RESUMEN
How animals adapt their behavior according to regular time intervals between events is not well understood, especially when intervals last several seconds. One possibility is that animals use disembodied internal neuronal representations of time to decide when to initiate a given action at the end of an interval. However, animals rarely remain immobile during time intervals but tend to perform stereotyped behaviors, raising the possibility that motor routines improve timing accuracy. To test this possibility, we used a task in which rats, freely moving on a motorized treadmill, could obtain a reward if they approached it after a fixed interval. Most animals took advantage of the treadmill length and its moving direction to develop, by trial-and-error, the same motor routine whose execution resulted in the precise timing of their reward approaches. Noticeably, when proficient animals did not follow this routine, their temporal accuracy decreased. Then, naïve animals were trained in modified versions of the task designed to prevent the development of this routine. Compared to rats trained in the first protocol, these animals didn't reach a comparable level of timing accuracy. Altogether, our results indicate that timing accuracy in rats is improved when the environment affords cues that animals can incorporate into motor routines.
Asunto(s)
Señales (Psicología) , Actividad Motora/fisiología , Conducta Estereotipada/fisiología , Percepción del Tiempo/fisiología , Animales , Conducta Animal/fisiología , Masculino , Cadenas de Markov , Modelos Animales , Modelos Neurológicos , Ratas , RecompensaRESUMEN
Whisker-guided decision making in mice is thought to critically depend on information processing occurring in the primary somatosensory cortex. However, it is not clear if neuronal activity in this "early" sensory region contains information about the timing and speed of motor response. To address this question we designed a new task in which freely moving mice learned to associate a whisker stimulus to reward delivery. The task was tailored in such a way that a wide range of delays between whisker stimulation and reward collection were observed due to differences of motivation and perception. After training, mice were anesthetized and neuronal responses evoked by stimulating trained and untrained whiskers were recorded across several cortical columns of barrel cortex. We found a strong correlation between the delay of the mouse behavioral response and the timing of multiunit activity evoked by the trained whisker, outside its principal cortical column, in layers 4 and 5A but not in layer 2/3. Circuit mapping ex vivo revealed this effect was associated with a weakening of layer 4 to layer 2/3 projection. We conclude that the processes controlling the propagation of key sensory inputs to naive cortical columns and the timing of sensory-guided action are linked.
Asunto(s)
Toma de Decisiones/fisiología , Desempeño Psicomotor/fisiología , Corteza Somatosensorial/fisiología , Vías Aferentes/fisiología , Animales , Masculino , Ratones , Ratones Endogámicos C57BL , Recompensa , Factores de Tiempo , VibrisasRESUMEN
Activation of type 1 cannabinoid receptors (CB1R) decreases GABA and glutamate release in cortical and subcortical regions, with complex outcomes on cortical network activity. To date there have been few attempts to disentangle the region- and cell-specific mechanisms underlying the effects of cannabinoids on cortical network activity in vivo. Here we addressed this issue by combining in vivo electrophysiological recordings with local and systemic pharmacological manipulations in conditional mutant mice lacking CB1R expression in different neuronal populations. First we report that cannabinoids induce hypersynchronous thalamocortical oscillations while decreasing the amplitude of faster cortical oscillations. Then we demonstrate that CB1R at striatonigral synapses (basal ganglia direct pathway) mediate the thalamocortical hypersynchrony, whereas activation of CB1R expressed in cortical glutamatergic neurons decreases cortical synchrony. Finally we show that activation of CB1 expressed in cortical glutamatergic neurons limits the cannabinoid-induced thalamocortical hypersynchrony. By reporting that CB1R activations in cortical and subcortical regions have contrasting effects on cortical synchrony, our study bridges the gap between cellular and in vivo network effects of cannabinoids. Incidentally, the thalamocortical hypersynchrony we report suggests a potential mechanism to explain the sensory "high" experienced during recreational consumption of marijuana.
