RESUMEN
The performance of an action relies on the initiation and execution of appropriate movement sequences. Two basal ganglia pathways have been classically hypothesized to regulate this process via opposing roles in movement facilitation and suppression. By using a series of state-dependent optogenetic manipulations, we dissected the contributions of each pathway and found that both the direct striatonigral pathway and the indirect striatopallidal pathway are necessary for smooth initiation and the execution of learned action sequences. Optogenetic inhibition or stimulation of each pathway before sequence initiation increased the latency for initiation: manipulations of the striatonigral pathway activity slowed action initiation, and those of the striatopallidal pathway aborted action initiation. The inhibition of each pathway after initiation also impaired ongoing execution. Furthermore, the subtle activation of striatonigral neurons sustained the performance of learned sequences, while striatopallidal manipulations aborted ongoing performance. These results suggest a supportive versus permissive model, where patterns of coordinated activity, rather than the relative amount of activity in these pathways, regulate movement initiation and execution.
Asunto(s)
Cuerpo Estriado/fisiología , Vías Nerviosas/fisiología , Desempeño Psicomotor/fisiología , Animales , Ganglios Basales/fisiología , Cuerpo Estriado/citología , Masculino , Ratones , Ratones Endogámicos C57BL , Modelos Neurológicos , Movimiento , Neuronas/fisiología , OptogenéticaRESUMEN
Detecting novelty is critical to consolidate declarative memories, such as spatial contextual recognition memory. It has been shown that stored memories, when retrieved, are susceptible to modification, incorporating new information through an updating process. Catecholamine release in the hippocampal CA1 region consolidates an object location memory (OLM). This work hypothesized that spatial contextual memory updating could be changed by decreasing catecholamine release in the hippocampal CA1 terminals from the locus coeruleus (LC). In a mouse model expressing Cre-recombinase under the control of the tyrosine hydroxylase (TH) promoter, memory updating was impaired by photoinhibition of the CA1 catecholaminergic terminals from the LC (LC-CA1) but not from the ventral tegmental area (VTA-CA1). In vivo microdialysis confirmed that the extracellular concentration of both dopamine (DA) and noradrenaline (NA) decreased after photoinhibition of the LC-CA1 terminals (but not VTA-CA1) during the OLM update session. Furthermore, DA D1/D5 and beta-adrenergic receptor antagonists disrupted behavior, but only the former impaired memory updating. Finally, photoinhibition of LC-CA1 terminals suppressed long-term potentiation (LTP) induction in Schaffer's collaterals as a plausible mechanism for memory updating. These data will help understand the underpinning mechanisms of DA in spatial contextual memory updating.
Asunto(s)
Dopamina , Locus Coeruleus , Animales , Ratones , Memoria Espacial , Hipocampo , CatecolaminasRESUMEN
Deciding when and whether to move is critical for survival. Loss of dopamine neurons (DANs) of the substantia nigra pars compacta (SNc) in patients with Parkinson's disease causes deficits in movement initiation and slowness of movement. The role of DANs in self-paced movement has mostly been attributed to their tonic activity, whereas phasic changes in DAN activity have been linked to reward prediction. This model has recently been challenged by studies showing transient changes in DAN activity before or during self-paced movement initiation. Nevertheless, the necessity of this activity for spontaneous movement initiation has not been demonstrated, nor has its relation to initiation versus ongoing movement been described. Here we show that a large proportion of SNc DANs, which did not overlap with reward-responsive DANs, transiently increased their activity before self-paced movement initiation in mice. This activity was not action-specific, and was related to the vigour of future movements. Inhibition of DANs when mice were immobile reduced the probability and vigour of future movements. Conversely, brief activation of DANs when mice were immobile increased the probability and vigour of future movements. Manipulations of dopamine activity after movement initiation did not affect ongoing movements. Similar findings were observed for the initiation and execution of learned action sequences. These findings causally implicate DAN activity before movement initiation in the probability and vigour of future movements.
