RESUMEN
Neurons in the cerebral cortex receive thousands of synaptic inputs per second from thousands of presynaptic neurons. How the dendritic location of inputs, their timing, strength, and presynaptic origin, in conjunction with complex dendritic physiology, impact the transformation of synaptic input into action potential (AP) output remains generally unknown for in vivo conditions. Here, we introduce a computational approach to reveal which properties of the input causally underlie AP output, and how this neuronal input-output computation is influenced by the morphology and biophysical properties of the dendrites. We demonstrate that this approach allows dissecting of how different input populations drive in vivo observed APs. For this purpose, we focus on fast and broadly tuned responses that pyramidal tract neurons in layer 5 (L5PTs) of the rat barrel cortex elicit upon passive single whisker deflections. By reducing a multi-scale model that we reported previously, we show that three features are sufficient to predict with high accuracy the sensory responses and receptive fields of L5PTs under these specific in vivo conditions: the count of active excitatory versus inhibitory synapses preceding the response, their spatial distribution on the dendrites, and the AP history. Based on these three features, we derive an analytically tractable description of the input-output computation of L5PTs, which enabled us to dissect how synaptic input from thalamus and different cell types in barrel cortex contribute to these responses. We show that the input-output computation is preserved across L5PTs despite morphological and biophysical diversity of their dendrites. We found that trial-to-trial variability in L5PT responses, and cell-to-cell variability in their receptive fields, are sufficiently explained by variability in synaptic input from the network, whereas variability in biophysical and morphological properties have minor contributions. Our approach to derive analytically tractable models of input-output computations in L5PTs provides a roadmap to dissect network-neuron interactions underlying L5PT responses across different in vivo conditions and for other cell types.
Asunto(s)
Potenciales de Acción , Modelos Neurológicos , Corteza Somatosensorial , Animales , Ratas , Corteza Somatosensorial/fisiología , Corteza Somatosensorial/citología , Potenciales de Acción/fisiología , Dendritas/fisiología , Vibrisas/fisiología , Tractos Piramidales/fisiología , Sinapsis/fisiología , Biología Computacional , Células Piramidales/fisiología , Simulación por Computador , Red Nerviosa/fisiologíaRESUMEN
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.
Asunto(s)
Neocórtex , Receptores de N-Metil-D-Aspartato , Ratas , Adulto , Animales , Humanos , Ratones , Receptores de N-Metil-D-Aspartato/fisiología , Ratas Wistar , Células Piramidales/fisiología , Transmisión Sináptica/fisiología , Sinapsis/fisiologíaRESUMEN
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.
Asunto(s)
Epilepsia Refractaria , Epilepsia del Lóbulo Temporal , Epilepsia del Lóbulo Temporal/diagnóstico por imagen , Humanos , Imagen por Resonancia Magnética/métodos , Magnetoencefalografía , Lóbulo TemporalRESUMEN
The posterior parietal cortex (PPC) in rodents is reciprocally connected to primary somatosensory and vibrissal motor cortices. The PPC neuronal circuitry could thus encode and potentially integrate incoming somatosensory information and whisker motor output. However, the information encoded across PPC layers during refined sensorimotor behavior remains largely unknown. To uncover the sensorimotor features represented in PPC during voluntary whisking and object touch, we performed loose-patch single-unit recordings and extracellular recordings of ensemble activity, covering all layers of PPC in anesthetized and awake, behaving male rats. First, using single-cell receptive field mapping, we revealed the presence of coarse somatotopy along the mediolateral axis in PPC. Second, we found that spiking activity was modulated during exploratory whisking in layers 2-4 and layer 6, but not in layer 5 of awake, behaving rats. Population spiking activity preceded actual movement, and whisker trajectory endpoints could be decoded by population spiking, suggesting that PPC is involved in movement planning. Finally, population spiking activity further increased in response to active whisker touch but only in PPC layers 2-4. Thus, we find layer-specific processing, which emphasizes the computational role of PPC during whisker sensorimotor behavior.SIGNIFICANCE STATEMENT The posterior parietal cortex (PPC) is thought to merge information on motor output and sensory input to orchestrate interaction with the environment, but the function of different PPC microcircuit components is poorly understood. We recorded neuronal activity in rat PPC during sensorimotor behavior involving motor and sensory pathways. We uncovered that PPC layers have dedicated function: motor and sensory information is merged in layers 2-4; layer 6 predominantly represents motor information. Collectively, PPC activity predicts future motor output, thus entailing a motor plan. Our results are important for understanding how PPC computationally processes motor output and sensory input. This understanding may facilitate decoding of brain activity when using brain-machine interfaces to overcome loss of function after, for instance, spinal cord injury.
