Effectiveness of osteopathic manipulative applications on hypothalamic-pituitary-adrenal (HPA) axis in youth with major depressive disorder: a randomized double-blind, placebo-controlled trial.

CONTEXT: Osteopathic treatments regulate the neurovegetative system through joint mobilizations and manipulations, and myofascial and craniosacral techniques. Despite the growing body of research, the precise impact of osteopathic medicine on the autonomic nervous system (ANS) is not yet fully elucidated. As to Kuchera's techniques, the stimulation of the sympathetic trunk and prevertebral ganglia contributed to harmonization of the sympathetic activity. However, potential relationships between the harmonization of the sympathetic nervous system (SNS) and the hypothalamic-pituitary-adrenal (HPA) axis largely remain uncertain and warrant further exploration. OBJECTIVES: This study was designed to evaluate the effectiveness of the osteopathic sympathetic harmonization (OSH) on the SNS and the HPA axis in youth with major depressive disorder (MDD). METHODS: The study included 39 youths aged 15-21 years and diagnosed with MDD. The participants were randomly assigned into either the OSH or the placebo group. Stimulation was performed on the sympathetic truncus and prevertebral ganglia in the OSH group. The stimulation of the placebo group was performed with a lighter touch and a shorter duration in similar areas. Each participant completed the Beck Depression Inventory (BDI) and the State and Trait Anxiety Inventory (SAI and TAI) before the application. Blood pressure (BP) and pulse measurements were made, and saliva samples were taken before, immediately after, and 20 min after application. RESULTS: The baseline BDI (p=0.617) and TAI (p=0.322) scores were similar in both groups. Although the SAI scores decreased in both groups postintervention, no statistically significant difference was found between the two groups. Subjects who received OSH had a decrease in α-amylase level (p=0.028) and an increase in cortisol level (p=0.009) 20 min after the procedure. CONCLUSIONS: Following OSH application in depressed youth, SNS activity may decrease, whereas HPA axis activity may increase. Future studies may examine the therapeutic efficacy of repeated OSH applications in depressed individuals.

The PGE2 receptor EP3 plays a positive role in the activation of hypothalamic-pituitary-adrenal axis and neuronal activity in the hypothalamus under immobilization stress.

BACKGROUND: Prostaglandin E2 (PGE2) binds to four receptor subtypes (EP1, EP2, EP3 and EP4) and plays an important role in response to stress. However, the identity of the receptor(s) responsible for PGE2 regulation of neuronal activity and signaling through activation of the hypothalamic-pituitary-adrenal (HPA) axis under immobilization stress is unknown. PURPOSE: The present study aimed to investigate the role of the hypothalamic PGE2 receptors in the activation of the HPA axis and neuronal activity in a rat model of stress. METHODS: Stress was induced by immobilization of the animals, after which the stress-induced profile of PGE2 receptor signaling in the rat hypothalamus was determined by real-time polymerase chain reaction and immunohistochemistry. The effect of a selective EP3 receptor antagonist on corticosterone concentrations and c-Fos immunoreactivity was measured. RESULTS: Expression of EP2 and EP3 receptor genes, but not EP1 and EP4, was increased following immobilization stress. The EP3 receptor was localized to the paraventricular nucleus (PVN) of the hypothalamus, and the integrated density of the EP3 receptor was increased after immobilization stress. Rats given L-798,106, a selective antagonist of the EP3 receptor, showed significant attenuation of stress-increased serum corticosterone levels. EP3 antagonist also significantly suppressed the increase in the gene expression of c-Fos and the number of c-Fos-immunoreactive cells in the PVN of the hypothalamus following immobilization stress. CONCLUSIONS: These results suggest that immobilization stress may result in increased activation of the HPA axis and neuronal activity through regulating the function of the EP3 receptor.

A combination of depression and liver Qi stagnation and spleen deficiency syndrome using a rat model.