Asunto(s)
Neuronas Dopaminérgicas/metabolismo , Movimiento/fisiología , Animales , Dopamina/metabolismo , Masculino , Ratones , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Enfermedad de Parkinson/fisiopatología , Probabilidad , Desempeño Psicomotor , Recompensa , Sustancia Negra/citología , Sustancia Negra/fisiologíaRESUMEN
The insular cortex (IC) has been linked to the processing of interoceptive and exteroceptive signals associated with addictive behavior. However, whether the IC modulates the acquisition of drug-related affective states by direct top-down connectivity with ventral tegmental area (VTA) dopamine neurons is unknown. We found that photostimulation of VTA terminals of the anterior insular cortex (aIC) induces rewarding contextual memory, modulates VTA activity, and triggers dopamine release within the VTA. Employing neuronal recordings and neurochemical and transsynaptic tagging techniques, we disclose the functional top-down organization tagging the aIC pre-synaptic neuronal bodies and identifying VTA recipient neurons. Furthermore, systemic administration of amphetamine altered the VTA excitability of neurons modulated by the aIC projection, where photoactivation enhances, whereas photoinhibition impairs, a contextual rewarding behavior. Our study reveals a key circuit involved in developing and retaining drug reward-related contextual memory, providing insight into the neurobiological basis of addictive behavior and helping develop therapeutic addiction strategies.
Asunto(s)
Neuronas Dopaminérgicas , Área Tegmental Ventral , Neuronas Dopaminérgicas/fisiología , Área Tegmental Ventral/fisiología , Corteza Insular , Anfetamina/farmacología , RecompensaRESUMEN
Cerebellar-thalamo-striatal synaptic communication has been implicated in a wide range of behaviors, including goal-directed actions, and is altered in cerebellar dystonia. However, its detailed connectivity through the thalamus and its contribution to the execution of forelimb movements is unclear. Here, we use trans-synaptic and retrograde tracing, ex vivo slice recordings, and optogenetic inhibitions during the execution of unidirectional or sequential joystick displacements to demonstrate that the deep cerebellar nuclei (DCN) influence the dorsal striatum with a very high probability. We show that this mainly occurs through the centrolateral (CL), parafascicular (PF), and ventrolateral (VL) nuclei of the thalamus, observing that the DCNâVL and DCNâCL pathways contribute to the execution of unidirectional forelimb displacements while the DCNâPF and DCNâthalamoâstriatal pathways contribute to the appropriate execution of forelimb reaching and sequential displacements. These findings highlight specific contributions of the different cerebellar-thalamo-striatal paths to the control of skilled forelimb movement.
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Núcleos Cerebelosos , Cuerpo Estriado , Animales , Tálamo , Cerebelo , Movimiento , Miembro AnteriorRESUMEN
We investigated the properties of neostriatal neuropeptide Y (NPY)-expressing interneurons in transgenic GFP (green fluorescent protein)-NPY reporter mice. In vitro whole-cell recordings and biocytin staining demonstrated the existence of a novel class of neostriatal NPY-expressing GABAergic interneurons that exhibit electrophysiological, neurochemical, and morphological properties strikingly different from those of previously described NPY-containing, plateau-depolarization low-threshold spike (NPY-PLTS) interneurons. The novel NPY interneuron type (NPY-neurogliaform) differed from previously described NPY-PLTS interneurons by exhibiting a significantly lower input resistance and hyperpolarized membrane potential, regular, nonaccommodating spiking in response to depolarizing current injections, and an absence of plateau depolarizations or low-threshold spikes. NPY-neurogliaform interneurons were also easily distinguished morphologically by their dense, compact, and highly branched dendritic and local axonal arborizations that contrasted sharply with the sparse and extended axonal and dendritic arborizations of NPY-PLTS interneurons. Furthermore, NPY-neurogliaform interneurons did not express immunofluorescence for somatostatin or nitric oxide synthase that was ubiquitous in NPY-PLTS interneurons. IPSP/Cs could only rarely be elicited in spiny projection neurons (SPNs) in paired recordings with NPY-PLTS interneurons. In contrast, the probability of SPN innervation by NPY-neurogliaform interneurons was extremely high, the synapse very reliable (no failures were observed), and the resulting postsynaptic response was a slow, GABA(A) receptor-mediated IPSC that has not been previously described in striatum but that has been elicited from NPY-GABAergic neurogliaform interneurons in cortex and hippocampus. These properties suggest unique and distinctive roles for NPY-PLTS and NPY-neurogliaform interneurons in the integrative properties of the neostriatum.