Asunto(s)
Cannabinoides/farmacología , Corteza Cerebral/citología , Cuerpo Estriado/citología , Neuronas GABAérgicas/metabolismo , Red Nerviosa/fisiología , Receptor Cannabinoide CB1/metabolismo , Animales , Corteza Cerebral/fisiología , Cuerpo Estriado/fisiología , Sincronización Cortical , Ciclohexanoles , Electromiografía , Ácido Glutámico/metabolismo , Ratones , Ratones Mutantes , Red Nerviosa/efectos de los fármacos , Piperidinas , Pirazoles , Receptor Cannabinoide CB1/deficiencia , Receptor Cannabinoide CB1/genética , Estadísticas no Paramétricas , Sustancia Negra/fisiología , Tálamo/fisiologíaRESUMEN
It is well-accepted in neuroscience that animals process time internally to estimate the duration of intervals lasting between one and several seconds. More than 100 years ago, Henri Bergson nevertheless remarked that, because animals have memory, their inner experience of time is ever-changing, making duration impossible to measure internally and time a source of change. Bergson proposed that quantifying the inner experience of time requires its externalization in movements (observed or self-generated), as their unfolding leaves measurable traces in space. Here, studies across species are reviewed and collectively suggest that, in line with Bergson's ideas, animals spontaneously solve time estimation tasks through a movement-based spatialization of time. Moreover, the well-known scalable anticipatory responses of animals to regularly spaced rewards can be explained by the variable pressure of time on reward-oriented actions. Finally, the brain regions linked with time perception overlap with those implicated in motor control, spatial navigation and motivation. Thus, instead of considering time as static information processed by the brain, it might be fruitful to conceptualize it as a kind of force to which animals are more or less sensitive depending on their internal state and environment.
Asunto(s)
Neurociencias , Percepción del Tiempo , Animales , Encéfalo/fisiología , Motivación , MovimientoRESUMEN
The integrity of the hippocampus is critical for both spatial navigation and episodic memory, but how its neuronal firing patterns underlie those functions is not well understood. In particular, the modality by which hippocampal place cells contribute to spatial memory is debated. We found that administration of the cannabinoid receptor agonist CP55940 (2-[(1S,2R,5S)-5-hydroxy-2-(3-hydroxypropyl)cyclohexyl]-5-(2-methyloctan-2-yl)phenol) induced a profound and reversible behavioral deficit in the hippocampus-dependent delayed spatial alternation task. On the one hand, despite severe memory impairment, the location-dependent firing of CA1 hippocampal place cells remained mostly intact. On the other hand, both spike-timing coordination between place cells at the theta timescale and theta phase precession of spikes were reversibly reduced. These results raise the possibility that cannabinoids impair memory primarily by altering short-term temporal dynamics of hippocampal neurons. We hypothesize that precise temporal coordination of hippocampal neurons is necessary for guiding behavior in spatial memory tasks.
Asunto(s)
Agonistas de Receptores de Cannabinoides , Cannabinoides/farmacología , Ciclohexanoles/farmacología , Hipocampo/efectos de los fármacos , Hipocampo/patología , Trastornos de la Memoria/inducido químicamente , Trastornos de la Memoria/patología , Animales , Conducta de Elección/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Células Piramidales/efectos de los fármacos , Células Piramidales/fisiología , Ratas , Ratas Long-Evans , Carrera/fisiología , Ritmo Teta/efectos de los fármacosRESUMEN
Cannabinoids impair hippocampus-dependent memory in both humans and animals, but the network mechanisms responsible for this effect are unknown. Here we show that the cannabinoids Delta(9)-tetrahydrocannabinol and CP55940 decreased the power of theta, gamma and ripple oscillations in the hippocampus of head-restrained and freely moving rats. These effects were blocked by a CB1 antagonist. The decrease in theta power correlated with memory impairment in a hippocampus-dependent task. By simultaneously recording from large populations of single units, we found that CP55940 severely disrupted the temporal coordination of cell assemblies in short time windows (<100 ms) yet only marginally affected population firing rates of pyramidal cells and interneurons. The decreased power of local field potential oscillations correlated with reduced temporal synchrony but not with firing rate changes. We hypothesize that reduced spike timing coordination and the associated impairment of physiological oscillations are responsible for cannabinoid-induced memory deficits.
Asunto(s)
Potenciales de Acción/efectos de los fármacos , Cannabinoides/farmacología , Hipocampo/efectos de los fármacos , Hipocampo/fisiología , Ritmo Teta/efectos de los fármacos , Potenciales de Acción/fisiología , Animales , Sincronización Cortical/efectos de los fármacos , Ciclohexanos/farmacología , Ciclohexanoles , Dronabinol/farmacología , Hipocampo/citología , Periodicidad , Fenoles/farmacología , Ratas , Receptores de Cannabinoides/efectos de los fármacos , Receptores de Cannabinoides/fisiologíaRESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMEN
The dorsal striatum (dS) has been implicated in storing procedural memories and controlling movement kinematics. Since procedural memories are expressed through movements, the exact nature of the dS function has proven difficult to delineate. Here, we challenged rats in complementary locomotion-based tasks designed to alleviate this confound. Surprisingly, dS lesions did not impair the rats' ability to remember the procedure for the successful completion of motor routines. However, the speed and initiation of the reward-oriented phase of the routines were irreversibly altered by the dS lesion. Further behavioral analyses, combined with modeling in the optimal control framework, indicated that these kinematic alterations were well explained by an increased sensitivity to effort. Our work provides evidence supporting a primary role of the dS in modulating the kinematics of reward-oriented actions, a function that may be related to the optimization of the energetic costs of moving.
