Hippocampal Dysfunction Research Articles

Investigation of fructose consumption on hippocampal insulin and glucagon-like peptide-1 receptors, and metabolic effects in rats.

The detrimental effects of high fructose consumption on metabolic health have been extensively studied. However, limited research has focused on the impact of fructose intake on neuroprotective mechanisms, specifically the expression of insulin receptor (INSR) and glucagon-like peptide-1 receptor (GLP-1R) in the hippocampus. Understanding the effects of fructose on these neuroprotective molecules can provide valuable insights into the potential role of fructose in hippocampal dysfunction. The goal of this study is to aim at the basal plasma levels of lipid profile, insulin, GLP-1, and HOMA-IR, as well as the mRNA and protein expression of neuroprotective molecules such as INSR and GLP-1R in Wistar rats fed a high fructose diet. Rats were separated into control (C) and high fructose (HF) groups. The HF group was given 20% fructose water to drink for 16 weeks. Fructose ingestion significantly increased abdominal fat (C=1.24±0.08 g, HF=1.79±0.19 g, P<0.05) and plasma triglyceride levels (C=179.22±22.85 µg/ml, HF=242.45±14.45 µg/ml, P<0.05), but had no statistically significant effect on body weight and plasma HDL, LDL, total cholesterol, insulin, and GLP-1 levels (P>0.05). Although INSR mRNA expression in the hippocampus was significantly lower in the HF group compared to the control group (P<0.05), GLP-1R mRNA expression did not differ significantly across the groups (P>0.05). Furthermore, whereas INSR and GLP-1R protein levels in the experimental group were on a declining trend, this trend was not substantially different (P>0.05). These data suggest that fructose consumption may be harmful to the hippocampus by lowering the expression of INSR.

Protective effect of melatonin on learning and memory impairment and hippocampal dysfunction in rats induced by high-fructose corn syrup.

We investigated the harmful effects of high fructose corn syrup (HFCS) on learning and memory in the hippocampus and the ameliorative effects of melatonin (Mel). Thirty-six adult male Sprague Dawley rats were divided into three groups: Group I, control; Group II, HFCS; and Group III, HFCS+Mel. HFCS form F55 was prepared as a 20% fructose syrup solution. Rats in HFCS and HFCS+Mel groups were given drinking water for 10 weeks. Rats in the HFCS+Mel group have been given 10 mg/kg/day melatonin orally for the 6 weeks, in addition to HFCS 55. The Morris water maze (MWM) test was applied to all animals for 5 days to determine their learning and memory levels. After decapitation, one-half of the hippocampus samples were collected for western blot analysis, and another half of the tissues were collected for histopathological and immunohistochemical analyses. In the HFCS group, there was a significant difference between the time to find the platform in the MWM test and time spent in the quadrant between days 1 and 5 (P=0.037 and P=0.001, respectively). In addition, a decreased level of MT1A receptor, TNF-α, iNOS, osteopontin (OPN), and interleukin-6 (IL-6) expressions were significantly increased in the HFCS group. Melatonin treatment reversed MT1A receptor levels and TNF-α, iNOS, OPN, and IL-6 expressions. During the histopathological examination, increased neuronal degenerations were observed in the HFCS group. Melatonin ameliorated these changes. Consumption of HFCS caused deterioration of learning and memory in adult rats. We suggest that melatonin is effective against learning and memory disorders.

Hippocampal Glutamate, Resting Perfusion and the Effects of Cannabidiol in Psychosis Risk.

