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1.
Cell ; 184(14): 3731-3747.e21, 2021 07 08.
Artículo en Inglés | MEDLINE | ID: mdl-34214470

RESUMEN

In motor neuroscience, state changes are hypothesized to time-lock neural assemblies coordinating complex movements, but evidence for this remains slender. We tested whether a discrete change from more autonomous to coherent spiking underlies skilled movement by imaging cerebellar Purkinje neuron complex spikes in mice making targeted forelimb-reaches. As mice learned the task, millimeter-scale spatiotemporally coherent spiking emerged ipsilateral to the reaching forelimb, and consistent neural synchronization became predictive of kinematic stereotypy. Before reach onset, spiking switched from more disordered to internally time-locked concerted spiking and silence. Optogenetic manipulations of cerebellar feedback to the inferior olive bi-directionally modulated neural synchronization and reaching direction. A simple model explained the reorganization of spiking during reaching as reflecting a discrete bifurcation in olivary network dynamics. These findings argue that to prepare learned movements, olivo-cerebellar circuits enter a self-regulated, synchronized state promoting motor coordination. State changes facilitating behavioral transitions may generalize across neural systems.


Asunto(s)
Movimiento/fisiología , Red Nerviosa/fisiología , Potenciales de Acción/fisiología , Animales , Calcio/metabolismo , Cerebelo/fisiología , Sincronización Cortical , Miembro Anterior/fisiología , Interneuronas/fisiología , Aprendizaje , Ratones Endogámicos C57BL , Ratones Transgénicos , Modelos Neurológicos , Actividad Motora/fisiología , Núcleo Olivar/fisiología , Optogenética , Células de Purkinje/fisiología , Conducta Estereotipada , Análisis y Desempeño de Tareas
2.
Cell ; 184(1): 243-256.e18, 2021 01 07.
Artículo en Inglés | MEDLINE | ID: mdl-33417861

RESUMEN

Craniosynostosis results from premature fusion of the cranial suture(s), which contain mesenchymal stem cells (MSCs) that are crucial for calvarial expansion in coordination with brain growth. Infants with craniosynostosis have skull dysmorphology, increased intracranial pressure, and complications such as neurocognitive impairment that compromise quality of life. Animal models recapitulating these phenotypes are lacking, hampering development of urgently needed innovative therapies. Here, we show that Twist1+/- mice with craniosynostosis have increased intracranial pressure and neurocognitive behavioral abnormalities, recapitulating features of human Saethre-Chotzen syndrome. Using a biodegradable material combined with MSCs, we successfully regenerated a functional cranial suture that corrects skull deformity, normalizes intracranial pressure, and rescues neurocognitive behavior deficits. The regenerated suture creates a niche into which endogenous MSCs migrated, sustaining calvarial bone homeostasis and repair. MSC-based cranial suture regeneration offers a paradigm shift in treatment to reverse skull and neurocognitive abnormalities in this devastating disease.


Asunto(s)
Cognición/fisiología , Suturas Craneales/fisiopatología , Craneosinostosis/fisiopatología , Regeneración/fisiología , Cráneo/fisiopatología , Animales , Conducta Animal/efectos de los fármacos , Cognición/efectos de los fármacos , Craneosinostosis/genética , Duramadre/patología , Duramadre/fisiopatología , Gelatina/farmacología , Perfilación de la Expresión Génica , Fuerza de la Mano , Presión Intracraneal/efectos de los fármacos , Presión Intracraneal/fisiología , Locomoción/efectos de los fármacos , Células Madre Mesenquimatosas/efectos de los fármacos , Metacrilatos/farmacología , Ratones Endogámicos C57BL , Actividad Motora/efectos de los fármacos , Tamaño de los Órganos/efectos de los fármacos , Regeneración/efectos de los fármacos , Cráneo/patología , Proteína 1 Relacionada con Twist/metabolismo , Vía de Señalización Wnt/efectos de los fármacos
3.
Cell ; 180(3): 536-551.e17, 2020 02 06.
Artículo en Inglés | MEDLINE | ID: mdl-31955849

