Learning differentially shapes prefrontal and hippocampal activity during classical conditioning

  1. Jan L. Klee
  2. Bryan C. Souza
  3. Francesco P. Battaglia

  • Curated by eLife

    eLife logo

    Evaluation Summary:

    The hippocampal CA1 area and the PFC are extensively studied in spatial navigation tasks but relatively less investigated in non-spatial, classical conditioning tasks. The different dynamics between CA1 and PFC during the trace and inter-trial interval periods identified here are insightful. Also, the ensemble reactivation during explicitly non-spatial tasks is novel and fills a critical gap in knowledge. However, the current form does not highlight these novel findings or does not make a strong case on how they contribute to learning. Furthermore, there are a number of experimental and analytical issues that need to be addressed.

    (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.)

Reviewed by

Read the full article See related articles

Listed in

Log in to save this article

Abstract

The ability to use sensory cues to inform goal directed actions is a critical component of intelligent behavior. To study how sound cues are translated into anticipatory licking during classical appetitive conditioning, we employed high-density electrophysiological recordings from the hippocampal CA1 area and the prefrontal cortex (PFC). CA1 and PFC neurons undergo distinct learning dependent changes at the single cell level and maintain representations of cue identity during anticipatory behavior at the population level. In addition, reactivation of task-related neuronal assemblies during hippocampal awake Sharp-Wave Ripples (aSWR) changed within individual sessions in CA1 and over the course of multiple sessions in PFC. Despite both areas being highly engaged and synchronized during the task, we found no evidence for coordinated single cell or assembly activity during conditioning trials or aSWR.

Article activity feed

  1. eLife

    Evaluation Summary:

    The hippocampal CA1 area and the PFC are extensively studied in spatial navigation tasks but relatively less investigated in non-spatial, classical conditioning tasks. The different dynamics between CA1 and PFC during the trace and inter-trial interval periods identified here are insightful. Also, the ensemble reactivation during explicitly non-spatial tasks is novel and fills a critical gap in knowledge. However, the current form does not highlight these novel findings or does not make a strong case on how they contribute to learning. Furthermore, there are a number of experimental and analytical issues that need to be addressed.

    (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.)

  2. eLife

    Reviewer #1 (Public Review):

    In this paper, the authors recorded in CA1 region of the dorsal hippocampus and medial prefrontal cortex (mPFC) while mice underwent appetitive trace conditioning tasks. The tasks included discrete trials presented every ~40 sec (ITI). In some trials, a neutral auditory stimulus preceded the delivery of reward after a 1-second delay, while in other trials, another stimulus was presented by itself. They reported that a sizable proportion of CA1 and mPFC neurons changed firing rates in response to the stimuli and reward. As ensembles, neurons in both regions differentiated the reward-predictive stimuli from the non-predictive one and between two different stimuli predictive of the same reward. Furthermore, these ensemble firing patterns were reactivated during ITIs, and the timing of the reactivation was locked to sharp-wave ripples (SWR) in CA1.

    The experiments were well designed and yielded exciting, valuable findings. The analyses were sophisticated and generally sound. In particular, direct comparisons of neural selectivity between CA1 and the mPFC in the same non-spatial task is unique and speaks to their potential functional differences. Furthermore, the reactivation of task-related ensemble activity is a relevant extension of the literature on memory trace reactivation, which is built exclusively based on spatial memory.

  3. eLife

    Reviewer #2 (Public Review):

    This manuscript by Klee et al describes their study on the dynamics of neuronal activities in the hippocampal CA1 and the prefrontal cortex (PFC) in an auditory trace conditioning task. The authors trained mice to respond (with anticipatory licking) to one or two sounds (CS+) associated with water reward delivered after a trace delay period, but not to a control sound (CS-). The authors recorded CA1 and PFC neurons and examined the dynamic changes in the activities of these neurons during a baseline period, the period of stimulus (CS+ or CS-) presentation, the delay period, the reward consumption period, and during the inter-trial interval afterwards. The results are complex. But mainly they found CA1 and PFC neurons responded to and distinguished stimulus identities (between CS+ and CS- or between two CS+ sounds) during the stimulus presentation. During the delay and later reward periods, PFC neurons maintained high level of activities after the CS+ presentation, but CA1 neurons reduced their activities. In both areas, the ensemble activities (states) deviated from the baseline after the stimulus onset and stayed so afterwards. In addition, they found that the CA1 neuronal ensembles reactivated during the inter-trial interval were related to those with decreased activities during the delay period and the activation increased with trials within a session. In contrast, the PFC ensembles were related to those PFC neurons with increased activities during reward consumption and increased slowly with training days.

