RESUMO
Fast-spiking interneurons (FSIs) are a prominent class of forebrain GABAergic cells implicated in two seemingly independent network functions: gain control and network plasticity. Little is known, however, about how these roles interact. Here, we use a combination of cell-type-specific ablation, optogenetics, electrophysiology, imaging, and behavior to describe a unified mechanism by which striatal FSIs control burst firing, calcium influx, and synaptic plasticity in neighboring medium spiny projection neurons (MSNs). In vivo silencing of FSIs increased bursting, calcium transients, and AMPA/NMDA ratios in MSNs. In a motor sequence task, FSI silencing increased the frequency of calcium transients but reduced the specificity with which transients aligned to individual task events. Consistent with this, ablation of FSIs disrupted the acquisition of striatum-dependent egocentric learning strategies. Together, our data support a model in which feedforward inhibition from FSIs temporally restricts MSN bursting and calcium-dependent synaptic plasticity to facilitate striatum-dependent sequence learning.
Assuntos
Sinalização do Cálcio/fisiologia , Interneurônios/metabolismo , Aprendizagem/fisiologia , Rede Nervosa/metabolismo , Plasticidade Neuronal/fisiologia , Animais , Interneurônios/citologia , Camundongos , Camundongos Transgênicos , N-Metilaspartato/metabolismo , Rede Nervosa/citologia , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico/metabolismoRESUMO
Food and water are rewarding in part because they satisfy our internal needs1,2. Dopaminergic neurons in the ventral tegmental area (VTA) are activated by gustatory rewards3-5, but how animals learn to associate these oral cues with the delayed physiological effects of ingestion is unknown. Here we show that individual dopaminergic neurons in the VTA respond to detection of nutrients or water at specific stages of ingestion. A major subset of dopaminergic neurons tracks changes in systemic hydration that occur tens of minutes after thirsty mice drink water, whereas different dopaminergic neurons respond to nutrients in the gastrointestinal tract. We show that information about fluid balance is transmitted to the VTA by a hypothalamic pathway and then re-routed to downstream circuits that track the oral, gastrointestinal and post-absorptive stages of ingestion. To investigate the function of these signals, we used a paradigm in which a fluid's oral and post-absorptive effects can be independently manipulated and temporally separated. We show that mice rapidly learn to prefer one fluid over another based solely on its rehydrating ability and that this post-ingestive learning is prevented if dopaminergic neurons in the VTA are selectively silenced after consumption. These findings reveal that the midbrain dopamine system contains subsystems that track different modalities and stages of ingestion, on timescales from seconds to tens of minutes, and that this information is used to drive learning about the consequences of ingestion.
Assuntos
Dopamina , Neurônios Dopaminérgicos , Hipotálamo , Vias Neurais , Nutrientes , Estado de Hidratação do Organismo , Área Tegmentar Ventral , Animais , Sinais (Psicologia) , Digestão , Dopamina/metabolismo , Neurônios Dopaminérgicos/fisiologia , Ingestão de Alimentos , Trato Gastrointestinal/metabolismo , Hipotálamo/citologia , Hipotálamo/fisiologia , Mesencéfalo/citologia , Mesencéfalo/fisiologia , Camundongos , Nutrientes/metabolismo , Estado de Hidratação do Organismo/efeitos dos fármacos , Recompensa , Fatores de Tempo , Área Tegmentar Ventral/citologia , Área Tegmentar Ventral/fisiologia , Água/metabolismo , Água/farmacologia , Equilíbrio HidroeletrolíticoRESUMO
Change history: In this Article, an extraneous label appeared in Fig. 4b, and has been removed in the online version.
