Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 618
Filtrar
1.
Proc Natl Acad Sci U S A ; 118(39)2021 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-34544873

RESUMO

The biological mechanisms underpinning learning are unclear. Mounting evidence has suggested that adult hippocampal neurogenesis is involved although a causal relationship has not been well defined. Here, using high-resolution genetic mapping of adult neurogenesis, combined with sequencing information, we identify follistatin (Fst) and demonstrate its involvement in learning and adult neurogenesis. We confirmed that brain-specific Fst knockout (KO) mice exhibited decreased hippocampal neurogenesis and demonstrated that FST is critical for learning. Fst KO mice exhibit deficits in spatial learning, working memory, and long-term potentiation (LTP). In contrast, hippocampal overexpression of Fst in KO mice reversed these impairments. By utilizing RNA sequencing and chromatin immunoprecipitation, we identified Asic4 as a target gene regulated by FST and show that Asic4 plays a critical role in learning deficits caused by Fst deletion. Long-term overexpression of hippocampal Fst in C57BL/6 wild-type mice alleviates age-related decline in cognition, neurogenesis, and LTP. Collectively, our study reveals the functions for FST in adult neurogenesis and learning behaviors.


Assuntos
Canais Iônicos Sensíveis a Ácido/metabolismo , Folistatina/fisiologia , Hipocampo/metabolismo , Neurogênese , Plasticidade Neuronal , Aprendizagem Espacial/fisiologia , Canais Iônicos Sensíveis a Ácido/genética , Animais , Cognição , Feminino , Potenciação de Longa Duração , Masculino , Memória , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Sinapses/fisiologia
2.
Clin Immunol ; 230: 108815, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34339843

RESUMO

Traumatic Brain Injury (TBI) is the most prevalent of all head injuries. Microglia play an essential role in homeostasis and diseases of the central nervous system. We hypothesize that microglia may play a beneficial or detrimental role in TBI depending on their state of activation and duration. In this study, we evaluated whether TBI results in a spatiotemporal change in microglia phenotype and whether it affects sensory-motor or learning and memory functions in male C57BL/6 mice. We used a panel of neurological and behavioral tests and a multi-color flow cytometry-based data analysis followed by unsupervised clustering to evaluate isolated microglia from injured brain tissue. We characterized several microglial phenotypes and their association with cognitive deficits. TBI results in a spatiotemporal increase in activated microglia that correlated negatively with spatial learning and memory at 35 days post-injury. These observations could define therapeutic windows and accelerate translational research to improve patient outcomes.


Assuntos
Lesões Encefálicas Traumáticas/complicações , Disfunção Cognitiva/etiologia , Microglia/fisiologia , Animais , Encéfalo/patologia , Encéfalo/fisiopatologia , Lesões Encefálicas Traumáticas/patologia , Lesões Encefálicas Traumáticas/psicologia , Disfunção Cognitiva/patologia , Disfunção Cognitiva/psicologia , Modelos Animais de Doenças , Citometria de Fluxo , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Microglia/classificação , Microglia/patologia , Modelos Neurológicos , Modelos Psicológicos , Dinâmica não Linear , Aprendizagem Espacial/fisiologia , Memória Espacial/fisiologia , Análise Espaço-Temporal , Pesquisa Médica Translacional
3.
Nat Neurosci ; 24(9): 1270-1279, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34326540

RESUMO

The behavioral strategies that mammals use to learn multi-step routes are unknown. In this study, we investigated how mice navigate to shelter in response to threats when the direct path is blocked. Initially, they fled toward the shelter and negotiated obstacles using sensory cues. Within 20 min, they spontaneously adopted a subgoal strategy, initiating escapes by running directly to the obstacle's edge. Mice continued to escape in this manner even after the obstacle had been removed, indicating use of spatial memory. However, standard models of spatial learning-habitual movement repetition and internal map building-did not explain how subgoal memories formed. Instead, mice used a hybrid approach: memorizing salient locations encountered during spontaneous 'practice runs' to the shelter. This strategy was also used during a geometrically identical food-seeking task. These results suggest that subgoal memorization is a fundamental strategy by which rodents learn efficient multi-step routes in new environments.


