RESUMEN
Balanced activity of canonical direct D1 and indirect D2 basal ganglia pathways is considered a core requirement for normal movement, and their imbalance is an etiologic factor in movement and neuropsychiatric disorders. We present evidence for a conceptually equivalent pair of direct-D1 and indirect-D2 pathways that arise from striatal projection neurons (SPNs) of the striosome compartment rather than from SPNs of the matrix, as do the canonical pathways. These S-D1 and S-D2 striosomal pathways target substantia nigra dopamine-containing neurons instead of basal ganglia motor output nuclei. They modulate movement oppositely to the modulation by the canonical pathways: S-D1 is inhibitory and S-D2 is excitatory. The S-D1 and S-D2 circuits likely influence motivation for learning and action, complementing and reorienting canonical pathway modulation. A major conceptual reformulation of the classic direct-indirect pathway model of basal ganglia function is needed, as well as reconsideration of the effects of D2-targeting therapeutic drugs.
RESUMEN
Striosomes form neurochemically specialized compartments of the striatum embedded in a large matrix made up of modules called matrisomes. Striosome-matrix architecture is multiplexed with the canonical direct-indirect organization of the striatum. Striosomal functions remain to be fully clarified, but key information is emerging. First, striosomes powerfully innervate nigral dopamine-containing neurons and can completely shut down their activity, with a following rebound excitation. Second, striosomes receive limbic and cognition-related corticostriatal afferents and are dynamically modulated in relation to value-based actions. Third, striosomes are spatially interspersed among matrisomes and interneurons and are influenced by local and global neuromodulatory and oscillatory activities. Fourth, striosomes tune engagement and the motivation to perform reinforcement learning, to manifest stereotypical behaviors, and to navigate valence conflicts and valence discriminations. We suggest that, at an algorithmic level, striosomes could serve as distributed scaffolds to provide formats of the striatal computations generated through development and refined through learning. We propose that striosomes affect subjective states. By transforming corticothalamic and other inputs to the functional formats of the striatum, they could implement state transitions in nigro-striato-nigral circuits to affect bodily and cognitive actions according to internal motives whose functions are compromised in neuropsychiatric conditions.
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Ganglios Basales , Volición , Ganglios Basales/fisiología , Cuerpo Estriado/fisiología , Interneuronas , Refuerzo en PsicologíaRESUMEN
Striatal projection neurons (SPNs), which progressively degenerate in human patients with Huntington's disease (HD), are classified along two axes: the canonical direct-indirect pathway division and the striosome-matrix compartmentation. It is well established that the indirect-pathway SPNs are susceptible to neurodegeneration and transcriptomic disturbances, but less is known about how the striosome-matrix axis is compromised in HD in relation to the canonical axis. Here we show, using single-nucleus RNA-sequencing data from male Grade 1 HD patient post-mortem brain samples and male zQ175 and R6/2 mouse models, that the two axes are multiplexed and differentially compromised in HD. In human HD, striosomal indirect-pathway SPNs are the most depleted SPN population. In mouse HD models, the transcriptomic distinctiveness of striosome-matrix SPNs is diminished more than that of direct-indirect pathway SPNs. Furthermore, the loss of striosome-matrix distinction is more prominent within indirect-pathway SPNs. These results open the possibility that the canonical direct-indirect pathway and striosome-matrix compartments are differentially compromised in late and early stages of disease progression, respectively, differentially contributing to the symptoms, thus calling for distinct therapeutic strategies.
Asunto(s)
Enfermedad de Huntington , Ratones , Animales , Humanos , Masculino , Enfermedad de Huntington/genética , Enfermedad de Huntington/metabolismo , Roedores , Cuerpo Estriado/metabolismo , Neuronas/metabolismo , Ganglios Basales/metabolismo , Modelos Animales de Enfermedad , Ratones TransgénicosRESUMEN
Prager et al. demonstrate an opposite regulation of activity in striosomes and matrix of the striatum. By a D1-receptor-linked L-VGCC-dependent mechanism, dopamine release can extend upstates in matrix D1-expressing direct pathway projection neurons (dSPNs) but shorten them in striosomal dSPNs.
