and a rationale to the practice of PEEP application to airflow limited patients. (shrink)

BackgroundMental stress and imbalance of its two neural stress systems, the autonomic nervous system and the hypothalamic–pituitary–adrenal axis, are associated with chronic prostatitis/chronic pelvic pain syndrome and erectile dysfunction. However, the comprehensive analyses of psychological stress and stress systems are under-investigated, particularly in CP/CPPS patients complicated by lower urinary tract symptoms and ED.Materials and methodsParticipants were 95 patients in CP/CPPS+ED group, 290 patients in CP/CPPS group, 124 patients in ED group and 52 healthy men in control group. The National Institutes (...) of Health Chronic Prostatitis Symptom Index, the International Index of Erectile Function-5 and the International Prostate Symptom Score were used for assessing the disease severity of CP/CPPS, LUTS and ED. Psychometric self-report questionnaires including the Beck Anxiety Inventory, Perceived Stress Scale, Type A Personality Test and Symptom Checklist 90 were completed for distress from physical symptoms. Twenty-five subjects per group were randomly selected for further investigating the changes of the HPA axis and ANS. Saliva samples were taken on 3 consecutive days at 8 specific times with strict reference to time of morning awakening for evaluation of free cortisol. Heart rate variability as marker of the ANS was measured using 24 h electrocardiography, and time-and frequency-domain variables were analyzed.ResultsThe BAI and SCL-90 scores were significantly higher in the CP/CPPS+ED, CP/CPPS and ED groups compared with the control group. The PSS scores of both groups with ED were significantly higher than the control group. Compared with the CP/CPPS group, the differences of PSS, SCL-90 and TAPT scores were statistically significant in CP/CPPS+ED patients. The IPSS scores were shown to have significantly positive correlations with BAI, PSS and SCL-90 in the CP/CPPS patients. However, in all subjects, the IIEF-5 scores were shown to have significantly negative correlations with BAI, PSS, SCL-90 and quality of life score in NIH-CPSI. Cortisol awakening response parameters and diurnal cortisol levels did not significantly vary between the four groups. Time-dependent parameters of HRV also did not differ significantly across groups. In the frequency domain analysis, low frequency was significantly lower in ED patients when compared with CP/CPPS+ED patients and healthy controls, high frequency power was significantly higher in healthy controls compared to patients with ED, CP/CPPS and CP/CPPS+ED, and the CP/CPPS+ED group had significantly higher LF/HF ratio than the control group.ConclusionCP/CPPS and ED patients score exceedingly high on most psychosocial variables. The symptom scores of LUTS and ED positively correlate with the severity of psychological stress. Our findings also suggest that the ANS sympathovagal imbalance is associated with ED and LUTS in CP/CPPS, whereas HPA axis activity is not. (shrink)

The coronavirus disease 2019 pandemic led to various government-imposed limitations on social interaction and strict home confinement. Such involuntary social-distancing policies can exacerbate feelings of loneliness and alter emotional well-being. Dysregulation of the hypothalamic-pituitary-adrenocortical axis is a potential mechanism for loneliness’ deleterious health effects. In this study, we explored whether pre-pandemic diurnal cortisol output, a measure of HPA axis function, may predict the propensity to changes in loneliness during long-term COVID-19 home confinement and if extraversion would moderate this relationship. This (...) association has been explored by analysing the impact of COVID-19 pandemic and strict home confinement on social and emotional loneliness in 45 Spanish young adults. Diurnal cortisol levels were measured from five saliva samples obtained across a day just before the pandemic, and data about participants’ perceived loneliness, empathic state, extraversion, and prospective volunteering were obtained both before and during the confinement. Participants’ social and family loneliness increased during long-term strict home confinement, while prospective volunteering tendencies and extraversion decreased. Importantly, after adjusting for relevant confounders, moderation analyses revealed that in young adults with high pre-pandemic extraversion, a higher AUCG predicted a larger increase in social loneliness during confinement, while in individuals with low extraversion, AUCG was negatively related to change in loneliness. Our findings highlight the utility of pre-pandemic diurnal cortisol output in predicting the social impact of COVID-19 home confinement, presenting this hormone as a potential biomarker for a priori identification of at-risk groups during public health crises. (shrink)

