Jun-Ichi Nishimura

Impairment of maze learning in rats following long-term glucocorticoid treatments

The present study examined the influence of long-term glucocorticoid treatment on a maze learning task on a radial 8-arm maze in rats. Either 100 mg cholesterol (as a control), or corticosterone, bead was implanted in rats for a period of 3 months, beginning at 12 weeks of age. The effect of this treatment on the maze learning task was evaluated during or 4 weeks after the treatments. In both experiments, corticosterone-implanted rats showed an increase in number of trials to attain at least seven correct choices in the first eight choices in five consecutive trials (P < 0.05). We concluded that long-term glucocorticoid exposure resulted in an impairment of the hippocampal functions, i.e. learning and memory, similar to that found in aged hippocampus.

A long-term stress exposure impairs maze learning performance in rats

To elucidate hippocampal dysfunctions following chronic stress exposure, we evaluated the effect of chronic stress on maze learning performance, as assessed by a radial eight-arm maze task. In the 12-week stress sessions, male rats in the stress group were exposed to the stress of a 15-min immersion in cold water once a day and, rats in the control group were slightly handled. Rats in the stress group performed significantly poorly during the acquisition period (P < 0.01) and required more trials to attain at least seven correct choices in the first eight choices for five consecutive trials (P < 0.05). Together with our previous findings that chronic stress exposure damages the hippocampus histologically, we concluded that chronic stress exposure resulted in an impairment of maze learning performance, probably due to hippocampal damages.

Noradrenergic excitatory inputs to median preoptic neurones in rats.

Extracellular single-unit activity was recorded from 21 median preoptic nucleus (MnPO) neurones, antidromically identified as projecting to the hypothalamic paraventricular nucleus (PVN), in urethane-anaesthetized male rats. Of these identified MnPO neurones, 14 displayed an excitatory response in neuronal excitability following electrical stimulation (5 Hz, 600 microA) of the A1 noradrenergic region of the ventrolateral medulla, while the remaining neurones were unresponsive. The excitatory response of MnPO neurones was blocked by microiontophoretically applied phentolamine, an alpha-adrenoceptor antagonist, but not by timolol, a beta-adrenoceptor antagonist. These results suggest that the A1 region acts to enhance the activity of MnPO neurones projecting to the PVN via an alpha-adrenoceptor mechanism.

Median preoptic neurons projecting to the hypothalamic paraventricular nucleus are sensitive to blood pressure changes

Twenty-one neurons in the median preoptic nucleus (MnPO) were antidromically activated by electrical stimulation of the hypothalamic paraventricular nucleus (PVN) in male rats under urethane anesthesia. The activity of these identified neurons was tested for a response to activation of peripheral baroreceptors, achieved by rising arterial blood pressure with an intravenous administration of the alpha-agonist metaraminol. Of the neurons tested, 14 displayed a reduction and 2 exhibited an increase in neuronal excitability that accompanied a 30- to 50-mmHg elevation in mean arterial pressure, while 5 were unresponsive. The results show that efferent pathways from the MnPO to the PVN may receive neural inputs from the peripheral baroreceptors, suggesting the involvement of the pathways in the control of cardiovascular function.

Chronic stress exposure influences local cerebral blood flow in the rat hippocampus

To examine the influence of chronic stress on the brain, we measured local cerebral blood flow in the hippocampus of rats which had been exposed to chronic stress by the hydrogen clearance method in the freely moving status. Rats were exposed, once a day for 12 weeks, to stress of a 15-min immersion in cold water at 4 degrees C (the stress group) or slightly handled for about 1 min (the control group). Local cerebral blood flow values in the hippocampus, which were measured after a 12-week recovery period, were lower in rats in the stress group than those of rats in the control group only in the dark cycle, but not in the light cycle. Accordingly, local cerebral blood flow in the hippocampus of rats in the stress group did not have a daily fluctuation, i.e. lower in the light cycle and higher in the dark cycle, as was shown in rats in the control group. There were no significant changes in motor activity in rats in the stress group as compared to those in the control group. Severe structural damages were observed in the CA2 and CA3 cell fields of the hippocampus of rats in the stress group. We found that an increase in local cerebral blood flow in the hippocampus in the dark cycle was blunted following chronic stress exposure, suggesting that chronic stress exposure caused hippocampal neurons to be less responsive to environmental stimuli derived from motor activity during the dark cycle.