Asunto(s)
Movimiento/fisiología , Lóbulo Parietal/fisiología , Corteza Somatosensorial/fisiología , Percepción del Tacto/fisiología , Vibrisas/fisiología , Animales , Masculino , Lóbulo Parietal/citología , Ratas , Ratas Wistar , Corteza Somatosensorial/citología , Vibrisas/citología , Vibrisas/inervaciónRESUMEN
There have been few quantitative characterizations of the morphological, biophysical, and cable properties of neurons in the human neocortex. We employed feature-based statistical methods on a rare data set of 60 3D reconstructed pyramidal neurons from L2 and L3 in the human temporal cortex (HL2/L3 PCs) removed after brain surgery. Of these cells, 25 neurons were also characterized physiologically. Thirty-two morphological features were analyzed (e.g., dendritic surface area, 36 333 ± 18 157 µm2; number of basal trees, 5.55 ± 1.47; dendritic diameter, 0.76 ± 0.28 µm). Eighteen features showed a significant gradual increase with depth from the pia (e.g., dendritic length and soma radius). The other features showed weak or no correlation with depth (e.g., dendritic diameter). The basal dendritic terminals in HL2/L3 PCs are particularly elongated, enabling multiple nonlinear processing units in these dendrites. Unlike the morphological features, the active biophysical features (e.g., spike shapes and rates) and passive/cable features (e.g., somatic input resistance, 47.68 ± 15.26 MΩ, membrane time constant, 12.03 ± 1.79 ms, average dendritic cable length, 0.99 ± 0.24) were depth-independent. A novel descriptor for apical dendritic topology yielded 2 distinct classes, termed hereby as "slim-tufted" and "profuse-tufted" HL2/L3 PCs; the latter class tends to fire at higher rates. Thus, our morpho-electrotonic analysis shows 2 distinct classes of HL2/L3 PCs.
Asunto(s)
Células Piramidales/citología , Células Piramidales/fisiología , Lóbulo Temporal/citología , Lóbulo Temporal/fisiología , Adulto , Animales , Neoplasias Encefálicas/cirugía , Tamaño de la Célula , Epilepsia/cirugía , Humanos , Imagenología Tridimensional/métodos , Ratones , Persona de Mediana Edad , Modelos Estadísticos , Técnicas de Placa-Clamp , Análisis de Componente Principal , Procesamiento de Señales Asistido por Computador , Especificidad de la Especie , Lóbulo Temporal/cirugía , Técnicas de Cultivo de Tejidos , Adulto JovenRESUMEN
Neuronal firing, synaptic transmission, and its plasticity form the building blocks for processing and storage of information in the brain. It is unknown whether adult human synapses are more efficient in transferring information between neurons than rodent synapses. To test this, we recorded from connected pairs of pyramidal neurons in acute brain slices of adult human and mouse temporal cortex and probed the dynamical properties of use-dependent plasticity. We found that human synaptic connections were purely depressing and that they recovered three to four times more swiftly from depression than synapses in rodent neocortex. Thereby, during realistic spike trains, the temporal resolution of synaptic information exchange in human synapses substantially surpasses that in mice. Using information theory, we calculate that information transfer between human pyramidal neurons exceeds that of mouse pyramidal neurons by four to nine times, well into the beta and gamma frequency range. In addition, we found that human principal cells tracked fine temporal features, conveyed in received synaptic inputs, at a wider bandwidth than for rodents. Action potential firing probability was reliably phase-locked to input transients up to 1,000 cycles/s because of a steep onset of action potentials in human pyramidal neurons during spike trains, unlike in rodent neurons. Our data show that, in contrast to the widely held views of limited information transfer in rodent depressing synapses, fast recovering synapses of human neurons can actually transfer substantial amounts of information during spike trains. In addition, human pyramidal neurons are equipped to encode high synaptic information content. Thus, adult human cortical microcircuits relay information at a wider bandwidth than rodent microcircuits.