RESUMEN

Goal-directed behavior requires the interaction of multiple brain regions. How these regions and their interactions with brain-wide activity drive action selection is less understood. We have investigated this question by combining whole-brain volumetric calcium imaging using light-field microscopy and an operant-conditioning task in larval zebrafish. We find global, recurring dynamics of brain states to exhibit pre-motor bifurcations toward mutually exclusive decision outcomes. These dynamics arise from a distributed network displaying trial-by-trial functional connectivity changes, especially between cerebellum and habenula, which correlate with decision outcome. Within this network the cerebellum shows particularly strong and predictive pre-motor activity (>10 s before movement initiation), mainly within the granule cells. Turn directions are determined by the difference neuroactivity between the ipsilateral and contralateral hemispheres, while the rate of bi-hemispheric population ramping quantitatively predicts decision time on the trial-by-trial level. Our results highlight a cognitive role of the cerebellum and its importance in motor planning.


Asunto(s)
Cerebelo/fisiología , Toma de Decisiones/fisiología , Tiempo de Reacción/fisiología , Pez Cebra/fisiología , Animales , Conducta Animal/fisiología , Mapeo Encefálico/métodos , Cerebro/fisiología , Cognición/fisiología , Condicionamiento Operante/fisiología , Objetivos , Habénula/fisiología , Calor , Larva/fisiología , Actividad Motora/fisiología , Movimiento , Neuronas/fisiología , Desempeño Psicomotor/fisiología , Rombencéfalo/fisiología
4.
Cell ; 164(3): 526-37, 2016 Jan 28.
Artículo en Inglés | MEDLINE | ID: mdl-26824660

RESUMEN

The basal ganglia (BG) are critical for adaptive motor control, but the circuit principles underlying their pathway-specific modulation of target regions are not well understood. Here, we dissect the mechanisms underlying BG direct and indirect pathway-mediated control of the mesencephalic locomotor region (MLR), a brainstem target of BG that is critical for locomotion. We optogenetically dissect the locomotor function of the three neurochemically distinct cell types within the MLR: glutamatergic, GABAergic, and cholinergic neurons. We find that the glutamatergic subpopulation encodes locomotor state and speed, is necessary and sufficient for locomotion, and is selectively innervated by BG. We further show activation and suppression, respectively, of MLR glutamatergic neurons by direct and indirect pathways, which is required for bidirectional control of locomotion by BG circuits. These findings provide a fundamental understanding of how BG can initiate or suppress a motor program through cell-type-specific regulation of neurons linked to specific actions.


Asunto(s)
Ganglios Basales/fisiología , Mapeo Encefálico , Mesencéfalo/citología , Actividad Motora , Vías Nerviosas , Animales , Neuronas GABAérgicas/citología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Neuronas/fisiología , Optogenética
5.
Cell ; 160(3): 503-15, 2015 Jan 29.
Artículo en Inglés | MEDLINE | ID: mdl-25635458

RESUMEN

Sensory circuits in the dorsal spinal cord integrate and transmit multiple cutaneous sensory modalities including the sense of light touch. Here, we identify a population of excitatory interneurons (INs) in the dorsal horn that are important for transmitting innocuous light touch sensation. These neurons express the ROR alpha (RORα) nuclear orphan receptor and are selectively innervated by cutaneous low threshold mechanoreceptors (LTMs). Targeted removal of RORα INs in the dorsal spinal cord leads to a marked reduction in behavioral responsiveness to light touch without affecting responses to noxious and itch stimuli. RORα IN-deficient mice also display a selective deficit in corrective foot movements. This phenotype, together with our demonstration that the RORα INs are innervated by corticospinal and vestibulospinal projection neurons, argues that the RORα INs direct corrective reflex movements by integrating touch information with descending motor commands from the cortex and cerebellum.


