Piriform cortex gates learned fear through a brain-spleen neuroimmune axis

Area of Science:

• Neuroscience
• Immunology
• Neuroimmunology

Background:

• Maladaptive learned fear responses are implicated in neuropsychiatric disorders.
• Stress-induced fear can become debilitating, yet the underlying neural mechanisms are not fully understood.

Purpose of the Study:

• To identify a novel brain-to-spleen neural pathway mediating learned fear.
• To elucidate the neuroimmune interactions involved in stress-related fear responses.

Main Methods:

• Utilized a chronic acquired olfactory stress (CAOS) model in rodents.
• Employed neural tracing, single-nucleus RNA sequencing, and chemogenetics.
• Investigated the role of piriform cortex (Pir) excitability and specific neuronal populations.

Main Results:

• Identified a tetrasynaptic circuit (Pir→vCA1→CeM→DVC→spleen) regulating T helper 17 (Th17) cell-dependent fear.
• Olfactomedin 3 (Olfm3)-expressing neurons in the Pir integrate olfactory stress.
• Disrupting this circuit abolished stress-induced splenic Th17 cell expansion and fear avoidance.

Conclusions:

• Established a complete neural circuit linking olfactory perception to peripheral immunity in learned fear.
• Demonstrated that the piriform cortex plays a crucial role in transforming olfactory stress into maladaptive fear.
• Highlighted the significance of neuroimmune interactions in the pathophysiology of stress-related disorders.