Asunto(s)
Neocórtex/fisiología , Células Piramidales/fisiología , Sinapsis/fisiología , Adolescente , Adulto , Animales , Humanos , Ratones Endogámicos C57BL , Persona de Mediana Edad , Adulto JovenRESUMEN
OBJECTIVE: Megalencephalic leukoencephalopathy with cysts (MLC) is a genetic disease characterized by infantile onset white matter edema and delayed onset neurological deterioration. Loss of MLC1 function causes MLC. MLC1 is involved in ion-water homeostasis, but its exact role is unknown. We generated Mlc1-null mice for further studies. METHODS: We investigated which brain cell types express MLC1, compared developmental expression in mice and men, and studied the consequences of loss of MLC1 in Mlc1-null mice. RESULTS: Like humans, mice expressed MLC1 only in astrocytes, especially those facing fluid-brain barriers. In mice, MLC1 expression increased until 3 weeks and then stabilized. In humans, MLC1 expression was highest in the first year, decreased, and stabilized from approximately 5 years. Mlc1-null mice had early onset megalencephaly and increased brain water content. From 3 weeks, abnormal astrocytes were present with swollen processes abutting fluid-brain barriers. From 3 months, widespread white matter vacuolization with intramyelinic edema developed. Mlc1-null astrocytes showed slowed regulatory volume decrease and reduced volume-regulated anion currents, which increased upon MLC1 re-expression. Mlc1-null astrocytes showed reduced expression of adhesion molecule GlialCAM and chloride channel ClC-2, but no substantial changes in other known MLC1-interacting proteins. INTERPRETATION: Mlc1-null mice replicate early stages of the human disease with early onset intramyelinic edema. The cellular functional defects, described for human MLC, were confirmed. The earliest change was astrocytic swelling, substantiating that in MLC the primary defect is in volume regulation by astrocytes. MLC1 expression affects expression of GlialCAM and ClC-2. Abnormal interplay between these proteins is part of the pathomechanisms of MLC.
Asunto(s)
Quistes/genética , Quistes/patología , Quistes/fisiopatología , Regulación del Desarrollo de la Expresión Génica/genética , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/genética , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/patología , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/fisiopatología , Adolescente , Adulto , Factores de Edad , Animales , Animales Recién Nacidos , Astrocitos/metabolismo , Astrocitos/patología , Edema Encefálico/etiología , Cerebelo/patología , Corteza Cerebral/citología , Corteza Cerebral/patología , Niño , Preescolar , Quistes/metabolismo , Modelos Animales de Enfermedad , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/metabolismo , Humanos , Lactante , Recién Nacido , Potenciales de la Membrana/genética , Proteínas de la Membrana/genética , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Actividad Motora/genética , Equilibrio Postural/genética , Subunidad beta de la Proteína de Unión al Calcio S100/metabolismo , Trastornos de la Sensación/genética , Sustancia Blanca/metabolismo , Sustancia Blanca/patología , Sustancia Blanca/ultraestructura , Adulto JovenRESUMEN
Vertical thalamocortical afferents give rise to the elementary functional units of sensory cortex, cortical columns. Principles that underlie communication between columns remain however unknown. Here we unravel these by reconstructing in vivo-labeled neurons from all excitatory cell types in the vibrissal part of rat primary somatosensory cortex (vS1). Integrating the morphologies into an exact 3D model of vS1 revealed that the majority of intracortical (IC) axons project far beyond the borders of the principal column. We defined the corresponding innervation volume as the IC-unit. Deconstructing this structural cortical unit into its cell type-specific components, we found asymmetric projections that innervate columns of either the same whisker row or arc, and which subdivide vS1 into 2 orthogonal [supra-]granular and infragranular strata. We show that such organization could be most effective for encoding multi whisker inputs. Communication between columns is thus organized by multiple highly specific horizontal projection patterns, rendering IC-units as the primary structural entities for processing complex sensory stimuli.
Asunto(s)
Red Nerviosa/fisiología , Neuronas/clasificación , Neuronas/fisiología , Corteza Somatosensorial/citología , Vibrisas/inervación , Potenciales de Acción/fisiología , Animales , Animales Recién Nacidos , Axones/fisiología , Simulación por Computador , Dendritas/fisiología , Lisina/análogos & derivados , Lisina/metabolismo , Modelos Neurológicos , Vías Nerviosas/fisiología , Neuronas/citología , Técnicas de Placa-Clamp , Ratas , Ratas WistarRESUMEN
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.
