RESUMEN
Significant evidence supports the view that dopamine shapes learning by encoding reward prediction errors. However, it is unknown whether striatal targets receive tailored dopamine dynamics based on regional functional specialization. Here, we report wave-like spatiotemporal activity patterns in dopamine axons and release across the dorsal striatum. These waves switch between activational motifs and organize dopamine transients into localized clusters within functionally related striatal subregions. Notably, wave trajectories were tailored to task demands, propagating from dorsomedial to dorsolateral striatum when rewards are contingent on animal behavior and in the opponent direction when rewards are independent of behavioral responses. We propose a computational architecture in which striatal dopamine waves are sculpted by inference about agency and provide a mechanism to direct credit assignment to specialized striatal subregions. Supporting model predictions, dorsomedial dopamine activity during reward-pursuit signaled the extent of instrumental control and interacted with reward waves to predict future behavioral adjustments.
Asunto(s)
Axones/metabolismo , Conducta Animal , Cuerpo Estriado/metabolismo , Dopamina/metabolismo , Recompensa , Animales , Femenino , Masculino , Ratones , Ratones MutantesRESUMEN
The ability to record transient cellular events in the DNA or RNA of cells would enable precise, large-scale analysis, selection, and reprogramming of heterogeneous cell populations. Here, we report a molecular technology for stable genetic tagging of cells that exhibit activity-related increases in intracellular calcium concentration (FLiCRE). We used FLiCRE to transcriptionally label activated neural ensembles in the nucleus accumbens of the mouse brain during brief stimulation of aversive inputs. Using single-cell RNA sequencing, we detected FLiCRE transcripts among the endogenous transcriptome, providing simultaneous readout of both cell-type and calcium activation history. We identified a cell type in the nucleus accumbens activated downstream of long-range excitatory projections. Taking advantage of FLiCRE's modular design, we expressed an optogenetic channel selectively in this cell type and showed that direct recruitment of this otherwise genetically inaccessible population elicits behavioral aversion. The specificity and minute resolution of FLiCRE enables molecularly informed characterization, manipulation, and reprogramming of activated cellular ensembles.
Asunto(s)
Conducta Animal , Calcio/metabolismo , Cuerpo Estriado/metabolismo , Animales , Femenino , Células HEK293 , Humanos , Cinética , Masculino , Ratones Endogámicos C57BL , Neuronas/metabolismo , Optogenética , Ratas , Análisis de la Célula Individual , Transcriptoma/genéticaRESUMEN
The striosome compartment within the dorsal striatum has been implicated in reinforcement learning and regulation of motivation, but how striosomal neurons contribute to these functions remains elusive. Here, we show that a genetically identified striosomal population, which expresses the Teashirt family zinc finger 1 (Tshz1) and belongs to the direct pathway, drives negative reinforcement and is essential for aversive learning in mice. Contrasting a "conventional" striosomal direct pathway, the Tshz1 neurons cause aversion, movement suppression, and negative reinforcement once activated, and they receive a distinct set of synaptic inputs. These neurons are predominantly excited by punishment rather than reward and represent the anticipation of punishment or the motivation for avoidance. Furthermore, inhibiting these neurons impairs punishment-based learning without affecting reward learning or movement. These results establish a major role of striosomal neurons in behaviors reinforced by punishment and moreover uncover functions of the direct pathway unaccounted for in classic models.
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Reacción de Prevención/fisiología , Cuerpo Estriado/fisiología , Proteínas de Homeodominio/genética , Proteínas Represoras/genética , Animales , Ganglios Basales , Femenino , Proteínas de Homeodominio/metabolismo , Aprendizaje/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Motivación , Neuronas/fisiología , Castigo , Refuerzo en Psicología , Proteínas Represoras/metabolismoRESUMEN
The control over the extent and timing of G protein signaling is provided by the regulator of G protein signaling (RGS) proteins that deactivate G protein α subunits (Gα). Mammalian genomes encode 20 canonical RGS and 16 Gα genes with key roles in physiology and disease. To understand the principles governing the selectivity of Gα regulation by RGS, we examine the catalytic activity of all canonical human RGS proteins and their selectivity for a complete set of Gα substrates using real-time kinetic measurements in living cells. The data reveal rules governing RGS-Gα recognition, the structural basis of its selectivity, and provide principles for engineering RGS proteins with defined selectivity. The study also explores the evolution of RGS-Gα selectivity through ancestral reconstruction and demonstrates how naturally occurring non-synonymous variants in RGS alter signaling. These results provide a blueprint for decoding signaling selectivity and advance our understanding of molecular recognition principles.