Assuntos
Aprendizagem Espacial/fisiologia , Memória Espacial/fisiologia , Navegação Espacial/fisiologia , Animais , Sinais (Psicologia) , Masculino , Camundongos , Camundongos Endogâmicos C57BL
4.
Nutrients ; 13(5)2021 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-34066827

RESUMO

Gestational diabetes (GD) has a negative impact on neurodevelopment, resulting in cognitive and neurological deficiencies. Oxidative stress (OS) has been reported in the brain of the first-generation offspring of GD rats. OS has been strongly associated with neurodegenerative diseases. In this work, we determined the effect of GD on the cognitive behavior, oxidative stress and metabolism of second-generation offspring. GD was induced with streptozotocin (STZ) in pregnant rats to obtain first-generation offspring (F1), next female F1 rats were mated with control males to obtain second-generation offspring (F2). Two and six-month-old F2 males and females were employed. Anxious-type behavior, spatial learning and spatial working memory were evaluated. In cerebral cortex and hippocampus, the oxidative stress and serum biochemical parameters were measured. Male F2 GD offspring presented the highest level of anxiety-type behavior, whilst females had the lowest level of anxiety-type behavior at juvenile age. In short-term memory, adult females presented deficiencies. The offspring F2 GD females presented modifications in oxidative stress biomarkers in the cerebral cortex as lipid-peroxidation, oxidized glutathione and catalase activity. We also observed metabolic disturbances, particularly in the lipid and insulin levels of male and female F2 GD offspring. Our results suggest a transgenerational effect of GD on metabolism, anxiety-like behavior, and spatial working memory.


Assuntos
Ansiedade/etiologia , Comportamento Animal/fisiologia , Fenômenos Fisiológicos da Nutrição Materna , Estresse Oxidativo/fisiologia , Efeitos Tardios da Exposição Pré-Natal/etiologia , Animais , Biomarcadores , Córtex Cerebral/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/psicologia , Diabetes Gestacional/metabolismo , Diabetes Gestacional/psicologia , Modelos Animais de Doenças , Feminino , Hipocampo/metabolismo , Peroxidação de Lipídeos/fisiologia , Masculino , Memória de Curto Prazo/fisiologia , Gravidez , Ratos , Aprendizagem Espacial/fisiologia , Estreptozocina
5.
Psychopharmacology (Berl) ; 238(8): 2297-2312, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33991198

RESUMO

RATIONALE AND OBJECTIVE: Environmental enrichment (EE) has been shown in old rats to improve learning and memory. Vitamin D (VitD) has also been shown to modulate age-related, cognitive dysfunction. As both EE and VitD could work to improve cognition via enhancement of neurotrophic factors, their effects might occlude one another. Therefore, a clinically relevant question is whether noted cognition-promoting effects of EE and VitD can co-occur. METHODS: Aged rats were housed for 6 weeks in one of three housing conditions: environmentally enriched (EE), socially enriched (SE), or standard condition (SC). Further, a 4th group was co-treated with VitD supplementation (400 IU kg-1 daily, 6 weeks) under EE conditions (EE + VitD). RESULTS: Treatment with VitD and EE housing were associated with higher score on measures of learning and memory and exhibited lower anxiety scores compared to EE alone, SE or SC as assayed in the elevated plus maze, Morris water maze, passive avoidance, and open field tasks. Additionally, in the EE + VitD group, mRNA expression levels of NGF, TrkA, BDNF, Nrf2, and IGF-1 were significantly higher compared to expression seen in the EE group. Furthermore, field potential recordings showed that EE + VitD resulted in a greater enhancement of hippocampal LTP and neuronal excitability when compared to EE alone. CONCLUSIONS: These findings demonstrate that in aged rats exposure to EE and VitD results in effects on hippocampal cognitive dysfunction and molecular mechanisms which are greater than effects of EE alone, suggesting potential for synergistic therapeutic effects for management of age-related cognitive decline.


Assuntos
Envelhecimento/fisiologia , Meio Ambiente , Memória/fisiologia , Plasticidade Neuronal/fisiologia , Aprendizagem Espacial/fisiologia , Vitamina D/administração & dosagem , Envelhecimento/efeitos dos fármacos , Envelhecimento/psicologia , Animais , Cognição/efeitos dos fármacos , Cognição/fisiologia , Suplementos Nutricionais , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Memória/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Aprendizagem Espacial/efeitos dos fármacos
6.
Elife ; 102021 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-33821790

RESUMO

The hippocampus plays a central role in long-term memory formation, and different hippocampal network states are thought to have different functions in this process. These network states are controlled by neuromodulatory inputs, including the cholinergic input from the medial septum. Here, we used optogenetic stimulation of septal cholinergic neurons to understand how cholinergic activity affects different stages of spatial memory formation in a reward-based navigation task in mice. We found that optogenetic stimulation of septal cholinergic neurons (1) impaired memory formation when activated at goal location but not during navigation, (2) reduced sharp wave ripple (SWR) incidence at goal location, and (3) reduced SWR incidence and enhanced theta-gamma oscillations during sleep. These results underscore the importance of appropriate timing of cholinergic input in long-term memory formation, which might help explain the limited success of cholinesterase inhibitor drugs in treating memory impairment in Alzheimer's disease.