Current empirical work suggests that early social experiences could have a substantial impact on the areas of the brain responsible for representation of the body. In this context, one aspect of functioning that may be particularly susceptible to social experiences is interoception. Interoceptive functioning has been linked to several areas of the brain which show protracted post-natal development, thus leaving a substantial window of opportunity for environmental input to impact the development of the interoceptive network. We first introduce a biopsychosocial (...) model of interoceptive development. In our proposed model of interoceptive development, attachment related processes are purported to affect the development of interoception by influencing the growth of neural architecture and by modifying functioning of the HPA axis. Further, the idea that patterns of caretaking affect children’s development of interoception is presented. This model explains both normatively developing interoception and accounts for instances in which dysfunctional attachment related processes can lead to either a hypersensitivity or a blunted awareness of bodily cues. Second, we report findings from two existing datasets showing significant relationships between attachment related processes and interoception. In the first study, looking at a sample of healthy young adults (n = 132, 66 males), we assessed self-reported interoceptive awareness and attachment style. We found relationships between aspects of interoception and attachment style such that avoidant individuals reported lower interoceptive functioning across several dimensions (r’s (130) = -.20 to -.26, p’s<.05). More anxious individuals, on the other hand, reported heightened interoceptive across several dimensions (r’s(130)=.18 to.43, p’s <.05). In the second study, we examined the congruence between a person’s self-reported negative emotion and a measure of sympathetic nervous system arousal (SCL). The congruence score was positively associated with parental rejection of negative emotion. These results suggest that parenting style, as reported by the mother, are associated with a child’s ability to coordinate their self-reported emotional and physiological responding across a series of independent assessments, r(108)= -.24, p<.05. In other words, the more maternal reported parental rejection of child negative emotions, the less congruent a child’s self and physiological reports of distress. (shrink)

Altered attachment characteristics may disturb the HPA and can even cause changes in the hippocampus. However, it is unknown if that will influence spatial navigation performance, learning and recalling. In this study we pretend to verify if there are differences in spatial navigation learning and was associated with attachment style dimensions of anxiety and close-depend. Sixty-five female participants were recruited and were evaluated using the Adult Attachment Scale-R and tested on a virtual maze navigation task (VMT) at one moment (exploratory (...) trial + 3 trials) and 24h later (3 trials). There was a significant Moment x Trial x Close-Depend interaction for the outcome time, F (2, 126) = 3.807, p = 0.025, with post-hoc analysis indicating that the High Close-Depend group displayed significant improvements between Trial 1 and Trial 3 in the post-test assessment. Conversely, the Low Close-Depend group displayed significant improvements between Trial 1and Trial 3 but on the pre-test assessment. Furthermore, the Low Close-Depend group presented significant better performance in pre-test Trial 3 in comparison to the High Close-Depend group. Thereby, it seems that low comfort with proximity and trust in others is associated with reduced spatial navigation recall, although spatial learning performance was actually superior in these participants. It is possible that reduced exposure to social interaction and meaning relationship may be reduced in the Low Close-Depend group, leading to modifications in hippocampal function and, ultimately, reduced spatial recall. Conversely, participants with high comfort with proximity and trust in others may not display typical spatial learning in the proposed task as they are more willing to freely explore the presented environment. (shrink)

Lewis proposes a solution for bridging the gap between cognitive-psychological and neurobiological theories of emotion in terms of dynamic systems modeling. However, an important brain network is absent in his account: the neuroendocrine system. In this commentary, the dynamic features of the cross-talk between the hypothalamic-pituitary-adrenal (HPA) and gonadal (HPG) axes are discussed within a triple-balance model of emotion.

This review portraits FK506 binding protein (FKBP) 51 as “reactivity protein” and collates recent publications to develop the concept of FKBP51 as contributor to different levels of adaptation. Adaptation is a fundamental process that enables unicellular and multicellular organisms to adjust their molecular circuits and structural conditions in reaction to environmental changes threatening their homeostasis. FKBP51 is known as chaperone and co‐chaperone of heat shock protein (HSP) 90, thus involved in processes ensuring correct protein folding in response to proteotoxic stress. (...) In mammals, FKBP51 both shapes the stress response and is calibrated by the stress levels through an ultrashort molecular feedback loop. More recently, it has been linked to several intracellular pathways related to the reactivity to drug exposure and stress. Through its role in autophagy and DNA methylation in particular it influences adaptive pathways, possibly also in a transgenerational fashion.Also see the video abstract here. (shrink)