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1.
J Neuroinflammation ; 21(1): 149, 2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38840141

RESUMO

Uncontrolled neuroinflammation mediates traumatic brain injury (TBI) pathology and impairs recovery. Interleukin-6 (IL-6), a pleiotropic inflammatory regulator, is associated with poor clinical TBI outcomes. IL-6 operates via classical-signaling through membrane-bound IL-6 receptor (IL-6R) and trans-signaling through soluble IL-6 receptor (s)IL-6R. IL-6 trans-signaling specifically contributes to neuropathology, making it a potential precision therapeutic TBI target. Soluble glycoprotein 130 (sgp130) prevents IL-6 trans-signaling, sparing classical signaling, thus is a possible treatment. Mice received either controlled cortical impact (CCI) (6.0 ± 0.2 m/s; 2 mm; 50-60ms) or sham procedures. Vehicle (VEH) or sgp130-Fc was subcutaneously administered to sham (VEH or 1 µg) and CCI (VEH, 0.25 µg or 1 µg) mice on days 1, 4, 7, 10 and 13 post-surgery to assess effects on cognition [Morris Water Maze (MWM)] and ipsilateral hemisphere IL-6 related biomarkers (day 21 post-surgery). CCI + sgp130-Fc groups (0.25 µg and 1 µg) were combined for analysis given similar behavior/biomarker outcomes. CCI + VEH mice had longer latencies and path lengths to the platform and increased peripheral zone time versus Sham + VEH and Sham + sgp130-Fc mice, suggesting injury-induced impairments in learning and anxiety. CCI + sgp130-Fc mice had shorter platform latencies and path lengths and had decreased peripheral zone time, indicating a therapeutic benefit of sgp130-Fc after injury on learning and anxiety. Interestingly, Sham + sgp130-Fc mice had shorter platform latencies, path lengths and peripheral zone times than Sham + VEH mice, suggesting a beneficial effect of sgp130-Fc, independent of injury. CCI + VEH mice had increased brain IL-6 and decreased sgp130 levels versus Sham + VEH and Sham + sgp130-Fc mice. There was no treatment effect on IL-6, sIL6-R or sgp130 in Sham + VEH versus Sham + sgp130-Fc mice. There was also no treatment effect on IL-6 in CCI + VEH versus CCI + sgp130-Fc mice. However, CCI + sgp130-Fc mice had increased sIL-6R and sgp130 versus CCI + VEH mice, demonstrating sgp130-Fc treatment effects on brain biomarkers. Inflammatory chemokines (MIP-1ß, IP-10, MIG) were increased in CCI + VEH mice versus Sham + VEH and Sham + sgp130-Fc mice. However, CCI + sgp130-Fc mice had decreased chemokine levels versus CCI + VEH mice. IL-6 positively correlated, while sgp130 negatively correlated, with chemokine levels. Overall, we found that systemic sgp130-Fc treatment after CCI improved learning, decreased anxiety and reduced CCI-induced brain chemokines. Future studies will explore sex-specific dosing and treatment mechanisms for sgp130-Fc therapy.


Assuntos
Lesões Encefálicas Traumáticas , Receptor gp130 de Citocina , Modelos Animais de Doenças , Aprendizagem em Labirinto , Camundongos Endogâmicos C57BL , Animais , Lesões Encefálicas Traumáticas/tratamento farmacológico , Camundongos , Masculino , Receptor gp130 de Citocina/metabolismo , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Quimiocinas/metabolismo , Interleucina-6/metabolismo , Cognição/efeitos dos fármacos , Cognição/fisiologia
2.
CNS Neurosci Ther ; 30(5): e14716, 2024 05.
Artigo em Inglês | MEDLINE | ID: mdl-38698533

RESUMO

BACKGROUND: Sevoflurane is a superior agent for maintaining anesthesia during surgical procedures. However, the neurotoxic mechanisms of clinical concentration remain poorly understood. Sevoflurane can interfere with the normal function of neurons and synapses and impair cognitive function by acting on α5-GABAAR. METHODS: Using MWM test, we evaluated cognitive abilities in mice following 1 h of anesthesia with 2.7%-3% sevoflurane. Based on hippocampal transcriptome analysis, we analyzed the differential genes and IL-6 24 h post-anesthesia. Western blot and RT-PCR were performed to measure the levels of α5-GABAAR, Radixin, P-ERM, P-Radixin, Gephyrin, IL-6, and ROCK. The spatial distribution and expression of α5-GABAAR on neuronal somata were analyzed using histological and three-dimensional imaging techniques. RESULTS: MWM test indicated that partial long-term learning and memory impairment. Combining molecular biology and histological analysis, our studies have demonstrated that sevoflurane induces immunosuppression, characterized by reduced IL-6 expression levels, and that enhanced Radixin dephosphorylation undermines the microstructural stability of α5-GABAAR, leading to its dissociation from synaptic exterior and resulting in a disordered distribution in α5-GABAAR expression within neuronal cell bodies. On the synaptic cleft, the expression level of α5-GABAAR remained unchanged, the spatial distribution became more compact, with an increased fluorescence intensity per voxel. On the extra-synaptic space, the expression level of α5-GABAAR decreased within unchanged spatial distribution, accompanied by an increased fluorescence intensity per voxel. CONCLUSION: Dysregulated α5-GABAAR expression and distribution contributes to sevoflurane-induced partial long-term learning and memory impairment, which lays the foundation for elucidating the underlying mechanisms in future studies.


