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1.
Neurosci Lett ; 821: 137614, 2024 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-38159880

RESUMO

BACKGROUND: The vulnerability of hippocampal pyramidal (PY) neurons played a key role in the onset of cognitive impairment. Multiple researches revealed that neuroinflammation together with microglia activation and parvalbumin (PV) interneurons participated in the pathogenesis of cognitive dysfunction. However, the underlying mechanism was still unclear. This study aimed to determine whether microglia activation would induce PV interneurons impairment and PY neurons disinhibition, and as a result, promote cognitive dysfunction after lipopolysaccharide (LPS) challenge. METHODS: Male C57BL/6J mice were injected with LPS to establish systemic inflammation model, and animal behavioral tests were performed. For chemogenetics, the virus was injected bilaterally into the CA1 region. Clozapine N-Oxide (CNO) was used to activate the PV interneurons. Whole-cell patch clamp recording was applied to detect spontaneous inhibitory post synaptic current (sIPSC) and spontaneous excitatory post synaptic current (sEPSC) of PY neurons in the CA1 region. RESULTS: LPS induced hippocampal dependent memory impairment, which was accompanied with microglia activation. Meanwhile, PV protein level in hippocampus were decreased, and IPSCs of PY neurons in the CA1 were also suppressed. Minocycline reversed all the above changes. In addition, rescuing PV function with CNO improved memory impairment, sIPSCs of PY neurons and perisomatic PV boutons around PY neurons without affecting microglia activation. CONCLUSION: Disinhibition of hippocampal parvalbumin interneurons on pyramidal neurons participates in LPS-induced cognitive dysfunction.


Assuntos
Disfunção Cognitiva , Hipocampo , Interneurônios , Parvalbuminas , Células Piramidais , Animais , Masculino , Camundongos , Hipocampo/fisiopatologia , Interneurônios/fisiologia , Lipopolissacarídeos/farmacologia , Lipopolissacarídeos/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Parvalbuminas/metabolismo , Células Piramidais/fisiologia , Disfunção Cognitiva/fisiopatologia
2.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 39(7): 610-616, 2023 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-37403720

RESUMO

Objective To investigate the effects of formononetin (FMN) on cognitive behavior and inflammation in aging rats with chronic unpredictable mild stress (CUMS). Methods SD rats aged about 70 weeks were divided into healthy control group, CUMS model group, CUMS combined with 10 mg/kg FMN group, CUMS combined with 20 mg/kg FMN group and CUMS combined with 1.8 mg/kg fluoxetine hydrochloride (Flu) group. Except for healthy control group, other groups were stimulated with CUMS and administered drugs for 28 days. Sugar water preference, forced swimming experiment and open field experiment were used to observe the emotional behavior of rats in each group. HE staining was used to observe the pathological injury degree of brain equine area. The contents of 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) were detected by the kit. The apoptosis was tested by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) in the brain tissue. The levels of tumor necrosis factor α (TNF-α), inducible nitric oxide synthase (iNOS) and interleukin 6 (IL-6) in peripheral blood were measured by ELISA. Western blot analysis was used to detect Bcl2, Bcl2 associated X protein (BAX), cleaved caspase-9, cleaved caspase-3, Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), and phosphorylated nuclear factor κB p65 (p-NF-κB p65) in brain tissues. Results Compared with CUMS model group, sugar water consumption, open field activity time, open field travel distance and swimming activity time significantly increased in the CUMS combined with 20 mg/kg FMN group and the CUMS combined with 1.8 mg/kg Flu group. The number of new outarm entry increased significantly, while the number of initial arm entry and other arm entry decreased significantly. The pathological damage of brain equine area was alleviated, and the contents of 5-HT and 5-HIAA were significantly increased. The ratio of BAX/Bcl2 and the expression of cleaved caspase-9 and cleaved caspase-3 protein as well as the number of apoptotic cells were significantly decreased. The contents of TNF-α, iNOS and IL-6 were significantly decreased. The protein levels of TLR4, MyD88 and p-NF-κB p65 were significantly decreased. Conclusion FMN can inhibit the release of inflammatory factors by blocking NF-κB pathway and improve cognitive and behavioral ability of CUMS aged rats.


