Biology subjects

Assad, J. A.

Publications and source records attributed to Assad, J. A..

5 recordsLinked to original sources

bioRxiv2025

A mechanism linking dopamine's roles in reinforcement, movement and motivation

Dopamine neurons (DANs) play seemingly distinct roles in reinforcement,1-3 motivation,4,5 and movement,6,7 and DA-modulating therapies relieve symptoms across a puzzling spectrum of neurologic and psychiatric symptoms.8 Yet, the relationship among these roles is unknown. Here, we show DAs tripartite functions are causally linked by a process in which phasic striatal DA rapidly and persistently recalibrates the propensity to move, a measure of vigor. Using a self-timed movement task, we found that single exposures to reward-related DA transients (both endogenous and exogenously-induced) exerted one-shot updates to movement timing--but in a surprising fashion. Rather than reinforce specific movement times, DA transients quantitatively changed movement timing on the next trial, with larger transients leading to earlier movements (and smaller to later), consistent with a stochastic search process that calibrates the frequency of movement. Both abrupt and gradual changes in external and internal contingencies--such as timing criterion, reward content, and satiety state--caused changes to the amplitude of DA transients that causally altered movement timing. The rapidity and bidirectionality of the one-shot effects are difficult to reconcile with gradual synaptic plasticity, and instead point to more flexible cellular mechanisms, such as DA-dependent modulation of neuronal excitability. Our findings shed light on how natural reinforcement, as well as DA-related disorders such as Parkinsons disease, could affect behavioral vigor.

neuroscience↗

bioRxiv2021

Dopamine mediates the bidirectional update of interval timing

The role of dopamine as a reward prediction error signal in reinforcement learning tasks has been well-established over the past decades. Recent work has shown that the reward prediction error interpretation can also account for the effects of dopamine on interval timing by controlling the speed of subjective time. According to this theory, the timing of the dopamine signal relative to reward delivery dictates whether subjective time speeds up or slows down: Early DA signals speed up subjective time and late signals slow it down. To test this bidirectional prediction, we reanalyzed measurements of dopaminergic neurons in the substantia nigra pars compacta of mice performing a self-timed movement task. Using the slope of ramping dopamine activity as a read-out of subjective time speed, we found that trial-by-trial changes in the slope could be predicted from the timing of dopamine activity on the previous trial. This result provides a key piece of evidence supporting a unified computational theory of reinforcement learning and interval timing.

neuroscience↗

bioRxiv2020

Integrated tapered fibertrode for simultaneous control and readout of neural activity over small brain volumes with reduced light-induced artefacts

Recognizing the neural patterns underlying different brain functions is essential to achieve a more comprehensive view on how small sets of neurons organize in complex 3D networks to determine different behaviours. In this framework, optogenetic techniques have been successfully proven as a powerful tool to control brain functions achieving millisecond temporal resolution and cell-type specificity, by combining the use of light-gated opsins and ad-hoc light delivery optoelectronic devices. However, targeting small brain volumes with simultaneous electrical recording results in the introduction of photoelectric artefacts, in particular when light emission and recoding sites are very close one to each other. In this work we take advantage of the photonic properties of tapered fibers to present a fully integrated fibertrode to target small brain volumes with abated photoelectric noise. The device hosts a light emitting window just below a recording pad, and exploits the angled light emission from the window to achieve simultaneous activation and electrical readout of small groups of cells with no photoelectric artifacts in vivo. Despite the highly non-planar surface of the fiber taper, windows size, shape and electrodes impedance can be modulated by controlling the fabrication parameters during focused ion beam milling and deposition, thus resulting in a versatile, integrated and customizable optogenetic tool for neurobiology studies in closed-loop configuration over small brain volumes.

neuroscience↗

bioRxiv2020

Application of a unifying reward-prediction error (RPE)-based framework to explain underlying dynamic dopaminergic activity in timing tasks

Dopaminergic neurons (DANs) exhibit complex dynamics across a variety of behavioral contexts, often in ways that seem task-specific and even incompatible with results across different paradigms. Dopaminergic signaling during timing tasks has been a prime example. In behavioral timing, dopaminergic dynamics predict the initiation of self-timed movement via a seconds-long ramp up of activity prior to movement onset, similar to ramping seen in visuospatial reward approach and multi-step, goal-directed behaviors. By contrast, in perceptual timing, DANs exhibit more complex dynamics whose direction of modulation seems to be the opposite of that observed in behavioral timing. Mikhael et al. (2022) recently proposed a formal model in which dopaminergic dynamics encode reward expectation in the form of an "ongoing" reward-prediction error (RPE) that arises from resolving uncertainty of ones position in the value landscape (i.e., ones spatial-temporal distance to reward delivery/omission). Here, we show that application of this framework recapitulates and reconciles the seemingly contradictory dopaminergic dynamics observed in behavioral vs perceptual timing. These results suggest a common neural mechanism that broadly underlies timing behavior: trial-by-trial variation in the rate of the internal "pacemaker," manifested in DAN signals that reflect stretching or compression of the derivative of the subjective value function relative to veridical time. In this view, faster pacemaking is associated with relatively high amplitude dopaminergic signaling, whereas slower pacemaking is associated with relatively low levels of dopaminergic signaling, consistent with findings from pharmacological and lesion studies.

animal behavior and cognition↗

bioRxiv2020

Dynamic dopaminergic activity controls the timing of self-timed movement

Clues from human movement disorders have long suggested that the neurotransmitter dopamine plays a key role in motor control, but how the endogenous dopaminergic system regulates movement is unknown. Here we show dynamic dopaminergic signaling over seconds-long timescales controls movement timing in mice. Animals were trained to initiate licking after a self-timed interval following a start-timing cue. The movement time was variable from trial-to-trial, as expected from previous studies. Surprisingly, dopaminergic signals ramped-up over seconds between the start-timing cue and the self-timed movement, with variable dynamics that predicted the movement time on single trials. Steeply rising signals preceded early lick-initiation, whereas slowly rising signals preceded later initiation. Higher baseline signals also predicted earlier self-timed movements. Optogenetic activation of dopamine neurons during self-timing did not trigger immediate movements, but rather caused systematic early-shifting of movement initiation, whereas inhibition caused late-shifting, as if modulating the probability of movement. Consistent with this view, the dynamics of the endogenous dopaminergic signals quantitatively predicted the moment-by-moment probability of movement initiation on single trials. These results reveal a causal role for dynamic dopaminergic signaling unfolding over seconds in modulating the decision of when to move.

neuroscience↗