INFLUENCE OF SEX AND METABOLIC FACTORS ON PERINEURONAL NET DISTRIBUTION IN THE ADULT MOUSE BRAIN

Perineuronal nets (PNNs) are specialized extracellular matrix structures that emerge during postnatal development and contribute to the maturation, stabilization, and protection of neural circuits. While traditionally considered to be locally regulated, increasing evidence indicates that PNN dynamics are influenced by systemic factors, including sex, hormonal milieu, diet, and metabolic state. However, these influences have largely been examined in isolated brain regions, leaving the brain-wide organization of such regulation unresolved.
To explore the regulatory landscape of PNNs, we performed a whole-brain analysis of PNN distribution in male and female mice and examined their sensitivity to a metabolic challenge known to have profound effects on brain function: high-fat diet (HFD). Serial brain sections were processed for Wisteria floribunda agglutinin labeling (PNNs) and parvalbumin (PV) immunostaining. We then mapped fluorescence signals onto Allen Brain Atlas coordinates through a computational analysis pipeline, enabling region-resolved quantification across the entire brain.
This approach revealed the global anatomical organization and structural properties of PNNs. Preliminary analyses identify region-specific sexual dimorphisms in PNN density and in PNN–PV cell interactions. Notably, HFD exposure produced differential, region-dependent effects that varied by sex.
These findings support a model in which PNNs function as integrative substrates linking metabolic and hormonal signals to circuit plasticity, with regulation that is both sex-specific and anatomically specialized.