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1.
Biomed Eng Online ; 20(1): 25, 2021 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-33750406

RESUMO

BACKGROUND: Electrical pulse stimulations have been applied in brain for treating certain diseases such as movement disorders. High-frequency stimulations (HFS) of biphasic pulses have been used in clinic stimulations, such as deep brain stimulation (DBS), to minimize the risk of tissue damages caused by the electrical stimulations. However, HFS sequences of monophasic pulses have often been used in animal experiments for studying neuronal responses to the stimulations. It is not clear yet what the differences of the neuronal responses to the HFS of monophasic pulses from the HFS of biphasic pulses are. METHODS: To investigate the neuronal responses to the two types of pulses, orthodromic-HFS (O-HFS) and antidromic-HFS (A-HFS) of biphasic and monophasic pulses (1-min) were delivered by bipolar electrodes, respectively, to the Schaffer collaterals (i.e., afferent fibers) and the alveus fibers (i.e., efferent fibers) of the rat hippocampal CA1 region in vivo. Evoked population spikes of CA1 pyramidal neurons to the HFSs were recorded in the CA1 region. In addition, single pulses of antidromic- and orthodromic-test stimuli were applied before and after HFSs to evaluate the baseline and the recovery of neuronal activity, respectively. RESULTS: Spreading depression (SD) appeared during sequences of 200-Hz monophasic O-HFS with a high incidence (4/5), but did not appear during corresponding 200-Hz biphasic O-HFS (0/6). A preceding burst of population spikes appeared before the SD waveforms. Then, the SD propagated slowly, silenced neuronal firing temporarily and resulted in partial recovery of orthodromically evoked population spikes (OPS) after the end of O-HFS. No SD events appeared during the O-HFS with a lower frequency of 100 Hz of monophasic or biphasic pulses (0/5 and 0/6, respectively), neither during the A-HFS of 200-Hz pulses (0/9). The antidromically evoked population spikes (APS) after 200-Hz biphasic A-HFS recovered to baseline level within ~ 2 min. However, the APS only recovered partially after the 200-Hz A-HFS of monophasic pulses. CONCLUSIONS: The O-HFS with a higher frequency of monophasic pulses can induce the abnormal neuron activity of SD and the A-HFS of monophasic pulses can cause a persisting attenuation of neuronal excitability, indicating neuronal damages caused by monophasic stimulations in brain tissues. The results provide guidance for proper stimulation protocols in clinic and animal experiments.


Assuntos
Potenciais de Ação , Região CA1 Hipocampal/fisiologia , Estimulação Elétrica , Eletrodos , Células Piramidais/fisiologia , Animais , Artefatos , Axônios , Estimulação Encefálica Profunda , Masculino , Ratos , Ratos Sprague-Dawley
2.
Neuron ; 109(6): 1040-1054.e7, 2021 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-33539763

RESUMO

Memory models often emphasize the need to encode novel patterns of neural activity imposed by sensory drive. Prior learning and innate architecture likely restrict neural plasticity, however. Here, we test how the incorporation of synthetic hippocampal signals is constrained by preexisting circuit dynamics. We optogenetically stimulated small groups of CA1 neurons as mice traversed a chosen segment of a linear track, mimicking the emergence of place fields. Stimulation induced persistent place field remapping in stimulated and non-stimulated neurons. The emergence of place fields could be predicted from sporadic firing in the new place field location and the temporal relationship to peer neurons before the optogenetic perturbation. Circuit modification was reflected by altered spike transmission between connected pyramidal cells and inhibitory interneurons, which persisted during post-experience sleep. We hypothesize that optogenetic perturbation unmasked sub-threshold place fields. Plasticity in recurrent/lateral inhibition may drive learning through the rapid association of existing states.


