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Background: The postsynaptic density is an elaborate protein network beneath the postsynaptic membrane involved in the molecular processes underlying learning and memory. The postsynaptic density is built up from the same major proteins but its exact composition and organization differs between synapses. Mutations perturbing protein: protein interactions generally occurring in this network might lead to effects specific for cell types or processes, the understanding of which can be especially challenging. Results: In this work we use systems biology-based modeling of protein complex distributions in a simplified set of major postsynaptic proteins to investigate the effect of a hypomorphic Shank mutation perturbing a single well-defined interaction. We use data sets with widely variable abundances of the constituent proteins. Our results suggest that the effect of the mutation is heavily dependent on the overall availability of all the protein components of the whole network and no trivial correspondence between the expression level of the directly affected proteins and overall complex distribution can be observed. Conclusions: Our results stress the importance of context-dependent interpretation of mutations. Even the weakening of a generally occurring protein: protein interaction might have well-defined effects, and these can not easily be predicted based only on the abundance of the proteins directly affected. Our results provide insight on how cell-specific effects can be exerted by a mutation perturbing a generally occurring interaction even when the wider interaction network is largely similar. [ABSTRACT FROM AUTHOR]

Palmitoylation, a lipid-based posttranslational protein modification, plays a crucial role in regulating various aspects of neuronal function through altering protein membrane-targeting, stabilities, and protein–protein interaction profiles. Disruption of palmitoylation has recently garnered attention as disease mechanism in neurodegeneration. Many proteins implicated in neurodegenerative diseases and associated neuronal dysfunction, including but not limited to amyloid precursor protein, β-secretase (BACE1), postsynaptic density protein 95, Fyn, synaptotagmin-11, mutant huntingtin, and mutant superoxide dismutase 1, undergo palmitoylation, and recent evidence suggests that altered palmitoylation contributes to the pathological characteristics of these proteins and associated disruption of cellular processes. In addition, dysfunction of enzymes that catalyze palmitoylation and depalmitoylation has been connected to the development of neurological disorders. This review highlights some of the latest advances in our understanding of palmitoylation regulation in neurodegenerative diseases and explores potential therapeutic implications. [ABSTRACT FROM AUTHOR]

Rationale: Alzheimer's disease (AD), an age-dependent devastating neuropsychiatric disorder, is a leading cause of learning, memory and intellectual disabilities. Current therapeutic approaches for the amelioration of the anomalies of AD are not effective. Objective: In the present study, the molecular mechanisms underlying sporadic AD (sAD), the memory related behavioral analysis and neuroprotective effects of Ellagic acid (EA) were investigated. Method: sAD mouse model was developed by intracerebroventricular (ICV) injection of Streptozotocin (STZ). The efficacy of EA, a naturally occurring polyphenol, in amelioration of anomalies associated with sAD was assessed. EA was administered once daily for 28 days at a dose of 75 mg/kg body weight followed by neurobehavioral, biochemical, molecular and neuronal count analysis to delineate the mode of action of EA. Result: The ICV injection of STZ in mice significantly increased the expression of AD biomarkers in addition to enhanced oxidative stress. A decline in the discrimination index in Novel Object Recognition Test was observed indicating the compromise of recognition memory in AD. Studies on the expression of genes involved in synaptic plasticity reveal the dysregulation of the α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) of the glutamate and its scaffolding proteins in the postsynaptic density and thereby synaptic plasticity in AD. ICV-STZ led to significant upregulation of apoptotic markers which led to decrease in neuronal density of the cerebral cortex. EA significantly reversed the above and improved anomalies of sAD. Conclusion: EA was observed to profoundly modulate the genes involved in AD pathophysiology, restored antioxidant enzymes activity, reduced lipid peroxidation and neuronal loss in the sAD brain. Further, EA was observed to effectively modulate the genes involved in apoptosis and synaptic plasticity. Therefore, EA possesses promising anti-AD properties, which may improve AD-associated anomalies by modulating synaptic plasticity via AMPAR signaling. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a progressive neurodegenerative disorder pathologically characterized by the deposition of amyloid beta (Ab) plaques and neurofibrillary tangles (NFTs) in the brain. The accumulation of these aggregated proteins causes memory and synaptic dysfunction, neuroinflammation, and oxidative stress. This research study is significant as it aims to assess the neuroprotective properties of vitamin E (VE) analog Trolox in an Ab1-42-induced AD mouse model. Ab1-42 5µL/5min/mouse was injected intracerebroventricularly (i.c.v.) into wild-type adult mice brain to induce AD-like neurotoxicity. For biochemical analysis, Western blotting and confocal microscopy were performed. Remarkably, intraperitoneal (i.p.) treatment of Trolox (30 mg/kg/mouse for 2 weeks) reduced the AD pathology by reducing the expression of Ab, phosphorylated tau (p-tau), and b-site amyloid precursor protein cleaving enzyme1 (BACE1) in both cortex and hippocampus regions of mice brain. Furthermore, Trolox-treatment decreased neuroinflammation by inhibiting Toll-like receptor 4 (TLR4), phosphorylated nuclear factor-kB (pNF-kB) and interleukin-1b (IL-1b), and other inflammatory biomarkers of glial cells [ionized calcium-binding adaptor molecule 1 (Iba1) and glial fibrillary acidic protein (GFAP)]. Moreover, Trolox reduced oxidative stress by enhancing the expression of nuclear factor erythroid-related factor 2 (NRF2) and heme oxygenase 1 (HO1). Similarly, Trolox-induced synaptic markers, including synaptosomal associated protein 23 (SNAP23), synaptophysin (SYN), and post-synaptic density protein 95 (PSD-95), and memory functions in AD mice. Our findings could provide a useful and novel strategy for investigating new medications to treat AD-associated neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is a neurodegenerative disorder that can result in neurotoxicity and an imbalance in gut microbiota. Probiotics have been shown to play an important role in regulating the gut microbiota, but their viability and bioactivity are often compromised as they traverse the gastrointestinal tract, thereby reducing their efficacy and limiting their clinical utility. Results: In this work, layer-by-layer (LbL) encapsulation technology was used to encapsulate Lactiplantibacillus plantarum (LP) to improve the above shortcomings. Studies in APPswe/PS1dE9 (APP/PS1) transgenic mice show that LbL-encapsulated LP ((CS/SP)2-LP) protects LP from gastrointestinal damage while (CS/SP)2-LP treatment It improves brain neuroinflammation and neuronal damage in AD mice, reduces Aβ deposition, improves tau protein phosphorylation levels, and restores intestinal barrier damage in AD mice. In addition, post-synaptic density protein 95 (PSD-95) expression increased in AD mice after treatment, indicating enhanced synaptic plasticity. Fecal metabolomic and microbiological analyzes showed that the disordered intestinal microbiota composition of AD mice was restored and short-chain fatty acids (SCFAs) levels were significantly increased after (CS/SP)2-LP treatment. Conclusion: Overall, the above evidence suggests that (CS/SP)2-LP can improve AD symptoms by restoring the balance of intestinal microbiota, and (CS/SP)2-LP treatment will provide a new method to improve the symptoms of AD patients. [ABSTRACT FROM AUTHOR]

Background: Premature ejaculation (PE) is the most prevalent sexual dysfunction among men. Eejaculation involves a complex nervous mechanism in which the ejaculatory centers play a key role in modulating sperm emission. Although treatment possibilities span from psychotherapy to pharmacological approaches, results show inconsistent efficacy. In this context, the emergence of repetitive transcranial magnetic stimulation (rTMS) as a non‐invasive neuromodulatory approach represents a compelling avenue for potential therapeutic exploration. Objective: To investigate whether high‐frequency transcranial magnetic stimulation can modulate the ejaculatory behavior of rats with rapid ejaculation by altering neurotransmitter levels and neuroplasticity in the hippocampus. Methods: Rats have been screened for rapid ejaculation by observing behavioral indices of mating, and subsequently divided into two groups. The intervention group was administered with a 10 Hz rTMS stimulation, whereas the control group received a sham procedure. Upon the delivery of rTMS, we investigated ejaculation latency (EL), the hippocampal 5‐hydroxytryptamine (5‐HT) concentration, brain‐derived neurotrophic factor (BDNF), synaptophysin (SYN), and postsynaptic density protein 95 (PSD95) expressions, as well as BDNF‐receptor tyrosine kinase receptor B (TrkB) pathway upregulation. Results: After 14 days, EL was increased in the intervention group compared with the control group. 5‐HT concentration in the hippocampal region was increased, and high‐frequency rTMS activated the BDNF and TrkB pathways, including phosphorylation of cAMP response element‐binding protein (CREB), and upregulated the transcription and protein expression of SYN, and PSD95. Conclusion: RTMS upregulates BDNF, SYN, and PSD95 expression through activation of the BDNF–TrkB pathway and increases brain 5‐hydroxytryptamine thereby regulating neuroplasticity and improving ejaculation. [ABSTRACT FROM AUTHOR]

Neuroinflammation is being increasingly recognized as a vital factor in the development of various neurological and neuropsychiatric diseases. Lipopolysaccharides (LPS), an outer membrane component of gram-negative bacteria, can trigger innate immune responses, resulting in neuroinflammation and subsequent cognitive deficits. The expression of glutamate receptors (GluRs) on glial cells can induce glial activation. Therefore, we hypothesized that repeated LPS exposure can increase GluR levels, promoting microglial activation and ultimately affecting synaptic plasticity and cognitive function. In this study, C57/BL6 mice were repeatedly exposed to LPS to construct a neuroinflammation animal model. The levels of GluRs, inflammatory cytokines, ionized calcium-binding adaptor molecule 1, postsynaptic density protein 95, synaptophysin 38, NMDA receptor 2 A, and NMDA receptor 2B (GluN2B) were measured in the hippocampi. Furthermore, dendritic spine density in the CA1 hippocampal region was determined. Repeated LPS exposure induced cognitive impairments and microglial activation and increased GluR1 and GluR2 levels. This was accompanied by a significant decrease in GluN2B expression and dendritic spine density in the hippocampi. However, CFM-2, an α-amino-3- hydroxy-5-methyl-4-isoxazolepropionate receptor antagonist, reversed these anomalies. Furthermore, minocycline, a microglial inhibitor, reversed these anomalies and downregulated GluR2 but not GluR1 expression. In summary, we demonstrated that GluR2 plays an essential role in microglia-induced neuroinflammation, resulting in synaptic plasticity and cognitive impairment induced by repeated exposure to LPS. [ABSTRACT FROM AUTHOR]

