Summary: A comprehensive study mapped neuronal IL-1R1 (nIL-1R1) expression in the mouse brain, highlighting its role in sensory processing, mood, and memory regulation. Researchers found that neurons expressing IL-1R1 integrate immune and neural signals, revealing connections between inflammation and brain disorders like depression and anxiety.
The study pinpointed key regions, such as the somatosensory cortex and hippocampus, where IL-1 signaling influences synapse organization and neural circuit modulation. Notably, neuronal IL-1R1 modifies synaptic pathways without triggering inflammation, suggesting distinct functions in the central nervous system.
Key Facts:
- Immune-Neural Connection: Neuronal IL-1R1 integrates immune signals into neural circuits, influencing sensory, mood, and memory functions.
- Distinct Signaling Pathways: Unlike immune cells, neurons with IL-1R1 regulate synaptic organization without causing inflammation.
- Target Regions: IL-1R1 expression is prominent in areas like the hippocampus and sensory cortex, linked to mood regulation and sensory processing.
Source: FAU
Interleukin-1 (IL-1) is a key molecule involved in inflammation and plays an important role in both healthy and diseased states.
In disease, high levels of IL-1 in the brain are linked to neuroinflammation, which can disrupt the body’s stress response, cause sickness-like behaviors, worsen inflammation by activating brain immune cells, and allow immune cells from the body to enter the brain. It also can lead to brain damage by causing support cells to produce harmful molecules.
Elevated IL-1 levels are associated with mood disorders, such as depression, and problems with memory and thinking.
Conversely, in normal conditions without inflammation, IL-1 has essential roles in the brain. It helps regulate hormone activity, supports healthy sleep patterns, and improves cognitive functions such as memory and learning.
IL-1R1 is like a doorbell on cells that gets rung when there’s an infection or injury, and in immune cells, it signals the body to start an immune response.
However, neurons that express IL-1R1 are not thought to induce inflammation, suggesting that these cells may actually integrate immune signals into neural ones. It has yet to be revealed where or how IL-1R1 (Interleukin-1 Receptor Type 1) may control or modify normal brain function.
Now, a new study by Florida Atlantic University provides the most detailed and comprehensive mapping of neuronal IL-1R1 (nIL-1R1) expression in the mouse brain to date, resolving long-standing inconsistencies.
Previous research has suggested that IL-1 signaling in neurons is involved in sickness behaviors, anxiety, and changes in sleep, but the exact neural circuits involved have not been well-defined.
The study, published in the Journal of Neuroinflammation, narrows down the specific neuronal populations and neurotransmitter systems that could mediate these effects.
Researchers were able to tag neuronal populations that express nIL-1R1 using a clever cell tagging approach, offering new insights into the functional roles of this receptor in the central nervous system (CNS).
Previous studies conducted by the FAU Quan Laboratory, reveal that chronic IL-1 signaling in glutamatergic neurons influences cognitive and social-avoidance behaviors, particularly in the context of neuroinflammation and stress-related disorders.
This supports the idea that nIL-1R1 could play a crucial role in conditions such as chronic stress, depression and anxiety in the unique neural circuits described by the current study.
Using genetically modified mice, researchers identified neurons in certain brain areas such as the somatosensory cortex, hippocampus and others, which have neuronal IL-1R1. Most of these neurons use glutamate (a neurotransmitter for signaling), while some use serotonin (important for mood).
They found that these IL-1R1-positive neurons are involved in circuits that control sensory processing, mood regulation and memory.
“Our study shows how certain neurons are connected to immune signals and may help explain how inflammation contributes to sensory, mood and memory disorders,” said Ning Quan, Ph.D., senior author, professor of biomedical science, FAU Schmidt College of Medicine, and an investigator in the FAU Stiles-Nicholson Brain Institute.
“These findings could lead to new ways to treat brain disorders tied to inflammation. In terms of behavioral implications, our results support the hypothesis that nIL-1R1 signaling influences emotional and cognitive behavior.”
Results reveal that nIL-1R1 expression is most prominent in the somatosensory and glutamatergic systems, areas that had previously been understudied in this context.
Among the brain regions identified as expressing nIL-1R1, the dentate gyrus (DG) was consistently highlighted, reaffirming its role as a key site for neuronal IL-1R1 expression.
The study also pinpoints the thalamic relay centers and various sensory cortical regions, suggesting that IL-1 signaling could play a significant role in sensory processing.