A syndrome (Zheng in Chinese) plays a critical role in disease identification, diagnosis, and treatment in traditional Chinese medicine (TCM). Clinically, the liver Qi stagnation and spleen deficiency syndrome (LQSSDS) is one of the most common syndrome patterns. Over the past few decades, several animal models have been developed to understand the potential mechanisms of LQSSDS, but until now, simulation of the syndrome is still unclear. Recently, several studies have confirmed that an animal model combining a disease and a syndrome is appropriate for simulating TCM syndromes. Overlapping previous studies have reported that depression is highly associated with LQSSDS; hence, we attempted to develop a rat model combining depression and LQSSDS. We exposed the rats to different durations of chronic unpredictable mild stress (CUMS). Subsequently, the evaluation indicators at macrolevel consisted of behavioral tests including open field test, sucrose preference test, and forced swim test, food intake, body weight, white adipose tissue, fecal water content, visceral hypersensitivity, and small bowel transit, and the evaluation indicators at microlevel included changes of hypothalamic-pituitary-adrenal axis. Serum D-xylose absorption was used to comprehensively confirm and assess whether the model was successful during the CUMS-induced process. The results showed that rats exposed to 6-week CUMS procedure exhibited significantly similar traits to the phenotypes of LQSSDS and depression. This study provided a new rat model for the LQSSDS and could potentially lead to a better understanding of the pathophysiology of LQSSDS and the development of new drugs for this syndrome.

Acute Mono-Arthritis Activates the Neurohypophysial System and Hypothalamo-Pituitary Adrenal Axis in Rats.

Various types of acute/chronic nociceptive stimuli cause neuroendocrine responses such as activation of the hypothalamo-neurohypophysial [oxytocin (OXT) and arginine vasopressin (AVP)] system and hypothalamo-pituitary adrenal (HPA) axis. Chronic multiple-arthritis activates the OXT/AVP system, but the effects of acute mono-arthritis on the OXT/AVP system in the same animals has not been simultaneously evaluated. Further, AVP, not corticotropin-releasing hormone (CRH), predominantly activates the HPA axis in chronic multiple-arthritis, but the participation of AVP in HPA axis activation in acute mono-arthritis remains unknown. Therefore, we aimed to simultaneously evaluate the effects of acute mono-arthritis on the activity of the OXT/AVP system and the HPA axis. In the present study, we used an acute mono-arthritic model induced by intra-articular injection of carrageenan in a single knee joint of adult male Wistar rats. Acute mono-arthritis was confirmed by a significant increase in knee diameter in the carrageenan-injected knee and a significant decrease in the mechanical nociceptive threshold in the ipsilateral hind paw. Immunohistochemical analysis revealed that the number of Fos-immunoreactive (ir) cells in the ipsilateral lamina I-II of the dorsal horn was significantly increased, and the percentage of OXT-ir and AVP-ir neurons expressing Fos-ir in both sides of the supraoptic (SON) and paraventricular nuclei (PVN) was increased in acute mono-arthritic rats. in situ hybridization histochemistry revealed that levels of OXT mRNA and AVP hnRNA in the SON and PVN, CRH mRNA in the PVN, and proopiomelanocortin mRNA in the anterior pituitary were also significantly increased in acute mono-arthritic rats. Further, plasma OXT, AVP, and corticosterone levels were significantly increased in acute mono-arthritic rats. These results suggest that acute mono-arthritis activates ipsilateral nociceptive afferent pathways at the spinal level and causes simultaneous and integrative activation of the OXT/AVP system. In addition, the HPA axis is activated by both AVP and CRH in acute mono-arthritis with a distinct pattern compared to that in chronic multiple-arthritis.

Mindfulness-based focused attention training versus progressive muscle relaxation in remitted depressed patients: Effects on salivary cortisol and associations with subjective improvements in daily life.

