Impaired Spatial Learning Research Articles

Huntingtin plays an essential role in the adult hippocampus.

The consequences of non-pathogenic huntingtin (HTT) reduction in the mature brain are of substantial importance as clinical trials for numerous HTT-lowering therapies are underway; many of which are non-selective in that they reduce both mutant and wild type protein variants. In this study, we injected CaMKII-promoted AAV-Cre directly into the hippocampus of adult HTT floxed mice to explore the role of wild-type huntingtin (wtHTT) in adult hippocampal pyramidal neurons and the broader implications of its loss. Our findings reveal that wtHTT depletion results in profound macroscopic morphological abnormalities in hippocampal structure, accompanied by significant reactive gliosis. At the synaptic level, we identified a marked reduction in presynaptic terminals 1-2 months following wtHTT loss; this was contrasted by an increased density of postsynaptic mushroom spines and larger amplitudes of spontaneous excitatory postsynaptic currents, indicative of disrupted synaptic homeostasis. Furthermore, intrinsic neuronal excitability was significantly diminished in CA1 pyramidal neurons lacking wtHTT, and we observed a complete loss of NMDA receptor-dependent long-term potentiation. Unexpectedly, synapse density returned to control levels 6-8 months following wtHTT loss, despite the ongoing presence of macroscopic morphological abnormalities, altered anxiety-related behaviors and clear impairments in spatial learning and memory. Overall, these findings uncover a previously unrecognized role of wtHTT as a critical regulator of hippocampal function in the mature brain, and highlight the hippocampus as a potentially vulnerable region to the adverse effects of non-selective HTT reduction.

Tobacco cigarette smoking induces cerebrovascular dysfunction followed by oxidative neuronal injury with the onset of cognitive impairment

While chronic smoking triggers cardiovascular disease, controversy remains regarding its effects on the brain and cognition. We investigated the effects of long-term cigarette smoke (CS) exposure (CSE) on cerebrovascular function, neuronal injury, and cognition in a novel mouse exposure model. Longitudinal studies were performed in CS or air-exposed mice, 2 hours/day, for up to 60 weeks. Hypertension and carotid vascular endothelial dysfunction (VED) occurred by 16 weeks of CSE, followed by reduced carotid artery blood flow, with oxidative stress detected in the carotid artery, and subsequently in the brain of CS-exposed mice with generation of reactive oxygen species (ROS) and secondary protein and DNA oxidation, microglial activation and astrocytosis. Brain small vessels exhibited decreased levels of endothelial NO synthase (eNOS), enlarged perivascular spaces with blood brain barrier (BBB) leak and decreased levels of tight-junction proteins. In the brain, amyloid-β deposition and phosphorylated-tau were detected with increases out to 60 weeks, at which time mice exhibited impaired spatial learning and memory. Thus, long-term CSE initiates a cascade of ROS generation and oxidative damage, eNOS dysfunction with cerebral hypoperfusion, as well as cerebrovascular and BBB damage with intracerebral inflammation, and neuronal degeneration, followed by the onset of impaired cognition and memory.

Conductive hearing loss does not affect spatial learning and memory in middle-aged guinea pigs

Hearing loss (HL) in mid-life has been suggested as a risk factor for cognitive decline. It is unclear whether this relationship is due to deprivation of auditory input alone, degenerative processes, or a combination. Animal models are useful to investigate underlying neural mechanisms as human studies can be confounded by various factors. However, most animal studies use young animals and often exclude females. We used middle-aged guinea pigs of both sexes to investigate whether 8 weeks of auditory deprivation due to conductive HL caused spatial learning and memory impairments. Forty guinea pigs (20 M, 20 F, ~ 12 months) were tested in the Morris Water Maze (MWM) to assess baseline spatial learning and memory. In 20 of these animals (10 M, 10 F) the ear canal was plugged and 8 weeks later, animals were again assessed in MWM. No deficits in spatial learning or memory were observed in either sex. HL caused a small decline in body weight suggesting some stress associated with conductive HL, although adrenal weight, corrected for body weight, did not change. Our data suggest that auditory input deprivation alone does not affect spatial cognition in middle-age, in line with recent human data suggesting that additional risk factors need to be present.

Connectome-based prediction of functional impairment in experimental stroke models.

