Chronic Stress-Induced Elevation of Melanin-Concentrating Hormone in the Locus Coeruleus Inhibits Norepinephrine Production and Associated With Depression-Like Behaviors in Rats.

BACKGROUND: Melanin-concentrating hormone (MCH) is a hypothalamic neuropeptide that projects throughout the central nervous system, including the noradrenergic locus coeruleus (LC). Our previous study suggested that MCH/MCH receptor 1 (MCHR1) in the LC may be involved in the regulation of depression. The present study investigated whether the role of MCH/MCHR1 in the LC in depression-like behaviors is associated with the regulation of norepinephrine. METHOD: Chronic unpredictable stress (CUS) and an acute intra-LC microinjection of MCH induced depression-like behaviors in rats. The MCHR1 antagonist SNAP-94847 was also microinjected in the LC in rats that were suffering CUS or treated with MCH. The sucrose preference, forced swim, and locomotor tests were used for behavioral evaluation. Immunofluorescence staining, enzyme-linked immunosorbent assay, western blot, and high-performance liquid chromatography with electrochemical detection were used to explore the mechanism of MCH/MCHR1 in the regulation of depression-like behaviors. RESULTS: CUS induced an abnormal elevation of MCH levels and downregulated MCHR1 in the LC, which was highly correlated with the formation of depression-like behaviors. SNAP-94847 exerted antidepressant effects in CUS-exposed rats by normalizing tyrosine hydroxylase, dopamine ß hydroxylase, and norepinephrine in the LC. An acute microinjection of MCH induced depression-like behaviors through its action on MCHR1. MCHR1 antagonism in the LC significantly reversed the MCH-induced downregulation of norepinephrine production by normalizing MCHR1-medicated cAMP-PKA signaling. CONCLUSIONS: Our study confirmed that the MCH/MCHR1 system in the LC may be involved in depression-like behaviors by downregulating norepinephrine production. These results improve our understanding of the pathogenesis of depression that is related to the MCH/MCHR1 system in the LC.

Reduction of BDNF Levels and Biphasic Changes in Glutamate Release in the Prefrontal Cortex Correlate with Susceptibility to Chronic Stress-Induced Anhedonia.

Chronic stress has been considered to induce depressive symptoms, such as anhedonia, particularly in susceptible individuals. Synaptic plasticity in the prefrontal cortex (PFC) is closely associated with susceptibility or resilience to chronic stress-induced anhedonia. However, effects of chronic stress with different durations on the neurobiological mechanisms that underlie susceptibility to anhedonia remain unclear. The present study investigated effects of chronic mild stress (CMS) for 14, 21, and 35 d on anhedonia-like behavior and glutamate synapses in the PFC. We found that brain-derived neurotrophic factor (BDNF) levels in the PFC significantly decreased only in anhedonia-susceptible rats that were exposed to CMS for 14, 21, and 35 d. Additionally, 14 d of CMS increased prefrontal glutamate release, and 35 d of CMS decreased glutamate release, in addition to reducing synaptic proteins and spine density in the PFC. Moreover, we found that anhedonia-like behavior in a subset of rats spontaneously decreased, accompanied by the restoration of BDNF levels and glutamate release, on day 21 of CMS. Ketamine treatment restored the reduction of BDNF levels and biphasic changes in glutamate release that were induced by CMS. Our findings revealed a progressive reduction of synaptic plasticity and biphasic changes in glutamate release in the PFC during CMS. Reductions of BDNF levels may be key neurobiological markers of susceptibility to stress-induced anhedonia.

Anti-stress effects of combined block of glucocorticoid and mineralocorticoid receptors in the paraventricular nucleus of the hypothalamus.

