Hippocampal Neurotransmission Research Articles

Non-nutritive Sweetener Aspartame Disrupts Circadian Behavior and Causes Memory Impairment in Mice.

As a non-nutritive sweetener, aspartame is widely used in everyday life. However, its safety is highly controversial, especially its effects on neurobehavior. We evaluated the effects of chronic daily oral administration of aspartame-containing drinking water (at doses equivalent to 7-28% of the FDA-recommended human DIV) on memory and rhythm behaviors in mice and further investigated changes at the molecular level in the brains. Our results demonstrated that mice exposed to aspartame exhibited memory impairment. Disorders of hippocampal neurotransmitter metabolism and pathological damage may be responsible for the aspartame-induced memory impairment via inhibition of the BDNF/TrkB pathway. Furthermore, our findings suggested that disturbed clock gene expression in the hypothalamus after aspartame exposure led to altered rest-activity behavior, and this disruption of the circadian rhythm may exacerbate memory impairment. This study highlights the negative neurobehavioral effects of aspartame and provides valuable insights into its rational and safe use.

Thyroid hormone transporters MCT8/OATP1C1 deficient mice exhibit increased seizure susceptibility together with an imbalanced hippocampal neurotransmission

Thyroid hormone transporters MCT8/OATP1C1 deficient mice exhibit increased seizure susceptibility together with an imbalanced hippocampal neurotransmission

Treatment response of venlafaxine induced alterations of gut microbiota and metabolites in a mouse model of depression.

Antidepressants remain the first-line treatment for depression. However, the factors influencing medication response are still unclear. Accumulating evidence implicates an association between alterations in gut microbiota and antidepressant response. Therefore, the aim of this study is to investigate the role of the gut microbiota-brain axis in the treatment response of venlafaxine. After chronic social defeat stress and venlafaxine treatment, mice were divided into responders and non-responders groups. We compared the composition of gut microbiota using 16S ribosomal RNA sequencing. Meanwhile, we quantified metabolomic alterations in serum and hippocampus, as well as hippocampal neurotransmitter levels using liquid chromatography-mass spectrometry. We found that the abundances of 29 amplicon sequence variants (ASVs) were significantly altered between the responders and non-responders groups. These ASVs belonged to 8 different families, particularly Muribaculaceae. Additionally, we identified 38 and 39 differential metabolites in serum and hippocampus between the responders and non-responders groups, respectively. Lipid, amino acid, and purine metabolisms were enriched in both serum and hippocampus. In hippocampus, the concentrations of tryptophan, phenylalanine, gamma-aminobutyric acid, glutamic acid, and glutamine were increased, while the level of succinic acid was decreased in the responders group, compared with the non-responders group. Our findings suggest that the gut microbiota may play a role in the antidepressant effect of venlafaxine by modulating metabolic processes in the central and peripheral tissues. This provides a novel microbial and metabolic framework for understanding the impact of the gut microbiota-brain axis on antidepressant response.

Microbiome Metabolomic Analysis of the Anxiolytic Effect of Baihe Dihuang Decoction in a Rat Model of Chronic Restraint Stress.

The Baihe Dihuang decoction (BDD) is a representative traditional Chinese medicinal formula that has been used to treat anxiety disorders for thousands of years. This study aimed to reveal mechanisms of anxiolytic effects of BDD with multidimensional omics. First, 28-day chronic restraint stress (CRS) was used to create a rat model of anxiety, and the open field test and elevated plus maze were used to assess anxiety-like behavior. Enzyme-linked immunosorbent assay (ELISA), hematoxylin-eosin staining, and immunofluorescence staining were used to evaluate inflammatory response. Besides, 16S rRNA gene sequencing assessed fecal microbiota composition and differential microbiota. Non-targeted metabolomics analysis of feces was performed to determine fecal biomarkers, and targeted metabolomics was used to observe the levels of hippocampus neurotransmitters. Finally, Pearson correlation analysis was used to examine relationships among gut microbiota, fecal metabolites, and neurotransmitters. BDD significantly improved anxiety-like behaviors in CRS-induced rats and effectively ameliorated hippocampal neuronal damage and abnormal activation of hippocampal microglia. It also had a profound effect on the diversity of microbiota, as evidenced by significant changes in the abundance of 10 potential microbial biomarkers at the genus level. Additionally, BDD led to significant alterations in 18 fecal metabolites and 12 hippocampal neurotransmitters, with the majority of the metabolites implicated in amino acid metabolism pathways such as D-glutamine and D-glutamate, alanine, arginine and proline, and tryptophan metabolism. Furthermore, Pearson analysis showed a strong link among gut microbiota, metabolites, and neurotransmitters during anxiety and BDD treatment. BDD can effectively improve anxiety-like behaviors by regulating the gut-brain axis, including gut microbiota and metabolite modification, suppression of hippocampal neuronal inflammation, and regulation of neurotransmitters.

