Hippocampal CA1 Region Research Articles

Revealing the Mechanism of Hemerocallis citrina Baroni in Depression Treatment Through Integrated Network Pharmacology and Transcriptomic Analysis

Background/Objectives: Hemerocallis citrina Baroni (HCB) is a traditional herb for the treatment of depression in China. However, the active constituents and the underlying mechanisms of its antidepressant effects remain unclear. The aim of this study was to identify the bioactive constituents of HCB and elucidate its underlying mechanism for the treatment of depression. Methods: The constituents of HCB were systematically analyzed using UHPLC-Q-Orbitrap HRMS. Its antidepressant effect was evaluated by chronic unpredictable mild stress (CUMS)-induced depression. The mechanism of HCB in treating depression was investigated through network pharmacology and molecular docking. Subsequently, its potential mechanism for the treatment of depression was carried out by RNA sequencing. Finally, the mechanism was further verified by Western blot. Results: A total of 62 chemical constituents were identified from HCB using UHPLC-Q-Orbitrap HRMS, including 17 flavonoids, 11 anthraquinones, 11 alkaloids, 10 caffeoylquinic acid derivatives, five phenolic acids, five triterpenoids, and three phenylethanosides, 13 of which were identified as potential active constituents targeting 49 depression-associated proteins. Furthermore, HCB was found to significantly reduce cognitive impairment, anxiety-like behavior, and anhedonia-like behavior. The expression levels of 5-hydroxytryptamine (5-HT), dopamine (DA), and brain-derived neurotrophic factor (BDNF) were elevated in the hippocampal CA3 region. Results from network pharmacology and transcriptomics indicated that the PI3K/Akt/CREB signaling pathway is essential for the therapeutic effects of HCB on depression. Research in the field of molecular biology has conclusively demonstrated that HCB is associated with an increase in the expression levels of several important proteins. Specifically, there was a notable upregulation of phosphorylated PI3K (p-PI3K) relative to its unphosphorylated form PI3K, as well as an elevation in the ratio of phosphorylated Akt (p-Akt) to total Akt. Additionally, the study observed increased levels of phosphorylated CREB (p-CREB) compared to its unphosphorylated CREB. Conclusions: This study provides compelling evidence that HCB possesses the ability to mitigate the symptoms of depression through its influence on the PI3K/Akt/CREB signaling pathway. HCB could be developed as a promising therapeutic intervention for individuals struggling with depression, offering new avenues for treatment strategies that target this particular signaling mechanism.

Excitatory-Inhibitory Synaptic Imbalance Induced by Acute Intra-Hippocampus Injections of Amyloid-β Oligomers

Alzheimer's disease (AD) is characterized by the accumulation of soluble amyloid-β oligomers (AβOs) in the brain, which disrupt synaptic function and promote cognitive decline. Here, we investigated the effects of AβOs on excitatory and inhibitory synaptic transmission and plasticity by performing stereotaxic injections of AβOs directly into the hippocampal CA1 region, followed by hippocampal slice isolation for electrophysiological measurements. AβOs injections altered basal excitatory synaptic transmission, reducing field excitatory postsynaptic potentials (fEPSPs) and impairing excitatory long-term potentiation (LTP). Additionally, AβOs injections significantly increased basal inhibitory synaptic transmission, as evidenced by the increased amplitude of field inhibitory postsynaptic potentials (fIPSPs), but impaired the induction and maintenance of inhibitory long-term potentiation (iLTP). Accordingly, we propose that AβOs injections induce the saturation of the GABAergic system and thus disrupt the hippocampal excitatory-inhibitory balance. These findings highlight the dual impact of AβOs on both excitatory and inhibitory synapses, generating synaptic dysregulation and possibly worsening cognitive decline in AD. Understanding these mechanisms could provide new insights for developing therapies to restore synaptic balance and hippocampal function in AD.

