Hippocampus Of Mice Research Articles

Silencing of circular RNA PTP4A2 ameliorates depressive-like behaviors by inhibiting microglia activation in mice.

Major depressive disorder (MDD) is a prevalent mental illness and showed a strong link with inflammation. Microglia, as the main resident immune cells, play an important role in the occurrence and development of depression. Circular RNA PTP4A2 (circPTP4A2) was highly expressed in microglia inflammation induced by oxygen glucose deprivation/reperfusion. However, whether circPTP4A2 involves in microglia inflammation in MDD is not clear. Here, chronic unpredictable stress (CUS) induced depressive behaviors and microglia activation in mouse hippocampus, accompanied by the elevated expression of circPTP4A2. Knockdown circPTP4A2 in mouse hippocampus ameliorated depressive-like behaviors and microglia activation. Moreover, CUS promoted phosphorylation of ERK, JNK and P38 in mouse hippocampus as same as LPS-exposed BV2 microglia. Only P38 phosphorylation was inhibited by circPTP4A2 knockdown in the hippocampus. P38 inhibitor, sb203580, repressed circPTP4A2 overexpression-induced inflammatory reaction in BV2 cells. These findings suggest that circPTP4A2 promotes depressive-like behaviors and microglia activation via P38 phosphorylation.

Activation of spleen tyrosine kinase (SYK) contributes to neuronal pyroptosis and cognitive impairment in diabetic mice via the NLRP3/Caspase-1/GSDMD signaling pathway.

Diabetes mellitus (DM) patients are at increased risk of cognitive impairment. The precise mechanisms underlying the association between DM and cognitive impairment remain unclear. Spleen tyrosine kinase (SYK), a crucial regulator of signal transduction, has been implicated in microglial pyroptosis in experimental ischemic stroke models. The present study investigated the potential role of SYK in DM-associated cognitive impairment. Diabetes was induced by streptozotocin (STZ) in C57BL/6 mice, and cognitive function and cerebral injury were assessed 12weeks later using the Morris water maze (MWM), TUNEL assay and Western blotting. In vitro, the inhibition of SYK was investigated in a mouse hippocampal neuronal cell line cultured with high glucose. Compared with control mice, DM mice presented impaired spatial learning and memory. Additionally, SYK activation was linked to neuronal pyroptosis, as evidenced by increases in the number of TUNEL-positive cells and protein levels of NLRP3, ASC, procaspase-1, caspase-1, GSDMD, the GSDMD N-terminal fragment, pro-IL-1β, and IL-1β in the hippocampus of DM mice. Compared with no treatment, SYK knockdown markedly attenuated cognitive impairment and histologic and ultrastructural pathological changes in the hippocampus of DM mice. The increased expression of pyroptosis-associated proteins and the increased number of TUNEL-positive cells were also significantly reduced. In vitro, high glucose significantly activated SYK to trigger the canonical pyroptotic pathway in cultured HT22 cells. The inhibition of SYK with a small interfering RNA or specific inhibitor significantly ameliorated the neuronal pyroptosis mediated by high glucose. Our findings demonstrate that SYK activation plays a pivotal role in promoting the cognitive impairment associated with DM. This effect is mediated by triggering neuronal pyroptosis through the canonical NLRP3/Caspase-1/GSDMD pathway. These results suggest that SYK may serve as a potential target for preventing or mitigating cognitive impairment in patients with DM.

Integrating Network Pharmacology and Transcriptomic Strategies to Explore the Pharmacological Mechanism of Paeoniflorin Exerts Antidepressant Effects

Background: Paeoniflorin has been proven to have neuroprotective and antidepressant effects in several studies. However, there is currently no comprehensive elaboration of its antidepressant effects through network pharmacology combined with transcriptomics analysis. The purpose of this study is to explore the potential mechanisms by which paeoniflorin exerts its antidepressant effects using network pharmacology and transcriptomics sequencing approaches. Methods: We utilized metascape to enrich the intersecting targets for paeoniflorin and depression for enrichment analyses. Additionally, we employed Cytoscape software to construct target pathway networks. For the screening of differentially expressed genes (DEGs) altered by paeoniflorin, we sequenced mRNA from the hippocampal tissue of CUMS model mice using the BMKCloud platform. We further enriched their biological functions and signaling pathways by using the Omishare database. The study utilized a combination of network pharmacology and transcriptomics analysis to evaluate the interactions between paeoniflorin and key targets. The results were then verified through a molecular docking process and a subsequent Western blot experiment. Results: According to a comprehensive analysis, paeoniflorin has 19 key targets that are closely related to its therapeutic effect. Molecular docking revealed that paeoniflorin has a high affinity for HIF-1α, VEGFA, and other targets. Furthermore, protein expression and immunofluorescence staining analysis showed that paeoniflorin significantly increased the expression level of HIF-1α and VEGFA in the hippocampus of depression model mice. Conclusion: These findings suggest that paeoniflorin may have therapeutic potential in depression through the activation of the HIF-1α-VEGFA pathway.