Experimental rat models of stroke and hemorrhage are important tools to investigate cerebrovascular disease pathophysiology mechanisms, yet how significant patterns of functional impairment induced in various models of stroke are related to changes in connectivity at the level of neuronal populations and mesoscopic parcellations of rat brains remain unresolved. To address this gap in knowledge, we employed two middle cerebral artery occlusion models and one intracerebral hemorrhage model with variant extent and location of neuronal dysfunction. Motor and spatial memory function was assessed and the level of hippocampal activation via Fos immunohistochemistry. Contribution of connectivity change to functional impairment was analyzed for connection similarities, graph distances and spatial distances as well as the importance of regions in terms of network architecture based on the neuroVIISAS rat connectome. We found that functional impairment correlated with not only the extent but also the locations of the injury among the models. In addition, via coactivation analysis in dynamic rat brain models, we found that lesioned regions led to stronger coactivations with motor function and spatial learning regions than with other unaffected regions of the connectome. Dynamic modeling with the weighted bilateral connectome detected changes in signal propagation in the remote hippocampus in all 3 stroke types, predicting the extent of hippocampal hypoactivation and impairment in spatial learning and memory function. Our study provides a comprehensive analytical framework in predictive identification of remote regions not directly altered by stroke events and their functional implication.

Lactiplantibacillus plantarum 1008 Promotes Reproductive Function and Cognitive Activity in Aged Male Mice with High-Fat-Diet-Induced Obesity by Altering Metabolic Parameters and Alleviating Testicular Oxidative Damage, Inflammation and Apoptosis.

The effects of Lactiplantibacillus plantarum 1008 (LP1008) on age-related cognitive impairment and skeletal muscle atrophy have been reported previously. However, its role in obesity- and age-related hypogonadism has yet to be explored. This study investigates the therapeutic efficacy of low- and high-dose LP1008 in a high-fat-diet-fed male mouse model. Mice at 37 weeks of age were fed a standard diet (n = 8) or a 45% high-fat diet for 28 weeks, and the high-fat-diet-fed mice were divided into vehicle, low-dose and high-dose LP1008 groups (n = 8 per group) on the basis of the treatment administered for an additional 8 weeks. We found that LP1008 suppressed the increases in total cholesterol levels and liver function parameters and alleviated histological changes in the brain, ileum, gastrocnemius muscle and testes. In terms of reproductive function, LP1008 attenuated the decreases in sperm quality, sperm maturity, testosterone levels and levels of enzymes involved in testosterone biosynthesis. Furthermore, LP1008 altered impairments in spatial learning and memory and induced slight alterations in the gut microbiota. Moreover, LP1008 exerted antioxidant, anti-inflammatory and anti-apoptotic effects in aged, obese male mice. LP1008 reversed diet-induced obesity, age-related reproductive dysfunction and pathological damage by increasing testosterone levels and altering the gut microbiome through the regulation of mediators involved in oxidative stress, apoptosis and inflammation.

The X-linked intellectual disability gene CUL4B is critical for memory and synaptic function

Cullin 4B (CUL4B) is the scaffold protein in the CUL4B-RING E3 ubiquitin ligase (CRL4B) complex. Loss-of-function mutations in the human CUL4B gene lead to syndromic X-linked intellectual disability (XLID). Till now, the mechanism of intellectual disability caused by CUL4B mutation still needs to be elucidated. In this study, we used single-nucleus RNA sequencing (snRNA-seq) to investigate the impact of CUL4B deficiency on the transcriptional programs of diverse cell types. The results revealed that depletion of CUL4B resulted in impaired intercellular communication and elicited cell type-specific transcriptional changes relevant to synapse dysfunction. Golgi-Cox staining of brain slices and immunostaining of in vitro cultured neurons revealed remarkable synapse loss in CUL4B-deficient mice. Ultrastructural analysis via transmission electron microscopy (TEM) showed that the width of the synaptic cleft was significantly greater in CUL4B-deficient mice. Electrophysiological experiments found a decrease in the amplitude of AMPA receptor-mediated EPSCs in the hippocampal CA1 pyramidal neurons of CUL4B-deficient mice. These results indicate that depletion of CUL4B in mice results in morphological and functional abnormalities in synapses. Furthermore, behavioral tests revealed that depletion of CUL4B in the mouse nervous system results in impaired spatial learning and memory. Taken together, the findings of this study reveal the pathogenesis of neurological disorders associated with CUL4B mutations and promote the identification of therapeutic targets that can halt synaptic abnormalities and preserve memory in individuals.

