Neuroscientists have discovered that the receptor IL-1R1 is crucial for allowing neurons to communicate directly with the immune system. A recent study offers the most comprehensive mapping of neuronal IL-1R1 (nIL-1R1) expression in the mouse brain, helping to resolve past discrepancies. The researchers creatively tagged neuronal populations that express nIL-1R1, shedding light on the functional roles of this receptor in the central nervous system (CNS).
Researchers at FAU have found that the receptor IL-1R1 is vital for facilitating direct communication between neurons and the immune system. A new study presents the most thorough mapping of neuronal IL-1R1 (nIL-1R1) expression in the mouse brain, addressing previous inconsistencies. Using an innovative cell tagging method, scientists have identified neuronal populations that express nIL-1R1, providing fresh insights into the receptor’s roles within the central nervous system (CNS).
Interleukin-1 (IL-1) is a significant molecule involved in inflammatory responses, playing a crucial role in both healthy and ill conditions. In disease scenarios, elevated levels of IL-1 in the brain are linked to neuroinflammation, which can disrupt the body’s stress response, lead to sickness-like symptoms, enhance inflammation by activating brain immune cells, and facilitate the entry of peripheral immune cells into the brain. Moreover, it may result in brain damage by encouraging support cells to generate harmful molecules. Increased IL-1 levels are correlated with mood disorders such as depression and issues with memory and cognition.
On the other hand, under normal, non-inflammatory conditions, IL-1 performs essential functions in the brain. It helps regulate hormone functions, maintains healthy sleep cycles, and boosts cognitive abilities like memory and learning.
IL-1R1 functions like a doorbell for cells, signaling them when an infection or injury occurs and prompting immune cells to launch a response. However, neurons that express IL-1R1 are not thought to trigger inflammation; instead, it appears they may integrate immune signals with neural ones. The exact locations and mechanisms through which IL-1R1 (Interleukin-1 Receptor Type 1) may regulate normal brain activity remain unclear.
A new study from Florida Atlantic University delivers the most comprehensive mapping of neuronal IL-1R1 (nIL-1R1) expression in the mouse brain to date, clarifying long-standing uncertainties. Earlier studies have indicated that IL-1 signaling in neurons is linked to sickness behaviors, anxiety, and sleep alterations, but the precise neural circuits involved were not well-defined.
This study, published in the Journal of Neuroinflammation, identifies specific neuronal populations and neurotransmitter systems that could mediate these effects. By employing an ingenious cell tagging technique, researchers have gained new insights into this receptor’s functional roles within the central nervous system (CNS).
Prior research from the FAU Quan Laboratory has shown that ongoing IL-1 signaling in glutamatergic neurons influences cognitive and social-avoidance behaviors, especially regarding neuroinflammation and stress-related conditions. This points to the possibility that nIL-1R1 could have a significant impact on disorders like chronic stress, depression, and anxiety within the distinct neural circuits detailed in this study.
Researchers utilizing genetically modified mice identified neurons in specific areas of the brain, including the somatosensory cortex and hippocampus, where neuronal IL-1R1 is present. The majority of these neurons utilize glutamate (a signaling neurotransmitter), while some depend on serotonin (a key mood-regulating neurotransmitter). These IL-1R1-positive neurons are found to participate in circuits that govern sensory processing, mood control, and memory function.
“Our study illustrates how specific neurons are linked to immune signals, potentially clarifying how inflammation may affect sensory processing, mood, and memory disorders,” stated Ning Quan, Ph.D., the study’s senior author and a professor at FAU’s Schmidt College of Medicine, also associated with the FAU Stiles-Nicholson Brain Institute. “These discoveries may lead to new therapeutic strategies for brain disorders associated with inflammation. Behaviorally, our findings support the hypothesis that nIL-1R1 signaling influences emotional and cognitive behaviors.”
Data reveals that nIL-1R1 expression is particularly evident in the somatosensory and glutamatergic systems, areas that have previously garnered insufficient attention. The dentate gyrus (DG) was consistently noted as a key location for neuronal IL-1R1 expression. The study also highlights thalamic relay centers and various sensory cortical regions, indicating that IL-1 signaling could have a major role in sensory processing.
Dan Nemeth, Ph.D., the study’s first author and a postdoctoral fellow at FAU’s Schmidt College of Medicine and Stiles-Nicholson Brain Institute, remarked, “This discovery raises questions about how immune signals may influence sensory processing and whether changes in sensory signals mediated by IL-1R1 contribute to cognitive difficulties, anxiety, or depression.” He added that the research shows that neurons don’t respond to IL-1R1 in the same way as other IL-1R1-expressing cells.
While researchers did find neuronal IL-1R1 in brain areas associated with mood and cognition, they made an unexpected observation: IL-1R1 was also present in sensory system neurons. Utilizing advanced spatial transcriptomics, they discovered that neuronal IL-1R1 regulates gene pathways related to synapse organization without activating typical inflammation. This finding suggests that IL-1R1 can play a role in synaptic formation and modify the functions of neural circuits.
“With the most intricate mapping of nIL-1R1 expression in the mouse brain to date, this study offers unprecedented clarity regarding the influence of IL-1 signaling on the neural circuits that regulate behavior,” noted Randy D. Blakely, Ph.D., co-author, executive director of the FAU Stiles-Nicholson Brain Institute, and a distinguished professor in FAU’s Schmidt College of Medicine. “The findings pave the way for exploring new pathways, providing critical insights into the mechanisms underlying both typical and impaired behavioral states seen in stress-related disorders, depression, and anxiety.”