Assuntos
Região CA1 Hipocampal/fisiologia , Aprendizagem/fisiologia , Plasticidade Neuronal/fisiologia , Neurônios/fisiologia , Animais , Camundongos , Optogenética
3.
Neuron ; 109(6): 997-1012.e9, 2021 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-33529646

RESUMO

Interneurons expressing cholecystokinin (CCK) and parvalbumin (PV) constitute two key GABAergic controllers of hippocampal pyramidal cell output. Although the temporally precise and millisecond-scale inhibitory regulation of neuronal ensembles delivered by PV interneurons is well established, the in vivo recruitment patterns of CCK-expressing basket cell (BC) populations has remained unknown. We show in the CA1 of the mouse hippocampus that the activity of CCK BCs inversely scales with both PV and pyramidal cell activity at the behaviorally relevant timescales of seconds. Intervention experiments indicated that the inverse coupling of CCK and PV GABAergic systems arises through a mechanism involving powerful inhibitory control of CCK BCs by PV cells. The tightly coupled complementarity of two key microcircuit regulatory modules demonstrates a novel form of brain-state-specific segregation of inhibition during spontaneous behavior.


Assuntos
Região CA1 Hipocampal/fisiologia , Interneurônios/fisiologia , Células Piramidais/fisiologia , Transmissão Sináptica/fisiologia , Animais , Colecistocinina/metabolismo , Feminino , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Parvalbuminas/metabolismo
4.
Nat Commun ; 12(1): 100, 2021 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-33397954

RESUMO

Hippocampal synaptic plasticity includes both long-term potentiation (LTP) and long-term depression (LTD) of synaptic strength, and has been implicated in shaping place field representations that form upon initial exposure to a novel environment. However, direct evidence causally linking either LTP or LTD to place fields remains limited. Here, we show that hippocampal LTD regulates the acute formation and maintenance of place fields using electrophysiology and blocking specifically LTD in freely-moving rats. We also show that exploration of a novel environment produces a widespread and pathway specific de novo synaptic depression in the dorsal hippocampus. Furthermore, disruption of this pathway-specific synaptic depression alters both the dynamics of place field formation and the stability of the newly formed place fields, affecting spatial memory in rats. These results suggest that activity-dependent synaptic depression is required for the acquisition and maintenance of novel spatial information.


Assuntos
Região CA1 Hipocampal/fisiologia , Depressão Sináptica de Longo Prazo/fisiologia , Potenciais de Ação/fisiologia , Animais , Aprendizagem da Esquiva , Endocitose , Potenciais Pós-Sinápticos Excitadores/fisiologia , Comportamento Exploratório , Peptídeos/metabolismo , Ratos Sprague-Dawley , Receptores de AMPA/metabolismo
5.
Nat Commun ; 12(1): 413, 2021 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-33462202

RESUMO

Long-term potentiation (LTP) at hippocampal CA1 synapses can be expressed by an increase either in the number (N) of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors or in their single channel conductance (γ). Here, we have established how these distinct synaptic processes contribute to the expression of LTP in hippocampal slices obtained from young adult rodents. LTP induced by compressed theta burst stimulation (TBS), with a 10 s inter-episode interval, involves purely an increase in N (LTPN). In contrast, either a spaced TBS, with a 10 min inter-episode interval, or a single TBS, delivered when PKA is activated, results in LTP that is associated with a transient increase in γ (LTPγ), caused by the insertion of calcium-permeable (CP)-AMPA receptors. Activation of CaMKII is necessary and sufficient for LTPN whilst PKA is additionally required for LTPγ. Thus, two mechanistically distinct forms of LTP co-exist at these synapses.