Assuntos
Comportamento Animal , Hipocampo , Isoflavonas , NF-kappa B , Transdução de Sinais , Estresse Fisiológico , Animais , Ratos , Cognição/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/fisiopatologia , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Isoflavonas/farmacologia , Envelhecimento , Comportamento Animal/efeitos dos fármacos , Estresse Fisiológico/efeitos dos fármacos , Anti-Inflamatórios/farmacologia
3.
Acta Neuropathol ; 146(3): 415-432, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37382680

RESUMO

Hippocampal sclerosis of aging (HS-A) is a common age-related neuropathological lesion characterized by neuronal loss and astrogliosis in subiculum and CA1 subfield of hippocampus. HS-A is associated with cognitive decline that mimics Alzheimer's disease. Pathological diagnosis of HS-A is traditionally binary based on presence/absence of the lesion. We compared this traditional measure against our novel quantitative measure for studying the relationship between HS-A and other neuropathologies and cognitive impairment. We included 409 participants from The 90+ study with neuropathological examination and longitudinal neuropsychological assessments. In those with HS-A, we examined digitized H&E and LFB stained hippocampal slides. The length of HS-A in each subfield of hippocampus and subiculum, each further divided into three subregions, was measured using Aperio eSlide Manager. For each subregion, the proportion affected by HS-A was calculated. Using regression models, both traditional/binary and quantitative measures were used to study the relationship between HS-A and other neuropathological changes and cognitive outcomes. HS-A was present in 48 (12%) of participants and was always focal, primarily affecting CA1 (73%), followed by subiculum (9%); overlapping pathology (subiculum and CA1) affected 18% of individuals. HS-A was more common in the left (82%) than the right (25%) hemisphere and was bilateral in 7% of participants. HS-A traditional/binary assessment was associated with limbic-predominant age-related TDP-43 encephalopathy (LATE-NC; OR = 3.45, p < 0.001) and aging-related tau astrogliopathy (ARTAG; OR = 2.72, p = 0.008). In contrast, our quantitative approach showed associations between the proportion of HS-A (CA1/subiculum/combined) and LATE-NC (p = 0.001) and arteriolosclerosis (p = 0.005). While traditional binary assessment of HS-A was associated with impaired memory (OR = 2.60, p = 0.007), calculations (OR = 2.16, p = 0.027), and orientation (OR = 3.56, p < 0.001), our quantitative approach revealed additional associations with impairments in language (OR = 1.33, p = 0.018) and visuospatial domains (OR = 1.37, p = 0.006). Our novel quantitative method revealed associations between HS-A and vascular pathologies and impairment in cognitive domains that were not detected using traditional/binary measures.


Assuntos
Envelhecimento , Disfunção Cognitiva , Esclerose Hipocampal , Hipocampo , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Envelhecimento/patologia , Cognição , Disfunção Cognitiva/patologia , Disfunção Cognitiva/fisiopatologia , Estudos de Coortes , Esclerose Hipocampal/patologia , Esclerose Hipocampal/fisiopatologia , Hipocampo/patologia , Hipocampo/fisiopatologia , Modelos Logísticos , Neuropatologia
4.
Sheng Li Xue Bao ; 75(2): 231-240, 2023 Apr 25.
Artigo em Chinês | MEDLINE | ID: mdl-37089097

RESUMO

Persistent neurogenesis exists in the subventricular zone (SVZ) of the ventricles and the subgranular zone (SGZ) of the dentate gyrus of the hippocampus in the adult mammalian brain. Adult endogenous neurogenesis not only plays an important role in the normal brain function, but also has important significance in the repair and treatment of brain injury or brain diseases. This article reviews the process of adult endogenous neurogenesis and its application in the repair of traumatic brain injury (TBI) or ischemic stroke, and discusses the strategies of activating adult endogenous neurogenesis to repair brain injury and its practical significance in promoting functional recovery after brain injury.