Assuntos
Anestésicos Inalatórios , Hipocampo , Transtornos da Memória , Receptores de GABA-A , Sevoflurano , Sevoflurano/toxicidade , Animais , Camundongos , Masculino , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/metabolismo , Anestésicos Inalatórios/toxicidade , Receptores de GABA-A/metabolismo , Receptores de GABA-A/biossíntese , Receptores de GABA-A/genética , Hipocampo/metabolismo , Hipocampo/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia
3.
PLoS One ; 19(5): e0298116, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38722850

RESUMO

Spatial navigation is a multi-faceted behaviour drawing on many different aspects of cognition. Visuospatial abilities, such as mental rotation and visuospatial working memory, in particular, may be key factors. A range of tests have been developed to assess visuospatial processing and memory, but how such tests relate to navigation ability remains unclear. This understanding is important to advance tests of navigation for disease monitoring in various disorders (e.g., Alzheimer's disease) where spatial impairment is an early symptom. Here, we report the use of an established mobile gaming app, Sea Hero Quest (SHQ), as a measure of navigation ability in a sample of young, predominantly female university students (N = 78; 20; female = 74.3%; mean age = 20.33 years). We used three separate tests of navigation embedded in SHQ: wayfinding, path integration and spatial memory in a radial arm maze. In the same participants, we also collected measures of mental rotation (Mental Rotation Test), visuospatial processing (Design Organization Test) and visuospatial working memory (Digital Corsi). We found few strong correlations across our measures. Being good at wayfinding in a virtual navigation test does not mean an individual will also be good at path integration, have a superior memory in a radial arm maze, or rate themself as having a strong sense of direction. However, we observed that participants who were good in the wayfinding task of SHQ tended to perform well on the three visuospatial tasks examined here, and to also use a landmark strategy in the radial maze task. These findings help clarify the associations between different abilities involved in spatial navigation.


Assuntos
Navegação Espacial , Humanos , Feminino , Navegação Espacial/fisiologia , Masculino , Adulto Jovem , Adulto , Memória de Curto Prazo/fisiologia , Memória Espacial/fisiologia , Aprendizagem em Labirinto/fisiologia , Percepção Espacial/fisiologia , Adolescente , Aplicativos Móveis
4.
Methods Mol Biol ; 2799: 107-138, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38727905

RESUMO

NMDAR-dependent forms of synaptic plasticity in brain regions like the hippocampus are widely believed to provide the neural substrate for long-term associative memory formation. However, the experimental data are equivocal at best and may suggest a more nuanced role for NMDARs and synaptic plasticity in memory. Much of the experimental data available comes from studies in genetically modified mice in which NMDAR subunits have been deleted or mutated in order to disrupt NMDAR function. Behavioral assessment of long-term memory in these mice has involved tests like the Morris watermaze and the radial arm maze. Here we describe these behavioral tests and some of the different testing protocols that can be used to assess memory performance. We discuss the importance of distinguishing selective effects on learning and memory processes from nonspecific effects on sensorimotor or motivational aspects of performance.


Assuntos
Aprendizagem em Labirinto , Memória de Longo Prazo , Receptores de N-Metil-D-Aspartato , Memória Espacial , Animais , Receptores de N-Metil-D-Aspartato/metabolismo , Camundongos , Memória de Longo Prazo/fisiologia , Aprendizagem em Labirinto/fisiologia , Memória Espacial/fisiologia , Hipocampo/fisiologia , Hipocampo/metabolismo , Comportamento Animal/fisiologia , Plasticidade Neuronal/fisiologia
5.
CNS Neurosci Ther ; 30(5): e14758, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38757390

RESUMO

AIMS: Sepsis-associated encephalopathy (SAE) is manifested as a spectrum of disturbed cerebral function ranging from mild delirium to coma. However, the pathogenesis of SAE has not been clearly elucidated. Astrocytes play important roles in maintaining the function and metabolism of the brain. Most recently, it has been demonstrated that disorders of lipid metabolism, especially lipid droplets (LDs) dyshomeostasis, are involved in a variety of neurodegenerative diseases. The aim of this study was to investigate whether LDs are involved in the underlying mechanism of SAE. METHODS: The open field test, Y-maze test, and contextual fear conditioning test (CFCT) were used to test cognitive function in SAE mice. Lipidomics was utilized to investigate alterations in hippocampal lipid metabolism in SAE mice. Western blotting and immunofluorescence labeling were applied for the observation of related proteins. RESULTS: In the current study, we found that SAE mice showed severe cognitive dysfunction, including spatial working and contextual memory. Meanwhile, we demonstrated that lipid metabolism was widely dysregulated in the hippocampus by using lipidomic analysis. Furthermore, western blotting and immunofluorescence confirmed that LDs accumulation in hippocampal astrocytes was involved in the pathological process of cognitive dysfunction in SAE mice. We verified that LDs can be inhibited by specifically suppress hypoxia-inducible lipid droplet-associated protein (HILPDA) in astrocytes. Meanwhile, cognitive dysfunction in SAE was ameliorated by reducing A1 astrocyte activation and inhibiting presynaptic membrane transmitter release. CONCLUSION: The accumulation of astrocytic lipid droplets plays a crucial role in the pathological process of SAE. HILPDA is an attractive therapeutic target for lipid metabolism regulation and cognitive improvement in septic patients.


