by Ingrid Fadelli , Medical Xpress
The brain of humans and other animals is known to contribute to the protection of the body from infections. Past studies have unveiled the existence of the so-called conditioned immune response (CIR), which is a form of Pavlovian conditioning that entails the formation of mental associations between specific sensory stimuli (e.g., a specific odor, taste, etc.) and immunomodulatory agents (i.e., a substance that influences the immune system).
For instance, if an animal tastes a particular food shortly before becoming ill several times, re-experiencing the same taste can evoke an aversive response and even trigger an anticipatory immune response. While this CIR is now well-documented, its neural underpinnings so far remain poorly understood.
Researchers at University of Haifa recently carried out a study aimed at better understanding the neural pathways involved in these widely reported conditioned immune responses (CIRs). Their paper, published in Nature Neuroscience, outlines a neural pathway that appears to mediate the retrieval of CIRs in male mice.
"Our study was inspired by a long-standing question in neuroscience and immunology: how does the brain regulate immune function based on prior experiences?" Kobi Rosenblum, senior author of the paper, told Medical Xpress.
"While it is well-established that the immune system can 'remember' pathogens through adaptive immunity, it remained unclear how the brain could form associative memories linking sensory experiences—such as taste—to immune responses."
The main objective of the recent study by Rosenblum and his colleagues was to pin-point the exact neural circuitry that allows the mammalian brain to retrieve learned immune responses when presented with sensory stimuli encountered in the past.
To do this, they conducted a series of experiments involving mice, specifically examining their insular cortex (IC), a brain region known to play a part in sensory perception and the maintenance of the body's internal stability (i.e., homeostasis).
"We conducted a classical conditioning paradigm in which mice were first exposed to a novel taste (saccharin) paired with an immune challenge (lipopolysaccharide, LPS)," explained Rosenblum. "Later, upon re-exposure to the same taste alone, we observed a reactivation of the immune response, indicating a learned association."
The researchers selectively manipulated the neural activity in the IC using chemogenetic tools expressed in retro vadeno-associated virus, which specifically expressed Designer Receptors Exclusively Activated by Designer Drugs (DREADDs). These are essentially harmless viruses that neuroscientists use to express proteins in specific brain cells, in this case prompting them to produce the DREADDs.
"Using these chemogenetic tools, we were able to inhibit specific pathways at precise time points," said Rosenblum. "Additionally, we employed molecular markers of neuronal activation to map the specific neural networks engaged during the retrieval of the conditioned immune response."
The findings gathered by Rosenblum and his colleagues offer new insight about the neural pathways contributing to CIRs in mice. Specifically, they suggest that the anterior IC and posterior IC work together to retrieve these learned immune responses.
"The aIC encodes the sensory and associative component of the immune memory, while the pIC integrates this information with immune-related signals," said Rosenblum. "Disrupting the communication between these two regions prevented the conditioned immune response, demonstrating that the brain actively regulates immune function based on learned experiences."
This study unveiled a new neural mechanism that appears to modulate learned immunity in mice. This mechanism could be explored further in future studies, potentially informing the development of new strategies to treat autoimmune diseases with behavioral interventions and/or brain stimulation.
"We now plan to explore whether similar brain circuits are involved in other forms of brain-immune interactions, such as stress-induced immune suppression or the placebo effect," added Rosenblum. "Another exciting direction is identifying specific neurotransmitters and molecular pathways within the IC that mediate these processes, which could pave the way for novel neuromodulatory therapies."
More information: Haneen Kayyal et al, Retrieval of conditioned immune response in male mice is mediated by an anterior–posterior insula circuit, Nature Neuroscience (2025). DOI: 10.1038/s41593-024-01864-4.
Journal information: Nature Neuroscience
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