Asunto(s)
Axones , Dendritas , Neocórtex/citología , Células Piramidales/citología , Lóbulo Temporal/citología , Adulto , Anciano , Animales , Análisis por Conglomerados , Epilepsia/patología , Femenino , Humanos , Macaca fascicularis/anatomía & histología , Macaca mulatta/anatomía & histología , Masculino , Ratones/anatomía & histología , Ratones Endogámicos C57BL/anatomía & histología , Persona de Mediana Edad , Especificidad de la Especie , Adulto JovenRESUMEN
This study highlights a new and powerful direct impact of the dendritic tree (the input region of neurons) on the encoding capability of the axon (the output region). We show that the size of the dendritic arbors (its impedance load) strongly modulates the shape of the action potential (AP) onset at the axon initial segment; it is accelerated in neurons with larger dendritic surface area. AP onset rapidness is key in determining the capability of the axonal spikes to encode (phase lock to) rapid changes in synaptic inputs. Hence, our findings imply that neurons with larger dendritic arbors have improved encoding capabilities. This "dendritic size effect" was explored both analytically as well as numerically, in simplified and detailed models of 3D reconstructed layer 2/3 cortical pyramidal cells of rats and humans. The cutoff frequency of spikes phase locking to modulated inputs increased from 100 to 200 Hz in pyramidal cells of young rats to 400-600 Hz in human cells. In the latter case, phase locking reached close to 1 KHz in in vivo-like conditions. This work highlights new and functionally profound cross talk between the dendritic tree and the axon initial segment, providing new understanding of neurons as sophisticated nonlinear input/output devices.
Asunto(s)
Axones/fisiología , Dendritas/fisiología , Células Piramidales/citología , Corteza Somatosensorial/citología , Potenciales de Acción/fisiología , Animales , Simulación por Computador , Estimulación Eléctrica , Humanos , Modelos Neurológicos , RatasRESUMEN
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.
Asunto(s)
Potenciación a Largo Plazo , Depresión Sináptica a Largo Plazo , Neocórtex/fisiología , Receptores de N-Metil-D-Aspartato/metabolismo , Sinapsis/fisiología , Potenciales de Acción , Adolescente , Adulto , Canales de Calcio Tipo L/metabolismo , Dendritas/metabolismo , Dendritas/fisiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neocórtex/citología , Neocórtex/metabolismo , Células Piramidales/metabolismo , Células Piramidales/fisiologíaRESUMEN
Acetylcholine signaling through nicotinic receptors (nAChRs) in the prefrontal cortex (PFC) is crucial for attention. Nicotinic AChRs are expressed on glutamatergic inputs to layer V (LV) cells and on LV interneurons and LVI pyramidal neurons. Whether PFC layers are activated by nAChRs to a similar extent or whether there is layer-specific activation is not known. Here, we investigate nAChR modulation of all PFC layers and find marked layer specificity for pyramidal neurons: LII/III pyramidal neurons and glutamatergic inputs to these cells do not contain nAChRs, LV and LVI pyramidal neurons are modulated by α7 and ß2* nAChRs, respectively. Interneurons across layers contain mixed combinations of nAChRs. We then tested the hypothesis that nAChRs activate the PFC in a layer-specific manner using 2-photon population imaging. In all layers, nAChR-induced neuronal firing was dominated by ß2* nAChRs. In LII/III, only interneurons were activated. In LV and LVI, both interneurons and pyramidal neurons were activated, the latter most strongly in LVI. Together, these results suggest that in the PFC nAChR activation results in inhibition of LII/III pyramidal neurons. In LV and LVI, nAChR-induced activation of inhibitory and excitatory neurons results in a net augmentation of output neuron activity.
Asunto(s)
Red Nerviosa/fisiología , Plasticidad Neuronal/fisiología , Corteza Prefrontal/fisiología , Células Piramidales/fisiología , Receptores Nicotínicos/metabolismo , Animales , Células Cultivadas , Ratones , Ratones Endogámicos C57BL , Distribución Tisular , Receptor Nicotínico de Acetilcolina alfa 7RESUMEN
The ability to visualize neurons inside living brain tissue is a fundamental requirement in neuroscience and neurosurgery. Especially the development of a noninvasive probe of brain morphology with micrometer-scale resolution is highly desirable, as it would provide a noninvasive approach to optical biopsies in diagnostic medicine. Two-photon laser-scanning microscopy (2PLSM) is a powerful tool in this regard, and has become the standard for minimally invasive high-resolution imaging of living biological samples. However, while 2PLSM-based optical methods provide sufficient resolution, they have been hampered by the requirement for fluorescent dyes to provide image contrast. Here we demonstrate high-contrast imaging of live brain tissue at cellular resolution, without the need for fluorescent probes, using optical third-harmonic generation (THG). We exploit the specific geometry and lipid content of brain tissue at the cellular level to achieve partial phase matching of THG, providing an alternative contrast mechanism to fluorescence. We find that THG brain imaging allows rapid, noninvasive label-free imaging of neurons, white-matter structures, and blood vessels simultaneously. Furthermore, we exploit THG-based imaging to guide micropipettes towards designated neurons inside live tissue. This work is a major step towards label-free microscopic live brain imaging, and opens up possibilities for the development of laser-guided microsurgery techniques in the living brain.