Establishment of a pharmacokinetics and pharmacodynamics model of Schisandra lignans against hippocampal neurotransmitters in AD rats based on microdi-alysis liquid chromatography-mass spectrometry.

Objective: Our previous studies substantiated that the biological activity of Schisandra chinensis lignans during the treatment of Alzheimer's disease (AD) was mediated by neurotransmitter levels, and 15 of its active components were identified. However, the pharmacokinetic and pharmacodynamic relationship of Schisandra chinensis lignans has been less studied. The objective of this study was to investigate the relationship between the pharmacokinetics and pharmacodynamics of Schisandra chinensis lignans in the treatment of AD, and to establish a pharmacokinetic-pharmacodynamic (PK-PD) model. Methods and Results: Herein, we established a microdialysis-ultra performance liquid chromatography-triple quadruple mass spectrometry (MD-LC-TQ-MS) technique that could simultaneously and continuously collect and quantitatively analyze the active compounds and neurotransmitters related to the therapeutic effects of Schisandra chinensis in awake AD rats. Eight lignans were detected in the hippocampus, and a PK-PD model was established. The fitted curves highlighted a temporal lag between the maximum drug concentration and the peak drug effect. Following treatment, the levels of four neurotransmitters tended to converge with those observed in the sham operation group. Conclusion: By establishing a comprehensive concentration-time-effect relationship for Schisandra chinensis lignans in AD treatment, our study provides novel insights into the in vivo effects of these lignans in AD rats.

Essential oil of Pterocarpus santalinus L. alleviates behavioral impairments in social defeat stress-exposed mice by regulating neurotransmission and neuroinflammation

BackgroundPterocarpus santalinus L. essential oil (PSEO) is traditionally employed for treating fever and mental aberrations. We aim to explore the antidepressant potential of intranasal PSEO in social defeat stress (SDS)-expose mice and identify its mechanisms and components. MethodsPSEO components were analyzed using gas chromatography-mass spectrometry (GC-MS). C57BL/6 mice underwent a 10-day SDS with intranasal PSEO (10, 20 mg/kg) for 21 days. Efficacy was evaluated through changes in behaviors and serum corticosterone (CORT), hippocampal neurotransmitter, and inflammatory cytokine levels. In vitro effects were examined using primary hippocampal neurons, PC12 and BV2 cells. ResultsGC-MS identified 22 volatile compounds in PSEO, and (+)-ledene (16.7%), cedrol (13.5%), and isoaromadendrene epoxide (7.0%) as major components. PSEO (20 mg/kg) significantly reversed SDS-induced social withdrawal, increased open-area explorations in the open field test (OFT) and elevated plus maze (EPM) test, and reduced immobility time in the tail suspension test (TST) and forced swimming test (FST). PSEO downregulated serum CORT and hippocampal interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α levels, while increasing hippocampal gamma-aminobutyric acid (GABA), norepinephrine (NE), and serotonin (5-HT) levels. PSEO (0.1, 1, 10 µg/mL) reduced neurotoxicity and neuroinflammation in PC12 and BV2 cells, respectively. PSEO (10 µg/mL) enhanced glutamic acid decarboxylase 6 (GAD6)- and GABA B receptor 1 (GABABR1)-positive puncta in the hippocampal neurons and FM1-43 fluorescence intensity. ConclusionIntranasal PSEO exhibited antidepressant-like effects on SDS-exposed mice, potentially through modulating stress hormone, neurotransmission, and neuroinflammation. Further investigation into the pharmacokinetics, bioavailability, and mechanisms of (+)-ledene, cedrol, and isoaromadendrene epoxide is needed.