Assuntos
Neurônios Colinérgicos/fisiologia , Sono , Aprendizagem Espacial/fisiologia , Memória Espacial/fisiologia , Navegação Espacial , Animais , Objetivos , Masculino , Camundongos , Optogenética
7.
Biomolecules ; 11(5)2021 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-33924998

RESUMO

Ethanol exposure during pregnancy alters the mammalian target of rapamycin (mTOR) signaling pathway in the fetal brain. Hence, in adult rats exposed to ethanol during the neonatal period, we investigated the influence of rapamycin, an mTOR Complex 1 (mTORC1) inhibitor, on deficits in spatial memory and reversal learning in the Barnes maze task, as well as the ethanol-induced rewarding effects (1.0 or 1.5 g/kg) using the conditioning place preference (CPP) paradigm. Rapamycin (3 and 10 mg/kg) was given before intragastric ethanol (5 g/kg/day) administration at postnatal day (PND)4-9 (an equivalent to the third trimester of human pregnancy). Spatial memory/reversal learning and rewarding ethanol effect were evaluated in adult (PND60-70) rats. Additionally, the impact of rapamycin pre-treatment on the expression of the GluN2B subunit of NMDA receptor in the brain was assessed in adult rats. Our results show that neonatal ethanol exposure induced deficits in spatial memory and reversal learning in adulthood, but the reversal learning outcome may have been due to spatial learning impairments rather than cognitive flexibility impairments. Furthermore, in adulthood the ethanol treated rats were also more sensitive to the rewarding effect of ethanol than the control group. Rapamycin prevented the neonatal effect of ethanol and normalized the GluN2B down-regulation in the hippocampus and the prefrontal cortex, as well as normalized this subunit's up-regulation in the striatum of adult rats. Our results suggest that rapamycin and related drugs may hold promise as a preventive therapy for fetal alcohol spectrum disorders.


Assuntos
Etanol/toxicidade , Sirolimo/farmacologia , Aprendizagem Espacial/efeitos dos fármacos , Alcoolismo/metabolismo , Animais , Animais Recém-Nascidos/metabolismo , Encéfalo/efeitos dos fármacos , Feminino , Transtornos do Espectro Alcoólico Fetal/tratamento farmacológico , Hipocampo/efeitos dos fármacos , Masculino , Córtex Pré-Frontal/efeitos dos fármacos , Ratos , Ratos Wistar , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sirolimo/metabolismo , Aprendizagem Espacial/fisiologia
8.
Exp Neurol ; 341: 113721, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33852877

RESUMO

Traumatic brain injury (TBI) is often associated with sustained attention and memory deficits. As persisting neuroinflammation and neurodegeneration may contribute to posttraumatic psychomotor dysfunction, we studied the relationship of brain cellular reactions three months after a weight-drop closed head injury in male mice with posttraumatic learning and memory using automated home-cage monitoring of socially housed mice in IntelliCages as well as tests for locomotor activity, anxiety and forepaw fine motor skills. One month after TBI, deficits in place learning and cognitive flexibility in reverse learning were clearly detectable in IntelliCages and these memory deficits correlated with the initial trauma severity on the functional neuroscore. While sucrose preference or its extinction were not influenced by TBI, traumatized mice performed significantly worse in a complex episodic memory learning task. In consecutive locomotor and forepaw skilled use tests, posttraumatic hyperactivity and impairment of contralateral paw use were evident. Analysis of cellular reactions to TBI three months after injury in selected defined regions of interest in the immediate lesion, ipsi- and contralateral frontoparietal cortex and hippocampus revealed a persistent microgliosis and astrogliosis which were accompanied by iron-containing macrophages and myelin degradation in the lesion area as well as with axonal damage in the neighboring cortical regions. Microglial and astroglial reactions in cortex showed a positive correlation with the initial trauma severity and a negative correlation with the spatial and episodic memory indicating a role of brain inflammatory reactions in posttraumatic memory deficits.


