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

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.

Early postnatal stress alters the extinction of context-dependent conditioned fear in adult rats.

Fear extinction is hypothesized to be a learning process based on a new inhibitory memory. The present study was conducted to elucidate the effect of early postnatal stress on the extinction of context-dependent fear memory in adult rats, with a focus on the serotonergic system. Extinction was estimated by the expression of freezing behavior during repeated extinction trials (i.e., repeated exposure to contextual fear conditioning) on consecutive days. The decrease in fear expression was attenuated in adult rats that had been subjected to footshock (FS) at the third postnatal week (3wFS), but not in those exposed to footshock at the second postnatal week (2wFS). The decreased attenuation of freezing behavior observed in 3wFS was abolished by repeated treatment with the partial N-methyl-D-aspartate receptor agonist D-cycloserine (15 mg/kg, i.p., for 4 days), which has been shown to facilitate cue-dependent extinction. Repeated treatment with the serotonin 5-hydroxytryptamine-1A (5-HT(1A)) receptor agonist tandospirone (1 mg/kg, i.p., for 4 days) prevented the expression of freezing behavior in 3wFS, whereas diazepam treatment (1 mg/kg, i.p., for 4 days) in 3wFS did not. These results suggest that exposure to early postnatal stress at the third week is responsible for attenuating extinction of contextual fear conditioning and is mediated by a serotonergic 5-HT(1A) receptor mechanism. In other words, exposure to traumatic events during the early postnatal period might precipitate long-lasting alterations in synaptic function that underlie extinction processes of context-dependent fear memory.

Correlation between precise and simple tests in recovery of dynamic balance function after intravenous sedation with midazolam in the elderly.

PURPOSE: Assessing the recovery of dynamic balance after intravenous sedation in the elderly is important for ensuring their safe discharge, especially when they are walking. A reliable, simple dynamic balance test would be useful in daily clinical practice. We observed the recovery of balance after intravenous sedation with midazolam, using computerized dynamic posturography (CDP), and we evaluated the correlation between the CDP result and the results of simple dynamic balance tests. METHODS: Midazolam was administered in divided doses, until the Wilson sedation score reached 3, in 18 elderly male volunteers. The dynamic balance test using CDP with perturbation stimuli was performed before and after sedation. As simple dynamic balance tests, the usual-speed walking (USW) and maximum-speed walking (MSW) tests and a modified timed "up and go" (TUG) test (subjects stand up from a chair, walk 5 m forward and return to the chair with MSW, and sit down again) were performed. RESULTS: The recovery times (defined as the time until the significant difference between the value at each time point and the baseline value disappeared) in the dynamic balance test (CDP), USW test, MSW test, and TUG test, were 80, 40, 80, 80 min, respectively. There was a significant, strong positive correlation between the result of the dynamic balance test (CDP) and the TUG test (P < 0.01; r = 0.70). CONCLUSION: The TUG test is a useful simple dynamic balance/motor test that can be used in daily clinical practice in the elderly.

[Effects of aversive stress during brain development on hippocampal synaptic and behavioral responses to emotional stress at postadolescence].

The aim of the present study was to examine whether early postnatal stress during brain development alters the synaptic response to emotional stress, focusing on the behavioral expressions to contextual fear conditioning (CFC) at postadolescnece. Pups were exposed to an aversive stimulus, foot shock (FS), at the postnatal period of the second week (2w-FS) and the third week (3w-FS). At the postadolescent period (10- to 12-week old), the evoked potential in the hippocampal CA1 field was measured with simultaneous determination of fear-related freezing behavior. CFC-induced freezing behavior decreased remarkably in 2w-FS, but not 3w-FS, compared to non-FS controls. The evoked potential in the CA1 field was reduced during exposure to CFC in controls. Meanwhile this synaptic inhibition was attenuated in 2w-FS. Furthermore, the suppression of synaptic responses, including long-term potentiation (LTP), mediated via 5-HT(1A) receptors was not observed in 2w-FS. These results suggest that the second postnatal week appears to be the critical period for developing "proper" synaptic response underlying regulation of emotional stress, in which the 5-HTIA receptor-mediated regulation may be involved.

Recovery of dynamic balance after additional small divided doses of midazolam given intravenously for sedation.