Asunto(s)
Cuerpo Estriado/citología , Interneuronas/clasificación , Interneuronas/fisiología , Neuropéptido Y/metabolismo , Animales , Bicuculina/farmacología , Recuento de Células , Corteza Cerebral/fisiología , Estimulación Eléctrica , Antagonistas de Aminoácidos Excitadores/farmacología , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Potenciales Postsinápticos Excitadores/fisiología , Antagonistas del GABA/farmacología , Proteínas Fluorescentes Verdes/genética , Técnicas In Vitro , Potenciales Postsinápticos Inhibidores/efectos de los fármacos , Lisina/análogos & derivados , Lisina/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Factor de Crecimiento Nervioso/metabolismo , Vías Nerviosas/fisiología , Óxido Nítrico Sintasa/metabolismo , Técnicas de Placa-Clamp , Quinoxalinas/farmacología , Somatostatina/metabolismoRESUMEN
Excessive grooming of Sapap3-KO mice has been used as a model of obsessive-compulsive disorder (OCD). Previous studies suggest that dysregulation of cortico-striatal circuits is critically important in the generation of compulsive behaviors, and it has been proposed that the alteration in the activity patterns of striatal circuitry underlies the excessive grooming observed in Sapap3-KO mice. To test this hypothesis, we used in-vivo calcium imaging of individual cells to record striatal activity in these animals and optogenetic inhibition to manipulate this activity. We identified striatal neurons that are modulated during grooming behavior and found that their proportion is significantly larger in Sapap3-KO mice compared to wild-type littermates. Inhibition of striatal cells in Sapap3-KO mice increased the number of grooming episodes observed. Remarkably, the specific inhibition of indirect pathway neurons decreased the occurrence of grooming events. Our results indicate that there is striatal neural activity related to excessive grooming engagement in Sapap3-KO mice. We also demonstrate, for the first time, that specific inhibition of striatal indirect pathway neurons reduces this compulsive phenotype, suggesting that treatments that alleviate compulsive symptoms in OCD patients may exert their effects through this specific striatal population.
Asunto(s)
Proteínas del Tejido Nervioso , Optogenética , Animales , Cuerpo Estriado/metabolismo , Aseo Animal/fisiología , Humanos , Ratones , Ratones Noqueados , Proteínas del Tejido Nervioso/metabolismo , Neuronas/metabolismoRESUMEN
Whole-cell recordings were obtained from tyrosine hydroxylase-expressing (TH(+)) neurons in striatal slices from bacterial artificial chromosome transgenic mice that synthesize enhanced green fluorescent protein (EGFP) selectively in neurons expressing TH transcriptional regulatory sequences. Stereological cell counting indicated that there were approximately 2700 EGFP-TH(+) neurons/striatum. Whole-cell recordings in striatal slices demonstrated that EGFP-TH(+) neurons comprise four electrophysiologically distinct neuron types whose electrophysiological properties have not been reported previously in striatum. EGFP-TH(+) neurons were identified in retrograde tracing studies as interneurons. Recordings from synaptically connected pairs of EGFP-TH(+) interneurons and spiny neurons showed that the interneurons elicited GABAergic IPSPs/IPSCs in spiny neurons powerful enough to significantly delay evoked spiking. EGFP-TH(+) interneurons responded to local or cortical stimulation with glutamatergic EPSPs. Local stimulation also elicited GABA(A) IPSPs, at least some of which arose from identified spiny neurons. Single-cell reverse transcription-PCR showed expression of VMAT1 in EGFP-TH(+) interneurons, consistent with previous suggestions that these interneurons may be dopaminergic as well as GABAergic. All four classes of interneurons were medium sized with modestly branching, varicose dendrites, and dense, highly varicose axon collateral fields. These data show for the first time that there exists in the normal rodent striatum a substantial population of TH(+)/GABAergic interneurons comprising four electrophysiologically distinct subtypes whose electrophysiological properties differ significantly from those of previously described striatal GABAergic interneurons. These interneurons are likely to play an important role in striatal function through fast GABAergic synaptic transmission in addition to, and independent of, their potential role in compensation for dopamine loss in experimental or idiopathic Parkinson's disease.