Preclinical and human data suggest that psychosis onset involves hippocampal glutamatergic dysfunction, driving hyperactivity and hyperperfusion in a hippocampal-midbrain-striatal circuit. Whether glutamatergic dysfunction is related to cerebral perfusion in patients at clinical high risk (CHR) for psychosis, and whether cannabidiol (CBD) has ameliorative effects on glutamate or its relationship with perfusion remains unknown. Using a double-blind, parallel-group design, 33 CHR patients were randomized to a single 600 mg dose of CBD or placebo; 19 healthy controls did not receive any drug. Proton magnetic resonance spectroscopy was used to measure glutamate concentrations in left hippocampus. We examined differences relating to CHR status (controls vs placebo), effects of CBD (placebo vs CBD), and linear between-group effects, such that placebo>CBD>controls or controls>CBD>placebo. We also examined group × glutamate × cerebral perfusion (measured using Arterial Spin Labeling) interactions. Compared to controls, CHR-placebo patients had significantly lower hippocampal glutamate (P =.015) and a significant linear relationship was observed across groups, such that glutamate was highest in controls, lowest in CHR-placebo, and intermediate in CHR-CBD (P =.031). Moreover, there was a significant interaction between group (controls vs CHR-placebo), hippocampal glutamate, and perfusion in the putamen and insula (P FWE =.012), with a strong positive correlation in CHR-placebo vs a negative correlation in controls. Our findings suggest that hippocampal glutamate is lower in CHR patients and may be partially normalized by a single dose of CBD. Furthermore, we provide the first in vivo evidence of an abnormal relationship between hippocampal glutamate and perfusion in the striatum and insula in CHR.

Tetramethylpyrazine ameliorates systemic streptozotocin-induced Alzheimer-like pathology

Diabetes mellitus (DM) and its complications are the main threats to the global disease burden. DM-related cognitive dysfunction is a progressive neurodegenerative disease, similar to Alzheimer's disease (AD). The underlying pathophysiology remains unclear, and an effective treatment is unavailable. Tetramethylpyrazine (TMP) is a bioactive ingredient extracted from the plant Ligusticum wallichii, which has anti-diabetic and neuroprotective properties. In this study, streptozotocin (STZ) injection was used to establish a mouse STZ-AD model, and TMP was administered through the lateral ventricle (ICV) to evaluate the effects of TMP on cognitive ability and neurochemical changes and to explore the underlying cellular and molecular mechanisms. Using MWM and Y-maze behavioral paradigms, we observed that TMP protected against STZ-induced learning and memory impairment. STZ promoted the deposition of amyloid plaques, activation of glial cells, loss of neurons and synapses, and reduction of synaptic plasticity. In contrast, TMP restored these aberrations and improved cognitive deficits in STZ-induced diabetic animals. Moreover, TMP attenuated hippocampal mitochondrial dysfunction and oxidative stress through modulation of the SIRT1/Nrf2/ HO-1 pathway. This evidence shows that TMP exerts its therapeutic effects through multiple pathways. Our study provides new insights into the neuroprotective effects of TMP for the treatment of diabetes-related cognitive failure.

Curcumin-Nicotinate Attenuates Hippocampal Synaptogenesis Dysfunction in Hyperlipidemia Rats by the BDNF/TrkB/CREB Pathway: Involving Idol/LDLR Signaling to Eliminate Aβ Deposition

Hyperlipidemia has been demonstrated to evoke Alzheimer disease (AD) pathologies such as Amyloid-β (Aβ) deposition and synaptogenesis dysfunction in the hippocampus. Curcumin gives protection against anti-amyloid properties and synaptogenesis dysfunction. Curcumin-Nicotinate (CurTn), a new type of curcumin derivative, ameliorates cognitive impairment by rescuing autophagic flux in the CA1 hippocampus of diabetic rats. However, whether Curtn possesses an antagonistic effect on AD-related pathologies in the hippocampus induced by hyperlipidemia remains ill-defined. The present study aims to investigate whether CurTn alleviates synaptogenesis dysfunction by promoting the activation of brain-derived neurotrophic factor (BDNF)/tyrosine kinase receptor B (TrkB)/cAMP-response element binding protein (CREB) signaling and whether the underlying fundamental mechanism involves the elimination of Aβ deposition due to Idol/low-density lipoprotein receptor (LDLR) signaling in the hippocampus of high-fat diet (HFD)-induced hyperlipidemia rats. The results demonstrated that CurTn not only improved synaptogenesis dysfunction in the hippocampus of HFD rats, as evidenced by the increases in the expressions of synapse-related proteins postsynaptic density protein 95 (PSD-95), synapsin-1, and Glutamate receptor 1 (GluR1), but also activated BDNF/TrkB/CREB signaling, as evidenced by the elevation of the expressions of BDNF, pTrkB, and CREB. Moreover, CurTn modulated the Idol/LDLR pathway in the hippocampus of HFD rats, as evidenced by the decreased expression of Idol and the increased expression of LDLR. Furthermore, CurTn eliminated the deposition of Aβ, as evidenced by the reduction in the content of Aβ40 and Aβ42. These results reveal that CurTn may attenuate synaptogenesis dysfunction by activating BDNF/TrkB/CREB signaling, as the possible result of the modulation of Idol/LDLR signaling to eliminate Aβ deposition in the hippocampus of HFD rats.

