Crabp1 Modulates HPA Axis Homeostasis and Anxiety-like Behaviors by Altering FKBP5 Expression

Retinoic acid (RA), the principal active metabolite of vitamin A, is known to be involved in stress-related disorders. However, its mechanism of action in this regard remains unclear. This study reports that, in mice, endogenous cellular RA binding protein 1 (Crabp1) is highly expressed in the hypothalamus and pituitary glands. Crabp1 knockout (CKO) mice exhibit reduced anxiety-like behaviors accompanied by a lowered stress induced-corticosterone level. Furthermore, CRH/DEX tests show an increased sensitivity (hypersensitivity) of their feedback inhibition in the hypothalamic–pituitary–adrenal (HPA) axis. Gene expression studies show reduced FKBP5 expression in CKO mice; this would decrease the suppression of glucocorticoid receptor (GR) signaling thereby enhancing their feedback inhibition, consistent with their dampened corticosterone level and anxiety-like behaviors upon stress induction. In AtT20, a pituitary gland adenoma cell line elevating or reducing Crabp1 level correspondingly increases or decreases FKBP5 expression, and its endogenous Crabp1 level is elevated by GR agonist dexamethasone or RA treatment. This study shows, for the first time, that Crabp1 regulates feedback inhibition of the the HPA axis by modulating FKBP5 expression. Furthermore, RA and stress can increase Crabp1 level, which would up-regulate FKBP5 thereby de-sensitizing feedback inhibition of HPA axis (by decreasing GR signaling) and increasing the risk of stress-related disorders.     

The Role of Microglia in the (Mal)adaptive Response to Traumatic Experience in an Animal Model of PTSD

The present study investigates whether predator scent-stress (PSS) shifts the microglia from a quiescent to a chronically activated state and whether morphological alterations in microglial activation differ between individuals displaying resilient vs. vulnerable phenotypes. In addition, we examined the role that GC receptors play during PSS exposure in the impairment of microglial activation and thus in behavioral response. Adult male Sprague Dawley rats were exposed to PSS or sham-PSS for 15 min. Behaviors were assessed with the elevated plus-maze (EPM) and acoustic startle response (ASR) paradigms 7 days later. Localized brain expression of Iba-1 was assessed, visualized, and classified based on their morphology and stereological counted. Hydrocortisone and RU486 were administered systemically 10 min post PSS exposure and behavioral responses were measured on day 7 and hippocampal expression of Ionized calcium-binding adaptor molecule 1 (Iba-1) was subsequently evaluated. Animals whose behavior was extremely disrupted (PTSD-phenotype) selectively displayed excessive expression of Iba-1 with concomitant downregulation in the expression of CX3C chemokine receptor 1 (CX3CR1) in hippocampal structures as compared with rats whose behavior was minimally or partially disrupted. Changes in microglial morphology have also been related only to the PTSD-phenotype group. These data indicate that PSS-induced microglia activation in the hippocampus serves as a critical mechanistic link between the HPA-axis and PSS-induced impairment in behavioral responses.     

The Role of Estrogen Receptors and Their Signaling across Psychiatric Disorders

Increasing evidence suggests estrogen and estrogen signaling pathway disturbances across psychiatric disorders. Estrogens are not only crucial in sexual maturation and reproduction but are also highly involved in a wide range of brain functions, such as cognition, memory, neurodevelopment, and neuroplasticity. To add more, the recent findings of its neuroprotective and anti-inflammatory effects have grown interested in investigating its potential therapeutic use to psychiatric disorders. In this review, we analyze the emerging literature on estrogen receptors and psychiatric disorders in cellular, preclinical, and clinical studies. Specifically, we discuss the contribution of estrogen receptor and estrogen signaling to cognition and neuroprotection via mediating multiple neural systems, such as dopaminergic, serotonergic, and glutamatergic systems. Then, we assess their disruptions and their potential implications for pathophysiologies in psychiatric disorders. Further, in this review, current treatment strategies involving estrogen and estrogen signaling are evaluated to suggest a future direction in identifying novel treatment strategies in psychiatric disorders.     

