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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.
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
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.
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
5.
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
6.
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
7.
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
8.
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
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.
Neuropharmacology ; 253: 109982, 2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-38701943

RESUMO

Perioperative neurocognitive disorders (PND) are cognitive dysfunctions that usually occur in elderly patients after anesthesia and surgery. Microglial overactivation is a key underlying mechanism. Interleukin-33 (IL-33) is a member of the IL-1 family that orchestrates microglial function. In the present study, we explored how IL-33, which regulates microglia, contributes to cognitive improvement in a male mouse model of PND. An exploratory laparotomy was performed to establish a PND model. The expression levels of IL-33 and its receptor ST2 were evaluated using Western blot. IL-33/ST2 secretion, microglial density, morphology, phagocytosis of synapse, and proliferation, and dystrophic microglia were assessed using immunofluorescence. Synaptic plasticity was measured using Golgi staining and long-term potentiation. The Morris water maze and open field test were used to evaluate cognitive function and anxiety. Hippocampal expression of IL-33 and ST2 were elevated on postoperative day 3. We confirmed that IL-33 was secreted by astrocytes and neurons, whereas ST2 mainly colocalized with microglia. IL-33 treatment induced microgliosis after anesthesia and surgery. These microglia had larger soma sizes and shorter and fragmented branches. Compared to the Surgery group, IL-33 treatment reduced the synaptic phagocytosis of microglia and increased microglial proliferation and dystrophic microglia. IL-33 treatment also reversed the impaired synaptic plasticity and cognitive function caused by anesthesia and surgery. In conclusion, these results indicate that IL-33 plays a key role in regulating microglial state and synaptic phagocytosis in a PND mouse model. IL-33 treatment has a therapeutic potential for improving cognitive dysfunction in PND.


Assuntos
Interleucina-33 , Camundongos Endogâmicos C57BL , Microglia , Animais , Microglia/efeitos dos fármacos , Microglia/metabolismo , Interleucina-33/metabolismo , Masculino , Camundongos , Plasticidade Neuronal/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Complicações Cognitivas Pós-Operatórias/metabolismo , Fagocitose/efeitos dos fármacos , Astrócitos/metabolismo , Astrócitos/efeitos dos fármacos , Transtornos Neurocognitivos/metabolismo , Transtornos Neurocognitivos/tratamento farmacológico , Modelos Animais de Doenças , Neurônios/efeitos dos fármacos , Neurônios/metabolismo
11.
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 , Ansiedade/metabolismo , Camundongos , Depressão/fisiopatologia , Comportamento Animal/fisiologia , Hipocampo/metabolismo , Masculino , Proteínas Tirosina Quinases/metabolismo , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/deficiência , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças , Aprendizagem em Labirinto/fisiologia
12.
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
13.
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
14.
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
15.
Exp Brain Res ; 242(6): 1507-1515, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38719948

RESUMO

Alzheimer's disease is a progressive neurodegenerative disorder characterized by impairments in synaptic plasticity and cognitive performance. Current treatments are unable to achieve satisfactory therapeutic effects or reverse the progression of the disease. Calcineurin has been implicated as part of a critical signaling pathway for learning and memory, and neuronal calcineurin may be hyperactivated in AD. To investigate the effects and underlying mechanisms of FK506, a calcineurin inhibitor, on Alzheimer-like behavior and synaptic dysfunction in the 3 × Tg-AD transgenic mouse model of Alzheimer's disease, we investigated the effect of FK506 on cognitive function and synaptic plasticity in the 3 × Tg-AD transgenic mouse model of Alzheimer's disease. The results showed that FK506 treatment ameliorated cognitive deficits, as indicated by the decreased latency in the water maze, and attenuated tau hyperphosphorylation in 3 × Tg-AD mice. Treatment with FK506 also reduced the levels of certain markers of postsynaptic deficits, including PSD-95 and NR2B, and reversed the long-term potentiation deficiency and dendritic spine impairments in 3 × Tg-AD mice. These findings suggest that treatment with calcineurin inhibitors such as FK506 can be an effective therapeutic strategy to rescue synaptic deficit and cognitive impairment in familial Alzheimer's disease and related tauopathies.


Assuntos
Doença de Alzheimer , Inibidores de Calcineurina , Modelos Animais de Doenças , Camundongos Transgênicos , Tacrolimo , Animais , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Tacrolimo/farmacologia , Inibidores de Calcineurina/farmacologia , Camundongos , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Calcineurina/metabolismo , Plasticidade Neuronal/efeitos dos fármacos , Plasticidade Neuronal/fisiologia , Proteínas tau/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Masculino , Sinapses/efeitos dos fármacos , Sinapses/metabolismo , Proteína 4 Homóloga a Disks-Large/metabolismo
16.
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
17.
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
18.
J Comput Neurosci ; 52(2): 133-144, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38581476