Assuntos
Região CA1 Hipocampal/fisiologia , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Potenciais Pós-Sinápticos Excitadores/fisiologia , Potenciação de Longa Duração/fisiologia , Receptores de AMPA/metabolismo , Animais , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Masculino , Memória de Longo Prazo/fisiologia , Técnicas de Patch-Clamp , Ratos , Ritmo Teta/fisiologia
6.
Elife ; 92020 12 23.
Artigo em Inglês | MEDLINE | ID: mdl-33355091

RESUMO

Synapse formation and regulation require signaling interactions between pre- and postsynaptic proteins, notably cell adhesion molecules (CAMs). It has been proposed that the functions of neuroligins (Nlgns), postsynaptic CAMs, rely on the formation of trans-synaptic complexes with neurexins (Nrxns), presynaptic CAMs. Nlgn3 is a unique Nlgn isoform that localizes at both excitatory and inhibitory synapses. However, Nlgn3 function mediated via Nrxn interactions is unknown. Here we demonstrate that Nlgn3 localizes at postsynaptic sites apposing vesicular glutamate transporter 3-expressing (VGT3+) inhibitory terminals and regulates VGT3+ inhibitory interneuron-mediated synaptic transmission in mouse organotypic slice cultures. Gene expression analysis of interneurons revealed that the αNrxn1+AS4 splice isoform is highly expressed in VGT3+ interneurons as compared with other interneurons. Most importantly, postsynaptic Nlgn3 requires presynaptic αNrxn1+AS4 expressed in VGT3+ interneurons to regulate inhibitory synaptic transmission. Our results indicate that specific Nlgn-Nrxn signaling generates distinct functional properties at synapses.


Assuntos
Proteínas de Ligação ao Cálcio/fisiologia , Moléculas de Adesão Celular Neuronais/fisiologia , Neurônios GABAérgicos/fisiologia , Hipocampo/fisiologia , Proteínas de Membrana/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Moléculas de Adesão de Célula Nervosa/fisiologia , Animais , Região CA1 Hipocampal/fisiologia , Feminino , Técnicas de Silenciamento de Genes , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Sinapses/fisiologia
7.
Science ; 370(6513): 247-250, 2020 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-33033222

RESUMO

Neural networks display the ability to transform forward-ordered activity patterns into reverse-ordered, retrospective sequences. The mechanisms underlying this transformation remain unknown. We discovered that, during active navigation, rat hippocampal CA1 place cell ensembles are inherently organized to produce independent forward- and reverse-ordered sequences within individual theta oscillations. This finding may provide a circuit-level basis for retrospective evaluation and storage during ongoing behavior. Theta phase procession arose in a minority of place cells, many of which displayed two preferred firing phases in theta oscillations and preferentially participated in reverse replay during subsequent rest. These findings reveal an unexpected aspect of theta-based hippocampal encoding and provide a biological mechanism to support the expression of reverse-ordered sequences.


Assuntos
Adaptação Psicológica/fisiologia , Região CA1 Hipocampal/fisiologia , Ritmo Teta , Animais , Masculino , Ratos , Ratos Endogâmicos LEC
8.
Nat Commun ; 11(1): 4395, 2020 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-32879322

RESUMO

The formation and maintenance of spatial representations within hippocampal cell assemblies is strongly dictated by patterns of inhibition from diverse interneuron populations. Although it is known that inhibitory synaptic strength is malleable, induction of long-term plasticity at distinct inhibitory synapses and its regulation of hippocampal network activity is not well understood. Here, we show that inhibitory synapses from parvalbumin and somatostatin expressing interneurons undergo long-term depression and potentiation respectively (PV-iLTD and SST-iLTP) during physiological activity patterns. Both forms of plasticity rely on T-type calcium channel activation to confer synapse specificity but otherwise employ distinct mechanisms. Since parvalbumin and somatostatin interneurons preferentially target perisomatic and distal dendritic regions respectively of CA1 pyramidal cells, PV-iLTD and SST-iLTP coordinate a reprioritisation of excitatory inputs from entorhinal cortex and CA3. Furthermore, circuit-level modelling reveals that PV-iLTD and SST-iLTP cooperate to stabilise place cells while facilitating representation of multiple unique environments within the hippocampal network.