RESUMO
The dopamine projection from ventral tegmental area (VTA) to nucleus accumbens (NAc) is critical for motivation to work for rewards and reward-driven learning. How dopamine supports both functions is unclear. Dopamine cell spiking can encode prediction errors, which are vital learning signals in computational theories of adaptive behaviour. By contrast, dopamine release ramps up as animals approach rewards, mirroring reward expectation. This mismatch might reflect differences in behavioural tasks, slower changes in dopamine cell spiking or spike-independent modulation of dopamine release. Here we compare spiking of identified VTA dopamine cells with NAc dopamine release in the same decision-making task. Cues that indicate an upcoming reward increased both spiking and release. However, NAc core dopamine release also covaried with dynamically evolving reward expectations, without corresponding changes in VTA dopamine cell spiking. Our results suggest a fundamental difference in how dopamine release is regulated to achieve distinct functions: broadcast burst signals promote learning, whereas local control drives motivation.
Assuntos
Dopamina/metabolismo , Aprendizagem/fisiologia , Motivação/fisiologia , Recompensa , Animais , Sinais (Psicologia) , Tomada de Decisões/fisiologia , Neurônios Dopaminérgicos/citologia , Neurônios Dopaminérgicos/metabolismo , Masculino , Núcleo Accumbens/citologia , Núcleo Accumbens/fisiologia , Córtex Pré-Frontal/citologia , Córtex Pré-Frontal/fisiologia , Ratos , Ratos Long-Evans , Fatores de Tempo , Área Tegmentar Ventral/citologia , Área Tegmentar Ventral/fisiologiaRESUMO
Genetically encoded dopamine sensors based on green fluorescent protein (GFP) enable high-resolution imaging of dopamine dynamics in behaving animals. However, these GFP-based variants cannot be readily combined with commonly used optical sensors and actuators, due to spectral overlap. We therefore engineered red-shifted variants of dopamine sensors called RdLight1, based on mApple. RdLight1 can be combined with GFP-based sensors with minimal interference and shows high photostability, permitting prolonged continuous imaging. We demonstrate the utility of RdLight1 for receptor-specific pharmacological analysis in cell culture, simultaneous assessment of dopamine release and cell-type-specific neuronal activity and simultaneous subsecond monitoring of multiple neurotransmitters in freely behaving rats. Dual-color photometry revealed that dopamine release in the nucleus accumbens evoked by reward-predictive cues is accompanied by a rapid suppression of glutamate release. By enabling multiplexed imaging of dopamine with other circuit components in vivo, RdLight1 opens avenues for understanding many aspects of dopamine biology.
Assuntos
Comportamento Animal/fisiologia , Técnicas Biossensoriais/métodos , Encéfalo/metabolismo , Dopamina/metabolismo , Neurônios/metabolismo , Animais , Sinais (Psicologia) , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Células HEK293 , Humanos , Receptores Dopaminérgicos/genética , Receptores Dopaminérgicos/metabolismo , RecompensaRESUMO
Spindles and slow oscillations (SOs) both appear to play an important role in memory consolidation. Spindle and SO "nesting," or the temporal overlap between the two events, is believed to modulate consolidation. However, the neurophysiological processes modified by nesting remain poorly understood. We thus recorded activity from the primary motor cortex of 4 male sleeping rats to investigate how SO and spindles interact to modulate the correlation structure of neural firing. During spindles, primary motor cortex neurons fired at a preferred phase, with neural pairs demonstrating greater neural synchrony, or correlated firing, during spindle peaks. We found a direct relationship between the temporal proximity between SO and spindles, and changes to the distribution of neural correlations; nesting was associated with narrowing of the distribution, with a reduction in low- and high-correlation pairs. Such narrowing may be consistent with greater exploration of neural states. Interestingly, after animals practiced a novel motor task, pairwise correlations increased during nested spindles, consistent with targeted strengthening of functional interactions. These findings may be key mechanisms through which spindle nesting supports memory consolidation.SIGNIFICANCE STATEMENT Our analysis revealed changes in cortical spiking structure that followed the waxing and waning of spindles; firing rates increased, spikes were more phase-locked to spindle-band local field potential, and synchrony across units peaked during spindles. Moreover, we showed that the degree of nesting between spindles and slow oscillations modified the correlation structure across units by narrowing the distribution of pairwise correlations. Finally, we demonstrated that engaging in a novel motor task increased pairwise correlations during nested spindles. These phenomena suggest key mechanisms through which the interaction of spindles and slow oscillations may support sensorimotor learning. More broadly, this work helps link large-scale measures of population activity to changes in spiking structure, a critical step in understanding neuroplasticity across multiple scales.
