Adverse effect of the combination of hypothyroidism and chronic psychosocial stress on hippocampus-dependent memory in rats

Abstract

Both hypothyroidism and stress interfere with cognitive function in patients. This study examined the effect of hypothyroidism and stress on hippocampus-dependent learning and memory in rats using the novel radial arm water maze (RAWM), which measures spatial working memory. Hypothyroidism was accomplished by thyroidectomy and 2 weeks later a form of intruder stress was used as the chronic psychosocial stressor. After 4–6 weeks of stress, rats were trained to learn (during the acquisition phase; four trials) and then remember (during two memory test trials occurring 15 and 120 min after the acquisition phase) the within-day location of a hidden escape platform, which was in different arm every day. The number of errors (entry into arms other than the platform arm) was noted. Within-day learning of the platform location was largely unaffected by the experimental manipulations, indicating that rats in all groups were equally capable of finding the platform to escape from the water with similar numbers of errors (P>0.05). The number of days a rat took to reach a criterion (DTC; a maximum of one error in three consecutive days) indicated that chronic stress or hypothyroidism, alone, resulted in a mild impairment of spatial memory, and the combination of chronic stress and hypothyroidism resulted in a more severe and long-lasting memory impairment. The data indicated that the combination of stress and hypothyroidism produced more deleterious effects on hippocampal function than either chronic stress or hypothyroidism alone.

Introduction

The severe impairment of the structure and function of the developing central nervous system produced by thyroid hormone deficiency has been thoroughly studied (e.g. [1], [2], [3], [4], [5], [6], [7]). However, less attention has been focused on the impact of thyroid hormone deficiency on the mature brain, even though the prevalence of hypothyroidism increases with age [8].

Chronic stress, like hypothyroidism, diminishes health and increases susceptibility to mental disorders [9], [10]. With aging, there is an increased likelihood of the coincidence of hypothyroidism with chronic stress. It is also known that stress in aged rats and humans has a detrimental effect on the structure and function of the hippocampus presumably by the combined action of excitatory amino acid release and high levels of circulating glucocorticoids [11], [12], [13], [14]. Chronic stress or chronically elevated level of glucocorticoids impairs cognitive function in animal models and in humans in hippocampus-dependent learning and memory tasks [15], [16], [17], [18], [19], [20]. Therefore, it has been postulated that chronic stress impairs learning and memory largely through the production of high levels of glucocorticoids interacting with elevated levels of excitatory amino acids, including glutamate [21], [22], [23].

Similarly, hypothyroidism in patients is associated with increased concentration of cortisol with no change in circadian rhythmicity or normal endogenous production rates. However, hypothyroidism prolonged the half-life of cortisol disappearance [24]. Therefore, it is expected that the coincidence of psychological stress and hypothyroidism may lead to a greater impairment of memory than either condition alone due to potentiation of the same mechanism or pathway.

The basis of stress and hypothyroid effects on cognition may involve changes in synaptic plasticity in the hippocampus. Hippocampal synaptic plasticity is widely assumed to represent a mechanism by which memory is encoded, consolidated and stored [25], [26], [27], [28], [29], [30]. Long-term potentiation (LTP), a form of synaptic plasticity, is considered a leading model of the neurobiology of memory (reviewed in [31]). Numerous studies have shown that stress can block the induction of LTP (reviewed in [62]). Previously, we reported that either stress or hypothyroidism partially impaired LTP, but the combination of hypothyroidism and stress completely blocked LTP in the hippocampus [32], [33].

Based on electrophysiological results, we hypothesized that the combination of hypothyroidism and stress would exert greater effect on learning and memory than either disorder alone. We therefore investigated the effects of hypothyroidism and chronic psychosocial stress on hippocampus-dependent learning and memory.