Kruppel‐like factor 4 (Klf4) is a transcription factor that is involved in neuronal regeneration and the development of glutamatergic systems. However, it is unknown whether Klf4 is involved in acute seizure. To investigate the potential role of Klf4 in pentylenetetrazol (PTZ)‐induced seizure, western blotting, immunofluorescence, behaviour test and electrophysiology were conducted in this study. We found that Klf4 protein and mRNA expression were increased in both the hippocampus (HP) and prefrontal cortex (PFC) after PTZ‐induced seizure in mice. HP‐specific knockout (KO) of Klf4 in mice decreased protein expression of Klf4 and the down‐stream Klf4 target tumour protein 53 (TP53/P53). These molecular changes are accompanied by increased seizure latency, reduced immobility time in the forced swimming test and tail suspension test. Reduced hippocampal protein levels for synaptic proteins, including glutamate receptor 1 (GRIA1/GLUA1) and postsynaptic density protein 95 (DLG4/PSD95), were also observed after Klf4‐KO, while increased mRNA levels of complement proteins were observed for complement component 1q subcomponent A (C1qa), complement component 1q subcomponent B (C1qb), complement component 1q subcomponent C (C1qc), complement component 3 (C3), complement component 4A (C4a) and complement component 4B (C4b). Moreover, c‐Fos expression induced by PTZ was reduced by hippocampal conditional KO of Klf4. Electrophysiology showed that PTZ‐induced action potential frequency was decreased by overexpression of Klf4. In conclusion, these findings suggest that Klf4 plays an important role in regulating PTZ‐induced seizures and therefore constitutes a new molecular target that should be explored for the development of antiepileptic drugs. [ABSTRACT FROM AUTHOR]

Epigenetic mechanisms such as DNA methylation and hydroxymethylation play a significant role in depression. This research has shown that Ten‐eleven translocation 2 (Tet2) deficiency prompts depression‐like behaviors, but Tet2's transcriptional regulation remains unclear. In the study, bioinformatics is used to identify nuclear receptor subfamily 2 group E member 3 (Nr2e3) as a potential Tet2 regulator. Nr2e3 is found to enhance Tet2's transcriptional activity by binding to its promoter region. Nr2e3 knockdown in mouse hippocampus leads to reduced Tet2 expression, depression‐like behaviors, decreased hydroxymethylation of synaptic genes, and downregulation of synaptic proteins like postsynaptic density 95 KDa (PSD95) and N‐methy‐d‐aspartate receptor 1 (NMDAR1). Fewer dendritic spines are also observed. Nr2e3 thus appears to play an antidepressant role under stress. In search of potential treatments, small molecule compounds to increase Nr2e3 expression are screened. Azacyclonal (AZA) is found to enhance the Nr2e3/Tet2 pathway and exhibited antidepressant effects in stressed mice, increasing PSD95 and NMDAR1 expression and dendritic spine density. This study illuminates Tet2's upstream regulatory mechanism, providing a new target for identifying early depression biomarkers and developing treatments. [ABSTRACT FROM AUTHOR]

The melanocortin-4 receptor (MC4R) is a G protein-coupled receptor (GPCR) that is expressed in several brain locations encompassing the hypothalamus and the brainstem, where the receptor controls several body functions, including metabolism. In a well-defined pathway to decrease appetite, hypothalamic proopiomelanocortin (POMC) neurons localized in the arcuate nucleus (Arc) project to MC4R neurons in the paraventricular nuclei (PVN) to release the natural MC4R agonist α-melanocyte-stimulating hormone (α-MSH). Arc neurons also project excitatory glutamatergic fibers to the MC4R neurons in the PVN for a fast synaptic transmission to regulate a satiety pathway potentiated by α-MSH. By using super-resolution microscopy, we found that in hypothalamic neurons in a primary culture, postsynaptic density protein 95 (PSD95) colocalizes with GluN1, a subunit of the ionotropic N-methyl-D-aspartate receptor (NMDAR). Thus, hypothalamic neurons form excitatory postsynaptic specializations. To study the MC4R distribution at these sites, tagged HA-MC4R under the synapsin promoter was expressed in neurons by adeno-associated virus (AAV) gene transduction. HA-MC4R immunofluorescence peaked at the center and in proximity to the PSD95- and NMDAR-expressing sites. These data provide morphological evidence that MC4R localizes together with glutamate receptors at postsynaptic and peri-postsynaptic sites. [ABSTRACT FROM AUTHOR]

Simple Summary: During pregnancy, maternal glucocorticoids control fetal growth and the maturation of fetal tissues. Synthetic glucocorticoids are commonly used to stimulate lung differentiation in pregnancies at high risk of premature birth. Despite their beneficial effects on fetal survival, their impact on the developing brain is less clear. Among postnatal factors that might have a profound effect on both the cognitive capacity and behavior of the offspring, high fructose consumption in the young population is of particular concern. The present study aimed to investigate the effects of prenatal synthetic glucocorticoid exposure additionally challenged with postnatal fructose overconsumption on locomotion, anxiety, and memory in adult male rat offspring. According to our results, prenatal glucocorticoid treatment induced changes in reactions to novel situations in male rats that might represent advantageous fetal developmental adaptation, while increased exploratory behavior, reduced anxiety, and improved ability to recognize novel objects could improve survival in an adverse postnatal environment. On the other hand, moderate fructose consumption did not appear to alter the effects of prenatal glucocorticoid exposure, suggesting that fetal programming had a predominant influence. Early-life glucocorticoid overexposure induces diverse neurodevelopmental outcomes regarding stress reactivity and cognition. Increased fructose consumption has also been associated with alterations in cognitive capacity and behavior. The present study investigated the effects of prenatal dexamethasone exposure on synaptic plasticity, locomotion, anxiety, and recognition memory in adult male Wistar rat offspring, and whether these effects are potentiated by postnatal fructose consumption. Pregnant female rats were treated with dexamethasone during late gestation and male offspring were supplemented with a moderate dose of fructose. Recognition memory, locomotion, and anxiety-like behavior were assessed using a novel object recognition test, open-field test, and elevated plus maze, respectively. Hippocampal synaptic plasticity was estimated by the levels of growth-associated protein 43 (GAP-43), synaptophysin, postsynaptic density protein 95, calcium/calmodulin-dependent kinase IIα, and their activating phosphorylations. Additionally, protein levels of the glucocorticoid receptor (GR) and its transcriptionally active phosphorylated form were evaluated. Prenatal dexamethasone treatment induced an anxiolytic-like effect, stimulation of exploratory behavior, and novelty preference associated with an increase in GR and GAP-43 protein levels in the hippocampus. Fructose overconsumption after weaning did not modify the effects of prenatal glucocorticoid exposure. Applied prenatal dexamethasone treatment may induce changes in reactions to novel situations in male Wistar rats. [ABSTRACT FROM AUTHOR]

Exercise can induce beneficial improvements in cognition. However, the effects of different modes and intensities of exercise have yet to be explored in detail. This study aimed to identify the effects of different exercise modes (aerobic and resistance) and intensities (low and high) on cognitive performance, adult hippocampal neurogenesis and synaptic plasticity in mice. A total of 40 C57BL/6J mice were randomised into 5 groups (n = 8 mice per group): control, low-intensity aerobic exercise, high-intensity aerobic exercise, low-intensity resistance exercise, and high-intensity resistance exercise. The aerobic exercise groups underwent treadmill training, while the resistance exercise groups underwent ladder climbing training. At the end of the exercise period, cognitive performance was assessed by the Y-maze and Barnes maze. In addition, adult hippocampal neurogenesis was evaluated immunohistochemically by 5-bromo-2'-deoxyuridine (BrdU)/ neuronal nuclei (NeuN) co-labeling. The levels of synaptic plasticity-related proteins in the hippocampus, including synaptophysin (SYP) and postsynaptic density protein 95 (PSD-95), were analyzed by western blotting. Our results showed no significant differences in cognitive performance among the groups. However, high-intensity aerobic exercise significantly increased hippocampal adult neurogenesis relative to the control. A trend towards increased adult neurogenesis was observed in the low-intensity aerobic group compared to the control group. No significant changes in synaptic plasticity were observed among all groups. Our results indicate that high-intensity aerobic exercise may be the most potent stimulator of adult hippocampal neurogenesis. [ABSTRACT FROM AUTHOR]

Background: Comorbid chronic neuropathic pain (NPP) and anxio-depressive disorders (ADD) have become a serious global publichealth problem. The SLIT and NTRK-like 1 (SLITRK1) protein is important for synaptic remodeling and is highly expressed in the amygdala, an important brain region involved in various emotional behaviors. We examined whether SLITRK1 protein in the amygdala participates in NPP and comorbid ADD. Methods: A chronic NPP mouse model was constructed by L5 spinal nerve ligation; changes in chronic pain and ADD-like behaviors were measured in behavioral tests. Changes in SLITRK1 protein and excitatory synaptic functional proteins in the amygdala were measured by immunofluorescence and Western blot. Adeno-associated virus was transfected into excitatory synaptic neurons in the amygdala to up-regulate the expression of SLITRK1. Results: Chronic NPP-related ADD-like behavior was successfully produced in mice by L5 ligation. We found that chronic NPP and related ADD decreased amygdalar expression of SLITRK1 and proteins important for excitatory synaptic function, including Homer1, postsynaptic density protein 95 (PSD95), and synaptophysin. Virally-mediated SLITRK1 overexpression in the amygdala produced a significant easing of chronic NPP and ADD, and restored the expression levels of Homer1, PSD95, and synaptophysin. Conclusion: Our findings indicated that SLITRK1 in the amygdala plays an important role in chronic pain and related ADD, and may prove to be a potential therapeutic target for chronic NPP-ADD comorbidity. [ABSTRACT FROM AUTHOR]

