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The basal ganglia are important for action initiation, selection, and motor learning. The input level, the striatum, receives input preferentially from the cortex and thalamus and is to 95% composed of striatal projection neurons (SPNs) with sparse GABAergic collaterals targeting distal dendrites of neighboring SPNs, in a distance-dependent manner. The remaining 5% are GABAergic and cholinergic interneurons. Our aim here is to investigate the role of surround inhibition for the intrinsic function of the striatum. Large-scale striatal networks of 20 to 40 thousand neurons were simulated with detailed multicompartmental models of different cell types, corresponding to the size of a module of the dorsolateral striatum, like the forelimb area (mouse). The effect of surround inhibition on dendritic computation and network activity was investigated, while groups of SPNs were activated. The SPN-induced surround inhibition in distal dendrites shunted effectively the corticostriatal EPSPs. The size of dendritic plateau-like potentials within the specific dendritic segment was both reduced and enhanced by inhibition, due to the hyperpolarized membrane potential of SPNs and the reversal-potential of GABA. On a population level, the competition between two subpopulations of SPNs was found to depend on the distance between the two units, the size of each unit, the activity level in each subgroup and the dopaminergic modulation of the dSPNs and iSPNs. The SPNs provided the dominating source of inhibition within the striatum, while the fast-spiking interneuron mainly had an initial effect due to short-term synaptic plasticity as shown in with ablation of the synaptic interaction.
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Cuerpo Estriado , Neuronas , Animales , Ratones , Ganglios Basales , Cuerpo Estriado/metabolismo , Interneuronas/fisiología , Neostriado , Neuronas/fisiologíaRESUMEN
Biophysically detailed multi-compartment models are powerful tools to explore computational principles of the brain and also serve as a theoretical framework to generate algorithms for artificial intelligence (AI) systems. However, the expensive computational cost severely limits the applications in both the neuroscience and AI fields. The major bottleneck during simulating detailed compartment models is the ability of a simulator to solve large systems of linear equations. Here, we present a novel Dendritic Hierarchical Scheduling (DHS) method to markedly accelerate such a process. We theoretically prove that the DHS implementation is computationally optimal and accurate. This GPU-based method performs with 2-3 orders of magnitude higher speed than that of the classic serial Hines method in the conventional CPU platform. We build a DeepDendrite framework, which integrates the DHS method and the GPU computing engine of the NEURON simulator and demonstrate applications of DeepDendrite in neuroscience tasks. We investigate how spatial patterns of spine inputs affect neuronal excitability in a detailed human pyramidal neuron model with 25,000 spines. Furthermore, we provide a brief discussion on the potential of DeepDendrite for AI, specifically highlighting its ability to enable the efficient training of biophysically detailed models in typical image classification tasks.
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Inteligencia Artificial , Neuronas , Humanos , Algoritmos , Células Piramidales , EncéfaloRESUMEN
The motor areas of the cortex and the basal ganglia both contribute to determining which motor actions will be recruited at any moment in time, and their functions are intertwined. Here, we review the basal ganglia mechanisms underlying the selection of behavior of the downstream control of motor centers in the midbrain and brainstem and show that the basic organization of the forebrain motor system is evolutionarily conserved throughout vertebrate phylogeny. The output level of the basal ganglia (e.g. substantia nigra pars reticulata) has GABAergic neurons that are spontaneously active at rest and inhibit a number of specific motor centers, each of which can be relieved from inhibition if the inhibitory output neurons themselves become inhibited. The motor areas of the cortex act partially via the dorsolateral striatum (putamen), which has specific modules for the forelimb, hindlimb, trunk, etc. Each module operates in turn through the two types of striatal projection neurons that control the output modules of the basal ganglia and thereby the downstream motor centers. The mechanisms for lateral inhibition in the striatum are reviewed as well as other striatal mechanisms contributing to action selection. The motor cortex also exerts a direct excitatory action on specific motor centers. An overview is given of the basal ganglia control exerted on the different midbrain/brainstem motor centers, and the efference copy information fed back via the thalamus to the striatum and cortex, which is of importance for the planning of future movements.