Asunto(s)
Mecanotransducción Celular , Vías Nerviosas , Asta Dorsal de la Médula Espinal/metabolismo , Tacto , Animales , Interneuronas/metabolismo , Ratones , Actividad Motora , Neuronas Motoras/metabolismo , Miembro 1 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Asta Dorsal de la Médula Espinal/citología , Sinapsis
6.
Annu Rev Cell Dev Biol ; 31: 669-98, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26393773

RESUMEN

Control of movement is a fundamental and complex task of the vertebrate nervous system, which relies on communication between circuits distributed throughout the brain and spinal cord. Many of the networks essential for the execution of basic locomotor behaviors are composed of discrete neuronal populations residing within the spinal cord. The organization and connectivity of these circuits is established through programs that generate functionally diverse neuronal subtypes, each contributing to a specific facet of motor output. Significant progress has been made in deciphering how neuronal subtypes are specified and in delineating the guidance and synaptic specificity determinants at the core of motor circuit assembly. Recent studies have shed light on the basic principles linking locomotor circuit connectivity with function, and they are beginning to reveal how more sophisticated motor behaviors are encoded. In this review, we discuss the impact of developmental programs in specifying motor behaviors governed by spinal circuits.


Asunto(s)
Actividad Motora/fisiología , Red Nerviosa/fisiología , Médula Espinal/fisiología , Animales
7.
Annu Rev Neurosci ; 42: 459-483, 2019 07 08.
Artículo en Inglés | MEDLINE | ID: mdl-31018098

RESUMEN

Deciding what to do and when to move is vital to our survival. Clinical and fundamental studies have identified basal ganglia circuits as critical for this process. The main input nucleus of the basal ganglia, the striatum, receives inputs from frontal, sensory, and motor cortices and interconnected thalamic areas that provide information about potential goals, context, and actions and directly or indirectly modulates basal ganglia outputs. The striatum also receives dopaminergic inputs that can signal reward prediction errors and also behavioral transitions and movement initiation. Here we review studies and models of how direct and indirect pathways can modulate basal ganglia outputs to facilitate movement initiation, and we discuss the role of cortical and dopaminergic inputs to the striatum in determining what to do and if and when to do it. Complex but exciting scenarios emerge that shed new light on how basal ganglia circuits modulate self-paced movement initiation.


Asunto(s)
Ganglios Basales/fisiología , Cognición/fisiología , Movimiento/fisiología , Vías Nerviosas/fisiología , Animales , Humanos , Actividad Motora/fisiología , Recompensa
8.
PLoS Biol ; 22(4): e3002572, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38603542

RESUMEN

The circadian clock controls behavior and metabolism in various organisms. However, the exact timing and strength of rhythmic phenotypes can vary significantly between individuals of the same species. This is highly relevant for rhythmically complex marine environments where organismal rhythmic diversity likely permits the occupation of different microenvironments. When investigating circadian locomotor behavior of Platynereis dumerilii, a model system for marine molecular chronobiology, we found strain-specific, high variability between individual worms. The individual patterns were maintained for several weeks. A diel head transcriptome comparison of behaviorally rhythmic versus arrhythmic wild-type worms showed that 24-h cycling of core circadian clock transcripts is identical between both behavioral phenotypes. While behaviorally arrhythmic worms showed a similar total number of cycling transcripts compared to their behaviorally rhythmic counterparts, the annotation categories of their transcripts, however, differed substantially. Consistent with their locomotor phenotype, behaviorally rhythmic worms exhibit an enrichment of cycling transcripts related to neuronal/behavioral processes. In contrast, behaviorally arrhythmic worms showed significantly increased diel cycling for metabolism- and physiology-related transcripts. The prominent role of the neuropeptide pigment-dispersing factor (PDF) in Drosophila circadian behavior prompted us to test for a possible functional involvement of Platynereis pdf. Differing from its role in Drosophila, loss of pdf impacts overall activity levels but shows only indirect effects on rhythmicity. Our results show that individuals arrhythmic in a given process can show increased rhythmicity in others. Across the Platynereis population, rhythmic phenotypes exist as a continuum, with no distinct "boundaries" between rhythmicity and arrhythmicity. We suggest that such diel rhythm breadth is an important biodiversity resource enabling the species to quickly adapt to heterogeneous or changing marine environments. In times of massive sequencing, our work also emphasizes the importance of time series and functional tests.