Altered expression of Presenilin2 impacts endolysosomal homeostasis and synapse function in Alzheimer’s disease-relevant brain circuits

Rare mutations in the gene encoding presenilin2 (PSEN2) are known to cause familial Alzheimer’s disease (FAD). Here, we explored how altered PSEN2 expression impacts on the amyloidosis, endolysosomal abnormalities, and synaptic dysfunction observed in female APP knock-in mice. We demonstrate that PSEN2 knockout (KO) as well as the FAD-associated N141IKI mutant accelerate AD-related pathologies in female mice. Both models showed significant deficits in working memory that linked to elevated PSEN2 expression in the hippocampal CA3 region. The mossy fiber circuit of APPxPSEN2KO and APPxFADPSEN2 mice had smaller pre-synaptic compartments, distinct changes in synaptic vesicle populations and significantly impaired long term potentiation compared to APPKI mice. At the cellular level, altered PSEN2 expression resulted in endolysosomal defects and lowered surface expression of synaptic proteins. As PSEN2/γ-secretase is restricted to late endosomes/lysosomes, we propose PSEN2 impacts endolysosomal homeostasis, affecting synaptic signaling in AD-relevant vulnerable brain circuits; which could explain how mutant PSEN2 accelerates AD pathogenesis.

Long-term exposure to excessive norepinephrine in the brain induces tau aggregation, neuronal death, and cognitive deficits in early tau transgenic mice.

Alzheimer's disease (AD) is marked by the presence of intraneuronal neurofibrillary tangles (NFTs), which are primarily composed of hyperphosphorylated tau protein. The locus coeruleus (LC), the brain's main source of norepinephrine (NE), is one of the earliest regions to develop NFTs and experience neurodegeneration in AD. While LC-derived NE plays beneficial roles in cognition, emotion, locomotion, and the sleep-wake cycle, its impact on tau pathology is unclear. To explore this relationship, we administered intraperitoneal injections of either N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4), a selective neurotoxin for noradrenergic neurons, or reboxetine (RBX), a norepinephrine reuptake inhibitor, to decrease or increase NE levels, respectively, in early tau transgenic mice expressing mutant human P301L tau (ADLPTau) for two months. Only the RBX-treated mice exhibited cognitive deficits, as evidenced by their performance in the Y-maze, novel object recognition, and contextual fear conditioning tests. Immunohistochemical analysis revealed increased hyperphosphorylated tau aggregates in the LC and hippocampus of the RBX-treated mice. Furthermore, neuronal apoptosis was observed in the hippocampal CA1 region of these mice. Western blotting showed that RBX injections led to the overactivation of tau kinases PKA and GSK3β, resulting in hyperphosphorylated tau, neuronal loss, and cognitive impairments. Consistent with these findings, human brain organoids exposed to higher NE concentrations also displayed elevated hyperphosphorylated tau and increased activity of the same tau kinases. These findings suggest that excessive NE exposure accelerates tau pathology by overactivating the tau kinases. Thus, modulating NE levels in the brain via the LC-NE system could be a potential therapeutic strategy for tau-related AD.

Effect of electroacupuncture on synaptic ultrastructure and synaptic function related proteins PSD95 and MeCP2 in sleep deprivation rats

To observe the effect of electroacupuncture (EA) on the expression of synaptic function related proteins PSD95 and MeCP2 and synaptic ultrastructure in sleep deprived rats, so as to explore its mechanism underlying improvement of learning and memory ability caused by sleep deprivation. SD rats were randomly divided into normal, model, EA and sham EA groups (n=10). The sleep deprivation model was prepared by modified multi-platform water environment. Rats of the EA group received EA stimulation at "Baihui" (GV20) and "Dazhui" (GV14), while the sham EA group received shallow needling 4 mm away from the above acupoints without electrical stimulation. The learning and memory ability was evaluated with Morris water maze test. The density of dendritic spines in hippocampal CA1 region was detected by Golgi staining. The synaptic ultrastructure of hippocampus was observed by electron microscope. The protein expression levels of PSD95 and MeCP2 in hippocampus was detected by Western blot. Compared with the normal group, the escaping latency of the positioning navigation experiment in the model group was prolonged (P<0.05), the number of crossing the platform and the residence time in the target quadrant were decreased(P<0.05), the density of dendritic spines in the hippocampal CA1 area was decreased (P<0.05), the number of synapses was reduced, with swollen synaptosomes, blurred synaptic structure, disappeared and narrowed synaptic clefts, the protein expression levels of PSD95 and MeCP2 were significantly decreased (P<0.05) in the model group. Compared with the model group, the escape latency of the positioning navigation experiment was shortened (P<0.05), the number of crossing platforms and the time spent in the target quadrant were increased (P<0.05), the density of dendritic spines in the hippocampal CA1 region was increased (P<0.05), the morphology of synaptic improved, the protein expression levels of PSD95 and MeCP2 were increased (P<0.01) in the EA and sham EA groups. The improvement of the above indexes in EA group was more obvious than those in sham EA group. EA can improve the learning and memory of sleep deprivation rats, which may be related to its function in regulating the expressions of synaptic related proteins PSD95 and MeCP2, and improving the synaptic structure.