Assuntos
Ondas Encefálicas/fisiologia , Consolidação da Memória/fisiologia , Córtex Motor/fisiologia , Neurônios/fisiologia , Sono/fisiologia , Animais , Eletroencefalografia , Masculino , Ratos , Fases do Sono/fisiologiaRESUMO
Neural implants with large numbers of electrodes have become an important tool for examining brain functions. However, these devices typically displace a large intracranial volume compared with the neurons they record. This large size limits the density of implants, provokes tissue reactions that degrade chronic performance, and impedes the ability to accurately visualize recording sites within intact circuits. Here we report next-generation silicon-based neural probes at a cellular scale (5 × 10 µm cross section), with ultra-high-density packing (as little as 66 µm between shanks) and 64 or 256 closely spaced recording sites per probe. We show that these probes can be inserted into superficial or deep brain structures and record large spikes in freely behaving rats for many weeks. Finally, we demonstrate a slice-in-place approach for the precise registration of recording sites relative to nearby neurons and anatomical features, including striatal µ-opioid receptor patches. This scalable technology provides a valuable tool for examining information processing within neural circuits and potentially for human brain-machine interfaces.NEW & NOTEWORTHY Devices with many electrodes penetrating into the brain are an important tool for investigating neural information processing, but they are typically large compared with neurons. This results in substantial damage and makes it harder to reconstruct recording locations within brain circuits. This paper presents high-channel-count silicon probes with much smaller features and a method for slicing through probe, brain, and skull all together. This allows probe tips to be directly observed relative to immunohistochemical markers.
Assuntos
Encéfalo/fisiologia , Eletrodos Implantados , Neurônios/fisiologia , Neurofisiologia/instrumentação , Neurofisiologia/métodos , Animais , Masculino , Ratos Long-Evans , SilícioRESUMO
The cortical cholinergic input system has been described as a neuromodulator system that influences broadly defined behavioral and brain states. The discovery of phasic, trial-based increases in extracellular choline (transients), resulting from the hydrolysis of newly released acetylcholine (ACh), in the cortex of animals reporting the presence of cues suggests that ACh may have a more specialized role in cognitive processes. Here we expressed channelrhodopsin or halorhodopsin in basal forebrain cholinergic neurons of mice with optic fibers directed into this region and prefrontal cortex. Cholinergic transients, evoked in accordance with photostimulation parameters determined in vivo, were generated in mice performing a task necessitating the reporting of cue and noncue events. Generating cholinergic transients in conjunction with cues enhanced cue detection rates. Moreover, generating transients in noncued trials, where cholinergic transients normally are not observed, increased the number of invalid claims for cues. Enhancing hits and generating false alarms both scaled with stimulation intensity. Suppression of endogenous cholinergic activity during cued trials reduced hit rates. Cholinergic transients may be essential for synchronizing cortical neuronal output driven by salient cues and executing cue-guided responses.