Assuntos
Hemorragia Encefálica Traumática , Encéfalo , AVC Isquêmico , Neurogênese , Adulto , Animais , Humanos , Encéfalo/fisiologia , Encéfalo/fisiopatologia , Hipocampo/fisiologia , Hipocampo/fisiopatologia , Mamíferos/fisiologia , Neurogênese/fisiologia , Hemorragia Encefálica Traumática/fisiopatologia , Hemorragia Encefálica Traumática/terapia , AVC Isquêmico/fisiopatologia , AVC Isquêmico/terapia , Recuperação de Função Fisiológica , Medula Espinal/fisiologia , Medula Espinal/fisiopatologia
5.
Neuropharmacology ; 225: 109373, 2023 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-36502868

RESUMO

Pathological accumulation of Aß oligomers has been linked to neuronal networks hyperexcitability, potentially underpinned by glutamatergic AMPA receptors (AMPARs) dysfunction. We aimed to investigate whether the non-competitive block of AMPARs was able to counteract the alteration of hippocampal epileptic threshold, and of synaptic plasticity linked to Aß oligomers accumulation, being this glutamate receptor a valuable specific therapeutic target. In this work, we showed that the non-competitive AMPARs antagonist perampanel (PER) which, per se, did not affect physiological synaptic transmission, was able to counteract Aß-induced hyperexcitability. Moreover, AMPAR antagonism was able to counteract Aß-induced hippocampal LTP impairment and hippocampal-based cognitive deficits in Aß oligomers-injected mice, while retaining antiseizure efficacy. Beside this, AMPAR antagonism was also able to reduce the increased expression of proinflammatory cytokines in this mice model, also suggesting the presence of an anti-inflammatory activity. Thus, targeting AMPARs might be a valuable strategy to reduce both hippocampal networks hyperexcitability and synaptic plasticity deficits induced by Aß oligomers accumulation.


Assuntos
Angiopatia Amiloide Cerebral , Disfunção Cognitiva , Antagonistas de Aminoácidos Excitatórios , Hipocampo , Receptores de AMPA , Animais , Camundongos , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico , Peptídeos beta-Amiloides/metabolismo , Cognição/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/fisiopatologia , Receptores de AMPA/antagonistas & inibidores , Angiopatia Amiloide Cerebral/terapia , Disfunção Cognitiva/terapia
6.
Acta Physiologica Sinica ; (6): 231-240, 2023.
Artigo em Chinês | WPRIM (Pacífico Ocidental) | ID: wpr-981000

RESUMO

Persistent neurogenesis exists in the subventricular zone (SVZ) of the ventricles and the subgranular zone (SGZ) of the dentate gyrus of the hippocampus in the adult mammalian brain. Adult endogenous neurogenesis not only plays an important role in the normal brain function, but also has important significance in the repair and treatment of brain injury or brain diseases. This article reviews the process of adult endogenous neurogenesis and its application in the repair of traumatic brain injury (TBI) or ischemic stroke, and discusses the strategies of activating adult endogenous neurogenesis to repair brain injury and its practical significance in promoting functional recovery after brain injury.


Assuntos
Adulto , Animais , Humanos , Encéfalo/fisiopatologia , Hipocampo/fisiopatologia , Mamíferos/fisiologia , Neurogênese/fisiologia , Hemorragia Encefálica Traumática/terapia , AVC Isquêmico/terapia , Recuperação de Função Fisiológica , Medula Espinal/fisiopatologia
7.
Transl Psychiatry ; 12(1): 507, 2022 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-36481769