Asunto(s)
Cuerpo Estriado/fisiología , Carrera/fisiología , Animales , Cuerpo Estriado/cirugía , Metabolismo Energético/fisiología , Masculino , Modelos Animales , Ratas , Ratas Long-Evans , Recompensa , Técnicas EstereotáxicasRESUMEN
Perceptual decisions are based on sensory information but can also be influenced by expectations built from recent experiences. Can the impact of expectations be flexibly modulated based on the outcome of previous decisions? Here, rats perform an auditory task where the probability to repeat the previous stimulus category is varied in trial-blocks. All rats capitalize on these sequence correlations by exploiting a transition bias: a tendency to repeat or alternate their previous response using an internal estimate of the sequence repeating probability. Surprisingly, this bias is null after error trials. The internal estimate however is not reset and it becomes effective again after the next correct response. This behavior is captured by a generative model, whereby a reward-driven modulatory signal gates the impact of the latent model of the environment on the current decision. These results demonstrate that, based on previous outcomes, rats flexibly modulate how expectations influence their decisions.
Asunto(s)
Estimulación Acústica , Conducta Animal/fisiología , Toma de Decisiones/fisiología , Discriminación en Psicología/fisiología , Filtrado Sensorial/fisiología , Animales , Mapeo Encefálico , Masculino , Motivación , Ratas , Ratas Long-Evans , Tiempo de Reacción/fisiología , RecompensaRESUMEN
The ability to flexibly navigate an environment relies on a hippocampal-dependent cognitive map. External space can be internally mapped at different spatial resolutions. However, whether hippocampal spatial coding resolution can rapidly adapt to local features of an environment remains unclear. To explore this possibility, we recorded the firing of hippocampal neurons in mice navigating virtual reality environments, embedding or not local visual cues (virtual 3D objects) in specific locations. Virtual objects enhanced spatial coding resolution in their vicinity with a higher proportion of place cells, smaller place fields, increased spatial selectivity and stability. This effect was highly dynamic upon objects manipulations. Objects also improved temporal coding resolution through improved theta phase precession and theta timescale spike coordination. We propose that the fast adaptation of hippocampal spatial coding resolution to local features of an environment could be relevant for large-scale navigation.
Asunto(s)
Señales (Psicología) , Hipocampo/fisiología , Orientación Espacial , Células de Lugar/fisiología , Animales , Potenciales Evocados , Ratones Endogámicos C57BLRESUMEN
Glutamate transmission between prefrontal cortex (PFC) and accumbens (NAc) plays a crucial role in the establishment and expression of addictive behaviors. At these synapses exogenous cannabinoid receptor 1 (CB1R) agonists reversibly inhibit excitatory transmission, and the sustained release of endogenous cannabinoids (eCB) following prolonged cortical stimulation leads to long-term depression (LTD). Activation of presynaptic K(+) channels mediates the effects of exocannabinoids, but the transduction pathway underlying the protracted phase of eCB-LTD is unknown. Here we report that the maintenance of eCB-LTD does not involve presynaptic K(+) channels: eCB-LTD was not affected by blockade of K(+) channels with 4-AP (100 microM) and BaCl(2) (300 microM) (fEPSP=78.9+/-5.4% of baseline 58-60 min after tetanus, compared to 78.9+/-5.9% in control slices). In contrast, eCB-LTD was blocked by treatment of the slices with the adenylyl cyclase (AC) activator forskolin (10 microM), and with the protein kinase A (PKA) inhibitor KT5720 (1 microM) (fEPSP=108.9+/-5.7% in forskolin and 110.5+/-7.7% in KT5720, compared to 80.6+/-3.9% in control conditions). Additionally, selective blockade of P/Q-type Ca(2+) channels with omega-agatoxin-IVA (200 nM) occluded the expression of eCB-LTD (fEPSP=113.4+/-15.9% compared to 78.6+/-4.4% in control slices), while blockade of N- with omega-conotoxin-GVIA (1 microM) or L-type Ca(2+) channels with nimodipine (1 microM), was without effect (fEPSP was 83.7+/-5.3% and 87+/-8.9% respectively). These data show that protracted inhibition of AC/PKA activity and P/Q-type Ca(2+) channels are necessary for expression of eCB-LTD at NAc synapses.