The primary studies of epigallocatechin-3-gallate in improving brain injury induced by chronic high-altitude natural environment in rats by 7.0T high-field MR imaging

BackgroundEpigallocatechin-3-gallate (EGCG) is one of the most abundant and important bioactive polyphenolic compounds in green tea. However, despite its potent antioxidant effects, its neuroprotective effects on chronic high altitude (HA)-induced nerve damage have not been reported. The purpose of this study is to use quantitative susceptibility mapping (QSM) with pathology to dynamically evaluate the status of brain damage and the effect of EGCG. MethodsA model of HA environments-induced brain injury was established of Sprague-Dawley (SD) rats in a natural plateau environment for 4 weeks, 8 weeks, 12 weeks and 20 weeks. Behavioral alterations were then observed and assessed with the open field test (OFT) and Morris water maze (MWM) test. The microglial activation, nissl staining and neural degeneration by Fluoro Jade B in the hippocampus of the rats were observed by immunohistochemistry. In the rats, serum erythropoietin (EPO), hippocampal inflammatory cytokines (interleukin-1β [IL-1β], interleukin-6 [IL-6] and tumor necrosis factor-α [TNF-α]), ferritin, oxidative stress (superoxide dismutase [SOD], glutathione peroxidase [GSH-Px], catalase [CAT] and malondialdehyde [MDA]) were detected using ELISA kits and biochemical methods. Iron accumulation was observed by QSM and colorimetry. Iron metabolisms (ceruloplasmin [Cp], transferrin [Tf], divalent metal transport1 [DMT1] and hepcidin [Hep]) were detected using qPCR. Neural ultrastructural changes were evaluated with electron microscope. Salidroside treatment was chosen as the positive control group in ELISA, biochemical detection and electron microscopy. ResultsThe susceptibility values in the left and right hippocampus, the hippocampal ferritin, serum and hippocampal iron content increased significantly after HA exposure. The expression of hippocampal Cp and Hep decreased and the expression of Tf increased. Nissl staining revealed that the neurons of hippocampal CA1 region of h-20w group were small and irregular, atrophied, and nuclear shrinkage. Tissue oxidative stress and inflammatory indicators (MDA, TNF-α, IL-1β, IL-6) increased while antioxidant enzymes (SOD, CAT, GSH-Px) decreased. EGCG attenuated HA environments-induced cognitive impairment, iron accumulation, microglial activation and neural degeneration. The effects of EGCG in reducing EPO and the metal chelating property with respect to iron were dose-dependent, with effects of EGCG (50 mg/kg) being similar to those of salidroside (50 mg/kg). ConclusionsEGCG can act as a neuroprotective agent against chronic HA environments-mediated neural injuries. QSM provides a potential complementary imaging technique to detect the effect of treating HA diseases.

Depression like-behavior and memory loss induced by methylglyoxal is associated with tryptophan depletion and oxidative stress: a new in vivo model of neurodegeneration

BackgroundDepression and memory loss are prevalent neurodegenerative disorders, with diabetic patients facing an elevated risk of brain dysfunction. Methylglyoxal (MGO) formation, which is heightened in diabetes owing to hyperglycemia and gut dysbiosis, may serve as a critical link between diabetes and brain diseases. Despite the high prevalence of MGO, the precise mechanisms underlying MGO-induced depression and memory loss remain unclear.ResultsWe investigated the effect of MGO stress on depression like-behavior and memory loss to elucidate the potential interplay between MGO-induced tryptophan (Trp) metabolism impairment and oxidative stress in the brain. It demonstrates that MGO induces depression-like behavior in mice, as confirmed by the OFT, TST, FST, SPT, and EPM behavioral tests. MGO led to the depletion of Trp and related neurotransmitters as 5-HT, EPI, and DA in the mouse brain. Additionally, MGO reduced the cell count in the DG, CA1, and CA3 hippocampal regions and modulated TPH2 levels in the brain. Notably, co-treatment with MGO and Trp mirrored the effects observed after Trp-null treatment in neurons, including reduced TPH1 and TPH2 levels and inhibition of neuronal outgrowth. Furthermore, MGO significantly altered the expression of key proteins associated with neurodegeneration, such as p-Tau, p-GSK-3β, APP, oAβ, BDNF, NGF, and p-TrkB. Concurrently, MGO activated MAPKs through ROS induction, triggering a redox imbalance by downregulating Nrf-2, Ho-1, TXNRD1, Trx, Sirt-3, and Sirt-5 expression levels, NAD+, and CAT activity in the mouse brain. This led to an accelerated neuroinflammatory response, as evidenced by increased expression of Iba-1, p-NF-κB, and the secretion of IL-6 and TNF-α. Importantly, Trp treatment ameliorated MGO-induced depression like-behavior and memory loss in mice and markedly mitigated increased expression of p-Tau, APP, p-ERK1/2, p-pJNK, and p-NF-κB in the brain. Likewise, Trp treatment also induced the expression of MGO detoxifying factors GLO-I and GLO-II and CAT activity, suggesting the induction of an antioxidant system and reduced inflammation by inhibiting IL-6 and TNF-α secretion.ConclusionsOur data revealed that MGO-induced depression like-behavior and memory deficits resulted from disturbances in Trp, 5-HT, BDNF, and NGF levels, increased p-Tau and APP expression, neuroinflammation, and impaired redox status (Nrf-2/Ho-1/TXNRD1/Sirt3/5) in the brain.