Neonatal Maternal Separation Impairs Cognitive Function and Synaptic Plasticity in Adult Male CD-1 Mice

Maternal separation (MS) increases the risk of occurrence of anxiety, depression, and learning and memory impairment in offspring. However, the underlying molecular biological mechanisms remain unclear. In the current study, offspring CD-1 mice were separated from their mothers from postnatal day 4 to postnatal day 21. At 3 months of age, the male offspring were selected for the evaluation of anxiety- and depression-like behaviors and learning and memory function. Western blotting and RT-PCR were used to examine the expression levels of brain-derived neurotrophic factor, tyrosine kinase receptor B, postsynaptic density-95, and synaptophysin. Long-term potentiation (LTP) and long-term depression (LTD) were recorded at Schaffer collateral/CA1 synapses. Furthermore, basal synaptic transmission was evaluated via the recording of the frequency and amplitude of miniature excitatory postsynaptic currents (mEPSCs). The results showed that adult offspring CD-1 mice displayed anxiety- and depressive-like behaviors as well as impaired spatial learning and memory abilities. Electrophysiological analysis indicated that MS impaired LTP, enhanced LTD, and reduced the frequency of mEPSCs in pyramidal neurons in the CA1 region. Our findings suggested that MS can lead to anxiety, depression, and cognitive deficits, and these effects are associated with alterations in the levels of synaptic plasticity-associated proteins, consequently, also synaptic plasticity.

A preclinical and phase I clinical study of ex vivo-expanded amyloid beta-specific human regulatory T cells in Alzheimer’s disease

IntroductionDespite advancements in adoptive regulatory T cell (Treg) therapy, its application in Alzheimer’s disease (AD) remains constrained by challenges in ex vivo Treg selection and expansion with antigen specificity. Our previous findings demonstrated the bystander suppressive immunomodulatory mechanism of ex vivo expanded amyloid β-specific mouse Tregs in AD models, prompting inquiry into the efficacy of ex vivo expanded human Tregs in AD. MethodsWe developed an effective ex vivo expansion method for manufacturing amyloid β-specific human Tregs (Aβ-hTreg) and evaluated their safety and efficacy in 3xTg mouse models of AD and a phase 1 clinical trial with six AD patients. The phenotype of Aβ-hTreg was analyzed using single-cell transcriptomics. The clinical trial involved intravenous administration of Aβ-hTreg, with three patients receiving a low dose and three receiving a high dose. Exploratory assessments of effectiveness, including cognitive tasks and functional evaluations, were conducted ninety days post-treatment. ResultsBehavioral spatial learning and memory impairment, neuroinflammatory and amyloid pathology were dramatically ameliorated by single intrathecal administration of ex vivo expanded Aβ−hTreg to 3xTg AD mice. Single cell transcriptomics analysis revealed alterations in five key genes within a cluster of Tregs under antigen-specific manufacturing conditions. In the clinical trial with six AD patients, dose-limiting toxicity was experienced by none of the participants within five days of receiving GMP-grade Aβ-hTreg (VT301), indicating its good tolerability. Although exploratory assessments of effectiveness did not reach statistically significant values among the groups, these findings offer valuable insights for AD treatment and management, guiding the planning of the next phase of clinical trials. DiscussionThis study suggests that hTregs may modulate Alzheimer's disease pathology by suppressing neuroinflammation, while VT301 shows promise as a safe treatment option. However, further research is necessary to confirm its clinical efficacy and optimize treatment strategies. Trial registrationTitle: A Study of Possibility of Using Regulatory T Cells (VT301) for Treatment of Alzheimer's Disease, ClinicalTrials.gov NCT05016427, Study approval date: Ministry of Food and Drug Safety of the Republic of Korea (MFDS) - August 31st, 2020, Institutional Review Board (IRB) of Seoul National University Hospital, Republic of Korea - September 29th, 2020, The date of first patient enrollment: December 7th, 2020. https://clinicaltrials.gov/study/NCT05016427

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.

TSC2-mTORC1 axis regulates morphogenesis and neurological function of Gli1+ adult-born dentate granule cells.

