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1.
PLoS One ; 15(12): e0243767, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33382724

RESUMO

Hippocampal-cortical dialogue, during which hippocampal ripple oscillations support information transfer, is necessary for long-term consolidation of spatial memories. Whereas a vast amount of work has been carried out to understand the cellular and molecular mechanisms involved in the impairments of memory formation in Alzheimer's disease (AD), far less work has been accomplished to understand these memory deficiencies at the network-level interaction that may underlie memory processing. We recently demonstrated that freely moving 8 to 9-month-old APP/PS1 mice, a model of AD, are able to learn a spatial reference memory task despite a major deficit in Sharp-Wave Ripples (SWRs), the integrity of which is considered to be crucial for spatial memory formation. In order to test whether reconfiguration of hippocampal-cortical dialogue could be responsible for the maintenance of this ability for memory formation, we undertook a study to identify causal relations between hippocampal and cortical circuits in epochs when SWRs are generated in hippocampus. We analyzed the data set obtained from multielectrode intracranial recording of transgenic and wild-type mice undergoing consolidation of spatial memory reported in our previous study. We applied Directed Transfer Function, a connectivity measure based on Granger causality, in order to determine effective coupling between distributed circuits which express oscillatory activity in multiple frequency bands. Our results showed that hippocampal-cortical coupling in epochs containing SWRs was expressed in the two frequency ranges corresponding to ripple (130-180 Hz) and slow gamma (20-60 Hz) band. The general features of connectivity patterns were similar in the 8 to 9-month-old APP/PS1 and wild-type animals except that the coupling in the slow gamma range was stronger and spread to more cortical sites in APP/PS1 mice than in the wild-type group. During the occurrence of SWRs, the strength of effective coupling from the cortex to hippocampus (CA1) in the ripple band undergoes sharp increase, involving cortical areas that were different in the two groups of animals. In the wild-type group, retrosplenial cortex and posterior cingulate cortex interacted with the hippocampus most strongly, whereas in the APP/PS1 group more anterior structures interacted with the hippocampus, that is, anterior cingulate cortex and prefrontal cortex. This reconfiguration of cortical-hippocampal interaction pattern may be an adaptive mechanism responsible for supporting spatial memory consolidation in AD mice model.


Assuntos
Precursor de Proteína beta-Amiloide/genética , Córtex Cerebral/fisiologia , Eletroencefalografia , Hipocampo/fisiologia , Neocórtex/fisiologia , Memória Espacial/fisiologia , Animais , Feminino , Masculino , Camundongos , Camundongos Transgênicos
2.
Nat Commun ; 11(1): 4571, 2020 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-32917871

RESUMO

Early therapeutic interventions are essential to prevent Alzheimer Disease (AD). The association of several inflammation-related genetic markers with AD and the early activation of pro-inflammatory pathways in AD suggest inflammation as a plausible therapeutic target. Inflammatory Caspase-1 has a significant impact on AD-like pathophysiology and Caspase-1 inhibitor, VX-765, reverses cognitive deficits in AD mouse models. Here, a one-month pre-symptomatic treatment of Swedish/Indiana mutant amyloid precursor protein (APPSw/Ind) J20 and wild-type mice with VX-765 delays both APPSw/Ind- and age-induced episodic and spatial memory deficits. VX-765 delays inflammation without considerably affecting soluble and aggregated amyloid beta peptide (Aß) levels. Episodic memory scores correlate negatively with microglial activation. These results suggest that Caspase-1-mediated inflammation occurs early in the disease and raise hope that VX-765, a previously Food and Drug Administration-approved drug for human CNS clinical trials, may be a useful drug to prevent the onset of cognitive deficits and brain inflammation in AD.


Assuntos
Envelhecimento/metabolismo , Doença de Alzheimer/metabolismo , Disfunção Cognitiva/metabolismo , Serpinas/metabolismo , Proteínas Virais/metabolismo , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Animais , Comportamento Animal , Disfunção Cognitiva/tratamento farmacológico , Citocinas/metabolismo , Dipeptídeos/sangue , Dipeptídeos/farmacologia , Modelos Animais de Doenças , Encefalite/metabolismo , Encefalite/patologia , Feminino , Humanos , Inflamação/metabolismo , Masculino , Transtornos da Memória/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Serpinas/sangue , Serpinas/farmacologia , Memória Espacial/fisiologia , Proteínas Virais/sangue , Proteínas Virais/farmacologia , para-Aminobenzoatos/sangue , para-Aminobenzoatos/farmacologia
3.
Neuron ; 107(4): 731-744.e3, 2020 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-32526196

RESUMO

Hippocampal theta oscillations coordinate neuronal firing to support memory and spatial navigation. The medial septum (MS) is critical in theta generation by two possible mechanisms: either a unitary "pacemaker" timing signal is imposed on the hippocampal system, or it may assist in organizing target subcircuits within the phase space of theta oscillations. We used temperature manipulation of the MS to test these models. Cooling of the MS reduced both theta frequency and power and was associated with an enhanced incidence of errors in a spatial navigation task, but it did not affect spatial correlates of neurons. MS cooling decreased theta frequency oscillations of place cells and reduced distance-time compression but preserved distance-phase compression of place field sequences within the theta cycle. Thus, the septum is critical for sustaining precise theta phase coordination of cell assemblies in the hippocampal system, a mechanism needed for spatial memory.