Assuntos
Astrócitos , Disfunção Cognitiva , Gotículas Lipídicas , Camundongos Endogâmicos C57BL , Encefalopatia Associada a Sepse , Animais , Gotículas Lipídicas/metabolismo , Encefalopatia Associada a Sepse/metabolismo , Astrócitos/metabolismo , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/etiologia , Camundongos , Masculino , Hipocampo/metabolismo , Metabolismo dos Lipídeos/fisiologia , Aprendizagem em Labirinto/fisiologia
6.
Sci Rep ; 14(1): 10187, 2024 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-38702381

RESUMO

Neurexins (Nrxns) are critical for synapse organization and their mutations have been documented in autism spectrum disorder, schizophrenia, and epilepsy. We recently reported that conditional deletion of Nrxn2, under the control of Emx1Cre promoter, predominately expressed in the neocortex and hippocampus (Emx1-Nrxn2 cKO mice) induced stereotyped patterns of behavior in mice, suggesting behavioral inflexibility. In this study, we investigated the effects of Nrxn2 deletion through two different conditional approaches targeting presynaptic cortical neurons projecting to dorsomedial striatum on the flexibility between goal-directed and habitual actions in response to devaluation of action-outcome (A-O) contingencies in an instrumental learning paradigm or upon reversal of A-O contingencies in a water T-maze paradigm. Nrxn2 deletion through both the conditional approaches induced an inability of mice to discriminate between goal-directed and habitual action strategies in their response to devaluation of A-O contingency. Emx1-Nrxn2 cKO mice exhibited reversal learning deficits, indicating their inability to adopt new action strategies. Overall, our studies showed that Nrxn2 deletion through two distinct conditional deletion approaches impaired flexibility in response to alterations in A-O contingencies. These investigations can lay the foundation for identification of novel genetic factors underlying behavioral inflexibility.


Assuntos
Comportamento Animal , Camundongos Knockout , Proteínas do Tecido Nervoso , Fatores de Transcrição , Animais , Camundongos , Proteínas do Tecido Nervoso/genética , Masculino , Moléculas de Adesão de Célula Nervosa/genética , Deleção de Genes , Aprendizagem em Labirinto/fisiologia , Reversão de Aprendizagem/fisiologia , Proteínas de Homeodomínio/genética , Hipocampo/metabolismo , Moléculas de Adesão Celular Neuronais/genética , Condicionamento Operante
7.
Behav Brain Funct ; 20(1): 9, 2024 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-38702776

RESUMO

BACKGROUND: In the present study, we investigated the effect of high-intensity interval training (HIIT) on cognitive behaviors in female rats with a high-fat diet + streptozotocin (STZ)-induced type 2 diabetes. METHODS: Twenty-four female rats were divided into four groups randomly (n = 6): control (C), control + exercise (Co + EX), diabetes mellitus (type 2) (T2D), and diabetes mellitus + exercise (T2D + EX). Diabetes was induced by a two-month high-fat diet and a single dose of STZ (35 mg/kg) in the T2D and T2D + EX groups. The Co + EX and T2D + EX groups performed HIIT for eight weeks (five sessions per week, running on a treadmill at 80-100% of VMax, 4-10 intervals). Elevated plus maze (EPM) and open field test (OFT) were used for assessing anxiety-like behaviors, and passive avoidance test (PAT) and Morris water maze (MWM) were applied for evaluating learning and memory. The hippocampal levels of beta-amyloid (Aß) and Tau were also assessed using Western blot. RESULTS: An increase in fasting blood glucose (FBG), hippocampal level of Tau, and a decrease in the percentage of open arm time (%OAT) as an index of anxiety-like behavior were seen in the female diabetic rats which could be reversed by HIIT. In addition, T2D led to a significant decrease in rearing and grooming in the OFT. No significant difference among groups was seen for the latency time in the PAT and learning and memory in the MWM. CONCLUSIONS: HIIT could improve anxiety-like behavior at least in part through changes in hippocampal levels of Tau.


Assuntos
Peptídeos beta-Amiloides , Ansiedade , Diabetes Mellitus Experimental , Hipocampo , Condicionamento Físico Animal , Proteínas tau , Animais , Feminino , Hipocampo/metabolismo , Proteínas tau/metabolismo , Ratos , Condicionamento Físico Animal/fisiologia , Condicionamento Físico Animal/métodos , Condicionamento Físico Animal/psicologia , Ansiedade/terapia , Ansiedade/psicologia , Ansiedade/metabolismo , Peptídeos beta-Amiloides/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/psicologia , Diabetes Mellitus Experimental/terapia , Treinamento Intervalado de Alta Intensidade/métodos , Aprendizagem em Labirinto/fisiologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/psicologia , Diabetes Mellitus Tipo 2/terapia , Comportamento Animal/fisiologia , Dieta Hiperlipídica/efeitos adversos , Ratos Sprague-Dawley
8.
J Vis Exp ; (207)2024 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-38801269

RESUMO

Thread-embedding therapy (TEAT) is a treatment that prevents and manages diseases by inserting a biodegradable suture into an acupoint, providing long-lasting stimulation. TEAT is a simple approach that avoids the discomfort of regular acupuncture and provides sustained therapeutic effects. This article discusses the potential impact of TEAT on the learning and memory abilities of rats with Alzheimer's disease-like symptoms. Since chemically induced neuronal degeneration and cognitive impairments in rats does not entirely reflect the true pathological changes observed in Alzheimer's disease. Consequently, our research group has designated these manifestations as Alzheimer's disease-like symptoms. A protocol has been established to outline the selection of acupoints, the operation process, and necessary precautions for the head and lower back. The experiment was conducted on three groups: a control group, a model group, and a TEAT group, each containing 6 rats. To induce Alzheimer's disease-like symptoms, rats were intraperitoneally injected with D-galactose for 7 weeks (49 days). The rats in the TEAT group received acupoint catgut embedding treatment. Following the intervention period, a Morris Water Maze (MWM) was conducted to evaluate the rats' learning and memory. Subsequently, the rats were sacrificed, and their brain tissue was examined. A histological examination was performed to understand the effects of TEAT on the pathology of rats exhibiting symptoms of Alzheimer's disease. This study suggests that TEAT may improve learning and memory in rats with Alzheimer's disease-like symptoms, indicating a potentially promising new treatment approach for this neurodegenerative condition.