Effects of Black Rice Anthocyanin Extract on Depression-Like Behavior in Chronic Unpredictable Mild Stress Model Mice

Objective: To investigate the effects of black rice anthocyanins extract (BSE) on depression-like behavior in mice with chronic unpredictable mild stress (CUMS). Methods: A total of 30 male Kunming mice were randomly divided into Control group, model group (CUMS) and black rice anthocyanin extract group (300 mg/kg). Except the blank group, all mice were treated with CUMS to induce depression. After 21 days of intragastric administration, the behavioral changes of the mice were analyzed by body weight, sucrose preference test, open field test, and water maze test. Enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH) and corticosterone (CORT). Hematoxylin-eosin staining (HE) was used to observe the pathological changes of neurons in hippocampal CA1 and CA3 regions. Cell apoptosis in hippocampus was detected by terminal deoxynucleotidyl transferase-mediated dutP Nick end labeling (TUNEL) staining. Results: Compared with the model group, the brown-rice anthocyanin treatment group showed significantly increased sucrose preference, increased horizontal movement distance and vertical standing times in the open field test, decreased escape latency in the water maze test, increased residence time in the target quadrant and the number of crossing the platform, and alleviated the damage of hippocampal neurons. Plasma ACTH, CORT, and CRH levels were decreased, and apoptosis rates in the hippocampus were decreased. Conclusion: Black rice anthocyanins have a significant antidepressant effect possibly by regulating the function of HPA axis.

Berberine-loaded iron oxide nanoparticles alleviate cuprizone-induced astrocytic reactivity in a rat model of multiple sclerosis.

Berberine (BBN) is a naturally occurring alkaloid as a secondary metabolite in many plants and exhibits several benefits including neuroprotective activities. However, data on the neuromodulating potential of nanoformulated BBN are still lacking. In the present study, BBN loaded within iron oxide nanoparticles (BBN-IONP) were prepared and characterized by transmission electron microscopy FTIR, X-ray photoelectron spectroscopy particle-size distribution, zeta potential, and HPLC. The remyelinating neuroprotective potential of BBN-IONP relative to free BBN was evaluated against cuprizone (CPZ)-induced neurotoxicity (rats administered 0.2% CPZ powder (w/w) for five weeks). CPZ rats were treated with either free BBN or IONP-BBN (50 mg/kg/day, orally) for 14 days. Cognitive function was estimated using Y-maze. Biochemically, total antioxidant capacity lipid peroxides and reduced glutathione in the brain tissue, as well as, serum interferon-gamma levels were estimated. Moreover, the genetic expression contents of myelin basic protein Matrix metallopeptidase-9 Tumor necrosis factor-α (TNF-α), and S100β were measured. The histopathological patterns and immunohistochemical assessment of Glial Fibrillary Acidic Protein in both cerebral cortex and hippocampus CA1 regions were investigated. CPZ-rats treated with either free BBN or IONP-BBN demonstrated memory restoring, anti-oxidative, anti-inflammatory, anti-astrocytic, and remyelinating activities. Comparing free BBN with IONP-BBN revealed that the latter altered the neuromodulating activities of BBN, showing superior neuroprotective activities of IONP-BBN relative to BBN. In conclusion, both forms of BBN possess neuroprotective potential. However, the use of IONPs for brain delivery and the safety of these nano-based forms need further investigation.

