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1.
Biomed Pharmacother ; 149: 112897, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35378503

RESUMO

A great number of pediatric patients undergoing varied procedures make neonatal surgery plus anesthesia become a matter of great concern owing to underlying neurotoxicity in developing brain. The authors set out to assess long-term effects of surgery plus anesthesia in mouse model. Six-day-old C57BL/6 mice were randomized to receive either anesthesia with 3% sevoflurane, abdominal surgery under the same anesthesia, or the control condition. These mice were examined of learning and memory at juvenile age in Morris water maze test. The brain tissues of mice were harvested for Western blot analysis, including purinergic receptors P2X family, CaMKII and NF-κB. Another battery of mice were administered with inhibitors of P2RX2/3 (e.g., A317491) into hippocampal dentate gyrus before behavioral testing. We found that neonatal surgery plus anesthesia, but not sevoflurane anesthesia alone, impaired the learning and memory of juvenile mice, as evidenced by delayed escape latency and reduced platform-crossing times. Immunoblotting analysis showed that behavioral abnormalities were associated with increased levels of P2RX2, phosphorylated-CaMKIIß and activated NF-κB in mouse hippocampus. Injection of A317491 ameliorated the impaired learning and memory of juvenile mice undergoing neonatal surgery plus anesthesia, and it also mitigated the neonatal surgery-induced signaling enhancement of P2RX2/CaMKII/NF-κB. Together, these results indicate that neonatal surgery plus anesthesia may cause long-term cognitive dysfunction, with potential mechanism of increasing P2RX2 and downstream signaling of phosphorylated-CaMKII and NF-κB. Our findings will promote more studies to assess detrimental effects of surgery and accompanying inflammation, diverse anesthetics and even sleeping deprivation on mouse neurodevelopment and neurobehavioral performance.


Assuntos
Anestesia , Hipocampo , Aprendizagem em Labirinto , Transtornos da Memória , Anestesia/efeitos adversos , Animais , Animais Recém-Nascidos , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina , Hipocampo/efeitos dos fármacos , Hipocampo/fisiopatologia , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Transtornos da Memória/epidemiologia , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Receptores Purinérgicos P2X2 , Sevoflurano/farmacologia
2.
Cell Mol Life Sci ; 79(3): 180, 2022 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-35254515

RESUMO

Abnormal mossy fiber connections in the hippocampus have been implicated in schizophrenia. However, it remains unclear whether this abnormality in the patients is genetically determined and whether it contributes to the onset of schizophrenia. Here, we showed that iPSC-derived hippocampal NPCs from schizophrenia patients with the A/A allele at SNP rs16864067 exhibited abnormal NPC polarity, resulting from the downregulation of SOX11 by this high-risk allele. In the SOX11-deficient mouse brain, abnormal NPC polarity was also observed in the hippocampal dentate gyrus, and this abnormal NPC polarity led to defective hippocampal neurogenesis-specifically, irregular neuroblast distribution and disrupted granule cell morphology. As granule cell synapses, the mossy fiber pathway was disrupted, and this disruption was resistant to activity-induced mossy fiber remodeling in SOX11 mutant mice. Moreover, these mutant mice exhibited diminished PPI and schizophrenia-like behaviors. Activation of hippocampal neurogenesis in the embryonic brain, but not in the adult brain, partially alleviated disrupted mossy fiber connections and improved schizophrenia-related behaviors in mutant mice. We conclude that disrupted mossy fiber connections are genetically determined and strongly correlated with schizophrenia-like behaviors in SOX11-deficient mice. This disruption may reflect the pathological substrate of SOX11-associated schizophrenia.


Assuntos
Fibras Musgosas Hipocampais/metabolismo , Neurogênese , Fatores de Transcrição SOXC/fisiologia , Esquizofrenia/metabolismo , Animais , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Camundongos , Camundongos Transgênicos , Fibras Musgosas Hipocampais/fisiopatologia , Fatores de Transcrição SOXC/genética , Esquizofrenia/fisiopatologia , Sinapses
3.
J Integr Neurosci ; 21(1): 6, 2022 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-35164442

RESUMO

Insulin is known to act in the central nervous system to regulate several physiological and behavioural outcomes, including energy balance, glucose homeostasis and cognitive functioning. However, the neuronal populations through which insulin enhances cognitive performance remain unidentified. Insulin receptors are found in neuropeptide-Y (NPY) expressing neurons, which are abundant in the hypothalamus and hippocampus; regions involved in feeding behaviour and spatial memory, respectively. Here we show that mice with a tissue specific knockout of insulin receptors in NPY expressing neurons (IRl⁢o⁢x/l⁢o⁢x; NPYC⁢r⁢e⁣/+) display an impaired performance in the probe trial of the Morris Water Maze compared with control mice at both the 6 and the 12, but not at the 24 months time point, consistent with a crucial role of insulin and NPY in cognitive functioning. By 24 months of age all groups demonstrated similar reductions in spatial memory performance. Together, these data suggest that the mechanisms through which insulin influences cognitive functioning are, at least in part, via insulin receptor signaling in NPY expressing neurons. These results also highlight that cognitive impairments observed in aging may be due to impaired insulin signaling.