RESUMO

Early-life stress (ELS) leads to increased vulnerability to psychiatric disorders including depression later in life. Neuroinflammatory processes have been implicated in ELS-induced negative health outcomes, but how ELS impacts microglia, the main tissue-resident macrophages of the central nervous system, is unknown. Here, we determined the effects of ELS-induced by limited bedding and nesting material during the first week of life (postnatal days [P]2-9) on microglial (i) morphology; (ii) hippocampal gene expression; and (iii) synaptosome phagocytic capacity in male pups (P9) and adult (P200) mice. The hippocampus of ELS-exposed adult mice displayed altered proportions of morphological subtypes of microglia, as well as microglial transcriptomic changes related to the tumor necrosis factor response and protein ubiquitination. ELS exposure leads to distinct gene expression profiles during microglial development from P9 to P200 and in response to an LPS challenge at P200. Functionally, synaptosomes from ELS-exposed mice were phagocytosed less by age-matched microglia. At P200, but not P9, ELS microglia showed reduced synaptosome phagocytic capacity when compared to control microglia. Lastly, we confirmed the ELS-induced increased expression of the phagocytosis-related gene GAS6 that we observed in mice, in the dentate gyrus of individuals with a history of child abuse using in situ hybridization. These findings reveal persistent effects of ELS on microglial function and suggest that altered microglial phagocytic capacity is a key contributor to ELS-induced phenotypes.


Assuntos
Experiências Adversas da Infância , Maus-Tratos Infantis , Microglia , Animais , Criança , Masculino , Camundongos , Transcriptoma , Humanos , Microglia/patologia , Fagocitose , Sinaptossomos , Hipocampo/fisiopatologia , Giro Denteado/fisiopatologia
8.
Sci Rep ; 12(1): 21022, 2022 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-36471155

RESUMO

The Alzheimer's disease-associated peptide amyloid-beta (Aß) has been associated with neuronal hyperactivity under anesthesia, but clinical trials of anticonvulsants or neural system suppressors have, so far, failed to improve symptoms in AD. Using simultaneous hippocampal calcium imaging and electrophysiology in freely moving mice expressing human Aß, here we show that Aß aggregates perturbed neural systems in a state-dependent fashion, driving neuronal hyperactivity in exploratory behavior and slow wave sleep (SWS), yet suppressing activity in quiet wakefulness (QW) and REM sleep. In exploratory behavior and REM sleep, Aß impaired hippocampal theta-gamma phase-amplitude coupling and altered neuronal synchronization with theta. In SWS, Aß reduced cortical slow oscillation (SO) power, the coordination of hippocampal sharp wave-ripples with both the SO and thalamocortical spindles, and the coordination of calcium transients with the sharp wave-ripple. Physostigmine improved Aß-associated hyperactivity in exploratory behavior and hypoactivity in QW and expanded the range of gamma that coupled with theta phase, but exacerbated hypoactivity in exploratory behavior. Together, these findings show that the effects of Aß alone on hippocampal circuit function are profoundly state dependent and suggest a reformulation of therapeutic strategies aimed at Aß induced hyperexcitability.


Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Hipocampo , Animais , Humanos , Camundongos , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/metabolismo , Cálcio/metabolismo , Modelos Animais de Doenças , Hipocampo/fisiopatologia , Camundongos Transgênicos
9.
Proc Natl Acad Sci U S A ; 119(31): e2204901119, 2022 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-35881790

RESUMO

Although a wide variety of genetic tools has been developed to study learning and memory, the molecular basis of memory encoding remains incompletely understood. Here, we undertook an unbiased approach to identify novel genes critical for memory encoding. From a large-scale, in vivo mutagenesis screen using contextual fear conditioning, we isolated in mice a mutant, named Clueless, with spatial learning deficits. A causative missense mutation (G434V) was found in the voltage-gated potassium channel, subfamily C member 3 (Kcnc3) gene in a region that encodes a transmembrane voltage sensor. Generation of a Kcnc3G434V CRISPR mutant mouse confirmed this mutation as the cause of the learning defects. While G434V had no effect on transcription, translation, or trafficking of the channel, electrophysiological analysis of the G434V mutant channel revealed a complete loss of voltage-gated conductance, a broadening of the action potential, and decreased neuronal firing. Together, our findings have revealed a role for Kcnc3 in learning and memory.


