Sex-specific mechanisms underlie long-term potentiation at hippocampus-medium spiny neuron synapses in the medial shell of the nucleus accumbens
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2024-05-24
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Copenhaver, Ashley E., and Tara A. LeGates. “Sex-Specific Mechanisms Underlie Long-Term Potentiation at Hippocampus-Medium Spiny Neuron Synapses in the Medial Shell of the Nucleus Accumbens.” Journal of Neuroscience, May 24, 2024. https://doi.org/10.1523/JNEUROSCI.0100-24.2024.
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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 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 mice can establish learned associations between LTP of these synapses and the contextual environment in which LTP occurred. Here, we investigated sex differences in the mechanisms underlying Hipp→NAc LTP using whole-cell electrophysiology and pharmacology. We observed similarities in basal synaptic strength between males and females and found that LTP occurs postsynaptically with similar magnitudes in both sexes. However, key sex differences emerged as LTP in males required NMDA receptors (NMDAR) whereas LTP in females utilized an NMDAR-independent mechanism involving L-type voltage-gated Ca²⁺ channels (VGCC) and estrogen receptor α (ERα). We also uncovered sex-similar features as LTP in both sexes depended on CaMKII activity and occurred independently of dopamine-1 receptor (D1R) activation. Our results have elucidated sex-specific molecular mechanisms for LTP in an integral 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. Significance statement Strengthening of hippocampus-nucleus accumbens (Hipp-NAc) synapses drives reward-related behaviors. Long-term potentiation (LTP) occurs with a similar magnitude in males and females, and both sexes have a predicted postsynaptic locus of plasticity. Despite these similarities, here we illustrate that sex-specific molecular mechanisms underlie LTP at Hipp-NAc synapses. Given the bidirectional relationship between Hipp-NAc synaptic strength in mediating reward-related behaviors, the use of distinct molecular mechanisms may explain sex differences observed in stress susceptibility or response to rewarding stimuli. Uncovering these latent sex differences offers a deeper understanding of the sex-specific function of this behaviorally-relevant synapse with widespread implications for circuits that underlie learning and reward-related behavior.