A night without sleep produced increased markers of connections between brain cells, showing that sleep in humans may be important for restoring cellular balance in the brain, according to a study published in PLOS Biology by David Elmenhorst from the Forschungszentrum Jülich Institute of Neuroscience and Medicine in North Rhine-Westphalia, Germany, and colleagues.

Scientists have long wondered why humans and other animals need to sleep. One potential mechanism is that sleep is required to restore synaptic connections and homeostasis in the brain. Synapses—the connections between brain cells—become stronger during wakefulness.

This increases the amount of energy the brain needs and leads to a buildup of proteins in the brain. Sleep is thought to reset these levels, reducing synaptic connections and restoring homeostasis, but evidence has thus far been limited to animal models.

Physical pain is essential for survival, as it allows animals to detect when they are injured or unwell, seek shelter and address their ailments. Yet when it becomes chronic, pain can also become highly distressing and debilitating.

While there are now several therapeutic strategies for managing chronic pain, an emerging one that has been found to be particularly promising is vagus nerve stimulation (VNS). VNS entails the delivery of mild electrical pulses to the nerve that connects the brain to organs throughout the body.

Past studies suggest that VNS-based therapy can reduce the pain associated with various medical conditions, including chronic headaches, fibromyalgia and joint inflammation. The neural processes by which it can ease pain, however, are still poorly understood.

In this study, we characterized PAC-832, a small-molecule GalR1 antagonist with sub-micromolar potency (IC₅₀ = 0.28 μM), 30-fold selectivity over GalR2 and GalR3, and excellent brain penetration and drug-like properties. In functional cell-based assays, PAC-832 reversed galanin-mediated suppression of acetylcholine release. In a scopolamine challenge model, PAC-832 attenuated cognitive deficits in the Y-maze and NOR tasks, with effect sizes comparable to donepezil.

The scopolamine model is widely used in behavioral mouse research to evaluate compounds for procognitive activity. However, because scopolamine impairs cognition by blocking muscarinic receptors rather than by reducing acetylcholine release, our behavioral results do not directly assess whether PAC-832 acts by restoring cholinergic signaling in vivo, or whether it acts through an alternative downstream mechanism. Establishing the former will require direct measurement of acetylcholine release in the CNS (e.g. using microdialysis or biosensor-based approaches) and/or GalR1-dependent in vivo validation (e.g. using transgenic GalR1-knockout mice).

Nonetheless, our work addresses a longstanding pharmacological gap in the galanin field. Despite decades of work implicating galanin signaling in CNS function and disease, translational progress has been limited by a lack of subtype-selective, brain-penetrant small molecule galanin modulators. Recent therapeutic development within the galanin field has largely focused on GalR2 agonism, while GalR1-targeting approaches have remained dependent on peptide tools unable to pass the blood-brain barrier. PAC-832 is, to our knowledge, the first GalR1-selective small molecule antagonist with sufficient brain exposure to test the effects of GalR1 antagonism following peripheral administration.