Assuntos
Hipocampo/fisiologia , Interneurônios/metabolismo , Células Piramidais/fisiologia , Potenciais de Ação , Animais , Região CA1 Hipocampal/citologia , Região CA1 Hipocampal/fisiologia , Canais de Cálcio Tipo T/metabolismo , Channelrhodopsins/metabolismo , Hipocampo/citologia , Camundongos , Optogenética/métodos , Parvalbuminas/metabolismo , Técnicas de Patch-Clamp , Transdução de Sinais , Somatostatina/metabolismo , Sinapses/metabolismo
9.
Nat Commun ; 11(1): 4559, 2020 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-32917906

RESUMO

The temporal embryonic origins of cortical GABA neurons are critical for their specialization. In the neonatal hippocampus, GABA cells born the earliest (ebGABAs) operate as 'hubs' by orchestrating population synchrony. However, their adult fate remains largely unknown. To fill this gap, we have examined CA1 ebGABAs using a combination of electrophysiology, neurochemical analysis, optogenetic connectivity mapping as well as ex vivo and in vivo calcium imaging. We show that CA1 ebGABAs not only operate as hubs during development, but also maintain distinct morpho-physiological and connectivity profiles, including a bias for long-range targets and local excitatory inputs. In vivo, ebGABAs are activated during locomotion, correlate with CA1 cell assemblies and display high functional connectivity. Hence, ebGABAs are specified from birth to ensure unique functions throughout their lifetime. In the adult brain, this may take the form of a long-range hub role through the coordination of cell assemblies across distant regions.


Assuntos
Neurônios GABAérgicos/fisiologia , Hipocampo/fisiologia , Animais , Axônios , Encéfalo , Região CA1 Hipocampal/fisiologia , Feminino , Masculino , Camundongos , Modelos Animais , Vias Neurais/fisiologia , Optogenética , Sinapses/fisiologia
10.
PLoS Comput Biol ; 16(7): e1007955, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32649658

RESUMO

During the exploration of novel environments, place fields are rapidly formed in hippocampal CA1 neurons. Place cell firing rate increases in early stages of exploration of novel environments but returns to baseline levels in familiar environments. Although similar in amplitude and width, place fields in familiar environments are more stable than in novel environments. We propose a computational model of the hippocampal CA1 network, which describes the formation, dynamics and stabilization of place fields. We show that although somatic disinhibition is sufficient to form place fields, dendritic inhibition along with synaptic plasticity is necessary for place field stabilization. Our model suggests that place cell stability can be attributed to strong excitatory synaptic weights and strong dendritic inhibition. We show that the interplay between somatic and dendritic inhibition balances the increased excitatory weights, such that place cells return to their baseline firing rate after exploration. Our model suggests that different types of interneurons are essential to unravel the mechanisms underlying place field plasticity. Finally, we predict that artificially induced dendritic events can shift place fields even after place field stabilization.


Assuntos
Região CA1 Hipocampal , Dendritos/fisiologia , Inibição Neural/fisiologia , Células de Lugar/fisiologia , Potenciais de Ação/fisiologia , Animais , Região CA1 Hipocampal/citologia , Região CA1 Hipocampal/fisiologia , Biologia Computacional , Camundongos , Modelos Neurológicos , Plasticidade Neuronal/fisiologia
11.
Nat Commun ; 11(1): 3451, 2020 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-32651370

RESUMO

When our experience violates our predictions, it is adaptive to upregulate encoding of novel information, while down-weighting retrieval of erroneous memory predictions to promote an updated representation of the world. We asked whether mnemonic prediction errors promote hippocampal encoding versus retrieval states, as marked by distinct network connectivity between hippocampal subfields. During fMRI scanning, participants were cued to internally retrieve well-learned complex room-images and were then presented with either an identical or a modified image (0-4 changes). In the left hemisphere, we find that CA1-entorhinal connectivity increases, and CA1-CA3 connectivity decreases, with the number of changes. Further, in the left CA1, the similarity between activity patterns during cued-retrieval of the learned room and during the image is lower when the image includes changes, consistent with a prediction error signal in CA1. Our findings provide a mechanism by which mnemonic prediction errors may drive memory updating-by biasing hippocampal states.