We have previously reported that a dynamic balance test with perturbation stimuli and computerised dynamic posturography sensitively reflected the inhibitory effect on balance of intravenous midazolam sedation given intravenously as a single dose, and recovery time was within 80 min. The purpose of this study was to investigate the recovery of dynamic balance after additional doses of midazolam. Eighteen young adult male volunteers were sedated with midazolam given intravenously. The initial dose was given until the Wilson sedation score reached 3, and an additional dose was given until the same score was obtained 40 min later. They were tested with perturbation stimuli 40, 80, 100, and 120 min after the additional doses had been given. Their recovery time was recorded. The mean (S.D.) initial dose of midazolam was 0.07 (0.005) mg kg(-1), and additional doses were 41 (7)% of the initial dose. The serial changes in bispectral index after initial and additional doses were similar. The recovery time for the dynamic balance test (within 80 min) was the same as that recorded in the previous single-dose study. The recovery time of the psychomotor function test was within 75 min. Additional doses of midazolam aiming for a Wilson sedation score of 3 at a dose about 40% of the initial dose and given 40 min after the initial dose are valid in terms of the maintenance of sedation and recovery of dynamic balance. Complete recovery time, including psychomotor function, was within 80 min of the additional dose of the drug.

Electrophysiological and neurochemical characterization of the effect of repeated treatment with milnacipran on the rat serotonergic and noradrenergic systems.

The present study was undertaken to elucidate the effects of repeated treatment with milnacipran, a serotonin (5-HT) and noradrenaline (NA) reuptake inhibitor (SNRI), on the synaptic plasticity in the hippocampal CA1 field, focusing on the interaction between the serotonergic and noradrenergic system. Repeated treatment with milnacipran (30 mg/kg, i.p. after 30 mg/kg, p.o. x 14 days) completely restored the suppression of the long-term potentiation (LTP) induced by single milnacipran treatment (30 mg/kg, i.p.). Single and repeated milnacipran increased to a similar extent extracellular NA in the hippocampus. Single milnacipran increased extracellular 5-HT and this effect tended to be enhanced by repeated treatment. The restoration of LTP and facilitation of the 5-HT level were not shown after repeated treatment with a selective 5-HT reuptake inhibitor (SSRI) fluvoxamine (30 mg/kg, p.o. x 14 days). These results suggest that milnacipran-induced restoration of LTP suppression is responsible for the enhancement of 5-HT neurotransmission, which appears to be associated with noradrenergic neuronal activity. In addition, the 5-HT1A receptor agonist tandospirone-induced suppression of LTP was completely blocked by repeated treatment with milnacipran, indicating the possibility that this reversal effect is due to the functional changes in postsynaptic 5-HT1A receptors. Taken together, the present data suggest that the interaction between the serotonergic and noradrenergic mechanism play an important role in the modulation of synaptic plasticity caused by repeated treatment with milnacipran, which may be implicated in the therapeutic effects of SNRI on psychiatric disorders.

Early postnatal stress alters the 5-HTergic modulation to emotional stress at postadolescent periods of rats.

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.

Assessment of the recovery of dynamic balance after intravenous sedation with midazolam.

PURPOSE: To assess street fitness after sedation, computerized dynamic posturography (CDP) involving movement of the center of gravity may be more accurate than the conventional computerized static posturography (CSP). The purpose of this study was to evaluate the recovery of dynamic balance function after intravenous sedation by CDP in comparison with CSP, and to find a simple dynamic balance test that is well correlated with CDP. METHODS: The subjects were 20 male volunteers aged 20-27 years. After intravenous injection of midazolam (0.07 mg . kg(-1)), four balance tests were performed. The recovery time and the percentage of subjects showing recovery (difference from the baseline value < or =10%) were compared. As CDP, a test in which unexpected perturbation stimuli are given using an unstable platform was performed. As CSP, standing sway tests were performed. Maximum speed walking (MSW) and usual speed walking (USW) tests were performed as simple balance tests. RESULTS: The recovery time in CDP (80 min) was longer than that in CSP (40-60 min). The percentage of subjects showing recovery in CDP (20%) was significantly lower than that in CSP (55%-70%) 60 min after the administration of midazolam. There was a significant positive correlation between the CDP test and the MSW test (r = 0.67). CONCLUSION: 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.