Major Depression is a stress-related disorder characterized by altered hypothalamic-pituitary-adrenal axis function. Mindfulness-based interventions have shown to improve subjective parameters of stress and to reduce relapse rates in depressed patients. However, research on their effects on diurnal patterns of cortisol and associations with subjective outcomes is lacking. The present Ambulatory Assessment study investigated possible changes in daily rhythm cortisol parameters (cortisol awakening response (CAR), daily slope, total cortisol) in currently remitted individuals with recurrent depression who were randomized to a four-week mindfulness-based focused attention training (MBAT, n = 39) or a progressive muscle relaxation training (PMR, n = 39). A second aim was to investigate whether changes in cortisol were linked to improvements in affective and cognitive daily life states. On three weekdays before and after the intervention, seven saliva cortisol samples per day were collected. For analysis, multilevel models were applied. Results revealed no group-specific or general change in CAR and daily slopes from pre- to postintervention. In contrast, total cortisol increased across groups, which was however moderated by group and subjective improvement status. While cortisol increased irrespective of subjective improvement in PMR participants, MBAT participants with larger reductions in negative affect and rumination maintained their initial cortisol levels, whereas those with lower improvement paralleled the PMR group. Thereby, MBAT appeared to buffer an increase in overall cortisol secretion over time, but only in patients showing marked improvements in those affective and cognitive states that constitute core elements for depressive relapses in the vulnerability model of mindfulness-based cognitive therapy.

Transcendental meditation and hypothalamic-pituitary-adrenal axis functioning: a pilot, randomized controlled trial with young adults.

Transcendental meditation (TM) is effective in alleviating stress and anxiety and promoting well-being. While the underlying biological mechanisms of TM are not yet fully explored, the hypothalamic-pituitary-adrenal (HPA) axis represents an index providing important clues embodying the stress system cascade. In this pilot study, young adults were randomly assigned to TM training followed by 8 weeks of meditation practice or a wait-list control condition. TM was conducted over 8 weeks. Thirty-four young adult participants were randomized; 27 participants completed the HPA outcome assessments (41% male). To assess HPA axis functioning, salivary samples to assess cortisol awakening response (CAR) that were collected in the morning, both at baseline and at week-4. Salivary cortisol in the context of a social stressor using the Trier Social Stress Test (TSST) was collected at week-8. The results indicate that participants who were randomly assigned to TM had lower awakening salivary cortisol levels and a greater drop in CAR from baseline to week-4 than the control group. There were no significant differences in HPA axis functioning in the context of the TSST. Primary limitations of this randomized controlled trial were the small sample size, the use of a wait-list as opposed to an active control, and the limited scope of HPA axis assessments. The results of this pilot study provide tentative evidence that TM may impact biological stress system functioning and suggests that this may be a worthwhile avenue to continue to examine. It will also be useful to extend these findings to a broader array of meditative and mindful practices, particularly for those who are experiencing more distress.

Repeated caffeine administration aggravates post-traumatic stress disorder-like symptoms in rats.

BACKGROUND: Caffeine is the widely consumed central nervous system stimulant in form of coffee and other beverages. However, the repeated administration of caffeine induces anxiety, disturbance in hypothalamic-pituitary-adrenal (HPA) axis and psychiatric symptoms in humans. As much evidence links PTSD to HPA axis dysfunction, and anxiety is a hallmark symptom, repeated and/or large doses of caffeine may exacerbate symptoms of PTSD. OBJECTIVE: In our present study, we evaluated the effect of repeated administration of caffeine on stress re-stress (SRS) model of PTSD. METHODS: As per the protocol, male rats were restrained for 2 h followed by 20 min forced swim and halothane anaesthesia on day 2 (D-2). Then the rats were re-stressed (forced swim) at 6-days interval between D-8 to D-32. After exposure to SRS, depressive, anxiety-like behaviour, and cognitive functions were evaluated by forced swim test (FST), elevated plus maze (EPM) and Y-maze tests respectively. Caffeine (10, 20 and 30 mg/kg, i.p.) dosing was started from D-8 and continued up to D-32. The corticosterone level was measured in plasma followed by serotonin and glucocorticoid receptor (GR) and mineralocorticoid receptors (MR) estimation in hippocampus (HIP), prefrontal cortex (PFC) and amygdala (AMY). RESULTS: SRS-induced depressive and anxiety-like behaviour was aggravated by caffeine at dose of 20 and 30 mg/kg. Caffeine (30 mg/kg) treated control animals showed depressive, anxiety-like behaviour and cognitive impairments. SRS-induced decrease in plasma corticosterone level and increase in serotonin (5HT) levels in the PFC, HIP and AMY were not altered by caffeine. Caffeine did not modulate the SRS-induced decrease in glucocorticoid receptor (GR) and mineralocorticoid receptor (MR). In contrast, caffeine per se decreased GR and MR expression and their ratio in unstressed animals. CONCLUSION: Repeated intake of caffeine aggravates PTSD-like symptoms in stress-exposed rats and induces PTSD-like symptoms in unstressed rats by altering the expression of glucocorticoid receptors.