Asunto(s)
Cuerpo Estriado/citología , Neuronas/citología , Neuronas/fisiología , Sinapsis/fisiología , Tirosina 3-Monooxigenasa/metabolismo , 6-Ciano 7-nitroquinoxalina 2,3-diona/farmacología , Potenciales de Acción/efectos de los fármacos , Potenciales de Acción/fisiología , Análisis de Varianza , Animales , Antiinflamatorios/farmacología , Bicuculina/farmacología , Bloqueadores de los Canales de Calcio/farmacología , Fármacos Cardiovasculares/farmacología , Recuento de Células/métodos , Colchicina/farmacología , Cuerpo Estriado/efectos de los fármacos , Estimulación Eléctrica/métodos , Antagonistas de Aminoácidos Excitadores/farmacología , Ácido Flufenámico/farmacología , Antagonistas del GABA/farmacología , Proteínas Fluorescentes Verdes/genética , Técnicas In Vitro , Lisina/análogos & derivados , Lisina/metabolismo , Ratones , Ratones Transgénicos , Vías Nerviosas/fisiología , Neuronas/clasificación , Nimodipina/farmacología , Técnicas de Placa-Clamp/métodos , Pirimidinas/farmacología , Transmisión Sináptica/efectos de los fármacos , Factores de Tiempo , Moduladores de Tubulina/farmacología , Tirosina 3-Monooxigenasa/genética , Proteínas de Transporte Vesicular de Monoaminas/genética , Proteínas de Transporte Vesicular de Monoaminas/metabolismoRESUMEN
Recent evidence suggests the intriguing possibility that midbrain dopaminergic (DAergic) neurons may use fast glutamatergic transmission to communicate with their postsynaptic targets. Because of technical limitations, direct demonstration of the existence of this signaling mechanism has been limited to experiments using cell culture preparations that often alter neuronal function including neurotransmitter phenotype. Consequently, it remains uncertain whether glutamatergic signaling between DAergic neurons and their postsynaptic targets exists under physiological conditions. Here, using an optogenetic approach, we provide the first conclusive demonstration that mesolimbic DAergic neurons in mice release glutamate and elicit excitatory postsynaptic responses in projection neurons of the nucleus accumbens. In addition, we describe the properties of the postsynaptic glutamatergic responses of these neurons during experimentally evoked burst firing of DAergic axons that reproduce the reward-related phasic population activity of the mesolimbic projection. These observations indicate that, in addition to DAergic mechanisms, mesolimbic reward signaling may involve glutamatergic transmission.
