The team, led by Brinda Gurung and Timothy M. Brown of the Centre for Biological Timing, together with John Gigg of the Division of Neuroscience, focused on a network that is central to learning and memory: the hippocampus, the medial prefrontal cortex, and the nucleus reuniens, a relay station in the thalamus that connects the two. The hippocampus is famous for encoding new memories, while the medial prefrontal cortex is involved in working memory and decision-making. The nucleus reuniens acts as a critical bridge, carrying information between these regions in both directions. Understanding how this three-part circuit behaves across the day-night cycle has been difficult because it requires recording from multiple brain regions simultaneously in a living animal.

To do this, the researchers used large-scale in vivo electrophysiological recordings in anaesthetised mice. They delivered precise electrical stimulation to specific pathways within the circuit and measured the resulting synaptic responses, effectively mapping how strongly and how flexibly each connection could transmit signals. They compared recordings taken during the day with those taken at night, using Zeitgeber time, the standard laboratory measure of the light-dark cycle, to define the two phases. They also examined what happened when the animals were exposed to acute light at different times, testing whether illumination itself, independent of the clock, could alter synaptic function.

The results revealed a striking split. Synaptic excitability in the CA1 region of the hippocampus, the area where memories are thought to be written into long-term storage, was higher during the day than at night. In other words, the basic responsiveness of these synapses to incoming signals peaked when the mice, which are nocturnal, would normally be sleeping. But when the researchers probed synaptic plasticity, the capacity of synapses to strengthen in response to repeated activation, they found the opposite pattern. Both short-term plasticity, measured through paired-pulse responses, and long-term potentiation, the long-lasting strengthening widely regarded as a cellular building block of memory, were enhanced at night. Remarkably, these nocturnal increases were localised specifically to the CA1 molecular layer, suggesting that different layers and pathways within the same region follow their own daily schedules.

This antiphase arrangement, with excitability peaking during the day and plasticity peaking at night, implies that the brain does not simply turn memory circuits up or down as a unit. Instead, it appears to trade off different synaptic properties across the cycle. A synapse that is highly excitable during the day may be primed for rapid, reliable transmission, while the same circuitry at night becomes more capable of long-lasting change. Such a division of labour could help explain why behavioural studies in rodents and humans have found that memory performance varies with the time of day, and why sleep, which occupies the rodents’ active night phase, is so closely associated with memory consolidation.

The most surprising discovery, however, concerned light itself. When the researchers exposed the mice to acute light, they found that its effects depended strongly on the time of day, and that these effects were selective to particular pathways. Light exposure changed the responses of the medial prefrontal cortex to input arriving from the nucleus reuniens, but it did not alter the responses of the prefrontal cortex to input arriving directly from the hippocampus. During the day, light drove an increase in synaptic facilitation along the nucleus reuniens to prefrontal cortex pathway, meaning the connection became more effective with repeated stimulation. At night, the same light exposure suppressed that facilitation. Light, in effect, acts like a switch that flips the behaviour of this specific thalamo-cortical connection depending on the phase of the clock.

This pathway selectivity is significant because it shows that light does not blanket the brain with a uniform influence. Instead, it targets particular routes of communication within the memory network. The nucleus reuniens to prefrontal cortex pathway is thought to be important for top-down control of hippocampal activity, allowing the prefrontal cortex to bias which memories and contexts the hippocampus retrieves. Modulating this connection with light, in a time-dependent manner, provides a plausible mechanism by which environmental illumination could influence cognition, attention and memory retrieval at different points in the day.

How might light exert such precise control? The leading candidate is the circadian system, anchored by the suprachiasmatic nucleus of the hypothalamus, the brain’s master clock, which receives direct input from the retina. Light is the primary signal that synchronises this clock to the external world, and the clock in turn coordinates daily rhythms in hormones, neurotransmitters and cellular processes throughout the brain. But the authors also note that light can influence the brain through other, non-circadian routes, including pathways involved in alertness and mood. The new data do not settle which mechanism is responsible, but they demonstrate that the downstream consequence, a phase-dependent change in synaptic function within a defined memory circuit, is real and measurable.