Assuntos
Hipocampo , Deficiências da Aprendizagem , Memória , Mutação de Sentido Incorreto , Canais de Potássio Shaw , Potenciais de Ação/fisiologia , Animais , Hipocampo/fisiopatologia , Deficiências da Aprendizagem/genética , Camundongos , Camundongos Endogâmicos C57BL , Canais de Potássio Shaw/genética , Canais de Potássio Shaw/fisiologia
10.
Proc Natl Acad Sci U S A ; 119(28): e2206415119, 2022 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-35867768

RESUMO

Chemotherapy-induced cognitive impairment (CICI) has emerged as a significant medical problem without therapeutic options. Using the platinum-based chemotherapy cisplatin to model CICI, we revealed robust elevations in the adenosine A2A receptor (A2AR) and its downstream effectors, cAMP and CREB, by cisplatin in the adult mouse hippocampus, a critical brain structure for learning and memory. Notably, A2AR inhibition by the Food and Drug Administration-approved A2AR antagonist KW-6002 prevented cisplatin-induced impairments in neural progenitor proliferation and dendrite morphogenesis of adult-born neurons, while improving memory and anxiety-like behavior, without affecting tumor growth or cisplatin's antitumor activity. Collectively, our study identifies A2AR signaling as a key pathway that can be therapeutically targeted to prevent cisplatin-induced cognitive impairments.


Assuntos
Antagonistas do Receptor A2 de Adenosina , Antineoplásicos , Comprometimento Cognitivo Relacionado à Quimioterapia , Cisplatino , Neurogênese , Purinas , Receptor A2A de Adenosina , Antagonistas do Receptor A2 de Adenosina/uso terapêutico , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Comprometimento Cognitivo Relacionado à Quimioterapia/prevenção & controle , Cisplatino/efeitos adversos , Cognição/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/fisiologia , Neurogênese/efeitos dos fármacos , Purinas/administração & dosagem , Purinas/uso terapêutico , Receptor A2A de Adenosina/metabolismo
11.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 47(4): 443-452, 2022 Apr 28.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-35545339

RESUMO

OBJECTIVES: During pregnancy, pregnant women are prone to stress reactions due to external stimuli, affecting their own health and fetal development. At present, there is no good treatment for the stress reactions from pregnant women during pregnancy. This study aims to explore the effect of probiotics on abnormal behavior and hippocampal injury in pregnant stressed offspring. METHODS: SD pregnant rats were divided into a control group, a stress group, and a probiotics group, with 6 rats in each group. The control group was untreated; the stress group was given restraint stress on the 15th-20th day of pregnancy; the probiotics group was given both bifidobacterium trisporus capsules and restraint stress on the 15th-20th day of pregnancy, and the offspring continued to be fed with probiotics until 60 days after birth (P60). The offspring rats completed behavioral tests such as the open field test, the elevated plus maze test, the new object recognition test, and the barnes maze test at 60-70 d postnatally. Nissl's staining was used to reflect the injury of hippocampal neurons; immunohistochemical staining was used to detect the expression of microglia marker ionized calcium binding adapter molecule 1 (IBA-1) which can reflect microglia activation; ELISA was used to detect the content of plasma TNF-α and IL-1ß; Western blotting was used to detect the expression of Bax, Bcl-2, and caspase-3. RESULTS: The retention time of offspring rats in the stress group in the central area of the open field was significantly less than that in the control group (P<0.01), and the retention time of offspring rats in the probiotic group in the central area of the open field was significantly more than that in the stress group (P<0.05). The offspring rats in the stress group stayed in the open arm for a shorter time than the control group (P<0.05) and entered the open arm less often than the control group (P<0.01); the offspring rats in the probiotic group stayed in the open arm for a longer time than the stress group and entered the open arm more often than the stress group (both P<0.05). The discrimination ratio for new to old objects in the offspring rats of the stress group was significantly lower than that of the control group (P<0.01), and the discrimination ratio for new to old objects in the offspring rats of the probiotic group was significantly higher than that of the stress group (P<0.05). The offspring rats in the stress group made significantly more mistakes than the control group (P<0.05), and the offspring rats in the probiotic group made significantly fewer mistakes than the stress group (P<0.05). Compared with the control group, the numbers of Nissl bodies in CA1, CA3, and DG area were significantly reduced in the offspring rats of the stress group (all P<0.001), the number of activated microglia in DG area of hippocampus was significantly increased (P<0.01), the contents of TNF-α and IL-1ß in peripheral blood were significantly increased (P<0.05 or P<0.01), the protein expression level of Bcl-2 was significantly down-regulated, and the protein expression levels of Bax and caspase-3 were significantly up-regulated (all P<0.001). Compared with the stress group, the numbers of Nissl bodies in CA1, CA3, and DG area were significantly increased in the probiotic group offspring rats (P<0.001, P<0.01, P<0.05), the number of activated microglia in the DG area of hippocampus was significantly reduced (P<0.05), and the TNF-α and IL-1ß levels in peripheral blood were significantly decreased (both P<0.05), the protein expression level of Bcl-2 was significantly up-regulated, and the protein expression levels of Bax and caspase-3 were significantly down-regulated (all P<0.001). CONCLUSIONS: Probiotic intervention partially ameliorated anxiety and cognitive impairment in rats offspring of pregnancy stress, and the mechanism may be related to increasing the number of neurons, inhibiting the activation of hippocampal microglia, and reducing inflammation and apoptosis.