Assuntos
Terapia por Acupuntura , Doença de Alzheimer , Animais , Doença de Alzheimer/terapia , Terapia por Acupuntura/métodos , Ratos , Modelos Animais de Doenças , Pontos de Acupuntura , Suturas , Masculino , Ratos Sprague-Dawley , Aprendizagem em Labirinto/fisiologia
9.
CNS Neurosci Ther ; 30(5): e14719, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38783536

RESUMO

BACKGROUND: Methamphetamine (METH) is a psychostimulant substance with highly addictive and neurotoxic effects, but no ideal treatment option exists to improve METH-induced neurocognitive deficits. Recently, mesenchymal stem cells (MSCs)-derived exosomes have raised many hopes for treating neurodegenerative sequela of brain disorders. This study aimed to determine the therapeutic potential of MSCs-derived exosomes on cognitive function and neurogenesis of METH-addicted rodents. METHODS: Male BALB/c mice were subjected to chronic METH addiction, followed by intravenous administration of bone marrow MSCs-derived exosomes. Then, the spatial memory and recognition memory of animals were assessed by the Barnes maze and the novel object recognition test (NORT). The neurogenesis-related factors, including NeuN and DCX, and the expression of Iba-1, a microglial activation marker, were assessed in the hippocampus by immunofluorescence staining. Also, the expression of inflammatory cytokines, including TNF-α and NF-κB, were evaluated by western blotting. RESULTS: The results showed that BMSCs-exosomes improved the time spent in the target quadrant and correct-to-wrong relative time in the Barnes maze. Also, NORT's discrimination index (DI) and recognition index (RI) were improved following exosome therapy. Additionally, exosome therapy significantly increased the expression of NeuN and DCX in the hippocampus while decreasing the expression of inflammatory cytokines, including TNF-α and NF-κB. Besides, BMSC-exosomes down-regulated the expression of Iba-1. CONCLUSION: Our findings indicate that BMSC-exosomes mitigated METH-caused cognitive dysfunction by improving neurogenesis and inhibiting neuroinflammation in the hippocampus.


Assuntos
Transtornos Relacionados ao Uso de Anfetaminas , Proteína Duplacortina , Exossomos , Hipocampo , Células-Tronco Mesenquimais , Metanfetamina , Camundongos Endogâmicos BALB C , Neurogênese , Animais , Exossomos/metabolismo , Masculino , Neurogênese/efeitos dos fármacos , Neurogênese/fisiologia , Camundongos , Metanfetamina/toxicidade , Transtornos Relacionados ao Uso de Anfetaminas/terapia , Transtornos Relacionados ao Uso de Anfetaminas/psicologia , Transtornos Relacionados ao Uso de Anfetaminas/metabolismo , Hipocampo/metabolismo , Hipocampo/efeitos dos fármacos , Cognição/efeitos dos fármacos , Cognição/fisiologia , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Reconhecimento Psicológico/efeitos dos fármacos , Reconhecimento Psicológico/fisiologia , Proteínas do Tecido Nervoso/metabolismo , Estimulantes do Sistema Nervoso Central/toxicidade , Memória Espacial/efeitos dos fármacos , Memória Espacial/fisiologia , Proteínas dos Microfilamentos/metabolismo , Transplante de Células-Tronco Mesenquimais/métodos , Proteínas de Ligação ao Cálcio , Proteínas de Ligação a DNA
10.
CNS Neurosci Ther ; 30(5): e14743, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38780008

RESUMO

AIMS: Nerve growth factor (NGF) loss is a potential factor for the degeneration of basal forebrain cholinergic neurons (BFCNs) in Alzheimer's disease (AD), and Rab5a is a key regulatory molecule of NGF signaling transduction. Here, we investigated the changes of Rab5a in 5 × FAD mice and further explored the mechanism of Electroacupuncture (EA) treatment in improving cognition in the early stage of AD. METHODS: The total Rab5a and Rab5a-GTP in 5-month-old 5 × FAD mice and wild-type mice were detected using WB and IP technologies. 5 × FAD mice were treated with EA at the Bai hui (DU20) and Shen ting (DU24) acupoints for 4 weeks and CRE/LOXP technology was used to confirm the role of Rab5a in AD mediated by EA stimulation. The Novel Object Recognition and Morris water maze tests were used to evaluate the cognitive function of 5 × FAD mice. The Nissl, immunohistochemistry, and Thioflavin S staining were used to observe pathological morphological changes in the basal forebrain circuit. The Golgi staining was used to investigate the synaptic plasticity of the basal forebrain circuit and WB technology was used to detect the expression levels of cholinergic-related and NGF signal-related proteins. RESULTS: The total Rab5a was unaltered, but Rab5a-GTP increased and the rab5a-positive early endosomes appeared enlarged in the hippocampus of 5 × FAD mice. Notably, EA reduced Rab5a-GTP in the hippocampus in the early stage of 5 × FAD mice. EA could improve object recognition memory and spatial learning memory by reducing Rab5a activity in the early stage of 5 × FAD mice. Moreover, EA could reduce Rab5a activity to increase NGF transduction and increase the levels of phosphorylated TrkA, AKT, and ERK in the basal forebrain and hippocampus, and increase the expression of cholinergic-related proteins, such as ChAT, vAchT, ChT1, m1AchR, and m2AchR in the basal forebrain and ChAT, m1AchR, and m2AchR in the hippocampus, improving synaptic plasticity in the basal forebrain hippocampal circuit in the early stage of 5 × FAD mice. CONCLUSIONS: Rab5a hyperactivation is an early pathological manifestation of 5 × FAD mice. EA could suppress Rab5a-GTP to promote the transduction of NGF signaling, and enhance the synaptic plasticity of the basal forebrain hippocampal circuit improving cognitive impairment in the early stage of 5 × FAD mice.