Assuntos
Acetilcolina/metabolismo , Comportamento Animal/fisiologia , Neurônios Colinérgicos/metabolismo , Córtex Pré-Frontal/metabolismo , Transmissão Sináptica/fisiologia , Animais , Neurônios Colinérgicos/citologia , Halorrodopsinas/biossíntese , Halorrodopsinas/genética , Camundongos , Camundongos Transgênicos , Córtex Pré-Frontal/citologiaRESUMO
The capacity for using external cues to guide behavior ("cue detection") constitutes an essential aspect of attention and goal-directed behavior. The cortical cholinergic input system, via phasic increases in prefrontal acetylcholine release, plays an essential role in attention by mediating such cue detection. However, the relationship between cholinergic signaling during cue detection and neural activity dynamics in prefrontal networks remains unclear. Here we combined subsecond measures of cholinergic signaling, neurophysiological recordings, and cholinergic receptor blockade to delineate the cholinergic contributions to prefrontal oscillations during cue detection in rats. We first confirmed that detected cues evoke phasic acetylcholine release. These cholinergic signals were coincident with increased neuronal synchrony across several frequency bands and the emergence of theta-gamma coupling. Muscarinic and nicotinic cholinergic receptors both contributed specifically to gamma synchrony evoked by detected cues, but the effects of blocking the two receptor subtypes were dissociable. Blocking nicotinic receptors primarily attenuated high-gamma oscillations occurring during the earliest phases of the cue detection process, while muscarinic (M1) receptor activity was preferentially involved in the transition from high to low gamma power that followed and corresponded to the mobilization of networks involved in cue-guided decision making. Detected cues also promoted coupling between gamma and theta oscillations, and both nicotinic and muscarinic receptor activity contributed to this process. These results indicate that acetylcholine release coordinates neural oscillations during the process of cue detection.SIGNIFICANCE STATEMENT The capacity of learned cues to direct attention and guide responding ("cue detection") is a key component of goal-directed behavior. Rhythmic neural activity and increases in acetylcholine release in the prefrontal cortex contribute to this process; however, the relationship between these neuronal mechanisms is not well understood. Using a combination of in vivo neurochemistry, neurophysiology, and pharmacological methods, we demonstrate that cue-evoked acetylcholine release, through distinct actions at both nicotinic and muscarinic receptors, triggers a procession of neural oscillations that map onto the multiple stages of cue detection. Our data offer new insights into cholinergic function by revealing the temporally orchestrated changes in prefrontal network synchrony modulated by acetylcholine release during cue detection.
Assuntos
Acetilcolina/metabolismo , Neurônios Colinérgicos/fisiologia , Sinais (Psicologia) , Ritmo Gama/fisiologia , Córtex Pré-Frontal/fisiologia , Ritmo Teta/fisiologia , Animais , Comportamento Animal/fisiologia , Relógios Biológicos/fisiologia , Masculino , Neurotransmissores/metabolismo , Ratos , Recompensa , Transmissão Sináptica/fisiologia , Percepção Visual/fisiologiaRESUMO
Striatal projection neurons form a sparsely-connected inhibitory network, and this arrangement may be essential for the appropriate temporal organization of behavior. Here we show that a simplified, sparse inhibitory network of Leaky-Integrate-and-Fire neurons can reproduce some key features of striatal population activity, as observed in brain slices. In particular we develop a new metric to determine the conditions under which sparse inhibitory networks form anti-correlated cell assemblies with time-varying activity of individual cells. We find that under these conditions the network displays an input-specific sequence of cell assembly switching, that effectively discriminates similar inputs. Our results support the proposal that GABAergic connections between striatal projection neurons allow stimulus-selective, temporally-extended sequential activation of cell assemblies. Furthermore, we help to show how altered intrastriatal GABAergic signaling may produce aberrant network-level information processing in disorders such as Parkinson's and Huntington's diseases.
Assuntos
Corpo Estriado/fisiologia , Modelos Neurológicos , Rede Nervosa/fisiologia , Neurônios/fisiologia , Algoritmos , Animais , Biologia Computacional , CamundongosRESUMO
The development of methodology to identify specific cell populations and circuits within the basal ganglia is rapidly transforming our ability to understand the function of this complex circuit. This mini-symposium highlights recent advances in delineating the organization and function of neural circuits in the external segment of the globus pallidus (GPe). Although long considered a homogeneous structure in the motor-suppressing "indirect-pathway," the GPe consists of a number of distinct cell types and anatomical subdomains that contribute differentially to both motor and nonmotor features of behavior. Here, we integrate recent studies using techniques, such as viral tracing, transgenic mice, electrophysiology, and behavioral approaches, to create a revised framework for understanding how the GPe relates to behavior in both health and disease.