Asunto(s)
Relojes Circadianos , Proteínas de Drosophila , Humanos , Animales , Proteínas de Drosophila/metabolismo , Ritmo Circadiano/genética , Drosophila/metabolismo , Relojes Circadianos/genética , Actividad Motora , Drosophila melanogaster/metabolismo
9.
Annu Rev Neurosci ; 41: 25-40, 2018 07 08.
Artículo en Inglés | MEDLINE | ID: mdl-29490196

RESUMEN

The development of advanced noninvasive techniques to image the human brain has enabled the demonstration of structural plasticity during adulthood in response to motor learning. Understanding the basic mechanisms of structural plasticity in the context of motor learning is essential to improve motor rehabilitation in stroke patients. Here, we review and discuss the emerging evidence for motor-learning-related structural plasticity and the implications for stroke rehabilitation. In the clinical context, a few studies have started to assess the effects of rehabilitation on structural measures to understand recovery poststroke and additionally to predict intervention outcomes. Structural imaging will likely have a role in the future in providing measures that inform patient stratification for optimal outcomes.


Asunto(s)
Encéfalo/patología , Aprendizaje/fisiología , Actividad Motora/fisiología , Plasticidad Neuronal/fisiología , Rehabilitación de Accidente Cerebrovascular/métodos , Accidente Cerebrovascular , Encéfalo/diagnóstico por imagen , Humanos , Imagen por Resonancia Magnética , Accidente Cerebrovascular/diagnóstico por imagen , Accidente Cerebrovascular/patología
10.
Nat Methods ; 20(11): 1802-1809, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-37857906

RESUMEN

We develop soft and stretchable fatigue-resistant hydrogel optical fibers that enable optogenetic modulation of peripheral nerves in naturally behaving animals during persistent locomotion. The formation of polymeric nanocrystalline domains within the hydrogels yields fibers with low optical losses of 1.07 dB cm-1, Young's modulus of 1.6 MPa, stretchability of 200% and fatigue strength of 1.4 MPa against 30,000 stretch cycles. The hydrogel fibers permitted light delivery to the sciatic nerve, optogenetically activating hindlimb muscles in Thy1::ChR2 mice during 6-week voluntary wheel running assays while experiencing repeated deformation. The fibers additionally enabled optical inhibition of pain hypersensitivity in an inflammatory model in TRPV1::NpHR mice over an 8-week period. Our hydrogel fibers offer a motion-adaptable and robust solution to peripheral nerve optogenetics, facilitating the investigation of somatosensation.


Asunto(s)
Fibras Ópticas , Optogenética , Ratones , Animales , Hidrogeles , Actividad Motora , Nervio Ciático/fisiología , Locomoción
11.
Immunity ; 46(6): 1030-1044.e8, 2017 06 20.
Artículo en Inglés | MEDLINE | ID: mdl-28636953

RESUMEN

Microglia seed the embryonic neuro-epithelium, expand and actively sculpt neuronal circuits in the developing central nervous system, but eventually adopt relative quiescence and ramified morphology in the adult. Here, we probed the impact of post-transcriptional control by microRNAs (miRNAs) on microglial performance during development and adulthood by generating mice lacking microglial Dicer expression at these distinct stages. Conditional Dicer ablation in adult microglia revealed that miRNAs were required to limit microglial responses to challenge. After peripheral endotoxin exposure, Dicer-deficient microglia expressed more pro-inflammatory cytokines than wild-type microglia and thereby compromised hippocampal neuronal functions. In contrast, prenatal Dicer ablation resulted in spontaneous microglia activation and revealed a role for Dicer in DNA repair and preservation of genome integrity. Accordingly, Dicer deficiency rendered otherwise radio-resistant microglia sensitive to gamma irradiation. Collectively, the differential impact of the Dicer ablation on microglia of the developing and adult brain highlights the changes these cells undergo with time.