Assuntos
Hipocampo/fisiologia , Neurônios/fisiologia , Núcleos Septais/fisiologia , Memória Espacial/fisiologia , Ritmo Teta/fisiologia , Potenciais de Ação/fisiologia , Animais , Temperatura Baixa , Masculino , Modelos Neurológicos , Células de Lugar/fisiologia , Ratos , Ratos Long-Evans
4.
Nat Commun ; 11(1): 3247, 2020 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-32591544

RESUMO

The brain derives cognitive maps from sensory experience that guide memory formation and behavior. Despite extensive efforts, it still remains unclear how the underlying population activity unfolds during spatial navigation and how it relates to memory performance. To examine these processes, we combined 7T-fMRI with a kernel-based encoding model of virtual navigation to map world-centered directional tuning across the human cortex. First, we present an in-depth analysis of directional tuning in visual, retrosplenial, parahippocampal and medial temporal cortices. Second, we show that tuning strength, width and topology of this directional code during memory-guided navigation depend on successful encoding of the environment. Finally, we show that participants' locomotory state influences this tuning in sensory and mnemonic regions such as the hippocampus. We demonstrate a direct link between neural population tuning and human cognition, where high-level memory processing interacts with network-wide visuospatial coding in the service of behavior.


Assuntos
Comportamento/fisiologia , Navegação Espacial/fisiologia , Percepção Visual/fisiologia , Adulto , Feminino , Humanos , Lógica , Masculino , Memória Espacial/fisiologia , Análise e Desempenho de Tarefas , Realidade Virtual , Adulto Jovem
5.
Nat Neurosci ; 23(8): 1016-1024, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32572236

RESUMO

Persistent neuronal spiking has long been considered the mechanism underlying working memory, but recent proposals argue for alternative 'activity-silent' substrates. Using monkey and human electrophysiology data, we show here that attractor dynamics that control neural spiking during mnemonic periods interact with activity-silent mechanisms in the prefrontal cortex (PFC). This interaction allows memory reactivations, which enhance serial biases in spatial working memory. Stimulus information was not decodable between trials, but remained present in activity-silent traces inferred from spiking synchrony in the PFC. Just before the new stimulus, this latent trace was reignited into activity that recapitulated the previous stimulus representation. Importantly, the reactivation strength correlated with the strength of serial biases in both monkeys and humans, as predicted by a computational model that integrates activity-based and activity-silent mechanisms. Finally, single-pulse transcranial magnetic stimulation applied to the human PFC between successive trials enhanced serial biases, thus demonstrating the causal role of prefrontal reactivations in determining working-memory behavior.


Assuntos
Memória de Curto Prazo/fisiologia , Neurônios/fisiologia , Córtex Pré-Frontal/fisiologia , Memória Espacial/fisiologia , Adolescente , Adulto , Animais , Eletroencefalografia , Feminino , Humanos , Macaca mulatta , Masculino , Tempo de Reação/fisiologia , Movimentos Sacádicos/fisiologia , Estimulação Magnética Transcraniana , Adulto Jovem
6.
Nat Commun ; 11(1): 2469, 2020 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-32424312

RESUMO

Based on rodent models, researchers have theorized that the hippocampus supports episodic memory and navigation via the theta oscillation, a ~4-10 Hz rhythm that coordinates brain-wide neural activity. However, recordings from humans have indicated that hippocampal theta oscillations are lower in frequency and less prevalent than in rodents, suggesting interspecies differences in theta's function. To characterize human hippocampal theta, we examine the properties of theta oscillations throughout the anterior-posterior length of the hippocampus as neurosurgical subjects performed a virtual spatial navigation task. During virtual movement, we observe hippocampal oscillations at multiple frequencies from 2 to 14 Hz. The posterior hippocampus prominently displays oscillations at ~8-Hz and the precise frequency of these oscillations correlates with the speed of movement, implicating these signals in spatial navigation. We also observe slower ~3 Hz oscillations, but these signals are more prevalent in the anterior hippocampus and their frequency does not vary with movement speed. Our results converge with recent findings to suggest an updated view of human hippocampal electrophysiology. Rather than one hippocampal theta oscillation with a single general role, high- and low-frequency theta oscillations, respectively, may reflect spatial and non-spatial cognitive processes.