Intranasal administration of the essential oil from Perillae Folium ameliorates social defeat stress-induced behavioral impairments in mice

Ethnopharmacological relevancePerillae Folium, the leaves and twigs of Perilla frutescens (L.) Britton, has been included in many traditional Chinese medicine herbal formulas to treat depression. However, the precise antidepressant mechanism of the essential oil from Perillae Folium (PFEO) has not been fully investigated. Aim of the studyTo assess the effects and potential mechanisms of PFEO on depression using animal models and network pharmacology analysis. Materials and methodsPFEO was intranasally administered to a mouse model of social defeat stress (SDS). The antidepressant effects of PFEO on SDS-induced mice were evaluated using behavioral tests. Enzyme-linked immunosorbent assay (ELISA) and western blot were performed to measure the levels of depression-related biomarkers in the hippocampus and serum of the mice. The chemical compounds of PFEO were determined using gas chromatography-mass spectrometry (GC-MS). Network pharmacology and molecular docking analyses were conducted to investigate the potential bioactive components of PFEO and the mechanisms underlying the antidepressant effects. To validate the mechanisms of the bioactive compounds, in vitro models using PC12 and BV2 cells were established and the blood-brain barrier (BBB) permeability was evaluated. ResultsThe intranasal administration of PFEO suppressed SDS-induced depression in mice by increasing the time spent in the social zone and the social interactions in the social interaction test and by decreasing the immobility time in the tail suspension and forced swimming tests. Moreover, the PFEO treatment reduced the SDS-induced anxiety-like behavior, as inferred from the increased activity in the central zone observed in the open field test and in the open arms observed in the elevated plus maze test. PFEO administration recovered the SDS-induced decrease in the levels of 5-HT, NE, gamma-aminobutyric acid (GABA), and p-ERK in the hippocampus of mice. Furthermore, the increased serum corticosterone level was also attenuated by the PFEO treatment. A total of 21 volatile compounds were detected in PFEO using GC-MS, among which elemicin (15.52%), apiol (15.16%), and perillaldehyde (12.79%) were the most abundant ones. The PFEO compounds targeted 32 depression-associated genes, which were mainly related to neural cells and neurotransmission pathways. Molecular docking indicated good binding affinities between the bioactive components of PFEO (apiol, β-caryophyllene, elemicin, and myristicin) and the key targets, including ACHE, IL1B, IL6, MAOB, SLC6A2, SLC6A3, SLC6A4, and tumor necrosis factor. Among the four compounds, β-caryophyllene, elemicin, and myristicin were more effective in reducing neurotoxicity and neuroinflammation. Elemicin showed the highest BBB permeability rate. ConclusionsThis study shows the antidepressant activities of PFEO in an SDS-induced mouse model and suggests its potential mechanisms of action: regulation of the corticosterone levels, hippocampal neurotransmitters, and ERK signaling. Apiol, β-caryophyllene, elemicin, and myristicin may be the main contributors to the observed effects induced by PFEO. Further studies are needed to fully elucidate the underlying mechanisms and the main PFEO bioactive components.

Amaranthus viridis improves relative anxiety behaviour and cognitive deficit in rotenone induced Parkinsonism in albino rats

Background: Parkinson’s disease (PD) is typically characterised by motor shortfalls. However, non-motor symptoms like mood disorders (anxiety, depression) and impaired cognition are also associated features. Previous studies have demonstrated a neuroprotective effect a plant against a disease. Consequently, this current study was focused on assessing its efficacy in extenuating non-motor shortfalls such as anxiety-like behaviour and impaired cognition induced by rotenone. Methods: PD was induced in rats by administering rotenone (10 mg/kg BW orally) for 28 days. The vehicle and the test drug were given orally daily for one hour prior to rotenone administration. The protective effect of methanol extract of A. viridis (500 mg/kg BW) was assessed through an array of tests; elevated plus maze test, Morris water maze test, and novel object recognition test. The rats were sacrificed on day 28th and neurobiochemical analyses of the hippocampus were performed using HPLC. Results: The findings of this study showed that co-administration of A. viridis reversed the rotenone-induced anxiety-like behaviour and cognitive shortfalls to a significant extent (p<0.001). It also restored the hippocampal neurotransmitters [(5-hydroxytryptamine (5-HT), 5-hydroxy indole acetic acid (5-HIAA), and dopamine (Da)] significantly (p<0.001). Conclusions: Amaranthus viridis offered neuroprotective effects that ameliorate non-motor symptoms in PD. This could be a novel insight into the therapy of PD. This study provides scientific evidence that A. viridis attenuates non-motor symptoms like anxiety-like behaviour and cognitive deficits in Parkinsonism. This extract can be a potential candidate in herbal formulations as a neuroprotectant against PD.

