Summary: Researchers have created a light-sensitive compound that boosts adenosine signaling in the brain and can induce sleep in mice without the need for genetic modification. This optochemical approach targets adenosine A2A receptors in the nucleus accumbens, enabling precise, reversible control of sleep and motivational states while avoiding several limitations of earlier photosensitive agents.
The work illustrates the growing potential of optochemistry as a method for brain-specific drug targeting and modulation of neural circuits involved in sleep and motivation.
Key Facts:
- Innovative approach: A visible-light–activated drug increases adenosine activity and promotes slow-wave sleep by acting on A2A receptors in the nucleus accumbens.
- Addresses prior limitations: The new molecule overcomes common obstacles for in vivo photopharmacology such as phototoxicity, limited blood–brain barrier permeability, and inefficient photoreactions.
- Funding and support: Research funded by the World Premier International Research Center Initiative (WPI), Japan Science and Technology Agency CREST, Grants-in-Aid for Scientific Research, and AMED.
Source: University of Tsukuba
The nucleus accumbens is central to both motivational behavior and sleep regulation through adenosine A2A receptors (A2AR). Targeting A2AR selectively within this brain region offers a route to control sleep and motivation, but systemic A2A receptors are expressed throughout the body (including the heart), making precise brain-specific modulation challenging without genetic tools.
To address these challenges, a multidisciplinary team led by Professor Michael Lazarus and Associate Professor Tsuyoshi Saitoh at the University of Tsukuba developed a photoactivatable positive allosteric modulator that enhances extracellular adenosine signaling selectively in the nucleus accumbens. By administering this compound to freely moving mice and illuminating the nucleus accumbens with visible light, the researchers were able to trigger slow-wave sleep in animals without any genetic modification.
Previous photosensitive compounds encountered practical problems that limited their effectiveness in living mammals. Ultraviolet activation raises concerns about phototoxicity and tissue damage, while many molecules lacked the ability to cross the blood–brain barrier efficiently or to switch cleanly between active and inactive states with visible light. The new compound was designed to be brain-permeable and activatable by visible wavelengths (λ > 400 nm), reducing these risks and enabling rapid, localized control over receptor activity.
The compound functions as an allosteric modulator of A2A receptors: in its inactive state it remains largely inert, and upon illumination it enhances the receptor’s responsiveness to extracellular adenosine. In behavioral experiments, this optoallosteric activation of A2AR in the nucleus accumbens increased adenosine-mediated signaling derived from both astrocytes and neurons, which in turn promoted slow-wave sleep in male mice. Importantly, the approach accomplished temporally precise modulation without permanently altering the animals’ genetics.
Funding: This research was supported by the World Premier International Research Center Initiative (WPI), Japan Science and Technology Agency CREST Grant (JPMJCR1655), Grants-in-Aid for Scientific Research (JP21H02802, JP23H04148), and AMED (JP21zf0127005).
About this neurotechnology and sleep research
Author: YAMASHINA Naoko
Source: University of Tsukuba
Contact: YAMASHINA Naoko – University of Tsukuba
Image: The image is credited to Neuroscience News
Original research (open access): Optochemical control of slow-wave sleep in the nucleus accumbens of male mice by a photoactivatable allosteric modulator of adenosine A2A receptors, by Michael Lazarus et al., published in Nature Communications.
Abstract
Optochemical control of slow-wave sleep in the nucleus accumbens of male mice by a photoactivatable allosteric modulator of adenosine A2A receptors
Optochemistry uses light to selectively activate or deactivate pharmaceutical agents, offering the promise of precise spatial and temporal control over drug actions. This strategy can reduce unwanted systemic effects and enable targeted modulation of neural circuits to alleviate symptoms or improve quality of life.
Translating optochemical methods to in vivo brain applications without relying on genetic engineering has been slow, in part because of the need for compounds that are both brain-permeable and activatable by tissue-safe wavelengths. The nucleus accumbens (NAc) integrates motivational signals and plays a key role in regulating slow-wave sleep (SWS). Adenosine, acting through A2A receptors on indirect-pathway neurons in the NAc, is a strong candidate mediator of SWS induction.
In this study, the team developed a brain-penetrant positive allosteric modulator of A2A receptors that is rapidly photoactivatable by visible light (λ > 400 nm). Using this optoallosteric compound, they were able to increase extracellular adenosine signaling arising from astrocytes and neurons and induce slow-wave sleep in the nucleus accumbens of freely moving male mice. The results demonstrate a non-genetic, light-controlled approach for selectively modulating sleep-related circuits and highlight the broader potential of optochemistry for targeting central nervous system receptors.