Assuntos
Hipocampo/fisiologia , Ritmo Teta/fisiologia , Adulto , Eletrodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Memória Espacial/fisiologia , Análise e Desempenho de Tarefas , Adulto Jovem
7.
J Neurosci ; 40(24): 4644-4660, 2020 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-32376781

RESUMO

Experience powerfully influences neuronal function and cognitive performance, but the cellular and molecular events underlying the experience-dependent enhancement of mental ability have remained elusive. In particular, the mechanisms that couple the external environment to the genomic changes underpinning this improvement are unknown. To address this, we have used male mice harboring an inactivating mutation of mitogen- and stress-activated protein kinase 1 (MSK1), a brain-derived neurotrophic factor (BDNF)-activated enzyme downstream of the mitogen-activated protein kinase (MAPK) pathway. We show that MSK1 is required for the full extent of experience-induced improvement of spatial memory, for the expansion of the dynamic range of synapses, exemplified by the enhancement of hippocampal long-term potentiation (LTP) and long-term depression (LTD), and for the regulation of the majority of genes influenced by enrichment. In addition, and unexpectedly, we show that experience is associated with an MSK1-dependent downregulation of key MAPK and plasticity-related genes, notably of EGR1/Zif268 and Arc/Arg3.1, suggesting the establishment of a novel genomic landscape adapted to experience. By coupling experience to homeostatic changes in gene expression MSK1, represents a prime mechanism through which the external environment has an enduring influence on gene expression, synaptic function, and cognition.SIGNIFICANCE STATEMENT Our everyday experiences strongly influence the structure and function of the brain. Positive experiences encourage the growth and development of the brain and support enhanced learning and memory and resistance to mood disorders such as anxiety. While this has been known for many years, how this occurs is not clear. Here, we show that many of the positive aspects of experience depend on an enzyme called mitogen- and stress-activated protein kinase 1 (MSK1). Using male mice with a mutation in MSK1, we show that MSK1 is necessary for the majority of gene expression changes associated with experience, extending the range over which the communication between neurons occurs, and for both the persistence of memory and the ability to learn new task rules.


Assuntos
Cognição/fisiologia , Hipocampo/metabolismo , Plasticidade Neuronal/fisiologia , Proteínas Quinases S6 Ribossômicas 90-kDa/metabolismo , Memória Espacial/fisiologia , Sinapses/metabolismo , Animais , Espinhas Dendríticas/metabolismo , Técnicas de Silenciamento de Genes , Masculino , Memória de Curto Prazo/fisiologia , Camundongos , Proteínas Quinases S6 Ribossômicas 90-kDa/genética , Transmissão Sináptica/fisiologia
8.
J Neurosci ; 40(25): 4888-4899, 2020 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-32376783

RESUMO

Age-related cognitive impairments are associated with differentially expressed genes (DEGs) linked to defined neural systems; however, studies examining multiple regions of the hippocampus fail to find links between behavior and transcription in the dentate gyrus (DG). We hypothesized that use of a task requiring intact DG function would emphasize molecular signals in the DG associated with a decline in performance. We used a water maze beacon discrimination task to characterize young and middle-age male F344 rats, followed by a spatial reference memory probe trial test. Middle-age rats showed increased variability in discriminating two identical beacons. Use of an allocentric strategy and formation of a spatial reference memory were not different between age groups; however, older animals compensated for impaired beacon discrimination through greater reliance on spatial reference memory. mRNA sequencing of hippocampal subregions indicated DEGs in the DG of middle-age rats, linked to synaptic function and neurogenesis, correlated with beacon discrimination performance, suggesting that senescence of the DG underlies the impairment. Few genes correlated with spatial memory across age groups, with a greater number in region CA1. Age-related CA1 DEGs, correlated with spatial memory, were linked to regulation of neural activity. These results indicate that the beacon task is sensitive to impairment in middle age, and distinct gene profiles are observed in neural circuits that underlie beacon discrimination performance and allocentric memory. The use of different strategies in older animals and associated transcriptional profiles could provide an animal model for examining cognitive reserve and neural compensation of aging.SIGNIFICANCE STATEMENT Hippocampal subregions are thought to differentially contribute to memory. We took advantage of age-related variability in performance on a water maze beacon task and next-generation sequencing to test the hypothesis that aging of the dentate gyrus is linked to impaired beacon discrimination and compensatory use of allocentric memory. The dentate gyrus expressed synaptic function and neurogenesis genes correlated with beacon discrimination in middle-age animals. Spatial reference memory was associated with CA1 transcriptional correlates linked to regulation of neural activity and use of an allocentric strategy. This is the first study examining transcriptomes of multiple hippocampal subregions to link age-related impairments associated with discrimination of feature overlap and alternate response strategies to gene expression in specific hippocampal subregions.