Assuntos
Envelhecimento/fisiologia , Disfunção Cognitiva , Hipocampo , Neurônios/metabolismo , Neuropeptídeo Y/metabolismo , Receptor de Insulina/fisiologia , Envelhecimento/metabolismo , Animais , Comportamento Animal/fisiologia , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/fisiopatologia , Modelos Animais de Doenças , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptor de Insulina/deficiência , Memória Espacial/fisiologia
4.
Nat Commun ; 13(1): 787, 2022 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-35136052

RESUMO

The hippocampus is critical to the temporal organization of our experiences. Although this fundamental capacity is conserved across modalities and species, its underlying neuronal mechanisms remain unclear. Here we recorded hippocampal activity as rats remembered an extended sequence of nonspatial events unfolding over several seconds, as in daily life episodes in humans. We then developed statistical machine learning methods to analyze the ensemble activity and discovered forms of sequential organization and coding important for order memory judgments. Specifically, we found that hippocampal ensembles provide significant temporal coding throughout nonspatial event sequences, differentiate distinct types of task-critical information sequentially within events, and exhibit theta-associated reactivation of the sequential relationships among events. We also demonstrate that nonspatial event representations are sequentially organized within individual theta cycles and precess across successive cycles. These findings suggest a fundamental function of the hippocampal network is to encode, preserve, and predict the sequential order of experiences.


Assuntos
Hipocampo/fisiopatologia , Memória , Estimulação Acústica/métodos , Animais , Percepção Auditiva , Eletrodos Implantados , Aprendizado de Máquina , Masculino , Modelos Animais , Rede Nervosa/fisiologia , Odorantes , Percepção Olfatória , Ratos , Técnicas Estereotáxicas , Fatores de Tempo
5.
J Biosci ; 472022.
Artigo em Inglês | MEDLINE | ID: mdl-35092409

RESUMO

Depression is characterized by indifferent and slow thinking, leading to highly unfavorable social and economic burden. Hydroxysafflor yellow A (HSYA) is a traditional Chinese medicine and has many pharmacological properties, such as anti-oxidative and anti-inflammatory activities. However, the underlying mechanism unraveling the effect of HSYA on depression is still unclear. Here, depression animal model was established. It was demonstrated that HSYA improved depressive behavior in rat model of depression, which increased horizontal movement, vertical movement, sucrose percent index and decreased immobility of depressed rats. Moreover, HSYA inhibited the activation of HPA signaling, inflammation and oxidative stress in brain of depressed rats. HSYA played an opposite effect on production of chronic unpredicted mild stress (CUMS)-induced pro-inflammatory cytokines (TNF-α, IL-6 and IL-1ß). CUMS increased MDA expression but decreased SOD and GSH-Px expression, which were reversed by HSYA treatment. Furthermore, HSYA exerted a suppressive role in TLR4/NF-jB signaling pathway in brain of depressed rats. In conclusion, these findings indicted that HSYA can improve depressive behavior through inhibiting HPA signaling, repressing hippocampal inflammation and oxidative stress, which will provide a new therapeutic method for treating depression.


Assuntos
Chalcona/análogos & derivados , Transtorno Depressivo/tratamento farmacológico , Encefalite/tratamento farmacológico , Hipocampo/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Quinonas/farmacologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Chalcona/farmacologia , Citocinas/metabolismo , Transtorno Depressivo/metabolismo , Modelos Animais de Doenças , Encefalite/metabolismo , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Masculino , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Ratos Wistar , Receptor 4 Toll-Like/metabolismo
6.
Toxins (Basel) ; 14(1)2022 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-35051025

RESUMO

Chronic exposure to the mycotoxin deoxynivalenol (DON) from grain-based food and feed affects human and animal health. Known consequences include entereopathogenic and immunotoxic defects; however, the neurotoxic potential of DON has only come into focus more recently due to the observation of behavioural disorders in exposed farm animals. DON can cross the blood-brain barrier and interfere with the homeostasis/functioning of the nervous system, but the underlying mechanisms of action remain elusive. Here, we have investigated the impact of DON on mouse astrocyte and microglia cell lines, as well as on primary hippocampal cultures by analysing different toxicological endpoints. We found that DON has an impact on the viability of both glial cell types, as shown by a significant decrease of metabolic activity, and a notable cytotoxic effect, which was stronger in the microglia. In astrocytes, DON caused a G1 phase arrest in the cell cycle and a decrease of cyclic-adenosine monophosphate (cAMP) levels. The pro-inflammatory cytokine tumour necrosis factor (TNF)-α was secreted in the microglia in response to DON exposure. Furthermore, the intermediate filaments of the astrocytic cytoskeleton were disturbed in primary hippocampal cultures, and the dendrite lengths of neurons were shortened. The combined results indicated DON's considerable potential to interfere with the brain cell physiology, which helps explain the observed in vivo neurotoxicological effects.