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Gaze stabilization compensates for movements of the head or external environment to minimize image blurring. Multisensory information stabilizes the scene on the retina via the vestibulo-ocular (VOR) and optokinetic (OKR) reflexes. While the organization of neuronal circuits underlying VOR is well-described across vertebrates, less is known about the contribution and evolution of the OKR and the basic structures allowing visuo-vestibular integration. To analyze these neuronal pathways underlying visuo-vestibular integration, we developed a setup using a lamprey eye-brain-labyrinth preparation, which allowed coordinating electrophysiological recordings, vestibular stimulation with a moving platform, and visual stimulation via screens. Lampreys exhibit robust visuo-vestibular integration, with optokinetic information processed in the pretectum that can be downregulated from tectum. Visual and vestibular inputs are integrated at several subcortical levels. Additionally, saccades are present in the form of nystagmus. Thus, all basic components of the visuo-vestibular control of gaze were present already at the dawn of vertebrate evolution.
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Reflejo Vestibuloocular , Vestíbulo del Laberinto , Animales , Movimientos Oculares , Estimulación Luminosa , Reflejo Vestibuloocular/fisiología , Movimientos Sacádicos , Vestíbulo del Laberinto/fisiologíaRESUMEN
Cerebrospinal fluid-contacting (CSF-c) neurons line the central canal of the spinal cord and a subtype of CSF-c neurons expressing somatostatin, forms a homeostatic pH regulating system. Despite their importance, their intricate spatial organization is poorly understood. The function of another subtype of CSF-c neurons expressing dopamine is also investigated. Imaging methods with a high spatial resolution (5-10 nm) are used to resolve the synaptic and ciliary compartments of each individual cell in the spinal cord of the lamprey to elucidate their signalling pathways and to dissect the cellular organization. Here, light-sheet and expansion microscopy resolved the persistent ventral and lateral organization of dopamine- and somatostatin-expressing CSF-c neuronal subtypes. The density of somatostatin-containing dense-core vesicles, resolved by stimulated emission depletion microscopy, was shown to be markedly reduced upon each exposure to either alkaline or acidic pH and being part of a homeostatic response inhibiting movements. Their cilia symmetry was unravelled by stimulated emission depletion microscopy in expanded tissues as sensory with 9 + 0 microtubule duplets. The dopaminergic CSF-c neurons on the other hand have a motile cilium with the characteristic 9 + 2 duplets and are insensitive to pH changes. This novel experimental workflow elucidates the functional role of CSF-c neuron subtypes in situ paving the way for further spatial and functional cell-type classification.
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Cilios , Dopamina/química , Microscopía/métodos , Somatostatina/química , Animales , Dopamina/líquido cefalorraquídeo , Lampreas , Ratones , Ratones Endogámicos C57BL , Proteínas de Microtúbulos/química , Proteínas de Microtúbulos/metabolismo , Neuronas/fisiología , Somatostatina/líquido cefalorraquídeo , Médula Espinal , Coloración y EtiquetadoRESUMEN
The primary driver of the evolution of the vertebrate nervous system has been the necessity to move, along with the requirement of controlling the plethora of motor behavioural repertoires seen among the vast and diverse vertebrate species. Understanding the neural basis of motor control through the perspective of evolution, mandates thorough examinations of the nervous systems of species in critical phylogenetic positions. We present here, a broad review of studies on the neural motor infrastructure of the lamprey, a basal and ancient vertebrate, which enjoys a unique phylogenetic position as being an extant representative of the earliest group of vertebrates. From the central pattern generators in the spinal cord to the microcircuits of the pallial cortex, work on the lamprey brain over the years, has provided detailed insights into the basic organization (a bauplan) of the ancestral vertebrate brain, and narrates a compelling account of common ancestry of fundamental aspects of the neural bases for motion control, maintained through half a billion years of vertebrate evolution. This article is part of the theme issue 'Systems neuroscience through the lens of evolutionary theory'.