Changes in the Neuronal Architecture of the Hippocampus in a 6-Hydroxydopamine-Lesioned Rat Model of Parkinson Disease.

Parkinson disease (PD) is a progressive neurodegenerative disorder in which dopaminergic (DAergic) systems are destroyed (particularly in the nigrostriatal system), causing both motor and nonmotor symptoms. Hippocampal neuroplasticity is altered in PD animal models, resulting in nonmotor dysfunctions. However, little is known about the precise mechanism underlying the hippocampal dysfunctions in PD. Striatal 6-hydroxydopamine (6-OHDA) infusions were performed unilaterally in adult Sprague Dawley rats. Both motor and nonmotor symptoms alongside the expression of tyrosine hydroxylase (TH) in the substantia nigra and striatum were confirmed in 6-OHDA-lesioned rats. The neuronal architecture in the hippocampus was analyzed by Golgi staining. During the 7-8 weeks after infusion, the 6-OHDA-lesioned rats exhibited motor and nonmotor dysfunctions (especially anxiety/depression-like behaviors). Rats with unilateral 6-OHDA infusion displayed reduced TH+ immunoreactivity in the ipsilateral nigrostriatal pathway of the brain. Golgi staining revealed that striatal 6-OHDA infusion significantly decreased the dendritic complexity (i.e., number of crossing dendrites, total dendritic length, and branch points) in the ipsilateral hippocampal conus ammonis 1 (CA1) apical/basal and dentate gyrus (DG) subregions. Additionally, the dendritic spine density and morphology were significantly altered in the CA1 apical/basal and DG subregions following striatal 6-OHDA infusion. However, alteration of microglial and astrocytic distributions did not occur in the hippocampus following striatal 6-OHDA infusion. The present study provides anatomical evidence that the structural plasticity in the hippocampus is altered in the late phase following striatal 6-OHDA infusion in rats, possibly as a result of the prolonged suppression of the DAergic system, and independent of neuroinflammation.

Transcriptome Profiling in the Hippocampi of Mice with Experimental Autoimmune Encephalomyelitis.

Experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), approximates the key histopathological, clinical, and immunological features of MS. Hippocampal dysfunction in MS and EAE causes varying degrees of cognitive and emotional impairments and synaptic abnormalities. However, the molecular alterations underlying hippocampal dysfunctions in MS and EAE are still under investigation. The purpose of this study was to identify differentially expressed genes (DEGs) in the hippocampus of mice with EAE in order to ascertain potential genes associated with hippocampal dysfunction. Gene expression in the hippocampus was analyzed by RNA-sequencing and validated by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Gene expression analysis revealed 1202 DEGs; 1023 were upregulated and 179 were downregulated in the hippocampus of mice with EAE (p-value < 0.05 and fold change >1.5). Gene ontology (GO) analysis showed that the upregulated genes in the hippocampi of mice with EAE were associated with immune system processes, defense responses, immune responses, and regulation of immune responses, whereas the downregulated genes were related to learning or memory, behavior, and nervous system processes in the GO biological process. The expressions of hub genes from the search tool for the retrieval of interacting genes/proteins (STRING) analysis were validated by RT-qPCR. Additionally, gene set enrichment analysis showed that the upregulated genes in the hippocampus were associated with inflammatory responses: interferon-γ responses, allograft rejection, interferon-α responses, IL6_JAK_STAT3 signaling, inflammatory responses, complement, IL2_STAT5 signaling, TNF-α signaling via NF-κB, and apoptosis, whereas the downregulated genes were related to synaptic plasticity, dendritic development, and development of dendritic spine. This study characterized the transcriptome pattern in the hippocampi of mice with EAE and signaling pathways underpinning hippocampal dysfunction. However, further investigation is needed to determine the applicability of these findings from this rodent model to patients with MS. Collectively, these results indicate directions for further research to understand the mechanisms behind hippocampal dysfunction in EAE.

