Mati Joshua

Midbrain Dopaminergic Neurons and Striatal Cholinergic Interneurons Encode the Difference between Reward and Aversive Events at Different Epochs of Probabilistic Classical Conditioning Trials

Midbrain dopaminergic neurons (DANs) typically increase their discharge rate in response to appetitive predictive cues and outcomes, whereas striatal cholinergic tonically active interneurons (TANs) decrease their rate. This may indicate that the activity of TANs and DANs is negatively correlated and that TANs can broaden the basal ganglia reinforcement teaching signal, for instance by encoding worse than predicted events. We studied the activity of 106 DANs and 180 TANs of two monkeys recorded during the performance of a classical conditioning task with cues predicting the probability of food, neutral, and air puff outcomes. DANs responded to all cues with elevations of discharge rate, whereas TANs depressed their discharge rate. Nevertheless, although dopaminergic responses to appetitive cues were larger than their responses to neutral or aversive cues, the TAN responses were more similar. Both TANs and DANs responded faster to an air puff than to a food outcome; however, DANs responded with a discharge elevation, whereas the TAN responses included major negative and positive deflections. Finally, food versus air puff omission was better encoded by TANs. In terms of the activity of single neurons with distinct responses to the different behavioral events, both DANs and TANs were more strongly modulated by reward than by aversive related events and better reflected the probability of reward than aversive outcome. Thus, TANs and DANs encode the task episodes differentially. The DANs encode mainly the cue and outcome delivery, whereas the TANs mainly encode outcome delivery and omission at termination of the behavioral trial episode.

Statistical Properties of Pauses of the High-Frequency Discharge Neurons in the External Segment of the Globus Pallidus

The neurons of many basal ganglia nuclei, including the external and internal globus pallidus (GPe and GPi, respectively) and the substantia nigra pars reticulata (SNr) are characterized by their high-frequency (50–100 spikes/s) tonic discharge (HFD). However, the high firing rate of GPe neurons is interrupted by long pauses. We studied the extracellularly recorded spiking activity of 212 well-isolated HFD GPe and 52 GPi/SNr neurons from five monkeys during different states of behavioral activity. An algorithm that maximizes the surprise function was used to detect pauses and pauser cells (“pausers”). Only 6% of the GPi/SNr neurons versus as many as 56% of the GPe neurons were classified as pausers. The GPe average pause duration equals 0.62 s. The interpause intervals follow a Poissonian distribution with a frequency of 13 pauses/minute. No linear relationship was found between pause parameters (duration or frequency) and the firing rate of the cell. Pauses were preceded by various changes in firing rate but not dominantly by a decrease. The average amplitude and duration of the spike waveform was modulated only after the pause but not before it. Pauses of pairs of cells that were recorded simultaneously were not correlated. The probability of GPe cells to pause spontaneously was extremely variable among monkeys (30–90%) and inversely related to the degree of the monkeys motor activity. These findings suggest that spontaneous GPe pauses are related to low-arousal periods and are generated by a process that is independent of the discharge properties of the cells.

The dynamics of dopamine in control of motor behavior.

The basal ganglia are known to control behavior using reward information; however, recent experiments have revealed that the basal ganglia contribute to the processing of salient non-rewarding events as well. Here, we suggest that the temporal dynamics of the response of dopaminergic neurons (DANs) enable the basal ganglia to have a dual role. The fast DAN response to salient events is mediated thorough the brainstem-basal ganglia loop. Forebrain loops enable the second phase of the dopaminergic responses that require highly processed information. The convergent encoding of fast/salient and slow/detailed information suggests that the basal ganglia control the tradeoff between fast and immediate responses to environmental events and slow responses that are only executed after substantial environmental information has been gathered.

Synchronization of midbrain dopaminergic neurons is enhanced by rewarding events.

The basal ganglia network is divided into two functionally related subsystems: the neuromodulators and the main axis. It is assumed that neuromodulators adjust cortico-striatal coupling. This adjustment might depend on the response properties and temporal interactions between neuromodulators. We studied functional interactions between simultaneously recorded pairs of neurons in the basal ganglia while monkeys performed a classical conditioning task that included rewarding, neutral, and aversive events. Neurons that belong to a single neuromodulator group exhibited similar average responses, whereas main axis neurons responded in a highly diverse manner. Dopaminergic neuromodulators transiently increased trial-to-trial (noise) correlation following rewarding but not aversive events, whereas cholinergic neurons of the striatum decreased their trial-to-trial correlation. These changes in functional connectivity occurred at different epochs of the trial. Thus, the coding scheme of neuromodulators (but not main axis neurons) can be viewed as a single-dimensional code that is further enriched by dynamic neuronal interactions.

Encoding of Probabilistic Rewarding and Aversive Events by Pallidal and Nigral Neurons

Previous studies have rarely tested whether the activity of high-frequency discharge (HFD) neurons of the basal ganglia (BG) is modulated by expectation, delivery, and omission of aversive events. Therefore the full value domain encoded by the BG network is still unknown. We studied the activity of HFD neurons of the globus pallidus external segment (GPe, n=310), internal segment (GPi, n=149), and substantia nigra pars reticulata (SNr, n=145) in two monkeys during a classical conditioning task with cues predicting the probability of food, neutral, or airpuff outcomes. The responses of BG HFD neurons were long-lasting and diverse with coincident increases and decreases in discharge rate. The population responses to reward-related events were larger than the responses to aversive and neutral-related events. The latter responses were similar, except for the responses to actual airpuff delivery. The fraction of responding cells was larger for reward-related events, with better discrimination between rewarding and aversive trials in the responses with an increase rather than a decrease in discharge rate. GPe and GPi single units were more strongly modulated and better reflected the probability of reward- than aversive-related events. SNr neurons were less biased toward the encoding of the rewarding events, especially during the outcome epoch. Finally, the latency of SNr responses to all predictive cues was shorter than the latency of pallidal responses. These results suggest preferential activation of the BG HFD neurons by rewarding compared with aversive events.

