The review begins with a deceptively simple question: how do signals generated by an infection or injury in the body gain access to the brain at all? The answer, the authors explain, involves two complementary routes. The first is neural. Sensory neurons — including spinal afferents with cell bodies in the dorsal root ganglia and cranial afferents housed in the nodose ganglia of the vagus nerve — detect immune molecules and pathogens directly. TRPV1-expressing nociceptors, best known for transmitting pain, can also sense bacterial components and toxins. These neurons relay what the authors call immune information to the brainstem through canonical spinothalamic pathways, providing a rapid, topographically organized mechanism for monitoring physiological threats.

The vagus nerve has emerged as a particularly sophisticated sensory conduit for immune information. Early electrophysiological recordings and c-Fos staining showed that vagal neurons respond to interleukin-1β, but more recent work has revealed a remarkable degree of specificity. Tumor necrosis factor and IL-1β evoke distinct afferent neurograms, and in vivo calcium imaging has shown that pro- and anti-inflammatory cytokines activate two discrete, non-overlapping populations of nodose neurons — one expressing CALCA and the other TRPA1. Individual neurons produce stereotyped, concentration-dependent responses that are cytokine-specific in amplitude and kinetics, with some tuned to a single cytokine and others encoding several through distinct activity patterns. How the vagus achieves this specificity remains unresolved: cultured nodose neurons show surface expression of TNF and IL-1β receptors, yet IL-1 receptor binding sites have also been localized to glomus cells of vagal paraganglia, leaving open whether the neurons themselves or neighboring stromal cells do the sensing.

Vagal afferents project primarily to the nucleus of the solitary tract, the first central site where organ-specific immune signals converge. TRPA1-positive and CALCA-positive afferents synapse monosynaptically onto dopamine β-hydroxylase-expressing neurons in the caudal NTS, which bidirectionally regulate peripheral immune responses and function as a central rheostat balancing pro- and anti-inflammatory reflexes. Repeated allergen exposure activates these same neurons in a vagus-dependent manner, and they relay signals through the nucleus ambiguus to drive airway hyperreactivity. Through projections to the hypothalamus, the NTS also transforms immune signals into sickness behavior: lipopolysaccharide, a bacterial mimic, activates ADCYAP1-positive neurons that are both necessary and sufficient for LPS-induced anorexia, adipsia, and lethargy.

The second route is humoral. Soluble circulating mediators can reach the brain through circumventricular organs, specialized regions that lack a complete blood-brain barrier and are permeable to inflammatory mediators even under homeostatic conditions. Their fenestrated vasculature and efferent projections make them well suited to transduce systemic immune signals into neural activity. Work by Osterhout and colleagues showed that two hallmarks of sickness behavior — fever and appetite suppression — are driven by neurons in the ventral medial preoptic area of the hypothalamus, engaged by a local paracrine mechanism in which non-neuronal cells at the adjacent organum vasculosum of the lamina terminalis detect circulating immune signals and activate nearby VMPO neurons. Beyond this local action, CVOs project directly to regions involved in affective regulation, including the cortex, forming a key anatomical link between circulating cytokines and behaviors associated with affective dysregulation.

Even the intact blood-brain barrier actively participates in this signaling. Endothelial cells and pericytes respond to circulating cytokines by producing secondary messengers such as prostaglandins, which diffuse into the parenchyma and propagate the inflammatory signal into neural tissue. Under strong or prolonged inflammation, the balance shifts from signal transduction toward structural compromise: pro-inflammatory cytokines including TNF and IL-17 induce matrix metalloproteinase activity, driving tight junction remodeling, increased permeability, and ultimately leukocyte infiltration into the brain. These effects are amplified through sphingosine-1-phosphate receptor signaling and chemokine-MMP interactions. Inflammatory states such as sepsis are consistently associated with increased BBB permeability and elevated central cytokine levels, and under chronic stress, MMP8 — a myeloid-derived proteinase elevated in major depressive disorder — can enter the nucleus accumbens, remodel the extracellular space, and alter behavior.

With the delivery routes established, the review turns to the cortical regions that transform these signals into altered behavior. The prefrontal cortex, which supports executive control and behavioral flexibility, is well positioned to receive immune signals: its prelimbic and infralimbic subregions lie close to the immunologically rich meninges and receive projections from circumventricular organs. Allgire and colleagues showed that severe airway inflammation disrupts fear extinction — the suppression of learned fear in the absence of threat, whose failure defines anxiety and trauma-related disorders — through IL-17A signaling in the subfornical organ, a CVO that projects to the infralimbic cortex. Blocking IL-17A or silencing SFO-to-ILA projections restored normal extinction, confirming this circuit as a conduit between peripheral immunity and prefrontal function. PFC neurons also respond directly to cytokines: at homeostasis, meningeal γδ T cell-derived IL-17A engages IL-17Ra on PFC glutamatergic neurons, and neuronal deletion of the receptor reduces anxiety-like behavior, while interferon gamma increases inhibitory input onto pyramidal cells to set baseline anxiety levels. Under challenge, IL-6 alters the intrinsic excitability of PFC neurons and reduces inhibitory input onto pyramidal cells, promoting disinhibition and a social defeat phenotype. Consistent with these rodent findings, postmortem tissue from suicide victims shows elevated proinflammatory cytokine and chemokine expression in the PFC.