Assuntos
Envelhecimento Cognitivo/fisiologia , Giro Denteado/fisiologia , Hipocampo/fisiologia , Transcriptoma , Animais , Aprendizagem em Labirinto/fisiologia , Ratos , Ratos Endogâmicos F344 , Memória Espacial/fisiologia
9.
Life Sci ; 255: 117828, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32454160

RESUMO

AIMS: To explore the role of chemokine CC motif ligand 2 (CCL2) in spatial memory and cognition impairment, and the underlying mechanisms focused on inflammatory, glutamate metabolistic and apoptotic- associated mRNA expression. MATERIALS AND METHODS: Stereotaxic surgery was performed here to establish a rat model by bilateral intra-hippocampal injection of CCL2. Morris water maze (MWM) and Novel object recognition test (NORT) were used to assess the learning, memory and cognitive ability respectively. RT-PCR was used to detect the relative mRNA expression of inflammatory, glutamate metabolistic and apoptotic- associated indexes. Nissl and TUNEL staining were performed to observe the morphological changes of hippocampal CA1 zone and quantified the apoptosis of hippocampal neurons of CA1 zones respectively. KEY FINDINGS: We found CCL2 injured cognitive function in rats. Six days after CCL2 injection, we revealed the following obvious mRNA expression changes: (1) increasing of the neuroinflammatory cytokines IL-1ß, CXCL-10, IL-6; (2) decreasing of the glutamate transporters GLT-1 and GLAST and increasing of PAG; (3) increasing of the apoptotic genes caspase-8, caspase-3 and Bax, while decreasing the anti-apoptotic gene Bcl-2. Further, Nissl staining and TUNEL confirmed the injury of the structure of hippocampal CA1 zones and the apoptosis of hippocampal neurons. SIGNIFICANCE: Our results indicated that CCL2 impaired spatial memory and cognition, the involving mechanisms may link to the up-regulation of mRNA expression of the three major pathological events: inflammation, excitotoxicity and neuronal apoptosis, which were involved in HIV-associated neurocognitive disorder (HAND). Taken together, these findings suggest a potential therapeutic strategy against CCL2.


Assuntos
Quimiocina CCL2/metabolismo , Infecções por HIV/complicações , Inflamação/patologia , Transtornos da Memória/fisiopatologia , Transtornos Neurocognitivos/fisiopatologia , Animais , Apoptose/fisiologia , Quimiocina CCL2/administração & dosagem , Cognição/fisiologia , Modelos Animais de Doenças , Ácido Glutâmico/metabolismo , Hipocampo/patologia , Masculino , Aprendizagem em Labirinto/fisiologia , Transtornos Neurocognitivos/virologia , Neurônios/patologia , Ratos , Ratos Sprague-Dawley , Memória Espacial/fisiologia
10.
Psychopharmacology (Berl) ; 237(7): 1943-1957, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32399634

RESUMO

RATIONALE: The recreational use of naphyrone, a potent synthetic cathinone with a pyrovalerone structure, has raised questions about possible deleterious neurobehavioral consequences. OBJECTIVE: To investigate naphyrone-induced neurobehavioral effects and alterations in brain monoamines using two patterns of abuse, i.e., single and repeated (binge) use. METHODS: We studied naphyrone dose/induced locomotor activity relationship at 3, 10, 30, and 100 mg/kg in mice. We investigated the effects of single (30 mg/kg; acute injection) versus repeated (30 mg/kg ×3/day for 3 days; binge injection) intraperitoneal naphyrone administration on locomotor activity, anxiety-like behavior, spatial recognition memory, anhedonia, behavioral despair, and social interaction. We measured post-mortem prefrontal cortex levels of monoamines and modeled naphyrone pharmacokinetics and concentration/locomotor effect relationship. RESULTS: Both naphyrone administration patterns induced time-dependent increases in locomotor activity (p < 0.001 and p < 0.0001, respectively) and social interaction (p < 0.05 and p < 0.001, respectively) but did not alter spatial recognition memory or anhedonia. Acute naphyrone injection induced anxiety-like behavior (p < 0.01) and reduced resignation (p < 0.01) whereas binge administration induced non-anxiety-like behavior (p < 0.05) and did not alter behavioral despair. Both patterns increased the prefrontal cortex dopamine (p < 0.0001) and norepinephrine (p < 0.05 and p < 0.01, respectively) but not serotonin content. Naphyrone pharmacokinetics followed a two-compartment model with an overall elimination half-life of 0.3 h. The naphyrone concentration/locomotor effect relationship was described by an additive Emax model with an EC50 of 672 µg/L. CONCLUSIONS: Single naphyrone administration increases locomotor activity according to a direct concentration/effect relationship. The neurobehavioral effects after binge differs from those after single administration and are not explained by drug accumulation given the relatively fast elimination.