Assuntos
Doença de Alzheimer , Eletroacupuntura , Camundongos Transgênicos , Fator de Crescimento Neural , Proteínas rab5 de Ligação ao GTP , Animais , Proteínas rab5 de Ligação ao GTP/metabolismo , Fator de Crescimento Neural/metabolismo , Camundongos , Eletroacupuntura/métodos , Doença de Alzheimer/terapia , Doença de Alzheimer/metabolismo , Transdução de Sinais/fisiologia , Masculino , Memória/fisiologia , Aprendizagem/fisiologia , Aprendizagem em Labirinto/fisiologia , Camundongos Endogâmicos C57BL , Plasticidade Neuronal/fisiologia
11.
Cortex ; 175: 12-27, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38701643

RESUMO

Navigation through space is based on memory representations of landmarks ('place') or movement sequences ('response'). Over time, memory representations transform through consolidation. However, it is unclear how the transformation affects place and response navigation in humans. In the present study, healthy adults navigated to target locations in a virtual maze. The preference for using place and response strategies and the ability to recall place and response memories were tested after a delay of one hour (n = 31), one day (n = 30), or two weeks (n = 32). The different delays captured early-phase synaptic changes, changes after one night of sleep, and long-delay changes due to the reorganization of navigation networks. Our results show that the relative contributions of place and response navigation changed as a function of time. After a short delay of up to one day, participants preferentially used a place strategy and exhibited a high degree of visual landmark exploration. After a longer delay of two weeks, place strategy use decreased significantly. Participants now equally relied on place and response strategy use and increasingly repeated previously taken paths. Further analyses indicate that response strategy use predominantly occurred as a compensatory strategy in the absence of sufficient place memory. Over time, place memory faded before response memory. We suggest that the observed shift from place to response navigation is context-dependent since detailed landmark information, which strongly relied on hippocampal function, decayed faster than sequence information, which required less detail and depended on extra-hippocampal areas. We conclude that changes in place and response navigation likely reflect the reorganization of navigation networks during systems consolidation.


Assuntos
Consolidação da Memória , Navegação Espacial , Humanos , Masculino , Consolidação da Memória/fisiologia , Navegação Espacial/fisiologia , Feminino , Adulto , Adulto Jovem , Percepção Espacial/fisiologia , Memória Espacial/fisiologia , Hipocampo/fisiologia , Rememoração Mental/fisiologia , Aprendizagem em Labirinto/fisiologia
12.
Nature ; 629(8012): 630-638, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38720085

RESUMO

Hippocampal representations that underlie spatial memory undergo continuous refinement following formation1. Here, to track the spatial tuning of neurons dynamically during offline states, we used a new Bayesian learning approach based on the spike-triggered average decoded position in ensemble recordings from freely moving rats. Measuring these tunings, we found spatial representations within hippocampal sharp-wave ripples that were stable for hours during sleep and were strongly aligned with place fields initially observed during maze exploration. These representations were explained by a combination of factors that included preconfigured structure before maze exposure and representations that emerged during θ-oscillations and awake sharp-wave ripples while on the maze, revealing the contribution of these events in forming ensembles. Strikingly, the ripple representations during sleep predicted the future place fields of neurons during re-exposure to the maze, even when those fields deviated from previous place preferences. By contrast, we observed tunings with poor alignment to maze place fields during sleep and rest before maze exposure and in the later stages of sleep. In sum, the new decoding approach allowed us to infer and characterize the stability and retuning of place fields during offline periods, revealing the rapid emergence of representations following new exploration and the role of sleep in the representational dynamics of the hippocampus.


Assuntos
Hipocampo , Sono , Memória Espacial , Animais , Ratos , Potenciais de Ação/fisiologia , Teorema de Bayes , Hipocampo/citologia , Hipocampo/fisiologia , Aprendizagem em Labirinto/fisiologia , Modelos Neurológicos , Neurônios/fisiologia , Sono/fisiologia , Memória Espacial/fisiologia , Ritmo Teta/fisiologia , Vigília/fisiologia
13.
Behav Brain Res ; 468: 115022, 2024 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-38697301

RESUMO

Abl2/Arg (ABL-related gene) is a member of the Abelson family of nonreceptor tyrosine kinases, known for its role in tumor progression, metastasis, tissue injury responses, inflammation, neural degeneration, and other diseases. In this study, we developed Abl2/Arg knockout (abl2-/-) mice to explore its impact on sensory/motor functions and emotion-related behaviors. Our findings show that abl2-/- mice exhibit normal growth and phenotypic characteristics, closely resembling their wild-type (WT) counterparts. Behavioral tests, including the elevated plus maze, marble-burying behavior test, and open field test, indicated pronounced anxiety-like behaviors in abl2-/- mice compared to WT mice. Furthermore, in the tail suspension test, abl2-/- mice showed a significant decrease in mobility time, suggesting depressive-like behavior. Conversely, in the Y-maze and cliff avoidance reaction tests, no notable differences were observed between abl2-/- and WT mice, suggesting the absence of working memory deficits and impulsivity in abl2-/- mice. Proteomic analysis of the hippocampus in abl2-/- mice highlighted significant alterations in proteins related to anxiety and depression, especially those associated with the GABAergic synapse in inhibitory neurotransmission. The expression of Gabbr2 was significantly reduced in the hippocampus of abl2-/- compared to WT mice, and intraperitoneal treatment of GABA receptor agonist Gaboxadol normalized anxiety/depression-related behaviors of abl2-/- mice. These findings underscore the potential role of Abl2/Arg in influencing anxiety and depressive-like behaviors, thereby contributing valuable insights into its broader physiological and pathological functions.


