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Isope, P.

Publications and source records attributed to Isope, P..

9 recordsLinked to original sources

Medial prefrontal cortex encodes implicit temporal expectations in mice

Temporal prediction allows animals to align their actions with upcoming events, yet most work has focused on explicit duration judgments rather than the implicit timing that shapes ongoing behavior. Here, we ask how medial prefrontal cortex implements such latent temporal expectations and how cerebellar input contributes. Head-fixed mice learned a cued water-delivery task in which reward occurred after either a short or long delay, or after a single fixed delay. During variable delays, running and licking became anticipatory, and medial prefrontal local field potentials and single neurons showed ramping and reward-locked activity patterns aligned to expected reward time. Switching to a fixed delay rapidly sharpened behavioral anticipation and temporal coding. Optogenetic activation of cerebellar Purkinje cells selectively perturbed these dynamics and biased behavior around the earliest possible reward time. These results identify a cerebello-prefrontal circuit that encodes implicit temporal predictions on the sub-second scale.

neuroscience↗

Subthreshold violations of trajectory predictions are sensitive to TMS of Cerebellum CRUS I/II

Temporal prediction can help to follow a trajectory. In case of an error, the prediction can be adjusted. However, processing the error and adjusting the prediction can take time. What happens immediately after a prediction error, and can the processing of the prediction be modulated? We use a newly found illusion based on moving squares and requiring trajectory regularity to be elicited. We examined the conscious consequences of a sub-threshold manipulation of the square trajectories, and transcranial magnetic stimulation (TMS) on the cerebellum (right CRUS I/II) to study the modulation of the processing of the trajectory manipulations. The TMS was a typical intermittent theta-burst stimulation, but only one sequence of around 3 minutes, compared with a placebo stimulation. The trajectory manipulation had a reliable effect on the illusion, even though the illusion emerged within less than 100 ms after the trajectory manipulation. The results suggest that the prediction is temporarily stopped after the trajectory change. The illusion was accompanied by EEG signals whose amplitude was modulated by TMS on the cerebellum, at least in those participants who received verum TMS after having performed the task three times. Those EEG signals resembled a late LPP (Late Positive Potential). As LPP spontaneously decreased over time, the results suggest the effect of TMS may represent a reinstation of the EEG consequences of the prediction error, i.e., a modulation of its significance.

neuroscience↗

Excitation and inhibition delays within a feedforward inhibitory pathway modulate cerebellar Purkinje cell output in mice

The cerebellar cortex computes sensorimotor information from many brain areas through a feedforward inhibitory (FFI) microcircuit between the input stage, the granule cell layer, and the output stage, the Purkinje cells. While in other brain areas FFI underlies a precise excitation vs inhibition temporal correlation, recent findings in the cerebellum highlighted more complex behaviors at the granule cell (GC) - molecular layer interneuron (MLI) - Purkinje cell (PC) FFI pathway. To dissect the temporal organization of the cerebellar FFI pathway, we combined ex vivo patch clamp recordings of PCs with a viral-based strategy to express Channelrhodopsin2 in a subset of mossy fibers (MFs), a major excitatory input to GCs. We show that light-mediated MF activation elicits excitatory and inhibitory currents in PCs with a wide range of temporal delays. Furthermore, in many recordings, excitation and inhibition were initiated by different groups of GCs, expanding PCs synaptic temporal integration. Using a computational model of the FFI pathway we demonstrated that this temporal expansion could strongly influence how PCs integrate MF inputs. Our findings suggest that MF inputs are also encoded by specific delays between excitation and inhibition in PCs.

neuroscience↗

Cerebellar connectivity maps embody individual adaptive behavior

From planification to execution, cerebellar microcircuits encode different features of skilled movements. However, it is unknown whether cerebellar synaptic connectivity maps encode movement features in a motor context specific manner. Here we investigated the spatial organization of excitatory synaptic connectivity in mice cerebellar cortex in different locomotor contexts: during development and in normal, trained or altered locomotor conditions. We combined optical, electrophysiological and graph modelling approaches to describe synaptic connectivity between granule cells (GCs) and Purkinje cells (PCs). Synaptic map maturation during development revealed a critical period in juvenile animals before the establishment of a stereotyped functional organization in adults. However, different locomotor conditions lead to specific GC-PC connectivity maps in PCs. Ultimately, we demonstrated that the variability in connectivity maps directly accounts for individual specific behavioral features of mice locomotion, suggesting that GC-PC networks encode a general motor context as well as individual specific internal models underlying motor adaptation.

