In Alzheimer's disease (AD), memory impairment is the most prominent feature that afflicts patients and their families. Although reactive astrocytes have been observed around amyloid plaques since ...the disease was first described, their role in memory impairment has been poorly understood. Here, we show that reactive astrocytes aberrantly and abundantly produce the inhibitory gliotransmitter GABA by monoamine oxidase-B (Maob) and abnormally release GABA through the bestrophin 1 channel. In the dentate gyrus of mouse models of AD, the released GABA reduces spike probability of granule cells by acting on presynaptic GABA receptors. Suppressing GABA production or release from reactive astrocytes fully restores the impaired spike probability, synaptic plasticity, and learning and memory in the mice. In the postmortem brain of individuals with AD, astrocytic GABA and MAOB are significantly upregulated. We propose that selective inhibition of astrocytic GABA synthesis or release may serve as an effective therapeutic strategy for treating memory impairment in AD.
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•Prenatal exposure to Polyethylene (PE) lead to Autism spectrum disorder (ASD) like traits in mice.•Exposure to PE leads to impaired social interaction and repetitive behaviors in ...mice model.•Exposure to PE leads to disturbance of metabolites and gene expression in brain.•Exposure to PE leads gut microbiome change revealed ASD like traits in mice.•Our finding on ASD in prenatal model was well supported based on already revealed findings.
In common with the increase in environmental pollution in the past 10 years, there has also been a recent increase in the prevalence of autism spectrum disorder (ASD). In this regard, we hypothesized that exposure to microplastics is a potential risk factor for ASD. To evaluate the validity of this hypothesis, we initially examined the accumulation of polyethylene (PE) in the brains of mice and then assessed the behavioral effects using mouse models at different life stages, namely, prenatal, post-weaning, puberty, and adult models. Based on typical behavioral assessments of autistic traits in the model mice, we established that ASD-like traits were induced in mice after PE feeding. In addition, we examined the induction of ASD-like traits in response to microplastic exposure using positron emission tomography, magnetic resonance spectroscopy, quantitative real-time polymerase chain reaction, microarray, and microbiome analysis. We believe these findings provide evidence in microplastics as a potential risk factor for ASD.
Treatment of sleep disorders promotes the long-term use of commercially available sleep inducers that have several adverse effects, including addiction, systemic fatigue, weakness, loss of ...concentration, headache, and digestive problems. Therefore, we aimed to limit these adverse effects by investigating a natural product, the extract of the Hibiscus syriacus Linnaeus flower (HSF), as an alternative treatment. In the electric footshock model, we measured anxiety and assessed the degree of sleep improvement after administering HSF extract. In the restraint model, we studied the sleep rate using PiezoSleep, a noninvasive assessment system. In the pentobarbital model, we measured sleep improvement and changes in sleep-related factors. Our first model confirmed the desirable effects of HSF extract and its active constituent, saponarin, on anxiolysis and Wake times. HSF extract also increased REM sleep time. Furthermore, HSF extract and saponarin increased the expression of cortical GABAA receptor α1 (GABAAR α1) and c-Fos in the ventrolateral preoptic nucleus (VLPO). In the second model, HSF extract and saponarin restored the sleep rate and the sleep bout duration. In the third model, HSF extract and saponarin increased sleep maintenance time. Moreover, HSF extract and saponarin increased cortical cholecystokinin (CCK) mRNA levels and the expression of VLPO c-Fos. HSF extract also increased GABAAR α1 mRNA level. Our results suggest that HSF extract and saponarin are effective in maintaining sleep and may be used as a novel treatment for sleep disorder. Eventually, we hope to introduce HSF and saponarin as a clinical treatment for sleep disorders in humans.
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•HSF attenuates sleep disorder caused by foot shock stress by regulating Wake and REM sleep time in male rats.•HSF improves sleep maintenance after pentobarbital injection in male mice.•HSF may influence sleep improvement through increased VLPO c-Fos and cortical GABAAR αl and CCK.•SP attenuates sleep disorder caused by foot shock stress by regulating Wake time, and increased VLPO c-Fos and cortical CCK in the pentobarbital-induced sleep.•HSF and SP has potential for use as an alternative to conventional benzodiazepines and non-benzodiazepines.
