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1.
Cereb Cortex ; 33(6): 2857-2878, 2023 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-35802476

RESUMO

Synaptic transmission constitutes the primary mode of communication between neurons. It is extensively studied in rodent but not human neocortex. We characterized synaptic transmission between pyramidal neurons in layers 2 and 3 using neurosurgically resected human middle temporal gyrus (MTG, Brodmann area 21), which is part of the distributed language circuitry. We find that local connectivity is comparable with mouse layer 2/3 connections in the anatomical homologue (temporal association area), but synaptic connections in human are 3-fold stronger and more reliable (0% vs 25% failure rates, respectively). We developed a theoretical approach to quantify properties of spinous synapses showing that synaptic conductance and voltage change in human dendritic spines are 3-4-folds larger compared with mouse, leading to significant NMDA receptor activation in human unitary connections. This model prediction was validated experimentally by showing that NMDA receptor activation increases the amplitude and prolongs decay of unitary excitatory postsynaptic potentials in human but not in mouse connections. Since NMDA-dependent recurrent excitation facilitates persistent activity (supporting working memory), our data uncovers cortical microcircuit properties in human that may contribute to language processing in MTG.


Assuntos
Neocórtex , Receptores de N-Metil-D-Aspartato , Ratos , Adulto , Animais , Humanos , Camundongos , Receptores de N-Metil-D-Aspartato/fisiologia , Ratos Wistar , Células Piramidais/fisiologia , Transmissão Sináptica/fisiologia , Sinapses/fisiologia
2.
Cereb Cortex ; 32(11): 2424-2436, 2022 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-34564728

RESUMO

Temporal lobe epilepsy (TLE) patients are at risk of memory deficits, which have been linked to functional network disturbances, particularly of integration of the default mode network (DMN). However, the cellular substrates of functional network integration are unknown. We leverage a unique cross-scale dataset of drug-resistant TLE patients (n = 31), who underwent pseudo resting-state functional magnetic resonance imaging (fMRI), resting-state magnetoencephalography (MEG) and/or neuropsychological testing before neurosurgery. fMRI and MEG underwent atlas-based connectivity analyses. Functional network centrality of the lateral middle temporal gyrus, part of the DMN, was used as a measure of local network integration. Subsequently, non-pathological cortical tissue from this region was used for single cell morphological and electrophysiological patch-clamp analysis, assessing integration in terms of total dendritic length and action potential rise speed. As could be hypothesized, greater network centrality related to better memory performance. Moreover, greater network centrality correlated with more integrative properties at the cellular level across patients. We conclude that individual differences in cognitively relevant functional network integration of a DMN region are mirrored by differences in cellular integrative properties of this region in TLE patients. These findings connect previously separate scales of investigation, increasing translational insight into focal pathology and large-scale network disturbances in TLE.


Assuntos
Epilepsia Resistente a Medicamentos , Epilepsia do Lobo Temporal , Epilepsia do Lobo Temporal/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética/métodos , Magnetoencefalografia , Lobo Temporal
3.
Cell Rep ; 43(4): 114100, 2024 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-38607921

RESUMO

Hippocampal pyramidal neuron activity underlies episodic memory and spatial navigation. Although extensively studied in rodents, extremely little is known about human hippocampal pyramidal neurons, even though the human hippocampus underwent strong evolutionary reorganization and shows lower theta rhythm frequencies. To test whether biophysical properties of human Cornu Amonis subfield 1 (CA1) pyramidal neurons can explain observed rhythms, we map the morpho-electric properties of individual CA1 pyramidal neurons in human, non-pathological hippocampal slices from neurosurgery. Human CA1 pyramidal neurons have much larger dendritic trees than mouse CA1 pyramidal neurons, have a large number of oblique dendrites, and resonate at 2.9 Hz, optimally tuned to human theta frequencies. Morphological and biophysical properties suggest cellular diversity along a multidimensional gradient rather than discrete clustering. Across the population, dendritic architecture and a large number of oblique dendrites consistently boost memory capacity in human CA1 pyramidal neurons by an order of magnitude compared to mouse CA1 pyramidal neurons.