The study also carries methodological weight. By recording evoked responses across multiple layers and regions simultaneously, and by using current source density analysis to localise synaptic currents, the researchers could distinguish effects that would be invisible in single-electrode or slice-based experiments. Their supplementary analyses showed that epochs of ocular illumination did not change basal synaptic excitability or short-term plasticity in the hippocampus to prefrontal cortex pathway, nor did they alter hippocampal or prefrontal oscillation dynamics, underscoring how specific the light effects were. Notably, the high-frequency stimulation protocol used in the study did not produce long-term plasticity in the hippocampus to prefrontal cortex or nucleus reuniens to prefrontal cortex pathways, which may itself reflect the constraints of these connections in the anaesthetised preparation.

For the broader field, the work opens several avenues. If synaptic excitability and plasticity in the hippocampal-prefrontal network are scheduled by the circadian clock, then interventions aimed at boosting memory, whether pharmacological, behavioural or stimulation-based, might need to be timed to the brain’s own rhythm to be effective. The findings may also be relevant to conditions in which circadian disruption and cognitive impairment go hand in hand, such as shift work, jet lag, ageing and neurodegenerative disease. And they raise an intriguing practical question for daily life: how much of the difference between a sharp morning mind and a foggy evening one, or vice versa, is written into the synapses themselves? For now, the mouse data make one thing clear: the circuits we use to learn and remember are continuously retuned by the interplay of light and time, and understanding that retuning may be key to understanding memory itself.

Subject of Research: Circadian and light-dependent modulation of synaptic excitability and plasticity in the mouse hippocampus-prefrontal cortex memory circuit

Article Title: Light and time-of-day differentially impact synaptic excitability and plasticity across the mouse hippocampus-prefrontal cortex network

Article References: Gurung, B., Gigg, J., & Brown, T. M. (2026). Light and time-of-day differentially impact synaptic excitability and plasticity across the mouse hippocampus-prefrontal cortex network. BMC Biology. https://doi.org/10.1186/s12915-026-02714-4

Image Credits: AI Generated

DOI: 10.1186/s12915-026-02714-4

Keywords: hippocampus, medial prefrontal cortex, nucleus reuniens, circadian rhythm, synaptic plasticity, long-term potentiation, synaptic excitability, light exposure, learning and memory, in vivo electrophysiology, CA1, time-of-day

The central component of this new technology is a meticulously engineered microneedle electrode that measures just 5 micrometers in diameter. What sets it apart is the unique fabrication method applied on a flexible substrate, utilizing cutting-edge silicon-growth technology. This flexible design alleviates the rigid constraints typically associated with traditional electrodes, reducing tissue damage upon implantation. As a result, this microneedle electrode represents a leap forward in electrophysiological research, allowing for prolonged and stable monitoring of neuronal activity.

In an experimental study involving mouse models, the research team demonstrated the impressive capabilities of their novel microneedle electrode. After a mere 24 hours post-implantation, the electrodes enabled successful in vivo recordings, and importantly, they maintained their performance for more than a year without significant increase in neuronal death rates. This achievement effectively addresses a long-standing challenge in neural recording: the balance between obtaining high-quality data and minimizing the physiological damage inflicted by electrode insertion.

The implications of these findings are profound, extending beyond fundamental neuroscience research. Long-term recordings of neuronal activity are critical for not only advancing scientific knowledge but also for developing clinical applications in the fields of neurology and neuroengineering. The ability to capture high-resolution, spatiotemporal neural signals using microelectrode devices has previously been impeded by the adverse effects of tissue damage. This new technology holds the promise of overcoming these barriers, offering a more reliable approach to studying brain function and its myriad disorders.

