Intranasal Oxytocin following Uncontrollable Stress Blocks Impairments in Hippocampal Plasticity and Recognition Memory in Stressed Rats

Abstract

Background: Nasal pretreatment with the neuropeptide oxytocin has been reported to prevent stress-induced impairments in hippocampal synaptic plasticity and spatial memory in rats. However, no study has asked if oxytocin application following a stress experience is effective in rescuing stress-induced impairments.

Methods: Synaptic plasticity was measured in hippocampal Schaffer collateral-CA1 synapses of rats subjected to uncontrollable stress; their cognitive function was examined using an object recognition task.

Results: Impaired induction of long-lasting, long-term potentiation by uncontrollable stress was rescued, as demonstrated both in rats and hippocampal slices. Intranasal oxytocin after experiencing uncontrollable stress blocked cognitive impairments in stressed rats and in stressed hippocampal slices treated with a perfused bath solution containing oxytocin.

Conclusions: These results indicated that posttreatment with oxytocin after experiencing a stressful event can keep synaptic plasticity and cognition function intact, indicating the therapeutic potential of oxytocin for stress-related disorders, including posttraumatic stress disorder.

Keywords: hippocampus; oxytocin; posttraumatic stress disorder; synaptic plasticity.

Figure 1.

Intranasal administration of oxytocin rescued impaired synaptic plasticity and recognition memory in the uncontrollable stress-treated rat. (A) theta-burst stimulation (TBS)-induced long-lasting, long-term potentiation (L-LTP) induction was monitored by measuring the Field excitatory postsynaptic potentials (fEPSPs) slope in the rat Schaffer collateral-CA1 synapse at 1 day (blue), 2 days (yellow), or 5 days (orange) after receiving uncontrollable stress. (B) Quantification of L-LTP in the stressed rats was calculated from fEPSP responses at 170 to 180 minutes after TBS. (C) Rats were treated with nasally applied oxytocin (1mg/mL, 200 μL, orange) or vehicle (blue) at 1 day after receiving uncontrollable stress, and 2 hours later. TBS-induced L-LTP induction was monitored. (D) Quantification of L-LTP in the oxytocin-treated rats. (E) (top) Schematic of the experimental design for assessing the effects of oxytocin on stress-induced cognitive impairments. Following the treatment of uncontrollable stress, oxytocin or vehicle was applied to rat’s intranasal cavity. One hour later, the object recognition test with a 3-hour delay between the familiarization and test phases was conducted. (bottom) Time exploring the 2 identical objects during the familiarization phase (left) and 3 hours later one previously explored object (F) and one novel object (N) during the test phase (left). (F) Percentage of the preference for the novel object during the test phase (30-second exploration time). n = 8 for CTL + Veh, STR + Veh, and CTL + Oxy, n = 9 for STR + Oxy. All values represent the average ± SEM. *P < .05; *P < .01; ***P < .001.

Figure 2.

Bath application of oxytocin to the hippocampus from uncontrollable stress-treated rats rescued impaired synaptic plasticity. Hippocampal slices were prepared from rats 1 day after receiving uncontrollable stress. Effects of bath-applied oxytocin (1 μM) on synaptic transmission were examined by measuring the field excitatory postsynaptic potential (fEPSP) slope at Schaffer collateral-CA1 synapses. Vehicle treatment in slices from the control rats (black), vehicle treatment in slices from the stressed rats (blue), oxytocin treatment in slices from the control rats (yellow), oxytocin treatment in slices from the stressed rats (orange). (A) Input–output relationship between the amplitude of the fiber volley (FV) and the slope of the fEPSP with different stimulus intensities. (B) The ratio of paired-pulse-induced responses achieved by 2 stimulation pulses separated by the indicated time intervals. (C) Theta-burst stimulation (TBS)-induced long-lasting, long-term potentiation (L-LTP). (D) Quantification of L-LTP. All values represent the average ± SEM. *P < .05; *P < .01; ***P < .001.