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Lampreas , Vertebrados , Animales , Evolución Biológica , Lampreas/fisiología , Filogenia , Médula Espinal/fisiología , Vertebrados/fisiologíaRESUMEN
The forebrain plays a critical role in a broad range of neural processes encompassing sensory integration and initiation/selection of behaviour. The forebrain functions through an interaction between different cortical areas, the thalamus, the basal ganglia with the dopamine system, and the habenulae. The ambition here is to compare the mammalian forebrain with that of the lamprey representing the oldest now living group of vertebrates, by a review of earlier studies. We show that the lamprey dorsal pallium has a motor, a somatosensory, and a visual area with retinotopic representation. The lamprey pallium was previously thought to be largely olfactory. There is also a detailed similarity between the lamprey and mammals with regard to other forebrain structures like the basal ganglia in which the general organisation, connectivity, transmitters and their receptors, neuropeptides, and expression of ion channels are virtually identical. These initially unexpected results allow for the possibility that many aspects of the basic design of the vertebrate forebrain had evolved before the lamprey diverged from the evolutionary line leading to mammals. Based on a detailed comparison between the mammalian forebrain and that of the lamprey and with due consideration of data from other vertebrate groups, we propose a compelling account of a pan-vertebrate schema for basic forebrain structures, suggesting a common ancestry of over half a billion years of vertebrate evolution.
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Evolución Biológica , Lampreas , Animales , Mamíferos , Prosencéfalo , VertebradosRESUMEN
Neuromodulation is present throughout the nervous system and serves a critical role for circuit function and dynamics. The computational investigations of neuromodulation in large scale networks require supportive software platforms. Snudda is a software for the creation and simulation of large scale networks of detailed microcircuits consisting of multicompartmental neuron models. We have developed an extension to Snudda to incorporate neuromodulation in large scale simulations. The extended Snudda framework implements neuromodulation at the level of single cells incorporated into large-scale microcircuits. We also developed Neuromodcell, a software for optimizing neuromodulation in detailed multicompartmental neuron models. The software adds parameters within the models modulating the conductances of ion channels and ionotropic receptors. Bath application of neuromodulators is simulated and models which reproduce the experimentally measured effects are selected. In Snudda, we developed an extension to accommodate large scale simulations of neuromodulation. The simulator has two modes of simulation - denoted replay and adaptive. In the replay mode, transient levels of neuromodulators can be defined as a time-varying function which modulates the receptors and ion channels within the network in a cell-type specific manner. In the adaptive mode, spiking neuromodulatory neurons are connected via integrative modulating mechanisms to ion channels and receptors. Both modes of simulating neuromodulation allow for simultaneous modulation by several neuromodulators that can interact dynamically with each other. Here, we used the Neuromodcell software to simulate dopaminergic and muscarinic modulation of neurons from the striatum. We also demonstrate how to simulate different neuromodulatory states with dopamine and acetylcholine using Snudda. All software is freely available on Github, including tutorials on Neuromodcell and Snudda-neuromodulation.
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Colinérgicos , Dopamina , Acetilcolina , Cuerpo Estriado , NeuronasRESUMEN
A comparison of the vertebrate motor systems of the oldest group of now living vertebrates (lamprey) with that of mammals shows that there are striking similarities not only in the basic organization but also with regard to synaptic properties, transmitters and neuronal properties. The lamprey dorsal pallium (cortex) has a motor, a visual and a somatosensory area, and the basal ganglia, including the dopamine system, are organized in a virtually identical way in the lamprey and rodents. This also applies to the midbrain, brainstem and spinal cord. However, during evolution additional capabilities such as systems for the control of foreleg/arms, hands and fingers have evolved. The findings suggest that when the evolutionary lineages of mammals and lamprey became separate around 500 million years ago, the blueprint of the vertebrate motor system had already evolved.