Long-term glucocorticoid treatments decrease local cerebral blood flow in the rat hippocampus, in association with histological damage.

The present study examined the influence of a long-term treatment with glucocorticoid on local cerebral blood flow of the hippocampus in rats, estimated with the hydrogen clearance method. Either a cholesterol (100 mg, as a control) or corticosterone (100 mg) bead was implanted subcutaneously in rats for a period of three months, beginning at 12 weeks of age. The effects of the treatments on the local circulation of the hippocampus were evaluated three to four months after the termination of the treatments. Hippocampal cerebral blood flow in corticosterone-treated rats was significantly lower (P<0.05) than that in control rats, and fluctuated over a day in lower amplitude than the controls. Severe histological damage was observed in the CA1 and CA3 cell fields of the hippocampus in corticosterone-treated rats. These neuropathological changes were characterized by soma shrinkage and condensation, or nuclear pyknosis, as reported previously. We concluded that a long-term glucocorticoid exposure resulted in an impairment of the hippocampal functions, accompanied by neuronal damage similar to that found in aged hippocampus. The present results support the hypothesis that glucocorticoids accelerate age-related changes in the brain.

Adrenalectomy increases local cerebral blood flow in the rat hippocampus.

The present study examined the effect of glucocorticoid manipulations on local cerebral blood flow in the hippocampus. We measured local cerebral blood flow in the hippocampus at 1-h intervals over a 1-day period in freely moving rats, by means of the H2 clearance method, before and after sham adrenalectomy, adrenalectomy or adrenalectomy with corticosterone replacement. We also measured local cerebral blood flow in the prefrontal cortex before and after adrenalectomy. Four weeks after the adrenalectomy, hippocampal blood flow at each time of day was an average of 47% greater than before the operation, showing diurnal variation as before. After the sham adrenalectomy or adrenalectomy with corticosterone replacement, hippocampal blood flow did not change significantly with respect to either its level or its diurnal variation. Local cerebral blood flow in the prefrontal cortex increased by only 19% after adrenalectomy. The present study demonstrates that adrenalectomy causes a remarkable increase in hippocampal blood flow, probably due to a lack of corticosterone.

Increases in cerebral blood flow in rat hippocampus after medial septal injection of naloxone.

Background and Purpose: In a previous study, we occasionally found that the rat given naloxone in the preoptic region develops behavioral seizures. In view of knowledge that the forebrain including the medial septal nucleus provides cholinergic projections to the hippocampal formation, the present study examined the effects of naloxone injected into the medial septal nucleus on the local blood flow in the hippocampus. Methods: A polyurethane-coated platinum electrode with a l-mm bare tip for measurement of blood flow and a guide cannula made of stainless steel tube for naloxone injection were implanted chronically into the brain. The cerebral blood flow was measured by the hydrogen clearance method in freely moving rats. Results: The injection of 50 μg naloxone caused a significant increase in hippocampal blood flow, with its peak at 20 minutes. Twenty micrograms naloxone caused a similar increase, but 10 μg caused only a slight increase that peaked at 30 minutes, suggesting a dose-response of naloxone effect. Hippocampal blood flow was not changed after the injection of saline into the medial septal nucleus and after the injection of naloxone into the caudate nucleus. Conclusions: Taken together with previous findings, the results suggest that endogenous opioids exert decreasing effect on the local blood flow in the hippocampus, probably mediated by the magnocellular cholinergic neurons projecting to the hippocampus.