Assuntos
Astrócitos/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Microglia/efeitos dos fármacos , Neurotoxinas/farmacologia , Tricotecenos/farmacologia , Animais , Astrócitos/patologia , Linhagem Celular , Hipocampo/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Microglia/patologia
7.
Nat Commun ; 13(1): 161, 2022 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-35013317

RESUMO

Dravet syndrome is a severe epileptic encephalopathy caused primarily by haploinsufficiency of the SCN1A gene. Repetitive seizures can lead to endurable and untreatable neurological deficits. Whether this severe pathology is reversible after symptom onset remains unknown. To address this question, we generated a Scn1a conditional knock-in mouse model (Scn1a Stop/+) in which Scn1a expression can be re-activated on-demand during the mouse lifetime. Scn1a gene disruption leads to the development of seizures, often associated with sudden unexpected death in epilepsy (SUDEP) and behavioral alterations including hyperactivity, social interaction deficits and cognitive impairment starting from the second/third week of age. However, we showed that Scn1a gene re-activation when symptoms were already manifested (P30) led to a complete rescue of both spontaneous and thermic inducible seizures, marked amelioration of behavioral abnormalities and normalization of hippocampal fast-spiking interneuron firing. We also identified dramatic gene expression alterations, including those associated with astrogliosis in Dravet syndrome mice, that, accordingly, were rescued by Scn1a gene expression normalization at P30. Interestingly, regaining of Nav1.1 physiological level rescued seizures also in adult Dravet syndrome mice (P90) after months of repetitive attacks. Overall, these findings represent a solid proof-of-concept highlighting that disease phenotype reversibility can be achieved when Scn1a gene activity is efficiently reconstituted in brain cells.


Assuntos
Disfunção Cognitiva/genética , Epilepsias Mioclônicas/genética , Hipocampo/metabolismo , Interneurônios/metabolismo , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Morte Súbita Inesperada na Epilepsia/prevenção & controle , Potenciais de Ação/fisiologia , Animais , Cerebelo/metabolismo , Cerebelo/fisiopatologia , Córtex Cerebral/metabolismo , Córtex Cerebral/fisiopatologia , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/fisiopatologia , Disfunção Cognitiva/prevenção & controle , Corpo Estriado/metabolismo , Corpo Estriado/fisiopatologia , Dependovirus/genética , Dependovirus/metabolismo , Modelos Animais de Doenças , Epilepsias Mioclônicas/metabolismo , Epilepsias Mioclônicas/fisiopatologia , Epilepsias Mioclônicas/prevenção & controle , Técnicas de Introdução de Genes , Terapia Genética/métodos , Hipocampo/fisiopatologia , Humanos , Interneurônios/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Canal de Sódio Disparado por Voltagem NAV1.1/deficiência , Morte Súbita Inesperada na Epilepsia/patologia
8.
Proc Natl Acad Sci U S A ; 119(4)2022 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-35074912

RESUMO

Balanced synaptic inhibition, controlled by multiple synaptic adhesion proteins, is critical for proper brain function. MDGA1 (meprin, A-5 protein, and receptor protein-tyrosine phosphatase mu [MAM] domain-containing glycosylphosphatidylinositol anchor protein 1) suppresses synaptic inhibition in mammalian neurons, yet the molecular mechanisms underlying MDGA1-mediated negative regulation of GABAergic synapses remain unresolved. Here, we show that the MDGA1 MAM domain directly interacts with the extension domain of amyloid precursor protein (APP). Strikingly, MDGA1-mediated synaptic disinhibition requires the MDGA1 MAM domain and is prominent at distal dendrites of hippocampal CA1 pyramidal neurons. Down-regulation of APP in presynaptic GABAergic interneurons specifically suppressed GABAergic, but not glutamatergic, synaptic transmission strength and inputs onto both the somatic and dendritic compartments of hippocampal CA1 pyramidal neurons. Moreover, APP deletion manifested differential effects in somatostatin- and parvalbumin-positive interneurons in the hippocampal CA1, resulting in distinct alterations in inhibitory synapse numbers, transmission, and excitability. The infusion of MDGA1 MAM protein mimicked postsynaptic MDGA1 gain-of-function phenotypes that involve the presence of presynaptic APP. The overexpression of MDGA1 wild type or MAM, but not MAM-deleted MDGA1, in the hippocampal CA1 impaired novel object-recognition memory in mice. Thus, our results establish unique roles of APP-MDGA1 complexes in hippocampal neural circuits, providing unprecedented insight into trans-synaptic mechanisms underlying differential tuning of neuronal compartment-specific synaptic inhibition.


