Role of Paternal Small Non-Coding RNAs and Dopamine Signaling in High-Fat Diet-Induced Transgenerational Reward Memory

Parental environmental exposure can affect offspring through hereditary germline changes without changing the DNA sequence. Ongoing studies show that parental diet can induce heritable molecular changes, thereby affecting offspring metabolism, behavior, and neurological function. However, the mechanism behind these persistent neurobehavioral effects remains unclear. In order to solve this problem, this study explored whether the parent HFD will produce cross-generational memory, thereby changing the reward-related behavior of the offspring. Specifically, it studied the role of dopamine regulation and sperm small non-coding RNA in this process. F0 male mice received a control diet or a high-fat diet before mating, while F1 and F2 male mice maintained a normal diet. Reward-related behaviors will be evaluated through various hedonic preferences and reward learning tests. The functional contribution of dopamine will be evaluated at the molecular, behavioral, and electrophysiological levels by methods such as Neuropixels and high-performance liquid chromatography. Small RNA sequencing will identify persistent sperm small non-coding RNA candidates between generations. Ultimately, this study aims to determine how paternal HFD causes cross-generational changes in reward-related behaviors through dopamine regulation and sperm small non-coding RNA. These findings may contribute to a better understanding of how paternal diet shapes the transgenerational memory of neurobehavior and to identify this genetic causal reproductive mechanism.