Assuntos
Probióticos , Estresse Psicológico , Animais , Caspase 3/metabolismo , Feminino , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Humanos , Gravidez , Probióticos/uso terapêutico , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Estresse Psicológico/terapia , Fator de Necrose Tumoral alfa/metabolismo , Proteína X Associada a bcl-2/metabolismo
12.
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
13.
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
14.
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
15.
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
16.
Int J Radiat Biol ; 98(8): 1316-1329, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35130116

RESUMO

PURPOSE: To clarify the preventive and therapeutic effects of repetitive transcranial magnetic stimulation (rTMS) on brain injury induced by X-ray cranial irradiation, preliminarily identify the mechanism and provide a novel clinical approach for the prevention and treatment of radiation-induced brain injury (RBI). MATERIALS AND METHODS: Male C57BL/6 mice were randomly divided into the sham group, large fractionated dose (5 Gy × 4 d) group, large fractionated dose + rTMS (5 Gy × 4 d + rTMS) group, conventional fractionated dose (2 Gy × 10 d) group and conventional fractionated dose + rTMS (2 Gy × 10 d + rTMS) group. After cranial irradiation and rTMS, behavioral experiments, morphological staining and molecular biology experiments were performed. We further determined the mechanism of rTMS on the prevention and treatment of RBI, including changes in hippocampal neuronal apoptosis, neural stem cell (NSC) proliferation and differentiation, and neuronal synaptic plasticity. RESULTS: rTMS alleviated the negative effects of cranial radiation on the general health of mice and promoted their recovery. rTMS ameliorated the impairment of spatial learning and memory induced by cranial radiation, and this beneficial effect was more robust in the conventional fractionated dose group than the large fractionated dose group. Moreover, rTMS alleviated the alterations in hippocampal structure and neuronal death and had preventive and therapeutic effects against RBI. In addition, rTMS reduced hippocampal cell apoptosis, promoted NSC proliferation and differentiation in the hippocampus after cranial irradiation, and enhanced neuronal synaptic plasticity in the hippocampus. Subsequent studies showed that rTMS upregulated the expression of learning- and memory-related proteins. CONCLUSION: rTMS could alleviate learning and memory impairment caused by RBI, and the preventive and therapeutic effects of rTMS were better for the conventional fraction radiation paradigms.


Assuntos
Lesões Encefálicas , Lesões Experimentais por Radiação , Estimulação Magnética Transcraniana , Animais , Lesões Encefálicas/etiologia , Lesões Encefálicas/prevenção & controle , Hipocampo/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Plasticidade Neuronal/fisiologia , Lesões Experimentais por Radiação/terapia , Resultado do Tratamento
17.
Neuroimmunomodulation ; 29(4): 359-368, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35130556

