A brainstem-to-mediodorsal thalamic pathway mediates sound-induced arousal from slow-wave sleep

Individuals utilize alarms as a means of waking up independently from their natural sleep-wake cycle. This takes advantage of the defense mechanism present in animals to protect against potential dangers during sleep, such as the presence of predators. The thalamus, a neural substrate, is responsible for relaying external sensory signals to the cortex during the waking state. However, during slow-wave sleep (SWS), which is a deep sleep stage, thalamic neurons undergo burst firing instead of tonic firing, preventing sensory information from reaching the cortex. This sensory gating mechanism of the thalamus explains the brain's overall insensitivity to external sensory stimuli during deep sleep.

Studies have shown that midline thalamic neurons, including the mediodorsal (MD) thalamus, play a role in mediating cortical activation and arousal. These neurons have broad thalamocortical projections across the entire cortical column and multiple layers, while sensory thalamic nuclei send outputs only to specific cortical areas. This anatomical difference may allow the MD thalamus to facilitate broader cortical connectivity, which is otherwise lost during SWS sleep. Clinical investigations have shown that patients with lesions in the midline thalamic area have reduced arousal, indicating the importance of the midline thalamus in arousal. Additionally, the activity of midline thalamic neurons has been found to be correlated with wakefulness on the sleep-wake axis, and photostimulation of these midline thalamic nuclei has been shown to induce arousal in sleeping mice.

These midline thalamic neurons receive inputs from brainstem sites that regulate the sleep-wake cycle and are also responsive to auditory stimuli. This suggests a connection between auditory input and arousal. However, it remains unknown whether direct activation of this pathway can influence arousal or if a thalamic mechanism for auditory-induced arousal exists.

A recent study conducted by Anna Shin and colleagues (2023) tested these ideas through single-unit recordings, fiber photometry, and manipulation of the midline thalamus activity. Utilizing optogenetic tools, they identified a brainstem-to-midline thalamic circuit that can drive arousal and modulate auditory-induced arousal.

The study uncovered a circuit in the brainstem-thalamic area that is responsible for maintaining wakefulness and modulating the EEG and EMG activity during auditory-induced arousal. This circuit was discovered through the examination of previous research which primarily focused on the role of the cholinergic pathways in thalamic regulation. Additionally, the study results suggested that the MD thalamus was influenced by glutamatergic neurons in the MN, which may be more in line with the rapid and sensory-driven nature of arousal. This result may also suggest that the MD thalamus translates the activity from the IC-MN projection into cortical activation. However, the specific roles of the MD or the MN-MD projection over a longer time period or across an entire circadian period still need to be identified.

The recovery of consciousness from REM sleep and SWS involves different mechanisms, and the MN-MD thalamic projection has been shown to only modulate arousal from SWS but not REM sleep. This suggests that the MN-MD thalamic projection may represent a specialized circuit that can bypass the inability of the thalamus to relay sensory signals during SWS. There may be several redundant circuits that allow rapid arousal from SWS in response to potential dangers. The relationship between BFGABA neurons and MD thalamic neurons is currently unknown and may be resolved through future research.

This study highlights the importance of understanding the mechanisms behind arousal in the brain and its potential implications for managing various neurological disorders associated with the dysregulation of arousal or minimally conscious states. The diversity of each circuitry in sleep/wake transitions should also be carefully considered due to the varying protocols used for inducing wakefulness.

References:

Shin, A., Park, S., Shin, W., Jeong, M., Kim, J., & Kim, D. (2023). A brainstem-to-mediodorsal thalamic pathway mediates sound-induced arousal from slow-wave sleep. Current Biology, 33, R98-R109. https://doi.org/10.1016/j.cub.2023.01.033