Emergence of Context-Dependent Variability across a Basal Ganglia Network

Context dependence is a key feature of cortical-basal ganglia circuit activity, and in songbirds the cortical outflow of a basal ganglia circuit specialized for song, LMAN, shows striking increases in trial-by-trial variability and bursting when birds sing alone rather than to females. To reveal where this variability and its social regulation emerge, we recorded stepwise from corticostriatal (HVC) neurons and their target spiny and pallidal neurons in Area X. We find that corticostriatal and spiny neurons both show precise singing-related firing across both social settings. Pallidal neurons, in contrast, exhibit markedly increased trial-by-trial variation when birds sing alone, created by highly variable pauses in firing. This variability persists even when recurrent inputs from LMAN are ablated. These data indicate that variability and its context sensitivity emerge within the basal ganglia network, suggest a network mechanism for this emergence, and highlight variability generation and regulation as basal ganglia functions.

Descending Systems Translate Transient Cortical Commands into a Sustained Muscle Activation Signal

Controlling motor actions requires online adjustments of time-varying parameters. Although numerous studies have attempted to identify the parameters coded in different motor sites, the relationships between the temporal profile of neuronal responses and the dynamics of motor behavior remain poorly understood in particular because motor parameters such as force and movement direction often change over time. We studied time-dependent coding of cortical and spinal neurons in primates performing an isometric wrist task with an active hold period, which made it possible to segregate motor behavior into its phasic and sustained components. Here, we show that cortical neurons transiently code motor-related parameters when actively acquiring a goal, whereas spinal interneurons provide persistent information regarding maintained torque level and posture. Moreover, motor cortical neurons differed substantially from spinal neurons with regard to the evolvement of parameter-specific coding over the course of a trial. These results suggest that the motor cortex and spinal cord use different control policies: Cortical neurons produce transient motor commands governing ensuing actions, whereas spinal neurons exhibit sustained coding of ongoing motor states. Hence, motor structures downstream to M1 need to integrate cortical commands to produce state-dependent spinal firing.

A noninvasive, fast and inexpensive tool for the detection of eye open/closed state in primates.

Accurate detection of the eye state (i.e., open or closed) of animals during electrophysiological recordings is often crucial for analyzing physiological data. This requires a system which is reliable, and preferably noninvasive and inexpensive. Here we present such a tool incorporating a standard digital camera and a semi-automatic eye state detection (ESD) algorithm that can be used easily in typical primate electrophysiological setups. The ESD algorithm is based on the high light absorbance of the iris and pupil relative to the eyelid and takes advantage of the unique conditions found in primate physiological recordings (minimal area of sclera and head fixation). The ESD algorithm is as accurate as a human observer, and is not vulnerable to variance inherent to human decisions that it requires (i.e., eye location setting, training set classification and threshold setting). The temporal resolution with standard interlaced digital cameras is 17-20 ms. This is sufficient for the detection of eye state changes during electrophysiological recordings including spontaneous blinking and eye blink conditioning, as demonstrated here. Furthermore, the ESD tool can be applied to other physiological areas of research in which changes in eye state are critical to analyzing neuronal activity.

Diversity of neural responses in the brainstem during smooth pursuit eye movements constrains the circuit mechanisms of neural integration

Neural integration converts transient events into sustained neural activity. In the smooth pursuit eye movement system, neural integration is required to convert cerebellar output into the sustained discharge of extraocular motoneurons. We recorded the expression of integration in the time-varying firing rates of cerebellar and brainstem neurons in the monkey during pursuit of step-ramp target motion. Electrical stimulation with single shocks in the cerebellum identified brainstem neurons that are monosynaptic targets of inhibition from the cerebellar floccular complex. They discharge in relation to eye acceleration, eye velocity, and eye position, with a stronger acceleration signal than found in most other brainstem neurons. The acceleration and velocity signals can be accounted for by opponent contributions from the two sides of the cerebellum, without integration; the position signal implies participation in the integrator. Other neurons in the vestibular nucleus show a wide range of blends of signals related to eye velocity and eye position, reflecting different stages of integration. Neurons in the abducens nucleus discharge homogeneously in relation mainly to eye position, and reflect almost perfect integration of the cerebellar outputs. Average responses of neural populations and the diverse individual responses of large samples of individual neurons are reproduced by a hierarchical neural circuit based on a model suggested the anatomy and physiology of the larval zebrafish brainstem. The model uses a combination of feedforward and feedback connections to support a neural circuit basis for integration in monkeys and other species.

Signal, Noise, and Variation in Neural and Sensory-Motor Latency

Analysis of the neural code for sensory-motor latency in smooth pursuit eye movements reveals general principles of neural variation and the specific origin of motor latency. The trial-by-trial variation in neural latency in MT comprises a shared component expressed as neuron-neuron latency correlations and an independent component that is local to each neuron. The independent component arises heavily from fluctuations in the underlying probability of spiking, with an unexpectedly small contribution from the stochastic nature of spiking itself. The shared component causes the latency of single-neuron responses in MT to be weakly predictive of the behavioral latency of pursuit. Neural latency deeper in the motor system is more strongly predictive of behavioral latency. A model reproduces both the variance of behavioral latency and the neuron-behavior latency correlations in MT if it includes realistic neural latency variation, neuron-neuron latency correlations in MT, and noisy gain control downstream of MT.