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Subunidades alfa de la Proteína de Unión al GTP/metabolismo , Subunidades alfa de la Proteína de Unión al GTP/fisiología , Proteínas RGS/genética , Animales , Femenino , Reguladores de Proteínas de Unión al GTP/metabolismo , Subunidades alfa de la Proteína de Unión al GTP/genética , Células HEK293 , Humanos , Cinética , Masculino , Ratones , Ratones Endogámicos C57BL , Neuronas/metabolismo , Cultivo Primario de Células , Unión Proteica , Proteínas RGS/metabolismo , Proteínas RGS/fisiología , Transducción de Señal/genéticaRESUMEN
Hyperactivity and disturbances of attention are common behavioral disorders whose underlying cellular and neural circuit causes are not understood. We report the discovery that striatal astrocytes drive such phenotypes through a hitherto unknown synaptic mechanism. We found that striatal medium spiny neurons (MSNs) triggered astrocyte signaling via γ-aminobutyric acid B (GABAB) receptors. Selective chemogenetic activation of this pathway in striatal astrocytes in vivo resulted in acute behavioral hyperactivity and disrupted attention. Such responses also resulted in upregulation of the synaptogenic cue thrombospondin-1 (TSP1) in astrocytes, increased excitatory synapses, enhanced corticostriatal synaptic transmission, and increased MSN action potential firing in vivo. All of these changes were reversed by blocking TSP1 effects. Our data identify a form of bidirectional neuron-astrocyte communication and demonstrate that acute reactivation of a single latent astrocyte synaptogenic cue alters striatal circuits controlling behavior, revealing astrocytes and the TSP1 pathway as therapeutic targets in hyperactivity, attention deficit, and related psychiatric disorders.
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Astrocitos/metabolismo , Trastorno por Déficit de Atención con Hiperactividad/metabolismo , Conducta Animal , Comunicación Celular , Neuronas/metabolismo , Transducción de Señal , Sinapsis/metabolismo , Animales , Astrocitos/patología , Trastorno por Déficit de Atención con Hiperactividad/genética , Trastorno por Déficit de Atención con Hiperactividad/patología , Trastorno por Déficit de Atención con Hiperactividad/fisiopatología , Femenino , Masculino , Ratones , Ratones Transgénicos , Neuronas/patología , Receptores de GABA-B/genética , Receptores de GABA-B/metabolismo , Sinapsis/genética , Trombospondina 1/genética , Trombospondina 1/metabolismo , Ácido gamma-Aminobutírico/genética , Ácido gamma-Aminobutírico/metabolismoRESUMEN
The mammalian brain is composed of diverse, specialized cell populations. To systematically ascertain and learn from these cellular specializations, we used Drop-seq to profile RNA expression in 690,000 individual cells sampled from 9 regions of the adult mouse brain. We identified 565 transcriptionally distinct groups of cells using computational approaches developed to distinguish biological from technical signals. Cross-region analysis of these 565 cell populations revealed features of brain organization, including a gene-expression module for synthesizing axonal and presynaptic components, patterns in the co-deployment of voltage-gated ion channels, functional distinctions among the cells of the vasculature and specialization of glutamatergic neurons across cortical regions. Systematic neuronal classifications for two complex basal ganglia nuclei and the striatum revealed a rare population of spiny projection neurons. This adult mouse brain cell atlas, accessible through interactive online software (DropViz), serves as a reference for development, disease, and evolution.