Assessment of Biochemical and Neuroactivities of Cultural Filtrate from Trichoderma harzianum in Adjusting Electrolytes and Neurotransmitters in Hippocampus of Epileptic Rats.

Epilepsy is a serious chronic neurological disorder, which is accompanied by recurrent seizures. Repeated seizures cause physical injuries and neuronal dysfunction and may be a risk of cancer and vascular diseases. However, many antiepileptic drugs (AEDs) have side effects of mood alteration or neurocognitive function, a reduction in neuron excitation, and the inhibition of normal activity. Therefore, the present study aimed to evaluate the effect of secondary metabolites of Trichoderma harzianum cultural filtrate (ThCF) when adjusting different electrolytes and neurotransmitters in the hippocampus of epileptic rats. Cytotoxicity of ThCF against LS-174T cancer cells was assessed using a sulforhodamine B (SRB) assay. Quantitative estimation for some neurotransmitters, electrolytes in sera or homogenate of hippocampi tissues, and mRNA gene expression for ion or voltage gates was assessed by quantitative Real-Time PCR. Treatment with ThCF reduces the proliferative percentage of LS-174T cells in a concentration-dependent manner. ThCF administration improves hyponatremia, hyperkalemia, and hypocalcemia in the sera of the epilepticus model. ThCF rebalances the elevated levels of many neurotransmitters and reduces the release of GABA and acetylcholine-esterase. Also, treatments with ThCF ameliorate the downregulation of mRNA gene expression for some gate receptors in hippocampal homogenate tissues and recorded a highly significant elevation in the expression of SCN1A, CACNA1S, and NMDA. Secondary metabolites of Trichoderma (ThCF) have cytotoxic activity against LS-174T (colorectal cancer cell line) and anxiolytic-like activity through a GABAergic mechanism of action and an increase in GABA as inhibitory amino acid in the selected brain regions and reduced levels of NMDA and DOPA. The present data suggested that ThCF may inhibit intracellular calcium accumulation by triggering the NAADP-mediated Ca2+ signaling pathway. Therefore, the present results suggested further studies on the molecular pathway for each metabolite of ThCF, e.g., 6-pentyl-α-pyrone (6-PP), harzianic acid (HA), and hydrophobin, as an alternative drug to mitigate the side effects of AEDs.

Carbamoylated Erythropoietin-Induced Cerebral Blood Perfusion and Vascular Gene Regulation.

Cerebral hypoperfusion is associated with enhanced cognitive decline and increased risk of neuropsychiatric disorders. Erythropoietin (EPO) is a neurotrophic factor known to improve cognitive function in preclinical and clinical studies of neurodegenerative and psychiatric disorders. However, the clinical application of EPO is limited due to its erythropoietic activity that can adversely elevate hematocrit in non-anemic populations. Carbamoylated erythropoietin (CEPO), a chemically engineered non-erythropoietic derivative of EPO, does not alter hematocrit and maintains neurotrophic and behavioral effects comparable to EPO. Our study aimed to investigate the role of CEPO in cerebral hemodynamics. Magnetic resonance imaging (MRI) analysis indicated increased blood perfusion in the hippocampal and striatal region without altering tight junction integrity. In vitro and in vivo analyses indicated that hippocampal neurotransmission was unaltered and increased cerebral perfusion was likely due to EDRF, CGRP, and NOS-mediated vasodilation. In vitro analysis using human umbilical vein endothelial cells (HUVEC) and hippocampal vascular gene expression analysis showed CEPO to be a non-angiogenic agent which regulates the MEOX2 gene expression. The results from our study demonstrate a novel role of CEPO in modulating cerebral vasodilation and blood perfusion.

Meloxicam Targets COX-2/NOX1/NOX4/Nrf2 Axis to Ameliorate the Depression-like Neuropathology Induced by Chronic Restraint Stress in Rats.