Wogonin mitigates microglia-mediated synaptic over-pruning and cognitive impairment following epilepsy

BackgroundEpilepsy, a neurological disorder characterized by recurrent abnormal neuronal discharges, leading to brain dysfunction and imposing significant psychological and economic burdens on patients. Microglia, the resident immune cells within the central nervous system (CNS), play a crucial role in maintaining CNS homeostasis. However, activated microglia can excessively prune synapses, exacerbating neuronal damage and cognitive dysfunction following epilepsy. Wogonin, a flavonoid from Scutellaria Baicalensis, has known neuroprotective effects via anti-inflammatory and antioxidative mechanisms, but its impact on microglial activation and synaptic pruning in neurons post-epilepsy remains unclear. MethodsSynaptic density was assessed using presynaptic marker Synaptophysin and postsynaptic marker Psd-95, and microglial phagocytosis was evaluated with fluorescent microspheres. Pilocarpine-induced mouse model of status epilepticus was used to evaluate synaptic density changes of mouse hippocampus following an intraperitoneal injection of wogonin (50 and 100 mg/kg). Memory and cognitive function in mice were subsequently evaluated using the Y-maze, object recognition, and Morris water maze tests. Single-cell sequencing was employed to investigate the underlying causes of microglial state alterations, followed by experimental validation. ResultsMicroglia were transitioned to an activated state post-epilepsy, exhibiting significantly enhanced phagocytic capacity. Correspondingly, levels of synaptophysin and Psd-95 were markedly reduced in neurons. Treatment with wogonin (100 mg/kg) significantly increased neuronal synaptic density and improved learning and memory deficits in epileptic mice. Further investigation revealed that wogonin inhibits the release of pro-inflammatory cytokines and synaptic phagocytosis of microglia by activating the AKT/FoxO1 pathway. ConclusionsWogonin could alleviate excessive synaptic pruning of epileptic neurons by microglia and improve cognitive dysfunction of epileptic mice via the AKT/FoxO1 pathway.

Exploring the anti-depressant effects and nitric oxide modulation of quercetin: A preclinical study in Socially Isolated mice.

This study investigates the effects of quercetin, an antioxidant and nitric oxide (NO) modulator, on depressive-like behaviours triggered by social isolation stress (SIS) in mice. SIS, known to harm psychosocial functioning and increase the risk of depression, involves oxidative stress and NO in its pathophysiology. 72 male mice were divided into nine groups, including the social (SC) group as the control group (stress-free with normal saline intake). The isolation (IC) groups received normal saline, quercetin at doses of 10, 20, and 40 mg/kg, the nitric oxide synthetase inhibitor L-NAME at a dose of 5 mg/kg, the NO precursor L-arginine at a dose of 100 mg/kg, an ineffective dose of quercetin combined with L-NAME and an effective dose of quercetin combined with L-arginine. Behavioural tests (open-field, forced swimming, and splash tests) were conducted, followed by measuring hippocampal nitrite levels. Quercetin significantly reduced immobility in the forced swimming test, increased activity in the open-field test, and enhanced grooming behaviour, particularly at 40 mg/kg. Co-administration of an ineffective dose of quercetin (10 mg/kg) with L-NAME increased immobility and grooming activity time. Interestingly, co-administration of the effective dose of quercetin (40 mg/kg) with L-arginine increased immobility time in the FST. Additionally, administration of quercetin at doses of 20 and 40 mg/kg significantly reduced the nitrite level in the hippocampus of SIS mice. Furthermore, co-administration of L-NAME and L-arginine with ineffective and effective doses of quercetin decreased and increased nitrite levels in the hippocampus and increased immobility time in the FST compared to their respective counterparts administered alone. These results suggest quercetin's potential in alleviating depression by modulating NO levels, pointing to its promise in treating depression associated with chronic stressors like social isolation.