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Encéfalo/metabolismo , Linaje de la Célula , Regulación del Desarrollo de la Expresión Génica , Redes Reguladoras de Genes , Análisis de la Célula Individual/métodos , Transcriptoma , Animales , Encéfalo/crecimiento & desarrollo , Perfilación de la Expresión Génica , Secuenciación de Nucleótidos de Alto Rendimiento , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
The organization of action into sequences underlies complex behaviors that are essential for organismal survival and reproduction. Despite extensive studies of innate sequences in relation to central pattern generators, how learned action sequences are controlled and whether they are organized as a chain or a hierarchy remain largely unknown. By training mice to perform heterogeneous action sequences, we demonstrate that striatal direct and indirect pathways preferentially encode different behavioral levels of sequence structure. State-dependent closed-loop optogenetic stimulation of the striatal direct pathway can selectively insert a single action element into the sequence without disrupting the overall sequence length. Optogenetic manipulation of the striatal indirect pathway completely removes the ongoing subsequence while leaving the following subsequence to be executed with the appropriate timing and length. These results suggest that learned action sequences are not organized in a serial but rather a hierarchical structure that is distinctly controlled by basal ganglia pathways.
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Aprendizaje , Neuronas/metabolismo , Optogenética , Animales , Conducta Animal/efectos de los fármacos , Conducta Animal/efectos de la radiación , Toxina Diftérica/farmacología , Electrodos Implantados , Potenciales Evocados Visuales , Femenino , Rayos Láser , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Muscimol/farmacología , Proteínas del Tejido Nervioso/deficiencia , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Neuronas/efectos de los fármacos , Proteínas RGS/genética , Receptores de N-Metil-D-Aspartato/deficiencia , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismoRESUMEN
Huntington's disease (HD) is characterized by preferential loss of the medium spiny neurons in the striatum. Using CRISPR/Cas9 and somatic nuclear transfer technology, we established a knockin (KI) pig model of HD that endogenously expresses full-length mutant huntingtin (HTT). By breeding this HD pig model, we have successfully obtained F1 and F2 generation KI pigs. Characterization of founder and F1 KI pigs shows consistent movement, behavioral abnormalities, and early death, which are germline transmittable. More importantly, brains of HD KI pig display striking and selective degeneration of striatal medium spiny neurons. Thus, using a large animal model of HD, we demonstrate for the first time that overt and selective neurodegeneration seen in HD patients can be recapitulated by endogenously expressed mutant proteins in large mammals, a finding that also underscores the importance of using large mammals to investigate the pathogenesis of neurodegenerative diseases and their therapeutics.
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Proteína Huntingtina/genética , Enfermedad de Huntington/patología , Animales , Peso Corporal , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Encéfalo/patología , Sistemas CRISPR-Cas/genética , Corteza Cerebral/patología , Corteza Cerebral/ultraestructura , Cuerpo Estriado/patología , Cuerpo Estriado/ultraestructura , Modelos Animales de Enfermedad , Proteína Huntingtina/metabolismo , Enfermedad de Huntington/mortalidad , Imagen por Resonancia Magnética , Neuronas/metabolismo , Neuronas/patología , Técnicas de Transferencia Nuclear , Tasa de Supervivencia , Porcinos , Repeticiones de TrinucleótidosRESUMEN
Many naturalistic behaviors are built from modular components that are expressed sequentially. Although striatal circuits have been implicated in action selection and implementation, the neural mechanisms that compose behavior in unrestrained animals are not well understood. Here, we record bulk and cellular neural activity in the direct and indirect pathways of dorsolateral striatum (DLS) as mice spontaneously express action sequences. These experiments reveal that DLS neurons systematically encode information about the identity and ordering of sub-second 3D behavioral motifs; this encoding is facilitated by fast-timescale decorrelations between the direct and indirect pathways. Furthermore, lesioning the DLS prevents appropriate sequence assembly during exploratory or odor-evoked behaviors. By characterizing naturalistic behavior at neural timescales, these experiments identify a code for elemental 3D pose dynamics built from complementary pathway dynamics, support a role for DLS in constructing meaningful behavioral sequences, and suggest models for how actions are sculpted over time.
