The Role of Phasic Cholinergic Modulation in the Medial Prefrontal Cortex During Threat Learning

To survive, animals learn the predictive relationships between threats and preceding cues or actions and later use these associations to guide adaptive decisions. This ability relies on the prelimbic region (PL) of the medial prefrontal cortex, which is critical for evaluating predictive relationships to inform learning and decision-making. Concurrently, the PL receives strong neuromodulatory signals, specifically acetylcholine from the basal forebrain (BF) cholinergic neurons. These neurons release precisely timed signals upon threats during cognitive tasks. However, the function of these signals in the PL during threat learning remains unknown. To address this, I first investigated the real-time dynamics of phasic cholinergic signals in the PL during an aversive associative learning task. Fiber photometric recordings of BF cholinergic terminals revealed that innate threat-locked phasic cholinergic activity diminished with learning, while a strong response to the cue developed as mice formed the cue-threat association. Using optogenetics, I further demonstrated that phasic cholinergic signals exerted opposite effects on learning depending on their temporal alignment: suppression of threat-locked phasic cholinergic signals facilitated learning, while stimulation of these signals impeded learning. In contrast, inhibition of cue-locked phasic cholinergic signals impaired learning, while their excitation had no effect. Next, using an aversive spatial learning task, I examined how threat-locked phasic cholinergic signals influenced learning when mice needed to discriminate between two maze paths that differed in threat probabilities. I found that optogenetically enhancing threat-locked phasic cholinergic signals impaired optimal decisions by making mice abandon correct choices when confronted with occasional, surprising threats. Importantly, this impairment was only seen when threats were delivered probabilistically but spared learning when threats were delivered deterministically. To uncover the underlying mechanism, I combined in vivo one-photon calcium imaging of PL cells with optogenetic stimulation of BF cholinergic terminals. I found that enhanced threat-locked phasic cholinergic signals modified PL coding of prediction errors by increasing its selectivity to signed but not unsigned prediction errors. Together, these findings suggest that threat-locked phasic cholinergic signals transmitted via the BF-PL pathways are crucial for threat learning and modulate PL computation of prediction error coding, thereby influencing how much outcomes dictate future choices under uncertainty.

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