In-Depth Proteome Profiling of the Hippocampus of LDLR Knockout Mice Reveals Alternation in Synaptic Signaling Pathway.

The low-density lipoprotein receptor (LDLR) is a major apolipoprotein receptor that regulates cholesterol homeostasis. LDLR deficiency is associated with cognitive impairment by the induction of synaptopathy in the hippocampus. Despite the close relationship between LDLR and neurodegenerative disorders, proteomics research for protein profiling in the LDLR knockout (KO) model remains insufficient. Therefore, understanding LDLR KO-mediated differential protein expression within the hippocampus is crucial for elucidating a role of LDLR in neurodegenerative disorders. In this study, we conducted first-time proteomic profiling of hippocampus tissue from LDLR KO mice using tandem mass tag (TMT)-based MS analysis. LDLR deficiency induces changes in proteins associated with the transport of diverse molecules, and activity of kinase and catalyst within the hippocampus. Additionally, significant alterations in the expression of components in the major synaptic pathways were found. Furthermore, these synaptic effects were verified using a data-independent acquisition (DIA)-based proteomic method. Our data will serve as a valuable resource for further studies to discover the molecular function of LDLR in neurodegenerative disorders.

Activation of Hippocampal Neuronal NADPH Oxidase NOX2 Promotes Depressive-Like Behaviour and Cognition Deficits in Chronic Restraint Stress Mouse Model.

Nicotinamide adenosine dinucleotide phosphate oxidases (NOX) play important roles in mediating stress-induced depression. Three NOX isotypes are expressed mainly in the brain: NOX2, NOX3 and NOX4. In this study, the expression and cellular sources of these NOX isoforms was investigated in the context of stress-induced depression. Chronic restraint stress (CRS)-induced depressive-like behaviour and cognitive deficits were evaluated by tail suspension tests, forced swimming tests and the Morris water maze test. Hippocampal NOX expression was determined by immunofluorescence staining and western blotting. The hippocampal levels of the brain-derived neurotrophic factor (BDNF) mRNA were determined via quantitative real-time -polymerase chain reaction. Glucocorticoid levels in the hippocampus were measured using ELISA kits. In the mouse CRS model, a significant increase in NOX2 expression was observed in the hippocampus, whereas no significant changes in NOX3 and NOX4 expression were detected. Next, NOX2 expression was primarily localised to neurons (NeuN+) but not microglia (Iba-1+) or astrocytes (GFAP+). Treatment with gp91ds-tat, a specific NOX2 inhibitor, effectively mitigated the behavioural deficits induced by CRS. The decreased expression of the BDNF mRNA in the hippocampus of CRS mice was restored upon gp91ds-tat treatment. A positive correlation was identified between neuronal NOX2 expression and serum glucocorticoid levels. Our study indicated that neuronal NOX2 may be a critical mediator of depression-like behaviours and spatial cognitive deficits in mice subjected to CRS. Blockade of NOX2 signalling may be a promising therapeutic strategy for depression.

Aged hippocampal single-cell atlas screening unveils disrupted neuroglial system in postoperative cognitive impairment.

Glia-neuron interaction is a crucial feature in aged hippocampus during the occurrence of postoperative cognitive impairment. However, the regulatory effects of microglia, astrocytes, and oligodendrocytes in this glia-neuron interaction, the potential mechanisms and gene targets are still to be elucidated. Here, single-cell RNA sequencing was performed to detect the perioperative genomic expression characteristics of neuroglial system in the hippocampus of aged mice, and to investigate the potential cross-cellular mechanisms and valuable treatment options for glia-neuron interaction-related cognitive impairment. We found that postoperative neurons and glia cells exhibited protein dysmetabolism and mitochondrial electron misrouting. Impaired autophagy and circadian rhythm worsened microglia activation/neuroinflammation, and exacerbated these metabolic alterations. Reactive microglia also aggravated astrocyte and oligodendrocyte cytotoxicity through the PGD2/DP and complement pathways, altering glutamate level and synaptic function via the "tripartite synapses" model, and affecting neuronal myelination. Ligand-receptor communication also indicated these synaptic and axonal dysfunctions via enhanced MDK and PTN pathways. Additionally, we found that anesthetic dexmedetomidine hold therapeutic potential within the disrupted neuroglial system. It enhanced neuronal metabolic rebalance (Atf3-related) and reduced neuroinflammation from a multicellular perspective, therefore improving postoperative cognitive impairment. Together, our study proposes an aged hippocampal cell atlas and provides insights into the role of disrupted glia-neuron cycle in postoperative cognitive impairment. Our findings also elucidate the therapeutic potential and mechanism of dexmedetomidine intervention.