Assuntos
Drogas Desenhadas/farmacocinética , Drogas Ilícitas/farmacocinética , Locomoção/efeitos dos fármacos , Pentanonas/farmacocinética , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Pirrolidinas/farmacocinética , Animais , Relação Dose-Resposta a Droga , Locomoção/fisiologia , Masculino , Camundongos , Memória Espacial/efeitos dos fármacos , Memória Espacial/fisiologia
11.
Nat Commun ; 11(1): 2626, 2020 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-32457293

RESUMO

Path integration plays a vital role in navigation: it enables the continuous tracking of one's position in space by integrating self-motion cues. Path integration abilities vary widely across individuals, and tend to deteriorate in old age. The specific causes of path integration errors, however, remain poorly characterized. Here, we combine tests of path integration performance in participants of different ages with an analysis based on the Langevin equation for diffusive dynamics, which allows us to decompose errors into distinct causes that can corrupt path integration computations. We show that, across age groups, the dominant error source is unbiased noise that accumulates with travel distance not elapsed time, suggesting that the noise originates in the velocity input rather than within the integrator. Age-related declines are primarily traced to a growth in this noise. These findings shed light on the contributors to path integration error and the mechanisms underlying age-related navigational deficits.


Assuntos
Envelhecimento Cognitivo/fisiologia , Navegação Espacial/fisiologia , Processamento Espacial/fisiologia , Adulto , Idoso , Percepção de Distância/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Neurológicos , Memória Espacial/fisiologia , Caminhada/fisiologia , Adulto Jovem
12.
Neuron ; 106(6): 992-1008.e9, 2020 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-32320644

RESUMO

Astrocytes play essential roles in brain function by supporting synaptic connectivity and associated circuits. How these roles are regulated by transcription factors is unknown. Moreover, there is emerging evidence that astrocytes exhibit regional heterogeneity, and the mechanisms controlling this diversity remain nascent. Here, we show that conditional deletion of the transcription factor nuclear factor I-A (NFIA) in astrocytes in the adult brain results in region-specific alterations in morphology and physiology that are mediated by selective DNA binding. Disruptions in astrocyte function following loss of NFIA are most pronounced in the hippocampus, manifested by impaired interactions with neurons, coupled with diminution of learning and memory behaviors. These changes in hippocampal astrocytes did not affect basal neuronal properties but specifically inhibited synaptic plasticity, which is regulated by NFIA in astrocytes through calcium-dependent mechanisms. Together, our studies reveal region-specific transcriptional dependencies for astrocytes and identify astrocytic NFIA as a key transcriptional regulator of hippocampal circuits.


Assuntos
Astrócitos/metabolismo , Encéfalo/metabolismo , Cálcio/metabolismo , Regulação da Expressão Gênica , Aprendizagem/fisiologia , Fatores de Transcrição NFI/genética , Animais , Astrócitos/fisiologia , Encéfalo/citologia , Encéfalo/fisiopatologia , Tronco Encefálico/citologia , Tronco Encefálico/metabolismo , Tronco Encefálico/fisiopatologia , Região CA1 Hipocampal/citologia , Região CA1 Hipocampal/metabolismo , Região CA1 Hipocampal/fisiopatologia , Hipocampo/citologia , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Potenciação de Longa Duração/fisiologia , Memória/fisiologia , Camundongos , Camundongos Knockout , Vias Neurais , Plasticidade Neuronal , Neurônios , Bulbo Olfatório/citologia , Bulbo Olfatório/metabolismo , Bulbo Olfatório/fisiopatologia , Técnicas de Patch-Clamp , Córtex Pré-Frontal/citologia , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/fisiopatologia , Memória Espacial/fisiologia
13.
Nat Commun ; 11(1): 1855, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-32296057

RESUMO

Gravity sensing provides a robust verticality signal for three-dimensional navigation. Head direction cells in the mammalian limbic system implement an allocentric neuronal compass. Here we show that head-direction cells in the rodent thalamus, retrosplenial cortex and cingulum fiber bundle are tuned to conjunctive combinations of azimuth and tilt, i.e. pitch or roll. Pitch and roll orientation tuning is anchored to gravity and independent of visual landmarks. When the head tilts, azimuth tuning is affixed to the head-horizontal plane, but also uses gravity to remain anchored to the allocentric bearings in the earth-horizontal plane. Collectively, these results demonstrate that a three-dimensional, gravity-based, neural compass is likely a ubiquitous property of mammalian species, including ground-dwelling animals.