Meloxicam has shown significant neuroprotection in experimental models of stroke, Alzheimer's disease, and Parkinson's disease. However, the potential of meloxicam to treat depression-like neuropathology in a chronic restraint stress (CRS) model and the associated molecular changes has been insufficiently explored. The current work aimed to explore the potential neuroprotective actions of meloxicam against CRS-evoked depression in rats. In the current experiments, animals received meloxicam (10 mg/kg/day; i.p.) for 21 days, and CRS was instigated by restraining the animals for 6 h/day during the same period. The sucrose preference test and the forced swimming test were used to explore the depression-linked anhedonia/despair, whereas the open-field test examined the animals' locomotor activity. The current findings revealed that CRS elicited typical depression behavioral anomalies in the animals, including anhedonia, despair, and diminished locomotor activity; these findings were reinforced with Z-normalization scores. These observations were corroborated by brain histopathological changes and increased damage scores. In CRS-exposed animals, serum corticosterone spiked, and the hippocampi revealed decreased monoamine neurotransmitter levels (norepinephrine, serotonin, and dopamine). Mechanistically, neuroinflammation was evident in stressed animals, as shown by elevated hippocampal TNF-α and IL-1β cytokines. Moreover, the hippocampal COX-2/PGE2 axis was activated in the rats, confirming the escalation of neuroinflammatory events. In tandem, the pro-oxidant milieu was augmented, as seen by increased hippocampal 8-hydroxy-2'-deoxyguanosine alongside increased protein expression of the pro-oxidants NOX1 and NOX4 in the hippocampi of stressed animals. In addition, the antioxidant/cytoprotective Nrf2/HO-1 cascade was dampened, as evidenced by the lowered hippocampal protein expression of Nrf2 and HO-1 signals. Interestingly, meloxicam administration mitigated depression manifestations and brain histopathological anomalies in the rats. These beneficial effects were elicited by meloxicam's ability to counteract the corticosterone spike and hippocampal neurotransmitter decrease while also inhibiting COX-2/NOX1/NOX4 axis and stimulating Nrf2/HO-1 antioxidant pathway. Together, the present findings prove the neuroprotective/antidepressant actions of meloxicam in CRS-induced depression by ameliorating hippocampal neuroinflammation and pro-oxidant changes, likely by modulating COX-2/NOX1/NOX4/Nrf2 axis.

Prelimbic Cortical Stimulation Induces Antidepressant-like Responses through Dopaminergic-Dependent and -Independent Mechanisms.

High-frequency stimulation (HFS) is a promising therapy for patients with depression. However, the mechanisms underlying the HFS-induced antidepressant-like effects on susceptibility and resilience to depressive-like behaviors remain obscure. Given that dopaminergic neurotransmission has been found to be disrupted in depression, we investigated the dopamine(DA)-dependent mechanism of the antidepressant-like effects of HFS of the prelimbic cortex (HFS PrL). We performed HFS PrL in a rat model of mild chronic unpredictable stress (CUS) together with 6-hydroxydopamine lesioning in the dorsal raphe nucleus (DRN) and ventral tegmental area (VTA). Animals were assessed for anxiety, anhedonia, and behavioral despair. We also examined levels of corticosterone, hippocampal neurotransmitters, neuroplasticity-related proteins, and morphological changes in dopaminergic neurons. We found 54.3% of CUS animals exhibited decreased sucrose consumption and were designated as CUS-susceptible, while the others were designated CUS-resilient. HFS PrL in both the CUS-susceptible and CUS-resilient animals significantly increased hedonia, reduced anxiety, decreased forced swim immobility, enhanced hippocampal DA and serotonin levels, and reduced corticosterone levels when compared with the respective sham groups. The hedonic-like effects were abolished in both DRN- and VTA-lesioned groups, suggesting the effects of HFS PrL are DA-dependent. Interestingly, VTA-lesioned sham animals had increased anxiety and forced swim immobility, which was reversed by HFS PrL. The VTA-lesioned HFS PrL animals also had elevated DA levels, and reduced p-p38 MAPK and NF-κB levels when compared to VTA-lesioned sham animals. These findings suggest that HFS PrL in stressed animals leads to profound antidepressant-like responses possibly through both DA-dependent and -independent mechanisms.