RESUMO

INTRODUCTION: Diabetes mellitus (DM) is a risk factor for Alzheimer's disease (AD). Increasing evidence indicates that the triggering receptor expressed on myeloid cells (TREM)-1 amplifies chronic inflammation, as well as the roles of prolactin (PRL) and metformin (MET) in tau hyperphosphorylation. However, the associations among TREM-1, tau hyperphosphorylation, PRL expression, and MET in DM remain unclear. METHODS: Streptozotocin was used to induce experimental DM in C57BL/6N mice. MET was orally administered at a dose of 400 mg/kg body weight for 6 weeks prior to hippocampal collection in DM mice. Various parameters pertaining to the TREM-1 pathway, tau hyperphosphorylation, PRL, and related factors were analyzed. RESULTS: Quantitative polymerase chain reaction and Western blot analysis demonstrated that the expression levels of TREM-1, DAP12, casp1, interleukin-1ß, Cox2, inducible nitric oxide synthase, pituitary transcriptional factor-1 (Pit-1), and PRL were significantly increased in the hippocampus of DM mice; the expression levels of these pro-inflammatory mediators, PRL receptor (PRLR) short or long (PRLR-S and PRLR-L), and PRL regulatory element-binding (Preb) protein in DM mice treated with MET (DM + MET) were significantly decreased compared with those in control (CON) mice. The levels of p-Tau and glycogen synthase kinase-3 in the DM group were significantly higher than those in the CON group and significantly lower than those in the DM + MET group. CONCLUSION: We confirmed the therapeutic potential of MET for both DM and neurodegeneration. Our findings shed new light on the effects of DM on the pathophysiology of AD via the TREM-1 pathway and PRL expression. Thus, an improved understanding of the TREM-1 pathway in hyperglycemic conditions, as well as PRL, Preb, Pit-1, PRLR-L, and PRLR-S gene expression in the liver, brain, and other sites, may help unravel the pathogenesis of insulin resistance and neurodegeneration.


Assuntos
Doença de Alzheimer , Diabetes Mellitus , Metformina , Prolactina , Animais , Camundongos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/genética , Diabetes Mellitus/metabolismo , Metformina/farmacologia , Metformina/uso terapêutico , Camundongos Endogâmicos C57BL , Prolactina/genética , Prolactina/metabolismo , Prolactina/farmacologia , Receptores da Prolactina/genética , Receptores da Prolactina/metabolismo , Receptor Gatilho 1 Expresso em Células Mieloides , Fosforilação , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Hipocampo/fisiopatologia
18.
J Dent Res ; 101(8): 992-1001, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35193423

RESUMO

Alzheimer's disease (AD) is the most common type of dementia. Tau hyperphosphorylation and amyloid ß (Aß) deposition are the key pathological hallmarks of AD. Recent studies have shown that periodontitis is a significant risk factor for AD. The periodontal pathogen Porphyromonas gingivalis and its virulence factors have been shown to initiate and promote the hallmark pathologies and behavioral symptoms of AD. A possible link between Treponema denticola, another main periodontal pathogen, and AD has been reported. However, the role of T. denticola in AD pathogenesis is still unclear, and whether T. denticola and P. gingivalis exert a synergistic effect to promote AD development needs to be further studied. In this study, we investigated whether oral infection with T. denticola caused tau hyperphosphorylation in the hippocampi of mice and explored the underlying mechanisms. Orally administered T. denticola induced alveolar bone resorption, colonized brain tissues, and increased the activity of the phosphokinase GSK3ß by activating neuroinflammation in the hippocampus, thus promoting the hyperphosphorylation of the tau protein at Ser396, Thr181, and Thr231 in mice. An in vitro study with BV2 and N2a cell models of T. denticola invasion also verified the role of this pathogen in tau phosphorylation. T. denticola and P. gingivalis were not found to exert a synergistic effect on tau phosphorylation. In summary, these findings provide new insight into the important role of T. denticola in AD pathogenesis, providing biological connections between periodontal diseases and AD.


Assuntos
Doença de Alzheimer , Doenças Neuroinflamatórias , Infecções por Treponema , Perda do Osso Alveolar/microbiologia , Doença de Alzheimer/microbiologia , Peptídeos beta-Amiloides/metabolismo , Animais , Hipocampo/fisiopatologia , Camundongos , Doenças Neuroinflamatórias/microbiologia , Porphyromonas gingivalis , Treponema denticola , Infecções por Treponema/patologia , Proteínas tau/metabolismo
19.
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
20.
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
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