RESUMEN
Learning valence-based responses to favorable and unfavorable options requires judgments of the relative value of the options, a process necessary for species survival. We found, using engineered mice, that circuit connectivity and function of the striosome compartment of the striatum are critical for this type of learning. Calcium imaging during valence-based learning exhibited a selective correlation between learning and striosomal but not matrix signals. This striosomal activity encoded discrimination learning and was correlated with task engagement, which, in turn, could be regulated by chemogenetic excitation and inhibition. Striosomal function during discrimination learning was disturbed with aging and severely so in a mouse model of Huntington's disease. Anatomical and functional connectivity of parvalbumin-positive, putative fast-spiking interneurons (FSIs) to striatal projection neurons was enhanced in striosomes compared with matrix in mice that learned. Computational modeling of these findings suggests that FSIs can modulate the striosomal signal-to-noise ratio, crucial for discrimination and learning.
Asunto(s)
Envejecimiento/patología , Cuerpo Estriado/patología , Enfermedad de Huntington/patología , Aprendizaje , Potenciales de Acción , Animales , Conducta Animal , Biomarcadores/metabolismo , Cuerpo Estriado/fisiopatología , Aprendizaje Discriminativo , Modelos Animales de Enfermedad , Enfermedad de Huntington/fisiopatología , Interneuronas/patología , Ratones Transgénicos , Modelos Neurológicos , Red Nerviosa/fisiopatología , Parvalbúminas/metabolismo , Fotometría , Recompensa , Análisis y Desempeño de TareasRESUMEN
Circuit influences on the midbrain dopamine system are crucial to adaptive behavior and cognition. Recent developments in the study of neuropeptide systems have enabled high-resolution investigations of the intersection of neuromodulatory signals with basal ganglia circuitry, identifying the nociceptin/orphanin FQ (N/OFQ) endogenous opioid peptide system as a prospective regulator of striatal dopamine signaling. Using a prepronociceptin-Cre reporter mouse line, we characterized highly selective striosomal patterning of Pnoc mRNA expression in mouse dorsal striatum, reflecting early developmental expression of Pnoc . In the ventral striatum, Pnoc expression was was clustered across the nucleus accumbens core and medial shell, including in adult striatum. We found that Pnoc tdTomato reporter cells largely comprise a population of dopamine receptor D1 ( Drd1 ) expressing medium spiny projection neurons localized in dorsal striosomes, known to be unique among striatal projections neurons for their direct innervation of midbrain dopamine neurons. These findings provide new understanding of the intersection of the N/OFQ system among basal ganglia circuits with particular implications for developmental regulation or wiring of striatal-nigral circuits.
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
Learning from successes and failures often improves the quality of subsequent decisions. Past outcomes, however, should not influence purely perceptual decisions after task acquisition is complete since these are designed so that only sensory evidence determines the correct choice. Yet, numerous studies report that outcomes can bias perceptual decisions, causing spurious changes in choice behavior without improving accuracy. Here we show that the effects of reward on perceptual decisions are principled: past rewards bias future choices specifically when previous choice was difficult and hence decision confidence was low. We identified this phenomenon in six datasets from four laboratories, across mice, rats, and humans, and sensory modalities from olfaction and audition to vision. We show that this choice-updating strategy can be explained by reinforcement learning models incorporating statistical decision confidence into their teaching signals. Thus, reinforcement learning mechanisms are continually engaged to produce systematic adjustments of choices even in well-learned perceptual decisions in order to optimize behavior in an uncertain world.
