The Effect of Early Life Stress on Emotional Behaviors in GPR37KO Mice

GPR37 is an orphan G-protein-coupled receptor, a substrate of parkin which is linked to Parkinson’s disease (PD) and affective disorders. In this study, we sought to address the effects of early life stress (ELS) by employing the paradigm of limited nesting material on emotional behaviors in adult GPR37 knockout (KO) mice. Our results showed that, while there was an adverse effect of ELS on various domains of emotional behaviors in wild type (WT) mice in a sex specific manner (anxiety in females, depression and context-dependent fear memory in males), GPR37KO mice subjected to ELS exhibited less deteriorated emotional behaviors. GPR37KO female mice under ELS conditions displayed reduced anxiety compared to WT mice. This was paralleled by lower plasma corticosterone in GPR37KO females and a lower increase in P-T286-CaMKII by ELS in the amygdala. GPR37KO male mice, under ELS conditions, showed better retention of hippocampal-dependent emotional processing in the passive avoidance behavioral task. GPR37KO male mice showed increased immobility in the forced swim task and increased P-T286-CaMKII in the ventral hippocampus under baseline conditions. Taken together, our data showed overall long-term effects of ELS—deleterious or beneficial depending on the genotype, sex of the mice and the emotional context.

Born without night: The consequence of the no-night environment on reproductive performance in diurnal zebra finches

We investigated the consequence of no night environment (constant light, LL) on reproductive performance in zebra finches in the parent (P) and subsequent F1 generation. As a measure of the overall effects on the metabolic reproductive health, we monitored daily activity behaviour, recorded song and cheek patch size in males, and measured body size and hormone levels. As compared to controls under 12 h light: 12 h darkness (12:12 h LD), both P and F1 pairs showed a compromised reproductive success, as evidenced by fewer fledglings and viable offsprings with longer fledging durations, and increased offspring mortality with successive three clutches under LL. The overall negative effect of the no-night environment was increased in the F1generation. As compared to P pairs, F1pairs had more failed nesting and breeding attempts, took longer to initiate reproduction, incubated fewer eggs, produced fewer viable offspring with longer fledging duration, and showed increased offspring mortality. Consistent with negative reproductive effects, P males showed significant changes in the motif duration and other spectral features of song, and both F1 and F2 males copied poorly the song of their parent under LL. Plasma corticosterone and sex hormones (testosterone in males and estradiol in females) levels were significantly lower under LL. Daily plasma melatonin rhythm persisted but with a reduced amplitude under LL. These results demonstrate the importance of night in reproduction in a continuously breeding diurnal species, and give insights into the possible impact on physiology of animals whose surrounding environment is consistently losing the darkness of night.

Environmental Enrichment Ameliorates Anxiety-Like Behavior in Rats without Altering Plasma Corticosterone Level

BACKGROUND: Anxiety disorder is one of the most common psychiatric problems. Prolonged stress gives rise to anxiety-like behavior in animals. Environmental interventions influence the outcome of anxiety treatment. Environmental enrichment (EE) can modulate brain’s structure and function. AIM: The objective of the study was to evaluate EE effects on anxiety-like behavior and corticosterone (CORT) level after unpredictable chronic mild stress (UCMS). METHODS: A total of 28 rats were assigned into four groups randomly: Control, UCMS, UCMS+EE, and UCMS+fluoxetine. UCMS, EE, and fluoxetine were given for 21 days. Anxiety behavior was measured on day 22nd using Elevated Plus Maze. Behavioral measurement was based on the total time spent and total entries onto open and closed arms. CORT was measured using ELISA. RESULTS: UCMS increased anxiety-like behavior as seen from reduced number of entries and time spent in open arms as well as increased number of entries and time spent in in closed arms in UCMS group than control. Rats in EE group spent more time and made more entries in the open arms than UCMS group (both p = 0.002). Anxiolytic effect of EE was stronger than fluoxetine. Plasma CORT level among groups did not differ significantly (p = 0.351). CONCLUSION: EE can ameliorate stress-induced anxiety-like behavior without affecting CORT level.