Asunto(s)
Canales de Calcio Tipo P/fisiología , Moduladores de Receptores de Cannabinoides/metabolismo , AMP Cíclico/metabolismo , Endocannabinoides , Depresión Sináptica a Largo Plazo/fisiología , Núcleo Accumbens/fisiología , 4-Aminopiridina/farmacología , Potenciales de Acción/efectos de los fármacos , Potenciales de Acción/fisiología , Potenciales de Acción/efectos de la radiación , Animales , Compuestos de Bario/farmacología , Calcio/metabolismo , Bloqueadores de los Canales de Calcio/farmacología , Moduladores de Receptores de Cannabinoides/antagonistas & inhibidores , Carbazoles/farmacología , Cloruros/farmacología , Colforsina/farmacología , Estimulación Eléctrica/métodos , Inhibidores Enzimáticos/farmacología , Técnicas In Vitro , Indoles/farmacología , Depresión Sináptica a Largo Plazo/efectos de los fármacos , Depresión Sináptica a Largo Plazo/efectos de la radiación , Masculino , Ratones , Ratones Endogámicos C57BL , Núcleo Accumbens/efectos de los fármacos , Técnicas de Placa-Clamp/métodos , Bloqueadores de los Canales de Potasio/farmacología , Pirroles/farmacología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiologíaRESUMEN
Endogenous cannabinoids (eCB) mediate synaptic plasticity in brain regions involved in learning and reward. Here we show that in mice, a single in-vivo exposure to Delta 9-tetrahydrocannabinol (THC) abolishes the retrograde signaling that underlies eCB-mediated synaptic plasticity in both nucleus accumbens (NAc) and hippocampus in vitro. This effect is reversible within 3 days and is associated with a transient modification in the functional properties of cannabinoid receptors.
Asunto(s)
Moduladores de Receptores de Cannabinoides/antagonistas & inhibidores , Dronabinol/administración & dosificación , Endocannabinoides , Plasticidad Neuronal/efectos de los fármacos , Sinapsis/efectos de los fármacos , Animales , Moduladores de Receptores de Cannabinoides/fisiología , Relación Dosis-Respuesta a Droga , Hipocampo/efectos de los fármacos , Hipocampo/fisiología , Técnicas In Vitro , Ratones , Plasticidad Neuronal/fisiología , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/fisiología , Sinapsis/fisiologíaRESUMEN
A long-standing hypothesis postulates that the striatum is essential for the concurrent selection of adaptive actions and repression of inappropriate alternatives. Here, classical and recent anatomical and physiological studies are reviewed to show that, in mammals, the striatum can detect discrete task-relevant sensory stimuli and continuously track somatosensory information associated with the generation of simple movements and more complex actions. Rather than contributing to the immediate selection of actions, the striatum may monitor the sensorimotor state of animals by integrating somatosensory information and motor-related signals on a moment-by-moment basis. Such function could be critical for the progressive acquisition or updating of adaptive actions and the emergence of an embodied sense of time.
Asunto(s)
Cuerpo Estriado/fisiología , Aprendizaje/fisiología , Actividad Motora/fisiología , Percepción/fisiología , Corteza Somatosensorial/fisiología , Animales , HumanosRESUMEN
A popular hypothesis is that the dorsal striatum generates discrete "traffic light" signals that initiate, maintain, and terminate the execution of learned actions. Alternatively, the striatum may continuously monitor the dynamics of movements associated with action execution by processing inputs from somatosensory and motor cortices. Here, we recorded the activity of striatal neurons in mice performing a run-and-stop task and characterized the diversity of firing rate modulations relative to run performance (tuning curves) across neurons. We found that the tuning curves could not be statistically clustered in discrete functional groups (start or stop neurons). Rather, their shape varied continuously according to the movement dynamics of the task. Moreover, striatal spiking activity correlated with running speed on a run-by-run basis and was modulated by task-related non-locomotor movements, such as licking. We hypothesize that such moment-to-moment movement monitoring by the dorsal striatum contributes to the learning of adaptive actions and/or updating their kinematics.