Asunto(s)
Encéfalo/citología , Encéfalo/fisiología , Microscopía/métodos , Neuronas/citología , Neuronas/fisiología , Técnicas de Placa-Clamp , Animales , Ratones , Ratones Endogámicos C57BLRESUMEN
The cortical output layer 5 contains two excitatory cell types, slender- and thick-tufted neurons. In rat vibrissal cortex, slender-tufted neurons carry motion and phase information during active whisking, but remain inactive after passive whisker touch. In contrast, thick-tufted neurons reliably increase spiking preferably after passive touch. By reconstructing the 3D patterns of intracortical axon projections from individual slender- and thick-tufted neurons, filled in vivo with biocytin, we were able to identify cell type-specific intracortical circuits that may encode whisker motion and touch. Individual slender-tufted neurons showed elaborate and dense innervation of supragranular layers of large portions of the vibrissal area (total length, 86.8 ± 5.5 mm). During active whisking, these long-range projections may modulate and phase-lock the membrane potential of dendrites in layers 2 and 3 to the whisking cycle. Thick-tufted neurons with soma locations intermingling with those of slender-tufted ones display less dense intracortical axon projections (total length, 31.6 ± 14.3 mm) that are primarily confined to infragranular layers. Based on anatomical reconstructions and previous measurements of spiking, we put forward the hypothesis that thick-tufted neurons in rat vibrissal cortex receive input of whisker motion from slender-tufted neurons onto their apical tuft dendrites and input of whisker touch from thalamic neurons onto their basal dendrites. During tactile-driven behavior, such as object location, near-coincident input from these two pathways may result in increased spiking activity of thick-tufted neurons and thus enhanced signaling to their subcortical targets.
Asunto(s)
Axones , Corteza Cerebral/fisiología , Neuronas/citología , Vibrisas/fisiología , Potenciales de Acción , Animales , Corteza Cerebral/citología , Ratas , Ratas WistarRESUMEN
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.
Asunto(s)
Región CA1 Hipocampal , Dendritas , Células Piramidales , Humanos , Células Piramidales/fisiología , Región CA1 Hipocampal/citología , Región CA1 Hipocampal/fisiología , Animales , Masculino , Ratones , Dendritas/fisiología , Femenino , Persona de Mediana Edad , Anciano , Ritmo Teta/fisiología , AdultoRESUMEN
The three-dimensional (3D) structure of neural circuits is commonly studied by reconstructing individual or small groups of neurons in separate preparations. Investigation of structural organization principles or quantification of dendritic and axonal innervation thus requires integration of many reconstructed morphologies into a common reference frame. Here we present a standardized 3D model of the rat vibrissal cortex and introduce an automated registration tool that allows for precise placement of single neuron reconstructions. We (1) developed an automated image processing pipeline to reconstruct 3D anatomical landmarks, i.e., the barrels in Layer 4, the pia and white matter surfaces and the blood vessel pattern from high-resolution images, (2) quantified these landmarks in 12 different rats, (3) generated an average 3D model of the vibrissal cortex and (4) used rigid transformations and stepwise linear scaling to register 94 neuron morphologies, reconstructed from in vivo stainings, to the standardized cortex model. We find that anatomical landmarks vary substantially across the vibrissal cortex within an individual rat. In contrast, the 3D layout of the entire vibrissal cortex remains remarkably preserved across animals. This allows for precise registration of individual neuron reconstructions with approximately 30 µm accuracy. Our approach could be used to reconstruct and standardize other anatomically defined brain areas and may ultimately lead to a precise digital reference atlas of the rat brain.