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Sensory gating precedes motor command in evolution of the corticospinal tract

It is generally assumed that the main function of the corticospinal tract (CST) is to convey motor commands to bulbar or spinal motoneurons. Yet the CST has also been shown to modulate sensory signals at their entry point in the spinal cord, through presynaptic inhibition. By sequentially investigating different routes of corticofugal pathways through electrophysiological recordings and an intersectional viral strategy, we here demonstrate that motor and sensory modulation commands in mice belong to segregated paths within the CST. Sensory modulation is excuted exclusively by the CST via a population of lumbar interneurons located in the deep dorsal horn. In contrast, the cortex conveys the motor command via a relay in the upper spinal cord or supraspinal motor centers. At lumbar level, the main role of the CST is thus the modulation of sensory inputs, which is an essential component of the selective tuning of sensory feedback, to ensure well-coordinated and skilled movement. Impact statementWhile the corticospinal tract is often considered exclusively as a motor path, this study demonstrates that, in the mouse lumbar cord, its main role is the modulation of sensory inputs.

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SUSD4 Controls Activity-Dependent Degradation of AMPA Receptor GLUA2 and Synaptic Plasticity

Fine control of protein stoichiometry at synapses underlies brain function and plasticity. How proteostasis is controlled independently for each type of synaptic protein in a synapse-specific and activity-dependent manner remains unclear. Here we show that SUSD4, a complement-related transmembrane protein, binds the AMPA receptor subunit GLUA2 and controls its activity-dependent degradation. Several proteins with known roles in the regulation of AMPA receptor turnover, in particular ubiquitin ligases of the NEDD4 subfamily, are identified as SUSD4 binding partners. SUSD4 is expressed by many neuronal populations starting at the time of synapse formation. Loss-of-function of Susd4 in the mouse prevents long-term depression at cerebellar synapses, and leads to impairment in motor coordination adaptation and learning. Our findings reveal that activity-dependent synaptic plasticity relies on a transmembrane CCP domain-containing protein that regulates the degradation of specific substrates. This mechanism potentially accounts for the role of SUSD4 mutations in neurodevelopmental diseases.

neuroscience↗

Gradients in the cerebellar cortex enable Fourier-like transformation and improve storing capacity

Cerebellar granule cells (GCs) making up majority of all the neurons in the vertebrate brain, but heterogeneities among GCs and potential functional consequences are poorly understood. Here, we identified unexpected gradients in the biophysical properties of GCs. GCs closer to the white matter (inner-zone GCs) had higher firing thresholds and could sustain firing with larger current inputs. Dynamic clamp experiments showed that inner- and outer-zone GCs preferentially respond to high- and low-frequency mossy fiber inputs, respectively, enabling to disperse the mossy fiber input into its frequency components as performed by a Fourier transformation. Furthermore, inner-zone GCs have faster axonal conduction velocity and elicit faster synaptic potentials in Purkinje cells. Neuronal network modeling revealed that these gradients improve spike-timing precision of Purkinje cells and decrease the number of GCs required to learn spike-sequences. Thus, our study uncovers biophysical gradients in the cerebellar cortex enabling a Fourier-like transformation of mossy fiber inputs.

neuroscience↗

Molecular and functional heterogeneity of cerebellar granule cell terminals expands temporal coding in molecular layer interneurons.

In the cerebellum, molecular layer interneurons (MLIs) play an essential role in motor behavior by exerting precise temporal control of Purkinje cells, the sole output of the cerebellar cortex. The recruitment of MLIs is tightly controlled by the release of glutamate from granule cells (GCs) during high-frequency activities. Here we study how single MLIs are recruited by their distinct unitary GC inputs during burst of GC stimulations. Stimulation of individual GC-MLI synapses revealed four classes of connections segregated by their profile of short-term plasticity. Each class of connection differentially drives MLI recruitment. Molecular and ultrastructural analyses revealed that GC-MLI synaptic diversity is underlain by heterogeneous expression of synapsin II at individual GC terminals. In synapsin II knock-out mice, the number of classes is reduced to profiles associated with slow MLI recruitment. Our study reveals that molecular diversity across GC terminals enables diversity in temporal coding by MLIs and thereby influences the processing of sensory information by cerebellar networks.

neuroscience↗

A frequency-dependent mobilization of heterogeneous pools of synaptic vesicles shapes presynaptic plasticity

The segregation of the readily releasable pool of synaptic vesicles (RRP) in sub-pool which are differentially poised for exocytosis shapes short-term plasticity at depressing synapses. Here, we used in vitro recording and modeling of synaptic activity at the facilitating mice cerebellar granule cell to Purkinje cell synapse to demonstrate the existence of two sub-pools of vesicles in the RRP that can be differentially recruited upon fast changes in the stimulation frequency. We show that upon low-frequency stimulation, a population of fully-releasable vesicles is silenced, leading to full blockage of synaptic transmission. A second population of vesicles, reluctant to release by simple stimuli, is recruited in a millisecond time scale by high-frequency stimulation to support an ultrafast recovery of neurotransmitter release after low-frequency depression. The frequency-dependent mobilization or silencing of sub-pools of vesicles in granule cell terminals should play a major role in the filtering of sensorimotor information in the cerebellum.

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