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Cuerpo Estriado , Dopamina , Sesgo , Neuronas , Receptores de Dopamina D1RESUMEN
Cortical pyramidal cells are generated locally, from pre-programmed progenitors, to form functionally distinct areas. By contrast, striatal projection neurons (SPNs) are generated remotely from a common source, undergo migration to form mosaics of striosomes and matrix, and become incorporated into functionally distinct sectors. Striatal circuits might thus have a unique logic of developmental organization, distinct from those of the neocortex. We explore this possibility in mice by mapping one set of SPNs, those in striosomes, with striatonigral projections to the dopamine-containing substantia nigra pars compacta (SNpc). Same-age SPNs exhibit topographic striatonigral projections, according to their resident sector. However, the different birth dates of resident SPNs within a given sector specify the destination of their axons within the SNpc. These findings highlight a logic intercalating birth date-dependent and birth date-independent factors in determining the trajectories of SPN axons and organizing specialized units of striatonigral circuitry that could influence behavioral expression and vulnerabilities to disease.
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Cuerpo Estriado/metabolismo , Vías Nerviosas/metabolismo , Neuronas/metabolismo , Sustancia Negra/metabolismo , Animales , Axones/metabolismo , Ganglios Basales/metabolismo , Dopamina/metabolismo , RatonesRESUMEN
In the field of molecular and cellular neuroscience, it is not a trivial task to see the forest for the trees, where numerous, and seemingly independent, molecules often work in concert to control critical steps of synaptic plasticity and signalling. Here, we will first summarize our current knowledge on essential activity-dependent transcription factors (TFs) such as CREB, MEF2, Npas4 and SRF, then examine how various transcription cofactors (TcoFs) also contribute to defining the transcriptional outputs during learning and memory. This review finally attempts a provisory synthesis that sheds new light on some of the emerging principles of neuronal circuit dynamics driven by activity-regulated gene transcription to help better understand the intricate relationship between activity-dependent gene expression and cognitive behavior.
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Cognición/fisiología , Regulación de la Expresión Génica/fisiología , Factores de Transcripción/fisiología , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/fisiología , Proteína de Unión a CREB/fisiología , Humanos , Proteínas de Interacción con los Canales Kv/fisiología , Aprendizaje/fisiología , Factores de Transcripción MEF2/fisiología , Memoria/fisiología , Proteína 2 de Unión a Metil-CpG/fisiología , Proteínas Represoras/fisiologíaRESUMEN
Humans can simultaneously track multiple moving objects with attention. The number of objects that can be tracked is known to be larger when visual stimuli are presented bilaterally rather than presented unilaterally. To elucidate the underlying neuronal mechanism, we trained monkeys to covertly track a single or multiple object(s). We found that neurons in the lateral prefrontal cortex exhibited greater activity for the target passing through the receptive field (RF) than for distractors. During multiple-object tracking, response enhancement for one target presented in the RF was stronger when the other target was located in the opposite than the same visual hemifield. Because the neuronal modulation did not differ depending on relative target locations with respect to upper and lower visual hemifields, the distance between the targets does not explain the results. We propose that inherent, anatomical separation of visual processing for contralateral and ipsilateral visual fields might constrain cognitive capacity.
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Atención/fisiología , Percepción de Movimiento/fisiología , Neuronas/fisiología , Estimulación Luminosa/métodos , Corteza Prefrontal/fisiología , Percepción Espacial/fisiología , Animales , Femenino , Macaca , Campos Visuales/fisiologíaRESUMEN
Spatial working memory is one of the most studied cognitive functions, serving as a model system to decipher computational principles of the brain. Although neuronal mechanisms for remembering a single location have been well elucidated, little is known about memory for multiple locations. Here, we examined the activities of prefrontal neurons during monkeys remembered positions of one or two visual cue(s). When the two cues were presented across the left and right visual fields, neurons exhibited a comparable response to the activity for the preferred cue presented alone. When the two cues were presented within the same hemifield, neurons exhibited an intermediate response between those to the individual cues. Subsequent computer simulations predicted a lower signal-to-noise ratio in the latter condition, which was further verified by behavioral experiments. Considering the separation of contralateral and ipsilateral visual processing, the lateral inhibition in local circuits might implicitly determine different neuronal computations and memory capacities for bilateral and unilateral displays.
