Cell-Type Specific Role of the Integrated Stress Response Pathway in Aged Brain

Protein synthesis in the brain is required for long-term memory formation, and its dysregulation is implicated in memory decline in aging. Aging is characterized by a decline in various cellular processes that lead to cellular stress. This cellular stress activates the integrated stress response (ISR), which inhibits protein synthesis by the phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 (eIF2α). Given the role of protein synthesis in long-term memory formation, increases in phosphorylated eIF2α (p-eIF2α) are associated with impairments in memory, which can be rescued through cell-type-specific suppression of the ISR. However, the cell-type-specific role of the ISR pathway is not well understood in relation to aging-related memory decline, which is investigated in the present study. To this end, aged wild-type mice will undergo behavioural tests to assess long-term memory, and immunohistochemistry and fluorescence microscopy will be performed to analyze the expression of p-eIF2α and cell-type specific markers in order to identify the cell-types with elevated p-eIF2α levels. By understanding these mechanisms, our study aims to inform potential therapeutic strategies targeting the ISR in specific cell-types to mitigate the age associated decline in long-term memory.