Assuntos
Encéfalo/fisiologia , Gravitação , Animais , Encéfalo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Percepção Espacial/fisiologia , Memória Espacial/fisiologia , Tálamo/metabolismo , Tálamo/fisiologia
14.
J Integr Neurosci ; 19(1): 11-19, 2020 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-32259882

RESUMO

The endocannabinoid system modulates many brain functions, including episodic memories, which contain memories of time and places. Most studies have focused on the involvement of the endocannabinoid system in spatial memory; however, its role in temporal memory is not well understood. Few studies have tested whether the unilateral endocannabinoid system is sufficient to modulate memory retrieval. Here, we tested whether type 1 cannabinoid receptors in the right hippocampal cornu ammonis area 1 region are enough to modulate the retrieval of episodic memories, specifically their spatial and temporal components. Because rats have innate preferences for displaced or old familiar objects, we changed the locations of "old familiar" and "recent familiar" objects in an open field and measured the rats' exploration times to evaluate spatial and temporal memory. To address the influence of the type 1 cannabinoid receptors on the retrieval of episodic-like memories, two doses of arachidonylcyclopropylamide, a selective type 1 cannabinoid receptor agonist, were infused into the cornu ammonis area 1 of rats ten minutes before the discrimination trials. We observed that rats injected with a low dose of arachidonylcyclopropylamide spent less time investigating displaced objects, suggesting spatial memory impairment, whereas those receiving a high dose explored old familiar objects less frequently, suggesting temporal memory impairment. This indicates that unilateral activation of type 1 cannabinoid receptors in the cornu ammonis area 1 impairs the spatial and temporal aspects of episodic memories. This research mimics the influence of marijuana intoxication effects in humans, such as spatial and temporal disintegration.


Assuntos
Região CA1 Hipocampal/fisiologia , Memória Episódica , Rememoração Mental/fisiologia , Receptor CB1 de Canabinoide/fisiologia , Memória Espacial/fisiologia , Animais , Masculino , Ratos Sprague-Dawley , Processamento Espacial/fisiologia , Fatores de Tempo
15.
PLoS One ; 15(3): e0229608, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32126075

RESUMO

Disoriented animals and humans use both the environmental geometry and visual landmarks to guide their spatial behavior. Although there is a broad consensus on the use of environmental geometry across various species of vertebrates, the nature of disoriented landmark-use has been greatly debated in the field. In particular, the discrepancy in performance under spontaneous choice conditions (sometimes called "working memory" task) and training over time ("reference memory" task) has raised questions about the task-dependent dissociability of mechanisms underlying the use of landmarks. Until now, this issue has not been directly addressed, due to the inclusion of environmental geometry in most disoriented navigation paradigms. In the present study, therefore, we placed our focus on landmark-based navigation in fish (Xenotoca eiseni), an animal model that has provided fruitful research in spatial reorientation. We began with a test of spontaneous navigation by geometry and landmarks (Experiment 1), showing a preference for the correct corner, even in the absence of reinforced training. We then proceeded to test landmarks without the influence of informative geometry through the use of square environments (Experiment 2-4), varying the numerosity of present landmarks, the distance of landmarks from the target corner, and the type of task (i.e., spontaneous cued memory or reference memory). We found marked differences in landmark-use in the absence of environmental geometry. In the spontaneous memory task, visual landmarks acquired perceptive salience (and attracted the fish) but without serving as a spatial cue to location when they were distal from the target. Across learning in the reference memory task, the fish overcame these effects and gradually improved in their performance, although they were still biased to learn visual landmarks near the target (i.e., as beacons). We discuss these results in relation to the existing literature on dissociable mechanisms of spatial learning.


Assuntos
Ciprinodontiformes/fisiologia , Aprendizagem Espacial/fisiologia , Animais , Meio Ambiente , Masculino , Memória de Curto Prazo/fisiologia , Modelos Animais , Modelos Neurológicos , Modelos Psicológicos , Orientação Espacial/fisiologia , Estimulação Luminosa , Reforço Psicológico , Memória Espacial/fisiologia
16.
J Neuroinflammation ; 17(1): 52, 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-32028971

RESUMO

BACKGROUND: Microglia play a key role in neuronal circuit and synaptic maturation in the developing brain. In the healthy adult, however, their role is less clear: microglial hyperactivation in adults can be detrimental to memory due to excessive synaptic pruning, yet learning and memory can also be impaired in the absence of these cells. In this study, we therefore aimed to determine how microglia contribute to short-term memory in healthy adults. METHODS: To this end, we developed a Cx3cr1-Dtr transgenic Wistar rat with a diphtheria toxin receptor (Dtr) gene inserted into the fractalkine receptor (Cx3cr1) promoter, expressed on microglia and monocytes. This model allows acute microglial and monocyte ablation upon application of diphtheria toxin, enabling us to directly assess microglia's role in memory. RESULTS: Here, we show that short-term memory in the novel object and place recognition tasks is entirely unaffected by acute microglial ablation. However, when microglia repopulate the brain after depletion, learning and memory performance in these tasks is improved. This transitory memory enhancement is associated with an ameboid morphology in the newly repopulated microglial cells and increased astrocyte density that are linked with a higher density of mature hippocampal synaptic spines and differences in pre- and post-synaptic markers. CONCLUSIONS: These data indicate that glia play a complex role in the healthy adult animal in supporting appropriate learning and memory and that subtle changes to the function of these cells may strategically enhance memory.