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Lateralidad Funcional/fisiología , Memoria a Corto Plazo/fisiología , Neuronas/fisiología , Percepción Espacial/fisiología , Corteza Visual/citología , Campos Visuales/fisiología , Potenciales de Acción/fisiología , Animales , Señales (Psicología) , Femenino , Macaca fascicularis , Aprendizaje por Laberinto/fisiología , Estimulación Luminosa , Valor Predictivo de las Pruebas , Tiempo de Reacción/fisiología , Relación Señal-RuidoRESUMEN
For each saccade, we select an object to direct gaze and to specify the direction and amplitude of eye movement. Although these 2 processes are inevitably interdependent when visual stimuli are held stationary, several lines of evidence suggest that the neuronal signals in the frontal eye fields (FEF) that underlie the selection of visual objects are distinct from those underlying the selection of saccades. In the present study, we overtly dissociated these 2 processes spatially and temporally using the covert object-tracking paradigm, in which 4 identical objects moved randomly for 3 s before monkeys made a saccade to a previously selected target. To assess the causal role of the FEF in the 2 selection processes, we applied electrical microstimulation to the FEF at various times during the motion period. When stimulation was delivered at the motion onset, animals tended to choose an object that was initially presented at a particular location depending on the stimulation site. In contrast, the same stimulation delivered at the motion end failed to alter saccade end points. These results indicate that manipulation of FEF activity can change the selection of a visual object without affecting saccade goals, suggesting the existence of neurons solely regulating visual selection.
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Conducta de Elección/fisiología , Lóbulo Frontal/fisiología , Percepción de Movimiento/fisiología , Neuronas/fisiología , Movimientos Sacádicos/fisiología , Animales , Estimulación Eléctrica , Femenino , Lóbulo Frontal/anatomía & histología , Macaca , Imagen por Resonancia Magnética , Microelectrodos , Actividad Motora/fisiología , Pruebas Neuropsicológicas , Estimulación Luminosa , Psicofísica , Análisis y Desempeño de TareasRESUMEN
Neurons in the lateral prefrontal cortex show sustained activity during the maintenance of visual memory. Previous studies have also indicated that prefrontal neurons show predictive activity in anticipation of upcoming visual stimuli. Because these retrospective and prospective coding of visual stimuli have been examined in separate experiments, how these processes interact in individual neurons remains unknown. To examine this, we recorded from single prefrontal neurons while monkeys performed two behavioural tasks. In one task, the animals passively viewed a moving object during fixation, whereas in the other, they remembered the location of a briefly presented visual cue for subsequent saccades. We found that many neurons were reactive and responded only after the visual stimulus appeared in their receptive field, while some neurons were predictive and increased their activity even before the moving stimulus entered the receptive field. In the memory-guided saccade trials, the reactive neurons exhibited sustained activity during the delay period, whereas the predictive neurons did not. Delays of visual response to a moving stimulus did not correlate with visual latency for a stationary stimulus. Instead, it correlated with the magnitude of sustained activity during the delay period in the memory-guided saccade task. Our data show that retrospective and prospective coding of visual information are represented by distinct neuronal populations, and that their temporal preferences are stable across different task conditions. Reactive signals may reflect the amount of temporal integration in short-term memory, whereas predictive signals may solely represent future events in isolation from the maintenance of past information.