Aberrant adult hippocampal neurogenesis is implicated in neurological and mood disorders associated with dysregulation of the mechanistic target of rapamycin (mTOR). Understanding how the mTOR pathway shapes the functional development of different subpopulations of adult-born hippocampal neural stem cells will enable insight into potential therapeutic pathways for these disorders. Here we study how loss of TSC2, a regulator of mTOR pathway and a causal gene for tuberous sclerosis complex (TSC), affects dentate gyrus granule cell morphogenesis and hippocampal-dependent function. We found that Tsc2KO mice with TSC2 specifically ablated from Gli1+ adult-born neural stem cells showed neuronal hypertrophy, reduced NEUN expression, increased dendritic arborization, premature cellular senescence, and hypervascularization of the dentate gyrus. Neurologically, Tsc2KO mice showed altered exploratory behavior, impaired spatial learning, abnormal contextual recall, and hypersensitivity to kainic acid-induced seizures. Importantly, genetic reduction of Raptor, essential for mTORC1 signaling, rebalanced mTORC1 signaling and mitigated molecular, cellular, and neurological deficits in Tsc2KO mice. This study uncovered functions of TSC2 in Gli1+ adult-born neural stem cells and highlights RAPTOR as a potential therapeutic target for reversing disease features associated with TSC2 mutations.

Neuronal plasticity changes in the central amygdala and prelimbic cortex network in mice with chronic unpredictable mild stress-induced depression

To explore the relationship between alterations of neural network plasticity and spatial learning and memory functions in mouse models with depression-like behaviors. C57Thy1-YFP/GAD67-GFP mice were randomized into control group (with no treatment) and chronic unpredictable mild stress (CUMS) group (n=15) subjected to CUMS for 8 weeks. Depression-like behaviors of the mice were assessed using sucrose preference test, open field test, and forced swimming test, and their spatial learning and memory abilities were evaluated using Morris water maze test. The changes in the firing patterns of different neuronal subtypes were detected in the central nucleus of the amygdala (CeA) and the prelimbic cortex (PrL) using whole-cell patch-clamp technique. Compared with the control mice, CUMS mice showed significantly decreased sucrose preference, total distance moved, number of grid-crossings, entries into the central area, and time spent in the central area in the open field test (P < 0.01). In the forced swimming test, CUMS mice exhibited obviously shortened time of struggling, swimming, and climbing with increased immobility time. In Morris water maze test, CUMS mice showed significantly increased escape latency and path length, decreased percentage of distance and swimming time within the target quadrant, and increased first entry latency into the target zone and swimming time within the opposite quadrant. Exposure to CUMS resulted in significantly enhanced energy barrier and increased absolute refractory period and inter-spike interval of glutamatergic neurons in the CeA and GABAergic neurons in the PrL, while the opposite changes were observed in GABAergic neurons in the CeA and glutamatergic neurons in the PrL. CUMS-induced depression may lead to plastic changes in the excitatory and inhibitory neuronal networks within the CeA and PrL to cause impairment of spatial learning and memory abilities in mice.

Compromised CD8+ T cell immunity in the aged brain increases severity of neurotropic coronavirus infection and postinfectious cognitive impairment.

Advanced age increases the risk of severe disease from SARS-CoV-2 infection, as well as incidence of long COVID and SARS-CoV-2 reinfection. We hypothesized that perturbations in the aged antiviral CD8+ T cell response predisposes elderly individuals to severe coronavirus infection, re-infection, and postinfectious cognitive sequelae. Using MHV-A59 as a murine model of respiratory coronavirus, we found that aging increased CNS infection and lethality to MHV infection. This was coupled with increased CD8+ T cells within the aged CNS but reduced antigen specificity. Aged animals also displayed a decreased proportion of CD103+ resident memory cells (TRM), which correlated with increased severity of secondary viral challenge. Using a reciprocal adoptive transfer paradigm, data show that not only were fewer aged CD8+ T cells retained within the adult brain post-infection, but also that adult CD8+ cells expressed lower levels of TRM marker CD103 when in the aged microenvironment. Furthermore, aged animals demonstrated spatial learning impairment following MHV infection, which worsened in both aged and adult animals following secondary viral challenge. Spatial learning impairment was accompanied by increased TUNEL positivity in hippocampal neurons, suggestive of neuronal apoptosis. Additionally, primary cell coculture showed that activated CD8+ T cells induced TUNEL positivity in neurons, independent of antigen-specificity. Altogether, these results show that non-antigen specific CD8+ T cells are recruited to the aged brain and cause broad neuronal death without establishing a TRM phenotype that confers lasting protection against a secondary infection.