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Conducta Animal , Cuerpo Estriado/metabolismo , Animales , Conducta Animal/efectos de los fármacos , Calcio/metabolismo , Cuerpo Estriado/efectos de los fármacos , Electrodos Implantados , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , N-Metilaspartato/farmacología , Neuronas/efectos de los fármacos , Neuronas/fisiología , Fotometría , Receptores de Dopamina D1/deficiencia , Receptores de Dopamina D1/genéticaRESUMEN
Dopamine controls essential brain functions through volume transmission. Different from fast synaptic transmission, where neurotransmitter release and receptor activation are tightly coupled by an active zone, dopamine transmission is widespread and may not necessitate these organized release sites. Here, we determine whether striatal dopamine secretion employs specialized machinery for release. Using super resolution microscopy, we identified co-clustering of the active zone scaffolding proteins bassoon, RIM and ELKS in â¼30% of dopamine varicosities. Conditional RIM knockout disrupted this scaffold and, unexpectedly, abolished dopamine release, while ELKS knockout had no effect. Optogenetic experiments revealed that dopamine release was fast and had a high release probability, indicating the presence of protein scaffolds for coupling Ca2+ influx to vesicle fusion. Hence, dopamine secretion is mediated by sparse, mechanistically specialized active zone-like release sites. This architecture supports spatially and temporally precise coding for dopamine and provides molecular machinery for regulation.
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Axones/metabolismo , Cuerpo Estriado/metabolismo , Dopamina/metabolismo , Transmisión Sináptica/fisiología , Transportadoras de Casetes de Unión a ATP/genética , Transportadoras de Casetes de Unión a ATP/metabolismo , Animales , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Cuerpo Estriado/citología , Dopamina/genética , Técnicas de Silenciamiento del Gen , Ratones , Ratones Transgénicos , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Proteínas de Unión al GTP rabRESUMEN
Effective evaluation of costs and benefits is a core survival capacity that in humans is considered as optimal, "rational" decision-making. This capacity is vulnerable in neuropsychiatric disorders and in the aftermath of chronic stress, in which aberrant choices and high-risk behaviors occur. We report that chronic stress exposure in rodents produces abnormal evaluation of costs and benefits resembling non-optimal decision-making in which choices of high-cost/high-reward options are sharply increased. Concomitantly, alterations in the task-related spike activity of medial prefrontal neurons correspond with increased activity of their striosome-predominant striatal projection neuron targets and with decreased and delayed striatal fast-firing interneuron activity. These effects of chronic stress on prefronto-striatal circuit dynamics could be blocked or be mimicked by selective optogenetic manipulation of these circuits. We suggest that altered excitation-inhibition dynamics of striosome-based circuit function could be an underlying mechanism by which chronic stress contributes to disorders characterized by aberrant decision-making under conflict. VIDEO ABSTRACT.
Asunto(s)
Toma de Decisiones , Corteza Prefrontal/fisiopatología , Estrés Fisiológico , Animales , Ganglios Basales/metabolismo , Interneuronas/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Vías Nerviosas , Optogenética , Ratas , Ratas Long-EvansRESUMEN
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
Electrophysiological field potential dynamics are of fundamental interest in basic and clinical neuroscience, but how specific cell types shape these dynamics in the live brain is poorly understood. To empower mechanistic studies, we created an optical technique, TEMPO, that records the aggregate trans-membrane voltage dynamics of genetically specified neurons in freely behaving mice. TEMPO has >10-fold greater sensitivity than prior fiber-optic techniques and attains the noise minimum set by quantum mechanical photon shot noise. After validating TEMPO's capacity to track established oscillations in the delta, theta, and gamma frequency bands, we compared the D1- and D2-dopamine-receptor-expressing striatal medium spiny neurons (MSNs), which are interspersed and electrically indistinguishable. Unexpectedly, MSN population dynamics exhibited two distinct coherent states that were commonly indiscernible in electrical recordings and involved synchronized hyperpolarizations across both MSN subtypes. Overall, TEMPO allows the deconstruction of normal and pathologic neurophysiological states into trans-membrane voltage activity patterns of specific cell types.
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Ondas Encefálicas , Ratones/fisiología , Neurofisiología/métodos , Imagen de Colorante Sensible al Voltaje/métodos , Animales , Femenino , Masculino , Ratones Endogámicos BALB CRESUMEN
Flexibly selecting appropriate actions in response to complex, ever-changing environments requires both cortical and subcortical regions, which are typically described as participating in a strict hierarchy. In this traditional view, highly specialized subcortical circuits allow for efficient responses to salient stimuli, at the cost of adaptability and context specificity, which are attributed to the neocortex. Their interactions are often described as the cortex providing top-down command signals for subcortical structures to implement; however, as available technologies develop, studies increasingly demonstrate that behavior is represented by brainwide activity and that even subcortical structures contain early signals of choice, suggesting that behavioral functions emerge as a result of different regions interacting as truly collaborative networks. In this review, we discuss the field's evolving understanding of how cortical and subcortical regions in placental mammals interact cooperatively, not only via top-down cortical-subcortical inputs but through bottom-up interactions, especially via the thalamus. We describe our current understanding of the circuitry of both the cortex and two exemplar subcortical structures, the superior colliculus and striatum, to identify which information is prioritized by which regions. We then describe the functional circuits these regions form with one another, and the thalamus, to create parallel loops and complex networks for brainwide information flow. Finally, we challenge the classic view that functional modules are contained within specific brain regions; instead, we propose that certain regions prioritize specific types of information over others, but the subnetworks they form, defined by their anatomical connections and functional dynamics, are the basis of true specialization.