Background: Brain lymphatic drainage impairment is a prevalent characteristic in both aging and neurodegeneration. Surgery is more likely to induce excessive neuroinflammation and postoperative neurocognitive disorder (PND) among patients with aging and neurodegeneration. We hypothesized that surgical trauma may aggravate PND through preexisting cerebral lymphatic drainage impairment. However, there remains limited understanding about the role of surgery in changes of neurocognitive function in the populations with preoperative brain lymphatic drainage impairment. This study aims to expand our insight into surgery-induced glymphatic dysfunction, neuroinflammation and PND in middle-aged mice with preoperative brain lymphatic drainage impairment. Materials and methods: Deep cervical lymph nodes ligation (LdcLNs) was performed on middle-aged mice to establish preoperative brain lymphatic drainage impairment. A month later, laparotomy was performed on these mice with or without LdcLNs followed by analysis of brain neuroinflammation, glymphatic function, neuronal damage, and behavioral test. Results: LdcLNs disrupted meningeal lymphatic drainage. In middle-aged mice with LdcLNs, surgery exacerbated more serious glymphatic dysfunction accompanied by aggravation of A1 astrocytes activation and AQP4 depolarization. Furthermore, surgery caused neuronal damage via reducing expression of neuronal nuclei (NeuN), post-synaptic density protein 95 (PSD95) and synaptophysin (SYP), as well as impairment in exploratory behavior and spatial working memory in middle-aged mice with LdcLNs. Additionally, surgery induced neuroinflammation with elevated microglia activation and increased the levels of tumor necrosis factor (TNF)-a, interleukin (IL)-1b and IL-6, as well as activated more expression of HMGB1/TLR-4/NF-kB pathway in middle-aged mice with LdcLNs. Conclusion: Surgery exacerbates neuroinflammation and glymphatic dysfunction, ultimately resulting in neuronal damage and neurocognitive disorder in middle-aged mice with preoperative brain lymphatic drainage impairment. These results suggest that brain lymphatic drainage impairment may be a deteriorating factor in the progression of PND, and restoring its function may serve as a potential strategy against PND. [ABSTRACT FROM AUTHOR]

AIM: To explore the expression and distribution of synaptic and extrasynaptic glutamate receptors under the action of amyloid p-protein 42 oligomers (Ap42Os) in Alzheimer disease. METHODS: In vitro, primary neurons from neonatal mice were treated with different concentrations of Ap42Os. In vivo, Ap42Os were stereotaxically injected into the lateral ventricle of C57BL/6 mice. Western blot was used to detect the protein levels of metabotropic gultamate receptor 5 (mGluR5) and N-methyl-D-aspartate receptor (NMDAR) subunits (NR2A, NR2B and NR1) in mouse primary neurons and mice. Immunofluorescence staining was performed to observe the distribution of mGluR5 and NMDAR. Additionally, Western blot was employed to examine the expression of mGluR5 downstream phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB/AKT) signaling pathway-related proteins, calcium signaling pathway-related proteins and synapse-related proteins in mouse hippocampal tissues. RESULTS: (1) High concentrations of Ap42Os increased mGluR5 expression in mouse primary neurons, but reduced the expression of NR2A, NR2B and NR1 (P<0. 01). Treatment of primary neurons with high concentration of Ap42Os resulted in aggregation of mGluR5 on the membrane surface, and reduced the expression of NR2A, NR2B and NR1 on the membrane surface. (2) High concentration of Ap42Os increased the expression of synaptic mGluR5 in mouse hippocampal tissues (P<0. 01), but reduced the expression of synaptic NR2A (P<0. 05) and NR2B (P<0. 01) and increased the expression of extrasynaptic NR2B (P<0. 01). High concentration of Ap42Os inhibited the expression of PI3II and the phosphorylation of AIIT and extracellular signal-regulated kinase (ERIK), and overactivated calcium/calmodulin-dependent protein kinase IIa ( CaMKIIa ). High concentration of Ap42 decreased the expression of postsynaptic density protein 95, spinophilin, synaptophysin and microtubule-associated protein CONCLUSION: (1) High concentrations of Ap42Os increase mGluR5 expression and decrease NR2A, NR2B and NR1 expression in synapse, along with an increase in extrasynaptic NR2B. (2) High concentrations of Ap42Os inhibit the PI3K/AKT and ERIK signaling pathways, overactivated the CaMKIIa pathway, and destroyed the synaptic structures. [ABSTRACT FROM AUTHOR]

A high-salt diet (HSD) has been associated with various health issues, including hypertension and cardiovascular diseases. However, recent studies have revealed a potential link between high salt intake and cognitive impairment. This study aims to investigate the effects of high salt intake on autophagy, tau protein hyperphosphorylation, and synaptic function and their potential associations with cognitive impairment. To explore these mechanisms, 8-month-old male C57BL/6 mice were fed either a normal diet (0.4% NaCl) or an HSD (8% NaCl) for 3 months, and Neuro-2a cells were incubated with normal medium or NaCl medium (80 mM). Behavioral tests revealed learning and memory deficits in mice fed the HSD. We further discovered that the HSD decreased autophagy, as indicated by diminished levels of the autophagy-associated proteins Beclin-1 and LC3, along with an elevated p62 protein level. HSD feeding significantly decreased insulin-like growth factor-1 receptor (IGF1R) expression in the brain of C57BL/6 mice and activated mechanistic target of rapamycin (mTOR) signaling. In addition, the HSD reduced synaptophysin and postsynaptic density protein 95 (PSD95) expression in the hippocampus and caused synaptic loss in mice. We also found amyloid β accumulation and hyperphosphorylation of tau protein at different loci both in vivo and in vitro. Overall, this study highlights the clinical significance of understanding the impact of an HSD on cognitive function. By targeting the IGF1R/mTOR/p70S6K pathway or promoting autophagy, it may be possible to mitigate the negative effects of high salt intake on cognitive function. [ABSTRACT FROM AUTHOR]

There is a significant co-occurrence of opioid use disorder (OUD) and post-traumatic stress disorder (PTSD) in clinical populations. However, the neurobiological mechanisms linking chronic opioid use, withdrawal, and the development of PTSD are poorly understood. Our previous research has shown that proinflammatory cytokines, expressed primarily by astrocytes in the dorsal hippocampus (DH), play a role in the development of heroin withdrawal-enhanced fear learning (HW-EFL), an animal model of PTSD-OUD comorbidity. Given the role of astrocytes in memory, fear learning, and opioid use, our experiments aimed to investigate their involvement in HW-EFL. Experiment 1 examined the effect of withdrawal from chronic heroin administration on GFAP surface area and volume, and identified increased surface area and volume of GFAP immunoreactivity in the dentate gyrus (DG) following 24-hour heroin withdrawal. Experiment 2 examined astrocyte morphology and synaptic interactions at the 24-hour withdrawal timepoint using an astroglial membrane-bound GFP (AAV5-GfaABC1D-lck-GFP). Although we did not detect significant changes in surface area and volume of GfaABC1D-Lck-GFP labelled astrocytes, we did observe a significant increase in the colocalization of astrocyte membranes with PSD-95 (postsynaptic density protein 95) in the DG. Experiment 3 tested if stimulating astroglial Gi signaling in the DH alters HW-EFL, and our results demonstrate this manipulation attenuates HW-EFL. Collectively, these findings contribute to our current understanding of the effects of heroin withdrawal on astrocytes and support the involvement of astrocytes in the comorbid relationship between opioid use and anxiety disorders. [ABSTRACT FROM AUTHOR]

The article "Advances in Pharmaceutical Crystals: Control over Nucleation and Polymorphism" is a collection of eight papers that explore various aspects of crystallization processes for pharmaceuticals. The papers cover both applied aspects, such as manufacturing and process monitoring, and more fundamental aspects, such as polymorphic transformations and co-crystallization. The research presented in the papers offers innovative solutions to current challenges in the production of crystalline drugs and the improvement of their physicochemical properties. The article also identifies new research directions in drug crystallization. [Extracted from the article]

Background: Infection with Angiostrongylus cantonensis (AC) in humans or mice can lead to severe eosinophilic meningitis or encephalitis, resulting in various neurological impairments. Developing effective neuroprotective drugs to improve the quality of life in affected individuals is critical. Methods: We conducted a Gene Ontology enrichment analysis on microarray gene expression (GSE159486) in the brains of AC-infected mice. The expression levels of melanin-concentrating hormone (MCH) were confirmed through real-time quantitative PCR (RT–qPCR) and immunofluorescence. Metabolic parameters were assessed using indirect calorimetry, and mice's energy metabolism was evaluated via pathological hematoxylin and eosin (H&E) staining, serum biochemical assays, and immunohistochemistry. Behavioral tests assessed cognitive and motor functions. Western blotting was used to measure the expression of synapse-related proteins. Mice were supplemented with MCH via nasal administration. Results: Postinfection, a marked decrease in Pmch expression and the encoded MCH was observed. Infected mice exhibited significant weight loss, extensive consumption of sugar and white fat tissue, reduced movement distance, and decreased speed, compared with the control group. Notably, nasal administration of MCH countered the energy imbalance and dyskinesia caused by AC infection, enhancing survival rates. MCH treatment also increased the expression level of postsynaptic density protein 95 (PSD95) and microtubule-associated protein-2 (MAP2), as well as upregulated transcription level of B cell leukemia/lymphoma 2 (Bcl2) in the cortex. Conclusions: Our findings suggest that MCH improves dyskinesia by reducing loss of synaptic proteins, indicating its potential as a therapeutic agent for AC infection. [ABSTRACT FROM AUTHOR]