Asunto(s)
Sesgo , Toma de Decisiones/fisiología , Refuerzo en Psicología , Animales , Conducta de Elección , Audición , Humanos , Ratones , Ratas , Olfato , Visión OcularRESUMEN
Leukocyte common antigen-related (LAR) family receptor protein tyrosine phosphatases (LAR-RPTP) bind to liprin-alpha (SYD2) and are implicated in axon guidance. We report that LAR-RPTP is concentrated in mature synapses in cultured rat hippocampal neurons, and is important for the development and maintenance of excitatory synapses in hippocampal neurons. RNA interference (RNAi) knockdown of LAR or dominant-negative disruption of LAR function results in loss of excitatory synapses and dendritic spines, reduction of surface AMPA receptors, impairment of dendritic targeting of the cadherin-beta-catenin complex, and reduction in the amplitude and frequency of miniature excitatory postsynaptic currents (mEPSCs). Cadherin, beta-catenin and GluR2/3 are tyrosine phosphoproteins that coimmunoprecipitate with liprin-alpha and GRIP from rat brain extracts. We propose that the cadherin-beta-catenin complex is cotransported with AMPA receptors to synapses and dendritic spines by a mechanism that involves binding of liprin-alpha to LAR-RPTP and tyrosine dephosphorylation by LAR-RPTP.
Asunto(s)
Regulación del Desarrollo de la Expresión Génica/fisiología , Hipocampo/citología , Hipocampo/crecimiento & desarrollo , Proteínas del Tejido Nervioso/metabolismo , Neuronas/metabolismo , Proteínas Tirosina Fosfatasas/metabolismo , Receptores de Superficie Celular/metabolismo , Sinapsis/fisiología , Proteínas Adaptadoras Transductoras de Señales , Animales , Animales Recién Nacidos , Western Blotting/métodos , Encéfalo/crecimiento & desarrollo , Encéfalo/metabolismo , Células COS , Células Cultivadas , Chlorocebus aethiops , Proteínas del Citoesqueleto/metabolismo , Dendritas/metabolismo , Diagnóstico por Imagen/métodos , Inhibidores Enzimáticos/farmacología , Potenciales Postsinápticos Excitadores/fisiología , Genisteína/farmacología , Proteínas Fluorescentes Verdes/metabolismo , Humanos , Inmunohistoquímica/métodos , Inmunoprecipitación/métodos , Potenciales de la Membrana/genética , Potenciales de la Membrana/efectos de la radiación , Datos de Secuencia Molecular , Mutagénesis/fisiología , Técnicas de Placa-Clamp/métodos , Péptido-N4-(N-acetil-beta-glucosaminil) Asparagina Amidasa/farmacología , Fosfoproteínas/metabolismo , Monoéster Fosfórico Hidrolasas/metabolismo , Fosforilación , Proteínas Proto-Oncogénicas c-myc/metabolismo , ARN sin Sentido/farmacología , ARN Interferente Pequeño , Ratas , Proteínas Tirosina Fosfatasas Clase 2 Similares a Receptores , Receptores AMPA/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Factores de Tiempo , Transactivadores/metabolismo , Transfección/métodos , Tirosina/metabolismo , Vanadatos/farmacología , beta CateninaRESUMEN
Appropriate choice about delayed reward is fundamental to the survival of animals. Although animals tend to prefer immediate reward, delaying gratification is often advantageous. The dorsal raphe (DR) serotonergic neurons have long been implicated in the processing of delayed reward, but it has been unclear whether or when their activity causally directs choice. Here, we transiently augmented or reduced the activity of DR serotonergic neurons, while mice decided between differently delayed rewards as they performed a novel odor-guided intertemporal choice task. We found that these manipulations, precisely targeted at the decision point, were sufficient to bidirectionally influence impulsive choice. The manipulation specifically affected choices with more difficult trade-off. Similar effects were observed when we manipulated the serotonergic projections to the nucleus accumbens (NAc). We propose that DR serotonergic neurons preempt reward delays at the decision point and play a critical role in suppressing impulsive choice by regulating decision trade-off.