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Objetivos , Placenta , Animales , Encéfalo/fisiología , Femenino , Humanos , Mamíferos , Embarazo , Tálamo/fisiologíaRESUMEN
Ventral tegmental area (VTA) dopamine (DA) neurons are often thought to uniformly encode reward prediction errors. Conversely, DA release in the nucleus accumbens (NAc), the prominent projection target of these neurons, has been implicated in reinforcement learning, motivation, aversion, and incentive salience. This contrast between heterogeneous functions of DA release versus a homogeneous role for DA neuron activity raises numerous questions regarding how VTA DA activity translates into NAc DA release. Further complicating this issue is increasing evidence that distinct VTA DA projections into defined NAc subregions mediate diverse behavioral functions. Here, we evaluate evidence for heterogeneity within the mesoaccumbal DA system and argue that frameworks of DA function must incorporate the precise topographic organization of VTA DA neurons to clarify their contribution to health and disease.
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Dopamina , Área Tegmental Ventral , Neuronas Dopaminérgicas , Motivación , Núcleo Accumbens/fisiología , Recompensa , Área Tegmental Ventral/fisiologíaRESUMEN
Microglia are activated in many neurological diseases and have been suggested to play an important role in the development of affective disorders including major depression. To investigate how microglial signaling regulates mood, we used bidirectional chemogenetic manipulations of microglial activity in mice. Activation of microglia in the dorsal striatum induced local cytokine expression and a negative affective state characterized by anhedonia and aversion, whereas inactivation of microglia blocked aversion induced by systemic inflammation. Interleukin-6 signaling and cyclooxygenase-1 mediated prostaglandin synthesis in the microglia were critical for the inflammation-induced aversion. Correspondingly, microglial activation led to a prostaglandin-dependent reduction of the excitability of striatal neurons. These findings demonstrate a mechanism by which microglial activation causes negative affect through prostaglandin-dependent modulation of striatal neurons and indicate that interference with this mechanism could milden the depressive symptoms in somatic and psychiatric diseases involving microglial activation.
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Anhedonia/fisiología , Cuerpo Estriado/inmunología , Depresión/inmunología , Microglía/inmunología , Neuronas/fisiología , Animales , Animales Modificados Genéticamente , Conducta Animal , Células Cultivadas , Modelos Animales de Enfermedad , Humanos , Inflamación , Interleucina-6/metabolismo , Activación de Macrófagos , Ratones , Inflamación Neurogénica , Prostaglandinas/metabolismoRESUMEN
This article reviews the behavioral neuroscience of extinction, the phenomenon in which a behavior that has been acquired through Pavlovian or instrumental (operant) learning decreases in strength when the outcome that reinforced it is removed. Behavioral research indicates that neither Pavlovian nor operant extinction depends substantially on erasure of the original learning but instead depends on new inhibitory learning that is primarily expressed in the context in which it is learned, as exemplified by the renewal effect. Although the nature of the inhibition may differ in Pavlovian and operant extinction, in either case the decline in responding may depend on both generalization decrement and the correction of prediction error. At the neural level, Pavlovian extinction requires a tripartite neural circuit involving the amygdala, prefrontal cortex, and hippocampus. Synaptic plasticity in the amygdala is essential for extinction learning, and prefrontal cortical inhibition of amygdala neurons encoding fear memories is involved in extinction retrieval. Hippocampal-prefrontal circuits mediate fear relapse phenomena, including renewal. Instrumental extinction involves distinct ensembles in corticostriatal, striatopallidal, and striatohypothalamic circuits as well as their thalamic returns for inhibitory (extinction) and excitatory (renewal and other relapse phenomena) control over operant responding. The field has made significant progress in recent decades, although a fully integrated biobehavioral understanding still awaits.