Assuntos
Cognição/fisiologia , Hipocampo/metabolismo , Hipocampo/fisiologia , Região CA1 Hipocampal/metabolismo , Região CA1 Hipocampal/fisiologia , Córtex Entorrinal/metabolismo , Córtex Entorrinal/fisiologia , Humanos , Aprendizagem/fisiologia , Imagem por Ressonância Magnética , Memória de Longo Prazo/fisiologia
12.
Neuron ; 107(4): 703-716.e4, 2020 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-32521223

RESUMO

Neurons are often considered specialized functional units that encode a single variable. However, many neurons are observed to respond to a mix of disparate sensory, cognitive, and behavioral variables. For such representations, information is distributed across multiple neurons. Here we find this distributed code in the dentate gyrus and CA1 subregions of the hippocampus. Using calcium imaging in freely moving mice, we decoded an animal's position, direction of motion, and speed from the activity of hundreds of cells. The response properties of individual neurons were only partially predictive of their importance for encoding position. Non-place cells encoded position and contributed to position encoding when combined with other cells. Indeed, disrupting the correlations between neural activities decreased decoding performance, mostly in CA1. Our analysis indicates that population methods rather than classical analyses based on single-cell response properties may more accurately characterize the neural code in the hippocampus.


Assuntos
Potenciais de Ação/fisiologia , Região CA1 Hipocampal/fisiologia , Cálcio/metabolismo , Giro Denteado/fisiologia , Neurônios/fisiologia , Comportamento Espacial/fisiologia , Animais , Camundongos
13.
Proc Natl Acad Sci U S A ; 117(27): 16000-16008, 2020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-32571910

RESUMO

Carbonic anhydrases (CAs; EC 4.2.1.1) are metalloenzymes present in mammals with 16 isoforms that differ in terms of catalytic activity as well as cellular and tissue distribution. CAs catalyze the conversion of CO2 to bicarbonate and protons and are involved in various physiological processes, including learning and memory. Here we report that the integrity of CA activity in the brain is necessary for the consolidation of fear extinction memory. We found that systemic administration of acetazolamide, a CA inhibitor, immediately after the extinction session dose-dependently impaired the consolidation of fear extinction memory of rats trained in contextual fear conditioning. d-phenylalanine, a CA activator, displayed an opposite action, whereas C18, a membrane-impermeable CA inhibitor that is unable to reach the brain tissue, had no effect. Simultaneous administration of acetazolamide fully prevented the procognitive effects of d-phenylalanine. Whereas d-phenylalanine potentiated extinction, acetazolamide impaired extinction also when infused locally into the ventromedial prefrontal cortex, basolateral amygdala, or hippocampal CA1 region. No effects were observed when acetazolamide or d-phenylalanine was infused locally into the substantia nigra pars compacta. Moreover, systemic administration of acetazolamide immediately after the extinction training session modulated c-Fos expression on a retention test in the ventromedial prefrontal cortex of rats trained in contextual fear conditioning. These findings reveal that the engagement of CAs in some brain regions is essential for providing the brain with the resilience necessary to ensure the consolidation of extinction of emotionally salient events.