Assuntos
Ansiedade , Comportamento Animal , Depressão , Hipocampo , Camundongos Knockout , Proteínas Tirosina Quinases , Animais , Masculino , Camundongos , Ansiedade/metabolismo , Comportamento Animal/fisiologia , Depressão/fisiopatologia , Modelos Animais de Doenças , Hipocampo/metabolismo , Aprendizagem em Labirinto/fisiologia , Camundongos Endogâmicos C57BL , Proteínas Tirosina Quinases/metabolismo , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/deficiência , Camundongos da Linhagem 129
14.
J Neuroinflammation ; 21(1): 141, 2024 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-38807149

RESUMO

The lectin pathway (LP) of complement mediates inflammatory processes linked to tissue damage and loss of function following traumatic brain injury (TBI). LP activation triggers a cascade of proteolytic events initiated by LP specific enzymes called MASPs (for Mannan-binding lectin Associated Serine Proteases). Elevated serum and brain levels of MASP-2, the effector enzyme of the LP, were previously reported to be associated with the severity of tissue injury and poor outcomes in patients with TBI. To evaluate the therapeutic potential of LP inhibition in TBI, we first conducted a pilot study testing the effect of an inhibitory MASP-2 antibody (α-MASP-2), administered systemically at 4 and 24 h post-TBI in a mouse model of controlled cortical impact (CCI). Treatment with α-MASP-2 reduced sensorimotor and cognitive deficits for up to 5 weeks post-TBI. As previous studies by others postulated a critical role of MASP-1 in LP activation, we conducted an additional study that also assessed treatment with an inhibitory MASP-1 antibody (α-MASP-1). A total of 78 mice were treated intraperitoneally with either α-MASP-2, or α-MASP-1, or an isotype control antibody 4 h and 24 h after TBI or sham injury. An amelioration of the cognitive deficits assessed by Barnes Maze, prespecified as the primary study endpoint, was exclusively observed in the α-MASP-2-treated group. The behavioral data were paralleled by a reduction of the lesion size when evaluated histologically and by reduced systemic LP activity. Our data suggest that inhibition of the LP effector enzyme MASP-2 is a promising treatment strategy to limit neurological deficits and tissue loss following TBI. Our work has translational value because a MASP-2 antibody has already completed multiple late-stage clinical trials in other indications and we used a clinically relevant treatment protocol testing the therapeutic mechanism of MASP-2 inhibition in TBI.


Assuntos
Lesões Encefálicas Traumáticas , Modelos Animais de Doenças , Serina Proteases Associadas a Proteína de Ligação a Manose , Camundongos Endogâmicos C57BL , Animais , Serina Proteases Associadas a Proteína de Ligação a Manose/antagonistas & inibidores , Serina Proteases Associadas a Proteína de Ligação a Manose/metabolismo , Lesões Encefálicas Traumáticas/tratamento farmacológico , Lesões Encefálicas Traumáticas/metabolismo , Lesões Encefálicas Traumáticas/patologia , Lesões Encefálicas Traumáticas/complicações , Lesões Encefálicas Traumáticas/psicologia , Camundongos , Masculino , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/tratamento farmacológico , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia
15.
Brain Res ; 1838: 148987, 2024 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-38718851

RESUMO

Dynamin is a microtubule (MT) binding protein playing a key role in vesicle endocytosis. In a brain slice model, tau loaded in presynaptic terminals assembles MTs, thereby impairing vesicle endocytosis via depletion of cytosolic dynamin. The peptide PHDP5, derived from the pleckstrin homology domain of dynamin 1, inhibits dynamin-MT interaction and rescues endocytosis and synaptic transmission impaired by tau when co-loaded in presynaptic terminals. We tested whether in vivo administration of PHDP5 could rescue the learning/memory deficits observed in Alzheimer's disease (AD) model mice. A modified PHDP5 incorporating a cell-penetrating peptide (CPP) and a FITC fluorescent marker was delivered intranasally to Tau609 transgenic (Tg) and 3xTg-AD mice. FITC-positive puncta were observed in the hippocampus of mice infused with PHDP5 or scrambled (SPHDP5) peptide, but not in saline-infused controls. In the Morris water maze (MWM) test for spatial learning/memory, AD model mice treated with FITC-PHDP5-CPP showed prominent improvements in learning and memory, performing close to the level of saline-infused WT mice control. In contrast, mice treated with a scrambled construct (FITC-SPHDP5-CPP) showed no significant improvement. We conclude that PHDP5 can be a candidate for human AD therapy.