Assuntos
Gânglios da Base/fisiologia , Corpo Estriado/fisiologia , Globo Pálido/fisiologia , Doença de Parkinson/fisiopatologia , Animais , Globo Pálido/anatomia & histologia , Humanos , Vias Neurais/fisiologia , Neuroglia/fisiologia , Neurônios/fisiologiaRESUMO
The direct and indirect efferent pathways from striatum ultimately reconverge to influence basal ganglia output nuclei, which in turn regulate behavior via thalamocortical and brainstem motor circuits. However, the distinct contributions of these two efferent pathways in shaping basal ganglia output are not well understood. We investigated these processes using selective optogenetic control of the direct and indirect pathways, in combination with single-unit recording in the basal ganglia output nucleus substantia nigra pars reticulata (SNr) in mice. Optogenetic activation of striatal direct and indirect pathway projection neurons produced diverse cellular responses in SNr neurons, with stimulation of each pathway eliciting both excitations and inhibitions. Despite this response heterogeneity, the effectiveness of direct pathway stimulation in producing movement initiation correlated selectively with the subpopulation of inhibited SNr neurons. In contrast, effective indirect pathway-mediated motor suppression was most strongly influenced by excited SNr neurons. Our results support the theory that key basal ganglia output neurons serve as an inhibitory gate over motor output that can be opened or closed by striatal direct and indirect pathways, respectively.
Assuntos
Gânglios da Base/citologia , Locomoção/fisiologia , Vias Neurais/fisiologia , Neurônios/fisiologia , Animais , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Channelrhodopsins , Estimulação Elétrica , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Inibição Neural/fisiologia , Optogenética , Proteínas Proto-Oncogênicas c-fos/metabolismo , Receptores A2 de Adenosina/genética , Receptores de Dopamina D1/genética , Substância Negra/citologiaRESUMO
Animals make predictions to guide their behavior and update those predictions through experience. Transient increases in dopamine (DA) are thought to be critical signals for updating predictions. However, it is unclear how this mechanism handles a wide range of behavioral timescales-from seconds or less (for example, if singing a song) to potentially hours or more (for example, if hunting for food). Here we report that DA transients in distinct rat striatal subregions convey prediction errors based on distinct time horizons. DA dynamics systematically accelerated from ventral to dorsomedial to dorsolateral striatum, in the tempo of spontaneous fluctuations, the temporal integration of prior rewards and the discounting of future rewards. This spectrum of timescales for evaluative computations can help achieve efficient learning and adaptive motivation for a broad range of behaviors.
Assuntos
Corpo Estriado , Dopamina , Ratos , Animais , Neostriado , Aprendizagem , RecompensaRESUMO
Acetylcholine is widely believed to modulate the release of dopamine in the striatum of mammals. Experiments in brain slices clearly show that synchronous activation of striatal cholinergic interneurons is sufficient to drive dopamine release via axo-axonal stimulation of nicotinic acetylcholine receptors. However, evidence for this mechanism in vivo has been less forthcoming. Mohebi, Collins and Berke recently reported that, in awake behaving rats, optogenetic activation of striatal cholinergic interneurons with blue light readily evokes dopamine release measured with the red fluorescent sensor RdLight1 (Mohebi et al., 2023). Here, we show that blue light alone alters the fluorescent properties of RdLight1 in a manner that may be misconstrued as phasic dopamine release, and that this artefactual photoactivation can account for the effects attributed to cholinergic interneurons. Our findings indicate that measurements of dopamine using the red-shifted fluorescent sensor RdLight1 should be interpreted with caution when combined with optogenetics. In light of this and other publications that did not observe large acetylcholine-evoked dopamine transients in vivo, the conditions under which such release occurs in behaving animals remain unknown.