Asunto(s)
Dopamina/metabolismo , Ácido Glutámico/metabolismo , Neuronas/metabolismo , Núcleo Accumbens/citología , Transducción de Señal/fisiología , Animales , Dopaminérgicos/farmacología , Estimulación Eléctrica/métodos , Electroquímica/métodos , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Femenino , Técnicas de Transferencia de Gen , Técnicas In Vitro , Proteínas Luminiscentes/genética , Masculino , Ratones , Neuronas/efectos de los fármacos , Técnicas de Placa-Clamp/métodos , Estimulación Luminosa/métodos , Transducción de Señal/efectos de los fármacos , Bloqueadores de los Canales de Sodio/farmacología , Transmisión Sináptica/efectos de los fármacos , Transmisión Sináptica/fisiología , Tetrodotoxina/farmacologíaRESUMEN
Striatal activity is necessary to initiate and execute sequences of actions. The main excitatory input to the striatum comes from the cortex. While it is hypothesized that motor and premotor cortico-striatal projections are important to guide striatal activity during the execution of sequences of actions, technical limitations have made this challenging to address. Here, we implemented a task in mice that allows for the study of different moments to execute a serial order sequence consisting of two subsequences of actions. Using this task, we performed electrophysiological recordings in the premotor (M2) and primary motor (M1) cortices, and state-dependent optogenetic inhibitions of their cortico-striatal projections. We show that while both M2 and M1 contain activity modulations related to the execution of self-paced sequences, mainly, the premotor cortico-striatal projections contribute to the proper execution/structuring of these sequences.
Asunto(s)
Cuerpo Estriado , Optogenética , Animales , Corteza Cerebral , Ratones , NeostriadoRESUMEN
Recent studies have demonstrated that GABAergic synaptic transmission among neostriatal spiny projection neurons (SPNs) is strongly modulated by dopamine with individual connections exhibiting either D(1) receptor (D(1)R)-mediated facilitation or D(2) receptor (D(2)R)-mediated inhibition and, at least in some preparations, a subset of connections exhibiting both of these effects. In light of the cell type-specific expression of D(1a)R in striatonigral and D(2)R in striatopallidal neurons and the differential expression of the other D(1) and D(2) family dopamine receptors, we hypothesize that the nature of the dopaminergic modulation is specific to the types of SPNs that participate in the connection. Here the biophysical properties and dopaminergic modulation of intrastriatal connections formed by striatopallidal neurons were examined. Contrary to previous expectation, synapses formed by striatopallidal neurons were biophysically and pharmacologically heterogeneous. Two distinct types of axon collateral connections could be distinguished among striatopallidal neurons. The more common, small-amplitude connections (80%) exhibited mean IPSC amplitudes several times smaller than their less frequent large-amplitude counterparts, principally because of a smaller number of release sites involved. The two types of connections were also differentially regulated by dopamine. Small-amplitude connections exhibited strong and exclusively D(2)R-mediated presynaptic inhibition, whereas large-amplitude connections were unresponsive to dopamine. Synaptic connections from striatopallidal to striatonigral neurons exhibited exclusively D(2)R-mediated presynaptic inhibition that was similar to the regulation of small-amplitude connections between pairs of striatopallidal cells. Together, these findings demonstrate a previously unrecognized complexity in the organization and dopaminergic control of synaptic communication among SPNs.
Asunto(s)
Axones/fisiología , Dopamina/metabolismo , Globo Pálido/citología , Neostriado/citología , Neuronas/citología , Sinapsis/fisiología , Animales , Fenómenos Biofísicos/efectos de los fármacos , Fenómenos Biofísicos/genética , Biofisica , Dopamina/farmacología , Dopaminérgicos/farmacología , Estimulación Eléctrica/métodos , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/genética , Proteínas Fluorescentes Verdes/genética , Técnicas In Vitro , Potenciales Postsinápticos Inhibidores/efectos de los fármacos , Potenciales Postsinápticos Inhibidores/genética , Masculino , Ratones , Ratones Transgénicos , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Vías Nerviosas/fisiología , Neuronas/clasificación , Técnicas de Placa-Clamp/métodos , Receptores de Dopamina D2/genética , Estadísticas no ParamétricasRESUMEN
The striatal cholinergic system is key in detecting changes in instrumental contingencies. While recent evidence supports this vision, cell type-specific online control on the activity of the cholinergic striatal neurons is necessary to empirically test it. In this study, we performed optogenetic manipulations of the activity of striatal cholinergic interneurons (CINs) to evaluate their contribution to the updating of a previously learned instrumental contingency. By modulating the activity of CINs, we identified that the inhibition of CINs impairs the update of actions to a contingency change. Remarkably, a manipulation that perturbs the activity of CINs, rather than inhibiting them also impaired the encoding of the change in contingency. These results emphasize that beyond an increase in the activity of CINs, the intact activity of these cells is required for the identification of an instrumental contingency change.