Detrimental Effects of Alcohol-Induced Inflammation on Brain Health: From Neurogenesis to Neurodegeneration.

Alcohol consumption is known to cause several brain anomalies. The pathophysiological changes associated with alcohol intoxication are mediated by various factors, most notable being inflammation. Alcohol intoxication may cause inflammation through several molecular mechanisms in multiple organs, including the brain, liver and gut. Alcohol-induced inflammation in the brain and gut are intricately connected. In the gut, alcohol consumption leads to the weakening of the intestinal barrier, resulting in bacteria and bacterial endotoxins permeating into the bloodstream. These bacterial endotoxins can infiltrate other organs, including the brain, where they cause cognitive dysfunction and neuroinflammation. Alcohol can also directly affect the brain by activating immune cells such as microglia, triggering the release of pro-inflammatory cytokines and neuroinflammation. Since alcohol causes the death of neural cells, it has been correlated to an increased risk of neurodegenerative diseases. Besides, alcohol intoxication has also negatively affected neural stem cells, affecting adult neurogenesis and causing hippocampal dysfunctions. This review provides an overview of alcohol-induced brain anomalies and how inflammation plays a crucial mechanistic role in alcohol-associated pathophysiology.

RETRACTED: Possible mechanisms involved in the protective effects of chrysin against lead-induced cognitive decline: An in vivo study in a rat model

Lead (Pb) is a highly poisonous environmental pollutant that can induce cognitive decline. Chrysin, a natural flavonoid compound, has anti-oxidative, anti-inflammatory, and neuroprotective properties in different neurodegenerative disorders. The present study was designed to examine the putative effects of chrysin against Pb-induced cognitive impairment and the possible involved mechanisms. Adult male Wistar rats were exposed to Pb acetate (500 ppm in standard drinking water) either alone or in combination with daily oral administration of chrysin (30 mg/kg) for eight consecutive weeks. During the eight-week period of the study, the cognitive capacity of the rats was evaluated by employing both novel object recognition and passive avoidance tests. On day 56, hippocampal synaptic plasticity (long-term potentiation; LTP) was recorded in perforant path-dentate gyrus (PP-DG) synapses to assess field excitatory postsynaptic potentials (fEPSPs) slope and population spike (PS) amplitude. Subsequently, pro- and anti-inflammatory cytokines and histological changes were evaluated in the cerebral cortex and hippocampus of the rats. Moreover, Pb levels in blood and brain tissues were assessed. The results showed that Pb exposure causes cognitive decline, inhibition of hippocampal LTP induction, imbalance of pro- and anti-inflammatory cytokines, enhancement of Pb levels in blood and brain tissues, and neuronal loss. However, chrysin treatment improved cognitive dysfunction, ameliorated hippocampal LTP impairment, modulated inflammatory status, reduced Pb concentration, and prevented neuronal loss in the Pb-exposed rats. The results suggest that chrysin alleviates Pb-induced cognitive deficit, possibly through mitigation of hippocampal synaptic dysfunction, modulation of inflammatory status, reduction of Pb concentration, and prevention of neuronal loss.

Light-intensity exercise improves memory dysfunction with the restoration of hippocampal MCT2 and miRNAs in type 2 diabetic mice.

