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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.
J Physiol ; 596(21): 5237-5249, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30144079

RESUMO

KEY POINTS: Ectopic action potentials (EAPs) arise at distal locations in axonal fibres and are often associated with neuronal pathologies such as epilepsy or nerve injury, but they also occur during physiological network conditions. This study investigates whether initiation of such EAPs is modulated by subthreshold synaptic activity. Somatic subthreshold potentials invade the axonal compartment to considerable distances (>350 µm), whereas spread of axonal subthreshold potentials to the soma is inefficient. Ectopic spike generation is entrained by conventional synaptic signalling mechanisms. Excitatory synaptic potentials promote EAPs, whereas inhibitory synaptic potentials block EAPs. The modulation of ectopic excitability depends on propagation of somatic voltage deflections to the axonal EAP initiation site. Synaptic modulation of EAP initiation challenges the view of the distal axon being independent of synaptic activity and may contribute to mechanisms underlying fast network oscillations and pathological network activity. ABSTRACT: While most action potentials are generated at the axon initial segment, they can also be triggered at more distal sites along the axon. Such ectopic action potentials (EAPs) occur during several neuronal pathologies such as epilepsy, nerve injuries and inflammation but have also been observed during physiological network activity. EAPs propagate antidromically towards the somato-dendritic compartment where they modulate synaptic plasticity. Here we investigate the converse signal direction: do somato-dendritic synaptic potentials affect the generation of ectopic spikes? We measured anti- and orthodromic spikes in the soma and axon of mouse hippocampal CA1 pyramidal cells. We found that synaptic potentials propagate reliably through the axon, causing significant voltage transients at distances >350 µm. At these sites, excitatory input efficiently facilitated EAP initiation in distal axons and, conversely, inhibitory input suppressed EAP initiation. Our data reveal a new mechanism by which ectopically generated spikes can be entrained by conventional synaptic signalling during normal and pathological network activity.


Assuntos
Potenciais de Ação , Região CA1 Hipocampal/fisiologia , Células Piramidais/fisiologia , Potenciais Sinápticos , Animais , Região CA1 Hipocampal/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL
3.
Cereb Cortex ; 25(12): 4839-53, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26318661

RESUMO

The size and shape of dendrites and axons are strong determinants of neuronal information processing. Our knowledge on neuronal structure and function is primarily based on brains of laboratory animals. Whether it translates to human is not known since quantitative data on "full" human neuronal morphologies are lacking. Here, we obtained human brain tissue during resection surgery and reconstructed basal and apical dendrites and axons of individual neurons across all cortical layers in temporal cortex (Brodmann area 21). Importantly, morphologies did not correlate to etiology, disease severity, or disease duration. Next, we show that human L(ayer) 2 and L3 pyramidal neurons have 3-fold larger dendritic length and increased branch complexity with longer segments compared with temporal cortex neurons from macaque and mouse. Unsupervised cluster analysis classified 88% of human L2 and L3 neurons into human-specific clusters distinct from mouse and macaque neurons. Computational modeling of passive electrical properties to assess the functional impact of large dendrites indicates stronger signal attenuation of electrical inputs compared with mouse. We thus provide a quantitative analysis of "full" human neuron morphologies and present direct evidence that human neurons are not "scaled-up" versions of rodent or macaque neurons, but have unique structural and functional properties.


Assuntos
Axônios , Dendritos , Neocórtex/citologia , Células Piramidais/citologia , Lobo Temporal/citologia , Adulto , Idoso , Animais , Análise por Conglomerados , Epilepsia/patologia , Feminino , Humanos , Macaca fascicularis/anatomia & histologia , Macaca mulatta/anatomia & histologia , Masculino , Camundongos/anatomia & histologia , Camundongos Endogâmicos C57BL/anatomia & histologia , Pessoa de Meia-Idade , Especificidade da Espécie , Adulto Jovem
4.
J Neurosci ; 33(43): 17197-208, 2013 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-24155324

RESUMO

The neocortex in our brain stores long-term memories by changing the strength of connections between neurons. To date, the rules and mechanisms that govern activity-induced synaptic changes at human cortical synapses are poorly understood and have not been studied directly at a cellular level. Here, we made whole-cell recordings of human pyramidal neurons in slices of brain tissue resected during neurosurgery to investigate spike timing-dependent synaptic plasticity in the adult human neocortex. We find that human cortical synapses can undergo bidirectional modifications in strength throughout adulthood. Both long-term potentiation and long-term depression of synapses was dependent on postsynaptic NMDA receptors. Interestingly, we find that human cortical synapses can associate presynaptic and postsynaptic events in a wide temporal window, and that rules for synaptic plasticity in human neocortex are reversed compared with what is generally found in the rodent brain. We show this is caused by dendritic L-type voltage-gated Ca2+ channels that are prominently activated during action potential firing. Activation of these channels determines whether human synapses strengthen or weaken. These findings provide a synaptic basis for the timing rules observed in human sensory and motor plasticity in vivo, and offer insights into the physiological role of L-type voltage-gated Ca2+ channels in the human brain.


