2026 Theses Doctoral

Modulation of Inhibitory Control and Prefrontal Population Activity by the Noradrenergic–Cholinergic Interplay

Liu, Yuxiang

The overarching purpose of this work is to understand how noradrenergic (NE)–cholinergic (ACh) interactions modulate inhibitory control and shape prefrontal population activity. The study investigated how perceptual decision making depends differently on heartbeat-linked and pupil-linked arousal systems (Liu et al., 2021), established the noradrenergic–cholinergic interplay as a mechanism for prefrontal modulation of inhibitory control behavior (Liu et al., 2025), and characterized the representation of cognitive effort in the prefrontal cortex during inhibitory control training.

We began by examining how two arousal systems indexed by peripheral physiological signals influence perceptual behavior. By simultaneously recording electrocardiogram (ECG) and pupil size in head-fixed rats performing a tactile discrimination task, we showed that heartbeat dynamics and pupil-linked arousal each covaried with behavioral outcomes. A Bayesian decoding analysis revealed that combining these signals improved prediction of perceptual decisions beyond either alone, indicating that they provide complementary information about internal state during pre-stimulus periods.

We next investigated how neuromodulators directly regulate higher-order cognitive processes. To establish NE–ACh interplay as a mechanism for prefrontal modulation of inhibitory control, we developed an inhibitory control task in mice and simultaneously measured NE/ACh dynamics in the prefrontal cortex (PFC), with observed NE–ACh phase synchrony at the 0.4–0.8 Hz frequency band. Disrupting locus coeruleus (LC) projections to the basal forebrain (BF) selectively impaired inhibitory control and abolished performance-related NE–ACh phase synchrony, whereas targeting LC–PFC or cholinergic projections to the LC had minimal effects. Neuropixels recordings further showed that LC–BF disruption degraded PFC population encoding of inhibitory control. Together, these findings identified phase synchrony between prefrontal NE and ACh signals as an important neuromodulatory feature which reliably indexes inhibitory control.

Finally, we showed that inhibitory control training progressively reshapes prefrontal population dynamics to encode an internal cognitive effort signal that accumulates during behavioral inhibition. By formalizing cognitive effort as a nonlinearly increasing control demand, we identified prefrontal neurons whose firing rates track this buildup. The proportion of effort-encoding neurons increased with task exposure. Selective inactivation of LC–BF projections reduced the recruitment of these prefrontal neural populations. Together, these findings suggested cognitive effort as a key variable encoded in the prefrontal cortex that supports sustained inhibitory control.

Together, this work spans multiple levels of analysis, from peripheral arousal signals that index internal brain states and influence perceptual behavior, to neuromodulatory interactions between NE and ACh that shape inhibitory control via prefrontal population dynamics, and to PFC activity that encodes cognitive effort during inhibitory control. Collectively, these findings provide a multi-level view of how arousal state, NE/ACh neuromodulation, and prefrontal neural plasticity contribute to cognitive control.