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1.
eNeuro ; 8(4)2021.
Artículo en Inglés | MEDLINE | ID: mdl-34348983

RESUMEN

Animals precisely coordinate their left and right limbs for various adaptive purposes. While the left and right limbs are clearly controlled by different cortical hemispheres, the neural mechanisms that determine the action sequence between them remains elusive. Here, we have established a novel head-fixed bimanual-press (biPress) sequence task in which mice sequentially press left and right pedals with their forelimbs in a predetermined order. Using this motor task, we found that the motor cortical neurons responsible for the first press (1P) also generate independent motor signals for the second press (2P) by the opposite forelimb during the movement transitions between forelimbs. Projection-specific calcium imaging and optogenetic manipulation revealed these motor signals are transferred from one motor cortical hemisphere to the other via corticocortical projections. Together, our results suggest the motor cortices coordinate sequential bimanual movements through corticocortical pathways.


Asunto(s)
Lateralidad Funcional , Corteza Motora , Animales , Miembro Anterior , Ratones , Movimiento , Desempeño Psicomotor
2.
Neuron ; 109(13): 2165-2182.e10, 2021 07 07.
Artículo en Inglés | MEDLINE | ID: mdl-34048697

RESUMEN

Drugs of abuse induce persistent remodeling of reward circuit function, a process thought to underlie the emergence of drug craving and relapse to drug use. However, how circuit-specific, drug-induced molecular and cellular plasticity can have distributed effects on the mesolimbic dopamine reward system to facilitate relapse to drug use is not fully elucidated. Here, we demonstrate that dopamine receptor D3 (DRD3)-dependent plasticity in the ventral pallidum (VP) drives potentiation of dopamine release in the nucleus accumbens during relapse to cocaine seeking after abstinence. We show that two distinct VP DRD3+ neuronal populations projecting to either the lateral habenula (LHb) or the ventral tegmental area (VTA) display different patterns of activity during drug seeking following abstinence from cocaine self-administration and that selective suppression of elevated activity or DRD3 signaling in the LHb-projecting population reduces drug seeking. Together, our results uncover how circuit-specific DRD3-mediated plasticity contributes to the process of drug relapse.


Asunto(s)
Prosencéfalo Basal/fisiología , Cocaína/administración & dosificación , Dopamina/fisiología , Comportamiento de Búsqueda de Drogas/fisiología , Habénula/fisiología , Neuronas/fisiología , Núcleo Accumbens/fisiología , Receptores de Dopamina D3/fisiología , Animales , Femenino , Masculino , Ratones Endogámicos C57BL , Ratones Transgénicos , Recompensa , Área Tegmental Ventral/fisiología
3.
Nat Neurosci ; 24(4): 504-515, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33723433

RESUMEN

The basal ganglia regulate a wide range of behaviors, including motor control and cognitive functions, and are profoundly affected in Parkinson's disease (PD). However, the functional organization of different basal ganglia nuclei has not been fully elucidated at the circuit level. In this study, we investigated the functional roles of distinct parvalbumin-expressing neuronal populations in the external globus pallidus (GPe-PV) and their contributions to different PD-related behaviors. We demonstrate that substantia nigra pars reticulata (SNr)-projecting GPe-PV neurons and parafascicular thalamus (PF)-projecting GPe-PV neurons are associated with locomotion and reversal learning, respectively. In a mouse model of PD, we found that selective manipulation of the SNr-projecting GPe-PV neurons alleviated locomotor deficit, whereas manipulation of the PF-projecting GPe-PV neurons rescued the impaired reversal learning. Our findings establish the behavioral importance of two distinct GPe-PV neuronal populations and, thereby, provide a new framework for understanding the circuit basis of different behavioral deficits in the Parkinsonian state.


Asunto(s)
Globo Pálido/fisiopatología , Vías Nerviosas/fisiopatología , Neuronas/fisiología , Trastornos Parkinsonianos/fisiopatología , Animales , Femenino , Trastornos Neurológicos de la Marcha/fisiopatología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Parvalbúminas , Aprendizaje Inverso/fisiología
4.
Neuron ; 104(6): 1126-1140.e6, 2019 12 18.
Artículo en Inglés | MEDLINE | ID: mdl-31706697

RESUMEN

The posterior parietal cortex (PPC) performs many functions, including decision making and movement control. It remains unknown which input and output pathways of PPC support different functions. We addressed this issue in mice, focusing on PPC neurons projecting to the dorsal striatum (PPC-STR) and the posterior secondary motor cortex (PPC-pM2). Projection-specific, retrograde labeling showed that PPC-STR and PPC-pM2 represent largely distinct subpopulations, with PPC-STR receiving stronger inputs from association areas and PPC-pM2 receiving stronger sensorimotor inputs. Two-photon calcium imaging during decision making revealed that the PPC-STR population encodes history-dependent choice bias more strongly than PPC-pM2 or general PPC populations. Furthermore, optogenetic inactivation of PPC-STR neurons or their terminals in STR decreased history-dependent bias, while inactivation of PPC-pM2 neurons altered movement kinematics. Therefore, PPC biases action selection through its STR projection while controlling movements through PPC-pM2 neurons. PPC may support multiple functions through parallel subpopulations, each with distinct input-output connectivity.