Hormonal Dynamics Effect of Serum Insulin-Like Growth Factor I and Cortisol/Dehydroepiandrosterone Sulfate Ratio on Symptom Severity of Major Depressive Disorder.

BACKGROUND: Insulin-like growth factor I (IGF-I) is a neurotrophic factor produced by the hypothalamic-pituitary-somatotropic axis and is considered a potential contributor to the pathology of major depressive disorder (MDD). Although it is known that the hypothalamic-pituitary-adrenal axis and cortisol are involved in the pathology of MDD, the association with dehydroepiandrosterone sulfate (DHEAS) remains unclear. The current study sought to clarify the relationship between these hormones and the pathology of MDD. METHODS: Subjects were 91 Japanese patients with a diagnosis of MDD. Serum IGF-I, cortisol, and DHEAS were measured. Samples were taken before breakfast after overnight fasting. Depressive symptoms were assessed using the Hamilton Rating Scale for Depression (HAM-D). RESULTS: Subjects included 59 men and 32 women with an average age of 44.1 ± 13.1 years (mean ± SD). The blood IGF-I level was 152.0 ± 50.0 ng/mL, the cortisol level was 10.1 ± 4.6, and the DHEAS level was 201.3 ± 112.7 µg/dL. The mean HAM-D score was 13.9 ± 9.0. Serum IGF-I levels were not correlated with cortisol. Higher IGF-I, cortisol, and cortisol/DHEAS ratios were associated with higher HAM-D scores (adjusted R = 0.240, P < 0.001), and higher IGF-I and cortisol were associated with higher melancholic or suicide subscores (adjusted R = 0.200, P < 0.001; adjusted R = 0.273, P < 0.001). CONCLUSIONS: Our findings suggest that hormonal dysregulation of the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-somatotropic axes may be related to the symptom severity of MDD, melancholia, and suicide-related factors.

Glucocorticoid-immune response to acute stress in women and men living with HIV.

Despite high risk for serious non-AIDS events (SNAEs) and accelerated age-related increases in inflammatory markers relative to HIV+ men, HIV+ women have been understudied, particularly in terms of stress impacts on immune parameters. The purpose of this study was to examine sex differences in glucocorticoid-immune stress response in mid-life HIV+ individuals, as poor glucocorticoid control of stress-induced inflammation may contribute to health risk in HIV+ women. Male and female participants completed a threat of shock laboratory stressor. Serum cortisol and cytokines [interleukin (IL)-6, IL-8, IL-10, IL-1ß, C-reactive protein (CRP), tumor necrosis factor (TNF)-α, interferon (IFN)-γ] were assessed at six timepoints prior to and in response to the stressor. Participants included 8 HIV- controls (n = 5 female) and 9 HIV+ (n = 5 female) who were virally suppressed. Repeated measures mixed models revealed a significant sex by HIV status by time interaction for IL-10, IL-1ß, TNF-α, and cortisol. IL-10 response, an anti-inflammatory cytokine, was larger in males than females, regardless of HIV status. TNF-α response was blunted in HIV+ individuals compared with HIV-, and specifically in HIV+ women, IL-1ß and cortisol response were blunted. Individuals living with HIV may have impaired coordination between the immune system and hypothalamic pituitary adrenal (HPA) axis. HIV+ women in particular exhibited dysregulated IL-1ß and cortisol response to acute stress. Future work should focus on relationships among proinflammatory cytokines, stress, and SNAEs in HIV, with attention to sex as a biological variable.