Assuntos
Precursor de Proteína beta-Amiloide/metabolismo , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Moléculas de Adesão de Célula Nervosa/genética , Inibição Neural , Sinapses/metabolismo , Precursor de Proteína beta-Amiloide/genética , Região CA1 Hipocampal , Proteínas de Transporte , Dendritos/metabolismo , Neurônios GABAérgicos/metabolismo , Interneurônios , Modelos Biológicos , Moléculas de Adesão de Célula Nervosa/química , Moléculas de Adesão de Célula Nervosa/metabolismo , Inibição Neural/genética , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Células Piramidais/metabolismo , Receptores de GABA-B/metabolismo , Transmissão Sináptica
9.
Int J Mol Sci ; 23(2)2022 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-35055048

RESUMO

Exposure to repeated social stress may cause maladaptive emotional reactions that can be reduced by healthy nutritional supplementation. Histaminergic neurotransmission has a central role in orchestrating specific behavioural responses depending on the homeostatic state of a subject, but it remains to be established if it participates in the protective effects against the insults of chronic stress afforded by a healthy diet. By using C57BL/6J male mice that do not synthesize histamine (Hdc-/-) and their wild type (Hdc+/+) congeners we evaluated if the histaminergic system participates in the protective action of a diet enriched with polyunsaturated fatty acids and vitamin A on the deleterious effect of chronic stress. Behavioural tests across domains relevant to cognition and anxiety were performed. Hippocampal synaptic plasticity, cytokine expression, hippocampal fatty acids, oxylipins and microbiota composition were also assessed. Chronic stress induced social avoidance, poor recognition memory, affected hippocampal long-term potentiation, changed the microbiota profile, brain cytokines, fatty acid and oxylipins composition of both Hdc-/- and Hdc+/+ mice. Dietary enrichment counteracted stress-induced deficits only in Hdc+/+ mice as histamine deficiency prevented almost all the diet-related beneficial effects. Interpretation: Our results reveal a previously unexplored and novel role for brain histamine as a mediator of many favorable effects of the enriched diet. These data present long-reaching perspectives in the field of nutritional neuropsychopharmacology.


Assuntos
Dieta , Disbiose , Microbioma Gastrointestinal , Histamina/metabolismo , Comportamento Social , Estresse Psicológico , Animais , Comportamento Animal , Biomarcadores , Peso Corporal , Citocinas/metabolismo , Ácidos Graxos/metabolismo , Expressão Gênica , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Locomoção , Masculino , Metagenoma , Metagenômica , Camundongos , Camundongos Knockout , Modelos Animais
10.
Am Fam Physician ; 105(1): 50-54, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-35029951

RESUMO

Transient global amnesia (TGA) is a clinical syndrome characterized by anterograde amnesia, mild retrograde amnesia, and confusion up to 24 hours. Most commonly seen in patients older than 50 years, TGA results from the temporary impairment of short-term memory formation. Clinically, patients have time disorientation and often ask repeated questions regarding the day's events. Vomiting, headache, blurry vision, dizziness, and nausea may be present. A physically or psychologically stressful precipitating event, such as emotional stress, significant physical exertion, exposure to extreme temperatures, high-altitude conditions, Valsalva maneuver, acute illness, or sexual intercourse, is often the cause. The pathophysiology of TGA is not well understood but may be related to impaired venous drainage of the hippocampus. The diagnosis is primarily clinical, but recent studies suggest that magnetic resonance imaging may be helpful. TGA is self-limited and resolves within 24 hours. There is no established treatment for episodes. The lifetime recurrence rate is 2.9% to 23.8%. Recent evidence suggests an association between TGA and migraine headaches as well as takotsubo cardiomyopathy. No apparent increased risk of cerebrovascular events occurs in patients who have had an episode of TGA. There is conflicting evidence as to whether an episode of TGA predisposes to future seizures or dementia.


Assuntos
Amnésia Global Transitória/diagnóstico , Amnésia Global Transitória/fisiopatologia , Adulto , Amnésia Global Transitória/epidemiologia , Coito , Confusão/epidemiologia , Feminino , Hipocampo/fisiopatologia , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Transtornos de Enxaqueca/epidemiologia , Esforço Físico , Fatores de Risco , Estresse Psicológico/epidemiologia , Cardiomiopatia de Takotsubo/epidemiologia , Fatores de Tempo
11.
PLoS One ; 17(1): e0262916, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35089938

