PMID- 38293132
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20240131
DP  - 2024 Jan 16
TI  - Sex-specific mechanisms underlie long-term potentiation at hippocampus-nucleus 
      accumbens synapses.
LID - 2024.01.15.575709 [pii]
LID - 10.1101/2024.01.15.575709 [doi]
AB  - 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 Ca (2+) channels (VGCC) for postsynaptic Ca 
      (2+) influx, while males rely on NMDA receptors (NMDAR). Additionally, females 
      require estrogen receptor alpha (ERalpha) 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. SIGNIFICANCE 
      STATEMENT: Strengthening of Hipp-NAc synapses drives reward-related behaviors. 
      Male and female mice have similar magnitudes of long-term potentiation (LTP) and 
      both sexes have a predicted postsynaptic locus of plasticity. Despite these 
      similarities, we illustrate here that sex-specific molecular mechanisms are used 
      to elicit LTP. 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. Discovery and characterization of convergent sex 
      differences provides mechanistic insight into the sex-specific function of 
      Hipp-NAc circuitry and has widespread implications for circuits mediating 
      learning and reward-related behavior.
FAU - Copenhaver, Ashley E
AU  - Copenhaver AE
FAU - LeGates, Tara A
AU  - LeGates TA
AUID- ORCID: 0000-0002-6005-4786
LA  - eng
PT  - Preprint
DEP - 20240116
PL  - United States
TA  - bioRxiv
JT  - bioRxiv : the preprint server for biology
JID - 101680187
PMC - PMC10827060
EDAT- 2024/01/31 06:43
MHDA- 2024/01/31 06:44
PMCR- 2024/01/30
CRDT- 2024/01/31 04:21
PHST- 2024/01/31 06:44 [medline]
PHST- 2024/01/31 06:43 [pubmed]
PHST- 2024/01/31 04:21 [entrez]
PHST- 2024/01/30 00:00 [pmc-release]
AID - 2024.01.15.575709 [pii]
AID - 10.1101/2024.01.15.575709 [doi]
PST - epublish
SO  - bioRxiv [Preprint]. 2024 Jan 16:2024.01.15.575709. doi: 
      10.1101/2024.01.15.575709.