Effect of stress gene-by-environment interactions on hippocampal volumes and cortisol secretion in adolescent girls.

OBJECTIVE: Adolescence is a time of increased susceptibility to environmental stress and mood disorders, and girls are particularly at risk. Genes interacting with the environment (G × E) are implicated in hypothalamic-pituitary-adrenal axis dysregulation, hippocampal volume changes and risk or resilience to mood disorders. In this study, we assessed the effects of stress system G × E interactions on hippocampal volumes and cortisol secretion in adolescent girls. METHODS: We recruited 229 girls aged 12-18 years, and scans were obtained from 202 girls. Of these, 76 had been exposed to higher emotional trauma (abuse or neglect). Hippocampal volumes were measured using Freesurfer and high-resolution structural magnetic resonance imaging scans. Saliva samples were collected for measurement of cortisol levels and genotyping of stress system genes: FKBP5, NR3C1 (both N = 194) and NR3C2 ( N = 193). RESULTS: Among girls with the 'G' allelic variant of the NR3C1 gene, those who had been exposed to higher emotional trauma had significantly smaller left hippocampal volumes ( N = 44; mean = 4069.58 mm3, standard deviation = 376.99) than girls who had been exposed to minimal emotional trauma with the same allelic variant ( N = 69; mean = 4222.34 mm3, standard deviation = 366.74). CONCLUSION: In healthy adolescents, interactions between emotional trauma and the 'protective' NR3C1 'GG' variant seem to induce reductions in left hippocampal volumes. These G × E interactions suggest that vulnerability to mood disorders is perhaps driven by reduced 'protection' that may be specific to emotional trauma. This novel but preliminary evidence has implications for targeted prevention of mood disorders and prospective multimodal neuroimaging and longitudinal studies are now needed to investigate this possibility.

Role of corticosterone in altered neurobehavioral responses to acute stress in a model of compromised hypothalamic-pituitary-adrenal axis function.

An organism's capacity to cope with stressful experiences is dependent on its ability to appropriately engage central and peripheral systems, such as the hypothalamic-pituitary-adrenal (HPA) axis, to adapt to changing environmental demands. The HPA axis is a primary neuroendocrine mediator of neural and behavioral responses to stress, and dysfunction of this system is linked to increased risk for developing mental health disorders such as depression, anxiety, and post-traumatic stress disorder. However, the mechanisms by which dysregulated HPA function results in abnormal behavioral responses to stress are poorly understood. Here, we tested how corticosterone (CORT)-induced HPA axis disruption affects behavioral responses to stress in male C57BL/6 N mice, and probed correlates of these behaviors in the brain. We show that chronic HPA disruption blunts acute stress-induced grooming and rearing behaviors in the open field test, effects which were accompanied by decreased FOS immunoreactivity in the paraventricular nucleus of the hypothalamus (PVH) and paraventricular nucleus of the thalamus (PVT). Blockade of CORT secretion with metyrapone injection prior to acute stress did not recapitulate the effects of chronic HPA disruption on open field behavior, and acute CORT replacement did not rescue normal behavioral stress responses following chronic HPA disruption. This suggests that under acute conditions, CORT is not necessary for these responses normally, nor sufficient to rescue the deficits of chronic HPA dysregulation. Together, these findings support the hypothesis that chronic HPA dysregulation causes adaptation in stress-related brain circuits and demonstrate that these changes can influence an organism's behavioral response to stress exposure.

Effects of Epigallocatechin Gallate on Behavioral and Cognitive Impairments, Hypothalamic-Pituitary-Adrenal Axis Dysfunction, and Alternations in Hippocampal BDNF Expression Under Single Prolonged Stress.