How Microbes Affect Depression: Underlying Mechanisms via the Gut–Brain Axis and the Modulating Role of Probiotics

Accumulating evidence suggests that the gut microbiome influences the brain functions and psychological state of its host via the gut–brain axis, and gut dysbiosis has been linked to several mental illnesses, including major depressive disorder (MDD). Animal experiments have shown that a depletion of the gut microbiota leads to behavioral changes, and is associated with pathological changes, including abnormal stress response and impaired adult neurogenesis. Short-chain fatty acids such as butyrate are known to contribute to the up-regulation of brain-derived neurotrophic factor (BDNF), and gut dysbiosis causes decreased levels of BDNF, which could affect neuronal development and synaptic plasticity. Increased gut permeability causes an influx of gut microbial components such as lipopolysaccharides, and the resultant systemic inflammation may lead to neuroinflammation in the central nervous system. In light of the fact that gut microbial factors contribute to the initiation and exacerbation of depressive symptoms, this review summarizes the current understanding of the molecular mechanisms involved in MDD onset, and discusses the therapeutic potential of probiotics, including butyrate-producing bacteria, which can mediate the microbiota–gut–brain axis.     

Heat-Stress Preconditioning Attenuates Behavioral Responses to Psychological Stress: The Role of HSP-70 in Modulating Stress Responses

Exposure to high ambient temperature is a stressor that influences both biological and behavioral functions and has been previously shown to have an extensive impact on brain structure and function. Physiological, cellular and behavioral responses to heat-stress (HS) (40–41 °C, 2 h) were evaluated in adult male Sprague-Dawley rats. The effect of HS exposure before predator-scent stress (PSS) exposure (i.e., HS preconditioning) was examined. Finally, a possible mechanism of HS-preconditioning to PSS was investigated. Immunohistochemical analyses of chosen cellular markers were performed in the hippocampus and in the hypothalamic paraventricular nucleus (PVN). Plasma corticosterone levels were evaluated, and the behavioral assessment included the elevated plus-maze (EPM) and the acoustic startle response (ASR) paradigms. Endogenous levels of heat shock protein (HSP)-70 were manipulated using an amino acid (L-glutamine) and a pharmacological agent (Doxazosin). A single exposure to an acute HS resulted in decreased body mass (BM), increased body temperature and increased corticosterone levels. Additionally, extensive cellular, but not behavioral changes were noted. HS-preconditioning provided behavioral resiliency to anxiety-like behavior associated with PSS, possibly through the induction of HSP-70. Targeting of HSP-70 is an attractive strategy for stress-related psychopathology treatment.     

Stress and the Role of the Gut–Brain Axis in the Pathogenesis of Schizophrenia: A Literature Review

Schizophrenia is a severe neuropsychiatric disorder, and its etiology remains largely unknown. Environmental factors have been reported to play roles in the pathogenesis of schizophrenia, and one of the major environmental factors identified for this disorder is psychosocial stress. Several studies have suggested that stressful life events, as well as the chronic social stress associated with city life, may lead to the development of schizophrenia. The other factor is the gut–brain axis. The composition of the gut microbiome and alterations thereof may affect the brain and may lead to schizophrenia. The main interest of this review article is in overviewing the major recent findings on the effects of stress and the gut–brain axis, as well as their possible bidirectional effects, in the pathogenesis of schizophrenia.     

New Insights into the Role of Insulin and Hypothalamic-Pituitary-Adrenal (HPA) Axis in the Metabolic Syndrome

Recent data suggests that (pre)diabetes onset is preceded by a period of hyperinsulinemia. Consumption of the “modern” Western diet, over-nutrition, genetic background, decreased hepatic insulin clearance, and fetal/metabolic programming may increase insulin secretion, thereby causing chronic hyperinsulinemia. Hyperinsulinemia is an important etiological factor in the development of metabolic syndrome, type 2 diabetes, cardiovascular disease, polycystic ovarian syndrome, and Alzheimer’s disease. Recent data suggests that the onset of prediabetes and diabetes are preceded by a variable period of hyperinsulinemia. Emerging data suggest that chromic hyperinsulinemia is also a driving force for increased activation of the hypothalamic-adrenal-pituitary (HPA) axis in subjects with the metabolic syndrome, leading to a state of “functional hypercortisolism”. This “functional hypercortisolism” by antagonizing insulin actions may prevent hypoglycemia. It also disturbs energy balance by shifting energy fluxes away from muscles toward abdominal fat stores. Synergistic effects of hyperinsulinemia and “functional hypercortisolism” promote abdominal visceral obesity and insulin resistance which are core pathophysiological components of the metabolic syndrome. It is hypothesized that hyperinsulinemia-induced increased activation of the HPA axis plays an important etiological role in the development of the metabolic syndrome and its consequences. Numerous studies have demonstrated reversibility of hyperinsulinemia with lifestyle, surgical, and pharmaceutical-based therapies. Longitudinal studies should be performed to investigate whether strategies that reduce hyperinsulinemia at an early stage are successfully in preventing increased activation of the HPA axis and the metabolic syndrome.     

