# Pharmacological and non-pharmacological methods of inducing wakefulness activate distinct neural populations in the mouse brain

## TL;DR

This study shows that different ways of inducing wakefulness in mice activate distinct brain regions, revealing new insights into how wakefulness is regulated.

## Contribution

The study identifies distinct neural populations activated by pharmacological and non-pharmacological wakefulness using whole-brain analysis in mice.

## Key findings

- Solriamfetol activates nine subcortical structures more than modafinil and non-pharmacological wakefulness.
- Orexin neurons and certain nuclei are strongly activated across all wakefulness types.
- Some classical wake systems show weak activation, suggesting alternative roles or mechanisms.

## Abstract

A large body of data indicate that the aminergic, cholinergic and hypocretin/orexin neurons are responsible for inducing wakefulness. However, recent data showed that other systems might also play a key role. Further, wakefulness induced by different drugs versus non-pharmacological means could be generated by different populations of neurons. To address these questions, we evaluated at the whole brain level in the same mice using TRAP2 model whether the same neurons were activated by the wake-inducing drugs modafinil and solriamfetol versus non-pharmacological wake. Our results show that nine subcortical structures namely the oval part of the bed nucleus of the stria terminalis, lateral part of the central amygdalar nucleus, paraventricular hypothalamic and thalamic and supraoptic nuclei, external part of the lateral parabrachial nucleus, caudal part of the nucleus of the solitary tract and the area postrema are significantly more activated by solriamfetol than modafinil and non-pharmacological wakefulness. In contrast, a second category of structures including the orexin neurons, the parasubthalamic and laterodorsal tegmental nucleus are strongly activated in all types of induced wake. Further, some classical wake systems like the dopaminergic neurons of the ventral tegmental area or the dorsal raphe nucleus and the noradrenergic neurons of the locus coeruleus are either very poorly or not strongly activated. These results reveal that many structures not previously involved in wakefulness might play a key role in regulating the state and that some structures might be more recruited by solriamfetol than modafinil or non-pharmacological wakefulness. Our results are particularly relevant for pathologies such as hypersomnia. They open a new era in the study of the mechanisms responsible for inducing wakefulness.

Wakefulness arises from multiple neuronal systems but it is unclear whether the same or different neurons are activated during pharmacological or non-pharmacological intervention. This study uses the TRAP2 mouse model to examine whole-brain activation patterns and shows that solriamfetol, modafinil and nonpharmacological arousal recruit overlapping but distinct subcortical populations.