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.

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Several lines of evidence have shown that traumatic events during the early postnatal stage might precipitate long-lasting alteration in the functional properties underlying emotional expression. The aim of the present study was to examine whether the early postnatal stress alters the 5-HTergic mechanism underlying regulation of emotional stress, focusing on the 5-HT(1A) receptor-mediated synaptic responses in adult rats. Pups were exposed to aversive stimulus, footshock (FS) at the postnatal period of the second (2W) and the third week (3W). At postadolescent period (10-12-week-old), electrophysiological and behavioral studies were performed. The 5-HT(1A) receptor agonist tandospirone (10 mg/kg body wt, i.p.) blocked the long-term potentiation (LTP) in the hippocampal CA1 field of 3W-FS, as well as non-FS control, whereas this inhibition was not observed in 2W-FS group. Fear-related freezing behavior observed during exposure to contextual fear conditioning markedly attenuated in 2W-FS, but not in 3W-FS. These data suggest that aversive stress exposed at 2W is attributable to changes in the 5-HT(1A) receptor-mediated synaptic plasticity, which may be responsible for the attenuation of freezing behavior. Thus, 5-HT(1A) receptors appear to play a key role in the 5-HTergic mechanism underlying regulation of emotional stress on the postnatal development of the brain. In other words, the second postnatal week may be the "critical period" for establishing proper behavioral responses to emotional stress in adult rats. (c) 2005 Wiley-Liss, Inc.

CDP with perturbation stimuli detects the balance inhibitory effects of midazolam with greater sensitivity than CSP. The MSW test is well correlated with CDP with perturbation stimuli.