RESUMO

The current study aimed to further address important questions regarding the therapeutic efficacy of omega-3 fatty acids for various behavioral and neuroimmune aspects of the Fmr1 phenotype. To address these questions, our experimental design utilized two different omega-3 fatty acid administration timepoints, compared to both standard laboratory chow controls ("Standard") and a diet controlling for the increase in fat content ("Control Fat"). In the first paradigm, post-weaning supplementation (after postnatal day 21) with the omega-3 fatty acid diet ("Omega-3") reversed deficits in startle threshold, but not deficits in prepulse inhibition, and the effect on startle threshold was not specific to the Omega-3 diet. However, post-weaning supplementation with both experimental diets also impaired acquisition of a fear response, recall of the fear memory and contextual fear conditioning compared to the Standard diet. The post-weaning Omega-3 diet reduced hippocampal expression of IL-6 and this reduction of IL-6 was significantly associated with diminished performance in the fear conditioning task. In the perinatal experimental paradigm, the Omega-3 diet attenuated hyperactivity and acquisition of a fear response. Additionally, perinatal exposure to the Control Fat diet (similar to a "Western" diet) further diminished nonsocial anxiety in the Fmr1 knockout. This study provides significant evidence that dietary fatty acids throughout the lifespan can significantly impact the behavioral and neuroimmune phenotype of the Fmr1 knockout model.


Assuntos
Ansiedade , Comportamento Animal/efeitos dos fármacos , Ácidos Graxos Ômega-3/farmacologia , Proteína do X Frágil de Retardo Mental/genética , Hipocampo , Aprendizagem em Labirinto/efeitos dos fármacos , Animais , Ansiedade/dietoterapia , Ansiedade/genética , Ansiedade/metabolismo , Ansiedade/fisiopatologia , Proteína do X Frágil de Retardo Mental/metabolismo , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Camundongos , Camundongos Knockout
12.
Cells ; 11(2)2022 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-35053360

RESUMO

Alzheimer's disease (AD) is characterized by deficits in learning and memory. A pathological feature of AD is the alterations in the number and size of synapses, axon length, dendritic complexity, and dendritic spine numbers in the hippocampus and prefrontal cortex. Treadmill exercise can enhance synaptic plasticity in mouse or rat models of stroke, ischemia, and dementia. The aim of this study was to examine the effects of treadmill exercise on learning and memory, and structural synaptic plasticity in 3×Tg-AD mice, a mouse model of AD. Here, we show that 12 weeks treadmill exercise beginning in three-month-old mice improves spatial working memory in six-month-old 3×Tg-AD mice, while non-exercise six-month-old 3×Tg-AD mice exhibited impaired spatial working memory. To investigate potential mechanisms for the treadmill exercise-induced improvement of spatial learning and memory, we examined structural synaptic plasticity in the hippocampus and prefrontal cortex of six-month-old 3×Tg-AD mice that had undergone 12 weeks of treadmill exercise. We found that treadmill exercise led to increases in synapse numbers, synaptic structural parameters, the expression of synaptophysin (Syn, a presynaptic marker), the axon length, dendritic complexity, and the number of dendritic spines in 3×Tg-AD mice and restored these parameters to similar levels of non-Tg control mice without treadmill exercise. In addition, treadmill exercise also improved these parameters in non-Tg control mice. Strengthening structural synaptic plasticity may represent a potential mechanism by which treadmill exercise prevents decline in spatial learning and memory and synapse loss in 3×Tg-AD mice.


Assuntos
Hipocampo/fisiopatologia , Transtornos da Memória/prevenção & controle , Transtornos da Memória/fisiopatologia , Plasticidade Neuronal/fisiologia , Condicionamento Físico Animal , Córtex Pré-Frontal/fisiopatologia , Aprendizagem Espacial , Animais , Axônios/metabolismo , Espinhas Dendríticas/metabolismo , Proteína 4 Homóloga a Disks-Large/metabolismo , Hipocampo/metabolismo , Masculino , Camundongos Transgênicos , Córtex Pré-Frontal/metabolismo , Sinapses/patologia , Sinaptofisina/metabolismo
13.
J Neurophysiol ; 127(2): 393-396, 2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-34986048

RESUMO

Epilepsy is often labeled as a network disorder, though a common view of seizures holds that they initiate in a singular onset zone before expanding contiguously outward. A recent report by Choy et al. (Choy M, Dadgar-Kiani E, Cron GO, Duffy BA, Schmid F, Edelman BJ, Asaad M, Chan RW, Vahdat S, Lee JH. Neuron 2021 Oct 23: S0896-6273(21)00778-9.) leverages new tools to study whole brain dynamics during epileptic seizures originating in the hippocampus. Cell-type-specific kindling and functional imaging revealed how various brain regions were recruited to seizures and uncovered a novel form of migrating seizure core.