The Role of the Gut Microbiota in the Gut–Brain Axis in Obesity: Mechanisms and Future Implications

Interaction between the gut and the brain is essential for energy homeostasis. In obesity, this homeostasis is disrupted, leading to a positive energy balance and weight gain. Obesity is a global epidemic that affects individual health and strains the socioeconomic system. Microbial dysbiosis has long been reported in obesity and obesity-related disorders. More recent literature has focused on the interaction of the gut microbiota and its metabolites on human brain and behavior. Developing strategies that target the gut microbiota could be a future approach for the treatment of obesity. Here, we review the microbiota–gut–brain axis and possible therapeutic options.     

Endocrine-Disrupting Air Pollutants and Their Effects on the Hypothalamus-Pituitary-Gonadal Axis

Anthropogenic endocrine-disrupting chemicals (EDCs) can contaminate air, soil, and water. Human exposures to EDCs occur through inhalation, absorption, and ingestion. EDCs act by disrupting various pathways in the endocrine system. When the hypothalamic–pituitary–gonadal (HPG) axis is disrupted by EDCs, there can be effects on fertility in both men and women. Not only can fertility be indirectly affected by EDC disruptions of the HPG axis, but EDCs can also directly affect the menstrual cycle and sperm morphology. In this review, we will discuss the current findings on EDCs that can be inhaled. This review examines effects of exposure to prominent EDCs: brominated and organophosphate flame retardants, diesel exhaust, polycyclic aromatic hydrocarbons, cadmium and lead, TCDD, and polychlorinated biphenyls on fertility through alterations that disrupt the HPG axis and fertility through inhalation. Although the studies included herein include multiple exposure routes, all the studies indicate receptor interactions that can occur from inhalation and the associated effects of all compounds on the HPG axis and subsequent fertility.     

The Enigma of the Adrenarche: Identifying the Early Life Mechanisms and Possible Role in Postnatal Brain Development

Dehydroepiandrosterone (DHEA) and its sulfated metabolite (DHEAS) are dynamically regulated before birth and the onset of puberty. Yet, the origins and purpose of increasing DHEA[S] in postnatal development remain elusive. Here, we draw attention to this pre-pubertal surge from the adrenal gland—the adrenarche—and discuss whether this is the result of intra-adrenal gene expression specifically affecting the zona reticularis (ZR), if the ZR is influenced by the hypothalamic-pituitary axis, and the possible role of spino-sympathetic innervation in prompting increased ZR activity. We also discuss whether neural DHEA[S] synthesis is coordinately regulated with the developing adrenal gland. We propose that DHEA[S] is crucial in the brain maturation of humans prior to and during puberty, and suggest that the function of the adrenarche is to modulate, adapt and rewire the pre-adolescent brain for new and ever-changing social challenges. The etiology of DHEA[S] synthesis, neurodevelopment and recently described 11-keto and 11-oxygenated androgens are difficult to investigate in humans owing to: (i) ethical restrictions on mechanistic studies, (ii) the inability to predict which individuals will develop specific mental characteristics, and (iii) the difficulty of conducting retrospective studies based on perinatal complications. We discuss new opportunities for animal studies to overcome these important issues.     