Assuntos
Lesões Encefálicas Traumáticas/patologia , Lesões Encefálicas Traumáticas/fisiopatologia , Gliose/patologia , Gliose/fisiopatologia , Índice de Gravidade de Doença , Aprendizagem Espacial/fisiologia , Animais , Lesões Encefálicas Traumáticas/complicações , Gliose/etiologia , Locomoção/fisiologia , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos C57BL
9.
J Neurosci ; 41(14): 3204-3221, 2021 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-33648956

RESUMO

Learning the spatial layout of a novel environment is associated with dynamic activity changes in the hippocampus and in medial parietal areas. With advancing age, the ability to learn spatial environments deteriorates substantially but the underlying neural mechanisms are not well understood. Here, we report findings from a behavioral and a fMRI experiment where healthy human older and younger adults of either sex performed a spatial learning task in a photorealistic virtual environment (VE). We modeled individual learning states using a Bayesian state-space model and found that activity in retrosplenial cortex (RSC)/parieto-occipital sulcus (POS) and anterior hippocampus did not change systematically as a function learning in older compared with younger adults across repeated episodes in the environment. Moreover, effective connectivity analyses revealed that the age-related learning deficits were linked to an increase in hippocampal excitability. Together, these results provide novel insights into how human aging affects computations in the brain's navigation system, highlighting the critical role of the hippocampus.SIGNIFICANCE STATEMENT Key structures of the brain's navigation circuit are particularly vulnerable to the deleterious consequences of aging, and declines in spatial navigation are among the earliest indicators for a progression from healthy aging to neurodegenerative diseases. Our study is among the first to provide a mechanistic account about how physiological changes in the aging brain affect the formation of spatial knowledge. We show that neural activity in the aging hippocampus and medial parietal areas is decoupled from individual learning states across repeated episodes in a novel spatial environment. Importantly, we find that increased excitability of the anterior hippocampus might constitute a potential neural mechanism for cognitive mapping deficits in old age.


Assuntos
Envelhecimento/fisiologia , Mapeamento Encefálico/métodos , Cognição/fisiologia , Hipocampo/fisiologia , Aprendizagem Espacial/fisiologia , Realidade Virtual , Adulto , Idoso , Envelhecimento/psicologia , Feminino , Hipocampo/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Lobo Parietal/diagnóstico por imagem , Lobo Parietal/fisiologia , Desempenho Psicomotor/fisiologia , Navegação Espacial/fisiologia , Adulto Jovem
10.
PLoS One ; 16(3): e0248530, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33724997

RESUMO

Sequential movements are often grouped into several chunks, as evidenced by the modulation of the timing of each elemental movement. Even during synchronized tapping with a metronome, we sometimes feel subjective accent for every few taps. To examine whether motor segmentation emerges during synchronized movements, we trained monkeys to generate a series of predictive saccades synchronized with visual stimuli which sequentially appeared for a fixed interval (400 or 600 ms) at six circularly arranged landmark locations. We found two types of motor segmentations that featured periodic modulation of saccade timing. First, the intersaccadic interval (ISI) depended on the target location and saccade direction, indicating that particular combinations of saccades were integrated into motor chunks. Second, when a task-irrelevant rectangular contour surrounding three landmarks ("inducer") was presented, the ISI significantly modulated depending on the relative target location to the inducer. All patterns of individual differences seen in monkeys were also observed in humans. Importantly, the effects of the inducer greatly decreased or disappeared when the animals were trained to generate only reactive saccades (latency >100 ms), indicating that the motor segmentation may depend on the internal rhythms. Thus, our results demonstrate two types of motor segmentation during synchronized movements: one is related to the hierarchical organization of sequential movements and the other is related to the spontaneous grouping of rhythmic events. This experimental paradigm can be used to investigate the underlying neural mechanism of temporal grouping during rhythm production.


Assuntos
Movimentos Sacádicos/fisiologia , Aprendizagem Espacial/fisiologia , Animais , Feminino , Fixação Ocular/fisiologia , Percepção de Forma/fisiologia , Macaca mulatta , Masculino , Modelos Animais , Estimulação Luminosa/métodos , Tempo de Reação/fisiologia
11.
J Vis ; 21(3): 10, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33683287

RESUMO

Visual perceptual learning (VPL) is an improvement in visual function following training. Although the practical utility of VPL was once thought to be limited by its specificity to the precise stimuli used during training, more recent work has shown that such specificity can be overcome with appropriate training protocols. In contrast, relatively little is known about the extent to which VPL exhibits motor specificity. Previous studies have yielded mixed results. In this work, we have examined the effector specificity of VPL by training observers on a motion discrimination task that maintains the same visual stimulus (drifting grating) and task structure, but that requires different effectors to indicate the response (saccade vs. button press). We find that, in these conditions, VPL transfers fully between a manual and an oculomotor response. These results are consistent with the idea that VPL entails the learning of a decision rule that can generalize across effectors.


