Time encoding migrates from prefrontal cortex to dorsal striatum during learning of a self-timed response duration task
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Evaluation Summary
This study investigates the question of whether distinct brain areas differentially encode time during the learning of a simple motor timing task. The key novel result is that early in training the dynamics of the medial prefrontal cortex (mPFC) provides the best code for time, but later in training, the basal ganglia and in particular, the striatum provides a better code. In addition, the study shows that inactivation of mPFC produces a delayed learning effect, while inactivation of the striatum after learning led to impaired performance. The observation that temporal coding and the necessity of brain area for task performance transfers from medial prefrontal cortex to the striatum during learning is an intriguing observation for our understanding of the neural mechanisms underlying temporal processing in sensorimotor control.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)
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Abstract
Although time is a fundamental dimension of life, we do not know how brain areas cooperate to keep track and process time intervals. Notably, analyses of neural activity during learning are rare, mainly because timing tasks usually require training over many days. We investigated how the time encoding evolves when animals learn to time a 1.5 s interval. We designed a novel training protocol where rats go from naive- to proficient-level timing performance within a single session, allowing us to investigate neuronal activity from very early learning stages. We used pharmacological experiments and machine-learning algorithms to evaluate the level of time encoding in the medial prefrontal cortex and the dorsal striatum. Our results show a double dissociation between the medial prefrontal cortex and the dorsal striatum during temporal learning, where the former commits to early learning stages while the latter engages as animals become proficient in the task.
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Evaluation Summary
This study investigates the question of whether distinct brain areas differentially encode time during the learning of a simple motor timing task. The key novel result is that early in training the dynamics of the medial prefrontal cortex (mPFC) provides the best code for time, but later in training, the basal ganglia and in particular, the striatum provides a better code. In addition, the study shows that inactivation of mPFC produces a delayed learning effect, while inactivation of the striatum after learning led to impaired performance. The observation that temporal coding and the necessity of brain area for task performance transfers from medial prefrontal cortex to the striatum during learning is an intriguing observation for our understanding of the neural mechanisms underlying temporal processing in …
Evaluation Summary
This study investigates the question of whether distinct brain areas differentially encode time during the learning of a simple motor timing task. The key novel result is that early in training the dynamics of the medial prefrontal cortex (mPFC) provides the best code for time, but later in training, the basal ganglia and in particular, the striatum provides a better code. In addition, the study shows that inactivation of mPFC produces a delayed learning effect, while inactivation of the striatum after learning led to impaired performance. The observation that temporal coding and the necessity of brain area for task performance transfers from medial prefrontal cortex to the striatum during learning is an intriguing observation for our understanding of the neural mechanisms underlying temporal processing in sensorimotor control.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)
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Reviewer #1 (Public Review):
This is an interesting study supporting the notion mPFC is involved in early learning stages while the striatum becomes more engaged as animals become proficient in a temporal task. However, I have several concerns about whether the results support the main conclusions of the paper. First and foremost, it is difficult to dissociate the role of mPFC and the striatum linked with a better representation of elapsed time with learning from the operational learning aspects of the task. The latter include the increase in attention of sensory inputs associated with the nose poke, an increase in precision of movement kinematics (less body and face movements during the nose poke), and a more developed reward expectation from learning to time the 1.5 s. The authors should perform careful analysis to try to dissociate …
Reviewer #1 (Public Review):
This is an interesting study supporting the notion mPFC is involved in early learning stages while the striatum becomes more engaged as animals become proficient in a temporal task. However, I have several concerns about whether the results support the main conclusions of the paper. First and foremost, it is difficult to dissociate the role of mPFC and the striatum linked with a better representation of elapsed time with learning from the operational learning aspects of the task. The latter include the increase in attention of sensory inputs associated with the nose poke, an increase in precision of movement kinematics (less body and face movements during the nose poke), and a more developed reward expectation from learning to time the 1.5 s. The authors should perform careful analysis to try to dissociate the learning of temporal and non-temporal factors and the involvement of the two areas. Second, I have comments of the decoding analysis. It is now well known that the neural activity associated with timed behaviors scales with time. Since the decoding was performed on truncated trials at 1.5s, the analysis will not capture the neural pattern of activation in longer trials. Thus, this is decoding of absolute elapsed time using activity of neurons that probably are encoding relative trial length. In addition, it seems that both areas encode the beginning and end of the trials, with high densities in the diagonal only on the initial and final bins, rather than the elapsed time across all the trials. These results could be related with learning of non-temporal factors discussed previously. Furthermore, the decoding of elapsed time both areas went down from early to late trials in the experiment of one session, supporting the notion that the striatum does not take over, although the rats learned to time the interval. This is contrary to the conclusions of the paper. Finally, animals with mPFC inactivations did not change behavior of the first session, but they partially learned on sessions two, three and five (with an increase mu2). How are these findings matching with the observation that mPFC decoding performance dramatically lowers on the second day?