The effect of a high-fat diet (HFD) on mood is a widely debated topic, with the underlying mechanisms being poorly understood. This study explores the anxiolytic effects of a four-week HFD in C57BL/6 mice. Five-week-old mice were exposed to either an HFD (60% calories from fat) or standard chow diet (CD) for four weeks, followed by cannula implantation, virus infusion, behavioral tests, and biochemical assays. Results revealed that four weeks of an HFD induced anxiolytic-like behaviors and increased the protein levels of mature brain-derived neurotrophic factor (mBDNF) and phosphorylated tyrosine kinase receptor B (p-TrkB) in the medial prefrontal cortex (mPFC). Administration of a BDNF-neutralizing antibody to the mPFC reversed HFD-induced anxiolytic-like behaviors. Elevated BDNF levels were observed in both neurons and astrocytes in the mPFC of HFD mice. Additionally, these mice exhibited a higher number of dendritic spines in the mPFC, as well as upregulation of postsynaptic density protein 95 (PSD95). Furthermore, mRNA levels of the N6-methyladenosine (m6A) demethylase, fat mass and obesity-associated protein (FTO), and the hydrolase matrix metalloproteinase-9 (MMP9), also increased in the mPFC. These findings suggest that an HFD may induce FTO and MMP9, which could potentially regulate BDNF processing, contributing to anxiolytic-like behaviors. This study proposes potential molecular mechanisms that may underlie HFD-induced anxiolytic behaviors. [ABSTRACT FROM AUTHOR]

Lactate has emerged as a key player in regulating neural functions and cognitive processes. Beyond its function as an energy substrate and signal molecule, recent research has revealed lactate to serve as an epigenetic regulator in the brain. However, the molecular mechanisms by which lactate regulates spatial memory and its role in the prevention of cognitive disorders remain unclear. Herein, we injected L-lactate (10 μmol/kg/d for 6 d) into the mouse's hippocampus, followed by the Morris water maze (MWM) test and molecular analyses. Improved spatial memory performances were observed in mice injected with lactate. Besides, lactate upregulated the expression of synaptic proteins post-synaptic density 95 (PSD95), synaptophysin (SYP), and growth associated protein 43 (GAP43) in hippocampal tissues and HT22 cells, suggesting a potential role in synaptic transmission and memory formation. The facilitative role of monocarboxylate transporter 2 (MCT2), a neuron-specific lactate transporter, in this process was confirmed, as MCT2 antagonists attenuated the lactate-induced upregulation of synaptic proteins. Moreover, lactate induced protein lactylation, a post-translational modification, which could be suppressed by MCT2 inhibition. RNA sequencing of lactated-injected hippocampal tissues revealed a comprehensive gene expression profile influenced by lactate, with significant changes in genes associated with transcriptional progress. These data demonstrate that hippocampal lactate injection enhances spatial memory in mice, potentially through the upregulation of synaptic proteins and induction of protein lactylation, with MCT2 playing a crucial role in these processes. Our findings shed light on the multi-faceted role of lactate in neural function and memory regulation, opening new avenues for therapeutic interventions targeting cognitive disorders. [ABSTRACT FROM AUTHOR]

We investigated the role of miR-99a in regulating depressant activity by administering crocin in an animal model of chronic unpredictable mild stress (CUMS). A CUMS rat model was built and crocin was intraperitoneally injected to examine its role in depression-like behaviors. Depression-like behaviors were analyzed using an open-field test (OFT), sucrose preference test (SPT), forced swimming test (FST), and elevated maze test (EPM). Representative depressant activity occurred in CUMS rats. The SPT/OFT/EPM/FST results also indicated that the administration of crocin could reduce depression-like activity in CUMS rats. Postsynaptic density protein 95 (PSD-95), SYN, P-TrkB, BDNF protein expression was remarkably downregulated in the hippocampal formation of CUMS rats but was recovered after treatment with crocin. In addition, crocin injection increased norepinephrine (NE)/ dopamine (DA)/ serotonin (5-HT) levels in the hippocampus of CUMS rats. miR-99a expression in the hippocampal formation of CUMS rats was remarkably lower than that in the control group; crocin administration increased hippocampal miR-99a levels. In addition, the upregulation of miR-99a in the hippocampus of CUMS rats resulted in a phenotype similar to that of the crocin injection group, whereas miR-99a downregulation in crocin-injected CUMS rats counteracted the effect of crocin on depression-like behaviors. Moreover, FKBP51 was identified as a direct target of miR-99a, which inhibits downstream FKBP51 in primary hippocampal neurons. Crocin exerts anti-depressant effects in hippocampal dysfunction by promoting miR-99a and activating the TrkB/BDNF signaling pathway in the hippocampal formation of CUMS rats. [ABSTRACT FROM AUTHOR]

Objective: The postsynaptic density protein of excitatory neurons PSD‐95 is encoded by discs large MAGUK scaffold protein 4 (DLG4), de novo pathogenic variants of which lead to DLG4‐related synaptopathy. The major clinical features are developmental delay, intellectual disability (ID), hypotonia, sleep disturbances, movement disorders, and epilepsy. Even though epilepsy is present in 50% of the individuals, it has not been investigated in detail. We describe here the phenotypic spectrum of epilepsy and associated comorbidities in patients with DLG4‐related synaptopathy. Methods: We included 35 individuals with a DLG4 variant and epilepsy as part of a multicenter study. The DLG4 variants were detected by the referring laboratories. The degree of ID, hypotonia, developmental delay, and motor disturbances were evaluated by the referring clinician. Data on awake and sleep electroencephalography (EEG) and/or video‐polygraphy and brain magnetic resonance imaging were collected. Antiseizure medication response was retrospectively assessed by the referring clinician. Results: A large variety of seizure types was reported, although focal seizures were the most common. Encephalopathy related to status epilepticus during slow‐wave sleep (ESES)/developmental epileptic encephalopathy with spike–wave activation during sleep (DEE‐SWAS) was diagnosed in >25% of the individuals. All but one individual presented with neurodevelopmental delay. Regression in verbal and/or motor domains was observed in all individuals who suffered from ESES/DEE‐SWAS, as well as some who did not. We could not identify a clear genotype–phenotype relationship even between individuals with the same DLG4 variants. Significance: Our study shows that a subgroup of individuals with DLG4‐related synaptopathy have DEE, and approximately one fourth of them have ESES/DEE‐SWAS. Our study confirms DEE as part of the DLG4‐related phenotypic spectrum. Occurrence of ESES/DEE‐SWAS in DLG4‐related synaptopathy requires proper investigation with sleep EEG. [ABSTRACT FROM AUTHOR]

• Ketamine-induced anxiety and impairment in mice reveal distinct proteomics in different brain regions. • Alterations in prefrontal cortex proteins may be primarily associated with immuno-inflammatory processes. • Proteins associated with synaptic plasticity and mitochondrial function are predominantly regulated in the hippocampus. • Changes were observed in the expression levels of glutamatergic system-related proteins in the hippocampus. Schizophrenia, a complex psychiatric disorder with diverse symptoms, has been linked to ketamine, known for its N-methyl-D-aspartate (NMDA) receptor antagonistic properties. Understanding the distinct roles and mechanisms of ketamine is crucial, especially regarding its induction of schizophrenia-like symptoms. Recent research highlights the impact of ketamine on key brain regions associated with schizophrenia, specifically the prefrontal cortex (PFC) and hippocampus (Hip). This study focused on these regions to explore proteomic changes related to anxiety and cognitive impairment in a chronic ketamine-induced mouse model of schizophrenia. After twelve consecutive days of ketamine administration, brain tissues from these regions were dissected and analyzed. Using tandem mass tag (TMT) labeling quantitative proteomics techniques, 34,797 and 46,740 peptides were identified in PFC and Hip, corresponding to 5,668 and 6,463 proteins, respectively. In the PFC, a total of 113 proteins showed differential expression, primarily associated with the immuno-inflammatory process, calmodulin, postsynaptic density protein, and mitochondrial function. In the Hip, 129 differentially expressed proteins were screened, mainly related to synaptic plasticity proteins and mitochondrial respiratory chain complex-associated proteins. Additionally, we investigated key proteins within the glutamatergic synapse pathway and observed decreased expression levels of phosphorylated CaMKII and CREB. Overall, the study unveiled a significant proteomic signature in the chronic ketamine-induced schizophrenia mouse model, characterized by anxiety and cognitive impairment in both the PFC and Hip, and this comprehensive proteomic dataset may not only enhance our understanding of the molecular mechanisms underlying ketamine-related mental disorders but also offer valuable insights for future disease treatments. [ABSTRACT FROM AUTHOR]

Synaptic transmission is essential for nervous system function and the loss of synapses is a known major contributor to dementia. Alzheimer's disease dementia (ADD) is characterized by synaptic loss in the mesial temporal lobe and cerebral neocortex, both of which are brain areas associated with memory and cognition. The association of synaptic loss and ADD was established in the late 1980s, and it has been estimated that 30–50% of neocortical synaptic protein is lost in ADD, but there has not yet been a quantitative profiling of different synaptic proteins in different brain regions in ADD from the same individuals. Very recently, positron emission tomography (PET) imaging of synapses is being developed, accelerating the focus on the role of synaptic loss in ADD and other conditions. In this study, we quantified the densities of two synaptic proteins, the presynaptic protein Synaptosome Associated Protein 25 (SNAP25) and the postsynaptic protein postsynaptic density protein 95 (PSD95) in the human brain, using enzyme-linked immunosorbent assays (ELISA). Protein was extracted from the cingulate gyrus, hippocampus, frontal, primary visual, and entorhinal cortex from cognitively unimpaired controls, subjects with mild cognitive impairment (MCI), and subjects with dementia that have different levels of Alzheimer's pathology. SNAP25 is significantly reduced in ADD when compared to controls in the frontal cortex, visual cortex, and cingulate, while the hippocampus showed a smaller, non-significant reduction, and entorhinal cortex concentrations were not different. In contrast, all brain areas showed lower PSD95 concentrations in ADD when compared to controls without dementia, although in the hippocampus, this failed to reach significance. Interestingly, cognitively unimpaired cases with high levels of AD pathology had higher levels of both synaptic proteins in all brain regions. SNAP25 and PSD95 concentrations significantly correlated with densities of neurofibrillary tangles, amyloid plaques, and Mini Mental State Examination (MMSE) scores. Our results suggest that synaptic transmission is affected by ADD in multiple brain regions. The differences were less marked in the entorhinal cortex and the hippocampus, most likely due to a ceiling effect imposed by the very early development of neurofibrillary tangles in older people in these brain regions. [ABSTRACT FROM AUTHOR]