Semaglutide promotes the transition of microglia from M1 to M2 type to reduce brain inflammation in APP/PS1/tau mice

A growing number of studies show that the diabetes drug Semaglutide is neuroprotective in Alzheimer’s disease (AD) animal models, but its mode of action is not fully understood. In order to explore the mechanism of Semaglutide, 7-month-old APP/PS1/tau transgenic (3xTg) mice and wild-type (WT) mice were randomly divided into four groups: control group (WT + PBS), AD model group (3xTg + PBS), Semaglutide control group (WT + Semaglutide) and Semaglutide treatment group (3xTg + Semaglutide). Semaglutide (25 nmol/kg) or PBS was administered intraperitoneally once every two days for 30 days, followed by behavioral and molecular experiments. The results show that Semaglutide can improve working memory and spatial reference memory of 3xTg-AD mice, promote the release of anti-inflammatory factors and inhibit the production of pro-inflammatory factors in the cortex and hippocampus, and reduce Aβ deposition in the hippocampal CA1 region of 3xTg mice. Semaglutide can inhibit the apoptosis of BV2 cells induced by Aβ1-42 in a dose-dependent manner and promote the transformation of microglia from M1 to M2, thereby exerting anti-inflammatory and neuroprotective effects. Therefore, we speculate that Semaglutide shows an anti-inflammatory effect by promoting the transformation of microglia from M1 to M2 type in the brain of 3xTg mice, and thus exerts a neuroprotective effect.

Therapeutic effects of pentoxifylline in propionic acid-induced autism symptoms in rat models: A behavioral, biochemical, and histopathological study.

The role of propionic acid (PPA) in eliciting behaviors analogous to autism in rat models is a documented phenomenon. This study examines the therapeutic implications of pentoxifylline-an agent traditionally used for peripheral vascular diseases-on these autism-like behaviors by modulating brain proteins and reducing pro-inflammatory cytokines like tumor necrosis factor-α (TNF-α) in a rat model. This research involved 30 male Wistar albino rats, which were divided into three distinct groups: a baseline control set, a PPA-treated cluster receiving a 250 mg/kg/day dose of PPA via intraperitoneal injection for a span of five days followed by saline orally, and a PPA group administered an oral dose of pentoxifylline at 300 mg/kg/day over 15 days. Subsequent to the treatment phase, euthanasia was carried out for the extraction of brain and blood samples, which were then analyzed for histopathological and biochemical markers. The pentoxifylline-treated subjects demonstrated a significant mitigation in the manifestation of autistic-like behaviors, as assessed through a triad of social interaction tests. A noteworthy decline in TNF-α levels was observed, alongside a significant rise in the concentration of adenosine triphosphate and nerve growth factor in brain tissue (p < 0.05). Histopathological analysis underscored a reduction in oxidative stress and a significant preservation of neuronal cell types, specifically pyramidal neurons in the hippocampal CA1 and CA3 regions and Purkinje cells in the cerebellum (p < 0.001). Pentoxifylline treatment has been found to effectively reduce the behavioral symptoms associated with autism, as well as biochemical and histopathological disruptions induced by PPA in rat models, highlighting its potential as a neurotherapeutic agent.

Distinct catecholaminergic pathways projecting to hippocampal CA1 transmit contrasting signals during navigation in familiar and novel environments.

Neuromodulatory inputs to the hippocampus play pivotal roles in modulating synaptic plasticity, shaping neuronal activity, and influencing learning and memory. Recently, it has been shown that the main sources of catecholamines to the hippocampus, ventral tegmental area (VTA) and locus coeruleus (LC), may have overlapping release of neurotransmitters and effects on the hippocampus. Therefore, to dissect the impacts of both VTA and LC circuits on hippocampal function, a thorough examination of how these pathways might differentially operate during behavior and learning is necessary. We therefore utilized two-photon microscopy to functionally image the activity of VTA and LC axons within the CA1 region of the dorsal hippocampus in head-fixed male mice navigating linear paths within virtual reality (VR) environments. We found that within familiar environments some VTA axons and the vast majority of LC axons showed a correlation with the animals' running speed. However, as mice approached previously learned rewarded locations, a large majority of VTA axons exhibited a gradual ramping-up of activity, peaking at the reward location. In contrast, LC axons displayed a pre-movement signal predictive of the animal's transition from immobility to movement. Interestingly, a marked divergence emerged following a switch from the familiar to novel VR environments. Many LC axons showed large increases in activity that remained elevated for over a minute, while the previously observed VTA axon ramping-to-reward dynamics disappeared during the same period. In conclusion, these findings highlight distinct roles of VTA and LC catecholaminergic inputs in the dorsal CA1 hippocampal region. These inputs encode unique information, with reward information in VTA inputs and novelty and kinematic information in LC inputs, likely contributing to differential modulation of hippocampal activity during behavior and learning.