RESUMO

Spatial navigation through novel spaces and to known goal locations recruits multiple integrated structures in the mammalian brain. Within this extended network, the hippocampus enables formation and retrieval of cognitive spatial maps and contributes to decision making at choice points. Exploration and navigation to known goal locations produce synchronous activity of hippocampal neurons resulting in rhythmic oscillation events in local networks. Power of specific oscillatory frequencies and numbers of these events recorded in local field potentials correlate with distinct cognitive aspects of spatial navigation. Typically, oscillatory power in brain circuits is analyzed with Fourier transforms or short-time Fourier methods, which involve assumptions about the signal that are likely not true and fail to succinctly capture potentially informative features. To avoid such assumptions, we applied a method that combines manifold discovery techniques with dynamical systems theory, namely diffusion maps and Takens' time-delay embedding theory, that avoids limitations seen in traditional methods. This method, called diffusion mapped delay coordinates (DMDC), when applied to hippocampal signals recorded from juvenile rats freely navigating a Y-maze, replicates some outcomes seen with standard approaches and identifies age differences in dynamic states that traditional analyses are unable to detect. Thus, DMDC may serve as a suitable complement to more traditional analyses of LFPs recorded from behaving subjects that may enhance information yield.


Assuntos
Hipocampo , Animais , Hipocampo/fisiologia , Masculino , Ratos , Ratos Long-Evans , Neurônios/fisiologia , Navegação Espacial/fisiologia , Aprendizagem em Labirinto/fisiologia , Modelos Neurológicos , Potenciais de Ação/fisiologia
19.
Behav Neurosci ; 138(2): 125-141, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38661671

RESUMO

Selenium is an essential trace element that is delivered to the brain by the selenium transport protein selenoprotein P (SEPP1), primarily by binding to its receptor low-density lipoprotein receptor-related protein 8 (LRP8), also known as apolipoprotein E receptor 2 (ApoER2), at the blood-brain barrier. Selenium transport is required for several important brain functions, with transgenic deletion of either Sepp1 or Lrp8 resulting in severe neurological dysfunction and death in mice fed a selenium-deficient diet. Previous studies have reported that although feeding a standard chow diet can prevent these severe deficits, some motor coordination and cognitive dysfunction remain. Importantly, no single study has directly compared the motor and cognitive performance of the Sepp1 and Lrp8 knockout (KO) lines. Here, we report the results of a comprehensive parallel analysis of the motor and spatial learning and memory function of Sepp1 and Lrp8 knockout mice fed a standard mouse chow diet. Our results revealed that Sepp1 knockout mice raised on a selenium-replete diet displayed motor and cognitive function that was indistinguishable from their wild-type littermates. In contrast, we found that although Lrp8-knockout mice fed a selenium-replete diet had normal motor function, their spatial learning and memory showed subtle deficits. We also found that the deficit in baseline adult hippocampal neurogenesis exhibited by Lrp8-deficit mice could not be rescued by dietary selenium supplementation. Taken together, these findings further highlight the importance of selenium transport in maintaining healthy brain function. (PsycInfo Database Record (c) 2024 APA, all rights reserved).


Assuntos
Proteínas Relacionadas a Receptor de LDL , Camundongos Knockout , Selênio , Aprendizagem Espacial , Animais , Camundongos , Dieta , Hipocampo/metabolismo , Proteínas Relacionadas a Receptor de LDL/genética , Proteínas Relacionadas a Receptor de LDL/metabolismo , Aprendizagem em Labirinto/fisiologia , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/fisiologia , Memória/efeitos dos fármacos , Selênio/administração & dosagem , Selênio/deficiência , Selênio/farmacologia , Selenoproteína P/genética , Selenoproteína P/metabolismo , Aprendizagem Espacial/fisiologia , Aprendizagem Espacial/efeitos dos fármacos , Memória Espacial/fisiologia , Memória Espacial/efeitos dos fármacos
20.
J Vis ; 24(4): 22, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38662347

RESUMO

Solving a maze effectively relies on both perception and cognition. Studying maze-solving behavior contributes to our knowledge about these important processes. Through psychophysical experiments and modeling simulations, we examine the role of peripheral vision, specifically visual crowding in the periphery, in mental maze-solving. Experiment 1 measured gaze patterns while varying maze complexity, revealing a direct relationship between visual complexity and maze-solving efficiency. Simulations of the maze-solving task using a peripheral vision model confirmed the observed crowding effects while making an intriguing prediction that saccades provide a conservative measure of how far ahead observers can perceive the path. Experiment 2 confirms that observers can judge whether a point lies on the path at considerably greater distances than their average saccade. Taken together, our findings demonstrate that peripheral vision plays a key role in mental maze-solving.


Assuntos
Resolução de Problemas , Movimentos Sacádicos , Humanos , Resolução de Problemas/fisiologia , Movimentos Sacádicos/fisiologia , Campos Visuais/fisiologia , Aprendizagem em Labirinto/fisiologia , Masculino , Adulto Jovem , Psicofísica/métodos , Estimulação Luminosa/métodos , Feminino , Adulto , Percepção Visual/fisiologia
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