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Evolución Biológica , Vertebrados , Animales , Lampreas/fisiología , Mamíferos , Prosencéfalo , Médula Espinal , Vertebrados/fisiologíaRESUMEN
The superior colliculus, or tectum in the case of non-mammalian vertebrates, is a part of the brain that registers events in the surrounding space, often through vision and hearing, but also through electrosensation, infrared detection, and other sensory modalities in diverse vertebrate lineages. This information is used to form maps of the surrounding space and the positions of different salient stimuli in relation to the individual. The sensory maps are arranged in layers with visual input in the uppermost layer, other senses in deeper positions, and a spatially aligned motor map in the deepest layer. Here, we will review the organization and intrinsic function of the tectum/superior colliculus and the information that is processed within tectal circuits. We will also discuss tectal/superior colliculus outputs that are conveyed directly to downstream motor circuits or via the thalamus to cortical areas to control various aspects of behavior. The tectum/superior colliculus is evolutionarily conserved among all vertebrates, but tailored to the sensory specialties of each lineage, and its roles have shifted with the emergence of the cerebral cortex in mammals. We will illustrate both the conserved and divergent properties of the tectum/superior colliculus through vertebrate evolution by comparing tectal processing in lampreys belonging to the oldest group of extant vertebrates, larval zebrafish, rodents, and other vertebrates including primates.
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Corteza Cerebral/fisiología , Procesamiento Espacial/fisiología , Colículos Superiores/fisiología , Vertebrados/fisiología , Vías Visuales , Animales , Humanos , Lampreas/fisiología , Primates/fisiología , Roedores/fisiología , Pez Cebra/fisiologíaRESUMEN
The neuronal networks that generate locomotion are well understood in swimming animals such as the lamprey, zebrafish and tadpole. The networks controlling locomotion in tetrapods remain, however, still enigmatic with an intricate motor pattern required for the control of the entire limb during the support, lift off, and flexion phase, and most demandingly when the limb makes contact with ground again. It is clear that the inhibition that occurs between bursts in each step cycle is produced by V2b and V1 interneurons, and that a deletion of these interneurons leads to synchronous flexor-extensor bursting. The ability to generate rhythmic bursting is distributed over all segments comprising part of the central pattern generator network (CPG). It is unclear how the rhythmic bursting is generated; however, Shox2, V2a and HB9 interneurons do contribute. To deduce a possible organization of the locomotor CPG, simulations have been elaborated. The motor pattern has been simulated in considerable detail with a network composed of unit burst generators; one for each group of close synergistic muscle groups at each joint. This unit burst generator model can reproduce the complex burst pattern with a constant flexion phase and a shortened extensor phase as the speed increases. Moreover, the unit burst generator model is versatile and can generate both forward and backward locomotion.
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Generadores de Patrones Centrales/fisiología , Interneuronas/fisiología , Locomoción/fisiología , Actividad Motora/fisiología , Redes Neurales de la Computación , Médula Espinal/fisiología , Animales , Gatos , Generadores de Patrones Centrales/citología , Simulación por Computador , Extremidades/inervación , Extremidades/fisiología , Humanos , Interneuronas/citología , Lampreas/fisiología , Larva/fisiología , Neuronas Motoras/citología , Neuronas Motoras/fisiología , Músculo Esquelético/inervación , Músculo Esquelético/fisiología , Roedores/fisiología , Médula Espinal/citología , Pez Cebra/fisiologíaRESUMEN
In this issue of Neuron, McElvain et al. (2021) show that the major output of the basal ganglia, the substantia nigra pars reticulata, targets no fewer than 42 midbrain and brainstem structures and conveys an efference copy of the downstream commands back via thalamus to the cortex and striatum.
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Ganglios Basales , Porción Reticular de la Sustancia Negra , Corteza Cerebral , Mesencéfalo , NeuronasRESUMEN
The presence of two separate afferent channels from the olfactory glomeruli to different targets in the brain is unravelled in the lamprey. The mitral-like cells send axonal projections directly to the piriform cortex in the ventral part of pallium, whereas the smaller tufted-like cells project separately and exclusively to a relay nucleus called the dorsomedial telencephalic nucleus (dmtn). This nucleus, located at the interface between the olfactory bulb and pallium, in turn projects to a circumscribed area in the anteromedial, ventral part of pallium. The tufted-like cells are activated with short latency from the olfactory nerve and terminate with mossy fibers on the dmtn cells, wherein they elicit large unitary excitatory postsynaptic potentials (EPSPs). In all synapses along this tufted-like cell pathway, there is no concurrent inhibition, in contrast to the mitral-like cell pathway. This is similar to recent findings in rodents establishing two separate exclusive projection patterns, suggesting an evolutionarily conserved organization.