Electric foot-shock induces neurobehavioral aberrations due to imbalance in oxidative status, stress hormone, neurochemical profile, and irregular cortical-beta wave pattern in rats: A validated animal model of anxiety

Neuropsychiatric disorders can be modeled on animals to investigate the neural mechanism underlying these disorders. Models of neuropsychiatric disorders, such as anxiety, basically aim to produce the signs and symptoms of human anxiety disorders in laboratory animals. Electric foot-shock is recommended to induce anxiety-like symptoms in rodents. For this purpose, however, a range of current intensities is available in the literature. The present study aims to modify the existing practices of generating anxiety-like symptoms through electric foot-shock by identifying an optimum current intensity and combining it with behavioral paradigms to produce a rat model of anxiety. Furthermore, the validity of the model was confirmed by checking the fulfillment of three validity criteria necessary for the development of any disease model including face validity, construct validity, and predictive validity. In the current study, after pre-testing, 1.0 mA electric intensity was selected to produce the model of anxiety. The results showed that the induction of 1.0 mA electric foot-shock induces abnormal behavioral effects which were similar to anxiety-like effects as evident by social interaction test, light-dark transition test, and open field test. Moreover, aberrations in the levels of the stress hormone, oxidative stress parameters, hippocampal neurotransmitter levels, and cortical-EEG wave pattern were also observed in the rat model of anxiety which were successfully overcome using diazepam. In conclusion, the outcome of our study suggests that electric foot-shock can be an adequate stressor to produce a validated animal model of anxiety and this model can be confidently used to identify and screen new and/or novel anxiolytics.

Extracellular vesicles from hyperammonemic rats induce neuroinflammation in hippocampus and impair cognition in control rats.

Patients with liver cirrhosis show hyperammonemia and peripheral inflammation and may show hepatic encephalopathy with cognitive impairment, reproduced by rats with chronic hyperammonemia. Peripheral inflammation induces neuroinflammation in hippocampus of hyperammonemic rats, altering neurotransmission and leading to cognitive impairment. Extracellular vesicles (EVs) may transmit pathological effects from the periphery to the brain. We hypothesized that EVs from peripheral blood would contribute to cognitive alterations in hyperammonemic rats. The aims were to assess whether EVs from plasma of hyperammonemic rats (HA-EVs) induce cognitive impairment and to identify the underlying mechanisms. Injection of HA-EVs impaired learning and memory, induced microglia and astrocytes activation and increased TNFα and IL-1β. Ex vivo incubation of hippocampal slices from control rats with HA-EVs reproduced these alterations. HA-EVs increased membrane expression of TNFR1, reduced membrane expression of TGFβR2 and Smad7 and IκBα levels and increased IκBα phosphorylation. This led to increased activation of NF-κB and IL-1β production, altering membrane expression of NR2B, GluA1 and GluA2 subunits, which would be responsible for cognitive impairment. All these effects of HA-EVs were prevented by blocking TNFα, indicating that they were mediated by enhanced activation of TNFR1 by TNFα. We show that these mechanisms are very different from those leading to motor incoordination, which is due to altered GABAergic neurotransmission in cerebellum. This demonstrates that peripheral EVs play a key role in the transmission of peripheral alterations to the brain in hyperammonemia and hepatic encephalopathy, inducing neuroinflammation and altering neurotransmission in hippocampus, which in turn is responsible for the cognitive deficits.

Targeting the Endoplasmic Reticulum Stress-Linked PERK/GRP78/CHOP Pathway with Magnesium Sulfate Attenuates Chronic-Restraint-Stress-Induced Depression-like Neuropathology in Rats.

Magnesium sulfate has demonstrated marked neuroprotection in eclampsia, hypoxia, stroke, and post-traumatic brain injury rodent models. However, its potential impact against chronic-restraint-stress (CRS)-induced depression-like neuropathology and associated alterations in endoplasmic reticulum (ER) stress have not been adequately examined. The present study aimed to investigate the neuroprotective potential of magnesium sulfate in a rat model of CRS-triggered depression-like behavioral disturbance and the underlying molecular mechanisms. Herein, CRS was induced by placing rats into restraining tubes for 6 h/day for 21 days and the animals were intraperitoneally injected with magnesium sulfate (100 mg/kg/day) during the study period. After stress cessation, the depression-like behavior was examined by the open-field test, sucrose preference test, and forced swimming test. The present data demonstrated that CRS triggered typical depression-like behavioral changes which were confirmed by the Z-normalization scores. Mechanistically, serum circulating corticosterone levels spiked, and the hippocampi of CRS-exposed animals demonstrated a significant decline in serotonin, norepinephrine, and dopamine neurotransmitters. At the molecular level, the hippocampal pro-inflammatory TNF-alpha and IL-1β cytokines and the oxidative stress marker 8-hydroxy-2'-deoxyguanosine (8-HG) increased in stressed animals. In tandem, enhancement of hippocampal ER stress was evidenced by the activation of iNOS/PERK/GRP78/CHOP axis seen by increased protein expression of iNOS, PERK, GRP78, and CHOP signal proteins in the hippocampi of stressed rats. Interestingly, magnesium sulfate administration attenuated the depression-like behavioral outcomes and the histopathological changes in the brain hippocampi. These favorable actions were driven by magnesium sulfate's counteraction of corticosterone spike, and hippocampal neurotransmitter decline, alongside the attenuation of neuroinflammation, pro-oxidation, and ER stress. In conclusion, the current results suggest the promising neuroprotective/antidepressant actions of magnesium sulfate in CRS by dampening inflammation, ER stress, and the associated PERK/GRP78/CHOP pathway.