Assuntos
Anidrases Carbônicas/metabolismo , Medo/fisiologia , Memória/fisiologia , Animais , Complexo Nuclear Basolateral da Amígdala/fisiologia , Região CA1 Hipocampal/fisiologia , Emoções , Aprendizagem , Masculino , Camundongos , Córtex Pré-Frontal/fisiologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Wistar
14.
Nat Commun ; 11(1): 3012, 2020 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-32541656

RESUMO

The complex relationship between specific hippocampal oscillation frequency deficit and cognitive dysfunction in the ischemic brain is unclear. Here, using a mouse two-vessel occlusion (2VO) cerebral ischemia model, we show that visual stimulation with a 40 Hz light flicker drove hippocampal CA1 slow gamma and restored 2VO-induced reduction in CA1 slow gamma power and theta-low gamma phase-amplitude coupling, but not those of the high gamma. Low gamma frequency lights at 30 Hz, 40 Hz, and 50 Hz, but not 10 Hz, 80 Hz, and arrhythmic frequency light, were protective against degenerating CA1 neurons after 2VO, demonstrating the importance of slow gamma in cognitive functions after cerebral ischemia. Mechanistically, 40 Hz light flicker enhanced RGS12-regulated CA3-CA1 presynaptic N-type calcium channel-dependent short-term synaptic plasticity and associated postsynaptic long term potentiation (LTP) after 2VO. These results support a causal relationship between CA1 slow gamma and cognitive dysfunctions in the ischemic brain.


Assuntos
Região CA1 Hipocampal/fisiologia , Potenciais Pós-Sinápticos Excitadores/fisiologia , Ritmo Gama/fisiologia , Plasticidade Neuronal/fisiologia , Neurônios/fisiologia , Animais , Isquemia Encefálica/fisiopatologia , Região CA1 Hipocampal/irrigação sanguínea , Circulação Cerebrovascular/fisiologia , Estimulação Elétrica , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Atividade Motora/fisiologia , Estimulação Luminosa
15.
Nat Commun ; 11(1): 3026, 2020 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-32541860

RESUMO

Survival in complex environments necessitates a flexible navigation system that incorporates memory of recent behavior and associations. Yet, how the hippocampal spatial circuit represents latent information independent of sensory inputs and future goals has not been determined. To address this, we image the activity of large ensembles in subregion CA1 via wide-field fluorescent microscopy during a novel behavioral paradigm. Our results demonstrate that latent information is represented through reliable firing rate changes during unconstrained navigation. We then hypothesize that the representation of latent information in CA1 is mediated by pattern separation/completion processes instantiated upstream within the dentate gyrus (DG) and CA3 subregions. Indeed, CA3 ensemble recordings reveal an analogous code for latent information. Moreover, selective chemogenetic inactivation of DG-CA3 circuitry completely and reversibly abolishes the CA1 representation of latent information. These results reveal a causal and specific role of DG-CA3 circuitry in the maintenance of latent information within the hippocampus.


Assuntos
Região CA3 Hipocampal/fisiologia , Giro Denteado/fisiologia , Animais , Região CA1 Hipocampal/fisiologia , Masculino , Memória , Camundongos Endogâmicos C57BL , Modelos Neurológicos , Reconhecimento Fisiológico de Modelo
16.
Neuron ; 107(2): 283-291.e6, 2020 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-32392472

RESUMO

Episodic memory requires linking events in time, a function dependent on the hippocampus. In "trace" fear conditioning, animals learn to associate a neutral cue with an aversive stimulus despite their separation in time by a delay period on the order of tens of seconds. But how this temporal association forms remains unclear. Here we use two-photon calcium imaging of neural population dynamics throughout the course of learning and show that, in contrast to previous theories, hippocampal CA1 does not generate persistent activity to bridge the delay. Instead, learning is concomitant with broad changes in the active neural population. Although neural responses were stochastic in time, cue identity could be read out from population activity over longer timescales after learning. These results question the ubiquity of seconds-long neural sequences during temporal association learning and suggest that trace fear conditioning relies on mechanisms that differ from persistent activity accounts of working memory.