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Potenciales Postsinápticos Excitadores , Lampreas/fisiología , Núcleo Talámico Mediodorsal/fisiología , Bulbo Olfatorio/fisiología , Nervio Olfatorio/fisiología , Telencéfalo/fisiología , Vías Aferentes/citología , Vías Aferentes/fisiología , Animales , Vías Eferentes/fisiología , Electrofisiología , Inmunohistoquímica , Núcleo Talámico Mediodorsal/citología , Neuronas/fisiología , Bulbo Olfatorio/citología , Nervio Olfatorio/citología , Vías Olfatorias/citología , Vías Olfatorias/fisiología , Corteza Piriforme/fisiología , Sinapsis/fisiología , Telencéfalo/citologíaRESUMEN
The striatum is the main input stage of the basal ganglia receiving extrinsic input from cortex and thalamus. The striatal projection neurons (SPN) constitute 95% of the neurons in the striatum in mice while the remaining 5% are cholinergic and GABAergic interneurons. The cholinergic (ChIN) and low-threshold spiking interneurons (LTS) are spontaneously active and form a striatal subnetwork involved in salience detection and goal-directed learning. Activation of ChINs has been shown to inhibit LTS via muscarinic receptor type 4 (M4R) and LTS in turn can modulate ChINs via nitric oxide (NO) causing a prolonged depolarization. Thalamic input prefentially excites ChINs, whereas input from motor cortex favours LTS, but can also excite ChINs. This varying extrinsic input with intrinsic reciprocal, yet opposing, effects raises the possibility of a slow input-dependent modulatory subnetwork. Here, we simulate this subnetwork using multicompartmental neuron models that incorporate data regarding known ion channels and detailed morphological reconstructions. The modelled connections replicate the experimental data on muscarinic (M4R) and nitric oxide modulation onto LTS and ChIN, respectively, and capture their physiological interaction. Finally, we show that the cortical and thalamic inputs triggering the opposing modulation within the network induce periods of increased and decreased spiking activity in ChINs and LTS. This could provide different temporal windows for selective modulation by acetylcholine and nitric oxide, and the possibility of interaction with the wider striatal microcircuit.
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Cuerpo Estriado , Interneuronas , Animales , Colinérgicos , Ratones , Ratones Transgénicos , TálamoRESUMEN
In this tribute to Reggie Edgerton, I briefly review the spinal mechanisms that coordinate locomotion and the interaction between the different sensory mechanisms that help coordinate the locomotor movements and the central locomotor network. The step cycle has four distinct parts, the support phase, the lift off, the flexion phase, and, the most complex, the touch down, when the limb makes a smooth contact with ground again. Each of these phases is affected by different sensory mechanisms, which interact with the central network [central pattern generator (CPG)] generating the basic movements with its four components. Conversely, the CPG also gates the sensory reflex pathways, so that they are active only in a given phase of the step cycle, or even produces opposite effects in different parts of the step cycle. These different examples from mammals are most likely important also to consider for human locomotion and, in particular, in patients with spinal cord injury, partial or complete.
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Médula Espinal/fisiología , Caminata , Animales , Generadores de Patrones Centrales/fisiología , Retroalimentación Sensorial , Humanos , Médula Espinal/citologíaRESUMEN
The basal ganglia represent an ancient part of the nervous system that have remained organized in a similar way over the last 500 million years and are of importance for our ability to determine which actions to choose at any given moment in time. Salient or reward stimuli act via the dopamine system and contribute to motor or procedural learning (reinforcement learning). The input stage of the basal ganglia, the striatum, is shaped by glutamatergic input from the cortex and thalamus and by the dopamine system. All intrinsic neurons of the striatum are GABAergic and inhibitory except for the cholinergic interneurons. Too little dopamine and all vertebrates show symptoms similar to that of a Parkinsonian patient, whereas too much dopamine results in hyperkinesia with involuntary movements. In this article, we discuss the detailed organization of the basal ganglia, with the different cell types, their properties, and contributions to basal ganglia functions. The striatal projection neurons represent 95% of all neurons in the striatum and are subdivided into two types, one that projects directly to the output stage, referred to as the "direct" pathway that promotes action, and the other subtype that targets the output nuclei via intercalated basal ganglia nuclei. This "indirect" pathway has an opposite effect. The striatal projection neurons express a set of ion channels that give them a high threshold for activation, whereas neurons in all other parts of the basal ganglia have a resting discharge that allows for modulation in both an increased and decreased direction. © 2020 American Physiological Society. Compr Physiol 10:1241-1275, 2020.
