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1.
Sci Rep ; 14(1): 14315, 2024 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-38906952

RESUMO

Head-fixation of mice enables high-resolution monitoring of neuronal activity coupled with precise control of environmental stimuli. Virtual reality can be used to emulate the visual experience of movement during head fixation, but a low inertia floating real-world environment (mobile homecage, MHC) has the potential to engage more sensory modalities and provide a richer experimental environment for complex behavioral tasks. However, it is not known whether mice react to this adapted environment in a similar manner to real environments, or whether the MHC can be used to implement validated, maze-based behavioral tasks. Here, we show that hippocampal place cell representations are intact in the MHC and that the system allows relatively long (20 min) whole-cell patch clamp recordings from dorsal CA1 pyramidal neurons, revealing sub-threshold membrane potential dynamics. Furthermore, mice learn the location of a liquid reward within an adapted T-maze guided by 2-dimensional spatial navigation cues and relearn the location when spatial contingencies are reversed. Bilateral infusions of scopolamine show that this learning is hippocampus-dependent and requires intact cholinergic signalling. Therefore, we characterize the MHC system as an experimental tool to study sub-threshold membrane potential dynamics that underpin complex navigation behaviors.


Assuntos
Hipocampo , Aprendizagem em Labirinto , Navegação Espacial , Animais , Camundongos , Navegação Espacial/fisiologia , Masculino , Hipocampo/fisiologia , Células Piramidais/fisiologia , Camundongos Endogâmicos C57BL , Potenciais da Membrana/fisiologia , Região CA1 Hipocampal/fisiologia , Realidade Virtual , Escopolamina/farmacologia , Técnicas de Patch-Clamp/métodos
3.
Nat Commun ; 12(1): 5475, 2021 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-34531380

RESUMO

Acetylcholine release in the hippocampus plays a central role in the formation of new memory representations. An influential but largely untested theory proposes that memory formation requires acetylcholine to enhance responses in CA1 to new sensory information from entorhinal cortex whilst depressing inputs from previously encoded representations in CA3. Here, we show that excitatory inputs from entorhinal cortex and CA3 are depressed equally by synaptic release of acetylcholine in CA1. However, feedforward inhibition from entorhinal cortex exhibits greater depression than CA3 resulting in a selective enhancement of excitatory-inhibitory balance and CA1 activation by entorhinal inputs. Entorhinal and CA3 pathways engage different feedforward interneuron subpopulations and cholinergic modulation of presynaptic function is mediated differentially by muscarinic M3 and M4 receptors, respectively. Thus, our data support a role and mechanisms for acetylcholine to prioritise novel information inputs to CA1 during memory formation.


Assuntos
Acetilcolina/metabolismo , Região CA1 Hipocampal/fisiologia , Córtex Entorrinal/fisiologia , Potenciais Pós-Sinápticos Excitadores/fisiologia , Retroalimentação Fisiológica/fisiologia , Transmissão Sináptica/fisiologia , Animais , Região CA1 Hipocampal/citologia , Carbacol/farmacologia , Agonistas Colinérgicos/farmacologia , Córtex Entorrinal/citologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Retroalimentação Fisiológica/efeitos dos fármacos , Interneurônios/metabolismo , Interneurônios/fisiologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Técnicas de Patch-Clamp , Células Piramidais/metabolismo , Células Piramidais/fisiologia , Receptor Muscarínico M3/genética , Receptor Muscarínico M3/metabolismo , Transmissão Sináptica/efeitos dos fármacos
4.
Curr Opin Neurobiol ; 54: 37-43, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30212713

RESUMO

Multiple neuromodulators including acetylcholine, noradrenaline, dopamine and serotonin are released in response to uncertainty to focus attention on events where the predicted outcome does not match observed reality. In these situations, internal representations need to be updated, a process that requires long-term synaptic plasticity. Through a variety of common and divergent mechanisms, it is recently shown that all these neuromodulators facilitate the induction and/or expression of long-term synaptic plasticity within the hippocampus. Under physiological conditions, this may be critical for suprathreshold induction of plasticity endowing neuromodulators with a gating function and providing a mechanism by which neuromodulators enable the targeted updating of memory with relevant information to improve the accuracy of future predictions.