BACKGROUND AND PURPOSE: Mineralocorticoid receptors (MRs), glucocorticoid receptors (GRs) and corticotropin-releasing factor (CRF) in the paraventricular nucleus of hypothalamus (PVN) are involved in the response to stress. The present study investigated the role of GRs and MRs in the PVN in regulating depressive and anxiety-like behaviours. EXPERIMENTAL APPROACH: To model chronic stress, rats were exposed to corticosterone treatment via drinking water for 21 days, and GR antagonist RU486 and MR antagonist spironolactone, alone and combined, were directly injected in the PVN daily for the last 7 days of corticosterone treatment. Behavioural tests were run on days 22 and 23. Depressive- and anxiety-like behaviours were evaluated in forced swim test, sucrose preference test, novelty-suppressed feeding test and social interaction test. The expression of GRs, MRs and CRF were detected by western blot. KEY RESULTS: Rats exposed to corticosterone exhibited depressive- and anxiety-like behaviours. The expression of GRs and MRs decreased, and CRF levels increased in the PVN. The intra-PVN administration of RU486 increased the levels of GRs and CRF without influencing depressive- or anxiety-like behaviours. The spironolactone-treated group exhibited an increase in MRs without influencing GRs and CRF in the PVN and improved anxiety-like behaviours. Interestingly, the intra-PVN administration of RU486 and spironolactone combined restored expression of GRs, MRs and CRF and improved depressive- and anxiety-like behaviours. CONCLUSION AND IMPLICATIONS: In this rat model of stress, the simultaneous restoration of GRs, MRs and CRF in the PVN might play an important role in the treatment of depression and anxiety.

Prophylactic effects of sporoderm-removed Ganoderma lucidum spores in a rat model of streptozotocin-induced sporadic Alzheimer's disease.

ETHNOPHARMACOLOGICAL RELEVANCE: Ganoderma lucidum (G. lucidum, Lingzhi), also known as "immortality mushroom" has been broadly used to improve health and longevity for thousands of years in Asia. G. lucidum and its spores have been used to promote health, based on its broad pharmacological and therapeutic activity. This species is recorded in Chinese traditional formula as a nootropic and has been suggested to improve cognitive dysfunction in Alzheimer's disease. However, little is known about the nootropic effects and molecular mechanism of action of G. lucidum spores. AIM OF THE STUDY: The present study investigated the protective effects of sporoderm-deficient Ganoderma lucidum spores (RGLS) against learning and memory impairments and its mechanism of action. MATERIALS AND METHODS: In the Morris water maze, the effects of RGLS on learning and memory impairments were evaluated in a rat model of sporadic Alzheimer's disease that was induced by an intracerebroventricular injection of streptozotocin (STZ). Changes in amyloid ß (Aß) expression, Tau expression and phosphorylation, brain-derived neurotrophic factor (BDNF), and the BDNF receptor tropomyosin-related kinase B (TrkB) in the hippocampus were evaluated by Western blot. RESULTS: Treatment with RGLS (360 and 720 mg/kg) significantly enhanced memory in the rat model of STZ-induced sporadic Alzheimer's disease and reversed the STZ-induced increases in Aß expression and Tau protein expression and phosphorylation at Ser199, Ser202, and Ser396. The STZ-induced decreases in neurotrophic factors, including BDNF, TrkB and TrkB phosphorylation at Tyr816, were reversed by treatment with RGLS. CONCLUSION: These findings indicate that RGLS prevented learning and memory impairments in the present rat model of STZ-induced sporadic Alzheimer's disease, and these effects depended on a decrease in Aß expression and Tau hyperphosphorylation and the modulation of BDNF-TrkB signaling in the hippocampus.

A common neuronal mechanism of hypertension and sleep disturbances in spontaneously hypertensive rats: Role of orexinergic neurons.

Epidemiologic studies have shown that sleep disorders are associated with the development of hypertension. The present study investigated dynamic changes in sleep patterns during the development of hypertension across the lifespan in spontaneously hypertensive rats (SHRs) and the neural mechanism that underlies these comorbidities, with a focus on the orexinergic system. Blood pressure in rats was measured using a noninvasive blood pressure tail cuff. Sleep was monitored by electroencephalographic and electromyographic recordings. Immunohistochemistry was used to detect the density and activity of orexinergic neurons in the perifornical nucleus. Hcrt2-SAP (400 or 800 ng) was microinjected in the lateral hypothalamus to lesion orexinergic neurons. Compared with Wistar-Kyoto rats, SHRs exhibited various patterns of sleep disturbances. In SHRs, dynamic changes in hypersomnia in the rats' active phase was not synchronized with the development of hypertension, but hyperarousal in the inactive phase and difficulties in falling asleep were observed concurrently with the development of hypertension. Furthermore, the density and activity of orexinergic neurons in the perifornical nucleus were significantly higher in SHRs than in age-matched Wistar-Kyoto rats. The reduction of orexinergic neurons in the lateral hypothalamus partially ameliorated the development of hypertension and prevented difficulties in falling asleep in SHRs. These results indicate that although the correlation between sleep disturbances and hypertension is very complex, common mechanisms may underlie these comorbidities in SHRs. Overactivity of the orexin system may be one such common mechanism.