Biology subjects

Hage, P.

Publications and source records attributed to Hage, P..

9 recordsLinked to original sources

bioRxiv2024

A vector calculus for neural computation in the cerebellum

Null space theory predicts that a neuron will often generate spikes not to produce behavior, but to prevent another neurons impact on behavior. Here, we present a direct test of this theory in the brain. In the marmoset cerebellum, spike-triggered averaging identified a vector for each Purkinje cell (P-cell) along which its spikes displaced the eyes. Two spikes in two different P-cells produced superposition of their vectors. In the resulting population activity, the spikes were canceled if their contributions were perpendicular to the intended movement. Mossy fibers provided a copy of the motor commands and the sensory goal of the movement. Molecular layer interneurons transformed these inputs so that the P-cell population predicted when the movement had reached the goal and should be stopped.

neuroscience↗

bioRxiv2024

Control of tongue movements by the Purkinje cells of the cerebellum

We use our tongue much like our hands: to interact with objects and transport them. For example, we use our hands to sense properties of objects and transport them in the nearby space, and we use our tongue to sense properties of food morsels and transport them through the oral cavity. But what does the cerebellum contribute to control of tongue movements? Here, we trained head-fixed marmosets to make skillful tongue movements to harvest food from small tubes that were placed at sharp angles to their mouth. We identified the lingual regions of the cerebellar vermis and then measured the contribution of each Purkinje cell (P-cell) to control of the tongue by relying on the brief but complete suppression that they experienced following an input from the inferior olive. When a P-cell was suppressed during protraction, the tongues trajectory became hypermetric, and when the suppression took place during retraction, the tongues return to the mouth was slowed. Both effects were amplified when two P-cells were simultaneously suppressed. Therefore, suppression of P-cells in the lingual vermis disrupted the forces that would normally decelerate the tongue as it approached the target. Notably, the population simple spike activity peaked near deceleration onset when the movement required precision (aiming for a tube), but not when the movement was for the purpose of grooming. Thus, the P-cells appeared to signal when to stop protrusion as the tongue approached its target.

neuroscience↗

bioRxiv2024

Rejuvenating silicon probes for acute electrophysiology

Electrophysiological recording with a new probe often yields better signal quality than with a used probe. Why does the signal quality degrade after only a few experiments? Here, we considered silicon probes in which the contacts are densely packed, and each is coated with a conductive polymer that increases its surface area. We tested 12 Cambridge Neurotech silicon probes during 61 recording sessions from the brain of 3 marmosets. Out of the box, each probe arrived with an electrodeposited polymer coating on 64 gold contacts, and an impedance of around 50k Ohms. With repeated use, the impedance increased and there was a corresponding decrease in the number of well-isolated neurons. Imaging of the probes suggested that the reduction in signal quality was due to a gradual loss of the polymer coating. To rejuvenate the probes, we first stripped the contacts, completely removing their polymer coating, and then recoated them in a solution of 10 mM EDOT monomer with 32 uM PSS using a current density of about 3mA/cm2 for 30 seconds. This recoating process not only returned probe impedance to around 50k Ohms, it also yielded significantly improved signal quality during neurophysiological recordings. Thus, insertion into the brain promoted loss of the polymer that coated the contacts of the silicon probes. This led to degradation of signal quality, but recoating rejuvenated the probes.

neuroscience↗

bioRxiv2023

Complex spikes perturb movements, revealing the sensorimotor map of Purkinje cells