Cognitive decline associated with type 2 diabetes mellitus (T2DM) is a risk factor to impair human health. Although light-intensity exercise prevents hippocampal memory dysfunction in pre-symptomatic T2DM animals by altering hippocampal lactate transport and neurotrophic factors, the effects of light-intensity exercise in an advanced stage of T2DM animals remain unclear. Here, ob/ob mice, an animal model of T2DM, were subjected to light-intensity exercise (5.0m/min) for 30min/day, five days/week for four weeks. The effects of light-intensity exercise on hippocampal complications, mRNA expressions of monocarboxylate transporter (MCT), and miRNA levels were assessed. The light-intensity exercise improved hippocampal memory retention in ob/ob mice. Downregulated hippocampal Mct2 mRNA levels in T2DM were improved with light-intensity exercise. Hippocampal mRNA levels of Mct1 and Mct4 were unchanged within groups. Based on miRNA sequencing, sedentary ob/ob mice exhibited that 71 miRNAs were upregulated, and 77 miRNAs were downregulated in the hippocampus. In addition, the exercise significantly increased 24 miRNAs and decreased 4 miRNAs in the T2DM hippocampus. The exercise reversed T2DM-induced alterations of hippocampal 9 miRNAs, including miR-200a-3p. Our findings imply that miR-200a-3p/Mct2 in the hippocampus would be a possible clinical target for treating T2DM-induced memory dysfunction.

Aberrant expression of FBXO22 is associated with propofol-induced synaptic plasticity and cognitive dysfunction in adult mice.

Recent observation demonstrated that prolonged anesthesia modifies brain synaptic architecture in all ages, including adult. Propofol is the most commonly utilized anesthetics at clinic. Whether repeated administration of propofol modulates cognitive impairment in adults and changes synaptic plasticity remains, however, to be explored. In this study, we first discovered that repeated and prolonged exposure to propofol-induced cognitive impairment in adult rodents. Then, we examined the property of hippocampal primary neurons and slices after propofol treatment in mice, including synaptic protein profile, dendritic spine density, as well as synaptic transmission. We found the distinctive change of the F-box only protein 22 (FBXO22), an F-box E3 ligase, during this process and further explored its role. Knockdown experiments showed the downregulation of FBXO22 restored the changes by propofol treatment on hippocampal primary neurons and attenuated propofol-induced hippocampal dependent cognitive dysfunction. Our results showed that FBXO22 is involved in the regulation of repeated propofol treatment induced changes of synaptic plasticity and cognitive dysfunction in adult mice. Repeated propofol treatment leads to cognitive dysfunction by regulating FBXO22 in adult rodents.

Prone positioning reduces frontal and hippocampal neuronal dysfunction in a murine model of ventilator-induced lung injury.

Prone positioning is an established treatment for severe acute lung injury conditions. Neuronal dysfunction frequently occurs with mechanical ventilation-induced acute lung injury (VILI) and clinically manifests as delirium. We previously reported a pathological role for systemic interleukin 6 (IL-6) in mediating neuronal injury. However, currently no studies have investigated the relationship between prone or supine positioning and IL-6 mediated neuronal dysfunction. Here, we hypothesize that prone positioning mitigates neuronal injury, via decreased IL-6, in a model of VILI. VILI was induced by subjecting C57BL/6J mice to high tidal volume (35 cc/kg) mechanical ventilation. Neuronal injury markers [cleaved caspase-3 (CC3), c-fos, heat shock protein 90 (Hsp90)] and inflammatory cytokines (IL-6, IL-1β, TNF-α) were measured in the frontal cortex and hippocampus. We found statistically significantly less neuronal injury (CC3, c-Fos, Hsp90) and inflammatory cytokines (IL-6, IL-1β, TNF-α) in the frontal cortex and hippocampus with prone compared to supine positioning (p < 0.001) despite no significant group differences in oxygen saturation or inflammatory infiltrates in the bronchoalveolar fluid (p > 0.05). Although there were no group differences in plasma IL-6 concentrations, there was significantly less cortical and hippocampal IL-6 in the prone position (p < 0.0001), indicating supine positioning may enhance brain susceptibility to systemic IL-6 during VILI via the IL-6 trans-signaling pathway. These findings call for future clinical studies to assess the relationship between prone positioning and delirium and for investigations into novel diagnostic or therapeutic paradigms to mitigate delirium by reducing expression of systemic and cerebral IL-6.