Impact of nonalcoholic fatty liver disease-related metabolic state on depression.

Nonalcoholic fatty liver disease (NAFLD), also recently referred as metabolic (dysfunction)-associated fatty liver disease (MAFLD), is characterized by hepatocyte steatosis in the setting of a metabolic risk conditions and in the absence of an underlying precursor, for instance alcohol consumption, hepatotropic viruses and hepatotoxic drugs. A possible association between NAFLD and depression has been proposed, owing to intersecting pathophysiological pathways. This narrative review aimed to summarize the current evidence that illustrate the potential pathophysiological and clinical linkage between NAFLD-related metabolic state and depression. Prefrontal cortex lesions are suggested to be a consequence of liver steatosis-associated systematic hyperinflammatory state, a phenomenon also occurring in depression. In addition, depressive symptoms are present in neurotransmitter imbalances. These abnormalities seem to be correlated with NAFLD/MAFLD, in terms of insulin resistance (IR), ammonia and gut dysbiosis' impact on serotonin, dopamine, noradrenaline levels and GABA (gamma aminobutyric acid) receptors. Furthermore, reduced levels of nesfatin-1 and copine-6-associated BDNF (brain-derived neurotrophic factor) levels have been considered as a probable link between NAFLD and depression. Regarding NAFLD-related gut dysbiosis, it stimulates mediators including lipopolysaccharides, short-chain fatty acids and bile acids, which play significant role in depression. Finally, western diet and IR, which are mainstay components of NAFLD/MAFLD, are, also, substantiated to affect neurotransmitters in hippocampus and produce neurotoxic lipids that contribute to neurologic dysfunction, and thus trigger emotional disturbances, mainly depressive symptoms.

Hippocampus: Molecular, Cellular, and Circuit Features in Anxiety.

Anxiety disorders are currently a major psychiatric and social problem, the mechanisms of which have been only partially elucidated. The hippocampus serves as a major target of stress mediators and is closely related to anxiety modulation. Yet so far, its complex anatomy has been a challenge for research on the mechanisms of anxiety regulation. Recent advances in imaging, virus tracking, and optogenetics/chemogenetics have permitted elucidation of the activity, connectivity, and function of specific cell types within the hippocampus and its connected brain regions, providing mechanistic insights into the elaborate organization of the hippocampal circuitry underlying anxiety. Studies of hippocampal neurotransmitter systems, including glutamatergic, GABAergic, cholinergic, dopaminergic, and serotonergic systems, have contributed to the interpretation of the underlying neural mechanisms of anxiety. Neuropeptides and neuroinflammatory factors are also involved in anxiety modulation. This review comprehensively summarizes the hippocampal mechanisms associated with anxiety modulation, based on molecular, cellular, and circuit properties, to provide tailored targets for future anxiety treatment.

Qinzhi Zhudan formula improves memory and alleviates neuroinflammation in vascular dementia rats partly by inhibiting the TNFR1-mediated TNF pathway