Assuntos
Doença de Alzheimer , Modelos Animais de Doenças , Transtornos da Memória , Camundongos Transgênicos , Aprendizagem Espacial , Animais , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Camundongos , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/metabolismo , Aprendizagem Espacial/efeitos dos fármacos , Microtúbulos/metabolismo , Microtúbulos/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/efeitos dos fármacos , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Dinaminas/metabolismo , Masculino , Proteínas tau/metabolismo
16.
Peptides ; 178: 171244, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38788901

RESUMO

The neuropeptide relaxin-3 and its cognate receptor, relaxin family peptide-3 receptors (RXFP3), have been implicated in modulating learning and memory processes, but their specific roles remain unclear. This study utilized behavioral and molecular approaches to investigate the effects of putatively reversible blockade of RXFP3 in the ventral dentate gyrus (vDG) of the hippocampus on spatial and fear memory formation in rats. Male Wistar rats received bilateral vDG cannula implantation and injections of the RXFP3 antagonist, R3(BΔ23-27)R/I5 (400 ng/0.5 µL per side), or vehicle at specific time points before acquisition, consolidation, or retrieval phases of the Morris water maze and passive avoidance learning tasks. RXFP3 inhibition impaired acquisition in the passive avoidance task but not the spatial learning task. However, both memory consolidation and retrieval were disrupted in both tasks following RXFP3 antagonism. Ventral hippocampal levels of the consolidation-related kinase p70-S6 kinase (p70S6K) were reduced RXFP3 blockade. These findings highlight a key role for ventral hippocampal RXFP3 signaling in the acquisition, consolidation, and retrieval of spatial and emotional memories, extending previous work implicating this neuropeptide system in hippocampal memory processing.


Assuntos
Giro Denteado , Medo , Ratos Wistar , Receptores Acoplados a Proteínas G , Animais , Giro Denteado/metabolismo , Ratos , Receptores Acoplados a Proteínas G/metabolismo , Masculino , Medo/fisiologia , Aprendizagem da Esquiva/fisiologia , Aprendizagem da Esquiva/efeitos dos fármacos , Memória/fisiologia , Relaxina/metabolismo , Memória Espacial/fisiologia , Memória Espacial/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Aprendizagem em Labirinto/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/efeitos dos fármacos , Receptores de Peptídeos/metabolismo
17.
Exp Neurol ; 378: 114838, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38801989

RESUMO

OBJECTIVE: Anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis results in chronic epilepsy and permanent cognitive impairment. One of the possible causes of cognitive impairment in anti-NMDAR could be aberrant neurogenesis, an established contributor to memory loss in idiopathic drug-resistant epilepsy. We developed a mouse model of anti-NMDAR encephalitis and showed that mice exposed to patient anti-NMDAR antibodies for 2 weeks developed seizures and memory loss. In the present study, we assessed the delayed effects of patient-derived antibodies on cognitive phenotype and examined the corresponding changes in hippocampal neurogenesis. METHODS: Monoclonal anti-NMDAR antibodies or control antibodies were continuously infused into the lateral ventricle of male C56BL/6J mice (8-12 weeks) via osmotic minipumps for 2 weeks. The motor and anxiety phenotypes were assessed using the open field paradigm, and hippocampal memory and learning were assessed using the object location, Y maze, and Barnes maze paradigms during weeks 1 and 3-4 of antibody washout. The numbers of newly matured granule neurons (Prox-1+) and immature progenitor cells (DCX+) as well as their spatial distribution within the hippocampus were assessed at these time points. Bromodeoxyuridine (BrdU, 50 mg/kg, i.p., daily) was injected on days 2-12 of the infusion, and proliferating cell immunoreactivity was compared in antibody-treated mice and control mice during week 4 of the washout. RESULTS: Mice infused with anti-NMDAR antibodies demonstrated spatial memory impairment during week 1 of antibody washout (p = 0.02, t-test; n = 9-11). Histological analysis of hippocampal sections from these mice revealed an increased ectopic displacement of Prox-1+ cells in the dentate hilus compared to the control-antibody-treated mice (p = 0.01; t-test). Mice exposed to anti-NMDAR antibodies also had an impairment of spatial memory and learning during weeks 3-4 of antibody washout (object location: p = 0.009; t-test; Y maze: p = 0.006, t-test; Barnes maze: p = 0.008, ANOVA; n = 8-10). These mice showed increased ratios of the low proliferating (bright) to fast proliferating (faint) BrdU+ cell counts and decreased number of DCX+ cells in the hippocampal dentate gyrus (p = 0.006 and p = 0.04, respectively; t-tests) suggesting ectopic migration and delayed cell proliferation. SIGNIFICANCE: These findings suggest that memory and learning impairments induced by patient anti-NMDAR antibodies are sustained upon removal of antibodies and are accompanied by aberrant hippocampal neurogenesis. Interventions directed at the manipulation of neuronal plasticity in patients with encephalitis and cognitive loss may be protective and therapeutically relevant.


Assuntos
Encefalite Antirreceptor de N-Metil-D-Aspartato , Proteína Duplacortina , Hipocampo , Aprendizagem em Labirinto , Transtornos da Memória , Camundongos Endogâmicos C57BL , Neurogênese , Animais , Neurogênese/efeitos dos fármacos , Neurogênese/fisiologia , Camundongos , Masculino , Transtornos da Memória/etiologia , Hipocampo/patologia , Encefalite Antirreceptor de N-Metil-D-Aspartato/imunologia , Aprendizagem em Labirinto/fisiologia , Aprendizagem em Labirinto/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/imunologia , Receptores de N-Metil-D-Aspartato/metabolismo , Humanos , Autoanticorpos/imunologia , Modelos Animais de Doenças
18.
Neuroscience ; 549: 55-64, 2024 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-38718917

RESUMO

The present research study aimed to investigate the role of Ascorbic acid (AA) on synaptic plasticity, learning, and memory impairment induced by unpredicted chronic mild stress (CUMS) in adolescent male rats. Adolescent male rats were divided into: 1) vehicle, 2) CUMS, 3-5) CUMS plus various doses of AA by oral gavage (CUMS-10/100/400 mg/kg), and 6) AA400 mg/kg by oral gavage. In Morris Water Maze, the time latency decreased, while the time spent in the target quadrant increased in CUMS group treated with AA at the dose of 400 mg/kg. In passive avoidance, the latency of entering into the dark chamber decreased in CUMS group treated with AA (400 mg/kg). In biochemical test results, nitrite and MDA significantly decreased, while thiol content, SOD, and catalase activity in CUMS group that received AA400mg/kg was increased. IL-10, BDNF and Ki67 increased, while TNF-a and AChE activity were decreased in CUMS group treated with AA simultaneously. The results of our study showed that chronic stress during adolescence could cause learning and memory disorders as well as synaptic plasticity. In addition, we showed that AA can prevent this problem by reducing oxidative stress, inflammation, increasing the amount of BDNF, and neurogenesis.