An Advanced Transcriptional Response to Corticosterone After Single Prolonged Stress in Male Rats

Stress-related neuropsychiatric disorders are often accompanied by dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis. In patients suffering from post-traumatic stress disorder (PTSD), increased sensitivity of glucocorticoid negative feedback has regularly been observed. The single prolonged stress (SPS) paradigm was developed to model increased negative feedback and other aspects of PTSD in rats. In this study, we used a setup that precluded the evaluation of negative feedback but rather served to test the hypothesis of the enhanced glucocorticoid receptor (GR) signaling in higher brain areas. We injected corticosterone or vehicle 7 days after SPS and evaluated plasma corticosterone, as well as gene expression in the dorsal hippocampus and amygdala. We observed a strikingly rapid change in the expression of established GR target genes (t = 30 min) only in the SPS group on exogenous corticosterone injection. Our results extend the notion of increased GR sensitivity in PTSD to include transcriptional responses in the hippocampus.

Glucocorticoid receptor antagonist alters corticosterone and receptor sensitive mRNAs in the hypoxic neonatal rat

Hypoxia, a common stressor with preterm birth, increases morbidity and mortality associated with prematurity. Glucocorticoids (GC) are administered to the preterm infant to improve oxygenation; prolonged use of GCs remains controversial. We evaluated a selective glucocorticoid receptor (GR) antagonist (CORT113176) in our neonatal rat model of human prematurity to assess how fasting and hypoxia-induced increases in neonatal corticosterone affects endogenous hormones and endocrine pancreas function. Neonatal rat pups at postnatal day (PD) 2, PD8, and PD15 were pretreated with CORT113176 and, after 60 min of separation and fasting, exposed to hypoxia (8% O2) or control (normoxia) for 30 or 60 minutes while fasting was continued. Plasma corticosterone, ACTH, glucose, and insulin were measured and fasting HOMA-IR (index of insulin resistance) calculated. Glucocorticoid and insulin receptor sensitive gene mRNAs were analyzed in liver, muscle, and adipose to evaluate target tissue biomarkers. CORT113176 pretreatment augmented baseline and hypoxia-induced increases in corticosterone and attenuated hypoxia-induced increases in insulin resistance at PD2. Normoxic and hypoxic stress increased the hepatic GR sensitive gene mRNAs, Gilz and Per1; this was eliminated by pretreatment with CORT113176. CORT113176 pretreatment decreased baseline insulin receptor sensitive gene mRNAs Akt2, Irs1, Pik3r1, and Srebp1c at PD2. We show that CORT113176 variably augments the stress-induced increases in corticosterone concentrations (attenuation of negative feedback) and that GR is critical for hepatic responses to stress in the hypoxic neonate. We also propose that measurement of Gilz and Per1 mRNA expression may be useful to evaluate the effectiveness of GR antagonism.

Immune and hormonal modulation in the postprandial period of bullfrogs (Lithobates catesbeianus)

Mammals show immune up-regulation and increased plasma and local (gastrointestinal tract) concentrations of some immunoregulatory hormones, such as corticosterone and melatonin, after feeding. However, little is known about the endocrine and immune modulation in the postprandial period of ectothermic animals. This study investigated the effects of feeding on endocrine and immune responses in the bullfrog (Lithobates catesbeianus). Frogs were fasted for 10 days and divided into two groups: fasted and fed with fish feed (5% of body mass). Blood and gastrointestinal tract tissues (stomach and intestine) were collected at 6, 24, 48, 96, and 168 h to measure neutrophil/lymphocyte ratio, plasma bacterial killing ability, phagocytosis of blood leukocytes, plasma corticosterone and melatonin; and stomach and intestine melatonin. Feeding increased plasma corticosterone at 24 h and decreased at 168 h; and increased neutrophil/lymphocyte ratio at 6, 24, and 96 h. We also observed decreased bacterial killing ability 48 h after feeding. Stomach melatonin increased after 17-days fasting. We show that feeding activates the hypothalamic-pituitary-interrenal axis and promotes transient immunosuppression, without stimulating an inflammatory response. Increased CORT may mobilize energy to support the digestive processes and melatonin may protect the stomach during fasting. We conclude feeding modulate secretion of immunoregulatory hormones, increasing plasma CORT levels in the beginning followed by a decrease in the end of meal digestion; and systemic immune cell redistribution, increasing NL ratio during almost all meal digestion in bullfrogs. Also, fasting modulate secretion of melatonin in the stomach.

