RESUMO
The perception of time is critical to adaptive behavior. While prefrontal cortex and basal ganglia have been implicated in interval timing in the seconds to minutes range, little is known about the role of the mediodorsal thalamus (MD), which is a key component of the limbic cortico-basal ganglia-thalamocortical loop. In this study, we tested the role of the MD in timing, using an operant temporal production task in male mice. In this task, that the expected timing of available rewards is indicated by lever pressing. Inactivation of the MD with muscimol produced rightward shifts in peak pressing on probe trials as well as increases in peak spread, thus significantly altering both temporal accuracy and precision. Optogenetic inhibition of glutamatergic projection neurons in the MD also resulted in similar changes in timing. The observed effects were found to be independent of significant changes in movement. Our findings suggest that the MD is a critical component of the neural circuit for interval timing, without playing a direct role in regulating ongoing performance.SIGNIFICANCE STATEMENT The mediodorsal nucleus (MD) of the thalamus is strongly connected with the prefrontal cortex and basal ganglia, areas which have been implicated in interval timing. Previous work has shown that the MD contributes to working memory and learning of action-outcome contingencies, but its role in behavioral timing is poorly understood. Using an operant temporal production task, we showed that inactivation of the MD significantly impaired timing behavior.
Assuntos
Condicionamento Operante/fisiologia , Núcleo Mediodorsal do Tálamo/fisiologia , Desempenho Psicomotor/fisiologia , Percepção do Tempo/fisiologia , Animais , Condicionamento Operante/efeitos dos fármacos , Agonistas de Receptores de GABA-A/administração & dosagem , Masculino , Núcleo Mediodorsal do Tálamo/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Muscimol/administração & dosagem , Optogenética , Desempenho Psicomotor/efeitos dos fármacos , Recompensa , Percepção do Tempo/efeitos dos fármacosRESUMO
Accurate and precise timing is crucial for complex and purposeful behaviors, such as foraging for food or playing a musical instrument. The brain is capable of processing temporal information in a coordinated manner, as if it contains an 'internal clock'. Similar to the need for the brain to orient itself in space in order to understand its surroundings, temporal orientation and tracking is an essential component of cognition as well. While there have been multiple models explaining the neural correlates of timing, independent lines of research appear to converge on the conclusion that populations of neurons in the dorsal striatum encode information relating to where a subject is in time relative to an anticipated goal. Similar to other learning processes, acquisition and maintenance of this temporal information is dependent on synaptic plasticity. Microtubules are cytoskeletal proteins that have been implicated in synaptic plasticity mechanisms and therefore are considered key elements in learning and memory. In this study, we investigated the role of microtubule dynamics in temporal learning by local infusions of microtubule stabilizing and destabilizing agents into the dorsolateral striatum. Our results suggested a bidirectional role for microtubules in timing, such that microtubule stabilization improves the maintenance of learned target durations, but impairs the acquisition of a novel duration. On the other hand, microtubule destabilization enhances the acquisition of novel target durations, while compromising the maintenance of previously learned durations. These findings suggest that microtubule dynamics plays an important role in synaptic plasticity mechanisms in the dorsolateral striatum, which in turn modulates temporal learning and time perception.
Assuntos
Aprendizagem/efeitos dos fármacos , Microtúbulos/efeitos dos fármacos , Neostriado/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Percepção do Tempo/efeitos dos fármacos , Moduladores de Tubulina/farmacologia , Animais , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/fisiologia , Aprendizagem/fisiologia , Proteínas dos Microtúbulos/efeitos dos fármacos , Proteínas dos Microtúbulos/fisiologia , Microtúbulos/fisiologia , Neostriado/fisiologia , Nocodazol/farmacologia , Paclitaxel/farmacologia , RatosRESUMO
Time perception is an essential element of conscious and subconscious experience, coordinating our perception and interaction with the surrounding environment. In recent years, major technological advances in the field of neuroscience have helped foster new insights into the processing of temporal information, including extending our knowledge of the role of the cerebellum as one of the key nodes in the brain for this function. This consensus paper provides a state-of-the-art picture from the experts in the field of the cerebellar research on a variety of crucial issues related to temporal processing, drawing on recent anatomical, neurophysiological, behavioral, and clinical research.The cerebellar granular layer appears especially well-suited for timing operations required to confer millisecond precision for cerebellar computations. This may be most evident in the manner the cerebellum controls the duration of the timing of agonist-antagonist EMG bursts associated with fast goal-directed voluntary movements. In concert with adaptive processes, interactions within the cerebellar cortex are sufficient to support sub-second timing. However, supra-second timing seems to require cortical and basal ganglia networks, perhaps operating in concert with cerebellum. Additionally, sensory information such as an unexpected stimulus can be forwarded to the cerebellum via the climbing fiber system, providing a temporally constrained mechanism to adjust ongoing behavior and modify future processing. Patients with cerebellar disorders exhibit impairments on a range of tasks that require precise timing, and recent evidence suggest that timing problems observed in other neurological conditions such as Parkinson's disease, essential tremor, and dystonia may reflect disrupted interactions between the basal ganglia and cerebellum.The complex concepts emerging from this consensus paper should provide a foundation for further discussion, helping identify basic research questions required to understand how the brain represents and utilizes time, as well as delineating ways in which this knowledge can help improve the lives of those with neurological conditions that disrupt this most elemental sense. The panel of experts agrees that timing control in the brain is a complex concept in whom cerebellar circuitry is deeply involved. The concept of a timing machine has now expanded to clinical disorders.