This study was investigated to examine the neuroprotective effect of fermented Protaetia brevitarsis larvae (FPB) in ethanol-induced-dementia mice. Consumption of FPB by mice resulted in improved memory dysfunction in the Y-maze, passive avoidance, and Morris water maze tests. FPB significantly decreased oxidative stress by regulating levels of malondialdehyde (MDA), superoxide dismutase (SOD), and reduced glutathione (GSH) in brain tissues. In addition, FPB restored cerebral mitochondrial dysfunction by modulating levels of reactive oxygen species (ROS), mitochondrial membrane potential (MMP), and ATP. In addition, FPB enhanced the cholinergic system via the regulation of acetylcholine (ACh) content, acetylcholinesterase (AChE) activity, and expressions of AChE and choline acetyltransferase (ChAT) in brain tissues. FPB ameliorated neuronal apoptosis through modulation of the protein kinase B (AKT)/B-cell lymphoma (BCL)-2 signaling pathway. Also, FPB improved inflammation response by down-regulating the toll-like receptor (TLR)-4/nuclear factor (NF)-κB pathway. Additionally, FPB ameliorated synaptic plasticity via the increase of the expressions of synaptophysin (SYP), postsynaptic density protein (PSD)-95, and growth-associated protein (GAP)-43. Treatment with FPB also reinforced the blood–brain barrier by increasing tight junctions including zonula occludens (ZO)-1, occludin, and claudin-1. In conclusion, these results show that FPB can improve cognitive impairment via AKT/NF-κB pathways in ethanol-induced-dementia mice. [ABSTRACT FROM AUTHOR]

Aging-related reduction in androgen levels may be a possible risk factor for neurodegenerative diseases and contribute to cognitive impairment. Androgens may affect synaptic function and cognition in an androgen receptor (AR)-independent manner; however, the mechanisms connecting theses effects are unknown. Therefore, we used testicular feminization mutation (Tfm) male mice, a model with AR mutation, to test the effects of testosterone on synaptic function and cognition. Our results showed that testosterone ameliorated spatial memory deficit and neuronal damage, and increased dendritic spines density and postsynaptic density protein 95 (PSD95) and glutamate receptor 1 (GluA1) expression in the hippocampus of Tfm male mice. And these effects of testosterone were not inhibited by anastrozole, which suppressed conversion of testosterone to estradiol. Mechanistically, testosterone activated the extracellular signal-related kinase 1/2 (Erk1/2) and cyclic adenosine monophosphate response element-binding protein (CREB) in the hippocampus of Tfm male mice. Meanwhile, Erk1/2 inhibitor SCH772984 blocked the upregulation of phospho-CREB, PSD95, and GluA1 induced by testosterone in HT22 cells pretreated with flutamide, an androgen antagonist. Collectively, our data indicate that testosterone may ameliorate hippocampal synaptic damage and spatial memory deficit by activating the Erk1/2--CREB signaling pathway in an AR-independent manner. [ABSTRACT FROM AUTHOR]

Conventional transnasal brain-targeted drug delivery strategies are limited by nasal cilia clearance and the nasal mucosal barrier. To address this challenge, we designed dissolving microneedles combined with nanocarriers for enhanced nose-to-brain drug delivery. To facilitate transnasal administration, a toothbrush-like microneedle patch was fabricated with hyaluronic acid-formed microneedles and tannic acid-crosslinked gelatin as the base, which completely dissolved in the nasal mucosa within seconds leaving only the base, thereby releasing the loaded cyclodextrin-based metal-organic frameworks (CD-MOFs) without affecting the nasal cilia and nasal microbial communities. As nanocarriers for high loading of huperzine A, these potassium-structured CD-MOFs, reinforced with stigmasterol and functionalized with lactoferrin, possessed improved physical stability and excellent biocompatibility, enabling efficient brain-targeted drug delivery. This delivery system substantially attenuated H 2 O 2 - and scopolamine-induced neurocyte damage. The efficacy of huperzine A on scopolamine- and D-galactose & AlCl 3 -induced memory deficits in rats was significantly improved, as evidenced by inhibiting acetylcholinesterase activity, alleviating oxidative stress damage in the brain, and improving learning function, meanwhile activating extracellular regulated protein kinases-cyclic AMP responsive element binding protein-brain derived neurotrophic factor pathway. Moreover, postsynaptic density protein PSD-95, which interacts with two important therapeutic targets Tau and β-amyloid in Alzheimer's disease, was upregulated. This fruitful treatment was further shown to significantly ameliorate Tau hyperphosphorylation and decrease β-amyloid by ways including modulating beta-site amyloid precursor protein cleaving enzyme 1 and a disintegrin and metalloproteinase 10. Collectively, such a newly developed strategy breaks the impasse for efficient drug delivery to the brain, and the potential therapeutic role of huperzine A for Alzheimer's disease is further illustrated. [Display omitted] • Lactoferrin-functionalized stigmasterol-reinforced CD-MOFs were developed for brain-targeting drug delivery. • Microneedles-mediated nose-to-brain drug delivery strategy were demonstrated. • Huperzine A improved memory deficits via regulating ERK-CREB-BDNF, PSD-95/Tau, and Aβ-BACE1-ADAM10 pathways. [ABSTRACT FROM AUTHOR]

Background: Morin is a flavonoid found in many edible fruits. The hippocampus and entorhinal cortex play crucial roles in memory formation and consolidation. This study aimed to characterize the effect of morin on recognition and space memory in healthy C57BL/6 adult mice and explore the underlying molecular mechanism. Methods: Morin was administered i.p. at 1, 2.5, and 5 mg/kg/24 h for 10 days. The Morris water maze (MWM), novel object recognition, novel context recognition, and tasks were conducted 1 day after the last administration. The mice's brains underwent histological characterization, and their protein expression was examined using immunohistochemistry and Western blot techniques. Results: In the MWM and novel object recognition tests, mice treated with 1 mg/kg of morin exhibited a significant recognition index increase compared to the control group. Besides, they demonstrated faster memory acquisition during MWM training. Additionally, the expression of pro‐brain‐derived neurotrophic factor (BDNF), BDNF, and postsynaptic density protein 95 proteins in the hippocampus of treated mice showed a significant increase. In the entorhinal cortex, only the pro‐BDNF increased. Morin‐treated mice exhibited a significant increase in the hippocampus's number and length of dendrites. Conclusion: This study shows that morin improves recognition memory and spatial memory in healthy adult mice. [ABSTRACT FROM AUTHOR]

Aims: Basolateral amygdala (BLA), as a center for stress responses and emotional regulation, is involved in visceral hypersensitivity of irritable bowel syndrome (IBS) induced by stress. In the present study, we aimed to investigate the role of EphB2 receptor (EphB2) in BLA and explore the underlying mechanisms in this process. Methods: Visceral hypersensitivity was induced by water avoidance stress (WAS). Elevated plus maze test, forced swimming test, and sucrose preference test were applied to assess anxiety‐ and depression‐like behaviors. Ibotenic acid or lentivirus was used to inactivate BLA in either the induction or maintenance stage of visceral hypersensitivity. The expression of protein was determined by quantitative PCR, immunofluorescence, and western blot. Results: EphB2 expression was increased in BLA in WAS rats. Inactivation of BLA or downregulation of EphB2 in BLA failed to induce visceral hypersensitivity as well as anxiety‐like behaviors. However, during the maintenance stage of visceral pain, visceral hypersensitivity was only partially relieved but anxiety‐like behaviors were abolished by inactivation of BLA or downregulation of EphB2 in BLA. Chronic WAS increased the expression of EphB2, N‐methyl‐D‐aspartate receptors (NMDARs), and postsynaptic density protein (PSD95) in BLA. Downregulation of EphB2 in BLA reduced NMDARs and PSD95 expression in WAS rats. However, activation of NMDARs after the knockdown of EphB2 expression still triggered visceral hypersensitivity and anxiety‐like behaviors. Conclusions: Taken together, the results suggest that EphB2 in BLA plays an essential role in inducing visceral hypersensitivity. In the maintenance stage, the involvement of EphB2 is crucial but not sufficient. The increase in EphB2 induced by WAS may enhance synaptic plasticity in BLA through upregulating NMDARs, which results in IBS‐like symptoms. These findings may give insight into the treatment of IBS and related psychological distress. [ABSTRACT FROM AUTHOR]

Introduction: Vascular dementia (VaD) is a common type of dementia. The aim of this study was to investigate the cellular and molecular mechanism of conditioned medium (CM) in VaD. Material and methods: The rats were divided into four groups of control (n = 9), sham‐operation (n = 10), VaD with vehicle (n = 9), and VaD with CM (n = 12) that received CM on days 4, 14, and 24 after 2VO. Before sacrificing the rats, cognitive performance was assessed through the open‐field (OP), passive‐avoidance, and Morris‐water maze. The field‐potential recording was used to investigate basal synaptic transmission (BST) and long‐term potentiation (LTP). Subsequently, the hippocampus was dissected, and real‐time PCR was used to quantify the expression levels of β1‐catenin, insulin‐like growth factor‐1 (IGF‐1), transforming growth factor‐beta (TGF‐β), glycogen synthase kinase‐3β (GSK‐3β), postsynaptic density protein 95 (PSD‐95), and NR2B genes. Results: The results indicated impaired performance in behavioral tests in 2VO rats, coupled with reductions in BST and LTP induction. The expression levels of β1‐catenin, IGF‐1, PSD‐95, and TGF‐β genes decreased, whereas NR2B and GSK‐3β expression increased. Treatment with CM restores the expression of PSD‐95 and GSK‐3β as well as fear‐memory, spatial learning, and grooming number without a positive effect on memory retrieval, time spent on the periphery and center of OP. The BST recovered upon administration of CM but, the LTP induction was still impaired. Conclusion: The recovery of BST in VaD rats appears to be the most important outcome of this study which is caused by the improvement of gene expression and leads to the restoration of fear memory. [ABSTRACT FROM AUTHOR]