Distinct catecholaminergic pathways projecting to hippocampal CA1 transmit contrasting signals during navigation in familiar and novel environments

Neuromodulatory inputs to the hippocampus play pivotal roles in modulating synaptic plasticity, shaping neuronal activity, and influencing learning and memory. Recently, it has been shown that the main sources of catecholamines to the hippocampus, ventral tegmental area (VTA) and locus coeruleus (LC), may have overlapping release of neurotransmitters and effects on the hippocampus. Therefore, to dissect the impacts of both VTA and LC circuits on hippocampal function, a thorough examination of how these pathways might differentially operate during behavior and learning is necessary. We therefore utilized two-photon microscopy to functionally image the activity of VTA and LC axons within the CA1 region of the dorsal hippocampus in head-fixed male mice navigating linear paths within virtual reality (VR) environments. We found that within familiar environments some VTA axons and the vast majority of LC axons showed a correlation with the animals’ running speed. However, as mice approached previously learned rewarded locations, a large majority of VTA axons exhibited a gradual ramping-up of activity, peaking at the reward location. In contrast, LC axons displayed a pre-movement signal predictive of the animal’s transition from immobility to movement. Interestingly, a marked divergence emerged following a switch from the familiar to novel VR environments. Many LC axons showed large increases in activity that remained elevated for over a minute, while the previously observed VTA axon ramping-to-reward dynamics disappeared during the same period. In conclusion, these findings highlight distinct roles of VTA and LC catecholaminergic inputs in the dorsal CA1 hippocampal region. These inputs encode unique information, with reward information in VTA inputs and novelty and kinematic information in LC inputs, likely contributing to differential modulation of hippocampal activity during behavior and learning.

Augmentation of Endogenous 2-Arachidonoylglycerol Mitigates Autistic Behaviors of BTBR Mice.

The lipid-based endocannabinoid (eCB) system regulates a host of developmental, physiological, and pathological processes in the mammalian brain, and recent studies have suggested that dysfunction of eCB system may contribute to the neuropathology of autism spectrum disorder (ASD). However, specific contributions to ASD-related developmental, cognitive, and behavioral phenotypes remain largely unexplored. The current study was designed to investigate if enhancing eCB signaling by blocking 2-arachidonoylglycerol (2-AG) hydrolase can mitigate ASD-like behaviors in a mouse model, and if such effects are associated with suppression of inflammatory signaling, oxidative stress, or neuronal apoptosis. Intraperitoneal injection of the 2-AG hydrolase monoacylglycerol lipase (MAGL) JZL184 (4, 16, or 40mg/kg) elevated 2-AG and reversed eCB system metabolic enzymes and receptors expression deficits in BTBR T + ltpr3tf/J (BTBR) mouse model of ASD. Moreover, the hyperactivity, excessive stereotypy, impaired social behavior, and cognitive deficits characteristic of this animal model were significantly improved by JZL184. Concomitantly, JZL184 administration reversed the abnormal pro- and anti-inflammatory cytokine concentrations measured in the hippocampus of BTBR mice. In addition, JZL184 reversed the observed overexpression of pro-apoptotic Bax and underexpression of anti-apoptotic Bcl-2 in BTBR mice and enhanced neuronal numbers in hippocampal CA1 and CA3 regions. We also found that the behavioral test battery influenced eCB concentrations independently of JZL184 treatment. Collectively, these findings suggest that augmenting eCB signaling can mitigate ASD-related phenotypes by suppressing neuroinflammation and neuronal apoptosis.

Community-based reconstruction and simulation of a full-scale model of the rat hippocampus CA1 region.