Assuntos
Cerebelo/fisiologia , Percepção do Tempo/fisiologia , Animais , Cerebelo/fisiopatologia , Humanos , Neurônios/fisiologiaRESUMO
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
Technologies such as spatial transcriptomics offer unique opportunities to define the spatial organization of the mouse brain. We developed an unsupervised training scheme and novel transformer-based deep learning architecture to detect spatial domains across the whole mouse brain using spatial transcriptomics data. Our model learns local representations of molecular and cellular statistical patterns which can be clustered to identify spatial domains within the brain from coarse to fine-grained. Discovered domains are spatially regular, even with several hundreds of spatial clusters. They are also consistent with existing anatomical ontologies such as the Allen Mouse Brain Common Coordinate Framework version 3 (CCFv3) and can be visually interpreted at the cell type or transcript level. We demonstrate our method can be used to identify previously uncatalogued subregions, such as in the midbrain, where we uncover gradients of inhibitory neuron complexity and abundance. Notably, these subregions cannot be discovered using other methods. We apply our method to a separate multi-animal whole-brain spatial transcriptomic dataset and show that our method can also robustly integrate spatial domains across animals.
RESUMO
A robust adaptation to environmental changes is vital for survival. Almost all living organisms have a circadian timing system that allows adjusting their physiology to cyclic variations in the surrounding environment. Among vertebrates, many birds are also seasonal species, adapting their physiology to annual changes in photoperiod (amplitude, length and duration). Tawny Owls (Strix aluco) are nocturnal birds of prey that use vocalization as their principal mechanism of communication. Diurnal and seasonal changes in vocalization have been described for several vocal species, including songbirds. Comparable studies are lacking for owls. In the present work, we show that male Tawny Owls present a periodic vocalization pattern in the seconds-to-minutes range that is subject to both daily (early vs. late night) and seasonal (spring vs. summer) rhythmicity. These novel theory-generating findings appear to extend the role of the circadian system in regulating temporal events in the seconds-to-minutes range to other species.
Assuntos
Relógios Circadianos/fisiologia , Fotoperíodo , Estações do Ano , Estrigiformes/fisiologia , Vocalização Animal/fisiologia , Animais , MasculinoRESUMO
The basal ganglia have been implicated in action selection and timing, but the relative contributions of the striatonigral (direct) and striatopallidal (indirect) pathways to these functions remain unclear. We investigated the effects of optogenetic stimulation of D1+ (direct) and A2A+ (indirect) neurons in the ventrolateral striatum in head-fixed mice on a fixed time reinforcement schedule. Direct pathway stimulation initiates licking, whereas indirect pathway stimulation suppresses licking and results in rebound licking after stimulation. Moreover, direct and indirect pathways also play distinct roles in timing. Direct pathway stimulation produced a resetting of the internal timing process, whereas indirect pathway stimulation transiently paused timing, and proportionally delayed the next bout of licking. Our results provide evidence for the continuous and opposing contributions of the direct and indirect pathways in the production and timing of reward-guided behavior.
Assuntos
Comportamento Animal , Corpo Estriado/fisiologia , Vias Neurais/fisiologia , Animais , Feminino , Masculino , Camundongos , Optogenética , Esquema de Reforço , Fatores de TempoRESUMO
Considerable evidence implicates the basal ganglia in interval timing, yet the underlying mechanisms remain poorly understood. Using a novel behavioral task, we demonstrate that head-fixed mice can be trained to show the key features of timing behavior within a few sessions. Single-trial analysis of licking behavior reveals stepping dynamics with variable onset times, which is responsible for the canonical Gaussian distribution of timing behavior. Moreover, the duration of licking bouts decreased as mice became sated, showing a strong motivational modulation of licking bout initiation and termination. Using optogenetics, we examined the role of the basal ganglia output in interval timing. We stimulated a pathway important for licking behavior, the GABAergic output projections from the substantia nigra pars reticulata to the deep layers of the superior colliculus. We found that stimulation of this pathway not only cancelled licking but also delayed the initiation of anticipatory licking for the next interval in a frequency-dependent manner. By combining quantitative behavioral analysis with optogenetics in the head-fixed setup, we established a new approach for studying the neural basis of interval timing.
Assuntos
Gânglios da Base/fisiologia , Neurônios GABAérgicos/fisiologia , Parte Reticular da Substância Negra/fisiologia , Animais , Comportamento Animal , Channelrhodopsins/metabolismo , Feminino , Masculino , Camundongos , Optogenética , Percepção do TempoRESUMO
The contributions of cortico-cerebellar and cortico-striatal circuits to timing and time perception have often been a point of contention. In this review we propose that the cerebellum principally functions to reduce variability, through the detection of stimulus onsets and the sub-division of longer durations, thus contributing to both sub-second and supra-second timing. This sensitivity of the cerebellum to stimulus dynamics and subsequent integration with motor control allows it to accurately measure intervals within a range of 100-2000ms. For intervals in the supra-second range (e.g., >2000ms), we propose that cerebellar output signals from the dentate nucleus pass through thalamic connections to the striatum, where cortico-thalamic-striatal circuits supporting higher-level cognitive functions take over. Moreover, the importance of intrinsic circuit dynamics as well as behavioral, neuroimaging, and lesion studies of the cerebellum and striatum are discussed in terms of a framework positing initiation, continuation, adjustment, and termination phases of temporal processing.