The Effect of Psilocybe cubensis on Spatial Memory and BDNF Expression in Male Rats Exposed to Chronic Unpredictable Mild Stress

ABSTRACT Psilocybin-containing mushrooms, commonly known as magic mushrooms, drastically affect mental processing, cognitive functioning, and the mood state. In the present study, we investigated the effect of the Psilocybe cubensis extract on spatial memory and the brain-derived neurotrophic factor (BDNF) in rats exposed to chronic unpredictable mild stress (CUMS). The duration of CUMS was 4 weeks. Spatial learning and memory were measured using the Morris water maze apparatus. The Psilocybe cubensis extract was intraperitoneally injected (20 mg/kg) in different time periods: 5 min before training, 24 h before training, 48 h before training, 5 min after training, and 5 min before the probe test. Results showed that CUMS impaired spatial learning and memory, and decreased BDNF in the hippocampus. Psilocybe cubensis (24 and 48 h before training) restored spatial learning, while (48 h before training) restored spatial memory impairment in CUMS rats. Psilocybe cubensis (24 and 48 h before training) increased BDNF in CUMS rats. Psilocybe cubensis administrations (expect 48 h before training) impaired spatial learning and memory and decreased BDNF levels in controls. In conclusion, we suggested that Psilocybe cubensis may be beneficial for the improvement of memory deficits induced by CUMS, while the time of injection seems to be an important factor in its final effect.

Acute glyphosate and aminomethylphosphonic acid (AMPA), its major metabolite, impaired spatial orientation, navigation, learning and/or memory in female rats

Human exposure to glyphosate-based herbicides (GBH) has been associated with a range of toxicological effects involving the central nervous system (CNS) such as alterations in learning and memory. Nevertheless, the effects of aminomethylphosphonic acid (AMPA), the main metabolite of glyphosate, remain essentially obscure. Previous preclinical reports suggest that acute intoxication with AMPA and glyphosate exerts decrease on hippocampal acetylcholinesterase activity and produces more metabolomic alterations in the female brain over the male one. Therefore, this work explored the effects of acute AMPA and glyphosate on spatial learning, memory and navigation in female rats. Sprague Dawley rats received a single injection (i.p.) of: (i) vehicle; (ii) 10 or 100 mg/kg of AMPA; or (iii) 10 or 100 mg/kg of glyphosate; subsequently, the Barnes maze paradigm was performance. Animals from the control group decreased latency and the attempts to solve the Barnes maze; and increased the degree of orientation when compared first training sessions (S1) vs. the last one (S4; p < 0.05). In contrast, both 10 and 100 mg/kg of glyphosate and 100 mg/kg of AMPA prevented the decrease in latency and attempts; and the increase of orientation (p > 0.05; S1 vs. S4). Both treatments decreased the use of the spatial navigation strategy (p < 0.05). Besides, glyphosate at the higher dose but not AMPA impaired the spatial memory during the test. Our findings suggest that acute exposure to glyphosate and AMPA similarly affected spatial orientation, navigations, learning and/or memory.

Experimental Periodontitis Increases Anxious Behavior and Worsens Cognitive Aspects and Systemic Oxidative Stress in Wistar Rats.

Periodontitis (PD) has the potential to induce systemic changes that affect both physical and behavioral aspects. These alterations may be associated with changes in both the inflammatory profile and the oxidative stress status of individuals with PD. Therefore, we aimed to evaluate the effects of PD on oxidative stress, as well as on behavioral parameters and cognitive impairment, in a preclinical model. Twenty-four male Wistar rats were randomly assigned to PD and sham groups. PD was induced by the ligature protocol for 14 days. Behavioral tests were initiated on the 9th day of the experiment to evaluate anxious behavior and cognition (learning and memory). After euthanasia, oxidative stress was evaluated in the gums, blood, hippocampus, and amygdala. Alveolar bone loss, bone microstructure, and elemental compositions of the mandibular bone were also assessed. PD increased alveolar bone loss, reduced the calcium and phosphorus content in the mandibular bone, and increased anxiety-like behavior and cognitive decline (p < 0.05). Furthermore, PD significantly affected the redox balance, as evidenced by increased total antioxidant capacity (TAC) in the gingiva and hippocampus (p < 0.05). It also led to increased lipid peroxidation in the gingiva and erythrocytes (p < 0.05), decreased antioxidant defenses in erythrocytes (superoxide dismutase) and the hippocampus (catalase), and increased antioxidant activity (catalase) in the amygdala (p < 0.05). PD resulted in cognitive alterations, including impairments in spatial learning and memory, as well as increased anxious behavior, likely due to redox imbalance in rats.

