Oxytocin Protects Hippocampal Memory and Plasticity from Uncontrollable Stress

Abstract

The hippocampus is vulnerable to uncontrollable stress and is enriched with oxytocin receptors, but their interactive influences on hippocampal functioning are unknown. This study aimed to determine the effects of intranasal oxytocin administration on stress-induced alterations in synaptic plasticity and spatial memory in male rats. While vehicle-administered stressed rats showed impairment in long-term potentiation, enhancement in long-term depression, and weakened spatial memory, these changes were not observed in oxytocin-administered stressed rats. To reveal the potential signaling mechanism mediating these effects, levels of phosphorylated extracellular signal-regulated kinases (pERK) in the hippocampus was examined. Western blotting showed that oxytocin treatment blocked stress-induced alterations of pERK. Additionally, the oxytocin receptor antagonist L-368,899 inhibited the oxytocin's protective effects on hippocampal memory to stress. Thus, intranasal administration of oxytocin reduced stress effects on hippocampal synaptic plasticity and memory in rats via acting on oxytocin receptors and regulating ERK activity. This study suggests that exogenous oxytocin may be a therapeutically effective means to counter the detrimental neurocognitive effects of stress.

Figure 1. Oxytocin, stress, and hippocampal synaptic plasticity.

(A) General experimental procedure (detailed methods). (B) Effects of oxytocin and stress on subsequent CA1 LTP in vitro. TBS of 10 stimulus trains (4 pulses at 100 Hz) delivered at 5 Hz was used to induce long-lasting LTP. Hippocampal slices from vehicle + stress animals exhibited markedly impaired LTP than those from other groups (*p < 0.05). Top traces show the representative average of 10 consecutive f-EPSPs before (solid lines) and after (dotted lines) TBS from four groups. Scale bar represents 20 ms and 1.0 mV. The bar graph shows the mean (±SEM) normalized slope 120–180 m after TBS: vehicle + control (122.9 ± 2.9%), vehicle + stress (105.5 ± 0.9%), oxytocin + control (146.7 ± 4.0%), and oxytocin + stress (118.0 ± 3.3%) groups. (C) Hippocampal slices from vehicle + stress animals showed greater CA1 LTD following LFS (900 pulses, 1 Hz) than those from other groups (*p < 0.05). The top traces show the representative average of 10 consecutive f-EPSPs before (solid) and after LFS (dotted line). The bar graph shows the mean (±SEM) normalized slope 40–60 m after LFS from vehicle + control (89.8 ± 1.7%), vehicle + stress (78.1 ± 1.6%), oxytocin + control (93.7 ± 1.5%), and oxytocin + stress (91.9 ± 0.6%) groups. (D) Reversal of oxytocin’s effects by prior administration of the oxytocin receptor antagonist L-368,899 (109.5 ± 1.2%) compared to vehicle (126.8 ± 1.9%; *p < 0.05). The number in the bar graph indicates the number of brain slices per group. Abbreviations: f-EPSP, field excitatory postsynaptic potential; LFS, low frequency stimulation; LTD, long-term depression; LTP, long-term potentiation; TBS, theta burst stimulation.

Figure 2. Oxytocin, stress, and spatial memory.

(A) Left, cumulative search error in finding a submerged platform over four blocks of four trials/block. Right, percentage of time spent in the annulus target (3X the platform diameter size) when the platform was removed and rats probed the next day. The stress-induced impairment of spatial memory retention was prevented by intranasal oxytocin treatment (*p < 0.05). (B) Swimming speed during training trials. (C) Prior administration of the oxytocin receptor antagonist L-368,899 blocked oxytocin’s anti-stress effects on spatial memory (*p < 0.05).

Figure 3. Oxytocin, stress, and extracellular signal-regulated kinase (ERK) signaling.

(A) Left, representative Western blots of hippocampal ERK and phosphorylated ERK (pERK). Right, the stress-induced reduction in hippocampal pERK levels was prevented by intranasal oxytocin treatment (*p < 0.05). (B) Left, representative Western blots of hippocampal MEK and phosphorylated MEK (pERK). Right, the stress-induced reduction in hippocampal pMEK levels was prevented by intranasal oxytocin treatment (*p < 0.05). (C) The anti-stress effect of oxytocin on hippocampal pERK levels was blocked by prior administration of the oxytocin receptor antagonist L-368,899 (*p < 0.05). The number in the bar graph represents the number of animals per group. (D) A hypothetical model describing the effects of oxytocin on hippocampal neurons and the ERK signaling pathway to restore stress-induced deficits in synaptic plasticity and memory.