Asunto(s)
Cuerpo Estriado , Interneuronas , Colinérgicos , Neuronas Colinérgicas , NeostriadoRESUMEN
Findings have shown that anterior insular cortex (aIC) lesions disrupt the maintenance of drug addiction, while imaging studies suggest that connections between amygdala and aIC participate in drug-seeking. However, the role of the BLA â aIC pathway in rewarding contextual memory has not been assessed. Using a cre-recombinase under the tyrosine hydroxylase (TH+) promoter mouse model to induce a real-time conditioned place preference (rtCPP), we show that photoactivation of TH+ neurons induced electrophysiological responses in VTA neurons, dopamine release and neuronal modulation in the aIC. Conversely, memory retrieval induced a strong release of glutamate, dopamine, and norepinephrine in the aIC. Only intra-aIC blockade of the glutamatergic N-methyl-D-aspartate receptor accelerated rtCPP extinction. Finally, photoinhibition of glutamatergic BLA â aIC pathway produced disinhibition of local circuits in the aIC, accelerating rtCPP extinction and impairing reinstatement. Thus, activity of the glutamatergic projection from the BLA to the aIC is critical for maintenance of rewarding contextual memory.
Asunto(s)
Complejo Nuclear Basolateral/metabolismo , Conducta Animal , Corteza Cerebral/metabolismo , Ácido Glutámico/metabolismo , Memoria , Vías Nerviosas/metabolismo , Recompensa , Neuronas Adrenérgicas/metabolismo , Animales , Complejo Nuclear Basolateral/citología , Corteza Cerebral/citología , Condicionamiento Psicológico , Dopamina/metabolismo , Neuronas Dopaminérgicas/metabolismo , Extinción Psicológica , Femenino , Integrasas/genética , Integrasas/metabolismo , Masculino , Ratones Endogámicos C57BL , Ratones Transgénicos , Inhibición Neural , Vías Nerviosas/citología , Norepinefrina/metabolismo , Tirosina 3-Monooxigenasa/genéticaRESUMEN
Medium spiny projection neurons (MSNs) are the main neuronal population in the neostriatum. MSNs are inhibitory and GABAergic. MSNs connect with other MSNs via local axon collaterals that produce lateral inhibition, which is thought to select cell assemblies for motor action. MSNs also receive inhibitory inputs from GABAergic local interneurons. This work shows, through the use of the paired pulse protocol, that somatostatin (SST) acts presynaptically to regulate GABA release from the terminals interconnecting MSNs. This SST action is reversible and not mediated through the release of dopamine. It is blocked by the SST receptor (SSTR) antagonist ciclosomatostatin (cicloSST). In contrast, SST does not regulate inhibition coming from interneurons. Because, SST is released by a class of local interneuron, it is concluded that this neuron helps to regulate the selection of motor acts.