Asunto(s)
Núcleo Caudado/fisiología , Cuerpo Estriado/fisiología , Aprendizaje/fisiología , Potenciales de Acción/fisiología , Animales , Ganglios Basales/fisiología , Conducta Animal/fisiología , Fenómenos Biomecánicos/fisiología , Señales (Psicología) , Masculino , Ratones , Ratones Endogámicos C57BL , Actividad Motora/fisiología , Movimiento/fisiología , Neuronas/fisiología , Desempeño Psicomotor/fisiología , Tiempo de Reacción/fisiologíaRESUMEN
In the cortex and hippocampus, neuronal oscillations of different frequencies can be observed in local field potentials (LFPs). LFPs oscillations in the theta band (6-10 Hz) have also been observed in the dorsolateral striatum (DLS) of rodents, mostly during locomotion, and have been proposed to mediate behaviorally-relevant interactions between striatum and cortex (or between striatum and hippocampus). However, it is unclear if these theta oscillations are generated in the striatum. To address this issue, we recorded LFPs and spiking activity in the DLS of rats performing a running sequence on a motorized treadmill. We observed an increase in rhythmical activity of the LFP in the theta-band during run compared to rest periods. However, several observations suggest that these oscillations are mainly generated outside of the striatum. First, theta oscillations disappeared when LFPs were rereferenced against a striatal recording electrode and the imaginary coherence between LFPs recorded at different locations within the striatum was null. Second, 8% of the recorded neurons had their spiking activity phase-locked to the theta rhythm. Third, Granger causality analyses between LFPs simultaneously recorded in the cortex and the striatum revealed that the interdependence between these two signals in the theta range was mostly accounted for by a common external source. The most parsimonious interpretation of these results is that theta oscillations observed in striatal LFPs are largely contaminated by volume-conducted signals. We propose that striatal LFPs are not optimal proxies of network dynamics in the striatum and should be interpreted with caution.
Asunto(s)
Potenciales de Acción/fisiología , Cuerpo Estriado/citología , Cuerpo Estriado/fisiología , Actividad Motora/fisiología , Neuronas/fisiología , Ritmo Teta/fisiología , Animales , Fenómenos Biomecánicos , Electroencefalografía , Prueba de Esfuerzo , Masculino , RatasRESUMEN
Alterations of long-term synaptic plasticity have been proposed to participate in the development of addiction. To preserve synaptic functions, homeostatic processes must be engaged after exposure to abused drugs. At the mouse cortico-accumbens synapses, a single in vivo injection of Delta9-tetrahydrocannabinol (THC) suppresses endocannabinoid-mediated long-term depression. Using biochemical and electrophysiological approaches, we now report that 1 week of repeated in vivo THC treatment reduces the coupling efficiency of cannabinoid CB1 receptors (CB1Rs) to G(i/o) transduction proteins, as well as CB1R-mediated inhibition of excitatory synaptic transmission at the excitatory synapses between the prefrontal cortex and the nucleus accumbens (NAc). Nonetheless, we found that cortico-accumbens synapses unexpectedly express normal long-term depression because of a reversible switch in its underlying mechanisms. The present data show that, in THC-treated mice, long-term depression is expressed because a presynaptic mGluR2/3 (metabotropic glutamate receptor 2/3)-dependent mechanism replaces the impaired endocannabinoid system. Thus, in the NAc, a novel form of presynaptic homeostasis rescues synaptic plasticity from THC-induced deficits.
Asunto(s)
Dronabinol/administración & dosificación , Homeostasis/efectos de los fármacos , Depresión Sináptica a Largo Plazo/efectos de los fármacos , Plasticidad Neuronal/efectos de los fármacos , Terminales Presinápticos/efectos de los fármacos , Animales , Relación Dosis-Respuesta a Droga , Homeostasis/fisiología , Técnicas In Vitro , Depresión Sináptica a Largo Plazo/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Plasticidad Neuronal/fisiología , Terminales Presinápticos/fisiologíaRESUMEN
The dentate gyrus, a major entry point to the hippocampus, gates (or filters) incoming information from the cortex. During sleep or anesthesia, the slow-wave oscillation (SWO) orchestrates hippocampus-neocortex communication, which is important for memory formation. The dentate gate is altered in temporal lobe epilepsy (TLE) early during epileptogenesis, which favors the propagation of pathological activities. Yet, whether the gating of physiological SWO by dentate granule cells (DGCs) is altered in TLE has remained unexplored. We combined intracellular recordings of membrane potential (V m) of DGCs and local field potential recordings of the SWO in parietal cortex in anesthetized rats early during epileptogenesis [post-status epilepticus (SE) rats]. As expected, in control rats, the V m of DGCs weakly and rarely oscillated in the SWO frequency range. In contrast, in post-SE rats, the V m of DGCs displayed strong and long-lasting SWO. In these cells, clear UP and DOWN states, in phase with the neocortical SWO, led to a bimodal V m distribution. In post-SE rats, the firing of DGCs was increased and more temporally modulated by the neocortical SWO. We conclude that UP/DOWN state dynamics dominate the V m of DGCs and firing early during epileptogenesis. This abnormally strong neocortical influence on the dynamics of DGCs may profoundly modify the hippocampus-neocortex dialogue during sleep and associated cognitive functions.