Balancing brain metabolic states during sickness and recovery sleep.

Sickness sleep and rebound following sleep deprivation share humoral signals including the rise of cytokines, in particular interleukins. Nevertheless, they represent unique physiological states with unique brain firing patterns and involvement of specific circuitry. Here, we performed untargeted metabolomics of mouse cortex and hippocampus to uncover changes with sickness and rebound sleep as compared with normal daily sleep. We found that the three settings are biochemically unique with larger differences in the cortex than in the hippocampus. Both sickness and rebound sleep shared an increase in tryptophan. Surprisingly, these two sleep conditions showed opposite modulation of the methionine-homocysteine cycle and differences in terms of the energetic signature, with sickness impinging on glycolysis intermediates whilst rebound increased the triphosphorylated form of nucleotides. These findings indicate that rebound following sleep deprivation stimulates an energy rich setting in the brain that is devoid during sickness sleep.

ACSL3 is a promising therapeutic target for alleviating anxiety and depression in Alzheimer's disease.

Alzheimer's disease (AD), the leading cause of dementia, affects over 55 million people worldwide and is often accompanied by depression and anxiety. Both significantly impact patients' quality of life and impose substantial societal and economic burdens on healthcare systems. Identifying the complex regulatory mechanisms that contribute to the psychological and emotional deficits in AD will provide promising therapeutic targets. Biosynthesis of omega-3 (ω3) and omega-6 fatty acids (ω6-FA) through long-chain acyl-CoA synthetases (ACSL) is crucial for cell function and survival. This is due to ω3/6-FA's imperative role in modulating the plasma membrane, energy production, and inflammation. While ACSL dysfunction is known to cause heart, liver, and kidney diseases, the role of ACSL in pathological conditions in the central nervous system (e.g., depression and anxiety) remains largely unexplored. The impact of ACSLs on AD-related depression and anxiety was investigated in a mouse model of Alzheimer's disease (3xTg-AD). ACSL3 levels were significantly reduced in the hippocampus of aged 3xTg-AD mice (via capillary-based immunoassay). This reduction in ACAL3 was closely associated with increased depression and anxiety-like behavior (via forced swim, tail suspension, elevated plus maze, and sucrose preference test). Upregulation of ACSL3 via adenovirus in aged 3xTg-AD mice led to increased protein levels of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor C (VEGF-C) (via brain histology, capillary-based immunoassay), resulting in alleviation of depression and anxiety symptoms. The present study highlights a novel neuroprotective role of ACSL3 in the brain. Targeting ACSL3 will offer an innovative approach for treating AD-related depression and anxiety.

Retraction Note: Effect of Curcumin on Cognitive Behavior and Pathological Characteristics of the Hippocampus in Mice with Inherent Alzheimer's Disease.

Retraction Note: Effect of Curcumin on Cognitive Behavior and Pathological Characteristics of the Hippocampus in Mice with Inherent Alzheimer's Disease.

Protective effects of berberine against diabetes-associated cognitive decline in mice.

Diabetes associated cognitive decline (DACD) is a common CNS-related consequence of diabetes. The primary clinical manifestation of DACD includes learning and memory impairment. Unfortunately, there is no cure to delay the cognitive symptoms of diabetes. Although berberine (BBR) has shown promising effect in the treating diabetes and cognitive dysfunction, more research is needed to understand the mechanism of its therapeutic effect. For better understanding, we investigated the functions of BBR involved in anti-inflammation, anti-oxidant and neuroprotection in the hippocampus of diabetic mice. Diabetes was induced in mice using STZ. BBR was administered for 4 weeks before (pre-treatment), and after (post-treatment) STZ administration. The effect of BBR on cognitive functions in diabetic mice was determined using neurobehavioural test. Moreover, how BBR affected neuroinflammation, oxidative stress, and acetylcholine levels in the hippocampus and BBB permeability were analyzed using standard biochemical assays. Lastly, we evaluated the mRNA expression of neuroprotective genes in the hippocampus to uncover the mechanism of BBR. Treatment with BBR improved cognition in diabetic mice. It significantly reduced the levels of IL-6, iNOS, TNF-α, IL-1β, ROS and MDA and increased the levels of TAC, GSH, SOD and Catalase. Moreover, levels of acetylcholine and BBB permeability were reduced in the diabetic mice which was reversed by BBR treatment and increased the expression of IGF and BDNF in the hippocampus of diabetic mice. Our results suggest that BBR might be a potential therapeutic candidate for the treatment of DACD. Our study might serve as a basis for developing novel drugs for treating DACD.