Asunto(s)
Cuerpo Estriado/metabolismo , Potenciales Postsinápticos Inhibidores/fisiología , Neuronas/metabolismo , Terminales Presinápticos/metabolismo , Somatostatina/metabolismo , 6-Ciano 7-nitroquinoxalina 2,3-diona/metabolismo , Potenciales de Acción/fisiología , Animales , Cuerpo Estriado/citología , Agonistas de Aminoácidos Excitadores/metabolismo , Antagonistas de Aminoácidos Excitadores/metabolismo , N-Metilaspartato/metabolismo , Neuronas/citología , Técnicas de Placa-Clamp , Ratas , Ratas Wistar , Valina/análogos & derivados , Valina/metabolismo , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico/metabolismoRESUMEN
The dopaminergic neurons of the ventral tegmental area (VTA) have been identified with the ability to co-release dopamine and glutamate. This ability was first documented in the nucleus accumbens but showed to be absent in the dorsal striatum. Recently the ability to release glutamate from a subpopulation of the VTA dopaminergic neurons has been shown to control the prefrontal cortex (PFC) excitation through the exclusive innervation of GABAergic fast spiking interneurons. Here, using an optogenetic approach, we expand this view by presenting that the VTA dopaminergic neurons do not only innervate interneurons but also pyramidal PFC neurons. This finding opens the range of possibilities for the VTA dopaminergic neurons to modulate the activity of PFC.
Asunto(s)
Neuronas Dopaminérgicas/metabolismo , Ácido Glutámico/metabolismo , Mesencéfalo/metabolismo , Corteza Prefrontal/metabolismo , Transducción de Señal/fisiología , Animales , Neuronas Dopaminérgicas/química , Femenino , Masculino , Mesencéfalo/química , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Optogenética/métodos , Técnicas de Cultivo de Órganos , Corteza Prefrontal/químicaRESUMEN
One of the main inputs driving striatal activity is the thalamostriatal projection. While the hypothesis postulating that the different thalamostriatal projections contribute differentially to shape the functions of the striatum is largely accepted, existing technical limitations have hampered efforts to prove it. Here, through the use of electrophysiological recordings of antidromically photo-identified thalamostriatal neurons and the optogenetic inhibition of thalamostriatal terminals, we identify that the thalamostriatal projections from the parafascicular and the ventroposterior regions of the thalamus contribute to the smooth initiation and the appropriate execution of a sequence of movements. Our results support a model in which both thalamostriatal projections have specific contributions to the initiation and execution of sequences, highlighting the specific contribution of the ventroposterior thalamostriatal connection for the repetition of actions.
Asunto(s)
Cuerpo Estriado/fisiología , Intención , Movimiento/fisiología , Red Nerviosa/fisiología , Tálamo/fisiología , Animales , Cuerpo Estriado/química , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Red Nerviosa/química , Optogenética/métodos , Tálamo/químicaRESUMEN
Our original review, "Heterogeneity and Diversity of Striatal GABAergic Interneurons," to which this is an invited update, was published in December, 2010 in Frontiers is Neuroanatomy. In that article, we reviewed several decades' worth of anatomical and electrophysiological data on striatal parvalbumin (PV)-, neuropeptide Y (NPY)- and calretinin(CR)-expressing GABAergic interneurons from many laboratories including our own. In addition, we reported on a recently discovered novel tyrosine hydroxylase (TH) expressing GABAergic interneuron class first revealed in transgenic TH EGFP reporter mouse line. In this review, we report on further advances in the understanding of the functional properties of previously reported striatal GABAergic interneurons and their synaptic connections. With the application of new transgenic fluorescent reporter and Cre-driver/reporter lines, plus optogenetic, chemogenetic and viral transduction methods, several additional subtypes of novel striatal GABAergic interneurons have been discovered, as well as the synaptic networks in which they are embedded. These findings make it clear that previous hypotheses in which striatal GABAergic interneurons modulate and/or control the firing of spiny neurons principally by simple feedforward and/or feedback inhibition are at best incomplete. A more accurate picture is one in which there are highly selective and specific afferent inputs, synaptic connections between different interneuron subtypes and spiny neurons and among different GABAergic interneurons that result in the formation of functional networks and ensembles of spiny neurons.