Assuntos
Aprendizagem Espacial/fisiologia , Percepção Visual/fisiologia , Adolescente , Adulto , Aprendizagem por Discriminação , Feminino , Humanos , Masculino , Método Simples-Cego , Adulto Jovem
12.
Mol Med Rep ; 23(4)2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33576461

RESUMO

Cognitive impairment is one of the primary features of vascular dementia (VD). However, the specific mechanism underlying the regulation of cognition function in VD is not completely understood. The present study aimed to explore the effects of microRNA (miR)­150 on VD. To determine the effects of miR­150 on cognitive function and hippocampal neurons in VD model rats, rats were subjected to intracerebroventricular injections of miR­150 antagomiR. The Morris water maze test results demonstrated that spatial learning ability was impaired in VD model rats compared with control rats. Moreover, compared with antagomiR negative control (NC), miR­150 antagomiR alleviated cognitive impairment and enhanced memory ability in VD model rats. The triphenyltetrazolium chloride, Nissl staining and immunohistochemistry results further demonstrated that miR­150 knockdown improved the activity of hippocampal neurons in VD model rats compared with the antagomiR NC group. To validate the role of miR­150 in neurons in vitro, the PC12 cell line was used. The flow cytometry and Hoechst 33342/PI double staining results indicated that miR­150 overexpression significantly increased cell apoptosis compared with the mimic NC group. Moreover, the dual­luciferase reporter gene assay results indicated that miR­150 targeted HOXA1 and negatively regulated HOXA1 expression. Therefore, the present study indicated that miR­150 knockdown ameliorated VD symptoms by upregulating HOXA1 expression in vivo and in vitro.


Assuntos
Apoptose/genética , Demência Vascular/genética , Modelos Animais de Doenças , Hipocampo/metabolismo , MicroRNAs/genética , Neurônios/metabolismo , Animais , Antagomirs/administração & dosagem , Antagomirs/genética , Cognição/fisiologia , Regulação da Expressão Gênica , Hipocampo/citologia , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Masculino , Aprendizagem em Labirinto/fisiologia , Células PC12 , Ratos , Ratos Sprague-Dawley , Aprendizagem Espacial/fisiologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
13.
Neurochem Res ; 46(5): 1188-1202, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33559105

RESUMO

Ovarian estrogens (mainly 17ß estradiol, E2) have been involved in the regulation of the structure of hippocampus, the center of spatial memory. In recent years, high levels of aromatase (AROM), the estrogen synthase, has been localized in hippocampus; and this hippocampus-derived E2 seems to be functional in synaptic plasticity and spatial memory as ovarian E2 does. However, the contribution of ovarian E2 and hippocampal E2 to spatial memory and neural plasticity remains unclear. In this study, AROM-specific RNA interference AAVs (shAROM) were constructed and injected into the hippocampus of control or ovariectomized (OVX) mice. Four weeks later the spatial learning and memory behavior was examined with Morris water maze, the expression of hippocampal Aß related proteins, selected synaptic proteins and CA1 synapse density, actin polymerization related proteins and CA1 spine density were also examined. The results showed that while OVX and hippocampal shAROM contributed similarly to most of the parameters examined, shAROM induced more increase in BACE1 (amyloidogenic ß-secretase), more decrease in neprilysin (Aß remover) and Profilin-1 (actin polymerization inducer). More importantly, combined OVX and shAROM treatment displayed most significant impairment of spatial learning and memory as well as decrease in synaptic plasticity compared to OVX or shAROM alone. In conclusion, the above results clearly demonstrated the crucial role of hippocampal E2 in the regulation of the structure and function of hippocampus besides ovarian E2, indicating that hippocampal E2 content should also be taken into consideration during estrogenic replacement.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Aromatase/metabolismo , Plasticidade Neuronal/fisiologia , Memória Espacial/fisiologia , Animais , Aromatase/genética , Sequência de Bases , Região CA1 Hipocampal/enzimologia , Região CA1 Hipocampal/metabolismo , Espinhas Dendríticas/metabolismo , Feminino , Técnicas de Silenciamento de Genes , Camundongos Endogâmicos C57BL , Teste do Labirinto Aquático de Morris/fisiologia , Proteínas do Tecido Nervoso/metabolismo , Ovariectomia/efeitos adversos , Ovário/enzimologia , RNA Interferente Pequeno/farmacologia , Aprendizagem Espacial/fisiologia , Sinapses/metabolismo
14.
Neuroimage ; 230: 117707, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33385560