The cerebellar cortex performs computations that are critical for control of our actions, and then transmits that information via simple spikes of Purkinje cells (P-cells) to downstream structures. However, because P-cells are many synapses away from muscles, we do not know how their output affects behavior. Furthermore, we do not know the level of abstraction, i.e., the coordinate system of the P-cells output. Here, we recorded spiking activities of hundreds of P-cells in the oculomotor vermis of marmosets during saccadic eye movements and found that following the presentation of a visual stimulus, the olivary input to a P-cell encoded a probabilistic signal that coarsely described both the direction and the amplitude of that stimulus. When this input was present, the resulting complex spike briefly suppressed the P-cells simple spikes, disrupting the P-cells output during that saccade. Remarkably, this brief suppression altered the saccades trajectory by pulling the eyes toward the part of the visual space that was preferentially encoded by the olivary input to that P-cell. Thus, analysis of behavior in the milliseconds following a complex spike unmasked how the P-cells output influenced behavior: the preferred location in the coordinates of the visual system as conveyed probabilistically from the inferior olive to a P-cell defined the action in the coordinates of the motor system for which that P-cells simple spikes directed behavior. SignificanceWe are lacking general principles that can describe how changes in a P-cells simple spikes might alter behavior. Here, we show that a brief suppression of a P-cells simple spikes in the oculomotor vermis consistently pulls the eyes in a direction that corresponds to the preferred location of the sensory space as conveyed probabilistically to that P-cell from the inferior olive. Thus, the inferior olive defines the coordinate system regarding the information that a P-cell is providing to the rest of the brain.

neuroscience↗

bioRxiv2023

Effort cost of harvest affects decisions and movement vigor of marmosets during foraging

Our decisions are guided by how we perceive the value of an option, but this evaluation also affects how we move to acquire that option. Why should economic variables such as reward and effort alter the vigor of our movements? In theory, both the option that we choose and the vigor with which we move contribute to a measure of fitness in which the objective is to maximize rewards minus efforts, divided by time. To explore this idea, we engaged marmosets in a foraging task in which on each trial they decided whether to work by making saccades to visual targets, thus accumulating food, or to harvest by licking what they had earned. We varied the effort cost of harvest by moving the food tube with respect to the mouth. Theory predicted that the subjects should respond to the increased effort costs by choosing to work longer, stockpiling food before commencing harvest, but reduce their movement vigor to conserve energy. Indeed, in response to an increased effort cost of harvest, marmosets extended their work duration, but slowed their movements. These changes in decisions and movements coincided with changes in pupil size. As the effort cost of harvest declined, work duration decreased, the pupils dilated, and the vigor of licks and saccades increased. Thus, when acquisition of reward became effortful, the pupils constricted, the decisions exhibited delayed gratification, and the movements displayed reduced vigor. Significance statementOur results suggest that as the brainstem neuromodulatory circuits that control pupil size respond to effort costs, they alter computations in the brain regions that control decisions, encouraging work and delaying gratification, and the brain regions that control movements, reducing vigor and suppressing energy expenditure. This coordinated response suggests that decisions and actions are part of a single control policy that aims to maximize a variable relevant to fitness: the capture rate.

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bioRxiv2022

Signaling the agency of an erroneous outcome via synchronization of spikes in the cerebellum

Neurons in the inferior olive are thought to anatomically organize the Purkinje cells (P-cells) of the cerebellum into computational modules. To better understand what is computed by these modules, we designed a saccade task in marmosets that dissociated sensory and motor events and then recorded the complex and simple spikes of hundreds of P-cells. We found that when a visual target was presented at a random location, the olive reported the direction of that sensory event to one group of P-cells, but not to a second group. However, just before movement onset it reported the direction of the planned movement to both groups, even if that movement was not toward the target. At the end of the movement if there was an error but the subject chose to withhold the corrective movement, only the first group received information about the sensory prediction error. We organized the P-cells based on the information content of their olivary input and found that in the group that received sensory information, the simple spikes were suppressed during fixation, then produced a burst before saccade onset in a direction consistent with assisting the movement. In the second group the simple spikes were not suppressed during fixation but burst near saccade deceleration in a direction consistent with stopping the movement. Thus, the olive differentiated the P-cells based on whether they would receive sensory or motor information, and this defined their contributions to control of movements as well as holding still. Significance statementWe found that in the oculomotor region of the vermis, the olive informed a subset of P-cells about sensory events that were prediction errors, but all P-cells about the forthcoming movement. Using the information content of the olivary input we labeled the P-cells and produced a population code, revealing two groups with simple spikes that were antagonistic to each other, one contributing to movement initiation, the other signaling movement end.