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Reviewer #2 (Public Review):
This study by Tunes et al. addresses a little-studied problem of how neural mechanisms supporting motor timing might be coordinated across brain areas during the learning of a task. The authors first developed a motor timing task in which rats exhibited significant learning in a little as a single day. The task required that rats learn to insert their snout into a nose-port and maintain its position there for at least 1.5s in order to trigger liquid reward delivery at a second location. Initially, rats frequently removed their snout from the port in advance of the 1.5s criteria, but adjusted their removal times later over the initial session(s). The authors proceeded to record from ensembles of neurons in medial prefrontal cortex (mPFC) or dorsal striatum during these initial sessions. They found that …
Reviewer #2 (Public Review):
This study by Tunes et al. addresses a little-studied problem of how neural mechanisms supporting motor timing might be coordinated across brain areas during the learning of a task. The authors first developed a motor timing task in which rats exhibited significant learning in a little as a single day. The task required that rats learn to insert their snout into a nose-port and maintain its position there for at least 1.5s in order to trigger liquid reward delivery at a second location. Initially, rats frequently removed their snout from the port in advance of the 1.5s criteria, but adjusted their removal times later over the initial session(s). The authors proceeded to record from ensembles of neurons in medial prefrontal cortex (mPFC) or dorsal striatum during these initial sessions. They found that decoding of elapsed time during the wait period improved in the striatum with experience, but degraded in the mPFC. They then performed a series of pharmacological inactivation experiments in mPFC and striatum and found that, consistent with the information they found in neural activity, mPFC was required for normal learning of the task, and striatum for expression of the behavior after learning. These represent potentially important observations, but I feel that more information is needed about the data set and methods in order to critically evaluate the robustness of their results.
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Reviewer #3 (Public Review):
Numerous studies have demonstrated that the neural dynamics on different brain areas encode elapsed time, yet it has proven challenging to examine how these population clocks emerge over the course of learning because most temporal tasks require many training sessions. In this manuscript the authors use a simple timing task that can be learned in a single day, and accompany the changes in neural dynamics in the mPFC and STR of the first and second day on the task. The most interesting finding is a switch in which the mPFC provides a better code than the STR for elapsed time on the first day, but the STR provides a better code than the mPFC on the second day. Consistent with the increased encoding of time in the mPFC early in training, muscimol inactivation of the mPFC impaired learning of the task, but not …
Reviewer #3 (Public Review):
Numerous studies have demonstrated that the neural dynamics on different brain areas encode elapsed time, yet it has proven challenging to examine how these population clocks emerge over the course of learning because most temporal tasks require many training sessions. In this manuscript the authors use a simple timing task that can be learned in a single day, and accompany the changes in neural dynamics in the mPFC and STR of the first and second day on the task. The most interesting finding is a switch in which the mPFC provides a better code than the STR for elapsed time on the first day, but the STR provides a better code than the mPFC on the second day. Consistent with the increased encoding of time in the mPFC early in training, muscimol inactivation of the mPFC impaired learning of the task, but not performance in trained animals. Overall this study provides a number of novel contributions to our understanding of temporal processing, and show the first example of learning-dependent switch from the dynamics of the mPFC to that of the STR encode time.
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