Sex-specific mechanisms underlie long-term potentiation at hippocampus-nucleus 2 accumbens synapses

Abstract

Sex differences have complicated our understanding of the neurobiological basis of many behaviors that are key for survival. As such, continued elucidation of the similarities and differences between sexes is necessary in order to gain insight into brain function and vulnerability. The connection between the hippocampus (Hipp) and nucleus accumbens (NAc) is a crucial site where modulation of neuronal activity mediates reward-related behavior. Our previous work demonstrated that long-term potentiation (LTP) of Hipp-NAc synapses is rewarding, and that mice can make learned associations between LTP of these synapses and the contextual environment in which LTP occurred. Here, we investigate sex differences in the mechanisms underlying Hipp-NAc LTP using whole-cell electrophysiology and pharmacology. We found that males and females display similar magnitudes of Hipp-NAc LTP which occurs postsynaptically. However, LTP in females requires L-type voltage-gated Ca²⁺ channels (VGCC) for postsynaptic Ca²⁺ influx, while males rely on NMDA receptors (NMDAR). Additionally, females require estrogen receptor α (ERα) activity for LTP while males do not. These differential mechanisms converge as LTP in both sexes depends on CAMKII activity and occurs independently of dopamine-1 receptor (D1R) activation. Our results have elucidated sex-specific molecular mechanisms for LTP in an integral excitatory pathway that mediates reward-related behaviors, emphasizing the importance of considering sex as a variable in mechanistic studies. Continued characterization of sex-specific mechanisms underlying plasticity will offer novel insight into the neurophysiological basis of behavior, with significant implications for understanding how diverse processes mediate behavior and contribute to vulnerability to developing psychiatric disorders.