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Ganglios Basales/fisiología , Movimiento/fisiología , Neuronas/fisiología , Animales , Conducta , Corteza Cerebral/fisiología , Humanos , Modelos Biológicos , Sinapsis/fisiologíaRESUMEN
In this review, we approach Parkinson's disease (PD) in the context of an evolutionary mismatch of central nervous system functions. The neurons at risk have hyperbranched axons, extensive transmitter release sites, display spontaneous spiking, and elevated mitochondrial stress. They function in networks largely unchanged throughout vertebrate evolution, but now connecting to the expanded human cortex. Their breakdown is favoured by longevity. At the cellular level, mitochondrial dysfunction starts at the synapses, then involves axons and cell bodies. At the behavioural level, network dysfunctions provoke the core motor syndrome of parkinsonism including freezing and failed gait automatization, and non-motor deficits including inactive blindsight and autonomic dysregulation. The proposed evolutionary re-interpretation of PD-prone cellular phenotypes and of prototypical clinical symptoms allows a new conceptual framework for future research.
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Enfermedad de Parkinson , Axones , Corteza Cerebral , Humanos , Mitocondrias , Neuronas , Enfermedad de Parkinson/genéticaRESUMEN
The basal ganglia play an important role in decision making and selection of action primarily based on input from cortex, thalamus, and the dopamine system. Their main input structure, striatum, is central to this process. It consists of two types of projection neurons, together representing 95% of the neurons, and 5% of interneurons, among which are the cholinergic, fast-spiking, and low threshold-spiking subtypes. The membrane properties, soma-dendritic shape, and intrastriatal and extrastriatal synaptic interactions of these neurons are quite well described in the mouse, and therefore they can be simulated in sufficient detail to capture their intrinsic properties, as well as the connectivity. We focus on simulation at the striatal cellular/microcircuit level, in which the molecular/subcellular and systems levels meet. We present a nearly full-scale model of the mouse striatum using available data on synaptic connectivity, cellular morphology, and electrophysiological properties to create a microcircuit mimicking the real network. A striatal volume is populated with reconstructed neuronal morphologies with appropriate cell densities, and then we connect neurons together based on appositions between neurites as possible synapses and constrain them further with available connectivity data. Moreover, we simulate a subset of the striatum involving 10,000 neurons, with input from cortex, thalamus, and the dopamine system, as a proof of principle. Simulation at this biological scale should serve as an invaluable tool to understand the mode of operation of this complex structure. This platform will be updated with new data and expanded to simulate the entire striatum.
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Simulación por Computador , Cuerpo Estriado/fisiología , Fenómenos Electrofisiológicos , Modelos Biológicos , Neuronas/fisiología , Animales , Corteza Cerebral/fisiología , Cuerpo Estriado/citología , Dopamina/metabolismo , Ratones , Receptores Dopaminérgicos/metabolismo , Tálamo/fisiologíaRESUMEN
Amniotes, such as mammals and reptiles, have vision and other senses represented in the pallium, whereas anamniotes, such as amphibians, fish and cyclostomes (including lampreys), which diverged much earlier, were historically thought to process olfactory information predominantly or even exclusively in the pallium. Here, we show that there is a separate visual area with retinotopic representation, and that somatosensory information from the head and trunk is represented in an adjacent area in the lamprey pallial cortex (lateral pallium). These cortical sensory areas flank a non-primary-sensory motor area. Both vision and somatosensation are relayed via the thalamus. These findings suggest that the basic sensorimotor representation of the mammalian neocortex, as well as the sensory thalamocortical relay, had already evolved in the last common ancestor of cyclostomes and gnathostomes around 560 million years ago.