Expression Profiles of Brain-Derived Neurotrophic Factor Splice Variants in the Hippocampus of Alzheimer's Disease Model Mouse.

Dysregulation of brain-derived neurotrophic factor (BDNF) has been implicated in Alzheimer's disease (AD). In this study, we investigated the temporal dynamics of BDNF expression in the hippocampus of 5xFAD mice, an AD model, focusing on sex and age differences and Bdnf mRNA splice variants. At 3 months of age, female wild-type (WT) mice exhibited significantly higher Bdnf mRNA levels compared to males. However, this difference was abolished in female 5xFAD mice. At 6 months of age, no sex differences in Bdnf mRNA levels were observed in WT mice, and the levels tended to be lower in female 5xFAD mice. Additionally, a significant decrease in the mRNA levels of full-length tropomyosin-related kinase B (TrkB), a BDNF receptor, was found in female 5xFAD mice at 6 months, while mRNA levels of the truncated TrkB were increased in both male and female 5xFAD mice. Specifically, among the Bdnf mRNA splice variants, the levels of Bdnf exon IIA-IX, exon IIB-IX, exon IIC-IX, and exon IXA mRNA were significantly higher in female WT mice compared to male WT mice at 3 months, but this difference was lost in female 5xFAD mice. These findings suggest that the expression of specific Bdnf splice variants would be maintained at higher levels in the hippocampus of young female mice than in males but may be disrupted in AD model mice. Our study may provide insights into the relationship between sex differences in AD onset and BDNF expression.

Alzheimer's Disease-Derived Outer Membrane Vesicles Exacerbate Cognitive Dysfunction, Modulate the Gut Microbiome, and Increase Neuroinflammation and Amyloid-β Production.

Although our understanding of the molecular biology of Alzheimer's disease (AD) continues to improve, the etiology of the disease, particularly the involvement of gut microbiota disturbances, remains a challenge. Outer membrane vesicles (OMVs) play a key role in central nervous system diseases, but the impact of OMVs on AD progression remains unclear. In this study, we hypothesized that AD-derived OMVs (OMVsAD) were a risk factor in AD pathology. To test our hypothesis, young APP/PS1 mice (AD mice) were given OMVsAD by gavage. Young AD mice were euthanized 120days after gavage to assess the intestinal barrier, gut microbiota diversity, mediators of neuroinflammation, glial markers, amyloid burden, and short-chain fatty acid (SCFA) levels. Our results showed that OMVsAD accelerated cognitive dysfunction after 120days of intragastric administration. Morris water maze experiment and new object recognition test showed that OMVsAD caused significantly poorer spatial ability learning and memory of the AD mice. We observed the OMVsAD-treated APP/PS1 mice display OMVs disrupting the intestinal barrier compared with controls of normal human-derived OMVs. Compared with the OMVsHC group, claudin-5 and ZO-1 related to the intestinal barrier were significantly downregulated in the OMVsAD group. The OMVsAD activate microglia in the cerebral cortex and hippocampus of AD mice, and the levels of IL-1β, IL-6, TNF-α, and NF-Κb were upregulated. We also found that OMVsAD increased Aβ production. 16S rRNA sequencing showed that OMVsAD negatively regulated the α- and β-diversity index of intestinal flora and reduced the levels of SCFA. OMVsAD may change the intestinal flora of young AD, damage the intestinal mucosa and blood-brain barrier, and accelerate AD neuropathological damage.