Methamphetamine and Modulation Functionality of the Prelimbic Cortex for Developing a Possible Treatment of Alzheimer’s Disease in an Animal Model

Alzheimer’s disease (AD) is a progressive neurodegenerative condition that causes cognitive impairment and other neuropsychiatric symptoms. Previously, little research has thus far investigated whether methamphetamine (MAMPH) can enhance cognitive function or ameliorate AD symptoms. This study examined whether a low dose of MAMPH can induce conditioned taste aversion (CTA) learning, or can increase plasma corticosterone levels, neural activity, and neural plasticity in the medial prefrontal cortex (mPFC) (responsible for cognitive function), the nucleus accumbens (NAc) and the amygdala (related to rewarding and aversive emotion), and the hippocampus (responsible for spatial learning). Furthermore, the excitations or lesions of the prelimbic cortex (PrL) can affect MAMPH-induced CTA learning, plasma corticosterone levels, and neural activity or plasticity in the mPFC [i.e., PrL, infralimbic cortex (IL), cingulate cortex 1 (Cg1)], the NAc, the amygdala [i.e., basolateral amygdala (BLA) and central amygdala (CeA)], and the hippocampus [i.e., CA1, CA2, CA3, and dentate gyrus (DG)]. In the experimental procedure, the rats were administered either saline or NMDA solutions, which were injected into the PrL to excite or destroy PrL neurons. Additionally, rats received 0.1% saccharin solution for 15 min, followed by intraperitoneal injections of either normal saline or 1 mg/kg MAMPH to induce CTA. A one-way ANOVA was performed to analyze the effects of saccharin intake on CTA, plasma corticosterone levels, and the expression of c-Fos and p-ERK. The results showed that the MAMPH induced CTA learning and increased plasma corticosterone levels. The mPFC, and particularly the PrL and IL and the DG of the hippocampus, appeared to show increased neural activity in c-Fos expression or neural plasticity in p-ERK expression. The excitation of the PrL neurons upregulated neural activity in c-Fos expression and neural plasticity in p-ERK expression in the PrL and IL. In summary, MAMPH may be able to improve cognitive and executive function in the brain and reduce AD symptoms. Moreover, the excitatory modulation of the PrL with MAMPH administration can facilitate MAMPH-induced neural activity and plasticity in the PrL and IL of the mPFC. The present data provide clinical implications for developing a possible treatment for AD in an animal model.

Locus Coeruleus Noradrenergic Modulation of Diurnal Corticosterone, Stress Reactivity and Cardiovascular Homeostasis in Male Rats

Introduction: Activation of the locus coeruleus-noradrenergic (LC-NA) system during awakening is associated with an increase in plasma corticosterone and cardiovascular tone. These studies evaluate the role of the LC in this corticosterone and cardiovascular response. Methods: Male rats, on day 0, were treated IP with either DSP4 (50 mg/ kg body weight) (DSP), a LC-NA specific neurotoxin, or normal saline (SAL). On day 10, animals were surgically prepared with jugular vein [Hypothalamic–pituitary–adrenal (HPA) axis] or carotid artery (hemodynamics) catheters and experiments performed on day 14. HPA axis activity, diurnally (circadian) and after stress [transient hemorrhage (14 mL/kg body weight) or airpuff-startle], and basal and post-hemorrhage hemodynamics were evaluated. On day 16, brain regions from a subset of rats were dissected for norepinephrine and corticotropin-releasing factor (CRF) assay. Results: In DSP rats compared to SAL rats: 1) regional brain norepinephrine was decreased but there was no change in median eminence or olfactory bulb CRF content; 2) during HPA axis acrophase, the plasma corticosterone response was blunted; 3) after hemorrhage and airpuff-startle, the plasma adrenocorticotropic hormone response was attenuated, whereas the corticosterone response was dependent on stressor category; 4) under basal conditions, hemodynamic measures exhibited altered blood flow dynamics and systemic vasodilation; and 5) after hemorrhage, hemodynamics exhibited asynchronous responses. Conclusion: LC-NA modulation of diurnal and stress-induced HPA axis reactivity occurs via distinct neurocircuits. The integrity of the LC-NA system is important to maintain blood flow dynamics. The importance of increases in plasma corticosterone at acrophase to maintain short- and long-term cardiovascular homeostasis is discussed.