Asunto(s)
Hipocampo/metabolismo , MicroARNs/genética , Microglía/fisiología , Neuronas/fisiología , Ribonucleasa III/metabolismo , Animales , Animales Recién Nacidos , Células Cultivadas , Reparación del ADN , Femenino , Hipocampo/embriología , Hipocampo/crecimiento & desarrollo , Humanos , Imagenología Tridimensional , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , MicroARNs/metabolismo , Actividad Motora , Plasticidad Neuronal , Ribonucleasa III/genética
12.
Cell ; 147(4): 922-33, 2011 Nov 11.
Artículo en Inglés | MEDLINE | ID: mdl-22078887

RESUMEN

C. elegans is widely used to dissect how neural circuits and genes generate behavior. During locomotion, worms initiate backward movement to change locomotion direction spontaneously or in response to sensory cues; however, the underlying neural circuits are not well defined. We applied a multidisciplinary approach to map neural circuits in freely behaving worms by integrating functional imaging, optogenetic interrogation, genetic manipulation, laser ablation, and electrophysiology. We found that a disinhibitory circuit and a stimulatory circuit together promote initiation of backward movement and that circuitry dynamics is differentially regulated by sensory cues. Both circuits require glutamatergic transmission but depend on distinct glutamate receptors. This dual mode of motor initiation control is found in mammals, suggesting that distantly related organisms with anatomically distinct nervous systems may adopt similar strategies for motor control. Additionally, our studies illustrate how a multidisciplinary approach facilitates dissection of circuit and synaptic mechanisms underlying behavior in a genetic model organism.


Asunto(s)
Caenorhabditis elegans/fisiología , Actividad Motora , Vías Nerviosas , Sinapsis/fisiología , Animales , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/fisiología , Electrofisiología , Interneuronas/fisiología , Mutación , Presión Osmótica , Receptores de Glutamato/genética , Receptores de Glutamato/fisiología
13.
Cell ; 144(4): 551-65, 2011 Feb 18.
Artículo en Inglés | MEDLINE | ID: mdl-21335237

RESUMEN

Kinesin and dynein are opposite-polarity microtubule motors that drive the tightly regulated transport of a variety of cargoes. Both motors can bind to cargo, but their overall composition on axonal vesicles and whether this composition directly modulates transport activity are unknown. Here we characterize the intracellular transport and steady-state motor subunit composition of mammalian prion protein (PrP(C)) vesicles. We identify Kinesin-1 and cytoplasmic dynein as major PrP(C) vesicle motor complexes and show that their activities are tightly coupled. Regulation of normal retrograde transport by Kinesin-1 is independent of dynein-vesicle attachment and requires the vesicle association of a complete Kinesin-1 heavy and light chain holoenzyme. Furthermore, motor subunits remain stably associated with stationary as well as with moving vesicles. Our data suggest a coordination model wherein PrP(C) vesicles maintain a stable population of associated motors whose activity is modulated by regulatory factors instead of by structural changes to motor-cargo associations.


Asunto(s)
Axones/metabolismo , Dineínas/metabolismo , Cinesinas/metabolismo , Proteínas PrPC/metabolismo , Animales , Hipocampo/metabolismo , Ratones , Ratones Endogámicos C57BL , Actividad Motora , Neuronas/metabolismo , Vesículas Transportadoras/metabolismo
14.
Nature ; 585(7825): 397-403, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32610343

