Kesharwani, A.; Lahamge, D.; Sharma, A.; Kumarasamy, M.; Velayutham, R.; Parihar, V.

This study addresses key gaps in our understanding of the cognitive changes associated with normal brain aging and their underlying structural and functional correlates. Declining levels of brain endocannabinoids (eCB), particularly 2-arachidonoylglycerol (2-AG), are thought to contribute to age-related cognitive impairment, but the mechanisms involved remain poorly understood. Here, we show that levels of 2-AG and its synthesizing enzyme, diacylglycerol lipase- (DAGL-), are significantly reduced in the medial prefrontal cortex (mPFC) of aged mice. This decline is associated with impairments in mood and memory, as demonstrated by behavioral analyses. Immunofluorescence studies further revealed reduced expression of cannabinoid receptors CB1 and CB2 on microglia in aged brains, suggesting that diminished eCB signaling may contribute to enhanced neuroinflammation. Consistent with this idea, microglia from aged mice exhibited increased HMGB1-TLR4-NF-{kappa}B signaling, indicative of a pro-inflammatory state. LC-HR-MS analysis also showed elevated glutamate levels and reduced glutamine and GABA levels in the mPFC, linking impaired eCB signaling to excitotoxic imbalance during aging. Importantly, intraperitoneal administration of cannabidiol (CBD) to aged mice reversed mood and memory deficits, restored CB1 and CB2 receptor expression, attenuated HMGB1-TLR4-NF-{kappa}B signaling, and normalized the glutamate-glutamine/GABA balance in the mPFC. Collectively, these findings identify eCB signaling as a critical regulator of age-associated cognitive decline and support CBD as a potential therapeutic strategy to promote healthy brain aging.