Summary: A new study uncovers a precise brain pathway that quickly converts emotional stress into sudden wakefulness during NREM sleep. The researchers found that GABAergic neurons in the BNST activate glutamatergic neurons in the DpMe, causing immediate arousal.
When DpMe neurons were removed, the arousal response was dramatically weakened, showing that they are essential for this stress-wake circuit. 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: GABAergic BNST neurons trigger rapid excitation via DpMe glutamatergic neurons. Essential function: Deletion of glutamatergic DpMe cells dramatically reduced stress-induced wakefulness. Clinical Potential: Targeting this circuit may help treat insomnia and stress-related 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 the regulation of 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 GABAergic BNST neurons during NREM sleep resulted in immediate awakening, accompanied by a strong increase in DpMe neuronal activity.
In contrast, selective ablation of glutamatergic neurons in DpMe significantly reduced this response, demonstrating its essential role in the process.
This study was the first to thoroughly describe a BNST-DpMe neural pathway that mediates emotional signals in arousal centers. Additionally, the findings offer novel insights into how mental stressors, such as fear and anxiety, can disrupt sleep and highlight potential therapeutic targets for insomnia and stress-related mood disorders.
Funds:
This study was supported by the World Premier International Research Center Initiative (WPI), a JSPS KAKENHI Grant for Scientific Research (B) (JP 18H02595) (TS), a JSPS KAKENHI Grant for Scientific Research (B) (JP 18H02595) (TS), a JSPS KAKENHI Grant for Scientific Research (A) (JP 21H05036) (TS), Grant Number JSPS KAKENHI JP 23H04941 (TS), AMED Moonshot Research and Development Programme, Grant Number JP21zf0127005 (TS), JSPS Fund for the Promotion of Joint International Research 22K213511(TS) and JST, CREST Grant Number JPMJCR24T4, JSPS Grant for Transformative Research Areas (A) 23H04941(TS).
Key questions answered:
A: Activating a BNST to DpMe circuit that instantly switches from NREM sleep to wakefulness.
A: The glutamatergic neurons of the DpMe are essential for transmitting the wake-up signal.
A: Identify a specific neural pathway that may be overactive in stress-related sleep disruption.
Editorial notes:
This article was edited by a Neuroscience News editor. Magazine article reviewed in its entirety. Additional context added by our staff.
About this news about stress and sleep research
Author: YAMASHINA Naoko
Source: University of Tsukuba
Contact: YAMASHINA Naoko – University of Tsukuba
Image: Image is credited to Neuroscience News.
Original Research: Closed access.
“The bed nucleus of the stria terminalis: circuit of the deep mesencephalic nucleus linking emotion and wakefulness” by SAKURAI, Takeshi et al. Neuroscience Magazine
Abstract
The bed nucleus of the stria terminalis: circuit of the deep mesencephalic nucleus that links emotion and wakefulness.
The bed nucleus of the stria terminalis (BNST), a part of the extended amygdala, integrates emotional and arousal-related signals.
Although GABAergic BNST neurons (GABABNST) have been implicated in promoting transitions from non-rapid eye movement (NREM) sleep to wakefulness, their downstream mechanisms remain unclear.
Here, we identify a neural circuit through which GABABNST neurons promote excitation through projections to a region of the midbrain 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, neuronal ablation, and tracing approaches to dissect this circuit.
Optogenetic stimulation of GABABNST terminals in DpMe during NREM sleep caused 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 puff of air activated GLUTDpMe neurons, suggesting the involvement of emotionally salient stimuli.
Ablation of GLUTDpMe neurons markedly attenuated the excitatory responses triggered by GABABNST stimulation, underscoring its essential role in this circuit.
While monosynaptic rabies tracing revealed input neurons local to GLUTDpMe cells, in situ hybridization identified few Vgat-positive interneurons among them.
These findings suggest that GABABNST neurons may influence GLUTDpMe neurons through non-canonical GABAergic mechanisms or through 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 disorders and represents a potential target for therapeutic treatments for sleep disorders associated with emotional dysregulation.