Assuntos
Epilepsia , Excitação Neurológica , Encéfalo/fisiopatologia , Epilepsia/fisiopatologia , Hipocampo/fisiopatologia , Humanos , Excitação Neurológica/fisiologia , Optogenética , Convulsões/fisiopatologia
14.
Neural Plast ; 2022: 9959044, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35075360

RESUMO

The mammalian hippocampal dentate gyrus is a niche for adult neurogenesis from neural stem cells. Newborn neurons integrate into existing neuronal networks, where they play a key role in hippocampal functions, including learning and memory. In the ageing brain, neurogenic capability progressively declines while in parallel increases the risk for developing Alzheimer's disease (AD), the main neurodegenerative disorder associated with memory loss. Numerous studies have investigated whether impaired adult neurogenesis contributes to memory decline in AD. Here, we review the literature on adult hippocampal neurogenesis (AHN) and AD by focusing on both human and mouse model studies. First, we describe key steps of AHN, report recent evidence of this phenomenon in humans, and describe the specific contribution of newborn neurons to memory, as evinced by animal studies. Next, we review articles investigating AHN in AD patients and critically examine the discrepancies among different studies over the last two decades. Also, we summarize researches investigating AHN in AD mouse models, and from these studies, we extrapolate the contribution of molecular factors linking AD-related changes to impaired neurogenesis. Lastly, we examine animal studies that link impaired neurogenesis to specific memory dysfunctions in AD and review treatments that have the potential to rescue memory capacities in AD by stimulating AHN.


Assuntos
Doença de Alzheimer/fisiopatologia , Hipocampo/fisiopatologia , Memória/fisiologia , Neurogênese/fisiologia , Animais , Humanos , Células-Tronco Neurais/fisiologia , Neurônios/fisiologia
15.
Oxid Med Cell Longev ; 2022: 8295580, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35087621

RESUMO

This study was designed to explore the potential mechanisms of electroacupuncture (EA) in treating inflammatory bowel disease- (IBD-) related anxiety and mood disorders. A colitis model was induced in rats with 2, 4, 6-trinitrohydrosulfonic acid (TNBS), followed by ST36 and SP6 targeted therapy by EA or sham EA treatment. The elevated plus maze (EPM) and open-field test (OFT) were performed to assess the state of anxiety and depression-like behavior. Tests were carried out by 16S rDNA amplification sequence, 1H nuclear magnetic resonance (1H NMR) spectroscopy, immunofluorescence staining, and enzyme-linked immunosorbent assay (ELISA). The analyses detailed metabolic alterations and the Toll-like receptor 4 (TLR4) signaling pathway/NOD-like receptor protein 3 (NLRP3) inflammasome in rats' hippocampal region. Furthermore, the activity of the hypothalamic-pituitary adrenal (HPA) axis and gut microbiome was assessed. As a result of treatment, EA significantly improved in the behavioral tests and altered the composition of the gut microbiome through a significant increase in the density of short chain fatty acids (SCFAs) producers mainly including Ruminococcaceae, Phascolarctobacterium, and Akkermansiaceae. EA upregulated the metabolites of the hippocampus mainly containing l-glutamine and gamma-aminobutyric acid (GABA), as well as ZO-1 expression. Whereas the treatment blocked the TLR4/nuclear factor- kappa B (NF-κB) signaling pathways and NLRP3 inflammasomes, along with downregulating the interleukin- (IL-) 1ß level. The hyperactivity of the HPA axis was also diminished. In conclusion, EA at ST36 and SP6 attenuated anxiety and depression-like behavior in colitis model rats through their effects on the gut microbiome by modulating the hippocampal inflammatory response and metabolic disorders, as well as the HPA axis. This study provides evidence for clinical application of EA to serve as an adjunctive treatment for IBD-related anxiety and depression.


Assuntos
Ansiedade/terapia , Encefalopatias Metabólicas/fisiopatologia , Depressão/terapia , Eletroacupuntura/métodos , Hipocampo/fisiopatologia , Inflamação/fisiopatologia , Doenças Inflamatórias Intestinais/terapia , Animais , Masculino , Ratos , Ratos Sprague-Dawley
16.
Toxicology ; 465: 153052, 2022 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-34838597

RESUMO

Bisphenol-A (BPA), an environmental endocrine disruptor, is toxic to the central nervous system. Although recent studies have shown BPA-induced neurotoxicity, it is far from clear what precisely epigenetic mechanisms are involved in BPA-induced cognitive deficits. In this study, pheochromocytoma (PC12) cells were treated with BPA at 1 µM for 36 h in vitro. In vivo, C57BL/6 mice were administered to BPA at a dose of 1 mg/kg/day for 10 weeks. The results showed that 1 µM BPA exposure for 36 h impaired neurite outgrowth of PC12 cells through decreasing the primary and secondary branches. Besides, BPA exposure decreased the level of Ac-H3K9 (histone H3 Lys9 acetylation) by upregulating the expression of HDAC2 (histone deacetylases 2) in PC12 cells. Furthermore, treatment of both TSA (Trichostatin A, inhibitor of the histone deacetylase) and shHDAC2 plasmid (HDAC2 knockdown construct) resulted in amelioration neurite outgrowth deficits induced by BPA. In addition, it was shown that repression of HDAC2 could markedly rescue the spine density impairment in the hippocampus and prevent the cognitive impairment caused by BPA exposure in mice. Collectively, HDAC2 plays an essential role in BPA-induced neurotoxicity, which provides a potential molecular target for medical intervention.