Asunto(s)
Toma de Decisiones/fisiología , Movimiento/fisiología , Vías Nerviosas/fisiología , Lóbulo Parietal/fisiología , Animales , Cuerpo Estriado/fisiología , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Corteza Motora/fisiología
5.
Nat Neurosci ; 21(9): 1229-1238, 2018 09.
Artículo en Inglés | MEDLINE | ID: mdl-30104734

RESUMEN

Voluntary urination ensures that waste is eliminated when safe and socially appropriate, even without a pressing urge. Uncontrolled urination, or incontinence, is a common problem with few treatment options. Normal urine release requires a small region in the brainstem known as Barrington's nucleus (Bar), but specific neurons that relax the urethral sphincter and enable urine flow are unknown. Here we identify a small subset of Bar neurons that control the urethral sphincter in mice. These excitatory neurons express estrogen receptor 1 (BarESR1), project to sphincter-relaxing interneurons in the spinal cord and are active during natural urination. Optogenetic stimulation of BarESR1 neurons rapidly initiates sphincter bursting and efficient voiding in anesthetized and behaving animals. Conversely, optogenetic and chemogenetic inhibition reveals their necessity in motivated urination behavior. The identification of these cells provides an expanded model for the control of urination and its dysfunction.


Asunto(s)
Tronco Encefálico/fisiología , Neuronas/fisiología , Uretra/inervación , Uretra/fisiología , Micción/fisiología , Animales , Tronco Encefálico/citología , Electromiografía , Receptor alfa de Estrógeno/genética , Receptor alfa de Estrógeno/fisiología , Masculino , Ratones , Vías Nerviosas/fisiología , Odorantes , Optogenética , Trastornos Urinarios/genética , Trastornos Urinarios/fisiopatología
6.
Cell ; 170(2): 284-297.e18, 2017 Jul 13.
Artículo en Inglés | MEDLINE | ID: mdl-28689640

RESUMEN

Major depressive disorder (MDD) patients display a common but often variable set of symptoms making successful, sustained treatment difficult to achieve. Separate depressive symptoms may be encoded by differential changes in distinct circuits in the brain, yet how discrete circuits underlie behavioral subsets of depression and how they adapt in response to stress has not been addressed. We identify two discrete circuits of parvalbumin-positive (PV) neurons in the ventral pallidum (VP) projecting to either the lateral habenula or ventral tegmental area contributing to depression. We find that these populations undergo different electrophysiological adaptations in response to social defeat stress, which are normalized by antidepressant treatment. Furthermore, manipulation of each population mediates either social withdrawal or behavioral despair, but not both. We propose that distinct components of the VP PV circuit can subserve related, yet separate depressive-like phenotypes in mice, which could ultimately provide a platform for symptom-specific treatments of depression.


Asunto(s)
Prosencéfalo Basal/fisiopatología , Depresión/patología , Neuronas/patología , Animales , Reacción de Prevención , Prosencéfalo Basal/patología , Depresión/fisiopatología , Trastorno Depresivo Mayor/patología , Trastorno Depresivo Mayor/fisiopatología , Femenino , Técnicas In Vitro , Masculino , Mesencéfalo/metabolismo , Mesencéfalo/patología , Ratones , Ratones Endogámicos C57BL , Neuronas/citología , Parvalbúminas/metabolismo
7.
Brain ; 139(Pt 2): 468-80, 2016 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-26685158

RESUMEN

Ischaemic stroke is the leading cause of severe long-term disability yet lacks drug therapies that promote the repair phase of recovery. This repair phase of stroke occurs days to months after stroke onset and involves brain remapping and plasticity within the peri-infarct zone. Elucidating mechanisms that promote this plasticity is critical for the development of new therapeutics with a broad treatment window. Inhibiting tonic (extrasynaptic) GABA signalling during the repair phase was reported to enhance functional recovery in mice suggesting that GABA plays an important function in modulating brain repair. While tonic GABA appears to suppress brain repair after stroke, less is known about the role of phasic (synaptic) GABA during the repair phase. We observed an increase in postsynaptic phasic GABA signalling in mice within the peri-infarct cortex specific to layer 5; we found increased numbers of α1 receptor subunit-containing GABAergic synapses detected using array tomography, and an associated increased efficacy of spontaneous and miniature inhibitory postsynaptic currents in pyramidal neurons. Furthermore, we demonstrate that enhancing phasic GABA signalling using zolpidem, a Food and Drug Administration (FDA)-approved GABA-positive allosteric modulator, during the repair phase improved behavioural recovery. These data identify potentiation of phasic GABA signalling as a novel therapeutic strategy, indicate zolpidem's potential to improve recovery, and underscore the necessity to distinguish the role of tonic and phasic GABA signalling in stroke recovery.


Asunto(s)
Sistemas de Liberación de Medicamentos , Agonistas de Receptores de GABA-A/administración & dosificación , Inhibición Neural/fisiología , Piridinas/administración & dosificación , Receptores de GABA-A/fisiología , Accidente Cerebrovascular/tratamiento farmacológico , Animales , Sistemas de Liberación de Medicamentos/tendencias , Masculino , Ratones , Ratones Endogámicos C57BL , Neocórtex/efectos de los fármacos , Neocórtex/fisiología , Inhibición Neural/efectos de los fármacos , Técnicas de Cultivo de Órganos , Recuperación de la Función/efectos de los fármacos , Recuperación de la Función/fisiología , Accidente Cerebrovascular/patología , Accidente Cerebrovascular/fisiopatología , Zolpidem
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