The Qinzhi Zhudan formula (QZZD) exhibits a prominent therapeutic effect in the treatment of vascular dementia (VaD). This study combined a network pharmacology approach and experimental validation to identify the underlying biological mechanism of QZZD against VaD. Male Wistar rats received bilateral common carotid artery occlusion (BCCAO) surgery, and after 4 weeks of intragastric administration of QZZD, the therapeutic effect was assessed using the Morris water maze test and cerebral blood flow (CBF) assessment. Hematoxylin and eosin staining, Nissl staining, and electron microscopy were used to measure the histopathological changes in the neurons of rats. The effect of QZZD treatment on hippocampal neurotransmitters was assessed by high-performance liquid chromatography with electrochemical detection and liquid chromatography mass spectrometry. Immunofluorescence was used to observe VaD-induced microglia activation. The inflammatory cytokine levels were assessed by enzyme linked immunosorbent assay. Western blot was used to examine the TNFR1-mediated TNF pathway, which was screened out by network pharmacology analysis. QZZD treatment alleviated pathological changes and neuronal damage in VaD rats and attenuated their cognitive impairment. In addition, QZZD increased CBF and the expression of acetylcholine and 5-hydroxytryptamine in the hippocampal region. Notably, QZZD inhibited microglial activation and the expression of IL-6 and TNF-α. Network pharmacology and western blot indicated that QZZD inhibited the levels of TNFR1, NF-κBp65, p-ERK, TNF-α, and IL-6, which are related to the TNFR1-mediated TNF signaling pathway. QZZD clearly improved learning and memory function, reduced brain pathological damage, elevated CBF and hippocampal neurotransmitter levels, and alleviated neuroinflammation of VaD rats partly by inhibiting the TNFR1-mediated TNF pathway, indicating its potential value in the clinical therapy of VaD.

Antidepressant-like Effects of Polygonum minus Aqueous Extract in Chronic Ultra-Mild Stress-Induced Depressive Mice Model.

Depression is the most common behavior disorder that leads to many disabilities. The main aim of this study was to evaluate the effects of a Polygonum minus (P. minus) aqueous extract on chronic ultra-mild stress (CUMS)-induced depressive mice model. Chronic ultra-mild stress can disturb the neurotransmitters levels and plasticity of the hippocampus. Balb/c male mice were used in this study, which consisted of six groups (n = 14). Treatment was given for eight weeks, and chronic ultra-mild stress was applied for six weeks. Commercially available P. minus extract (BioKesum®) was used in this study. The behavior and neurochemical parameters were investigated through behavioral Tests and ELISA assays. P. minus administration significantly (p < 0.05) restored CUMS-induced behavior abnormalities, decreased the immobility time, and increased the sucrose preference and increased the spatial memory. P. minus treatment also showed the decreased level of serum corticosterone and increased the level of hippocampal neurotransmitters (Serotonin and Norepinephrine) significantly (p < 0.05). The brain-derived neurotrophic factor (BDNF) level also increased significantly in both the prefrontal cortex and hippocampus (p < 0.05). P. minus treatment exhibited significant (p < 0.05) reduction of Monoamine Oxidase-A (MAO-A) in the hippocampus. These findings indicate that P. minus aqueous extract exhibits antidepressant effects, including decreased immobility time, increased spatial memory, reduced corticosterone, increased BDNF level, and reduced MAO-A enzyme level with increasing the monoamines (serotonin and norepinephrine) in the hippocampus.

Seasonal photoperiodic influence of pineal melatonin on hypothalamic-pituitary-adrenal axis-hippocampal-receptor in male rats

Based on the effect of seasonal changes on human visceral function, this study investigated the impact of seasonal photoperiod of the pineal body on hypothalamic-pituitary-adrenal axis-hippocampal-receptor in rats, aiming to reveal the mechanism by which pineal gland melatonin regulates the seasonal secretion of hippocampal neurotransmitters. Vernal equinox, summer solstice, autumn equinox, and winter solstice were selected as four experimental time points, and rats were randomly divided into normal control group, sham operation group, and pinealectomized group. The seasonal changes in corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), corticosterone, hypothalamic melatonin receptor (MTR), and hippocampal corticosterone receptor (CORTR) were examined by enzyme-linked immunosorbent assay. Comparing the same group between different seasons, we showed that in the normal control group, CRH, ACTH, corticosterone, and MTR were higher, while CORTR was lower in autumn and winter than in spring (all P < .05). Compared with the normal control group, the pinealectomized group showed higher levels of corticosterone ( P = .01), MTR ( P = .01), and CORTR ( P = .03) during spring; reduced levels of MTR and CORTR (both P < .001) during summer; higher levels of ACTH ( P = .001) and MTR ( P < .001), and lower levels of CRH ( P = .001), corticosterone ( P < .001), and CORTR ( P = .003) during autumn; and lower levels of CRH ( P < .001) and MTR ( P = .004), and higher level of ACTH ( P < .001) in winter. Seasonal photoperiod acts on the pineal gland to secrete different levels of melatonin, resulting in seasonal changes in the hypothalamic-pituitary-adrenal axis-hippocampal-receptor, which may be the pathophysiological basis for the onset of seasonal affective disorder.