Hinata Sasaki, a Ph.D. candidate and the first author of the study, shared her experiences of undertaking this significant research. Over two years, she diligently recorded neuronal activity in mice implanted with the new electrodes, an endeavor not for the faint of heart. Her tenacity and dedication, coupled with the collaborative efforts of her research group, allowed for the completion of a project that has the potential to reshape the canvas of neural recording technologies.

Delving into the development background reveals the innovative spirit of the research team. Led by Professor Takeshi Kawano, the group initially confronted the inherent limitations imposed by rigid silicon substrates, which were notorious for causing substantial damage to soft brain tissues. During a brainstorming session, an idea surfaced: to eliminate the rigidity of the silicon substrate by modifying the microneedle design. The team devised a method to ‘break’ the base of the silicon microneedle, leading to the successful assembly of the silicon electrode onto a flexible parylene film substrate. This creative approach proved essential in achieving the groundbreaking results observed in their experiments.

After establishing a method for the flexible electrode’s manufacturing process, the research group focused on testing its efficacy. The astonishing results confirmed that the minimal tissue damage allowed for unprecedented levels of neuronal activity recording, revealing stable data over extended periods. This achievement has opened up new avenues for exploration in the neurological sciences, where understanding the long-term dynamics of brain activity is critical.

Research like this provides renewed hope for advancements in the treatment of neurological conditions, including various developmental disorders, epilepsy, and Alzheimer’s disease. With the innovative microneedle electrode technology, scientists can now look forward to conducting in-depth studies without the daunting limitation of rapid tissue deterioration that has plagued previous efforts. The reduced neuronal death rates observed with this new device could significantly impact therapeutic strategies and improve patient outcomes in the future.

The future outlook presented by the research group embraces the vast potential of their new technology. They intend to apply their findings to a wide range of neuroscience studies, giving researchers the tools necessary to explore complex brain functions effectively. The ability to monitor neuronal activity in a minimally invasive manner is a significant stride in bridging the gaps between basic research and clinical applications.

Moreover, this innovative technology has implications for advancements in brain-computer interface (BCI) systems and neuroprosthetics, which rely on precise and reliable neural recordings. As research progresses, the team anticipates that their work will inspire further innovations aimed at unraveling the complexities of the central nervous system and ultimately lead to breakthroughs in treating neurological disorders.

This research underscores the importance of interdisciplinary collaboration in advancing scientific knowledge. With support from various funding agencies, including the Japan Society for the Promotion of Science and the Japan Science and Technology Agency, this project highlights how collective efforts can pave the way for significant medical and technological advancements.

The path forward for this research is indeed promising. By leveraging new technologies and methodologies, scientists stand on the brink of unveiling further mysteries of the human brain, all while pushing the boundaries of what is achievable in the field of neuroscience. The developments at Toyohashi University of Technology are proof that with innovation, dedication, and vision, researchers can turn ambitious ideas into tangible results that have the potential to change the landscape of brain research and therapy for years to come.

In summary, the development of the 5-micrometer-diameter flexible microneedle electrode represents a monumental leap in the field of electrophysiological recording. With its potential to minimize neuronal damage while facilitating long-term monitoring of neuronal activity, it paves the way for groundbreaking research in neuroscience and neurology. As this technology continues to evolve, it promises to deepen our understanding of the brain’s intricate networks and contribute significantly to the future of clinical applications.

Subject of Research: Electrophysiological neural recording technology
Article Title: A Flexible-Substrate 5-μm-Diameter Needle Electrode: Minimizing Neuronal Death and Enabling Year-Long Neural Recording
News Publication Date: 5-Jan-2025
Web References: Advanced Materials Interfaces
References: Hinata Sasaki, Koji Yamashita, Sayaki Shimizu, Kensei Sakamoto, Rika Numano, Kowa Koida, and Takeshi Kawano (2025).
Image Credits: © Toyohashi University of Technology

Keywords

Applied sciences, semiconductor technology, neural recording, electrophysiology, neuroscience, microneedle development, brain research, flexible electronics, silicon technology.