Abstract

It has been previously demonstrated that three months exposure to high physiological levels of corticosterone in young rats resulted in a pattern of hippocampal neuron loss similar to that observed in aged rats (Sapolsky, Krey and McEwen, 1985). The purpose of the present experiments was to examine the behavioral consequences of this treatment. In a series of experiments, young adult or mid-aged Long-Evans rats were treated for either one or three months with corticosterone, sufficient to mimic the elevated corticosterone levels seen in aged rats. Following the termination of the treatment period, the rats were tested in the Morris water maze (a task that is sensitive to hippocampal damage) to assess spatial learning. There was no observable behavioral deficit in young adult rats treated for either one or three months with corticosterone. A one-month treatment period also had no behavioral effect in mid-aged rats. However, after three months of exposure to elevated corticosterone levels, mid-aged rats took significantly longer to successfully navigate the maze, although their performance eventually approximated that of the control animals. A second experiment with mid-aged rats treated with either p.m. diurnal (Medium-B: $\approx$ 12-15 $\mu$g/dl) or stress (High-B $\approx$ 25-35 $\mu$g/dl) levels of corticosterone demonstrated that only the performance of the High-B rats was impaired on the Morris maze, relative to the Medium-B and controls. In addition, a threshold model of long-term potentiation (primed burst potentiation) suggested significantly reduced hippocampal synaptic plasticity in both the Medium- and High-B rats, relative to the controls. Finally, hippocampal neuropathology was assessed in two of the experiments and the cell counting data suggested that there was no significant neuron loss in either the CA$\sb1$ or CA$\sb3$ pyramidal cell layer of the hippocampus in the corticosterone-treated rats compared with age-matched controls. Finally, mid-aged rats were exposed to a six-month social stress regimen that elevated corticosterone levels ($\approx$12-18 $\mu$g/dl) throughout the diurnal cycle. A second group of mid-aged rats was adrenalectomized and given basal levels of corticosterone replacement prior to the commencement of the social stress regimen. Acquisition of the Morris swim task was impaired in the socially-stressed animals relative to both the adrenalectomized, stressed animals and age-matched controls. The data presented here suggested that long-term exposure to elevated corticosterone levels, either by exogenous treatment or social stress, resulted in spatial learning deficits, but only in mid-aged rats. Further, these impairments appeared to be related to reduced synaptic plasticity rather than hippocampal neuron loss. These findings are discussed in terms of the potential mechanisms by which long-term exposure to high glucocorticoid levels produces deficits in both behavior and hippocampal synaptic plasticity