The CA1 region of the hippocampus is one of the most studied regions of the rodent brain, thought to play an important role in cognitive functions such as memory and spatial navigation. Despite a wealth of experimental data on its structure and function, it has been challenging to integrate information obtained from diverse experimental approaches. To address this challenge, we present a community-based, full-scale in silico model of the rat CA1 that integrates a broad range of experimental data, from synapse to network, including the reconstruction of its principal afferents, the Schaffer collaterals, and a model of the effects that acetylcholine has on the system. We tested and validated each model component and the final network model, and made input data, assumptions, and strategies explicit and transparent. The unique flexibility of the model allows scientists to potentially address a range of scientific questions. In this article, we describe the methods used to set up simulations to reproduce in vitro and in vivo experiments. Among several applications in the article, we focus on theta rhythm, a prominent hippocampal oscillation associated with various behavioral correlates and use our computer model to reproduce experimental findings. Finally, we make data, code, and model available through the hippocampushub.eu portal, which also provides an extensive set of analyses of the model and a user-friendly interface to facilitate adoption and usage. This community-based model represents a valuable tool for integrating diverse experimental data and provides a foundation for further research into the complex workings of the hippocampal CA1 region.

The protective effect of DMI on hippocampus EEG, behavioral and biochemical parameters in hypoxia-induced seizure on neonatal period.

Hypoxia-Induced Neonatal Seizure (HINS) is a prevalent type of seizure in infants caused by hypoxic conditions, which can lead to an increased risk of epilepsy, learning disabilities, and cognitive impairments later in life. This study focuses on examining the effects of dimethyl itaconate (DMI) on cognition, motor coordination, and anxiety-like behavior in male rats that have experienced HINS. 42 male Wistar newborn rats (PND10) were randomly divided into six groups (n = 7). 1) Control (Vehicle only); received DMI solvent (0.1ml) without applying hypoxia. 2-3) DMI; receiving (20 and 50 mg/kg; i.p). 4) HINS; they were placed in a hypoxia chamber with 7% oxygen and 93% nitrogen concentration for 15 minutes. 5-6) DMI+HINS; received DMI (20 and 50 mg/kg; i.p) 24h before hypoxia. Behavioral tests including; Novel object recognition test, Rotarod, Parallel bar, Open field and elevated plus maze (EPM); started at age 45 after birth. After behavioral tests, the hippocampal CA1 region local EEG was recorded in all groups. Then the brain hippocampus tissue was isolated and the amount of MDA, SOD, NO, and Thiol was measured by ELISA method. Data showed that the administration of DMI improved motor symptoms, anxiety-like behaviors, and cognition in HINS rats (p<0.05). EEG power in the HINS group decreased significantly compared to other experimental groups (p<0.05). Biochemical observations showed that DMI significantly reduced oxidative stress and inflammation in the hippocampal tissue of HINS rats (p<0.05). Increased hippocampal oxidative stress and inflammation can be effective in the occurrence of behavioral disorders observed in HINS rats. While DMI improved these behavioral impairments by reducing oxidative stress and inflammation.

Extracellular matrix integrity regulates GABAergic plasticity in the hippocampus

The brain's extracellular matrix (ECM) is crucial for neural circuit functionality, synaptic plasticity, and learning. While the role of the ECM in excitatory synapses has been extensively studied, its influence on inhibitory synapses, particularly on GABAergic long-term plasticity, remains poorly understood. This study aims to elucidate the effects of ECM components on inhibitory synaptic transmission and plasticity in the hippocampal CA1 region. We focus on the roles of chondroitin sulfate proteoglycans (CSPGs) and hyaluronic acid in modulating inhibitory postsynaptic currents (IPSCs) at two distinct inhibitory synapses formed by somatostatin (SST)-positive and parvalbumin (PV)-positive interneurons onto pyramidal cells (PCs). Using optogenetic stimulation in brain slices, we observed that acute degradation of ECM constituents by hyaluronidase or chondroitinase-ABC did not affect basal inhibitory synaptic transmission. However, short-term plasticity, particularly burst-induced depression, was enhanced at PV→PC synapses following enzymatic treatments. Long-term plasticity experiments demonstrated that CSPGs are essential for NMDA-induced iLTP at SST→PC synapses, whereas the digestion of hyaluronic acid by hyaluronidase impaired iLTP at PV→PC synapses. This indicates a synapse-specific role of CSPGs and hyaluronic acid in regulating GABAergic plasticity. Additionally, we report the presence of cryptic GABAergic plasticity at PV→PC synapses induced by prolonged NMDA application, which became evident after CSPG digestion and was absent under control conditions. Our results underscore the differential impact of ECM degradation on inhibitory synaptic plasticity, highlighting the synapse-specific interplay between ECM components and specific GABAergic synapses. This offers new perspectives in studies on learning and critical period timing.

