Alteration of synaptic transmission in the hippocampal‐mPFC pathway during extinction trials of context‐dependent fear memory in juvenile rat stress models

Abstract

The medial prefrontal cortex (mPFC) has been proposed to be essential for extinction of fear memory, but its neural mechanism has been poorly understood. The present study examined whether synaptic transmission in the hippocampal-mPFC pathway is related to extinction of context-dependent fear memory in freely moving rats using electrophysiological approaches combined with behavioral analysis. Population spike amplitude in the mPFC was decreased during the first extinction trial by exposure to contextual fear conditioning. This synaptic inhibition was reversed by repeated extinction trials, accompanied by decreases in fear-related freezing behavior. These results suggest that alteration of synaptic transmission in the hippocampal-mPFC pathway is associated with the extinction processes of context-dependent fear memory. Further experiments were performed to elucidate whether early postnatal stress alters the synaptic response in the mPFC during extinction trials using a juvenile stress model, based on our previous findings that early postnatal stress affects the behavioral response to emotional stress. Adult rats that previously were exposed to five footshocks (FS) (shock intensity, 0.5 mA; intershock interval, 28 seconds; shock duration, 2 seconds) at postnatal day 21 to 25 (week 3; 3W-FS) exhibited impaired reversal of both inhibitory synaptic transmission and freezing behavior induced by repeated extinction trials. The neuronal and behavioral deficits observed in the 3W-FS group were prevented by pretreatment with the serotonin(1A) receptor agonist tandospirone (1 mg/kg, i.p.). These results indicate the possiblity that aversive stress exposure during the third postnatal week impaired extinction processes of context-dependent fear memory. The deficits in extinction observed in the 3W-FS group might be attributable to dysfunction of hippocampal-mPFC neural circuits involving 5-HT(1A) receptor mechanisms.

Juvenile stress attenuates the dorsal hippocampal postsynaptic 5-HT1A receptor function in adult rats

“…We have also recently reported that pups exposed to footshock (FS) stress from postnatal days 21 to 25 (3wFS) have an altered anxiety-related behavior as adult rats (Konno et al 2007;Matsumoto et al 2008;Koseki et al 2009;Matsuzaki et al 2009). In these studies, the 3wFS increased the ratio of spent time in open arms in an elevated plus-maze test and reduced the number of 5-HT-like immunoreactive cells in the median raphe nucleus (MRN) compared with the non-FS control group.…”

Diazepam-Induced Increases of Synaptic Efficacy in the Hippocampal – Medial Prefrontal Cortex Pathway Are Associated With Its Anxiolytic-like Effect in Rats

“…Acute stress has been shown to inhibit LTP formation in the hippocampal-mPFC pathway (30). Furthermore, our previous study indicated that the PSA in this pathway was reduced during exposure to the fearconditioned stimulus and that this reduction was attenuated in parallel with the extinction of conditioned fear (31). Thus, we inferred that the hippocampal-mPFC pathway was important for the regulation of emotion, especially during fear extinction.…”

Tandospirone Suppresses Impulsive Action by Possible Blockade of the 5-HT1A Receptor

“…We did not use higher doses of tandospirone because a higher dose (10 mg/kg) dramatically increased omissions (> 50) in our preliminary study. The dose of tandospirone (1 mg/kg) was chosen based on our previous reports (22,23). This dose of tandospirone has consistently exerted anxiolytic actions in rats.…”