Assuntos
Neurônios Colinérgicos , Dopamina , Interneurônios , Optogenética , Dopamina/metabolismo , Animais , Interneurônios/metabolismo , Interneurônios/fisiologia , Neurônios Colinérgicos/metabolismo , Neurônios Colinérgicos/fisiologia , Ratos , Optogenética/métodos , Motivação , Núcleo Accumbens/metabolismo , Núcleo Accumbens/fisiologia , Acetilcolina/metabolismoRESUMO
Motivation to work for potential rewards is critically dependent on dopamine (DA) in the nucleus accumbens (NAc). DA release from NAc axons can be controlled by at least two distinct mechanisms: (1) action potentials propagating from DA cell bodies in the ventral tegmental area (VTA), and (2) activation of ß2* nicotinic receptors by local cholinergic interneurons (CINs). How CIN activity contributes to NAc DA dynamics in behaving animals is not well understood. We monitored DA release in the NAc Core of awake, unrestrained rats using the DA sensor RdLight1, while simultaneously monitoring or manipulating CIN activity at the same location. CIN stimulation rapidly evoked DA release, and in contrast to slice preparations, this DA release showed no indication of short-term depression or receptor desensitization. The sound of unexpected food delivery evoked a brief joint increase in CIN population activity and DA release, with a second joint increase as rats approached the food. In an operant task, we observed fast ramps in CIN activity during approach behaviors, either to start the trial or to collect rewards. These CIN ramps co-occurred with DA release ramps, without corresponding changes in the firing of lateral VTA DA neurons. Finally, we examined the effects of blocking CIN influence over DA release through local NAc infusion of DHßE, a selective antagonist of ß2* nicotinic receptors. DHßE dose-dependently interfered with motivated approach decisions, mimicking the effects of a DA antagonist. Our results support a key influence of CINs over motivated behavior via the local regulation of DA release.
Assuntos
Dopamina , Receptores Nicotínicos , Ratos , Animais , Dopamina/farmacologia , Motivação , Área Tegmentar Ventral , Interneurônios , ColinérgicosRESUMO
Basal ganglia (BG) circuits help guide and invigorate actions using predictions of future rewards (values). Within the BG, the globus pallidus pars externa (GPe) may play an essential role in aggregating and distributing value information. We recorded from the GPe in unrestrained rats performing both Pavlovian and instrumental tasks to obtain rewards and distinguished neuronal subtypes by their firing properties across the wake/sleep cycle and optogenetic tagging. In both tasks, the parvalbumin-positive (PV+), faster-firing "prototypical" neurons showed strong, sustained modulation by value, unlike other subtypes, including the "arkypallidal" cells that project back to striatum. Furthermore, we discovered that a distinct minority (7%) of GP cells display slower, pacemaker-like firing and encode reward prediction errors (RPEs) almost identically to midbrain dopamine neurons. These cell-specific forms of GPe value representation help define the circuit mechanisms by which the BG contribute to motivation and reinforcement learning.
Assuntos
Gânglios da Base , Globo Pálido , Ratos , Animais , Globo Pálido/fisiologia , Corpo Estriado , Recompensa , Neurônios Dopaminérgicos/fisiologiaRESUMO
Dopamine in the nucleus accumbens helps motivate behavior based on expectations of future reward ("values"). These values need to be updated by experience: after receiving reward, the choices that led to reward should be assigned greater value. There are multiple theoretical proposals for how this credit assignment could be achieved, but the specific algorithms that generate updated dopamine signals remain uncertain. We monitored accumbens dopamine as freely behaving rats foraged for rewards in a complex, changing environment. We observed brief pulses of dopamine both when rats received reward (scaling with prediction error), and when they encountered novel path opportunities. Furthermore, dopamine ramped up as rats ran towards reward ports, in proportion to the value at each location. By examining the evolution of these dopamine place-value signals, we found evidence for two distinct update processes: progressive propagation along taken paths, as in temporal-difference learning, and inference of value throughout the maze, using internal models. Our results demonstrate that within rich, naturalistic environments dopamine conveys place values that are updated via multiple, complementary learning algorithms.