Dopamine and D1 receptor in hippocampal dentate gyrus involved in chronic stress-induced alteration of spatial learning and memory in rats

There is increasing evidence that chronic stress (CS), which occurs when the body is exposed to prolonged stressors, significantly impairs learning and memory. Dopamine (DA) plays a critical role in learning and memory in the hippocampus through the activation of D1-like receptors (D1R). However, the specific roles of DA and D1R in the hippocampal dentate gyrus (DG), particularly in CS-induced changes in spatial learning and memory, are not well understood. In this study, we established a CS rat model through the random application of various stressors. We assessed spatial learning and memory using the Morris water maze (MWM) and measured DA concentration and the amplitude of field excitatory postsynaptic potentials (fEPSP) in the DG during the MWM test in freely moving rats. We also examined the involvement of D1R in spatial learning and memory by microinjecting its antagonist (SCH23390) into the DG, and then analyzed the expressions of phosphorylated (p-) Ca2+/calmodulin-dependent protein kinase II (CaMKII), protein kinase A (PKA), and cAMP-response element binding protein (CREB) in the DG using Western blot. During the MWM test, compared with the control group, the escape latency was increased, and the percentage of distance in target quadrant and the number of platform crossings were decreased, in addition, the increase of fEPSP amplitude in the DG was significantly attenuated in CS group. In the control group, the DA concentration in the DG was significantly increased during the MWM test, and this response was enhanced in the CS group. Microinjection of SCH23390 into the DG significantly improved the spatial learning and memory impairments in CS rats, and reversed the inhibitory effect of CS on increase of fEPSP amplitude in the DG during the MWM test. Furthermore, SCH23390 partially reversed the inhibitory effects of CS on the expressions of p-CaMKII, p-PKA, and p-CREB in the DG. Our findings suggest that overactivation of the DA-D1R system in the hippocampal DG impairs spatial learning and memory and related synaptic plasticity in CS rats via downregulation of PKA-CREB signaling pathway.

Aerobic exercise remodels gut microbiota to alleviate cerebral ischemia-reperfusion injury.

Aerobic exercise exhibits a neuroprotective role against cerebral ischemia-reperfusion (I/R) injury, and the present study explored the underlying mechanisms. Adult Sprague-Dawley rats (n=87) were used in the study, and cerebral I/R injury in rats was modeled using middle cerebral artery occlusion and reperfusion (MCAOR), followed by interval aerobic exercise training at a moderate intensity. Colonization with gut microbiota from the trained rats was performed on MCAOR rats. Neurobehavioral assessments were performed. Cerebral infarction and neuronal damage were detected by tissue staining and molecular experiments. Gut microbiota composition was analyzed by 16S rRNA gene sequencing. Neuroinflammation was detected using an enzyme-linked immunosorbent assay. Aerobic exercise ameliorated neurological deficit, spontaneous locomotor activity, and spatial learning and memory impairment in MCAOR rats (P<0.001). Further, aerobic exercise decreased infarct volume, attenuated neuronal damage, increased SYN1 and PSD95 expression, as well as reduced neuroinflammation by upregulating IL-10 and downregulating IL-6, TNF-α, IL-17, and TGF-β in MCAOR rats (P<0.05). Aerobic exercise altered gut microbiota composition in MCAOR rats. Gut microbiota colonization in rats alleviated cerebral I/R injury by reducing neurological deficit scores, promoting spontaneous locomotor activity, decreasing infarct volume, elevating SYN1 and PSD95 expression, and improving neuroinflammation (P<0.05). In conclusion, aerobic exercise remodeled the gut microbiota in rats to attenuate cognitive dysfunction and neuroinflammation after cerebral I/R.