RESUMO

BACKGROUND: In Alzheimer`s disease (AD), regional heterogeneity of ß-amyloid burden and microglial activation of individual patients is a well-known phenomenon. Recently, we described a high incidence of inter-individual regional heterogeneity in terms of asymmetry of plaque burden and microglial activation in ß-amyloid mouse models of AD as assessed by positron-emission-tomography (PET). We now investigate the regional associations between amyloid plaque burden, microglial activation, and impaired spatial learning performance in transgenic mice in vivo. METHODS: In 30 AppNL-G-F mice (15 female, 15 male) we acquired cross-sectional 18 kDa translocator protein (TSPO-PET, 18F-GE-180) and ß-amyloid-PET (18F-florbetaben) scans at ten months of age. Control data were obtained from age- and sex-matched C57BI/6 wild-type mice. We assessed spatial learning (i.e. Morris water maze) within two weeks of PET scanning and correlated the principal component of spatial learning performance scores with voxel-wise ß-amyloid and TSPO tracer uptake maps in AppNL-G-F mice, controlled for age and sex. In order to assess the effects of hemispheric asymmetry, we also analyzed correlations of spatial learning performance with tracer uptake in bilateral regions of interest for frontal cortex, entorhinal/piriform cortex, amygdala, and hippocampus, using a regression model. We tested the correlation between regional asymmetry of PET biomarkers with individual spatial learning performance. RESULTS: Voxel-wise analyses in AppNL-G-F mice revealed that higher TSPO-PET signal in the amygdala, entorhinal and piriform cortices, the hippocampus and the hypothalamus correlated with spatial learning performance. Region-based analysis showed significant correlations between TSPO expression in the right entorhinal/piriform cortex and the right amygdala and spatial learning performance, whereas there were no such correlations in the left hemisphere. Right lateralized TSPO expression in the amygdala predicted better performance in the Morris water maze (ß = -0.470, p = 0.013), irrespective of the global microglial activation and amyloid level. Region-based results for amyloid-PET showed no significant associations with spatial learning. CONCLUSION: Elevated microglial activation in the right amygdala-entorhinal-hippocampal complex of AppNL-G-F mice is associated with better spatial learning. Our findings support a protective role of microglia on cognitive function when they highly express TSPO in specific brain regions involved in spatial memory.


Assuntos
Tonsila do Cerebelo/metabolismo , Precursor de Proteína beta-Amiloide/biossíntese , Córtex Entorrinal/metabolismo , Hipocampo/metabolismo , Microglia/metabolismo , Aprendizagem Espacial/fisiologia , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animais , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Tomografia por Emissão de Pósitrons/métodos , Receptores de GABA/biossíntese , Receptores de GABA/genética
15.
Proc Natl Acad Sci U S A ; 118(1)2021 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-33443144

RESUMO

Hippocampal cells are central to spatial and predictive representations, and experience replays by place cells are crucial for learning and memory. Nonetheless, how hippocampal replay patterns dynamically change during the learning process remains to be elucidated. Here, we designed a spatial task in which rats learned a new behavioral trajectory for reward. We found that as rats updated their behavioral strategies for a novel salient location, hippocampal cell ensembles increased theta-sequences and sharp wave ripple-associated synchronous spikes that preferentially replayed salient locations and reward-related contexts in reverse order. The directionality and contents of the replays progressively varied with learning, including an optimized path that had never been exploited by the animals, suggesting prioritized replays of significant experiences on a predictive map. Online feedback blockade of sharp wave ripples during a learning process inhibited stabilizing optimized behavior. These results implicate learning-associated experience replays that act to learn and reinforce specific behavioral strategies.