RESUMEN

Mutations in PLP1, the gene that encodes proteolipid protein (PLP), result in failure of myelination and neurological dysfunction in the X-chromosome-linked leukodystrophy Pelizaeus-Merzbacher disease (PMD)1,2. Most PLP1 mutations, including point mutations and supernumerary copy variants, lead to severe and fatal disease. Patients who lack PLP1 expression, and Plp1-null mice, can display comparatively mild phenotypes, suggesting that PLP1 suppression might provide a general therapeutic strategy for PMD1,3-5. Here we show, using CRISPR-Cas9 to suppress Plp1 expression in the jimpy (Plp1jp) point-mutation mouse model of severe PMD, increased myelination and restored nerve conduction velocity, motor function and lifespan of the mice to wild-type levels. To evaluate the translational potential of this strategy, we identified antisense oligonucleotides that stably decrease the levels of Plp1 mRNA and PLP protein throughout the neuraxis in vivo. Administration of a single dose of Plp1-targeting antisense oligonucleotides in postnatal jimpy mice fully restored oligodendrocyte numbers, increased myelination, improved motor performance, normalized respiratory function and extended lifespan up to an eight-month end point. These results suggest that PLP1 suppression could be developed as a treatment for PMD in humans. More broadly, we demonstrate that oligonucleotide-based therapeutic agents can be delivered to oligodendrocytes in vivo to modulate neurological function and lifespan, establishing a new pharmaceutical modality for myelin disorders.


Asunto(s)
Modelos Animales de Enfermedad , Proteína Proteolipídica de la Mielina/deficiencia , Enfermedad de Pelizaeus-Merzbacher/genética , Enfermedad de Pelizaeus-Merzbacher/terapia , Animales , Sistemas CRISPR-Cas , Femenino , Edición Génica , Hipoxia/metabolismo , Masculino , Ratones , Ratones Mutantes , Actividad Motora/genética , Proteína Proteolipídica de la Mielina/genética , Proteína Proteolipídica de la Mielina/metabolismo , Vaina de Mielina/metabolismo , Oligodendroglía/metabolismo , Oligonucleótidos Antisentido/administración & dosificación , Oligonucleótidos Antisentido/genética , Enfermedad de Pelizaeus-Merzbacher/metabolismo , Mutación Puntual , Pruebas de Función Respiratoria , Análisis de Supervivencia
15.
J Neurosci ; 44(19)2024 May 08.
Artículo en Inglés | MEDLINE | ID: mdl-38531632

RESUMEN

BMAL2 (ARNTL2) is a paralog of BMAL1 that can form heterodimers with the other circadian factors CLOCK and NPAS2 to activate transcription of clock and clock-controlled genes. To assess a possible role of Bmal2 in the circadian regulation of metabolism, we investigated daily variations of energy metabolism, feeding behavior, and locomotor behavior, as well as ability to anticipate restricted food access in male mice knock-out for Bmal2 (B2KO). While their amount of food intake and locomotor activity were normal compared with wild-type mice, B2KO mice displayed increased adiposity (1.5-fold higher) and fasted hyperinsulinemia (fourfold higher) and tended to have lower energy expenditure at night. Impairment of the master clock in the suprachiasmatic nuclei was evidenced by the shorter free-running period (-14 min/cycle) of B2KO mice compared with wild-type controls and by a loss of daily rhythmicity in expression of intracellular metabolic regulators (e.g., Lipoprotein lipase and Uncoupling protein 2). The circadian window of eating was longer in B2KO mice. The circadian patterns of food intake and meal numbers were bimodal in control mice but not in B2KO mice. In response to restricted feeding, food-anticipatory activity was almost prevented in B2KO mice, suggesting altered food clock that controls anticipation of food availability. In the mediobasal hypothalamus of B2KO mice, expression of genes coding orexigenic neuropeptides (including Neuropeptide y and Agouti-Related Peptide) was downregulated, while Lipoprotein lipase expression lost its rhythmicity. Together, these data highlight that BMAL2 has major impacts on brain regulation of metabolic rhythms, sleep-wake cycle, and food anticipation.