RESUMO
Animals frequently make decisions based on expectations of future reward ("values"). Values are updated by ongoing experience: places and choices that result in reward are assigned greater value. Yet, the specific algorithms used by the brain for such credit assignment remain unclear. We monitored accumbens dopamine as rats foraged for rewards in a complex, changing environment. We observed brief dopamine pulses both at reward receipt (scaling with prediction error) and at novel path opportunities. Dopamine also ramped up as rats ran toward reward ports, in proportion to the value at each location. By examining the evolution of these dopamine place-value signals, we found evidence for two distinct update processes: progressive propagation of value along taken paths, as in temporal difference learning, and inference of value throughout the maze, using internal models. Our results demonstrate that within rich, naturalistic environments dopamine conveys place values that are updated via multiple, complementary learning algorithms.
Assuntos
Tomada de Decisões , Dopamina , Ratos , Animais , Recompensa , EncéfaloRESUMO
Fast-spiking interneurons (FSIs) can exert powerful control over striatal output, and deficits in this cell population have been observed in human patients with Tourette syndrome and rodent models of dystonia. However, a direct experimental test of striatal FSI involvement in motor control has never been performed. We applied a novel pharmacological approach to examine the behavioral consequences of selective FSI suppression in mouse striatum. IEM-1460, an inhibitor of GluA2-lacking AMPARs, selectively blocked synaptic excitation of FSIs but not striatal projection neurons. Infusion of IEM-1460 into the sensorimotor striatum reduced the firing rate of FSIs but not other cell populations, and elicited robust dystonia-like impairments. These results provide direct evidence that hypofunction of striatal FSIs can produce movement abnormalities, and suggest that they may represent a novel therapeutic target for the treatment of hyperkinetic movement disorders.
Assuntos
Potenciais de Ação/fisiologia , Corpo Estriado/patologia , Discinesias/etiologia , Discinesias/patologia , Interneurônios/fisiologia , Adamantano/efeitos adversos , Adamantano/análogos & derivados , Análise de Variância , Animais , Área Sob a Curva , Antagonistas Colinérgicos/efeitos adversos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Interações Medicamentosas , Antagonistas de Aminoácidos Excitatórios/efeitos adversos , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/genética , Feminino , Lateralidade Funcional/efeitos dos fármacos , Lateralidade Funcional/fisiologia , Proteínas de Fluorescência Verde/genética , Interneurônios/classificação , Interneurônios/efeitos dos fármacos , Proteínas com Homeodomínio LIM/genética , Masculino , Mecamilamina/efeitos adversos , Camundongos , Camundongos Transgênicos , N-Metilaspartato/farmacologia , Proteínas do Tecido Nervoso/genética , Escopolamina/efeitos adversos , Fatores de Transcrição/genéticaRESUMO
Suppressing actions is essential for flexible behavior. Multiple neural circuits involved in behavioral inhibition converge upon a key basal ganglia output nucleus, the substantia nigra pars reticulata (SNr). To examine how changes in basal ganglia output contribute to self-restraint, we recorded SNr neurons during a proactive behavioral inhibition task. Rats responded to Go! cues with rapid leftward or rightward movements, but also prepared to cancel one of these movement directions on trials when a Stop! cue might occur. This action restraint - visible as direction-selective slowing of reaction times - altered both rates and patterns of SNr spiking. Overall firing rate was elevated before the Go! cue, and this effect was driven by a subpopulation of direction-selective SNr neurons. In neural state space, this corresponded to a shift away from the restrained movement. SNr neurons also showed more variable inter-spike intervals during proactive inhibition. This corresponded to more variable state-space trajectories, which may slow reaction times via reduced preparation to move. These findings open new perspectives on how basal ganglia dynamics contribute to movement preparation and cognitive control.