The Melatonergic System in Mood and Anxiety Disorders and the Role of Agomelatine: Implications for Clinical Practice

Melatonin exerts its actions through membrane MT1/MT2 melatonin receptors, which belong to the super family of G-protein-coupled receptors consisting of the typical seven transmembrane domains. MT1 and MT2 receptors are expressed in various tissues of the body either as single ones or together. A growing literature suggests that the melatonergic system may be involved in the pathophysiology of mood and anxiety disorders. In fact, some core symptoms of depression show disturbance of the circadian rhythm in their clinical expression, such as diurnal mood and other symptomatic variation, or are closely linked to circadian system functioning, such as sleep-wake cycle alterations. In addition, alterations have been described in the circadian rhythms of several biological markers in depressed patients. Therefore, there is interest in developing antidepressants that have a chronobiotic effect (i.e., treatment of circadian rhythm disorders). As melatonin produces chronobiotic effects, efforts have been aimed at developing agomelatine, an antidepressant with melatonin agonist activity. The present paper reviews the role of the melatonergic system in the pathophysiology of mood and anxiety disorders and the clinical characteristics of agomelatine. Implications of agomelatine in “real world” clinical practice will be also discussed.     

The Role of the Thalamus in Post-Traumatic Stress Disorder

Post-traumatic stress disorder (PTSD) has a high lifetime prevalence and is one of the more serious challenges in mental health care. Fear-conditioned learning involving the amygdala has been thought to be one of the main causative factors; however, recent studies have reported abnormalities in the thalamus of PTSD patients, which may explain the mechanism of interventions such as eye movement desensitization and reprocessing (EMDR). Therefore, I conducted a miniature literature review on the potential contribution of the thalamus to the pathogenesis of PTSD and the validation of therapeutic approaches. As a result, we noticed the importance of the retinotectal pathway (superior colliculus−pulvinar−amygdala connection) and discussed therapeutic indicators.     

The Role of Polyphenol in Modulating Associated Genes in Diabetes-Induced Vascular Disorders

Diabetes-induced vascular disorder is considered one of the deadly risk factors among diabetic patients that are caused by persistent hyperglycemia that eventually leads to cardiovascular diseases. Elevated reactive oxygen species (ROS) due to high blood glucose levels activate signaling pathways such as AGE/RAGE, PKC, polyol, and hexosamine pathways. The activated signaling pathway triggers oxidative stress, inflammation, and apoptosis which later lead to vascular dysfunction induced by diabetes. Polyphenol is a bioactive compound that can be found abundantly in plants such as vegetables, fruits, whole grains, and nuts. This compound exerts therapeutic effects in alleviating diabetes-induced vascular disorder, mainly due to its potential as an anti-oxidative, anti-inflammatory, and anti-apoptotic agent. In this review, we sought to summarize the recent discovery of polyphenol treatments in modulating associated genes involved in the progression of diabetes-induced vascular disorder.     

The Role of Endoplasmic Reticulum Stress and NLRP3 Inflammasome in Liver Disorders

The endoplasmic reticulum (ER) is a key organelle responsible for the synthesis, modification, folding and assembly of proteins; calcium storage; and lipid synthesis. When ER homeostatic balance is disrupted by a variety of physiological and pathological factors—such as glucose deficiency, environmental toxins, Ca²⁺ level changes, etc.—ER stress can be induced. Abnormal ER stress can be involved in many diseases. NOD-like receptor family pyrin domain-containing 3 (NLRP3), an intracellular receptor, can perceive internal and external stimuli. It binds to apoptosis-associated speck-like protein containing a CARD (ASC) and caspase-1 to assemble into a protein complex called the NLRP3 inflammasome. Evidence indicates that ER stress and the NLRP3 inflammasome participate in many pathological processes; however, the exact mechanism remains to be understood. In this review, we summarized the role of ER stress and the NLRP3 inflammasome in liver disorders and analyzed the mechanisms, to provide references for future related research.     

Mechanisms of Susceptibility and Resilience to PTSD: Role of Dopamine Metabolism and BDNF Expression in the Hippocampus

Susceptibility and resilience to post-traumatic stress disorder (PTSD) are recognized, but their mechanisms are not understood. Here, the hexobarbital sleep test (HST) was used to elucidate mechanisms of PTSD resilience or susceptibility. A HST was performed in rats 30 days prior to further experimentation. Based on the HST, the rats were divided into groups: (1) fast metabolizers (FM; sleep duration < 15 min); (2) slow metabolizers (SM; sleep duration ≥ 15 min). Then the SM and FM groups were subdivided into stressed (10 days predator scent, 15 days rest) and unstressed subgroups. Among stressed animals, only SMs developed experimental PTSD, and had higher plasma corticosterone (CORT) than stressed FMs. Thus, resilience or susceptibility to PTSD was consistent with changes in glucocorticoid metabolism. Stressed SMs had a pronounced decrease in hippocampal dopamine associated with increased expressions of catecholamine-O-methyl-transferase and DA transporter. In stressed SMs, a decrease in monoaminoxidase (MAO) A was associated with increased expressions of hippocampal MAO-A and MAO-B. BDNF gene expression was increased in stressed FMs and decreased in stressed SMs. These results demonstrate relationships between the microsomal oxidation phenotype, CORT concentration, and anxiety, and they help further the understanding of the role of the liver–brain axis during PTSD.     