Maternal exposure to inflammation may represent a major risk factor for neuropsychiatric disorders with associated cognitive dysfunction in offspring in later life. Growing evidence has suggested that resveratrol exerts a beneficial effect on cognitive impairment via its anti-inflammatory and antioxidant properties and by ameliorating synaptic dysfunction. However, how resveratrol affects maternal immune activation-induced cognitive dysfunction and the underlying mechanisms are unclear. In the present study, pregnant dams were given an intraperitoneal injection of lipopolysaccharide (LPS; 50 μg/kg) on gestational day 15. Subsequently, the offspring mice were treated or not with resveratrol (40 mg/kg) from postnatal day (PND) 60 to PND 88. Male offspring were selected for the evaluation of cognitive function using the Morris water maze test. The hippocampal levels of pro-inflammatory cytokines were examined by ELISA. The mRNA and protein levels of sirtuin-1 (SIRT1), brain-derived neurotrophic factor (BDNF), postsynaptic density protein 95 (PSD-95), and synaptophysin (SYP) were determined by RT-qPCR and western blot, respectively. The results showed that male offspring mice exposed to LPS in utero exhibited learning and memory impairment. Additionally, the levels of interleukin (IL)-1β, IL-6, and tumor necrosis factor-alpha (TNF-α) were increased while those of SIRT1, BDNF, PSD-95, and SYP were decreased in male offspring of LPS-treated mothers. Treatment with resveratrol reversed cognitive impairment and attenuated the increase in the levels of pro-inflammatory cytokines induced by maternal immune activation in the offspring mice. Furthermore, resveratrol reversed the deleterious effects of maternal immune activation on SIRT1, BDNF, PSD-95, and SYP levels in the hippocampus. Collectively, our results suggested that resveratrol can effectively improve learning and memory impairment induced by maternal immune activation via the modulation of inflammation and synaptic dysfunction. [ABSTRACT FROM AUTHOR]

Allergic rhinitis (AR) is a widespread disease that is frequently comorbid with depression. However, the mechanisms and treatments for depression in AR remain underexplored. Metformin, a widely used antidiabetic drug, has shown antidepressant effects. The aim of this study was to explore the effects and potential mechanisms of metformin on depression-like behaviors in an AR mouse model. In the present study, mice were sensitized and challenged with ovalbumin (OVA) to induce AR. Results showed that mice with AR exhibited significant depression-like behavior which was attenuated by metformin. In addition, the levels of expression of synaptic plasticity markers (anti-microtubule-associated protein 2, synaptophysin, postsynaptic density protein 95), neurogenesis markers (doublecortin and Ki-67), and brain-derived neurotrophic factor were decreased in the olfactory bulb (OB) of mice with AR, while metformin ameliorated all these alterations and reduced apoptosis in the OB of these mice. Furthermore, it enhanced the phosphorylation of AMP-activated kinase (AMPK) and the levels of ten-eleven translocation 2 (TET2) and 5-hydroxymethylcytosine in the OB. In conclusion, our findings suggest that metformin might be a viable strategy for treating AR-related depression, possibly by modulating neuroplasticity, neurogenesis, apoptosis, and BDNF signaling in the OB via the AMPK/TET2 pathway. [ABSTRACT FROM AUTHOR]

Background: Postoperative cognitive dysfunction (POCD) is a neurological complication occurring after anesthesia and surgery. Neuroinflammation plays a critical role in the pathogenesis of POCD, and the activation of the cluster of differentiation 200 (CD200)/CD200R1 axis improves neurological recovery in various neurological disorders by modulating inflammation. The aim of this study was to investigate the impact and underlying mechanism of CD200/CD200R1 axis on POCD in aged mice. Methods: The model of POCD was established in aged mice. To assess the learning and memory abilities of model mice, the Morris water maze test was implemented. CD200Fc (CD200 fusion protein), CD200R1 Ab (anti-CD200R1 antibody), and 740Y-P (a specific PI3K activator) were used to evaluate the effects of the CD200/CD200R1/PI3K/Akt/NF-κB signaling pathway on hippocampal microglial polarization, neuroinflammation, synaptic activity, and cognition in mice. Results: It was observed that anesthesia/surgery induced cognitive decline in aged mice, increased the levels of tumor necrosis factor alpha (TNF-α), interleukin (IL)-6, IL-1 β and decreased the levels of postsynaptic density protein 95 (PSD-95), synaptophysin (SYN) in the hippocampus. Moreover, CD200Fc and 740Y-P attenuated neuroinflammation and synaptic deficits and reversed cognitive impairment via the phosphatidylinositol 3-kinase (PI3K)/ protein kinase B (Akt)/nuclear factor-kappa B (NF-κB) signaling pathway, whereas CD200R1 Ab administration exerted the opposite effects. Our results further show that the CD200/CD200R1 axis modulates M1/M2 polarization in hippocampal microglia via the PI3K/Akt/NF-κB signaling pathway. Conclusions: Our findings indicate that the activation of the CD200/CD200R1 axis reduces neuroinflammation, synaptic deficits, and cognitive impairment in the hippocampus of aged mice by regulating microglial M1/M2 polarization via the PI3K/Akt/NF-κB signaling pathway. [ABSTRACT FROM AUTHOR]

Background: SHANKs are major scaffolding proteins at postsynaptic densities (PSDs) in the central nervous system. Mutations in all three family members have been associated with neurodevelopmental disorders such as autism spectrum disorders (ASDs). Despite the pathophysiological importance of SHANK2 and SHANK3 mutations in humans, research on the expression of these proteins is mostly based on rodent model organisms. Results: In the present study, cellular and neuropil SHANK2 expression was analyzed by immunofluorescence (IF) staining of post mortem human brain tissue from four male individuals (19 brain regions). Mouse brains were analyzed in comparison to evaluate the degree of phylogenetic conservation. Furthermore, SHANK2 and SHANK3 isoform patterns were compared in human and mouse brain lysates. While isoform expression and subcellular distribution were largely conserved, differences in neuropil levels of SHANK2 were found by IF staining: Maximum expression was concordantly measured in the cerebellum; however, higher SHANK2 expression was detected in the human brainstem and thalamus when compared to mice. One of the lowest SHANK2 levels was found in the human amygdala, a moderately expressing region in mouse. Quantification of SHANK3 IF in mouse brains unveiled a distribution comparable to humans. Conclusions: In summary, these data show that the overall expression pattern of SHANK is largely conserved in defined brain regions; however, differences do exist, which need to be considered in the translation of rodent studies. The summarized expression patterns of SHANK2 and SHANK3 should serve as a reference for future studies. [ABSTRACT FROM AUTHOR]

Background: The muscle excess 3 (MEX3C) protein comprises one of two conserved KH hnRNP K homology domains of the Caenorhabditis elegans protein family, a gene involved in the metabolism of key RNAs at posttranscriptional levels during the development of C. elegans, but its function in mammals is unclear. Methods and results: In this study, we found that MEX3C plays a key role in learning and cognitive function. The learning and cognitive abilities of MEX3C‐knockout (KO) mice were significantly decreased relative to those of wild‐type (WT) mice in behavioral experiments, including the shuttle box, Morris water maze, and new object recognition. Nissl staining showed a decrease in the number of Nissl bodies and in the maturation of hippocampal and cortical neurons. A Western blot analysis of the neuron‐specific nuclear (NeuN) protein NEUN protein showed that the expression of that protein was decreased, which was consistent with the results of Nissl staining. Of note, the expression of sequestosome I p62 and Parkin BCL‐2‐associated X (Bax) Bax and B‐cell lymphoma‐2 (Bcl‐2) Bcl‐2 proteins also showed a downward trend, suggesting that the MEX3C gene may cause a decrease in the number and maturity of neuronal cells by increasing apoptosis through the inhibition of autophagy. In addition, Golgi staining showed that the complexity of neurons in the hippocampus and cerebral cortex was reduced, and the postsynaptic density protein 95 and growth‐associated protein (GAP‐43) also showed different degrees of reduction. Conclusion: The KO of the MEX3C gene reduces the plasticity of synapses in various regions of the hippocampus, thereby affecting the function of the hippocampus and eventually causing the decline of cognitive function. On the other hand, compared with WT mice, MEX3C‐KO mice showed increased anxiety‐like behaviors in minefield and elevated plus maze tests. [ABSTRACT FROM AUTHOR]

Phospholipid phosphatase related 4 (PLPPR4), a neuron‐specific membrane protein located at the postsynaptic density of glutamatergic synapses, is a putative regulator of neuronal plasticity. However, PLPPR4 dysfunction has not been linked to genetic disorders. In this study, we report three unrelated patients with intellectual disability (ID) or autism spectrum disorder (ASD) who harbour a de novo heterozygous copy number loss of PLPPR4 in 1p21.2p21.3, a heterozygous nonsense mutation in PLPPR4 (NM_014839, c.4C > T, p.Gln2*) and a homozygous splice mutation in PLPPR4 (NM_014839: c.408 + 2 T > C), respectively. Bionano single‐molecule optical mapping confirmed PLPPR4 deletion contains no additional pathogenic genes. Our results suggested that the loss of function of PLPPR4 is associated with neurodevelopmental disorders. To test the pathogenesis of PLPPR4, peripheral blood mononuclear cells obtained from the patient with heterozygous deletion of PLPPR4 were induced to specific iPSCs (CHWi001‐A) and then differentiated into neurons. The neurons carrying the deletion of PLPPR4 displayed the reduced density of dendritic protrusions, shorter neurites and reduced axon length, suggesting the causal role of PLPPR4 in neurodevelopmental disorders. As the mTOR signalling pathway was essential for regulating the axon maturation and function, we found that mTOR signalling was inhibited with a higher level of p‐AKT, p‐mTOR and p‐ERK1/2, decreased p‐PI3K in PLPPR4‐iPSCs neurons. Additionally, we found silencing PLPPR4 disturbed the mTOR signalling pathway. Our results suggested PLPPR4 modulates neurodevelopment by affecting the plasticity of neurons via the mTOR signalling pathway. [ABSTRACT FROM AUTHOR]