Assuntos
Aprendizagem por Associação/fisiologia , Hipocampo/fisiologia , Memória Episódica , Rede Nervosa/fisiologia , Animais , Comportamento Animal , Região CA1 Hipocampal/fisiologia , Condicionamento Operante , Sinais (Psicologia) , Medo/psicologia , Hipocampo/citologia , Processamento de Imagem Assistida por Computador , Memória de Curto Prazo/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/fisiologia , Optogenética
17.
Nat Commun ; 11(1): 2217, 2020 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-32371879

RESUMO

Theta oscillations play a major role in temporarily defining the hippocampal rate code by translating behavioral sequences into neuronal representations. However, mechanisms constraining phase timing and cell-type-specific phase preference are unknown. Here, we employ computational models tuned with evolutionary algorithms to evaluate phase preference of individual CA1 pyramidal cells recorded in mice and rats not engaged in any particular memory task. We applied unbiased and hypothesis-free approaches to identify effects of intrinsic and synaptic factors, as well as cell morphology, in determining phase preference. We found that perisomatic inhibition delivered by complementary populations of basket cells interacts with input pathways to shape phase-locked specificity of deep and superficial pyramidal cells. Somatodendritic integration of fluctuating glutamatergic inputs defined cycle-by-cycle by unsupervised methods demonstrated that firing selection is tuneable across sublayers. Our data identify different mechanisms of phase-locking selectivity that are instrumental for flexible dynamical representations of theta sequences.


Assuntos
Região CA1 Hipocampal/fisiologia , Neurônios/fisiologia , Sinapses/fisiologia , Ritmo Teta/fisiologia , Potenciais de Ação/fisiologia , Algoritmos , Animais , Região CA1 Hipocampal/citologia , Simulação por Computador , Feminino , Cinética , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Modelos Neurológicos , Técnicas de Patch-Clamp , Células Piramidais/fisiologia , Ratos Wistar
18.
J Neurosci ; 40(19): 3741-3750, 2020 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-32321746

RESUMO

Structural plasticity of dendritic spines is a key component of the refinement of synaptic connections during learning. Recent studies highlight a novel role for the NMDA receptor (NMDAR), independent of ion flow, in driving spine shrinkage and LTD. Yet little is known about the molecular mechanisms that link conformational changes in the NMDAR to changes in spine size and synaptic strength. Here, using two-photon glutamate uncaging to induce plasticity at individual dendritic spines on hippocampal CA1 neurons from mice and rats of both sexes, we demonstrate that p38 MAPK is generally required downstream of non-ionotropic NMDAR signaling to drive both spine shrinkage and LTD. In a series of pharmacological and molecular genetic experiments, we identify key components of the non-ionotropic NMDAR signaling pathway driving dendritic spine shrinkage, including the interaction between NOS1AP (nitric oxide synthase 1 adaptor protein) and neuronal nitric oxide synthase (nNOS), nNOS enzymatic activity, activation of MK2 (MAPK-activated protein kinase 2) and cofilin, and signaling through CaMKII. Our results represent a large step forward in delineating the molecular mechanisms of non-ionotropic NMDAR signaling that can drive shrinkage and elimination of dendritic spines during synaptic plasticity.SIGNIFICANCE STATEMENT Signaling through the NMDA receptor (NMDAR) is vitally important for the synaptic plasticity that underlies learning. Recent studies highlight a novel role for the NMDAR, independent of ion flow, in driving synaptic weakening and dendritic spine shrinkage during synaptic plasticity. Here, we delineate several key components of the molecular pathway that links conformational signaling through the NMDAR to dendritic spine shrinkage during synaptic plasticity.