Assuntos
Região CA1 Hipocampal , Dendritos , Células Piramidais , Humanos , Células Piramidais/fisiologia , Região CA1 Hipocampal/citologia , Região CA1 Hipocampal/fisiologia , Animais , Masculino , Camundongos , Dendritos/fisiologia , Feminino , Pessoa de Meia-Idade , Idoso , Ritmo Teta/fisiologia , Adulto
4.
Nat Commun ; 14(1): 4188, 2023 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-37443107

RESUMO

GWAS have identified numerous genes associated with human cognition but their cell type expression profiles in the human brain are unknown. These genes overlap with human accelerated regions (HARs) implicated in human brain evolution and might act on the same biological processes. Here, we investigated whether these gene sets are expressed in adult human cortical neurons, and how their expression relates to neuronal function and structure. We find that these gene sets are preferentially expressed in L3 pyramidal neurons in middle temporal gyrus (MTG). Furthermore, neurons with higher expression had larger total dendritic length (TDL) and faster action potential (AP) kinetics, properties previously linked to intelligence. We identify a subset of genes associated with TDL or AP kinetics with predominantly synaptic functions and high abundance of HARs.


Assuntos
Neurônios , Células Piramidais , Adulto , Humanos , Neurônios/metabolismo , Células Piramidais/fisiologia , Cognição , Lobo Temporal , Encéfalo
5.
Sci Adv ; 9(41): eade3300, 2023 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-37824607

RESUMO

Human cortical pyramidal neurons are large, have extensive dendritic trees, and yet have unexpectedly fast input-output properties: Rapid subthreshold synaptic membrane potential changes are reliably encoded in timing of action potentials (APs). Here, we tested whether biophysical properties of voltage-gated sodium (Na+) and potassium (K+) currents in human pyramidal neurons can explain their fast input-output properties. Human Na+ and K+ currents exhibited more depolarized voltage dependence, slower inactivation, and faster recovery from inactivation compared with their mouse counterparts. Computational modeling showed that despite lower Na+ channel densities in human neurons, the biophysical properties of Na+ channels resulted in higher channel availability and contributed to fast AP kinetics stability. Last, human Na+ channel properties also resulted in a larger dynamic range for encoding of subthreshold membrane potential changes. Thus, biophysical adaptations of voltage-gated Na+ and K+ channels enable fast input-output properties of large human pyramidal neurons.


Assuntos
Neurônios , Células Piramidais , Humanos , Camundongos , Animais , Neurônios/fisiologia , Células Piramidais/fisiologia , Potenciais de Ação/fisiologia , Potenciais da Membrana/fisiologia , Sódio
6.
Sci Adv ; 9(41): eadf0708, 2023 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-37824618

RESUMO

Fast-spiking interneurons (FSINs) provide fast inhibition that synchronizes neuronal activity and is critical for cognitive function. Fast synchronization frequencies are evolutionary conserved in the expanded human neocortex despite larger neuron-to-neuron distances that challenge fast input-output transfer functions of FSINs. Here, we test in human neurons from neurosurgery tissue, which mechanistic specializations of human FSINs explain their fast-signaling properties in human cortex. With morphological reconstructions, multipatch recordings, and biophysical modeling, we find that despite threefold longer dendritic path, human FSINs maintain fast inhibition between connected pyramidal neurons through several mechanisms: stronger synapse strength of excitatory inputs, larger dendrite diameter with reduced complexity, faster AP initiation, and faster and larger inhibitory output, while Na+ current activation/inactivation properties are similar. These adaptations underlie short input-output delays in fast inhibition of human pyramidal neurons through FSINs, explaining how cortical synchronization frequencies are conserved despite expanded and sparse network topology of human cortex.