Asunto(s)
Corteza Cerebral/citología , Imagenología Tridimensional , Neuronas/citología , Vibrisas/citología , Animales , RatasRESUMEN
Neuronal theories of neurodevelopmental disorders (NDDs) of autism and mental retardation propose that abnormal connectivity underlies deficits in attentional processing. We tested this theory by studying unitary synaptic connections between layer 5 pyramidal neurons within medial prefrontal cortex (mPFC) networks in the Fmr1-KO mouse model for mental retardation and autism. In line with predictions from neurocognitive theory, we found that neighboring pyramidal neurons were hyperconnected during a critical period in early mPFC development. Surprisingly, excitatory synaptic connections between Fmr1-KO pyramidal neurons were significantly slower and failed to recover from short-term depression as quickly as wild type (WT) synapses. By 4-5 weeks of mPFC development, connectivity rates were identical for both KO and WT pyramidal neurons and synapse dynamics changed from depressing to facilitating responses with similar properties in both groups. We propose that the early alteration in connectivity and synaptic recovery are tightly linked: using a network model, we show that slower synapses are essential to counterbalance hyperconnectivity in order to maintain a dynamic range of excitatory activity. However, the slow synaptic time constants induce decreased responsiveness to low-frequency stimulation, which may explain deficits in integration and early information processing in attentional neuronal networks in NDDs.
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Trastorno Autístico/fisiopatología , Modelos Animales de Enfermedad , Discapacidad Intelectual/fisiopatología , Red Nerviosa/fisiopatología , Corteza Prefrontal/fisiopatología , Sinapsis/fisiología , Animales , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Red Nerviosa/crecimiento & desarrollo , Corteza Prefrontal/crecimiento & desarrollo , Sinapsis/patología , Transmisión Sináptica/fisiologíaRESUMEN
Soma location, dendrite morphology, and synaptic innervation may represent key determinants of functional responses of individual neurons, such as sensory-evoked spiking. Here, we reconstruct the 3D circuits formed by thalamocortical afferents from the lemniscal pathway and excitatory neurons of an anatomically defined cortical column in rat vibrissal cortex. We objectively classify 9 cortical cell types and estimate the number and distribution of their somata, dendrites, and thalamocortical synapses. Somata and dendrites of most cell types intermingle, while thalamocortical connectivity depends strongly upon the cell type and the 3D soma location of the postsynaptic neuron. Correlating dendrite morphology and thalamocortical connectivity to functional responses revealed that the lemniscal afferents can account for some of the cell type- and location-specific subthreshold and spiking responses after passive whisker touch (e.g., in layer 4, but not for other cell types, e.g., in layer 5). Our data provides a quantitative 3D prediction of the cell type-specific lemniscal synaptic wiring diagram and elucidates structure-function relationships of this physiologically relevant pathway at single-cell resolution.
Asunto(s)
Células Receptoras Sensoriales/citología , Células Receptoras Sensoriales/fisiología , Corteza Somatosensorial/citología , Corteza Somatosensorial/fisiología , Tálamo/citología , Tálamo/fisiología , Vibrisas/fisiología , Animales , Red Nerviosa/citología , Red Nerviosa/fisiología , Ratas , Ratas Wistar , Células Receptoras Sensoriales/clasificación , Tacto/fisiología , Vibrisas/citología , Vibrisas/inervaciónRESUMEN
Information transfer between principal neurons in neocortex occurs through (glutamatergic) synaptic transmission. In this focussed review, we provide a detailed overview on the strength of synaptic neurotransmission between pairs of excitatory neurons in human and laboratory animals with a specific focus on data obtained using patch clamp electrophysiology. We reach two major conclusions: (1) the synaptic strength, measured as unitary excitatory postsynaptic potential (or uEPSP), is remarkably consistent across species, cortical regions, layers and/or cell-types (median 0.5 mV, interquartile range 0.4-1.0 mV) with most variability associated with the cell-type specific connection studied (min 0.1-max 1.4 mV), (2) synaptic function cannot be generalized across human and rodent, which we exemplify by discussing the differences in anatomical and functional properties of pyramidal-to-pyramidal connections within human and rodent cortical layers 2 and 3. With only a handful of studies available on synaptic transmission in human, it is obvious that much remains unknown to date. Uncovering the shared and divergent principles of synaptic transmission across species however, will almost certainly be a pivotal step toward understanding human cognitive ability and brain function in health and disease.
RESUMEN
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.