Biology subjects

Bova, A.

Publications and source records attributed to Bova, A..

4 recordsLinked to original sources

bioRxiv2025

Ventral tegmental area dopamine controls timing variability

Precision defines successful behavior, yet the brain mechanisms promoting precision are unclear. Here, we dissect dopaminergic circuits controlling precision along a single behavioral dimension - the timing of action. We use an interval timing paradigm that requires participants to indicate their estimate of an interval of several seconds with a motor response. We find that humans with Parkinsons disease (PD) had increased timing variability that predicted PD-related cognitive deficits and executive dysfunction. Surprisingly, lesioning ventral tegmental area (VTA) dopamine neurons increased temporal variability. Further, GCaMP6s fiber photometry demonstrated that VTA dopamine neuron activity is strongly modulated at the start of temporal intervals, and that this trial start-related activity predicted temporal variability. Finally, we found that stimulation of VTA dopamine neurons improved timing by decreasing temporal variability in both intact and dopamine-depleted animals. Our data establish a model of cognitive symptoms of human PD and provide insight into the neuronal control of temporal variability, which impacts a wide range of executive functions.

neuroscience↗

bioRxiv2025

Timing, movement, and reward contributions to prefrontal and striatal ramping activity

Across species, prefrontal and striatal neurons exhibit time-dependent ramping activity, defined as a consistent monotonic change in firing rate across temporal intervals. However, it is unclear if ramping activity is related to the cognitive process of estimating time, or to other behavioral factors such as anticipating reward or regulating movements. Here, we harnessed two novel approaches to determine how these factors contribute to prefrontal and striatal ramping activity in mice performing an interval timing task. First, to determine how movement contributes to ramping activity, we tracked movement velocity using DeepLabCut as well as task-specific movements while recording prefrontal or striatal ensembles during interval timing. We found that time was more accurately decoded by ramping neurons than movement-modulated neurons, with the exception of prefrontal velocity-modulated neurons. Second, to disambiguate temporal signals from anticipatory reward signals we compared activity patterns in neurons that were recorded during interval timing to the same neurons recorded during a Pavlovian conditioning task. We found more ramping activity and more accurate temporal decoding by neuronal ensembles during interval timing compared to Pavlovian conditioning. Together, these data quantify contributions of time estimation, movement, and reward anticipation in prefrontal and striatal ensembles, and they suggest that ramping is a cognitive signal that estimates time. Our results provide insight into how prefrontal and striatal ensembles multiplex information to effect temporal control of action.

neuroscience↗

bioRxiv2023

Complementary cognitive roles for D2-MSNs and D1-MSNs in interval timing

The role of striatal pathways in cognitive processing is unclear. We studied dorsomedial striatal cognitive processing during interval timing, an elementary cognitive task that requires mice to estimate intervals of several seconds and involves working memory for temporal rules as well as attention to the passage of time. We harnessed optogenetic tagging to record from striatal D2- dopamine receptor-expressing medium spiny neurons (D2-MSNs) in the indirect pathway and from D1-dopamine receptor-expressing MSNs (D1-MSNs) in the direct pathway. We found that D2-MSNs and D1-MSNs exhibited distinct dynamics over temporal intervals as quantified by principal component analyses and trial-by-trial generalized linear models. MSN recordings helped construct and constrain a four-parameter drift-diffusion computational model in which MSN ensemble activity represented the accumulation of temporal evidence. This model predicted that disrupting either D2-MSNs or D1-MSNs would increase interval timing response times and alter MSN firing. In line with this prediction, we found that optogenetic inhibition or pharmacological disruption of either D2-MSNs or D1-MSNs increased interval timing response times. Pharmacologically disrupting D2-MSNs or D1-MSNs also changed MSN dynamics and degraded trial-by-trial temporal decoding. Together, our findings demonstrate that D2-MSNs and D1-MSNs had opposing dynamics yet played complementary cognitive roles, implying that striatal direct and indirect pathways work together to shape temporal control of action. These data provide novel insight into basal ganglia cognitive operations beyond movement and have implications for human striatal diseases and therapies targeting striatal pathways.

neuroscience↗

bioRxiv2020

Precisely-timed dopamine signals establish distinct kinematic representations of skilled movements

Brain dopamine is critical for normal motor control, as evidenced by its importance in Parkinson Disease and related disorders. Current hypotheses are that dopamine influences motor control by "invigorating" movements and regulating motor learning. Most evidence for these aspects of dopamine function comes from simple tasks (e.g., lever pressing). Therefore, the influence of dopamine on motor skills requiring multi-joint coordination is unknown. To determine the effects of precisely-timed dopamine manipulations on the performance of a complex, finely coordinated dexterous skill, we optogenetically stimulated or inhibited midbrain dopamine neurons as rats performed a skilled reaching task. We found that reach kinematics and coordination between gross and fine movements progressively changed with repeated manipulations. However, once established, rats transitioned abruptly between aberrant and baseline reach kinematics in a dopamine-dependent manner. These results suggest that precisely-timed dopamine signals have immediate and long-term influences on motor skill performance, distinct from simply "invigorating" movement.

neuroscience↗