Assuntos
Neocórtex , Neurônios , Humanos , Potenciais de Ação/fisiologia , Neurônios/fisiologia , Células Piramidais/fisiologia , Interneurônios/fisiologia
7.
Front Cell Neurosci ; 13: 315, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31354435

RESUMO

Group I metabotropic glutamate receptors (mGluRs) mediate a range of signaling and plasticity processes in the brain and are of growing importance as potential therapeutic targets in clinical trials for neuropsychiatric and neurodevelopmental disorders (NDDs). Fundamental knowledge regarding the functional effects of mGluRs upon pyramidal neurons and interneurons is derived largely from rodent brain, and their effects upon human neurons are predominantly untested. We therefore addressed how group I mGluRs affect microcircuits in human neocortex. We show that activation of group I mGluRs elicits action potential firing in Martinotti cells, which leads to increased synaptic inhibition onto neighboring neurons. Some other interneurons, including fast-spiking interneurons, are depolarized but do not fire action potentials in response to group I mGluR activation. Furthermore, we confirm the existence of group I mGluR-mediated depression of excitatory synapses in human pyramidal neurons. We propose that the strong increase in inhibition and depression of excitatory synapses onto layer 2/3 pyramidal neurons upon group I mGluR activation likely results in a shift in the balance between excitation and inhibition in the human cortical network.

8.
Elife ; 72018 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-30561325

RESUMO

It is generally assumed that human intelligence relies on efficient processing by neurons in our brain. Although grey matter thickness and activity of temporal and frontal cortical areas correlate with IQ scores, no direct evidence exists that links structural and physiological properties of neurons to human intelligence. Here, we find that high IQ scores and large temporal cortical thickness associate with larger, more complex dendrites of human pyramidal neurons. We show in silico that larger dendritic trees enable pyramidal neurons to track activity of synaptic inputs with higher temporal precision, due to fast action potential kinetics. Indeed, we find that human pyramidal neurons of individuals with higher IQ scores sustain fast action potential kinetics during repeated firing. These findings provide the first evidence that human intelligence is associated with neuronal complexity, action potential kinetics and efficient information transfer from inputs to output within cortical neurons.


Assuntos
Encéfalo/fisiologia , Inteligência , Células Piramidais/fisiologia , Potenciais de Ação , Adolescente , Adulto , Idoso , Simulação por Computador , Feminino , Humanos , Testes de Inteligência , Masculino , Pessoa de Meia-Idade , Modelos Neurológicos , Adulto Jovem
9.
Nat Commun ; 7: 12826, 2016 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-27604129

RESUMO

Individual cortical layers have distinct roles in information processing. All layers receive cholinergic inputs from the basal forebrain (BF), which is crucial for cognition. Acetylcholinergic receptors are differentially distributed across cortical layers, and recent evidence suggests that different populations of BF cholinergic neurons may target specific prefrontal cortical (PFC) layers, raising the question of whether cholinergic control of the PFC is layer dependent. Here we address this issue and reveal dendritic mechanisms by which endogenous cholinergic modulation of synaptic plasticity is opposite in superficial and deep layers of both mouse and human neocortex. Our results show that in different cortical layers, spike timing-dependent plasticity is oppositely regulated by the activation of nicotinic acetylcholine receptors (nAChRs) either located on dendrites of principal neurons or on GABAergic interneurons. Thus, layer-specific nAChR expression allows functional layer-specific control of cortical processing and plasticity by the BF cholinergic system, which is evolutionarily conserved from mice to humans.


Assuntos
Acetilcolina/metabolismo , Neocórtex/fisiologia , Plasticidade Neuronal/fisiologia , Neurônios/fisiologia , Animais , Regulação da Expressão Gênica , Humanos , Camundongos , Plasticidade Neuronal/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Nicotina/farmacologia , Células Piramidais/efeitos dos fármacos , Células Piramidais/fisiologia , Receptores Nicotínicos/fisiologia , Sinapses
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