Neuronal tuning to threat exposure remains stable in the mouse prefrontal cortex over multiple days.

Intense threat elicits action in the form of active and passive coping. The medial prefrontal cortex (mPFC) executes top-level control over the selection of threat coping strategies, but the dynamics of mPFC activity upon continuing threat encounters remain unexplored. Here, we used 1-photon calcium imaging in mice to probe the activity of prefrontal pyramidal cells during repeated exposure to intense threat in a tail suspension (TS) paradigm. A subset of prefrontal neurons displayed selective activation during TS, which was stably maintained over days. During threat, neurons showed specific tuning to active or passive coping. These responses were unrelated to general motion tuning and persisted over days. Moreover, the neural manifold traversed by low-dimensional population activity remained stable over subsequent days of TS exposure and was preserved across individuals. These data thus reveal a specific, temporally, and interindividually conserved repertoire of prefrontal tuning to behavioral responses under threat.

A persistent prefrontal reference frame across time and task rules.

Behavior can be remarkably consistent, even over extended time periods, yet whether this is reflected in stable or 'drifting' neuronal responses to task features remains controversial. Here, we find a persistently active ensemble of neurons in the medial prefrontal cortex (mPFC) of mice that reliably maintains trajectory-specific tuning over several weeks while performing an olfaction-guided spatial memory task. This task-specific reference frame is stabilized during learning, upon which repeatedly active neurons show little representational drift and maintain their trajectory-specific tuning across long pauses in task exposure and across repeated changes in cue-target location pairings. These data thus suggest a 'core ensemble' of prefrontal neurons forming a reference frame of task-relevant space for the performance of consistent behavior over extended periods of time.

Pro-cognitive effect of upregulating cyclic guanosine monophosphate signalling during memory acquisition or early consolidation is mediated by increased AMPA receptor trafficking.

BACKGROUND: Episodic memory consists of different mnemonic phases, including acquisition and early and late consolidation. Each of these phases is characterised by distinct molecular processes. Although both cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) are implicated in the acquisition phase, early consolidation only depends on cGMP, whereas late consolidation is mediated by cAMP. Accordingly, the cGMP-selective phosphodiesterase 5 (PDE5) inhibitor vardenafil or the cAMP-selective PDE4 inhibitor rolipram can improve memory acquisition or consolidation when applied during their respective time windows. AIMS: Considering the important role of glutamatergic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR) during normal memory function, we aimed to investigate whether the differential actions of these PDE inhibitors are mediated through AMPAR dynamics. METHODS: For biochemical analysis, mice were treated with either vardenafil or rolipram and sacrificed shortly after injection. For the behavioural studies, mice received either of the inhibitors during the different mnemonic phases, while their spatial memory was tested using the object location task, and they were sacrificed 24 hours later. RESULTS: Administration of either vardenafil or rolipram causes rapid changes in AMPARs. Moreover, treatment with vardenafil during the acquisition or early consolidation of spatial memory resulted in increased surface levels of AMPARs which were still augmented 24 hours after learning. Membrane levels of AMPARs were not affected anymore 24 hours after learning when rolipram was administrated at either the acquisition or late consolidation phase. CONCLUSIONS: These results suggest that dissociative molecular mechanisms could mediate the pro-cognitive function of different classes of PDE inhibitors, and in the case of vardenafil, this phenomenon could be explained by changes in AMPAR dynamics.