RESUMEN
The basal ganglia, and the striatum in particular, are critical for action reinforcement [1,2]. The dorsal striatum, which can be further subdivided into dorsomedial (DMS) and dorsolateral (DLS) striatum, is mainly composed of two subpopulations of striatal medium spiny projection neurons (MSNs): dopamine D1 receptor-expressing MSNs that constitute the striatonigral or direct pathway (dMSNs); and dopamine D2 receptor-expressing MSNs that constitute the striatopallidal or indirect pathway (iMSNs) [3]. It has been suggested that each pathway has opposing roles in reinforcement, with dMSNs being important to learn positive reinforcement and iMSNs to learn to avoid undesired actions (Go/No-Go) [1]. Furthermore, optogenetic self-stimulation of dMSNs in DMS leads to reinforcement of actions, while self-stimulation of iMSNs leads to avoidance of actions [2]. However, in DLS, which has been implicated in the consolidation of well-trained actions and habits in mice [4,5], both pathways are active during lever-pressing for reward [6]. Furthermore, extensive skill training leads to long-lasting potentiation of glutamatergic inputs into both dMSNs and iMSNs [4]. We report here that, in DLS, both dMSNs and iMSNs are involved in positive reinforcement, but support different action strategies.
Asunto(s)
Ganglios Basales/citología , Ganglios Basales/fisiología , Neuronas/citología , Animales , Channelrhodopsins , Integrasas/genética , Ratones , Vías Nerviosas , OptogenéticaRESUMEN
Chunking allows the brain to efficiently organize memories and actions. Although basal ganglia circuits have been implicated in action chunking, little is known about how individual elements are concatenated into a behavioral sequence at the neural level. Using a task in which mice learned rapid action sequences, we uncovered neuronal activity encoding entire sequences as single actions in basal ganglia circuits. In addition to neurons with activity related to the start/stop activity signaling sequence parsing, we found neurons displaying inhibited or sustained activity throughout the execution of an entire sequence. This sustained activity covaried with the rate of execution of individual sequence elements, consistent with motor concatenation. Direct and indirect pathways of basal ganglia were concomitantly active during sequence initiation, but behaved differently during sequence performance, revealing a more complex functional organization of these circuits than previously postulated. These results have important implications for understanding the functional organization of basal ganglia during the learning and execution of action sequences.
Asunto(s)
Ganglios Basales/fisiología , Aprendizaje/fisiología , Neuronas/fisiología , Desempeño Psicomotor/fisiología , Animales , Ganglios Basales/citología , Ganglios Basales/cirugía , Conducta Animal/fisiología , Electrodos Implantados , Femenino , Globo Pálido/citología , Globo Pálido/fisiología , Globo Pálido/cirugía , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas del Tejido Nervioso/genética , Vías Nerviosas/citología , Vías Nerviosas/fisiología , Neuronas/citología , Receptores de N-Metil-D-Aspartato/genética , Sustancia Negra/citología , Sustancia Negra/fisiología , Sustancia Negra/cirugía , Factores de TiempoRESUMEN
The basal ganglia, and the striatum in particular, have been implicated in the generation of contraversive movements. The striatum projects to downstream basal ganglia nuclei through two main circuits, originating in striatonigral and striatopallidal neurons, and different models postulate that the two pathways can work in opposition or synergistically. Here we show striatonigral and striatopallidal neurons are concurrently active during spontaneous contraversive movements. Furthermore, we show that unilateral optogenetic inhibition of either or both projection pathways disrupts contraversive movements. Consistently, simultaneous activation of both neuron types produces contraversive movements. Still, we also show that imbalanced activity between the pathways can result in opposing movements being driven by each projection pathway. These data show that balanced activity in both striatal projection pathways is critical for the generation of contraversive movements and highlights that imbalanced activity between the two projection pathways can result in opposing motor output.