Asunto(s)
Factores de Transcripción ARNTL , Ritmo Circadiano , Metabolismo Energético , Conducta Alimentaria , Hipotálamo , Ratones Noqueados , Animales , Ratones , Metabolismo Energético/fisiología , Metabolismo Energético/genética , Factores de Transcripción ARNTL/genética , Factores de Transcripción ARNTL/metabolismo , Masculino , Conducta Alimentaria/fisiología , Ritmo Circadiano/fisiología , Ritmo Circadiano/genética , Hipotálamo/metabolismo , Ratones Endogámicos C57BL , Actividad Motora/fisiología , Actividad Motora/genética , Ingestión de Alimentos/genética , Ingestión de Alimentos/fisiología
16.
Annu Rev Neurosci ; 40: 77-97, 2017 07 25.
Artículo en Inglés | MEDLINE | ID: mdl-28375768

RESUMEN

The motor cortex is far from a stable conduit for motor commands and instead undergoes significant changes during learning. An understanding of motor cortex plasticity has been advanced greatly using rodents as experimental animals. Two major focuses of this research have been on the connectivity and activity of the motor cortex. The motor cortex exhibits structural changes in response to learning, and substantial evidence has implicated the local formation and maintenance of new synapses as crucial substrates of motor learning. This synaptic reorganization translates into changes in spiking activity, which appear to result in a modification and refinement of the relationship between motor cortical activity and movement. This review presents the progress that has been made using rodents to establish the motor cortex as an adaptive structure that supports motor learning.


Asunto(s)
Aprendizaje/fisiología , Actividad Motora/fisiología , Corteza Motora/fisiología , Plasticidad Neuronal/fisiología , Sinapsis/fisiología , Animales , Vías Nerviosas/fisiología , Roedores
17.
PLoS Biol ; 20(4): e3001598, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-35389982

RESUMEN

Humans and other animals are able to adjust their speed-accuracy trade-off (SAT) at will depending on the urge to act, favoring either cautious or hasty decision policies in different contexts. An emerging view is that SAT regulation relies on influences exerting broad changes on the motor system, tuning its activity up globally when hastiness is at premium. The present study aimed to test this hypothesis. A total of 50 participants performed a task involving choices between left and right index fingers, in which incorrect choices led either to a high or to a low penalty in 2 contexts, inciting them to emphasize either cautious or hasty policies. We applied transcranial magnetic stimulation (TMS) on multiple motor representations, eliciting motor-evoked potentials (MEPs) in 9 finger and leg muscles. MEP amplitudes allowed us to probe activity changes in the corresponding finger and leg representations, while participants were deliberating about which index to choose. Our data indicate that hastiness entails a broad amplification of motor activity, although this amplification was limited to the chosen side. On top of this effect, we identified a local suppression of motor activity, surrounding the chosen index representation. Hence, a decision policy favoring speed over accuracy appears to rely on overlapping processes producing a broad (but not global) amplification and a surround suppression of motor activity. The latter effect may help to increase the signal-to-noise ratio of the chosen representation, as supported by single-trial correlation analyses indicating a stronger differentiation of activity changes in finger representations in the hasty context.


Asunto(s)
Corteza Motora , Animales , Potenciales Evocados Motores/fisiología , Dedos/fisiología , Humanos , Actividad Motora , Corteza Motora/fisiología , Músculo Esquelético/fisiología , Estimulación Magnética Transcraneal
18.
Nature ; 576(7785): 121-125, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31748749

RESUMEN

In the Drosophila brain, 'compass' neurons track the orientation of the body and head (the fly's heading) during navigation 1,2. In the absence of visual cues, the compass neuron network estimates heading by integrating self-movement signals over time3,4. When a visual cue is present, the estimate of the network is more accurate1,3. Visual inputs to compass neurons are thought to originate from inhibitory neurons called R neurons (also known as ring neurons); the receptive fields of R neurons tile visual space5. The axon of each R neuron overlaps with the dendrites of every compass neuron6, raising the question of how visual cues are integrated into the compass. Here, using in vivo whole-cell recordings, we show that a visual cue can evoke synaptic inhibition in compass neurons and that R neurons mediate this inhibition. Each compass neuron is inhibited only by specific visual cue positions, indicating that many potential connections from R neurons onto compass neurons are actually weak or silent. We also show that the pattern of visually evoked inhibition can reorganize over minutes as the fly explores an altered virtual-reality environment. Using ensemble calcium imaging, we demonstrate that this reorganization causes persistent changes in the compass coordinate frame. Taken together, our data suggest a model in which correlated pre- and postsynaptic activity triggers associative long-term synaptic depression of visually evoked inhibition in compass neurons. Our findings provide evidence for the theoretical proposal that associative plasticity of sensory inputs, when combined with attractor dynamics, can reconcile self-movement information with changing external cues to generate a coherent sense of direction7-12.