Tímabundið minnisleysi - tilfellaröð frá 2010-2021

BACKGROUND: Transient Global Amnesia (TGA) is a benign syndrome characterized by sudden anterograde memory loss, that resolves spontaneously within 24 hours. TGA appears without other focal neurological symptoms. The aim of this study was to study TGA in the greater Reykjavik-area. METHODS: We retrospectively analysed the medical history of patients with a diagnosis of TGA (ICD-10 G45.4) at the University Hospital in Iceland in 2010-2021. Medical records were reviewed, and information about year and age at diagnosis, sex, symptoms, precipitating events, imaging results and risk factors were collected. Statistical processing was performed with Excel and Rstudio. RESULTS: Overall, 348 attacks of TGA were identified with a mean frequency of 29 attacks/year, where 9.9% had an earlier history of TGA. The mean age was 64.1, with 50% of subjects between 58-70 years old. The sex distribution was equal (49.9% female). Possible precipitating events were found in 53.7% of cases, with physical activity being the most common one (24.4%), followed by sudden temperature change and emotional stress. In 96% of patients a computerized tomography was performed (no sign of acute changes were found), and magnetic resonance imaging (MRI) in 36.2% of cases. MRI showed restricted diffusion in the hippocampal area in 10.3% of cases. DISCUSSION: TGA is not a rare but a benign syndrome. Our findings regarding age, sex distribution and precipitating events were in accordance with other studies. TGA is thought to result from a temporary hippocampal dysfunction supported by the clinical presentation and MRI findings. The cause of TGA is however still unknown.

Transient Global Amnesia in the Reykjavik area

Transient Global Amnesia (TGA) is a benign syndrome characterized by sudden anterograde memory loss, that resolves spontaneously within 24 hours. TGA appears without other focal neurological symptoms. The aim of this study was to study TGA in the greater Reykjavik-area. We retrospectively analysed the medical history of patients with a diagnosis of TGA (ICD-10 G45.4) at the University Hospital in Iceland in 2010-2021. Medical records were reviewed, and information about year and age at diagnosis, sex, symptoms, precipitating events, imaging results and risk factors were collected. Statistical processing was performed with Excel and Rstudio. Overall, 348 attacks of TGA were identified with a mean frequency of 29 attacks/year, where 9.9% had an earlier history of TGA. The mean age was 64.1, with 50% of subjects between 58-70 years old. The sex distribution was equal (49.9% female). Possible precipitating events were found in 53.7% of cases, with physical activity being the most common one (24.4%), followed by sudden temperature change and emotional stress. In 96% of patients a computerized tomography was performed (no sign of acute changes were found), and magnetic resonance imaging (MRI) in 36.2% of cases. MRI showed restricted diffusion in the hippocampal area in 10.3% of cases. TGA is not a rare but a benign syndrome. Our findings regarding age, sex distribution and precipitating events were in accordance with other studies. TGA is thought to result from a temporary hippocampal dysfunction supported by the clinical presentation and MRI findings. The cause of TGA is however still unknown.

Impaired spatial navigation and age-dependent hippocampal synaptic dysfunction are associated with chronic inflammatory response in db/db mice.

Type 2 diabetes mellitus (T2DM) increases the risk of developing Alzheimer's disease (AD), which has been proposed to be driven by an abnormal neuroinflammatory response affecting cognitive function. However, the impact of T2DM on hippocampal function and synaptic integrity during aging has not been investigated. Here, we investigated the effects of aging in T2DM on AD-like pathology using the leptin receptor-deficient db/db mouse model of T2DM. Our results indicate that adult T2DM mice exhibited impaired spatial acquisition in the Morris water maze (MWM). Morphological analysis showed an age-dependent neuronal loss in the dentate gyrus. We found that astrocyte density was significantly decreased in all regions of the hippocampus in T2DM mice. Ouranalysis showed that microglial activation was increased in the CA3 and the dentate gyrus of the hippocampus in an age-dependent manner in T2DM mice. However, the expression of presynaptic marker protein (synaptophysin) and the postsynaptic marker protein [postsynaptic density protein 95 (PSD95)] was unchanged in the hippocampus of adult T2DM mice. Interestingly, synaptophysin and PSD95 expression significantly decreased in the hippocampus of aged T2DM mice, suggesting an impaired hippocampal synaptic integrity. Cytokine profiling analysis displayed a robust pro-inflammatory cytokine profile in the hippocampus of aged T2DM mice compared with the younger cohort, outlining the role of aging in exacerbating the neuroinflammatory profile in the diabetic state. Our results suggest that T2DM impairs cognitive function by promoting neuronal loss in the dentate gyrus and triggering an age-dependent deterioration in hippocampal synaptic integrity, associated with an aberrant neuroinflammatory response.