Assuntos
Potenciação de Longa Duração , Depressão Sináptica de Longo Prazo , Neocórtex/fisiologia , Receptores de N-Metil-D-Aspartato/metabolismo , Sinapses/fisiologia , Potenciais de Ação , Adolescente , Adulto , Canais de Cálcio Tipo L/metabolismo , Dendritos/metabolismo , Dendritos/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neocórtex/citologia , Neocórtex/metabolismo , Células Piramidais/metabolismo , Células Piramidais/fisiologia
5.
Biochim Biophys Acta ; 1833(7): 1672-9, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23360982

RESUMO

Both synaptic N-methyl-d-aspartate (NMDA) receptors and voltage-operated calcium channels (VOCCs) have been shown to be critical for nuclear calcium signals associated with transcriptional responses to bursts of synaptic input. However the direct contribution to nuclear calcium signals from calcium influx through NMDA receptors and VOCCs has been obscured by their concurrent roles in action potential generation and synaptic transmission. Here we compare calcium responses to synaptically induced bursts of action potentials with identical bursts devoid of any synaptic contribution generated using the pre-recorded burst as the voltage clamp command input to replay the burst in the presence of blockers of action potentials or ionotropic glutamate receptors. Synapse independent replays of bursts produced nuclear calcium responses with amplitudes around 70% of their original synaptically generated signals and were abolished by the L-type VOCC blocker, verapamil. These results identify a major direct source of nuclear calcium from local L-type VOCCs whose activation is boosted by NMDA receptor dependent depolarization. The residual component of synaptically induced nuclear calcium signals which was both VOCC independent and NMDA receptor dependent showed delayed kinetics consistent with a more distal source such as synaptic NMDA receptors or internal stores. The dual requirement of NMDA receptors and L-type VOCCs for synaptic activity-induced nuclear calcium dependent transcriptional responses most likely reflects a direct somatic calcium influx from VOCCs whose activation is amplified by synaptic NMDA receptor-mediated depolarization and whose calcium signal is boosted by a delayed input from distal calcium sources mostly likely entry through NMDA receptors and release from internal stores. This article is part of a Special Issue entitled: 12th European Symposium on Calcium.


Assuntos
Potenciais de Ação/fisiologia , Sinalização do Cálcio/fisiologia , Cálcio/metabolismo , Hipocampo/fisiologia , Neurônios/fisiologia , Sinapses/fisiologia , Animais , Animais Recém-Nascidos , Canais de Cálcio Tipo L/química , Canais de Cálcio Tipo L/metabolismo , Células Cultivadas , Hipocampo/citologia , Camundongos , Neurônios/citologia , Técnicas de Patch-Clamp , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/metabolismo
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.
Nat Commun ; 10(1): 5280, 2019 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-31754098

RESUMO

Neocortical choline acetyltransferase (ChAT)-expressing interneurons are a subclass of vasoactive intestinal peptide (ChAT-VIP) neurons of which circuit and behavioural function are unknown. Here, we show that ChAT-VIP neurons directly excite neighbouring neurons in several layers through fast synaptic transmission of acetylcholine (ACh) in rodent medial prefrontal cortex (mPFC). Both interneurons in layers (L)1-3 as well as pyramidal neurons in L2/3 and L6 receive direct inputs from ChAT-VIP neurons mediated by fast cholinergic transmission. A fraction (10-20%) of postsynaptic neurons that received cholinergic input from ChAT-VIP interneurons also received GABAergic input from these neurons. In contrast to regular VIP interneurons, ChAT-VIP neurons did not disinhibit pyramidal neurons. Finally, we show that activity of these neurons is relevant for behaviour and they control attention behaviour distinctly from basal forebrain ACh inputs. Thus, ChAT-VIP neurons are a local source of cortical ACh that directly excite neurons throughout cortical layers and contribute to attention.