Post-traumatic stress disorder (PTSD) is a traumatic stress-related psychiatric disorder stimulated by experience. Green tea has potent antioxidative properties, due, in part, to the catechin (-) epigallocatechin-3-gallate (EGCG). EGCG is an important polyphenol with advantageous effects on anxiety and depression. Nevertheless, the mechanism about the inhibition of PTSD-like symptoms of EGCG is still unidentified. We examined whether EGCG improved learning and memory deficit stimulated in rats after single prolonged stress (SPS). Rats were administrated intraperitoneally (i.p.) with EGCG for 14 successive days after the SPS process. The SPS procedure stimulated cognitive deficit in the Morris water maze test and the object recognition task, and this impairment was improved by EGCG (25 mg/kg, i.p.). Daily EGCG administration significantly decreased the freezing response to contextual fear conditioning. The administration of EGCG also significantly moderated memory-related decreases in the alternation of cAMP-response element-binding protein and brain-derived neurotrophic factor in the hippocampus. Our results suggest that EGCG alleviated SPS-stimulated learning and memory deficit by inhibiting the increase of neuroinflammation in the rat brain. In addition, EGCG reversed the alternation of allopregnanolone and progesterone in the brain, and diminished simultaneously the hypothalamic-pituitary-adrenal axis dysfunction. Thus, EGCG reversed learning and memory-related behavioral dysfunction and molecular alternation accelerated by traumatic stress and may be a useful therapeutic material for PTSD.

Endocannabinoid system, stress and HPA axis.

The endocannabinoid system (ECS), which is composed of the cannabinoid receptors types 1 and 2 (CB1 and CB2) for marijuana's psychoactive ingredient ∆9-tetrahydrocannabinol (∆9-THC), the endogenous ligands (AEA and 2-AG) and the enzymatic systems involved in their biosynthesis and degradation, recently emerged as important modulator of emotional and non-emotional behaviors. In addition to its recreational actions, some of the earliest reports regarding the effects of Cannabis use on humans were related to endocrine system changes. Accordingly, the ∆9-THC and later on, the ECS signalling have long been known to regulate the hypothalamic-pituitary-adrenocortical (HPA) axis, which is the major neuroendocrine stress response system of mammals. However, how the ECS could modify the stress hormone secretion is not fully understood. Thus, the present article reviews current available knowledge on the role of the ECS signalling as important mediator of interaction between HPA axis activity and stressful conditions, which, in turn could be involved in the development of psychiatric disorders.

Anxiety behavior and hypothalamic-pituitary-adrenal axis altered in a female rat model of vertical sleeve gastrectomy.

Surgical weight loss results in a host of metabolic changes that culminate in net positive health benefit to the patients. However, the psychological impact of these surgeries has not been fully studied. On one hand, surgical weight loss has been reported to improve standard quality of life and resolution of symptoms of depression. But on the other hand, reports of self-harm and increased ER visits for self-harm suggest other psychological difficulties. Inability to handle anxiety following surgical weight loss has alarming potential ramifications for these gastric surgery patients. In the present study, we used models of diet-induced obesity and vertical sleeve gastrectomy (VSG) to ask whether anxiety behavior and hypothalamic-pituitary-adrenal (HPA) axis gene changes were affected by surgical weight loss under two diet regimens: i.e. low-fat diet (LFD) and high-fat diet (HFD). We show reduced exploratory behavior in the open field test but increased time in the open arms of the elevated plus maze. Furthermore, we show increased plasma levels of corticosterone in female VSG recipients in the estrus phase and increased levels of hypothalamic arginine-vasopressin (avp), pro-opiomelanocortin (pomc), and tyrosine hydroxylase (th). We report reduced dopamine receptor D1 (drd1) gene in prefrontal cortex (PFC) in VSG animals in comparison to Sham. Further we report diet-driven changes in stress-relevant gene targets in the hypothalamus (oxt, pomc, crhr1) and adrenal (nr3c1, nr3c2, mc2r). Taken together, these data suggest a significant impact of both surgical weight loss and diet on the HPA axis and further impact on behavior. Additional assessment is necessary to determine whether molecular and hormonal changes of surgical weight loss are the source of these findings.

Bioenergetics and synaptic plasticity as potential targets for individualizing treatment for depression.