BACKGROUND: Brain aging can decline learning and memory functions, and the mechanism is not clear. Recent studies have found that ginsenoside Rb1 can improve the learning and memory ability of Alzheimer’s disease model mice, and its mechanism may be related to the improvement of postsynaptic density protein 95 expression. OBJECTIVE: To investigate whether ginsenoside Rg1 can improve the learning and memory function and postsynaptic density protein 95 expression in the hippocampus of D-galactose-induced aging mice through brain-derived neurotrophic factor/TrkB signaling pathway. METHODS: Fifty male SPF Kunlun mice were randomly divided into five groups, A, B, C, D, and E, with 10 mice in each group. Group A: normal blank control group with no treatment; group B: brain aging model was established through subcutaneous injection of D-galactose solution 300 mg/kg per day; group C: at 1 hour after modeling, donepezil hydrochloride was intragastrically administered daily; group D: at 1 hour after modeling, ginsenoside Rg1 was intragastrically given; group E: at 1 hour after modeling, ginsenoside Rg1 (30 mg/kg per day) was intragastrically given and selective TrkB blocker ANA-12 was intraperitoneally injected every 2 days. Mice in each group were administered according to the corresponding dose and frequency for 6 weeks. The following contents were observed: learning and memory ability (open field test, novel object recognition test, and Morris water maze test); morphological observation of brain tissue using hematoxylin-eosin staining and Nissl staining; and western blot detection of postsynaptic density protein 95 and brain-derived neurotrophic factor protein expression in mouse hippocampus. RESULTS AND CONCLUSION: Compared with group A, the learning and memory abilities of mice in group B were significantly decreased (P < 0.05); compared with group B, the learning and memory abilities of mice were significantly improved in groups C and D (P < 0.05); compared with group D, the learning and memory abilities of mice were significantly decreased in group E (P < 0.05). Results of hematoxylin-eosin staining and Nissl staining showed that: compared with group A, the number of normal neurons in the hippocampal CA1 region was reduced and the expression of Nissl bodies was significantly reduced in group B; compared with group B, the number of normal neurons increased and the number of Nissl corpuscle granules increased significantly in groups C and D; compared with group D, the number of normal neurons was reduced and the expression of Nissl bodies were significantly reduced in group E. Western blot results indicated that compared with group A, the expressions of postsynaptic density protein 95 and brain-derived neurotrophic factor in the hippocampus of mice were significantly decreased in group B (P < 0.05); compared with group B, the expressions of postsynaptic density protein 95 and brain-derived neurotrophic factor were significantly increased in groups C and D (P < 0.05); compared with group D, the expression of postsynaptic density protein 95 was significantly decreased in group E (P < 0.05), while the expression of brain-derived neurotrophic factor had no statistical difference (P > 0.05). To conclude, ginsenoside Rg1 can improve D-galactose-induced neuronal damage and learning and memory abilities in brain aging mice and promote the expression of postsynaptic density protein 95 in the hippocampus. The brain-derived neurotrophic factor/TrKB signaling pathway may be one of its mechanisms. [ABSTRACT FROM AUTHOR]

Neuropsychiatric disorders have a high incidence worldwide. Kinesins, a family of microtubule-based molecular motor proteins, play essential roles in intracellular and axonal transport. Variants of kinesins have been found to be related to many diseases, including neurodevelopmental/neurodegenerative disorders. Kinesin-12 (also known as Kif15) was previously found to affect the frequency of both directional microtubule transports. However, whether Kif15 deficiency impacts mood in mice is yet to be investigated. In this study, we used the CRISPR/Cas9 method to obtain Kif15−/− mice. In behavioral tests, Kif15−/− female mice exhibited prominent depressive characteristics. Further studies showed that the expression of BDNF was significantly decreased in the frontal cortex, corpus callosum, and hippocampus of Kif15−/− mice, along with the upregulation of Interleukin-6 and Interleukin-1β in the corpus callosum. In addition, the expression patterns of AnkG were notably changed in the developing brain of Kif15−/− mice. Based on our previous studies, we suggested that this appearance of altered AnkG was due to the maladjustment of the microtubule patterns induced by Kif15 deficiency. The distribution of PSD95 in neurites notably decreased after cultured neurons treated with the Kif15 inhibitor, but total PSD95 protein level was not impacted, which revealed that Kif15 may contribute to PSD95 transportation. This study suggested that Kif15 may serve as a potential target for future depression studies. [ABSTRACT FROM AUTHOR]

Sex-biased differences in schizophrenia are evident in several features of the disease, including symptomatology and response to pharmacological treatments. As a neurodevelopmental disorder, these differences might originate early in life and emerge later during adolescence. Considering that the disruption of the glutamatergic system during development is known to contribute to schizophrenia, we hypothesized that the neonatal phencyclidine model could induce sex-dependent behavioral and neurochemical changes associated with this disorder during adolescence. C57BL/6 mice received either saline or phencyclidine (5, 10, or 20 mg/kg) on postnatal days (PN) 7, 9, and 11. Behavioral assessment occurred in late adolescence (PN48-50), when mice were submitted to the open field, social interaction, and prepulse inhibition tests. Either olanzapine or saline was administered before each test. The NMDAR obligatory GluN1 subunit and the postsynaptic density protein 95 (PSD-95) were evaluated in the frontal cortex and hippocampus at early (PN30) and late (PN50) adolescence. Neonatal phencyclidine evoked dose-dependent deficits in all analyzed behaviors and males were more susceptible. Males also had reduced GluN1 expression in the frontal cortex at PN30. There were late-emergent effects at PN50. Cortical GluN1 was increased in both sexes, while phencyclidine increased cortical and decreased hippocampal PSD-95 in females. Olanzapine failed to mitigate most phencyclidine-evoked alterations. In some instances, this antipsychotic aggravated the deficits or potentiated subthreshold effects. These results lend support to the use of neonatal phencyclidine as a sex-biased neurodevelopmental preclinical model of schizophrenia. Olanzapine null effects and deleterious outcomes suggest that its use during adolescence should be further evaluated. [ABSTRACT FROM AUTHOR]

Introduction: Recent studies have highlighted the vital role of gut microbiota in traumatic brain injury (TBI). Fecal microbiota transplantation (FMT) is an effective means of regulating the microbiota-gut-brain axis, while the beneficial effect and potential mechanisms of FMT against TBI remain unclear. Here, we elucidated the anti-neuroinflammatory effect and possible mechanism of FMT against TBI in mice via regulating the microbiota-gut-brain axis. Methods: The TBI mouse model was established by heavy object falling impact and then treated with FMT. The neurological deficits, neuropathological change, synaptic damage, microglia activation, and neuroinflammatory cytokine production were assessed, and the intestinal pathological change and gut microbiota composition were also evaluated. Moreover, the population of Treg cells in the spleen was measured. Results: Our results showed that FMT treatment significantly alleviated neurological deficits and neuropathological changes and improved synaptic damage by increasing the levels of the synaptic plasticity-related protein such as postsynaptic density protein 95 (PSD-95) and synapsin I in the TBI mice model. Moreover, FMT could inhibit the activation of microglia and reduce the production of the inflammatory cytokine TNF-a, alleviating the inflammatory response of TBI mice. Meanwhile, FMT treatment could attenuate intestinal histopathologic changes and gut microbiota dysbiosis and increase the Treg cell population in TBI mice. Conclusion: These findings elucidated that FMT treatment effectively suppressed the TBI-induced neuroinflammation via regulating the gut microbiota-gut-brain axis, and its mechanism was involved in the regulation of peripheral immune cells, which implied a novel strategy against TBI. [ABSTRACT FROM AUTHOR]

Background and Purpose: High salt (HS) intake has been associated with hypertension and cognitive impairment. It is well known that the angiotensin II (Ang II)‐AT1 receptor and prostaglandin E2 (PGE2)‐EP1 receptor systems are involved in hypertension and neurotoxicity. However, the involvement of these systems in HS‐mediated hypertension and emotional and cognitive impairments remains unclear. Experimental Approach: Mice were loaded with HS solution (2% NaCl drinking water) for 12 weeks, and blood pressure was monitored. Subsequently, effects of HS intake on emotional and cognitive function and tau phosphorylation in the prefrontal cortex (PFC) and hippocampus (HIP) were investigated. The involvement of Ang II‐AT1 and PGE2‐EP1 systems in HS‐induced hypertension and neuronal and behavioural impairments was examined by treatment with losartan, an AT1 receptor blocker (ARB), or EP1 gene knockout. Key Results: We demonstrate that hypertension and impaired social behaviour and object recognition memory following HS intake may be associated with tau hyperphosphorylation, decreased phosphorylation of Ca2+/calmodulin‐dependent protein kinase II (CaMKII), and postsynaptic density protein 95 (PSD95) expression in the PFC and HIP of mice. These changes were blocked by pharmacological treatment with losartan or EP1 receptor gene knockout. Conclusions and Implications: Our findings suggest that the interaction of Ang II‐AT1 receptor and PGE2‐EP1 receptor systems could be novel therapeutic targets for hypertension‐induced cognitive impairment. [ABSTRACT FROM AUTHOR]

The demand for environmentally friendly foods with high nutritional value and low carbon emissions is increasing with the aging of the global population and the crisis of food resources. Edible insects are becoming increasingly well-known as such foods. This study evaluated the effects and mechanisms of Gryllus bimaculatus (Cricket) (Gb) and Oxya chinensis sinuosa (Grasshopper) (Ocs) extracts on epilepsy. A pentylenetetrazol (PTZ)-induced seizure mouse model was used for the study, and Gb and Ocs extracts were administered for 29 days on alternate days at concentrations of 8 g/kg and 16 g/kg. The integrity of the blood-brain barrier (BBB) and brain edema was measured using the perfusion of Evans blue dye and brain water content. Gb and Ocs extracts prevented BBB permeabilization and cerebral edema through increasing the expression of tight junction-associated proteins in the endothelial cells and reducing water content in PTZ-treated mice. Additionally, Gb and Ocs extracts protected neurons from oxidative stress and apoptosis in different brain areas. These protective effects were demonstrated through the restoration of the expression of neuronal nuclear protein and postsynaptic density protein-95, thus increasing the levels of glutathione and superoxide dismutase, decreasing lipid peroxidation, and recovering apoptosis-associated proteins, such as Bax, cleaved PARP, and cleaved caspase-3, in epileptic mice. In addition, Gb and Ocs extracts rescued PTZ-induced hyperexcitable neurons to control mice level, as supported by the restored expression of gamma-aminobutyric acid (GABA) transporter 1, the metabotropic glutamate receptors–GRM2/3, and BDNF. This study suggested that Gb and Ocs extracts are novel medicinal candidates that can help ameliorate epilepsy by improving BBB health and preventing oxidative stress-mediated apoptosis. [ABSTRACT FROM AUTHOR]