Asunto(s)
Cabeza , Neuronas/fisiología , Visión Ocular , Animales , Drosophila melanogaster , Actividad Motora , Movimiento
19.
Nature ; 570(7762): 509-513, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-31142844

RESUMEN

There is increased appreciation that dopamine neurons in the midbrain respond not only to reward1 and reward-predicting cues1,2, but also to other variables such as the distance to reward3, movements4-9 and behavioural choices10,11. An important question is how the responses to these diverse variables are organized across the population of dopamine neurons. Whether individual dopamine neurons multiplex several variables, or whether there are subsets of neurons that are specialized in encoding specific behavioural variables remains unclear. This fundamental question has been difficult to resolve because recordings from large populations of individual dopamine neurons have not been performed in a behavioural task with sufficient complexity to examine these diverse variables simultaneously. Here, to address this gap, we used two-photon calcium imaging through an implanted lens to record the activity of more than 300 dopamine neurons from the ventral tegmental area of the mouse midbrain during a complex decision-making task. As mice navigated in a virtual-reality environment, dopamine neurons encoded an array of sensory, motor and cognitive variables. These responses were functionally clustered, such that subpopulations of neurons transmitted information about a subset of behavioural variables, in addition to encoding reward. These functional clusters were spatially organized, with neighbouring neurons more likely to be part of the same cluster. Together with the topography between dopamine neurons and their projections, this specialization and anatomical organization may aid downstream circuits in correctly interpreting the wide range of signals transmitted by dopamine neurons.


Asunto(s)
Cognición , Neuronas Dopaminérgicas/fisiología , Actividad Motora , Sensación , Área Tegmental Ventral/citología , Animales , Fenómenos Biomecánicos , Calcio/metabolismo , Condicionamiento Clásico , Señales (Psicología) , Toma de Decisiones , Femenino , Masculino , Ratones , Recompensa , Navegación Espacial , Área Tegmental Ventral/fisiología , Realidad Virtual
20.
Nature ; 571(7763): 63-71, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-31270481

RESUMEN

Knowledge of connectivity in the nervous system is essential to understanding its function. Here we describe connectomes for both adult sexes of the nematode Caenorhabditis elegans, an important model organism for neuroscience research. We present quantitative connectivity matrices that encompass all connections from sensory input to end-organ output across the entire animal, information that is necessary to model behaviour. Serial electron microscopy reconstructions that are based on the analysis of both new and previously published electron micrographs update previous results and include data on the male head. The nervous system differs between sexes at multiple levels. Several sex-shared neurons that function in circuits for sexual behaviour are sexually dimorphic in structure and connectivity. Inputs from sex-specific circuitry to central circuitry reveal points at which sexual and non-sexual pathways converge. In sex-shared central pathways, a substantial number of connections differ in strength between the sexes. Quantitative connectomes that include all connections serve as the basis for understanding how complex, adaptive behavior is generated.


Asunto(s)
Caenorhabditis elegans/metabolismo , Conectoma , Sistema Nervioso/anatomía & histología , Sistema Nervioso/metabolismo , Caracteres Sexuales , Animales , Conducta Animal , Caenorhabditis elegans/citología , Femenino , Cabeza/anatomía & histología , Cabeza/inervación , Organismos Hermafroditas , Masculino , Microscopía Electrónica , Actividad Motora , Movimiento , Sistema Nervioso/citología , Vías Nerviosas
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