Assuntos
Encéfalo/metabolismo , Receptor 1 de Quimiocina CX3C/metabolismo , Memória de Curto Prazo/fisiologia , Microglia/metabolismo , Monócitos/metabolismo , Memória Espacial/fisiologia , Animais , Receptor 1 de Quimiocina CX3C/genética , Masculino , Regiões Promotoras Genéticas , Ratos , Ratos Transgênicos , Ratos Wistar
17.
Nat Commun ; 11(1): 789, 2020 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-32034157

RESUMO

Place cells are spatially modulated neurons found in the hippocampus that underlie spatial memory and navigation: how these neurons represent 3D space is crucial for a full understanding of spatial cognition. We wirelessly recorded place cells in rats as they explored a cubic lattice climbing frame which could be aligned or tilted with respect to gravity. Place cells represented the entire volume of the mazes: their activity tended to be aligned with the maze axes, and when it was more difficult for the animals to move vertically the cells represented space less accurately and less stably. These results demonstrate that even surface-dwelling animals represent 3D space and suggests there is a fundamental relationship between environment structure, gravity, movement and spatial memory.


Assuntos
Células de Lugar/fisiologia , Percepção Espacial/fisiologia , Memória Espacial/fisiologia , Animais , Gravitação , Aprendizagem em Labirinto , Ratos , Telemetria/métodos
18.
Brain Struct Funct ; 225(2): 751-761, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32036422

RESUMO

Rostral intralaminar thalamic deep brain stimulation (ILN-DBS) has been shown to enhance attention and cognition through neuronal activation and brain plasticity. We examined whether rostral ILN-DBS can also attenuate memory deficits and impaired synaptic plasticity and protect glutamatergic transmission in the rat intraventricular ß-amyloid (Aß) infusion model of Alzheimer's disease (AD). Spatial memory was tested in the Morris water maze (MWM), while structural synaptic plasticity and glutamatergic transmission strength were estimated by measuring dendritic spine densities in dye-injected neurons and tissue expression levels of postsynaptic density protein 95 (PSD-95) in medial prefrontal cortex (mPFC) and hippocampus. All these assessments were compared among the naïve control rats, AD rats, and AD rats with ILN-DBS. We found that a single rostral ILN-DBS treatment significantly improved MWM performance and reversed PSD-95 expression reductions in the mPFC and hippocampal region of Aß-infused rats. In addition, ILN-DBS preserved dendritic spine densities on mPFC and hippocampal pyramidal neurons. In fact, MWM performance, PSD-95 expression levels, and dendritic spine densities did not differ between naïve control and rostral ILN-DBS treatment groups, indicating near complete amelioration of Aß-induced spatial memory impairments and dendritic regression. These findings suggest that the ILN is critical for modulating glutamatergic transmission, neural plasticity, and spatial memory functions through widespread effects on distributed brain regions. Further, these findings provide a rationale for examining the therapeutic efficacy of ILN-DBS in AD patients.


Assuntos
Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/toxicidade , Dendritos/fisiologia , Hipocampo/fisiologia , Núcleos Intralaminares do Tálamo/fisiologia , Córtex Pré-Frontal/fisiologia , Aprendizagem Espacial/fisiologia , Memória Espacial/fisiologia , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/administração & dosagem , Animais , Dendritos/efeitos dos fármacos , Modelos Animais de Doenças , Estimulação Elétrica , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Injeções Intraventriculares , Núcleos Intralaminares do Tálamo/efeitos dos fármacos , Masculino , Córtex Pré-Frontal/citologia , Córtex Pré-Frontal/efeitos dos fármacos , Ratos Wistar , Aprendizagem Espacial/efeitos dos fármacos , Memória Espacial/efeitos dos fármacos
19.
Life Sci ; 248: 117468, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32105705

RESUMO

AIMS: Treatment with 5-fluorouracil (5-FU) can cause impairment to adult hippocampal neurogenesis, resulting in cognitive deficits. As melatonin has been shown to enhance memory and hippocampal neurogenesis in animal models, this research investigated the neuroprotective effects of melatonin against spatial memory and hippocampal neurogenesis impairment in 5-fluorouracil (5-FU)-treated rats. MATERIALS AND METHODS: Four-Five weeks old male Spraque-Dawley rats weighing between 180 and 200 g were used. Animals were maintained under standard laboratory conditions with 25 °C and 12 h light/dark cycle. Animal were administered intravenous (i.v.) injections of 5-FU (25 mg/kg) 5 times every 3 days starting on day 9 of the experiment. The rats were divided into preventive, recovery, and throughout groups and co-treated with melatonin (8 mg/kg, i.p.) once daily (at 7.00 pm) for 21 days prior to, after, and throughout 5-FU treatment, respectively. Spatial memory was assessed using a novel object location (NOL) test. Hippocampal neurogenesis was then examined using Ki67, bromodeoxyuridine (BrdU), and doublecortin (DCX) immunohistochemistry staining. KEY FINDINGS: Melatonin administration was able to both protect the subjects from and reverse spatial memory deficits. 5-FU was also found to reduce the generation of hippocampal newborn neurons. However, co-treatment with melatonin ameliorated the reductions in neurogenesis caused by 5-FU. SIGNIFICANCE: These findings suggest that melatonin administration was able to ameliorate the 5-FU-induced spatial memory deficits associated with neurogenesis. The present work will be valuable for patients who suffer memory deficits from 5-FU chemotherapy.