LPS regulates pro and anti-inflammatory cytokines, corticosterone, and melatonin in toads

Glucocorticoids and melatonin (MEL) show integrated and complex immunomodulatory effects, mostly described for endotherms, yet underexplored in amphibians. In this context, the RT-qPCR of molecules mediating inflammatory processes in amphibians is a valuable tool to explore the relationships among molecular biology, endocrine mediators, and immune response in these animals. In this study, toads (Rhinella diptycha) received an intraperitoneal saline injection or lipopolysaccharide (LPS; 2 mg/kg). Six hours post-injection, we analyzed plasma corticosterone (CORT) and MEL levels and pro and anti-inflammatory molecules (IL-1β, IL-6, IL-10, IFN-γ, and C1s). We found increased CORT and decreased MEL levels in response to LPS. Also, IL-1β, IL-6, and IL-10 were upregulated in LPS-injected toads compared with saline-injected. Overall, our results demonstrate an LPS-induced inflammatory response with endocrine and immune modulation in R. diptycha toads, exhibiting expected patterns for an inflammatory stimulus within this timeframe (6 h post-injection). Toads were responsive to LPS by secreting different cytokines, such as proinflammatory cytokines IL-1β and IL-6, related to immune cell attraction to inflammatory sites and the anti-inflammatory cytokine IL-10, which limits the rate of leukocyte infiltration, inflammation, and downregulates the expression of proinflammatory cytokines. Increased circulating CORT levels are probably associated with the activation of the hypothalamus-pituitary-interrenal axis by the LPS and the endocrine actions of IL-6. Furthermore, decreased circulating MEL levels are likely due to inhibited MEL secretion by the pineal gland by inflammatory stimuli, indicating the activation/existence of the immune-pineal axis in amphibians.

Behavioral alterations, brain oxidative stress, and elevated levels of corticosterone associated with a pressure injury model in male mice

Objectives Sustained stress can cause physiological disruption in crucial systems like the endocrine, autonomic, and central nervous system. In general, skin damages are physical stress present in hospitalized patients. Also, these pressure injuries lead to pathophysiological mechanisms involved in the neurobiology of mood disorders. Here, we aimed to investigate the behavioral alterations, oxidative stress, and corticosterone levels in the brain areas of mice submitted to the model of pressure injury (PI). Methods The male mice behaviors were assessed in the open field test (OFT), elevated plus maze test (EPM), tail suspension test (TST), and sucrose preference test (SPT). Then, we isolated the prefrontal cortex (PFC), hippocampus (HP), and striatum (ST) by brain dissection. The nonprotein sulfhydryl groups (NP-SH) and malondialdehyde (MDA) were measured in the brain, and also the plasma corticosterone levels were verified. Results PI model decreased the locomotor activity of animals (p<0.05). Considering the EPM test, the PI group showed a decrease in the open arm activity (p<0.01), and an increase in the closed arm activity (p<0.05). PI group showed an increment in the immobility time (p<0.001), and reduced sucrose consumption (p<0.0001) compared to the control groups. Regarding the oxidative/nitrosative profile, all brain areas from the PI group exhibited a reduction in the NP-SH levels (p<0.0001–p<0.01), and an increase in the MDA level (p<0.001–p<0.01). Moreover, the PI male mice presented increased levels of plasma corticosterone (p<0.05). Conclusions Our findings suggest that the PI model induces depressive and anxiety-like behaviors. Furthermore, it induces pathophysiological mechanisms like the neurobiology of depression.