Summary: A new study uncovers a precise brain pathway that rapidly converts emotional stress into sudden wakefulness during NREM sleep. Researchers found that GABAergic neurons in the BNST activate glutamatergic neurons in the DpMe, causing immediate arousal.
When the DpMe neurons were removed, the arousal response weakened dramatically, proving they are essential for this stress-to-wake circuitry. These findings reveal how fear and anxiety can instantly disrupt sleep and point to new therapeutic targets for stress-related insomnia.
Key Facts:
- Stress Pathway: BNST GABAergic neurons trigger fast arousal via DpMe glutamatergic neurons.
- Essential Role: Removing DpMe glutamatergic cells sharply reduced stress-induced wakefulness.
- Clinical Potential: Targeting this circuit may help treat stress-related insomnia and mood disorders.
Source: University of Tsukuba
Emotional states and stress strongly influence sleep-wake regulation.
The amygdala and its related structures have long been implicated in regulating arousal. However, the underlying neural mechanisms remain unclear.
In this study, the researchers examined how GABAergic neurons in the BNST interact with glutamatergic neurons in the DpMe to induce rapid arousal from non-rapid eye movement (NREM) sleep in mice.
Optogenetic stimulation of BNST GABAergic neurons during NREM sleep resulted in immediate arousal, accompanied by a robust increase in DpMe neuronal activity.
Conversely, selective ablation of glutamatergic neurons in the DpMe significantly reduced this response, demonstrating their essential role in the process.
This study was the first to thoroughly describe a BNST-DpMe neural pathway mediating emotional signals to arousal centers. In addition, the findings offer novel insights into how mental stressors such as fear and anxiety can disrupt sleep and highlights potential therapeutic targets for stress-related insomnia and mood disorders.
Funding:
This study was supported by the World Premier International Research Center Initiative (WPI), a JSPS KAKENHI Grant-in-Aid for JSPS KAKENHI Grant-in-Aid for Scientific Research (B) (JP 18H02595) (TS), Grant-in-Aid for Challenging Research (Exploratory) 21K19287(TS), JSPS KAKENHI Grant-in-Aid for Scientific Research (A) (JP 21H05036) (TS), JSPS KAKENHI Grant Number JP 23H04941 (TS), AMED Moonshot Research and Development Program, Grant Number JP21zf0127005 (TS), JSPS Fund for the Promotion of Joint International Research 22K213511(TS) and JST, CREST Grant Number JPMJCR24T4, JSPS Grant-in-Aid for Transformative Research Areas (A) 23H04941(TS).
Key Questions Answered:
A: By activating a BNST-to-DpMe circuit that instantly shifts NREM sleep into wakefulness.
A: Glutamatergic neurons in the DpMe are essential for transmitting the wake-up signal.
A: It identifies a concrete neural pathway that may be overactive in stress-related sleep disruption.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this stress and sleep research news
Author: YAMASHINA Naoko
Source: University of Tsukuba
Contact: YAMASHINA Naoko – University of Tsukuba
Image: The image is credited to Neuroscience News
Original Research: Closed access.
“The bed nucleus of the stria terminalis- deep mesencephalic nucleus circuit linking emotion and wakefulness” by SAKURAI, Takeshi et al. Journal of Neuroscience
Abstract
The bed nucleus of the stria terminalis- deep mesencephalic nucleus circuit linking emotion and wakefulness
The bed nucleus of the stria terminalis (BNST), a part of the extended amygdala, integrates emotional and arousal-related signals.
While GABAergic BNST (GABABNST) neurons have been implicated in promoting transitions from non-rapid eye movement (NREM) sleep to wakefulness, their downstream mechanisms remain unclear.
Here, we identify a neuronal circuit through which GABABNST neurons promote arousal via projections to a midbrain region known as the deep mesencephalic nucleus (DpMe), located within the broader mesencephalic reticular formation.
In male mice, we used a combination of optogenetics, fiber photometry, neural ablation, and tracing approaches to dissect this circuit.
Optogenetic stimulation of GABABNST terminals in the DpMe during NREM sleep elicited rapid transitions to wakefulness and increased activity of glutamatergic DpMe (GLUTDpMe) neurons, as assessed by c-fos mRNA expression and calcium imaging. Similarly, an aversive air-puff activated GLUTDpMe neurons, suggesting engagement by emotionally salient stimuli.
Ablation of GLUTDpMe neurons markedly attenuated arousal responses triggered by GABABNST stimulation, underscoring their essential role in this circuit.
While monosynaptic rabies tracing revealed local input neurons to GLUTDpMe cells, in situ hybridization identified few Vgat-positive interneurons among them.
These findings suggest that GABABNST neurons may influence GLUTDpMe neurons through noncanonical GABAergic mechanisms or via more complex local circuits beyond a simple disinhibition model.
Together, these findings delineate a previously uncharacterized BNST–DpMe circuit that allows emotionally relevant stimuli to override sleep and promote arousal.
This pathway may contribute to stress-related sleep disturbances and represents a potential target for therapeutic treatments for sleep disorders associated with emotional dysregulation.
