CA3 Pyramidal Neuron Activation Promotes Cognitive Resilience to Inflammation-Induced Cognitive Inflexibility

Cognitive dysfunction represents a prominent symptom in numerous prevalent mental illnesses, with systemic inflammation induced by cytokines recognized as a critical factor contributing to cognitive impairments. However, a significant proportion of individuals exposed to systemic inflammation do not develop cognitive dysfunction; instead, they exhibit adaptive responses to this adverse condition. This study aims to investigate the neural activity patterns within the hippocampus and the potential mechanisms that mediate cognitive resilience, particularly in the context of inflammation.

We investigated the effects of systemic IL-1β (Interleukin-1β) on learning, spatial memory, and cognitive flexibility using the Barnes maze test (BMT). We further analyzed specific activity changes in the hippocampus of mice exhibiting cognitive resilience versus susceptibility through immunofluorescence, fiber photometry, and behavioral assessments. Additionally, we employed chemogenetic modulation to explore the role of dCA3 pyramidal neurons in cognitive inflexibility induced by systemic inflammation.

Systemic inflammation induces cognitive inflexibility while leaving learning and memory intact. Notably, dCA3 activity was elevated in cognitively resilient mice compared to their susceptible counterparts. Fiber photometry data revealed higher activity in the dorsal CA3 (dCA3) when the mice approached the previous target quadrant during the reversal stage of BMT. Importantly, the activation of CaMKII⁺ pyramidal neurons in the dCA3 mitigated cognitive inflexibility induced by systemic IL-1β administration.

Activation of hippocampal dCA3 neurons, rather than dentate gyrus (DG) neurons, enhances cognitive resilience by improving cognitive flexibility during BMT-related paradigm shifting under sustained inflammation.