Hippocampal synaptic dysfunction and spatial memory impairment in omeprazole-treated rats.

Although the association of prolonged use of proton pump inhibitors, such as omeprazole, with memory impairment has been reported more than two decades ago, its underlying molecular mechanism is yet to be determined. Thus, in this study, we aimed to determine the mechanisms underlying the effect of prolonged omeprazole treatment on hippocampal synaptic function and spatial memory in male rats. Adult rats were subcutaneously administered with omeprazole for 12 or 24 weeks. Spatial memory was assessed using the Morris water maze (MWM) test. We examined the hippocampal protein expression of synaptic plasticity proteins, including the AMPA receptor subunit GluA1, postsynaptic density-95 (PSD-95), and activity-regulated cytoskeleton-associated protein (Arc), and the hippocampal expression and localization of androgen receptor (AR). In the MWM test, the escape latency was found to be significantly higher, and the number of platform crossings and the time spent in the target quadrant were significantly lower in the rats treated with omeprazole compared to the control rats. Hypomagnesemia and lower bone and brain Mg2+ content were also detected in the omeprazole-treated groups compared with the control group. The expression of GluA1, PSD-95, and Arc in the hippocampus and the expression of AR in the dentate gyrus and CA1 of the hippocampus were significantly lower in the omeprazole-treated groups than in the control group. These results suggest that prolonged omeprazole treatment might lead to memory deficit by impairing glutamate receptor trafficking or synaptic anchoring. Hypomagnesemia and brain Mg2+ deficiency may be, at least in part, involved in omeprazole-induced memory impairment.

Lactobacillus plantarum ST-III culture supernatant ameliorates alcohol-induced cognitive dysfunction by reducing endoplasmic reticulum stress and oxidative stress.

BackgroundLong-term alcohol exposure is associated with oxidative stress, endoplasmic reticulum (ER) stress, and neuroinflammation, which may impair cognitive function. Probiotics supplements can significantly improve cognitive function in neurodegenerative diseases such as Alzheimer’s disease. Nevertheless, the effect of Lactobacillus plantarum ST-III culture supernatant (LP-cs) on alcohol-induced cognitive dysfunction remains unclear.MethodsA mouse model of cognitive dysfunction was established by intraperitoneal injection of alcohol (2 g/kg body weight) for 28 days. Mice were pre-treated with LP-cs, and cognitive function was evaluated using the Morris water maze test. Hippocampal tissues were collected for biochemical and molecular analysis.ResultsLP-cs significantly ameliorated alcohol-induced decline in learning and memory function and hippocampal morphology changes, neuronal apoptosis, and synaptic dysfunction. A mechanistic study showed that alcohol activated protein kinase R-like endoplasmic reticulum kinase (PERK) signaling and suppressed brain derived neurotrophic factor (BDNF) levels via ER stress in the hippocampus, which LP-cs reversed. Alcohol activated oxidative stress and inflammation responses in the hippocampus, which LP-cs reversed.ConclusionLP-cs significantly ameliorated alcohol-induced cognitive dysfunction and cellular stress. LP-cs might serve as an effective treatment for alcohol-induced cognitive dysfunction.

Insight into the Effects of High-Altitude Hypoxic Exposure on Learning and Memory.