Assuntos
Hipocampo/citologia , Potenciação de Longa Duração/fisiologia , Neurônios/fisiologia , Neurotransmissores/metabolismo , Animais , Hipocampo/fisiologia , Humanos , Potenciação de Longa Duração/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurotransmissores/farmacologia , Canais de Potássio/fisiologia , Receptores de N-Metil-D-Aspartato/fisiologia
5.
Cereb Cortex ; 26(4): 1464-72, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25316333

RESUMO

When native and recombinant kainate receptors (KARs) are compared, there is a mismatch in several of their functional properties. While both generate currents, synaptic responses mediated by KARs have rarely observed in cultured hippocampal neurons. The recent discovery of auxiliary proteins for KARs, such as Netos, offers an explanation for these discrepancies. We found that the GluK5 KAR subunit and the ancillary proteins, Neto1 and Neto2, are not expressed by hippocampal neurons in culture. Therefore, we used this model to directly test whether these proteins are required for the synaptic localization of KARs. Transfection of GluK4, GluK5, Neto1, or Neto2 into hippocampal neurons was associated with the appearance of synaptic KAR-mediated EPSCs. However, GluK4 or GluK5 alone produced synaptic activity in a significant proportion of cells and with reliable event frequency. While neurons expressing GluK4 or GluK5 subunits displayed synaptic responses with rapid kinetics, the expression of Neto proteins conferred these synaptic responses with their characteristic slow onset and decay rates. These data reveal some requirements for KAR targeting to the synapse, indicating a fundamental role of high affinity KAR subunits in this process.


Assuntos
Hipocampo/metabolismo , Lipoproteínas LDL/metabolismo , Proteínas de Membrana/metabolismo , Neurônios/metabolismo , Receptores de Ácido Caínico/metabolismo , Sinapses/metabolismo , Animais , Células Cultivadas , Potenciais Pós-Sinápticos Excitadores , Células HEK293 , Hipocampo/fisiologia , Humanos , Proteínas Relacionadas a Receptor de LDL , Lipoproteínas LDL/fisiologia , Proteínas de Membrana/fisiologia , Camundongos , Neurônios/fisiologia , Subunidades Proteicas/metabolismo , Subunidades Proteicas/fisiologia , Transporte Proteico , Receptores de Ácido Caínico/fisiologia , Receptores de N-Metil-D-Aspartato , Sinapses/fisiologia
6.
Exp Neurol ; 229(2): 226-37, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21295028

RESUMO

With increasing life expectancy, Alzheimer's disease (AD) and other dementias pose an increasing and as yet unresolved health problem. A variety of cellular models of AD has helped to decipher some key aspects of amyloid and tau related degeneration. The initial approach of extracellular applications of synthetic peptides has now been replaced by the introduction of amyloid precursor protein (APP) and tau genes. In the present study adenoviral transductions were exploited for gene delivery into primary rat hippocampal and dorsal root ganglion (DRG) cultures to enable comparative and mechanistic studies at the cellular level and subsequent drug testing. Time lapse experiments revealed a different pattern of cell death: apoptotic-like for APP whereas tau positive cells joined and formed clusters. Mutated human APP or tau expression caused accelerated neuronal damage and cell death (cf. EGFP: -50% for APP at 5 days; -40% for tau at 3 days). This reduction in viability was preceded by decreased excitability, monitored via responses to depolarising KCl-challenges in Ca(2+) imaging experiments. Additionally, both transgenes reduced neurite outgrowth in DRG neurones. Treatment studies confirmed that APP induced-damage can be ameliorated by ß- and γ-secretase inhibitors (providing protection to 60-100% of control levels), clioquinol (80%) and lithium (100%); while anti-aggregation treatments were beneficial for tau-induced damage (60-90% recovery towards controls). Interestingly, caffeine was the most promising drug candidate for therapeutic intervention with high efficacy in both APP (77%) and tau-induced models (72% recovery). Overall, these cellular models offer advantages for mechanistic studies and target identification in AD and related disorders.


Assuntos
Adenoviridae/genética , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/genética , Morte Celular/genética , Degeneração Neural/genética , Transdução Genética/métodos , Proteínas tau/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Animais , Western Blotting , Cálcio/metabolismo , Linhagem Celular , Células Cultivadas , Dendritos/metabolismo , Dendritos/patologia , Gânglios Espinais/metabolismo , Gânglios Espinais/patologia , Vetores Genéticos , Hipocampo/metabolismo , Hipocampo/patologia , Degeneração Neural/metabolismo , Degeneração Neural/patologia , Neurônios/metabolismo , Neurônios/patologia , Ratos , Ratos Sprague-Dawley , Proteínas tau/metabolismo
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