Cell-type-dependent decline of IGF1 and IGF1R in the prefrontal cortex contributes to age-related behavioral changes

Insulin-like growth factor 1 (IGF1) signaling plays a critical role in brain function and declines significantly with aging. However, how these changes occur across different brain regions and cell types, and how they contribute to behavioral dysfunction, remains poorly understood. The prefrontal cortex (PFC), a key regulator of cognitive, emotional, and social behaviors, is particularly vulnerable to age-related changes. Here, we investigated age-associated changes in IGF1 and its receptor (IGF1R) in major neuronal populations of the PFC and examined their functional relevance. Using immunohistochemical analysis across young adult, middle-aged, and aged mice, we identified cell-type-dependent alterations in IGF1 and IGF1R expressions in the PFC of C57BL/6 mice, characterized by a reduction of IGF1 in both excitatory (CaMKII⁺) and inhibitory (GAD67⁺) neurons, and a selective decrease of IGF1R in excitatory neurons. To determine the functional consequences of these changes, we employed an excitatory neuron-specific Igf1r conditional knockdown (cKD) model in the PFC of young adult mice. IGF1R cKD in excitatory neurons of young adult mice resulted in behavioral dysfunction across multiple domains, including increased anxiety-like behavior, reduced sociability, and impaired cognitive performance. Furthermore, chronic intra-PFC infusion of IGF1 alleviated age-associated behavioral impairments in aged mice, and these recovery effects depend on IGF1R in excitatory neurons. Together, these findings support a critical role for region- and cell type-specific IGF1 and IGF1R system in regulating behavioral function during aging and provide insight into mechanisms underlying age-associated behavioral declines.