“This new discovery opens up questions about whether immune signals influence our sensory processing and whether IL-1R1-mediated alterations of sensory signals contribute to cognitive issues, anxiety or depression,” said Dan Nemeth, Ph.D., first author and a postdoctoral fellow, FAU Schmidt College of Medicine and Stiles-Nicholson Brain Institute.
“Furthermore, this study shows that neurons do not signal the same way other IL-1R1-expressing cells do.”
While researchers found neuronal IL-1R1 in brain regions related to mood, affect and cognition, an unexpected finding is that IL-1R1 is expressed in neurons in the sensory system.
Using high-tech spatial transcriptomics, they identified that neuronal IL-1R1 regulates gene pathways involved in synapse organization without triggering typical inflammation. This suggests that IL-1R1 has a role in synaptic formation and can modify neural circuits and their function.
“With the most detailed mapping of neuronal IL-1R1 expression in the mouse brain to date, this study brings an unprecedented level of clarity to how IL-1 signaling impacts the neural circuits that govern behavior,” said Randy D. Blakely, Ph.D., co-author, executive director of the FAU Stiles-Nicholson Brain Institute, the David J.S. Nicholson Distinguished Professor in Neuroscience, and a professor of biomedical science in FAU’s Schmidt College of Medicine.
“The findings open the door to new pathways of exploration, offering critical insights into the mechanisms underlying both normal and disrupted behavioral states seen in stress-related disorders, depression and anxiety.”
About this neuroscience research news
Author: Gisele Galoustian
Source: FAU
Contact: Gisele Galoustian – FAU
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Localization of brain neuronal IL-1R1 reveals specific neural circuitries responsive to immune signaling” by Ning Quan et al. Journal of Neuroinflammation
Abstract
Localization of brain neuronal IL-1R1 reveals specific neural circuitries responsive to immune signaling
Interleukin-1 (IL-1) is a pro-inflammatory cytokine that exerts a wide range of neurological and immunological effects throughout the central nervous system (CNS) and is associated with the etiology of affective and cognitive disorders.
The cognate receptor for IL-1, Interleukin-1 Receptor Type 1 (IL-1R1), is primarily expressed on non-neuronal cells (e.g., endothelial cells, choroidal cells, ventricular ependymal cells, astrocytes, etc.) throughout the brain. However, the presence and distribution of neuronal IL-1R1 (nIL-1R1) has been controversial.
Here, for the first time, a novel genetic mouse line that allows for the visualization of IL-1R1 mRNA and protein expression (Il1r1GR/GR) was used to map all brain nuclei and determine the neurotransmitter systems which express nIL-1R1 in adult male mice.
The direct responsiveness of nIL-1R1-expressing neurons to both inflammatory and physiological levels of IL-1β in vivo was tested.
Neuronal IL-1R1 expression across the brain was found in discrete glutamatergic and serotonergic neuronal populations in the somatosensory cortex, piriform cortex, dentate gyrus, and dorsal raphe nucleus.
Glutamatergic nIL-1R1 comprises most of the nIL-1R1 expression and, using Vglut2-Cre-Il1r1r/r mice, which restrict IL-1R1 expression to only glutamatergic neurons, an atlas of glutamatergic nIL-1R1 expression across the brain was generated.
Analysis of functional outputs of these nIL-1R1-expressing nuclei, in both Il1r1GR/GR and Vglut2-Cre-Il1r1r/r mice, reveals IL-1R1+ nuclei primarily relate to sensory detection, processing, and relay pathways, mood regulation, and spatial/cognitive processing centers.
Intracerebroventricular (i.c.v.) injections of IL-1 (20 ng) induces NFκB signaling in IL-1R1+ non-neuronal cells but not in IL-1R1+ neurons, and in Vglut2-Cre-Il1r1r/r mice IL-1 did not change gene expression in the dentate gyrus of the hippocampus (DG).
GO pathway analysis of spatial RNA sequencing 1mo following restoration of nIL-1R1 in the DG neurons reveals IL-1R1 expression downregulates genes related to both synaptic function and mRNA binding while increasing select complement markers (C1ra, C1qb).
Further, DG neurons exclusively express an alternatively spliced IL-1R Accessory protein isoform (IL-1RAcPb), a known synaptic adhesion molecule.
Altogether, this study reveals a unique network of neurons that can respond directly to IL-1 via nIL-1R1 through non-autonomous transcriptional pathways; earmarking these circuits as potential neural substrates for immune signaling-triggered sensory, affective, and cognitive disorders.