Assuntos
Espinhas Dendríticas/metabolismo , Plasticidade Neuronal/fisiologia , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Região CA1 Hipocampal/fisiologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/fisiologia
19.
J Neurosci ; 40(22): 4266-4276, 2020 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-32327534

RESUMO

Synaptic plasticity is triggered by different patterns of network activity. Here, we investigated how LTP in CA3-CA1 synapses induced by different stimulation patterns is affected by tonic GABAA conductances in rat hippocampal slices. Spike-timing-dependent LTP was induced by pairing Schaffer collateral stimulation with antidromic stimulation of CA1 pyramidal neurons. Theta-burst-induced LTP was induced by theta-burst stimulation of Schaffer collaterals. We mimicked increased tonic GABAA conductance by bath application of 30 µm GABA. Surprisingly, tonic GABAA conductance selectively suppressed theta-burst-induced LTP but not spike-timing-dependent LTP. We combined whole-cell patch-clamp electrophysiology, two-photon Ca2+ imaging, glutamate uncaging, and mathematical modeling to dissect the mechanisms underlying these differential effects of tonic GABAA conductance. We found that Ca2+ transients during pairing of an action potential with an EPSP were less sensitive to tonic GABAA conductance-induced shunting inhibition than Ca2+ transients induced by EPSP burst. Our results may explain how different forms of memory are affected by increasing tonic GABAA conductances under physiological or pathologic conditions, as well as under the influence of substances that target extrasynaptic GABAA receptors (e.g., neurosteroids, sedatives, antiepileptic drugs, and alcohol).SIGNIFICANCE STATEMENT Brain activity is associated with neuronal firing and synaptic signaling among neurons. Synaptic plasticity represents a mechanism for learning and memory. However, some neurotransmitters that escape the synaptic cleft or are released by astrocytes can target extrasynaptic receptors. Extrasynaptic GABAA receptors mediate tonic conductances that reduce the excitability of neurons by shunting. This results in the decreased ability for neurons to fire action potentials, but when action potentials are successfully triggered, tonic conductances are unable to reduce them significantly. As such, tonic GABAA conductances have minimal effects on spike-timing-dependent synaptic plasticity while strongly attenuating the plasticity evoked by EPSP bursts. Our findings shed light on how changes in tonic conductances can selectively affect different forms of learning and memory.


Assuntos
Região CA1 Hipocampal/metabolismo , Potenciais Pós-Sinápticos Excitadores , Potenciação de Longa Duração , Receptores de GABA-A/metabolismo , Ritmo Teta , Animais , Região CA1 Hipocampal/citologia , Região CA1 Hipocampal/fisiologia , Cálcio/metabolismo , Ácido Glutâmico/metabolismo , Masculino , Células Piramidais/metabolismo , Células Piramidais/fisiologia , Ratos , Ratos Sprague-Dawley
20.
Nat Commun ; 11(1): 1947, 2020 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-32327634

RESUMO

Bouts of high frequency activity known as sharp wave ripples (SPW-Rs) facilitate communication between the hippocampus and neocortex. However, the paths and mechanisms by which SPW-Rs broadcast their content are not well understood. Due to its anatomical positioning, the granular retrosplenial cortex (gRSC) may be a bridge for this hippocampo-cortical dialogue. Using silicon probe recordings in awake, head-fixed mice, we show the existence of SPW-R analogues in gRSC and demonstrate their coupling to hippocampal SPW-Rs. gRSC neurons reliably distinguished different subclasses of hippocampal SPW-Rs according to ensemble activity patterns in CA1. We demonstrate that this coupling is brain state-dependent, and delineate a topographically-organized anatomical pathway via VGlut2-expressing, bursty neurons in the subiculum. Optogenetic stimulation or inhibition of bursty subicular cells induced or reduced responses in superficial gRSC, respectively. These results identify a specific path and underlying mechanisms by which the hippocampus can convey neuronal content to the neocortex during SPW-Rs.


Assuntos
Ondas Encefálicas/fisiologia , Hipocampo/fisiologia , Neocórtex/fisiologia , Animais , Região CA1 Hipocampal/fisiologia , Camundongos , Camundongos Transgênicos , Vias Neurais/fisiologia , Neurônios/metabolismo , Neurônios/fisiologia , Transmissão Sináptica , Proteína Vesicular 2 de Transporte de Glutamato/genética , Proteína Vesicular 2 de Transporte de Glutamato/metabolismo , Vigília/fisiologia
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