Assuntos
Disfunção Cognitiva/tratamento farmacológico , Fluoruracila/antagonistas & inibidores , Melatonina/farmacologia , Transtornos da Memória/tratamento farmacológico , Neurogênese/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Memória Espacial/efeitos dos fármacos , Animais , Antimetabólitos/efeitos adversos , Biomarcadores/metabolismo , Proliferação de Células/efeitos dos fármacos , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/fisiopatologia , Giro Denteado/efeitos dos fármacos , Giro Denteado/metabolismo , Giro Denteado/patologia , Esquema de Medicação , Fluoruracila/efeitos adversos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Injeções Intravenosas , Antígeno Ki-67/genética , Antígeno Ki-67/metabolismo , Masculino , Transtornos da Memória/metabolismo , Transtornos da Memória/fisiopatologia , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Neurogênese/genética , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Neuropeptídeos/genética , Neuropeptídeos/metabolismo , Ratos , Ratos Sprague-Dawley , Memória Espacial/fisiologia
20.
J Neurosci ; 40(7): 1581-1593, 2020 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-31915254

RESUMO

Alzheimer's disease (AD) is the most common neurodegenerative disorder, resulting in the progressive decline of cognitive function in patients. Familial forms of AD are tied to mutations in the amyloid precursor protein, but the cellular mechanisms that cause AD remain unclear. Inflammation and amyloidosis from amyloid ß (Aß) aggregates are implicated in neuron loss and cognitive decline. Inflammation activates the protein-tyrosine phosphatase 1B (PTP1B), and this could suppress many signaling pathways that activate glycogen synthase kinase 3ß (GSK3ß) implicated in neurodegeneration. However, the significance of PTP1B in AD pathology remains unclear. Here, we show that pharmacological inhibition of PTP1B with trodusquemine or selective ablation of PTP1B in neurons prevents hippocampal neuron loss and spatial memory deficits in a transgenic AD mouse model with Aß pathology (hAPP-J20 mice of both sexes). Intriguingly, while systemic inhibition of PTP1B reduced inflammation in the hippocampus, neuronal PTP1B ablation did not. These results dissociate inflammation from neuronal loss and cognitive decline and demonstrate that neuronal PTP1B hastens neurodegeneration and cognitive decline in this model of AD. The protective effect of PTP1B inhibition or ablation coincides with the restoration of GSK3ß inhibition. Neuronal ablation of PTP1B did not affect cerebral amyloid levels or plaque numbers, but reduced Aß plaque size in the hippocampus. In summary, our preclinical study suggests that targeting PTP1B may be a new strategy to intervene in the progression of AD.SIGNIFICANCE STATEMENT Familial forms of Alzheimer's disease (AD) are tied to mutations in the amyloid precursor protein, but the cellular mechanisms that cause AD remain unclear. Here, we used a mouse model expressing human amyloid precursor protein bearing two familial mutations and asked whether activation of a phosphatase PTP1B participates in the disease process. Systemic inhibition of this phosphatase using a selective inhibitor prevented cognitive decline, neuron loss in the hippocampus, and attenuated inflammation. Importantly, neuron-targeted ablation of PTP1B also prevented cognitive decline and neuron loss but did not reduce inflammation. Therefore, neuronal loss rather than inflammation was critical for AD progression in this mouse model, and that disease progression could be ameliorated by inhibition of PTP1B.


Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Proteínas do Tecido Nervoso/fisiologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/fisiologia , Memória Espacial/fisiologia , Peptídeos beta-Amiloides/análise , Animais , Colestanos/farmacologia , Modelos Animais de Doenças , Feminino , Glicogênio Sintase Quinase 3 beta/fisiologia , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Humanos , Inflamação , Resistência à Insulina , Masculino , Aprendizagem em Labirinto , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação , Proteínas do Tecido Nervoso/antagonistas & inibidores , Fragmentos de Peptídeos/análise , Placa Amiloide/patologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Proteínas Recombinantes/metabolismo , Memória Espacial/efeitos dos fármacos , Espermina/análogos & derivados , Espermina/farmacologia
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