Assuntos
Atenção/efeitos dos fármacos , Colinérgicos/farmacologia , Interneurônios/fisiologia , Córtex Pré-Frontal/metabolismo , Acetilcolina/farmacologia , Animais , Atenção/fisiologia , Córtex Cerebral/citologia , Córtex Cerebral/metabolismo , Colina O-Acetiltransferase/metabolismo , Feminino , Interneurônios/efeitos dos fármacos , Interneurônios/metabolismo , Masculino , Camundongos da Linhagem 129 , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/fisiologia , Córtex Pré-Frontal/citologia , Ratos , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia , Peptídeo Intestinal Vasoativo/metabolismo
9.
Nat Commun ; 9(1): 4101, 2018 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-30291244

RESUMO

A variety of inhibitory pathways encompassing different interneuron types shape activity of neocortical pyramidal neurons. While basket cells (BCs) mediate fast lateral inhibition between pyramidal neurons, Somatostatin-positive Martinotti cells (MCs) mediate a delayed form of lateral inhibition. Neocortical circuits are under control of acetylcholine, which is crucial for cortical function and cognition. Acetylcholine modulates MC firing, however, precisely how cholinergic inputs affect cortical lateral inhibition is not known. Here, we find that cholinergic inputs selectively augment and speed up lateral inhibition between pyramidal neurons mediated by MCs, but not by BCs. Optogenetically activated cholinergic inputs depolarize MCs through activation of ß2 subunit-containing nicotinic AChRs, not muscarinic AChRs, without affecting glutamatergic inputs to MCs. We find that these mechanisms are conserved in human neocortex. Cholinergic inputs thus enable cortical pyramidal neurons to recruit more MCs, and can thereby dynamically highlight specific circuit motifs, favoring MC-mediated pathways over BC-mediated pathways.


Assuntos
Neurônios Colinérgicos/fisiologia , Interneurônios/fisiologia , Neocórtex/fisiologia , Inibição Neural , Células Piramidais/fisiologia , Adulto , Animais , Feminino , Humanos , Masculino , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade
10.
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
11.
Front Neural Circuits ; 11: 100, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29276477

RESUMO

Acetylcholine (ACh) signaling shapes neuronal circuit development and underlies specific aspects of cognitive functions and behaviors, including attention, learning, memory and motivation. During behavior, activation of muscarinic and nicotinic acetylcholine receptors (mAChRs and nAChRs) by ACh alters the activation state of neurons, and neuronal circuits most likely process information differently with elevated levels of ACh. In several brain regions, ACh has been shown to alter synaptic strength as well. By changing the rules for synaptic plasticity, ACh can have prolonged effects on and rearrange connectivity between neurons that outlasts its presence. From recent discoveries in the mouse, rat, monkey and human brain, a picture emerges in which the basal forebrain (BF) cholinergic system targets the neocortex with much more spatial and temporal detail than previously considered. Fast cholinergic synapses acting on a millisecond time scale are abundant in the mammalian cerebral cortex, and provide BF cholinergic neurons with the possibility to rapidly alter information flow in cortical microcircuits. Finally, recent studies have outlined novel mechanisms of how cholinergic projections from the BF affect synaptic strength in several brain areas of the rodent brain, with behavioral consequences. This review highlights these exciting developments and discusses how these findings translate to human brain circuitries.


Assuntos
Acetilcolina/metabolismo , Córtex Cerebral/anatomia & histologia , Córtex Cerebral/metabolismo , Animais , Haplorrinos , Humanos , Vias Neurais/anatomia & histologia , Vias Neurais/metabolismo , Plasticidade Neuronal/fisiologia , Receptores Colinérgicos/metabolismo , Roedores
12.
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
13.
Front Neural Circuits ; 10: 70, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27630545

RESUMO

Attending the sensory environment for cue detection is a cognitive operation that occurs on a time scale of seconds. The dorsal and ventral medial prefrontal cortex (mPFC) contribute to separate aspects of attentional processing. Pyramidal neurons in different parts of the mPFC are active during cognitive behavior, yet whether this activity is causally underlying attentional processing is not known. We aimed to determine the precise temporal requirements for activation of the mPFC subregions during the seconds prior to cue detection. To test this, we used optogenetic silencing of dorsal or ventral mPFC pyramidal neurons at defined time windows during a sustained attentional state. We find that the requirement of ventral mPFC pyramidal neuron activity is strictly time-locked to stimulus detection. Inhibiting the ventral mPFC 2 s before or during cue presentation reduces response accuracy and hampers behavioral inhibition. The requirement for dorsal mPFC activity on the other hand is temporally more loosely related to a preparatory attentional state, and short lapses in pyramidal neuron activity in dorsal mPFC do not affect performance. This only occurs when the dorsal mPFC is inhibited during the entire preparatory period. Together, our results reveal that a dissociable temporal recruitment of ventral and dorsal mPFC is required during attentional processing.


Assuntos
Atenção/fisiologia , Córtex Pré-Frontal/fisiologia , Células Piramidais/fisiologia , Animais , Comportamento Animal , Masculino , Optogenética , Ratos , Ratos Long-Evans
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