Gap Junctions in Different Neuronal Groups Exert Different Effects on Sharp Wave-ripples of a Neuronal Network in CA1

Abstract Gap junctions are indispensable for achieving brain functions. The direct coupling between neurons connected by gap junctions may contribute to synchronization of neuronal firing and emergence of sharp wave-ripples(SWR), which affect brain functions such as memory consolidation. However, considering the heterogeneity of excitatory and inhibitory neurons, it is not quite clear whether gap junctions have the same effect on the emergence of SWR in network activity in different neuron types. In order to explore the above problems, we constructed a neuronal network located in CA1 region of hippocampus, which contains excitatory pyramidal cells, PV+BCs and axo-axonic cells. Taking into account diverse connections between neurons and properties of neurons, we investigated effects of gap junctions on SWR in different kinds of neuronal populations in the constructed network with chemical synaptic connections by neurodynamical modeling. Numerical results show that gap junctions within pyramidal neurons and PV+BCs promote the emergence of SWR, whereas gap junctions within axo-axonic cells suppress it. At the same time, it is revealed that gap junctions in axo-axonic cells play a dominant role in modulating SWR. We hope that these findings provide some inspiration for studies on neuronal heterogeneity and the enhancement of synchronicity of oscillations by gap junctions.

Proteomic Alteration in Catalpol Treatment of Alzheimer's disease by regulating HSPA5/ GPX4

Alzheimer's disease (AD), a chronic and progressive neurodegenerative disease, is characterized by the deposition of extracellular amyloid plaques and intracellular neurofibrillary tangles. Conventional anti-AD drugs exhibit high toxicity and adversely impact patients' quality of life. Therefore, novel treatments for AD are urgently required. In recent years, targeting ferroptosis through the modulation of lipid oxidation has emerged as a new approach in the treatment of neurodegenerative diseases. Catalpol, an iridoid glycoside isolated from the roots of Rehmannia glutinosa, has exhibited anti-inflammatory, antioxidant, and neuroprotective properties. Therefore, in this study, we investigated the protective effects and associated underlying mechanisms of catalpol in an APP/PS1 AD mouse model. Catalpol treatment significantly improved the cognitive capabilities and decreased Aβ1-40 and Aβ1-42 levels in mice. Morphological testing revealed that catalpol prevented neuronal loss and reduced mitochondrial swelling in the hippocampal CA1 region. Proteomic studies identified 2,495 hippocampus proteins whose expression was associated with the mechanism of catalpol treatment, including 44 ferroptosis-related proteins. Bioinformatic analysis revealed that catalpol significantly increased the protein levels of HSPA5 and GPX4 in the hippocampus. Additionally, catalpol modulated biological pathways related to apoptosis, cytokine-mediated signaling, and ferroptosis. The considerable upregulation of HSPA5 and GPX4 with catalpol was further confirmed through western blotting. Catalpol exhibited neuroprotective effects through a variety of mechanisms. Among these, HSPA5 and GPX4, associated with ferroptosis, may play key roles in AD pathogenesis, and present promising therapeutic targets.

Hypothalamic regulation of hippocampal CA1 interneurons by the supramammillary nucleus

The hypothalamic supramammillary nucleus (SuM) projects heavily to the hippocampus to regulate hippocampal activity and plasticity. Although the projections from the SuM to the dentate gyrus (DG) and CA2 have been extensively studied, whether the SuM projects to CA1, the main hippocampal output region, is unclear. Here, we report a glutamatergic pathway from the SuM that selectively excites CA1 interneurons in the border between the stratum radiatum (SR) and the stratum lacunosum-moleculare (SLM). We find that the SuM projects selectively to a narrow band in the CA1 SR/SLM and monosynaptically excites SR/SLM interneurons, including vasoactive intestinal peptide-expressing (VIP+) and neuron-derived neurotrophic factor-expressing (NDNF+) cells, but completely avoids making monosynaptic contacts with CA1 pyramidal neurons (PNs) or parvalbumin-expressing (PV+) or somatostatin-expressing (SOM+) cells. Moreover, SuM activation drives spikes in most SR/SLM interneurons to suppress CA1 PN excitability. Taken together, our findings reveal that the SuM can directly regulate hippocampal output region CA1, bypassing CA2, CA3, and the DG.