Protective effects of licofelone on scopolamine-induced spatial learning and memory impairment by enhancing parkin-dependent mitophagy and promotion of neural regeneration and in adult mice

Inhibition of COX and LOX could contribute to memory formation and prevention of neurodegeneration, by alleviation of neuroinflammation and improvement of mitochondrial homeostasis. We aimed to assess the effect of licofelone, a dual COX and 5-LOX inhibitor on memory formation, neural apoptosis, neural regeneration, and mitophagy in acute and chronic dosages, given that licofelone could regulate nitric oxide levels. Y-maze and Passive Avoidance tests were used to evaluate memory function in NMRI mice using the EthoVision setting, following scopolamine administration (1 mg/kg, i.p.) as an acute amnestic drug. Hippocampi were used to evaluate the levels of apoptosis via TUNEL assay, neural regeneration via immunohistochemistry method detecting doublecortin and nestin, and mitophagy via Western blot of mitophagy proteins Parkin and ATG5. While acute high-dose licofelone (20 mg/kg) could reverse amnestic effects of scopolamine in passive avoidance test (p = 0.0001), Chronic licofelone (10 mg/kg for 10 consecutive days) could improve performance in Y-maze (p = 0.0007). Molecular analysis revealed that the chronic form of the drug could enhance neural regeneration in CA1 and SGZ regions, reset mitophagy levels as much as the healthy state, and reduce apoptosis rate. Licofelone appears to show a desirable anti-amnestic profile in a low dose chronically; it is hence recommended for future clinical studies on the prevention of neuroinflammation and memory deficit.

Melanin concentrating hormone regulates the JNK/ERK signaling pathway to alleviate influenza A virus infection-induced neuroinflammation

Melanin concentrating hormone (MCH) controls many brain functions, such as sleep/wake cycle and memory, and modulates the inflammation response. Previous studies have shown that influenza A virus (IAV) infection-induced neuroinflammation leads to central nervous damage. This study investigated the potential effects of MCH against neuroinflammation induced by IAV infection and its mechanism. MCH (1 and 2 mg/ml) was administrated for 5 consecutive days before IAV infection. Pentobarbital-induced sleep tests, an open-field test, and a Morris water maze were performed to measure sleep quality, spatial learning and memory ability. Neuronal loss and microglial activation were observed with Nissl staining and immunofluorescence assay. The levels of inflammatory cytokines and the expression of the JNK/ERK signaling pathway were examined by ELISA and western blot. IAV infection led to poor sleep quality, impaired the ability of spatial learning and memory, caused neuronal loss and microglial activation in mice’s hippocampus and cortex. Meanwhile the level of inflammatory cytokines increased, and the JNK/ERK signaling pathway was activated after IAV infection. MCH administration significantly alleviated IAV-induced neuroinflammation, cognitive impairment, and sleep disorder, decreased the levels of inflammatory cytokines, and inhibited neuronal loss and microglial activation in the hippocampus and cortex by regulating the JNK/ERK signaling pathway. Therefore, MCH alleviated the neuroinflammation, spatial learning and memory impairment, and sleep disorder in IAV-infected mice by regulating the JNK/ERK signaling pathway.

Continuous Theta Burst Stimulation Inhibits Oxidative Stress-Induced Inflammation and Autophagy in Hippocampal Neurons by Activating Glutathione Synthesis Pathway, Improving Cognitive Impairment in Sleep-Deprived Mice.

Sleep deprivation (SD) has been reported to have a negative impact on cognitive function. Continuous theta burst stimulation (cTBS) shows certain effects in improving sleep and neurological diseases, and its molecular or cellular role in SD-induced cognition impairment still need further exploration. In this study, C57BL/6 mice were subjected to 48h of SD and cTBS treatment, and cTBS treatment significantly improved SD-triggered impairment of spatial learning and memory abilities in mice. Additionally, cTBS reduced malondialdehyde levels, increased superoxide dismutase activities, and inhibited the production of inflammatory cytokines, alleviating oxidative stress and inflammation levels in hippocampal tissues of SD model mice. cTBS decreased LC3II/LC3I ratio, Beclin1 protein levels, and LC3B puncta intensity, and elevated p62 protein levels to suppress excessive autophagy in hippocampal tissues of SD-stimulated mice. Then, we proved that inhibiting oxidative stress alleviated inflammation, autophagy, and death of hippocampal neuron cells through an in vitro cellular model for oxidative stress, and cTBS treatment promoted the production of glutathione (GSH), the nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and the mRNA expression of GSH synthesis-related genes to enhance antioxidant capacity in hippocampal tissues of SD mice. An Nrf2 inhibitor ML385 or a GSH synthesis inhibitor BSO reversed the alleviating effects of cTBS treatment on oxidative stress-associated damage of hippocampal tissues and cognitive impairment in SD model mice. Altogether, our study demonstrated that cTBS mitigates oxidative stress-associated inflammation and autophagy through activating the Nrf2-mediated GSH synthesis pathway, improving cognitive impairment in SD mice.