    Both CA1 and PFC neurons have been extensively studied in spatial navigation tasks. Their activities and dynamics are relatively less examined in classical conditioning tasks, especially in trace conditioning, although important progress has been made. The different dynamics between CA1 and PFC during the delay and inter-trial interval periods identified here are new findings that are insightful. However, these findings are broad and general in nature, and thus are limited in new understanding of how the stimulus identity is encoded during the delay period and how the reactivation during the inter-trial interval contributes to the task.

  4. eLife

    Reviewer #3 (Public Review):

    Klee et al. investigate prefrontal and hippocampal ensemble activity patterns before and after learning of an appetitive trace conditioning task using auditory cues. They report evoked and sustained firing in both regions during trace periods that retains stimulus identity, with distinct prevalence of trace-period activity suppression in CA1 and enhancement in PFC that emerges after learning for conditioned stimuli. A novel finding reported is the reactivation of task-related neuronal assemblies during awake hippocampal Sharp-Wave Ripples (aSWRs) in inter-trial intervals that shows different learning-dependent changes in the two regions.

    The manuscript adds to our understanding of prefrontal and hippocampal activity patterns in trace conditioning tasks, with the primary novel finding being assembly reactivation during aSWRs. However, there are some key weaknesses in the current form. The findings need to be better grounded in existing literature on prefrontal and hippocampal activity in such tasks. Results are presented separately for the two regions throughout the manuscript, and there is no examination of relationships or coordination across the two regions. Several results will benefit from additional analyses for clarification.

    1. The study uses recordings in both medial prefrontal cortex (PFC) and hippocampal area CA1 to investigate how neuronal activity patterns can encode and maintain stimulus information during delay period of an appetitive auditory trace conditioning task. Animals learned to discriminate between two stimuli, CS+ and CS-, over several days with only CS+ stimulus paired with reward at the end of a trace period, resulting in anticipatory licking behavior. Neural populations in CA1 and PFC showed emergence of distinct response profiles when animals learned the task. Evoked response for CS+ stimuli were selectivity enhanced for CS+ stimuli in both regions. During the trace period, CA1 population activity showed overall suppression of activity compared to baseline firing for CS+ stimuli, whereas PFC showed enhanced trace-period activity.

    This analysis primarily use a subtractive measure (change in firing rate from baseline), and averages across all neurons to infer sustained trace-period suppression in CA1 and enhancement in PFC for CS+ stimuli. Since the population consists of neurons with variable baseline rates and variable levels of responsiveness, the results need to be confirmed using another metric, which can control for this variability and avoid outlier contributions from neurons with high firing rates.

    1. Both regions showed prevalence of Trace-Up and Trace-Down neurons, exhibiting increased and decreased firing during trace periods respectively. In CA1, Trace-Down neurons showed stronger suppression for CS+ stimuli, whereas in PFC, Trace-Up neurons showed stronger enhancement for CS+ stimuli. Population activity in both regions was able to distinguish stimulus identity during trace periods.

    In these analyses, the differing contributions of Trace-up and Trace-down neurons to the overall differential population response in the two regions is not clear.

    1. These results examining CA1 and PFC responses during task periods is presented separately for the two regions. Several previous studies have examined prefrontal and hippocampal activity patterns separately during learning of trace conditioning tasks, and the current results need to be discussed in context of existing findings in literature. Given the interpretation of activity patterns in the CA1-PFC circuit for learning and execution of the task, the manuscript will significantly benefit from examination of potential relationships or coordination between neuronal activity in the two regions.

    2. The key novel finding of the study is that during inter-trial periods, task-related neuronal assemblies were reactivated during awake hippocampal sharp-wave ripples (aSWRs) in both regions, which may play a role in learning of the task. This reactivation of cell assemblies increased significantly from pre- to post- learning sessions for PFC, and within individual pre-learning sessions for CA1. Strongly reactivated assemblies in PFC were related to reward responses, and those in CA1 were related to suppression of activity during trace periods.

    The authors conclude that this reactivation plays a role in learning the task. This claim requires further supporting evidence, including elucidation of relationship of reactivated cell assemblies with activity patterns described for CS+ and CS- stimuli, details about rate and distribution of aSWRs over learning, and examination of relationship of reactivation in the two regions and any potential changes over learning.

  5. Version 2 published on bioRxiv
  6. Version 1 published on bioRxiv