Background: Schizophrenia (SZ) is a disorder diagnosed by specific symptoms and duration and is highly heterogeneous, clinically and pathologically. Although there are an increasing number of studies on the association between genetic and environmental factors in the development of SZ, the actual distribution of the population with different levels of influence of these factors has not yet been fully elucidated. In this study, we focused on stress as an environmental factor and stratified SZ based on the expression levels of stress-responsive molecules in the postmortem prefrontal cortex. Methods: We selected the following stress-responsive molecules: interleukin (IL) -1β, IL-6, IL-10, tumor necrosis factor-α, interferon-γ, glucocorticoid receptor, brain-derived neurotrophic factor, synaptophysin, S100 calcium-binding protein B, superoxide dismutase, postsynaptic density protein 95, synuclein, apolipoprotein A1 (ApoA1), ApoA2, and solute carrier family 6 member 4. We performed RNA sequencing in the prefrontal gray matter of 25 SZ cases and 21 healthy controls and conducted a hierarchical cluster analysis of SZ based on the gene expression levels of stress-responsive molecules, which yielded two clusters. After assessing the validity of the clusters, they were designated as the high stress-response SZ group and the low stress-response SZ group, respectively. Ingenuity Pathway Analysis of differentially expressed genes (DEGs) between clusters was performed, and Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining was conducted on four cases each in the high and low stressresponse SZ groups to validate DNA damage. Results: We found higher prevalence of family history of SZ in the low stressresponse SZ group (0/3 vs. 5/4, p = 0.04). Pathway analysis of DEGs between clusters showed the highest enrichment for DNA double-strand break repair. TUNEL staining showed a trend toward a lower percentage of TUNEL-positive cells in the high stress-response SZ group. Conclusion: Our results suggest that there are subgroups of SZ with different degrees of stress impact. Furthermore, the pathophysiology of these subgroups may be associated with DNA damage repair. These results provide new insights into the interactions and heterogeneity between genetic and environmental factors. [ABSTRACT FROM AUTHOR]

Microglia, which are productively infected by HIV-1, are critical for brain development and maturation, as well as synaptic plasticity. The pathophysiology of HIV-infected microglia and their role in the pathogenesis of HIV-1-associated neurocognitive and affective alterations, however, remains understudied. Three complementary aims were undertaken to critically address this knowledge gap. First, the expression of HIV-1 mRNA in the dorsolateral prefrontal cortex of postmortem HIV-1 seropositive individuals with HAND was investigated. Utilization of immunostaining and/or RNAscope multiplex fluorescent assays revealed prominent HIV-1 mRNA in microglia of postmortem HIV-1 seropositive individuals with HAND. Second, measures of microglia proliferation and neuronal damage were evaluated in chimeric HIV (EcoHIV) rats. Eight weeks after EcoHIV inoculation, enhanced microglial proliferation was observed in the medial prefrontal cortex (mPFC) of EcoHIV rats, evidenced by an increased number of cells co-localized with both Iba1 + and Ki67 + relative to control animals. Neuronal damage in EcoHIV infected rats was evidenced by pronounced decreases in both synaptophysin and postsynaptic density protein 95 (PSD-95), markers of presynaptic and postsynaptic damage, respectively. Third, regression analyses were conducted to evaluate whether microglia proliferation mechanistically underlies neuronal damage in EcoHIV and control animals. Indeed, microglia proliferation accounted for 42–68.6% of the variance in synaptic dysfunction. Collectively, microglia proliferation induced by chronic HIV-1 viral protein exposure may underlie the profound synaptodendritic alterations in HIV-1. Understanding how microglia are involved in the pathogenesis of HAND and HIV-1-associated affective disorders affords a key target for the development of novel therapeutics. [ABSTRACT FROM AUTHOR]

Rates of Cannabis Use Disorder (CUD) are highest amongst young adults. Paucity of brain tissue samples limits the ability to examine the molecular basis of cannabis related neuropathology. Proteomic studies of neuron-derived extracellular vesicles (NDEs) isolated from the biofluids may reveal markers of neuropathology in CUD. NDEs were extracted using ExoSORT, an immunoaffinity method to enrich NDEs from plasma samples from patients with young onset CUD and matched controls. Differential proteomic profiles were explored with Label Free Quantification (LFQ) mass spectrometry. Selected proteins were validated using orthogonal methods. A total of 231 (±10) proteins were identified in NDE preparations from CUD and controls of which 28 were differentially abundant between groups. The difference in abundance of properdin (CFP gene) was statistically significant. SHANK1 (SHANK1 gene), an adapter protein at the post-synaptic density, was nominally depleted in the CUD NDE preparations. In this pilot study, we noted a decrease in SHANK1 protein, involved in the structural and functional integrity of glutamatergic post-synapse, a potential peripheral signature of CUD neuropathology. The study shows that LFQ mass spectrometry proteomic analysis of NDEs derived from plasma may yield important insights into the synaptic pathology associated with CUD. [ABSTRACT FROM AUTHOR]

Traumatic Brain Injury (TBI) remains one of the prevailing disorders that affect millions of people around the globe. There is a cascade of secondary attributes attached to TBI including excitotoxicity, axonal degeneration, neuroinflammation, oxidative stress, and apoptosis. Neuroinflammation is caused due to the activation of microglia along with pro-inflammatory cytokines. The activation of microglia triggers TNF-α which sequentially results in the triggering and upregulation of NF-kB. The aim of the current research was to investigate vitamin B1's potential as neuroprotective agent against TBI-induced neuroinflammation arbitrated memory impairment together with pre- and post-synaptic dysfunction in an adult albino male mice model. TBI was induced using the weight-drop method which caused the microglial activation resulting in neuroinflammation along with synaptic dysfunction leading to the memory impairment of the adult mice. Vitamin B1 was administered for seven days via the intraperitoneal pathway. To analyze the memory impairment and efficacy of vitamin B1, Morris water maze and Y-maze tests were performed. The escape latency time and short-term memories of the experimental mice treated with vitamin B1 were significantly different from the reference mice. The western blot results showed that vitamin B1 has reduced neuroinflammation by downregulating proinflammatory cytokines (NFκ-B, TNF- α). Vitamin B1 also proved its worthiness as a convincing neuroprotective agent by reducing memory dysfunction and recovering the activities of pre- and post-synapse via upregulation of synaptophysin and Postsynaptic density protein 95 (PSD-95). [ABSTRACT FROM AUTHOR]

Rationale: The management of depression continues to be challenging despite the variety of available antidepressants. Herbal medicines are used in many cultures but lack stringent testing to understand their efficacy and mechanism of action. Isoalantolactone (LAT) from Elecampane (Inula helenium) improved the chronic social defeat stress (CSDS)-induced anhedonia-like phenotype in mice comparable to fluoxetine, a selective serotonin reuptake inhibitor (SSRI). Objectives: Compare the effects of LAT and fluoxetine on depression-like behaviors in mice exposed to CSDS. Result: The CSDS-induced decrease in protein expression of postsynaptic density (PSD95), brain derived neurotrophic factor (BDNF), and glutamate receptor subunit-1 (GluA1) in the prefrontal cortex was restored by LAT. LAT showed robust anti-inflammatory activity and can lessen the increase in IL-6 and TNF-α caused by CSDS. CSDS altered the gut microbiota at the taxonomic level, resulting in significant changes in α- and β-diversity. LAT treatment reestablished the bacterial abundance and diversity and increased the production of butyric acid in the gut that was inhibited by CSDS. The levels of butyric acid were negatively correlated with the abundance of Bacteroidetes, and positively correlated with those of Proteobacteria and Firmicutes across all treatment groups. Conclusions: The current data suggest that, similar to fluoxetine, LAT show antidepressant-like effects in mice exposed to CSDS through the modulation of the gut-brain axis. [ABSTRACT FROM AUTHOR]

Metabotropic glutamate receptor 5 (mGlu5) is widely expressed throughout the central nervous system and is involved in neuronal function, synaptic transmission, and a number of neuropsychiatric disorders such as depression, anxiety, and autism. Recent work from this lab showed that mGlu5 is one of a growing number of G protein-coupled receptors that can signal from intracellular membranes where it drives unique signaling pathways, including upregulation of extracellular signal-regulated kinase (ERK1/2), ETS transcription factor Elk-1, and activity-regulated cytoskeleton-associated protein (Arc). To determine the roles of cell surface mGlu5 as well as the intracellular receptor in a well-known mGlu5 synaptic plasticity model such as long-term depression, we used pharmacological isolation and genetic and physiological approaches to analyze spatially restricted pools of mGlu5 in striatal cultures and slice preparations. Here we show that both intracellular and cell surface receptors activate the phosphatidylinositol-3-kinase–protein kinase B–mammalian target of rapamycin (PI3K/AKT/mTOR) pathway, whereas only intracellular mGlu5 activates protein phosphatase 2 and leads to fragile X mental retardation protein degradation and de novo protein synthesis followed by a protein synthesis–dependent increase in Arc and post-synaptic density protein 95. However, both cell surface and intracellular mGlu5 activation lead to α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor GluA2 internalization and chemically induced longterm depression albeit via different signaling mechanisms. These data underscore the importance of intracellular mGlu5 in the cascade of events associated with sustained synaptic transmission in the striatum. [ABSTRACT FROM AUTHOR]