Assuntos
Compostos Benzidrílicos/toxicidade , Espinhas Dendríticas/efeitos dos fármacos , Poluentes Ambientais/toxicidade , Hipocampo/efeitos dos fármacos , Histona Desacetilase 2/metabolismo , Neuritos/efeitos dos fármacos , Síndromes Neurotóxicas/etiologia , Fenóis/toxicidade , Animais , Comportamento Animal/efeitos dos fármacos , Cognição/efeitos dos fármacos , Espinhas Dendríticas/enzimologia , Espinhas Dendríticas/patologia , Feminino , Hipocampo/enzimologia , Hipocampo/patologia , Hipocampo/fisiopatologia , Histona Desacetilase 2/genética , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Neuritos/enzimologia , Neuritos/patologia , Crescimento Neuronal/efeitos dos fármacos , Síndromes Neurotóxicas/enzimologia , Síndromes Neurotóxicas/patologia , Síndromes Neurotóxicas/fisiopatologia , Células PC12 , Ratos , Regulação para Cima
17.
Aging Cell ; 21(1): e13521, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34894056

RESUMO

The increase in senescent cells in tissues, including the brain, is a general feature of normal aging and age-related pathologies. Senescent cells exhibit a specific phenotype, which includes an altered nuclear morphology and transcriptomic changes. Astrocytes undergo senescence in vitro and in age-associated neurodegenerative diseases, but little is known about whether this process also occurs in physiological aging, as well as its functional implication. Here, we investigated astrocyte senescence in vitro, in old mouse brains, and in post-mortem human brain tissue of elderly. We identified a significant loss of lamin-B1, a major component of the nuclear lamina, as a hallmark of senescent astrocytes. We showed a severe reduction of lamin-B1 in the dentate gyrus of aged mice, including in hippocampal astrocytes, and in the granular cell layer of the hippocampus of post-mortem human tissue from non-demented elderly. The lamin-B1 reduction was associated with nuclear deformations, represented by an increased incidence of invaginated nuclei and loss of nuclear circularity in senescent astrocytes in vitro and in the aging human hippocampus. We also found differences in lamin-B1 levels and astrocyte nuclear morphology between the granular cell layer and polymorphic layer in the elderly human hippocampus, suggesting an intra-regional-dependent aging response of human astrocytes. Moreover, we described senescence-associated impaired neuritogenic and synaptogenic capacity of mouse astrocytes. Our findings show that reduction of lamin-B1 is a conserved feature of hippocampal cells aging, including astrocytes, and shed light on significant defects in nuclear lamina structure which may contribute to astrocyte dysfunctions during aging.


Assuntos
Astrócitos/metabolismo , Hipocampo/fisiopatologia , Lamina Tipo B/metabolismo , Animais , Senescência Celular , Humanos , Camundongos
18.
J Ethnopharmacol ; 286: 114871, 2022 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-34856360

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Alzheimer's disease (AD), the most common disease in the brain, is associated with cognitive and mitochondrial dysfunction. Emerging evidence suggests that endurance training and Syzygium aromaticum (L.) Merrill and Perry (Myrtaceae) (commonly referred to as clove) are effective interventions to maintain oxidative balance and improve cognitive function. AIM OF THE STUDY: The present study aimed to investigate the effect of endurance training and clove oil affect spatial memory, apoptosis, mitochondrial homeostasis, and cognitive function in Alzheimer's rats. MATERIALS AND METHODS: 81 rats were randomly assigned to 9 groups: Healthy (H), sham (sh), Healthy-exercise (HE), Healthy-clove (HC), Healthy-exercise-clove (HEC), Alzheimer's (A), Alzheimer's-exercise (AE), Alzheimer's-clove (AC), and Alzheimer's-exercise-clove (AEC). Alzheimer's induction was induced by the injection of 1-42 amyloid into the CA1 region of the hippocampus. The exercise training protocol was performed for 3 weeks, every day for 30 min in swimming training, and clove oil supplementation (0.1 mg/kg) was gavaged daily for 3 weeks in the supplement rat. Shuttle box test was used to measure spatial memory after the last training session, and to determine the mRNAs and protein levels and apoptosis, Real-Time PCR, immunofluorescent, and tunnel methods were used, respectively. RESULTS: Alzheimer's caused a significant decrease in the PRDX6 and GCN5L1 mRNAs and protein levels and a significant increase in apoptosis in the hippocampus of the Alzheimer's group compared to the control group (P = 0.001). Alzheimer's also reduced the time delay in entering the dark environment and increased the time spent in the dark environment (P = 0.001). Following endurance training and consumption of clove oil, spatial memory (P = 0.001), apoptosis (P = 0.001) and mRNAs and protein levels of PRDX6 (P = 0.001) and GCN5L1 (P = 0.017), were recovered in AE, AC and AEC groups, as compared with A group. CONCLUSION: Swimming training and consumption of clove can possibly be considered as an effective intervention to maintain oxidative balance and improve mitochondrial homeostasis in Alzheimer's disease.