The insular cortex, the primary cortical hub for interoceptive processing, offers a complementary mechanism. Immune information likely reaches the IC through the neural pathway relayed via the NTS, parabrachial nucleus, and thalamus, and intestinal infection with Campylobacter jejuni induces c-Fos expression throughout the interoceptive network, including the vagal ganglia, NTS, and IC. Human imaging shows increased activity and microstructural changes in the IC following experimental immune activation, and notably, TNF-α neutralization therapy in patients with arthritis affects IC activity before it achieves anti-inflammatory effects in the joints — suggesting the IC may be among the earliest cortical regions to sense a change in immune state. The IC is especially suited to link inflammation with affective dysregulation because interoceptive signals are actively incorporated into its evaluation of threat: during fear conditioning, cardiac feedback shapes IC activity to balance fear expression and extinction, and artificially imposed tachycardia activates the IC and heightens anxiety, an effect abolished by IC inhibition. The IC therefore treats bodily state as information about external threat, and raising heart rate alone is enough to shift that evaluation. If inflammation is sustained, the same mechanism would report a threat that no longer exists and become maladaptive.

The primary somatosensory cortex adds a third cortical node to the model. Through its connections with the insular cortex and amygdala, S1 integrates sensory information with affective and interoceptive signals, assigning emotional salience to stimuli — particularly pain. The clearest mechanistic example comes from maternal immune activation, in which prenatal immune challenge elevates multiple pro-inflammatory cytokines including IL-17A, IL-6, and interferons, yielding offspring with increased anxiety-related behavior linked to hyperexcitability in the dysgranular zone of S1. Activating excitatory pyramidal neurons in S1DZ is sufficient to reproduce the behavioral phenotype, whereas suppressing them rescues it. Beyond the MIA model, deleting IL-17RA in S1DZ also reduces anxiety, causally linking cytokine signaling in S1 to affective behavior. The same pathway acts adaptively and maladaptively depending on when it is engaged — IL-17RA signaling sets anxiety levels at homeostasis, while developmental IL-17A exposure produces a lasting phenotype.

The behavioral consequences of these cortical changes depend on how the regions communicate with one another and with downstream targets. Both the PFC and IC are reciprocally connected with the amygdala, and dysfunction of these circuits is observed across anxiety disorders, PTSD, and specific phobia. The prelimbic cortex facilitates fear expression, whereas the infralimbic cortex suppresses fear and supports extinction. Optogenetic manipulation of a posterior IC-to-central amygdala pathway bidirectionally alters anxiety-like behavior, while anterior IC-to-BLA projections are activated during exploration of anxiogenic environments and are themselves anxiogenic. In the complete Freund’s adjuvant inflammatory pain model, IC-BLA connectivity is reportedly enhanced, and S1 projections to the caudal dorsolateral striatum drive comorbid anxiety in that same model, while S1 projections to the parafascicular thalamus contribute to anxiety-like behavior after formalin-induced acute inflammatory pain. However, the authors emphasize that causality for the PFC-amygdala and IC-BLA pathways under peripheral inflammation has not yet been established — these are established routes by which cortical changes are translated into altered affective states, but mostly inferred conduits for inflammation.

The review’s synthesis carries a striking evolutionary logic: the immune and emotional systems are tightly coupled survival mechanisms, with emotion assigning salience to threats and coordinating the physiological and behavioral responses required for effective immune defense. Acutely, the processes described are adaptive — hypervigilance and avoidance limit further exposure and prioritize recovery. When dysregulated, as in chronic or recurrent inflammation, the same signaling turns maladaptive, and anxiety emerges from altered representations of internal physiological state. The traffic is not one-way: reactivating insular cortex ensembles tagged during zymosan-induced peritonitis and dextran sulfate sodium-induced colitis is sufficient to reinstate inflammation in the same peripheral tissues originally affected, meaning the IC both monitors peripheral immune state and contributes to its anticipatory regulation. Whether the circuits that bias affect toward threat overlap with those that regulate immunity remains unresolved. The authors identify as a central open question which inflammatory conditions engage which circuits, and whether distinct immune challenges converge on shared substrates or recruit dedicated ones. Resolving this specificity, they argue, is essential to explain why inflammation produces heterogeneous psychiatric presentations — and if discrete circuits mediate the affective consequences of inflammation, they offer promising targets for interrupting the path from immune activation to maladaptive affective dysregulation.

Subject of Research: How peripheral inflammatory signals reach and alter cortical circuits governing anxiety and depression

Article Title: Cortical circuits linking peripheral inflammation to affective states

Article References: Cortical circuits linking peripheral inflammation to affective states. (n.d.). https://doi.org/10.3389/fncel.2026.1951226

Image Credits: AI Generated

DOI: 10.3389/fncel.2026.1951226

Keywords: inflammation, cortex, anxiety, depression, vagus nerve, cytokines, prefrontal cortex, insular cortex, somatosensory cortex, blood-brain barrier, interoception, neuroimmune