Menopause is a risk factor of anxiety and depression. Also, psychoneurological symptoms are shown in almost all women in the perimenopausal period. The present study investigated if repeated stress ...modulates behavioral changes or the balance of pro- and anti-inflammatory cytokines in ovariectomized (OVX) rats. Albino SD female rats were randomly divided into four groups: the naïve normal group (NOR), a surgically ovariectomized group (OVX), the only stressed group (ST), and the OVX and stressed groups (OVX + ST). We performed a battery of tests such as the forced swimming test (FST), the sucrose intake, and social exploration. In the same animals, corticosterone (CORT) was assessed in the serum, and also, two representative cytokines (IL-1β and IL-4) were examined in different brain regions after all the behavior sessions for all the experimental groups. The OVX + ST group showed more immobility time in FST than the OVX group or the ST group. Also, the OVX + ST group tended to have a decreased active social exploration and sucrose solution intake compared to the OVX group or ST group. The serum concentration of CORT of the OVX + ST group was higher than the OVX group or ST group and also the level of CORT in OVX + ST was markedly increased compared to the NOR group. In the brain, the number of IL-1β immunoreactive neurons of the OVX + ST group was increased compared to the NOR group. The OVX + ST group tended to have an increase in IL-1β-positive neurons compared to the OVX or ST group. However, the number of IL-4 immunoreactive neurons of the OVX + ST group was markedly decreased compared with the NOR group. Also, the IL-4-positive neurons in the OVX + ST group was significantly decreased when compared to the ST group. These results indicate that ovariectomy and stress combine to increase the depressive-like behaviors and neuroinflammatory responses. Together, these data show neuroinflammation as a potential contributor to depressive-like symptoms during menopausal transition.
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.
Tonic inhibition in the brain is mediated through an activation of extrasynaptic GABAA receptors by the tonically released GABA, resulting in a persistent GABAergic inhibitory action. It is one of ...the key regulators for neuronal excitability, exerting a powerful action on excitation/inhibition balance. We have previously reported that astrocytic GABA, synthesized by monoamine oxidase B (MAOB), mediates tonic inhibition via GABA-permeable bestrophin 1 (Best1) channel in the cerebellum. However, the role of astrocytic GABA in regulating neuronal excitability, synaptic transmission, and cerebellar brain function has remained elusive. Here, we report that a reduction of tonic GABA release by genetic removal or pharmacological inhibition of Best1 or MAOB caused an enhanced neuronal excitability in cerebellar granule cells (GCs), synaptic transmission at the parallel fiber-Purkinje cell (PF-PC) synapses, and motor performance on the rotarod test, whereas an augmentation of tonic GABA release by astrocyte-specific overexpression of MAOB resulted in a reduced neuronal excitability, synaptic transmission, and motor performance. The bidirectional modulation of astrocytic GABA by genetic alteration of Best1 or MAOB was confirmed by immunostaining and in vivo microdialysis. These findings indicate that astrocytes are the key player in motor coordination through tonic GABA release by modulating neuronal excitability and could be a good therapeutic target for various movement and psychiatric disorders, which show a disturbed excitation/inhibition balance.
Post-traumatic stress disorder (PTSD) is an important psychological disease that can develop following the physical experience or witnessing of traumatic events. The psychopathological response to ...traumatic stressors increases inflammation in the hippocampus and induces memory deficits. Melatonin (MTG) plays critical roles in circadian rhythm disorders, Alzheimer's disease, and other neurological disorders. However, the cognitive efficiency of MTG and its mechanisms of action in the treatment of PTSD remain unclear. Thus, the present study investigated the effects of MTG on spatial cognitive impairments stimulated by single prolonged stress (SPS) in rats, an animal model of PTSD. Male rats received intraperitoneal (i.p.) administration of various doses of MTG for 21 consecutive days after the SPS procedure.
SPS-stimulated cognitive impairments in the object recognition task and Morris water maze were reversed by MTG treatment (25 mg/kg, i.p). Additionally, MTG significantly increased cognitive memory-related decreases in cAMP-response element-binding (CREB) protein and mRNA levels in the hippocampus. Our results also demonstrate that MTG significantly inhibited SPS-stimulated cognitive memory impairments by inhibiting the expression of proinflammatory cytokines, including tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) in the rat brain.
The present results indicate that MTG can be beneficial for SPS-stimulated memory impairments via changes in CREB expression and proinflammatory mediators. Thus, MTG may be a prophylactic strategy for the prevention or mitigation of the progression of some features of the PTSD pathology.
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