Association of DNA Methylation of the NLRP3 Gene with Changes in Cortical Thickness in Major Depressive Disorder

The Nod-like receptor pyrin containing 3 (NLRP3) inflammasome has been reported to be a convergent point linking the peripheral immune response induced by psychological stress and neuroinflammatory processes in the brain. We aimed to identify differences in the methylation profiles of the NLRP3 gene between major depressive disorder (MDD) patients and healthy controls (HCs). We also investigated the correlation of the methylation score of loci in NLRP3 with cortical thickness in the MDD group using magnetic resonance imaging (MRI) data. A total of 220 patients with MDD and 82 HCs were included in the study, and genome-wide DNA methylation profiling of the NLRP3 gene was performed. Among the total sample, 88 patients with MDD and 74 HCs underwent T1-weighted structural MRI and were included in the neuroimaging–methylation analysis. We identified five significant differentially methylated positions (DMPs) in NLRP3. In the MDD group, the methylation scores of cg18793688 and cg09418290 showed significant positive or negative correlations with cortical thickness in the occipital, parietal, temporal, and frontal regions, which showed significant differences in cortical thickness between the MDD and HC groups. Our findings suggest that NLRP3 DNA methylation may predispose to depression-related brain structural changes by increasing NLRP3 inflammasome-related neuroinflammatory processes in MDD.     

Role of the Novel Peptide Phoenixin in Stress Response and Possible Interactions with Nesfatin-1

The novel peptide phoenixin was shown to be involved in several physiological processes ranging from reproduction to food intake. Interest in this protein has steadily increased over the last few years and its known implications have become much broader, playing a role in glucose homeostasis, anxiety, nociception, and pruritus. Phoenixin is expressed in a multitude of organs such as the small intestine, pancreas, and in the hypothalamus, as well as several other brain nuclei influencing numerous physiological functions. Its highly conserved amino-acid sequence amongst species leads to the assumption, that phoenixin might be involved in essential physiological functions. Its co-expression and opposing functionality to the extensively studied peptide nesfatin-1 has given rise to the idea of a possible counterbalancing role. Several recent publications focused on phoenixin’s role in stress reactions, namely restraint stress and lipopolysaccharide-induced inflammation response, in which also nesfatin-1 is known to be altered. This review provides an overview on the phoenixins and nesfatin-1 properties and putative effects, and especially highlights the recent developments on their role and interaction in the response to response.     

Role of Nociceptin/Orphanin FQ-NOP Receptor System in the Regulation of Stress-Related Disorders

Nociceptin/orphanin FQ (N/OFQ) is a 17-residue neuropeptide that binds the nociceptin opioid-like receptor (NOP). N/OFQ exhibits nucleotidic and aminoacidics sequence homology with the precursors of other opioid neuropeptides but it does not activate either MOP, KOP or DOP receptors. Furthermore, opioid neuropeptides do not activate the NOP receptor. Generally, activation of N/OFQ system exerts anti-opioids effects, for instance toward opioid-induced reward and analgesia. The NOP receptor is widely expressed throughout the brain, whereas N/OFQ localization is confined to brain nuclei that are involved in stress response such as amygdala, BNST and hypothalamus. Decades of studies have delineated the biological role of this system demonstrating its involvement in significant physiological processes such as pain, learning and memory, anxiety, depression, feeding, drug and alcohol dependence. This review discusses the role of this peptidergic system in the modulation of stress and stress-associated psychiatric disorders in particular drug addiction, mood, anxiety and food-related associated-disorders. Emerging preclinical evidence suggests that both NOP agonists and antagonists may represent a effective therapeutic approaches for substances use disorder. Moreover, the current literature suggests that NOP antagonists can be useful to treat depression and feeding-related diseases, such as obesity and binge eating behavior, whereas the activation of NOP receptor by agonists could be a promising tool for anxiety.