Assuntos
Hipocampo/metabolismo , Aprendizagem/fisiologia , Aprendizagem Espacial/fisiologia , Animais , Encéfalo/metabolismo , Encéfalo/fisiologia , Hipocampo/fisiologia , Masculino , Memória/fisiologia , Neurônios/fisiologia , Células de Lugar/metabolismo , Ratos , Ratos Long-Evans , Reforço Psicológico , Recompensa
16.
Cell Mol Life Sci ; 78(5): 2279-2298, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32959071

RESUMO

Learning and memory are known to depend on synaptic plasticity. Whereas the involvement of plastic changes at excitatory synapses is well established, plasticity mechanisms at inhibitory synapses only start to be discovered. Extracellular proteolysis is known to be a key factor in glutamatergic plasticity but nothing is known about its role at GABAergic synapses. We reveal that pharmacological inhibition of MMP3 activity or genetic knockout of the Mmp3 gene abolishes induction of postsynaptic iLTP. Moreover, the application of exogenous active MMP3 mimics major iLTP manifestations: increased mIPSCs amplitude, enlargement of synaptic gephyrin clusters, and a decrease in the diffusion coefficient of synaptic GABAA receptors that favors their entrapment within the synapse. Finally, we found that MMP3 deficient mice show faster spatial learning in Morris water maze and enhanced contextual fear conditioning. We conclude that MMP3 plays a key role in iLTP mechanisms and in the behaviors that presumably in part depend on GABAergic plasticity.


Assuntos
Hipocampo/fisiologia , Metaloproteinase 3 da Matriz/metabolismo , Inibição Neural/fisiologia , Plasticidade Neuronal/fisiologia , Aprendizagem Espacial/fisiologia , Sinapses/fisiologia , Animais , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Humanos , Potenciação de Longa Duração/genética , Potenciação de Longa Duração/fisiologia , Masculino , Metaloproteinase 3 da Matriz/genética , Aprendizagem em Labirinto/fisiologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , N-Metilaspartato/farmacologia , Inibição Neural/genética , Plasticidade Neuronal/genética , Receptores de GABA-A/genética , Receptores de GABA-A/metabolismo , Sinapses/genética
17.
J Mot Behav ; 53(2): 200-208, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32281907

RESUMO

Forty children with cerebral palsy (CP) and 120 typical developing children (TD) performed a topographic working memory (WalCT) test requiring to move their body in a walked vista-space and a visuo-spatial test (CBT) requiring just reaching movements. WalCT score was significantly higher in GMFCS II/III than in TD. CBT score was significantly lower in GMFCS I than in III/IV but lower than TD in all CP groups. Similar results in WalCT between GMFCS I and TD and GMFCS II and III/IV respectively indicate that mobility is associated with topographic working memory. Differently in CBT, the absence of bodily movement allows using different cognitive strategies. Children should be provided with opportunities and active participation to enhancing spatial awareness and navigational skills.


Assuntos
Paralisia Cerebral/psicologia , Memória de Curto Prazo/fisiologia , Aprendizagem Espacial/fisiologia , Navegação Espacial/fisiologia , Criança , Feminino , Humanos , Masculino , Movimento
18.
Acta Neurobiol Exp (Wars) ; 80(4): 400-410, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33350993

RESUMO

Prenatal stress causes learning and spatial memory deficits in adulthood by modifying hippocampal function. The dorsal hippocampus contains serotonergic and noradrenergic neuron terminals, which are related to cognitive processes. It is currently unknown whether prenatal stress modifies serotonin (5-HT) and noradrenaline (NA) content and their release in the hippocampus during cognitive performance. Therefore, we measured these variables in the dorsal hippocampus of prenatally stressed males during spatial learning and memory tests. Cognitive tests were performed in 3-month-old control and prenatally stressed male rats in the Morris Water Maze (MWM). After cognitive tests, the dorsal hippocampus was dissected to quantify 5-HT and NA content. In other males, 5-HT and NA release in the dorsal hippocampus was assessed by microdialysis, before and after cognitive tests. Prenatally stressed males showed longer latencies to reach the platform, compared to control animals. Hippocampal 5-HT content decreased during learning and memory tasks in both groups, while NA content was not modified in prenatally stressed males neither before, nor after learning and memory tests. 5-HT and NA release were significantly lower in prenatally stressed animals during spatial learning and memory tasks. Corticosterone response was greater in prenatally stressed animals compared to controls. These results show that cognitive disruption caused by prenatal stress is related to decreased 5-HT and NA release, and to higher adrenal axis response in prenatally stressed animals.