Assuntos
Ácido Ascórbico , Disfunção Cognitiva , Plasticidade Neuronal , Estresse Oxidativo , Estresse Psicológico , Animais , Masculino , Ácido Ascórbico/farmacologia , Estresse Psicológico/metabolismo , Estresse Psicológico/tratamento farmacológico , Ratos , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Plasticidade Neuronal/efeitos dos fármacos , Plasticidade Neuronal/fisiologia , Antioxidantes/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Ratos Wistar , Suplementos Nutricionais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Aprendizagem da Esquiva/efeitos dos fármacos
19.
Brain Res ; 1839: 149007, 2024 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-38763505

RESUMO

Alzheimer's disease (AD) is a common neurodegenerative disease. Previous studies have identified the critical role of astrocytes in the progression of AD. The focus of this study revolves around clarifying the regulatory mechanism of the STAT3/EZH2/BAI1 axis in astrocytes in AD. We successfully developed a rat model of AD, and measured the learning and cognitive ability of the rats by Morris water maze experiment. HE and Nissl's staining were used for histomorphological identification of the rat hippocampus. Meanwhile, immunofluorescence and immunohistochemistry were used to detect astrocyte activation and brain-specific angiogenesis inhibitor-1 (BAI1) expression in rat hippocampal tissue, respectively. The role of STAT3/EZH2/BAI1 regulating axis in astrocyte activation and neuronal cell apoptosis was verified by establishing the co-culture system of astrocytes and neuronal cells in vitro. Western Blot (WB) was used to detect the expression of associated proteins, and enzyme-linked immunosorbent assay (ELISA) was used to detect astrocyte neurotrophic factor secretion. Hochest/PI staining and flow cytometry were used to observe neuronal apoptosis. Compared with the sham group, AD rats showed significantly decreased cognitive and learning abilities, noticeable hippocampal tissue damage, and significantly low levels of BAI1 expression. In in vitro models, BAI1 was found to inhibit astrocyte activation and enhance the secretion of neurotrophins, resulting in decrease of neurone apoptosis. The regulation of BAI1 by the STAT3/EZH2 axis was shown to affect astrocyte activation and neuronal cell apoptosis. In conclusion, this study represents the pioneering discovery that regulated by the STAT3/EZH2 axis, BAI1 suppresses astrocyte activation, thus reducing neuronal apoptosis.


Assuntos
Doença de Alzheimer , Apoptose , Astrócitos , Proteína Potenciadora do Homólogo 2 de Zeste , Hipocampo , Neurônios , Ratos Sprague-Dawley , Fator de Transcrição STAT3 , Animais , Astrócitos/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Apoptose/fisiologia , Fator de Transcrição STAT3/metabolismo , Ratos , Neurônios/metabolismo , Hipocampo/metabolismo , Hipocampo/patologia , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Masculino , Modelos Animais de Doenças , Proteínas Angiogênicas/metabolismo , Aprendizagem em Labirinto/fisiologia , Técnicas de Cocultura , Transdução de Sinais/fisiologia
20.
Neurobiol Learn Mem ; 212: 107938, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38772444

RESUMO

Insulin is transported across the blood-brain barrier (BBB) endothelium to regulate aspects of metabolism and cognition. Brain insulin resistance often results from high-fat diet (HFD) consumption and is thought to contribute to spatial cognition deficits. To target BBB insulin function, we used Cre-LoxP genetic excision of the insulin receptor (InsR) from endothelial cells in adult male mice. We hypothesized that this excision would impair spatial cognition, and that high-fat diet consumption would exacerbate these effects. Excision of the endothelial InsR did not impair performance in two spatial cognition tasks, the Y-Maze and Morris Water Maze, in tests held both before and after 14 weeks of access to high-fat (or chow control) diet. The HFD increased body weight gain and induced glucose intolerance but did not impair spatial cognition. Endothelial InsR excision tended to increase body weight and reduce sensitivity to peripheral insulin, but these metabolic effects were not associated with impairments to spatial cognition and did not interact with HFD exposure. Instead, all mice showed intact spatial cognitive performance regardless of whether they had been fed chow or a HFD, and whether the InsR had been excised or not. Overall, the results indicate that loss of the endothelial InsR does not impact spatial cognition, which is in line with pharmacological evidence that other mechanisms at the BBB facilitate insulin transport and allow it to exert its pro-cognitive effects.


Assuntos
Barreira Hematoencefálica , Cognição , Dieta Hiperlipídica , Receptor de Insulina , Animais , Receptor de Insulina/metabolismo , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos , Masculino , Camundongos , Cognição/fisiologia , Cognição/efeitos dos fármacos , Resistência à Insulina/fisiologia , Células Endoteliais/metabolismo , Aprendizagem em Labirinto/fisiologia , Camundongos Endogâmicos C57BL
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