Asunto(s)
Giro Dentado/fisiopatología , Epilepsia del Lóbulo Temporal/fisiopatología , Potenciales de la Membrana/fisiología , Neocórtex/fisiopatología , Neuronas/fisiología , Animales , Giro Dentado/patología , Modelos Animales de Enfermedad , Epilepsia del Lóbulo Temporal/patología , Compuestos de Litio , Masculino , Microelectrodos , Neocórtex/patología , Vías Nerviosas/patología , Vías Nerviosas/fisiopatología , Neuronas/patología , Técnicas de Placa-Clamp , Periodicidad , Pilocarpina , Ratas WistarRESUMEN
The nucleus accumbens (NAc) is an important cerebral area involved in reward and spatial memory (Pennartz et al., 1994), but little is known about synaptic plasticity in this region. Here, electron microscopy revealed that, in the NAc, metabotropic glutamate receptors 2/3 (mGlu2/3) immunostaining was essentially associated with axonal terminals and glial processes, whereas postsynaptic dendrites and neuronal cell bodies were unstained. Electrophysiological techniques in the NAc slice preparation demonstrated that activation of mGlu2/3 with synaptically released glutamate or specific exogenous agonist, such as LY354740 (200 nm, 10 min), induced long-term depression of excitatory synaptic transmission (mGlu2/3-LTD). Tetanic-LTD and pharmacological mGlu2/3-LTD occluded each other, suggesting common mechanisms. The mGlu2/3-LTD did not require synaptic activity but depended on the cAMP-protein kinase A cascade. Selective inhibition of P/Q-type Ca(2+) channels with omega-agatoxin-IVA occluded the expression of mGlu2/3-LTD, and, conversely, the inhibitory effects of omega-agatoxin-IVA were abolished during mGlu2/3-LTD. Thus, mGlu2/3 play an important role in the control of use-dependent synaptic plasticity at prelimbic cortex-NAc synapses: their activation causes a form of LTD mediated by the long-lasting reduction of P/Q-type Ca(2+)channels contribution to transmitter release.
Asunto(s)
Canales de Calcio/metabolismo , Inhibición Neural/fisiología , Núcleo Accumbens/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Sinapsis/metabolismo , Aminoácidos/farmacología , Animales , Compuestos Bicíclicos con Puentes/farmacología , Calcio/metabolismo , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio Tipo P/metabolismo , Canales de Calcio Tipo Q/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Estimulación Eléctrica , Agonistas de Aminoácidos Excitadores/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Potenciales Postsinápticos Excitadores/fisiología , Técnicas In Vitro , Masculino , Ratones , Ratones Endogámicos C57BL , Plasticidad Neuronal/efectos de los fármacos , Plasticidad Neuronal/fisiología , Núcleo Accumbens/citología , Técnicas de Placa-Clamp , Terminales Presinápticos/metabolismo , Receptores de Glutamato Metabotrópico/agonistas , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Transmisión Sináptica/efectos de los fármacos , Transmisión Sináptica/fisiología , Xantenos/farmacologíaRESUMEN
The striatum is required for the acquisition of procedural memories, but its contribution to motor control once learning has occurred is unclear. We created a task in which rats learned a difficult motor sequence characterized by fine-tuned changes in running speed adjusted to spatial and temporal constraints. After training and extensive practice, we found that the behavior was habitual, yet tetrode recordings in the dorsolateral striatum (DLS) revealed continuous integrative representations of running speed, position and time. These representations were weak in naive rats that were hand-guided to perform the same sequence and developed slowly after learning. Finally, DLS inactivation in well-trained animals preserved the structure of the sequence while increasing its trial-by-trial variability. We conclude that, after learning, the DLS continuously integrates task-relevant information to constrain the execution of motor habits. Our results provide a straightforward mechanism by which the basal ganglia may contribute to habit formation and motor control.