Assuntos
Hipocampo/metabolismo , Norepinefrina/metabolismo , Serotonina/metabolismo , Aprendizagem Espacial/fisiologia , Memória Espacial/fisiologia , Animais , Corticosterona/metabolismo , Feminino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Ratos Wistar
19.
Sci Rep ; 10(1): 20687, 2020 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-33244175

RESUMO

Current clinical interest lies in the relationship between hearing loss and cognitive impairment. Previous work demonstrated that noise exposure, a common cause of sensorineural hearing loss (SNHL), leads to cognitive impairments in mice. However, in noise-induced models, it is difficult to distinguish the effects of noise trauma from subsequent SNHL on central processes. Here, we use cochlear hair cell ablation to isolate the effects of SNHL. Cochlear hair cells were conditionally and selectively ablated in mature, transgenic mice where the human diphtheria toxin (DT) receptor was expressed behind the hair-cell specific Pou4f3 promoter. Due to higher Pou4f3 expression in cochlear hair cells than vestibular hair cells, administration of a low dose of DT caused profound SNHL without vestibular dysfunction and had no effect on wild-type (WT) littermates. Spatial learning/memory was assayed using an automated radial 8-arm maze (RAM), where mice were trained to find food rewards over a 14-day period. The number of working memory errors (WME) and reference memory errors (RME) per training day were recorded. All animals were injected with DT during P30-60 and underwent the RAM assay during P90-120. SNHL animals committed more WME and RME than WT animals, demonstrating that isolated SNHL affected cognitive function. Duration of SNHL (60 versus 90 days post DT injection) had no effect on RAM performance. However, younger age of acquired SNHL (DT on P30 versus P60) was associated with fewer WME. This describes the previously undocumented effect of isolated SNHL on cognitive processes that do not directly rely on auditory sensory input.


Assuntos
Células Ciliadas Auditivas/fisiologia , Memória/fisiologia , Aprendizagem Espacial/fisiologia , Animais , Cognição/fisiologia , Surdez/metabolismo , Surdez/fisiopatologia , Potenciais Evocados Auditivos do Tronco Encefálico/fisiologia , Células Ciliadas Auditivas/metabolismo , Células Ciliadas Vestibulares/metabolismo , Células Ciliadas Vestibulares/fisiologia , Audição/fisiologia , Perda Auditiva Neurossensorial/metabolismo , Perda Auditiva Neurossensorial/fisiopatologia , Fator de Crescimento Semelhante a EGF de Ligação à Heparina/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Ruído , Fator de Transcrição Brn-3C/metabolismo
20.
Microbiome ; 8(1): 140, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33004079

RESUMO

BACKGROUND: The gut-brain axis and the intestinal microbiota are emerging as key players in health and disease. Shifts in intestinal microbiota composition affect a variety of systems; however, evidence of their direct impact on cognitive functions is still lacking. We tested whether faecal microbiota transplant (FMT) from aged donor mice into young adult recipients altered the hippocampus, an area of the central nervous system (CNS) known to be affected by the ageing process and related functions. RESULTS: Young adult mice were transplanted with the microbiota from either aged or age-matched donor mice. Following transplantation, characterization of the microbiotas and metabolomics profiles along with a battery of cognitive and behavioural tests were performed. Label-free quantitative proteomics was employed to monitor protein expression in the hippocampus of the recipients. We report that FMT from aged donors led to impaired spatial learning and memory in young adult recipients, whereas anxiety, explorative behaviour and locomotor activity remained unaffected. This was paralleled by altered expression of proteins involved in synaptic plasticity and neurotransmission in the hippocampus. Also, a strong reduction of bacteria associated with short-chain fatty acids (SCFAs) production (Lachnospiraceae, Faecalibaculum, and Ruminococcaceae) and disorders of the CNS (Prevotellaceae and Ruminococcaceae) was observed. Finally, the detrimental effect of FMT from aged donors on the CNS was confirmed by the observation that microglia cells of the hippocampus fimbria, acquired an ageing-like phenotype; on the contrary, gut permeability and levels of systemic and local (hippocampus) cytokines were not affected. CONCLUSION: These results demonstrate that age-associated shifts of the microbiota have an impact on protein expression and key functions of the CNS. Furthermore, these results highlight the paramount importance of the gut-brain axis in ageing and provide a strong rationale to devise therapies aiming to restore a young-like microbiota to improve cognitive functions and the declining quality of life in the elderly. Video Abstract.


Assuntos
Envelhecimento/fisiologia , Transplante de Microbiota Fecal , Hipocampo/fisiologia , Memória/fisiologia , Plasticidade Neuronal , Aprendizagem Espacial/fisiologia , Transmissão Sináptica , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Qualidade de Vida
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...