The Sexual Dimorphism of the Neuroimmune Response in the Brains of Taenia crassiceps-Infected Mice

Background: Helminth infections are associated with cognitive deficits, especially in school-age children. Deworming treatment in heavily infected children improves their short- and long-term memory recall. In mice, intraperitoneal helminth infection with Taenia crassiceps (T. crassiceps) shows sexual dimorphism in terms of the parasite load, immune response, hormone levels, and behavioral changes. We have previously shown poorer short-term memory performance and changes in the concentrations of cytokines and neurotransmitters in the hippocampus, which were replicated in this study. The molecular changes in other brain structures, such as those related to reproduction, are unknown. Methods: Male and female Balb/cAnN mice were chronically infected with T. crassiceps larvae. We determined the peritoneal parasite load and established the presence of cytokines and neurotransmitters in the hippocampus, olfactory bulb, and hypothalamus. Results: The parasite load was higher in female than male infected mice, as expected. In the hippocampus, the neurotransmitters norepinephrine and serotonin increased in males but decreased in females. In contrast, in the olfactory bulb and hypothalamus, the neurotransmitters assessed showed no statistical differences. The cytokine profiles were different in each brain structure. The TNF-α levels in the olfactory bulb and the IL-4 levels in the hippocampus of infected mice were dimorphic; IFN-γ was augmented in both male and female infected animals, although the increase was higher in infected males. Conclusions: The brain responds to peripheral infection with cytokine levels that vary from structure to structure. This could be a partial explanation for the dimorphic behavioral alterations associated with infection, it also demonstrates the synergic interaction between the immune, the endocrine, and the nervous systems.

Overexpression of TECPR1 improved cognitive function of P301S-tau mice via activation of autophagy in the early and late process.

Autophagy disorders in AD patients and animal models were well known, however, the effect of P301S-tau on autophagy is not clear. Here, we found that autophagy related protein Tectonin Beta-Propeller Repeat-Containing Protein 1 (TECPR1) decreased in the hippocampus of P301S-tau transgenic mice by proteomics, which was proved invivo and invitro, and P301S-tau induced autophagic deficits in early and late process. TECPR1 overexpression attenuated P301S-tau induced autophagy defects via promoting autophagosome generation and autophagosome and lysosomes fusion. We also found that TECPR1 overexpression ameliorated the behavior disorders of P301S-tau mice with promoting tau degradation, improving synaptic plasticity and neuron loss. Lastly, CQ or 3-MA treatment reversed TECPR1 induced improvement effects on autophagic and cognitive disorders, further proved that, TECPR1 activated the early and late process of autophagy to ameliorate the cognition of P301S-tau mice. Our data suggest that TECPR1 is a potential therapy target for AD.

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.

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.

Circadian Alterations in Brain Metabolism Linked to Cognitive Deficits During Hepatic Ischemia-Reperfusion Injury Using [1H-13C]-NMR Metabolomics

Background: Hepatic ischemia-reperfusion injury (HIRI) is known to affect cognitive functions, with particular concern for its impact on brain metabolic dynamics. Circadian rhythms, as a crucial mechanism for internal time regulation within organisms, significantly influence metabolic processes in the brain. This study aims to explore how HIRI affects hippocampal metabolism and its circadian rhythm differences in mice, and to analyze how these changes are associated with cognitive impairments. Methods: A C57BL/6 male mouse model was used, simulating HIRI through hepatic ischemia-reperfusion surgery, with a sham operation conducted for the control group. Cognitive functions were evaluated using open field tests, Y-maze tests, and novel object recognition tests. Magnetic resonance spectroscopic imaging (MRSI) technology, combined with intravenous injection of [2-13C]-acetate and [1-13C]-glucose, was utilized to analyze metabolic changes in the hippocampus of HIRI mice at different circadian time points (Zeitgeber Time ZT0, 8:00 and ZT12, 20:00). Circadian rhythms regulate behavioral, physiological, and metabolic rhythms through transcriptional feedback loops, with ZT0 at dawn (lights on) and ZT12 at dusk (lights off). Results: HIRI mice exhibited significant cognitive impairments in behavioral tests, particularly in spatial memory and learning abilities. MRSI analysis revealed significant circadian rhythm differences in the concentration of metabolites in the hippocampus, with the enrichment concentrations of lactate, alanine, glutamate, and taurine showing different trends at ZT0 compared to ZT12, highlighting the important influence of circadian rhythms on metabolic dysregulation induced by HIRI. Conclusions: This study highlights the significant impact of HIRI on brain metabolic dynamics in mice, especially in the hippocampal area, and for the first time reveals the differences in these effects within circadian rhythms. These findings not only emphasize the association between HIRI-induced cognitive impairments and changes in brain metabolism but also point out the crucial role of circadian rhythms in this process, offering new metabolic targets and timing considerations for therapeutic strategies against HIRI-related cognitive disorders.

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.