2026 Theses Doctoral

Contributions of the Locus Coeruleus-Norepinephrine System to Pupil-Linked Arousal and Cortical State Dynamics

Weiss, Evan

Neuromodulatory systems, particularly the locus coeruleus-norepinephrine (LC-NE) system, play a central role in regulating global brain state, coordinating shifts in arousal, and shaping the large-scale cortical dynamics that underlie sensory processing, cognition, and behavior. LC neurons project abundantly throughout the forebrain as the primary source of norepinephrine in the brain, and both their tonic and phasic firing modes are tightly linked to behavioral state, attentional engagement, and performance. Because fluctuations in pupil diameter strongly covary with LC activity, pupil size has become a widely used noninvasive readout of arousal-related neural dynamics. Yet the precise relationship between LC activation, pupil fluctuations, and the accompanying changes in cortical state remains unclear. In particular, spontaneous pupil dilations arise from a distributed network of neuromodulatory and premotor structures, raising the possibility that the cortical states associated with spontaneous arousal differ fundamentally from those driven directly by LC output. As a result, the mechanisms through which LC activity, neuromodulatory context, and cell-type heterogeneity shape cortical population dynamics remain largely unresolved.

This dissertation investigates how selective and non-selective activation of the LC contributes to the structure of cortical state transitions across multiple arousal contexts. Using optogenetics, cortical EEG, pupillometry, pharmacological manipulation, and neural decoding approaches, this work dissects the circuit mechanisms by which LC activity generates the neural signatures typically associated with arousal. The first component of this work directly compares spontaneous phasic pupil dilations with pupil dilations evoked by precise optogenetic LC stimulation. Although LC activation reliably produced phasic dilations and a shift toward cortical desynchronization, the spectral signatures accompanying these LC-evoked events differed markedly from those observed during spontaneous dilations of comparable amplitude. High-resolution spectral analysis and convolutional neural network decoding revealed that spontaneous and LC-evoked dilations arise from distinct neuromodulatory states, indicating that spontaneous pupil-linked arousal reflects integrated activity across multiple systems beyond the LC-NE pathway alone.

To further probe how neuromodulatory context shapes these cortical signatures, pharmacological perturbation of α- and β-adrenergic receptors was performed. Manipulating adrenergic tone altered the temporal structure of spontaneous dilations, reshaped cortical spectral dynamics, and reduced the separability between spontaneous and LC-evoked pupil dilations in low-frequency EEG bands. These results demonstrate that adrenergic receptor engagement actively maintains the geometry of cortical state transitions during phasic arousal, and that spontaneous arousal events recruit a broader neuromodulatory architecture than LC activation alone.

Finally, we investigated a stimulation paradigm that more closely reflects clinical deep brain stimulation of the LC region, where selective activation of LC-NE neurons is not feasible without genetic perturbations. This work compared selective activation of Dbh⁺ noradrenergic LC neurons with non-selective activation that recruits heterogeneous LC and peri-LC populations. Non-selective stimulation produced strong, frequency-dependent entrainment and clear harmonic structure in the cortical EEG, whereas selective activation of LC-NE neurons failed to produce robust entrainment, particularly in awake animals. Despite also evoking pupil dilations, selective LC activation did not impose rhythmic structure on cortical population activity, indicating that entrainment might be a circuit-level phenomenon requiring coordinated recruitment of multiple LC subtypes and adjacent brainstem structures. Entrainment was also strongly modulated by brain state, shifting from low-frequency regimes under anesthesia to higher-frequency regimes during wakefulness.

Together, these findings reveal that the LC’s contribution to arousal and cortical state regulation is determined by neuromodulatory conditions, receptor engagement, and the heterogeneity of LC population recruitment. Spontaneous and LC-evoked pupil dilations reflect distinct neuromodulatory states; adrenergic receptor tone shapes the cortical activity associated with phasic arousal; and that rhythmic entrainment of cortical circuits can arise through a broad, non-selective activation of heterogeneous LC subpopulations. This work provides a mechanistic reinterpretation of the LC’s role within a distributed arousal network, clarifies the limits of pupil diameter as a selective readout of LC activity, and offers new principles for designing neuromodulatory interventions and closed-loop stimulation paradigms aimed at manipulating cortical state and cognitive function.