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Conducta Animal/fisiología , Conducta/fisiología , Encéfalo/fisiología , Condicionamiento Clásico/fisiología , Extinción Psicológica/fisiología , Animales , Condicionamiento Operante , HumanosRESUMEN
Deciding what to do and when to move is vital to our survival. Clinical and fundamental studies have identified basal ganglia circuits as critical for this process. The main input nucleus of the basal ganglia, the striatum, receives inputs from frontal, sensory, and motor cortices and interconnected thalamic areas that provide information about potential goals, context, and actions and directly or indirectly modulates basal ganglia outputs. The striatum also receives dopaminergic inputs that can signal reward prediction errors and also behavioral transitions and movement initiation. Here we review studies and models of how direct and indirect pathways can modulate basal ganglia outputs to facilitate movement initiation, and we discuss the role of cortical and dopaminergic inputs to the striatum in determining what to do and if and when to do it. Complex but exciting scenarios emerge that shed new light on how basal ganglia circuits modulate self-paced movement initiation.
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Ganglios Basales/fisiología , Cognición/fisiología , Movimiento/fisiología , Vías Nerviosas/fisiología , Animales , Humanos , Actividad Motora/fisiología , RecompensaRESUMEN
In mammals, the accessory olfactory system is a distinct circuit that has received attention for its role in detecting and responding to pheromones. While the neuroscientific investigation of this system is comparatively new, recent advances and its compact size have made it an attractive model for developing an end-to-end understanding of such questions as regulation of essential behaviors, plasticity, and individual recognition. Recent discoveries have indicated a need to reevaluate our conception of this system, suggesting that ( a) physical principles-rather than biological necessity-play an underappreciated role in its raison d'être and that ( b) the anatomy of downstream projections is not dominated by unique specializations but instead consists of an abbreviated cortical/basal ganglia motif reminiscent of other sensorimotor systems. These observations suggest that the accessory olfactory system distinguishes itself primarily by the physicochemical properties of its ligands, but its architecture is otherwise a microcosm of mammalian neurocircuitry.
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Instinto , Red Nerviosa/fisiología , Vías Olfatorias/anatomía & histología , Vías Olfatorias/fisiología , Olfato/fisiología , Animales , Humanos , Mamíferos , FeromonasRESUMEN
Substance use disorder is a major concern, with few therapeutic options. Heparan sulfate (HS) and chondroitin sulfate (CS) interact with a plethora of growth factors and their receptors and have profound effects on cellular signaling. Thus, targeting these dynamic interactions might represent a potential novel therapeutic modality. In the present study, we performed mass spectrometry-based glycomic and proteomic analysis to understand the effects of cocaine and methamphetamine (METH) on HS, CS, and the proteome of two brain regions critically involved in drug addiction: the lateral hypothalamus and the striatum. We observed that cocaine and METH significantly alter HS and CS abundances as well as sulfate contents and composition. In particular, repeated METH or cocaine treatments reduced CS 4-O-sulfation and increased CS 6-O-sulfation. Since C4S and C6S exercise differential effects on axon growth, regeneration, and plasticity, these changes likely contribute to drug-induced neural plasticity in these brain regions. Notably, we observed that restoring these alterations by increasing CS 4-0 levels in the lateral hypothalamus by adeno-associated virus delivery of an shRNA to arylsulfatase B (N-acetylgalactosamine-4-sulfatase) ameliorated anxiety and prevented the expression of preference for cocaine in a novelty induced conditioned place preference test during cocaine withdrawal. Finally, proteomics analyses revealed a number of aberrant proteins in METH- and cocaine-treated versus saline-treated mice, including myelin proteolipid protein, calcium/calmodulin-dependent protein kinase type II subunit alpha, synapsin-2, tenascin-R, calnexin, annexin A7, hepatoma-derived growth factor, neurocan, and CSPG5, and oxidative phosphorylation among the top perturbed pathway. Taken together, these data support the role of HS, CS, and associated proteins in stimulants abuse and suggest that manipulation of HSPGs can represent a novel therapeutic strategy.