Asunto(s)
Conducta de Elección/fisiología , Núcleo Dorsal del Rafe/fisiología , Conducta Impulsiva/fisiología , Recompensa , Neuronas Serotoninérgicas/fisiología , Animales , Masculino , Ratones , Ratones Transgénicos , Factores de TiempoRESUMEN
A fundamental question in synaptic physiology is whether the unitary strength of a synapse can be regulated by presynaptic characteristics and, if so, what those characteristics might be. Here, we characterize a newly proposed mechanism for altering the strength of glutamatergic synapses based on the recently identified vesicular glutamate transporter VGLUT1. We provide direct evidence that filling in isolated synaptic vesicles is subject to a dynamic equilibrium that is determined by both the concentration of available glutamate and the number of vesicular transporters participating in loading. We observe that changing the number of vesicular transporters expressed at hippocampal excitatory synapses results in enhanced evoked and miniature responses and verify biophysically that these changes correspond to an increase in the amount of glutamate released per vesicle into the synaptic cleft. In addition, we find that this modulation of synaptic strength by vesicular transporter expression is endogenously regulated, both across development to coincide with a maturational increase in vesicle cycling and quantal amplitude and by excitatory and inhibitory receptor activation in mature neurons to provide an activity-dependent scaling of quantal size via a presynaptic mechanism. Together, these findings underscore that vesicular transporter expression is used endogenously to directly regulate the extent of glutamate release, providing a concise presynaptic mechanism for controlling the quantal efficacy of excitatory transmission during synaptic refinement and plasticity.
Asunto(s)
Terminales Presinápticos/fisiología , Sinapsis/fisiología , Transmisión Sináptica/fisiología , Vesículas Sinápticas/fisiología , Proteína 1 de Transporte Vesicular de Glutamato/fisiología , Animales , Secuencia de Bases , Clonación Molecular , Cartilla de ADN , Potenciales Evocados/fisiología , Ácido Glutámico/metabolismo , Homeostasis , Procesamiento de Imagen Asistido por Computador , Células PC12 , Técnicas de Placa-Clamp , Teoría Cuántica , Ratas , Proteína 1 de Transporte Vesicular de Glutamato/genéticaRESUMEN
Changes in neural activity influence synaptic plasticity/scaling, gene expression, and epigenetic modifications. We present the first evidence that short-term and persistent changes in neural activity can alter adenosine-to-inosine (A-to-I) RNA editing, a post-transcriptional site-specific modification found in several neuron-specific transcripts. In rat cortical neuron cultures, activity-dependent changes in A-to-I RNA editing in coding exons are present after 6 hr of high potassium depolarization but not after 1 hr and require calcium entry into neurons. When treatments are extended from hours to days, we observe a negative feedback phenomenon: Chronic depolarization increases editing at many sites and chronic silencing decreases editing. We present several different modulations of neural activity that change the expression of different mRNA isoforms through editing.
Asunto(s)
Adenosina/metabolismo , Corteza Cerebral/citología , Inosina/metabolismo , Neuronas/metabolismo , Edición de ARN , Animales , Calcio/metabolismo , Potenciales de la Membrana , Neuronas/citología , ARN Mensajero/metabolismo , Ratas , Sinapsis/metabolismo , Factores de TiempoRESUMEN
Hg/Pt hemispherical ultramicroelectrodes (UMEs) (25-microm diameter) were prepared either by electrodeposition from a mercuric ion solution or by simple contact of the Pt disk to a hanging mercury drop electrode. The two methods produced equivalent tips. Optical inspection and electrochemical characterization of these Hg tips with methyl viologen, cobalt sepulchrate trichloride, and hexamineruthenium(III) chloride confirm the hemispherical nature of the UME. The scanning electrochemical microscopy approach curves for all three redox couples over a conductive substrate fit theoretical plots for hemispherical electrodes. The numerical solution of the diffusion equations for substrate generation-tip collection (SG-TC) transients for a finite Pt disk and Hg/Pt hemispherical UME are reported and compared to experimental results. A diffusion layer approximation is presented, and diffusion coefficients are extracted from the simulation. The SG-TC results reveal the enhanced sensitivity of hemispherical UME to radial diffusion.