Maintenance of Hippocampal Cell Numbers in Young and Aged Rats Submitted to Chronic Unpredictable Stress. Comparison with the Effects of Corticosterone Treatment

Abstract

Exposure of rats to sustained stress has been associated with behavioural impairments, the degree of impairment being greater with increasing age of the subject. Although the behavioural deficits have been frequently attributed to stress-induced neuronal loss in the hippocampus, the validity of that view may be disputed since it is based on data collected using conventional morphometric methods which are subject to bias. The question of whether stress per se does indeed induce hippocampal cell losses was therefore re-examined using unbiased stereological tools in the present work. Specifically, we used the optical fractionator and the Cavalieri principle, to respectively estimate the total number of neurons and volumes of the main divisions of the hippocampal formation of young and old rats which had been exposed for 1 month to an unpredictable stress paradigm. The efficacy of the treatment was confirmed by elevated serum corticosterone levels measured at various intervals during the experimental period. In order to evaluate whether any deleterious effects might have occurred merely due to the stress-induced elevations in corticosterone secretion, we conducted a parallel study on animals that were injected with corticosterone over a similar duration. Neither stress nor treatment with corticosterone was found to result in significant cell losses in any division of the hippocampal formation; likewise, neither treatment produced significant volumetric differences. Further, these results were not influenced by age of the experimental subjects. The present findings therefore call for a reappraisal of the hypothesis that hippocampal cell loss accounts for the behavioural impairments observed by others following prolonged stress and/or chronic elevation of serum corticosterone levels.

Old-onset caloric restriction effects on neuropeptide Y- and somatostatin-containing neurons and on cholinergic varicosities in the rat hippocampal formation

“…Finally, and as expected (Andrade et al 2002;Cardoso et al 2013), the old-onset caloric restriction treatment did not induce neuronal loss in the aged animals. In fact, regarding the total number of neurons, the present study corroborates previous works (Rapp and Gallagher 1996;Sousa et al 1998) demonstrating that aging did not induce neuronal loss in the hilus of the dentate gyrus. Interestingly, we have found that oldonset caloric restriction treatment during 6 months did not induce neuronal death in the dentate hilus.…”

The Prefrontal Cortex as a Key Target of the Maladaptive Response to Stress

“…Although it can be argued that deficits in the hippocampus-to-PFC projections may be solely the conse- quence of damage to the projecting areas, there are several reasons why this is an unlikely explanation for the present results. First, although chronic stress can impose structural damage to particular hippocampal subfields (Sousa et al, 2000;McEwen, 2001), it does not affect the volume and number of neurons in the subiculum (present study) and CA1 (Sousa et al, 1998). Second, identical stimulation intensities produced similar baseline PSPs (waveform and amplitude) in stressed and control animals, which indicates the intactness of both the projecting area and connecting pathway.…”

“…Briefly, animals were exposed once daily to a stressor (1 h/d) of one of several aversive stimuli [cold water (18°C), vibration, restraint, overcrowding, exposure to a hot air stream]; the stressors were presented in random order for the duration of the experiment. This stress paradigm was shown previously to result in persistently elevated plasma levels of corticosterone, the primary glucocorticoid of the rat (for details, see Sousa et al, 1998). Another group of 10 rats were handled daily and served as controls (CONs).…”

“…Normally, after exposure to a stressor, adrenoglucocorticoids act in the brain to restore physiological and behavioral homeostasis (de Kloet et al, 2005); however, when the intensity or duration of stressors exceeds a certain individualspecific threshold, activation of the stress response can be deleterious (McEwen, 2005). Chronic stress induces profound behavioral changes in humans and rodents, manifested as depressive-like symptoms, a hyperanxious state, and learning/ memory deficits (Mizoguchi et al, 2000;McEwen, 2004), paralleled by structural damage (Sousa and Almeida, 2002) and impaired synaptic plasticity (Sousa et al, 1998;Kim and Diamond, 2002), mainly in the hippocampus. However, not all stressinduced dysfunctions can be explained by hippocampal injury, the deficits in executive function that characterize stress-related disorders being a prototypic example.…”

Effects ofGlycyrrhizae Radixon Repeated Restraint Stress-induced Neurochemical and Behavioral Responses

“…At the behavioral level, exposure to stress has been reported to increase anxiety-related behavior and to impair learning and memory [3,4]. Many animal studies have demonstrated that chronic stress, as well as chronic corticosterone treatment, results in learning and memory deficits on several behavioral tasks, including the water-maze and passive-avoidance tests, and this impairment was accompanied by hippocampal damage [5][6][7][8][9][10]. In addition, Ader and Cohen et al and McEwen and Stellar et al reported that repeated stress is a risk factor for psychosomatic psychiatric illness, such as anxiety [11,12].…”