Ventromedial prefrontal parvalbumin neurons are necessary for initiating cued threat avoidance

Joint Public Review:

This study examined the role of parvalbumin (PV) cells in the rodent ventromedial prefrontal cortex (vmPFC) in active avoidance behavior. Using behavior combined with fiber photometry and optogenetics, the results indicate that prefrontal parvalbumin (PV) neurons play a permissive role in acquiring and performing signaled active avoidance learning. Notably, parvalbumin neurons suppress conditional freezing, enabling subjects to acquire the instrumental avoidance contingency and its subsequent performance. These findings advance our understanding of how the prefrontal cortex supports aversively motivated instrumental behavior and may provide insight into both stress vulnerability and resilience processes.

Strengths

All reviewers noted that the paper is well-written and compelling. The experiments themselves were well-designed using state-of-the-art methods and impressive and rigorous analyses. The reviewers appreciated that the authors included multiple controls to demonstrate that the uncovered prefrontal mechanism is selective for the initiation of operant behavior under aversive circumstances, rather than a role for cue offset in triggering changes in PV neuron activity, and for a nonspecific role in movement initiation. The results are all consistent with a conceptual model in which vmPFC PV neurons inhibit freezing to enable avoidance movements

Weaknesses

In general, no substantive weaknesses were noted. Minor weaknesses were noted across two areas, noted below.

Additional Discussion Points

1. There is not much exploration of potential mechanisms, i.e., the impact of PV neuron activity on the broader circuit. Additionally, the study exclusively focuses on PV cells and does not explore the role of other prefrontal populations, particularly those known to respond to cue-evoked fear states. The discussion should consider how PV activity might impact the broader circuit and whether the present findings are specific to PV cells or applicable to other interneuron subtypes.

2. There is some discordance between changes in neural activity and behavior. For example, in Figure 4C, the relationship between PV neuron activity and movement emerges almost immediately during learning, but successful active avoidance emerges much more gradually. Why is this?

3. vmPFC was defined here as including the infralimbic (IL) and dorsal peduncular (DP) regions. While the role of IL has been frequently characterized for motivated behavior, relatively few studies have examined DP. Perhaps the authors are just being cautious, given the challenges involved in the viral targeting of the IL region without leakage to nearby regions such as DP. But since the optical fibers were positioned above the IL region, it is possible that DP did not contribute much to either the fiber photometry signals or the effects of the optogenetic manipulations. Perhaps DP should be completely omitted, which is more consistent with the definitions of vmPFC in the field.

4. In the Discussion, the authors should consider why PV cells exhibit increased activity during both movement initiation and successful chamber crossing during avoidance. While the functional contribution of the PV signal during movement initiation was tested with optogenetic inhibition, some discussion on the possible role of the additional PV signal during chamber crossing is of interest readers who are intrigued by the signaling of two events. Is the chamber crossing signal related to successful avoidance or learned safety (e.g., see Sangha, Diehl, Bergstrom, Drew 2020)?

5. The primary conclusion here that PV cells control the fear response should be considered within the context of prior findings by the Herry laboratory. Courtin et al (2014) demonstrated a select role of prefrontal PV cells in the regulation of fear states, accomplished through their control over prefrontal output to the basolateral amygdala. The observations in this paper, which used both ChR2 and Arch-T to address the impact of vmPFC PV activity on reactive behavior, are highly relevant to issues raised both in the Introduction and Discussion.

Additional analyses

1. As avoidance trials progress (particularly on days 2 and 3), do PFC PV responses attenuate? That is, does continued unreinforced tone presentations lead to reduced reliance of PV cell-mediated suppression in order for successful avoidance to occur?

2. In Figure 3D, it would be very informative and further support the claim of "no role for movement during reward" if the response of these cells during the "initiation of movement during reward-approach" was shown (similar to Figure 1F for threat avoidance).