Disruptions of bioenergetic signaling and neurogenesis are hallmarks of depression physiology and are often the product of dysregulation of the inflammatory, stress-response, and metabolic systems. These systems are extensively interrelated at the physiological level, yet the bulk of the literature to date addresses pathophysiological mechanisms in isolation. A more integrated understanding of the etiology, progression, and treatment response profiles of depression is possible through wider consideration of relevant preclinical and clinical studies that examine the result of disruptions in these systems. Here, we review recent data demonstrating the critical effects of bioenergetic disruption on neuroplasticity and the development and progression of depressive illness. We further highlight the interactive and dynamic nature of the inflammatory and stress response systems and how disruption of these systems influences bioenergetic signaling pathways critical to treatment outcomes. In so doing, we underscore the pressing need to reconsider the implications of treatment resistance and present a framework for developing novel, personalized treatment approaches for depression.

Seizure-induced activation of the HPA axis increases seizure frequency and comorbid depression-like behaviors.

Our laboratory recently demonstrated that seizures activate the hypothalamic-pituitary-adrenal (HPA) axis, increasing circulating levels of corticosterone (O'Toole et al., 2013). Given the well-established proconvulsant actions of corticosterone, we hypothesized that seizure-induced activation of the HPA axis may contribute to future seizure susceptibility. Further, since hypercortisolism is associated with depression, we propose that seizure-induced activation of the HPA axis may contribute to comorbid depression and epilepsy. To test this hypothesis, we generated mice lacking the GABAA receptor (GABAAR) δ subunit specifically in corticotropin-releasing hormone (CRH) neurons (Gabrd/Crh mice), which exhibit hyporeactivity of the HPA axis (Lee et al., 2014). Gabrd/Crh mice exhibit blunted seizure-induced elevations in corticosterone, establishing a useful tool to investigate the contribution of HPA axis dysfunction on epilepsy and associated comorbidities. Interestingly, Gabrd/Crh mice exhibit decreased acute seizure susceptibility following kainic acid (KA) administration. Furthermore, chronically epileptic Gabrd/Crh mice exhibit a decrease in both spontaneous seizure frequency and depression-like behaviors compared with chronically epileptic Cre-/- littermates. Seizure susceptibility and associated depression-like behaviors can be restored to wild type levels by treating Gabrd/Crh mice with exogenous corticosterone. Similarly, chemogenetic activation of CRH neurons in the paraventricular nucleus (PVN) is sufficient to increase seizure susceptibility; whereas, chemogenetic inhibition of CRH neurons in the PVN of the hypothalamus is sufficient to decrease seizure susceptibility and depression-like behaviors in chronically epileptic mice. These data suggest that seizure-induced activation of the HPA axis promotes seizure susceptibility and comorbid depression-like behaviors, suggesting that the HPA axis may be a novel target for seizure control.

Oxytocin inhibited stress induced visceral hypersensitivity, enteric glial cells activation, and release of proinflammatory cytokines in maternal separated rats.

Visceral hypersensitivity (VH) is a significant contributor to irritable bowel syndrome (IBS). Oxytocin (OT) possesses analgesic effects on the central nervous system (CNS) and attenuates microglial activation, however, little is known about its peripheral effects and involvement in VH of IBS. Reactive enteric glial cells (EGCs) contributes to abnormal motility in gastrointestinal (GI) diseases. The aim of this study was to evaluate the peripheral use of OT to maintain VH and activation of EGCs through involvement of the Toll-like receptor (TLR) 4/MyD88/NF-κB signaling. After assessing a baseline visceromotor response (VMR) to colorectal distension (CRD), rats were exposed to a 1h water avoidance stress (WAS) session. Before each WAS session, intraperitoneal injection of OT (1mg/kg body weight, in phosphate-buffered saline (PBS)) atosiban (0.5mg/kg body weight, in PBS) or PBS (as a vehicle control, 1ml/kg body weight) was administered. Animas are killed 24h after the last WAS session. EGCs activity, relative OT receptor expression, glial fibrillary acidic protein (GFAP) expression and TLR4/MyD88/NF-κB signaling were evaluated. Neonatal maternal separation (MS) significantly increased the OT receptor expression and enhanced VMR to CRD. WAS improved VMR to CRD only during neonatal MS. OT treatment prevented WAS-induced higher VMRs to CRD, which was reversed by an OT receptor antagonist administration. Compared to the vehicle, OT pre-treated rats reduced EGCs activation, GFAP expression and TLR4/MyD88/NF-κB signaling. We conclude that neonatal MS induces VH and visceral pain in rats. Furthermore, exogenous OT attenuated stress-induced VH and EGCs activation, which was mediated by TLR4/MyD88/NF-κB signaling.