The earth land area is heterogeneous in terms of elevation; about 45% of its land area belongs to higher elevation with altitude above 500 meters compared to sea level. In most cases, oxygen concentration decreases as altitude increases. Thus, high-altitude hypoxic stress is commonly faced by residents in areas with an average elevation exceeding 2500 meters and those who have just entered the plateau. High-altitude hypoxia significantly affects advanced neurobehaviors including learning and memory (L&M). Hippocampus, the integration center of L&M, could be the most crucial target affected by high-altitude hypoxia exposure. Based on these points, this review thoroughly discussed the relationship between high-altitude hypoxia and L&M impairment, in terms of hippocampal neuron apoptosis and dysfunction, neuronal oxidative stress disorder, neurotransmitters and related receptors, and nerve cell energy metabolism disorder, which is of great significance to find potential targets for medical intervention. Studies illustrate that the mechanism of L&M damaged by high-altitude hypoxia should be further investigated based on the entire review of issues related to this topic.

Integrated transcriptomics and metabolomics analysis of the hippocampus reveals altered neuroinflammation, downregulated metabolism and synapse in sepsis-associated encephalopathy.

Sepsis-associated encephalopathy (SAE) is an intricated complication of sepsis that brings abnormal emotional and memory dysfunction and increases patients’ mortality. Patients’ alterations and abnormal function seen in SAE occur in the hippocampus, the primary brain region responsible for memory and emotional control, but the underlying pathophysiological mechanisms remain unclear. In the current study, we employed an integrative analysis combining the RNA-seq-based transcriptomics and liquid chromatography/mass spectrometry (LC-MS)-based metabolomics to comprehensively obtain the enriched genes and metabolites and their core network pathways in the endotoxin (LPS)-injected SAE mice model. As a result, SAE mice exhibited behavioral changes, and their hippocampus showed upregulated inflammatory cytokines and morphological alterations. The omics analysis identified 81 differentially expressed metabolites (variable importance in projection [VIP] > 1 and p < 0.05) and 1747 differentially expressed genes (Foldchange >2 and p < 0.05) were detected in SAE-grouped hippocampus. Moreover, 31 compounds and 100 potential target genes were employed for the Kyoto Encyclopedia of Genes and Genomes (KEGG) Markup Language (KGML) network analysis to explore the core signaling pathways for the progression of SAE. The integrative pathway analysis showed that various dysregulated metabolism pathways, including lipids metabolism, amino acids, glucose and nucleotides, inflammation-related pathways, and deregulated synapses, were tightly associated with hippocampus dysfunction at early SAE. These findings provide a landscape for understanding the pathophysiological mechanisms of the hippocampus in the progression of SAE and pave the way to identify therapeutic targets in future studies.

Adverse maternal environment alters Oprl1 variant expression in mouse hippocampus.

An adverse maternal environment (AME) and Western diet (WD) in early life predispose offspring toward cognitive impairment in humans and mice. Cognitive impairment associates with hippocampal dysfunction. An important regulator of hippocampal function is the hippocampal Nociceptin/Orphanin FQ (N/OFQ) system. Previous studies find links between dysregulation of hippocampal N/OFQ receptor (NOP) expression and impaired cognitive function. NOP is encoded by the opioid receptor-like 1 (Oprl1) gene that contains multiple mRNA variants and isoforms. Regulation of Oprl1 expression includes histone modifications within the promoter. We tested the hypothesis that an AME and a postweaning WD increase the expression of hippocampal Oprl1 and select variants concurrent with altered histone code in the promoter. We created an AME-WD model combining maternal WD and prenatal environmental stress plus postweaning WD in the mouse. We analyzed the hippocampal expression of Oprl1, Oprl1 variants, and histone modifications in the Oprl1 promoter in offspring at postnatal day (P) 21 and P100. An AME and an AME-WD significantly increased the total hippocampal expression of Oprl1 and variant V4 concurrently with an increased accumulation of active histone marks in the promoter of male offspring. We concluded that an AME and an AME-WD alter hippocampal Oprl1 expression in offspring through an epigenetic mechanism in a variant-specific and sex-specific manner. Altered hippocampal Oprl1 expression may contribute to cognitive impairment seen in adult males in this model. Epigenetic regulation of Oprl1 is a potential mechanism by which an AME and a WD may contribute to neurocognitive impairment in male offspring.