Assuntos
Doença de Alzheimer/terapia , Condicionamento Físico Animal/métodos , Extratos Vegetais/farmacologia , Syzygium/química , Doença de Alzheimer/fisiopatologia , Animais , Apoptose/efeitos dos fármacos , Terapia Combinada , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Hipocampo/fisiopatologia , Masculino , Transtornos da Memória/fisiopatologia , Transtornos da Memória/terapia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Ratos , Ratos Wistar , Natação
19.
Neurosci Lett ; 770: 136354, 2022 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-34801642

RESUMO

Calcium Voltage-Gated Channel Subunit Alpha1 C (CACNA1C) is one of the most important genes associated with schizophrenia. In this study, 45 male Wistar rats were divided into 5 groups of saline, control, ketamine, clozapine, and risperidone. Animals in ketamine, risperidone, and clozapine groups received ketamine (30 mg/kg-i.p.) for 10 days. After the last injection of ketamine, we started injecting clozapine (7.5 mg/kg-i.p.), risperidone (1 mg/kg-i.p.), up to 28 days. Twenty-four hours after the last injection, open field, social interaction, and elevated plus-maze tests and gene expression in hippocampus were performed. The results of the social interaction test revealed a significant decrease in cumulative time with ketamine, compared with the saline group, and an increase with clozapine and risperidone compared with the ketamine group. Moreover, results from the elevated plus-maze test demonstrated a critical decrease in open arm time and increase in close arm time with ketamine compared with saline, as well as increased in open arm time with risperidone compared with ketamine. Further results revealed a significant increase in rearing and grooming with ketamine compared to saline, as well as a decrease with risperidone and clozapine compared to ketamine. There were no significant differences in CACNA1C gene expression between groups in the rat hippocampus. In brief, the results of this study indicated that clozapine and risperidone could partially improve cognitive impairments in the rat. However, our findings demonstrated that this treatment is not related to CACNA1C gene expression.


Assuntos
Antipsicóticos/farmacologia , Canais de Cálcio Tipo L/metabolismo , Clozapina/farmacologia , Hipocampo/efeitos dos fármacos , Risperidona/farmacologia , Esquizofrenia/metabolismo , Animais , Canais de Cálcio Tipo L/genética , Cognição , Antagonistas de Aminoácidos Excitatórios/toxicidade , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Ketamina/toxicidade , Masculino , Aprendizagem em Labirinto , Ratos , Ratos Wistar , Esquizofrenia/etiologia , Esquizofrenia/fisiopatologia , Comportamento Social
20.
Neurobiol Aging ; 110: 1-12, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34837869

RESUMO

Impaired memory is a hallmark of prodromal Alzheimer's disease (AD). Prior knowledge associated with the memoranda improves memory in healthy individuals, but we ignore whether the same occurs in early AD. We used functional MRI to investigate whether prior knowledge enhances memory encoding in early AD, and whether the nature of this prior knowledge matters. Patients with early AD and Controls underwent a task-based fMRI experiment where they learned face-scene associations. Famous faces carried pre-experimental knowledge (PEK), while unknown faces with which participants were familiarized prior to learning carried experimental knowledge (EK). Surprisingly, PEK strongly enhanced subsequent memory in healthy controls, but importantly not in patients. Partly nonoverlapping brain networks supported PEK vs. EK associative encoding in healthy controls. No such networks were identified in patients. In addition, patients displayed impaired activation in a right sub hippocampal region where activity predicted successful associative memory formation for PEK stimuli. Despite the limited sample sizes of this study, these findings suggest that the role prior knowledge in new learning might have been so far overlooked and underestimated in AD patients. Prior knowledge may drive critical differences in the way healthy elderly and early AD patients learn novel associations.


Assuntos
Doença de Alzheimer/fisiopatologia , Doença de Alzheimer/psicologia , Aprendizagem por Associação/fisiologia , Comportamento/fisiologia , Face/fisiologia , Hipocampo/fisiologia , Hipocampo/fisiopatologia , Conhecimento , Imageamento por Ressonância Magnética , Memória/fisiologia , Idade de Início , Idoso , Doença de Alzheimer/diagnóstico por imagem , Feminino , Envelhecimento Saudável/fisiologia , Envelhecimento Saudável/psicologia , Voluntários Saudáveis/psicologia , Humanos , Masculino , Estimulação Luminosa
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