Blunted basal corticosterone pulsatility predicts post-exposure susceptibility to PTSD phenotype in rats.

The basal activity of the hypothalamic-pituitary-adrenal axis is highly dynamic and is characterized by both circadian and ultradian (pulsatile) patterns of hormone secretion. Pulsatility of glucocorticoids has been determined to be critical for optimal transcriptional, neuroendocrine, and behavioral responses. We used an animal model of post-traumatic stress disorder (PTSD) to assess whether stress-induced impairment of behavioral responses is correlated with aberrant secretion of corticosterone. Serial blood samples were collected manually via the jugular vein cannula during the light-(inactive)-phase in conscious male rats at 20-min intervals for a period of 5h before and 6.5h after exposure to predator scent stress. The outcome measures included behavior in an elevated plus-maze and acoustic startle response 7days after exposure. Individual animals were retrospectively classified as having "extreme", "partial", or "minimal" behavioral responses according to pre-set cut-off criteria for behavioral response patterns. Corticosterone secretion patterns were analyzed retrospectively. Under basal conditions, the amplitude of ultradian oscillations of corticosterone levels, rather than the mean corticosterone level or the frequency of corticosterone pulsatility, was significantly reduced in individuals who displayed PTSD-phenotype 8days later. In addition, extreme disruption of behavior on day 8 post-exposure was also characterized by a blunting of corticosterone response to the stressor. Animals with behavior that was only partially affected or unaffected displayed none of the above changes. Blunted basal corticosterone pulse amplitude is a pre-existing susceptibility or risk factor for PTSD, which originates from prior (life) experiences and may therefore predict post-exposure PTSD-phenotype in rats.

Inability to suppress the stress-induced activation of the HPA axis during the peripartum period engenders deficits in postpartum behaviors in mice.

The stress-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis is normally suppressed during pregnancy. Dysregulation of the HPA axis has been proposed to play a role in postpartum depression. However, direct investigation into the relationship between the HPA axis and postpartum depression has been hindered by the lack of useful animal models. Building on our discovery of a role for the K+/Cl-co-transporter, KCC2, in the GABAergic regulation of CRH neurons in the paraventricular nucleus of the hypothalamus (PVN), critical for mounting the body's physiological response to stress, we assessed the role of KCC2 in the regulation of the HPA axis during pregnancy and the postpartum period. Here we demonstrate that the normal suppression of the stress-induced activation of the HPA axis during the peripartum period involves maintenance of KCC2 in the PVN. Mice lacking KCC2 specifically in corticosterone-releasing hormone (CRH) neurons, which govern the activity of the HPA axis (KCC2/Crh mice), exhibit dysregulation of the HPA axis and abnormal postpartum behaviors. Loss of KCC2 specifically in CRH neurons in the PVN is sufficient to reproduce the depression-like phenotype and deficits in maternal behaviors during the postpartum period. Similarly, chemogenetic activation of CRH neurons in the PVN is sufficient to induce abnormal postpartum behaviors and chemogenetic silencing of CRH neurons in the PVN can ameliorate abnormal postpartum behaviors observed in KCC2/Crh mice. This study demonstrates that dysregulation of the HPA axis is sufficient to induce abnormal postpartum behaviors and deficits in maternal behaviors in mice, providing empirical support for a role of HPA axis dysfunction in the pathophysiology of postpartum depression.