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Memoria a Corto Plazo/fisiología , Neuronas/fisiología , Corteza Prefrontal/fisiología , Movimientos Sacádicos/fisiología , Animales , Señales (Psicología) , Electrofisiología/métodos , Femenino , Macaca mulatta , Estimulación Luminosa/métodos , Valor Predictivo de las Pruebas , Factores de TiempoRESUMEN
Resistance to distraction is a key component of executive functions and is strongly linked to the prefrontal cortex. Recent evidence suggests that neural mechanisms exist for selective suppression of task-irrelevant information. However, neuronal signals related to selective suppression have not yet been identified, whereas nonselective surround suppression, which results from attentional enhancement for relevant stimuli, has been well documented. This study examined single neuron activities in the lateral PFC when monkeys covertly tracked one of randomly moving objects. Although many neurons responded to the target, we also found a group of neurons that exhibited a selective response to the distractor that was visually identical to the target. Because most neurons were insensitive to an additional distractor that explicitly differed in color from the target, the brain seemed to monitor the distractor only when necessary to maintain internal object segregation. Our results suggest that the lateral PFC might provide at least two top-down signals during covert object tracking: one for enhancement of visual processing for the target and the other for selective suppression of visual processing for the distractor. These signals might work together to discriminate objects, thereby regulating both the sensitivity and specificity of target choice during covert object tracking.
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Movimientos Oculares/fisiología , Percepción de Movimiento/fisiología , Neuronas/fisiología , Estimulación Luminosa/métodos , Corteza Prefrontal/fisiología , Animales , Femenino , MacacaRESUMEN
Secretogranin II (SgII), or chromogranin C, is thought to participate in the sorting and packaging of peptide hormones and neuropeptides into secretory granules and large dense-core vesicle (LDCVs), and also functions as a precursor of neuropeptide secretoneurin. Although SgII is widely distributed in the brain and is predominantly localized at terminals of mossy fibers in the hippocampus and cerebellum and climbing fibers in the cerebellum, its cellular expression and ultrastructural localization remain largely unknown. In the present study, we addressed this issue in the adult mouse brain by multiple-labeling fluorescence in situ hybridization and immunofluorescence and by preembedding and postembedding immunoelectron microscopies. SgII was expressed in various neurons, distributed as either tiny puncta or coarse aggregates in the neuropil, and intensely accumulated in perikarya of particular neurons, such as parvalbumin-positive interneurons and mossy cells in the hippocampus and Purkinje cells in the cerebellum. Coarse aggregates were typical of terminals of mossy fibers and climbing fibers. In these terminals, numerous immunogold particles were clustered on individual LDCVs, and one or two particles also fell within small synaptic vesicle-accumulating portions. SgII was further detected as tiny puncta in neural elements lacking LDCVs, such as parallel fibers of cerebellar granule cells, somatodendritic elements of various neurons and Bergmann glia. Thus, SgII is present in LDCV and non-LDCV compartments of various neural cells. The wide subcellular localization of SgII may reflect diverse release sites of neuropeptides and secretorneurin, or suggests its role in the sorting and packaging of molecules other than neuropeptides in non-LDCV compartments.
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Cerebelo/metabolismo , Hipocampo/metabolismo , Secretogranina II/metabolismo , Animales , Cerebelo/ultraestructura , Hipocampo/ultraestructura , Hibridación Fluorescente in Situ , Ratones , Ratones Endogámicos C57BL , Microscopía Inmunoelectrónica , Secretogranina II/genética , Vesículas Secretoras/química , Vesículas Secretoras/ultraestructura , Distribución TisularRESUMEN
Lampreys are one of the most primitive vertebrates diverged some 500 million years ago. It has long been known that parasitic lampreys secrete anticoagulant from their buccal glands and prevent blood coagulation of host fishes. We found two major protein components of 160 and 26 kDa in the buccal gland secretion of parasitic river lamprey, Lethenteron japonicum. The larger protein was identified as river lamprey plasma albumin. The complete primary structure of the 26-kDa protein was determined by protein and cDNA analysis. It belonged to the cysteine-rich secretory protein (CRISP) superfamily that includes recently identified reptile venom ion-channel blockers. Lamprey CRISP blocked depolarization-induced contraction of rat-tail arterial smooth muscle, but showed no effect on caffeine-induced contraction. The result suggests that lamprey CRISP is an L-type Ca(2+)-channel blocker and may act as a vasodilator, which facilitates the parasite to feed on the host's blood. The lamprey CRISP protein contains a number of short insertions throughout the sequence, when aligned with reptilian venom CRISP proteins, probably due to the large evolutionary distance between the Agnatha and the Reptilia, and may represent a novel class of venom CRISP family proteins.