neuroscience↗

bioRxiv2021

Synchronous spiking of cerebellar Purkinje cells during control of movements

The information that the brain transmits from one region to another is often viewed through the lens of firing rates. However, if the output neurons could vary the timing of their spikes with respect to each other, then through synchronization they could highlight information that may be critical for control of behavior. In the cerebellum, the computations that are performed by the cerebellar cortex are conveyed to the nuclei via inhibition. Yet, synchronous activity entrains nucleus neurons, making them fire. Does the cerebellar cortex rely on spike synchrony within populations of Purkinje cells (P-cells) to convey information to the nucleus? We recorded from multiple P-cells while marmosets performed saccadic eye movements and organized them into populations that shared a complex spike response to error. Before movement onset, P-cells transmitted information via a rate code: the simple spike firing rates predicted the direction and velocity of the impending saccade. However, during the saccade, the spikes became temporally aligned within the population, signaling when to stop the movement. Thus, the cerebellar cortex relies on spike synchronization within a population of P-cells, not individual firing rates, to convey to the nucleus when to stop a movement.

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bioRxiv2021

P-sort: an open-source software for cerebellar neurophysiology

Analysis of electrophysiological data from Purkinje cells (P-cells) of the cerebellum presents challenges for spike detection. Complex spikes have waveforms that vary significantly from one event to the next, raising the problem of misidentification. Even when complex spikes are detected correctly, the simple spikes may belong to a different P-cell, raising the danger of misattribution. Here, we analyzed data from over 300 P-cells in marmosets, macaques, and mice, using an open-source, semi-automated software called P-sort that addresses the spike identification and attribution problems. Like other sorting software, P-sort relies on nonlinear dimensionality reduction to cluster spikes. However, it also uses the statistical relationship between simple and complex spikes to merge seemingly disparate clusters, or split a single cluster. In comparison with expert manual curation, occasionally P-sort identified significantly more complex spikes, as well as prevented misattribution of clusters. Three existing automatic sorters performed less well, particularly for identification of complex spikes. To improve development of analysis tools for the cerebellum, we provide labeled data for 313 recording sessions, as well as statistical characteristics of waveforms and firing patterns.

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bioRxiv2019

Behavioral training of marmosets and electrophysiological recording from the cerebellum

The common marmoset (Callithrix Jacchus) is a promising new model for study of neurophysiological basis of behavior in primates. Like other primates, it relies on saccadic eye movements to monitor and explore its environment. Previous reports have demonstrated some success in training marmosets to produce goal-directed actions in the laboratory. However, the number of trials per session has been relatively small, thus limiting the utility of marmosets as a model for behavioral and neurophysiological studies. Here, we report the results of a series of new behavioral training and neurophysiological protocols aimed at increasing the number of trials per session while recording from the cerebellum. To improve the training efficacy, we designed a precisely calibrated food regulation regime that motivated the subjects to perform saccade tasks, resulting in about a thousand reward-driven trials on a daily basis. We then developed a multi-channel recording system that used imaging to target a desired region of the cerebellum, allowing for simultaneous isolation of multiple Purkinje cells in the vermis. In this report, we describe (1) the design and surgical implantation of a CT guided, subject specific head-post, (2) the design of a CT and MRI guided alignment tool for trajectory guidance of electrodes mounted on an absolute encoder microdrive, (3) development of a protocol for behavioral training of subjects, and (4) simultaneous recordings from pairs of Purkinje cells during a saccade task.\n\nNew and NoteworthyMarmosets present the opportunity to investigate genetically based neurological disease in primates; in particular, diseases that affect social behaviors, vocal communication, and eye movements. All of these behaviors depend on the integrity of the cerebellum. Here, we present training methods that better motivate the subjects, allowing for improved performance, and also present electrophysiological techniques that precisely target the subjects cerebellum, allowing for simultaneous isolation of multiple Purkinje cells.\n\nIn our parks, are there any trees more elegant and luxurious than the Purkinje cell from the cerebellum? Santiago Ramon y Cajal

neuroscience↗