Willy Mayo

Spatial memory performances of aged rats in the water maze predict levels of hippocampal neurogenesis

Neurogenesis occurs within the adult dentate gyrus of the hippocampal formation and it has been proposed that the newly born neurons, recruited into the preexistent neuronal circuits, might be involved in hippocampal-dependent learning processes. Age-dependent spatial memory impairments have been related to an alteration in hippocampal plasticity. The aim of the current study was to examine whether cognitive functions in aged rats are quantitatively correlated with hippocampal neurogenesis. To this end, we took advantage of the existence of spontaneous individual differences observed in aged subjects in a hippocampal-dependent task, the water maze. We expected that the spatial memory capabilities of aged rats would be related to the levels of hippocampal neurogenesis. Old rats were trained in the water maze, and, 3 weeks after training, rats were injected with 5-bromo-2′-deoxyuridine (BrdUrd, 50 or 150 mg/kg) to label dividing cells. Cell proliferation was examined one day after the last BrdUrd injection, whereas cell survival and differentiation were determined 3 weeks later. It is shown that a quantitative relationship exists between learning and the number of newly generated neurons. Animals with preserved spatial memory, i.e., the aged-unimpaired rats, exhibited a higher level of cell proliferation and a higher number of new neurons in comparison with rats with spatial memory impairments, i.e., the aged-impaired rats. In conclusion, the extent of memory dysfunction in aged rats is quantitatively related to the hippocampal neurogenesis. These data reinforce the assumption that neurogenesis is involved in memory processes and aged-related cognitive alterations.

Novelty-Seeking in Rats-Biobehavioral Characteristics and Possible Relationship with the Sensation-Seeking Trait in Man

A behavioral trait in rats which resembles some of the features of high-sensation seekers in man has been characterized. Given that the response to novelty is the basis of the definition of sensation-seeking, individual differences in reactivity to novelty have been studied on behavioral and biological levels. Certain individuals labeled as high responders (HR) as opposed to low responders (LR) have been shown to be highly reactive when exposed to a novel environment. These groups were investigated for free-choice responses to novel environments differing in complexity and aversiveness, and to other kinds of reinforcement, i.e. food and a drug. The HR rats appeared to seek novelty, variety and emotional stimulation. Only HR individuals have been found to be predisposed to drug-taking: they develop amphetamine self-administration whereas LR individuals do not. They also exhibit a higher sensitivity to the reinforcing properties of food. On a biological level, compared to LR rats, HR animals have an enhanced level of dopaminergic activity in the nucleus accumbens both under basal conditions or following a tail-pinch stress. HR and LR rats differ in reactivity of the corticotropic axis: HR rats exposed to a novel environment have a prolonged secretion of corticosterone compared to LR rats. The association of novelty, drug and food seeking in the same individual suggests that these characteristics share common processes. Differences in dopaminergic activity between HR and LR rats are consistent with results implicating these dopaminergic neurons in response to novelty and in drug-taking behavior. Given that rats self-administer corticosterone and that HR rats are more sensitive to the reinforcing properties of corticosteroids, it could be speculated that HR rats seek novelty for the reinforcing action of corticosterone. These characteristics may be analogous to some for the features found in human high-sensation seekers and this animal model may be useful in determinating the biological basis of this human trait.

Long-term effects of prenatal stress and postnatal handling on age-related glucocorticoid secretion and cognitive performance: a longitudinal study in the rat.

There is growing evidence that stress during prenatal and postnatal periods of life can modify adaptive capacities in adulthoods. The hypothalamo–pituitary–adrenal axis may mediate an animals responses to perinatal stressful events and thus serve as a neurobiological substrate of the behavioural consequences of these early events. However, little is known about the long‐term effects of prenatal stressors throughout the entire life of the animals. The focus of the present study was to examine the long‐term influences of a prenatal and postnatal stress on glucocorticoid secretion and cognitive performance. Prenatal stress of rat dams during the last week of pregnancy and postnatal daily handling of rat pups during the first 3 weeks of life were used as stressors. The long‐term effects of these manipulations were analysed using a longitudinal approach throughout the entire life of the animals, and were repeatedly tested in adulthood (4–7 months), middle age (13–16 months) and in later life (20–24 months). The study demonstrated that prenatal stress and postnatal handling induced opposite effects on both glucocorticoid secretion and cognitive performance. Prenatal stress accelerated the age‐related hypothalamo–pituitary–adrenal axis dysfunctions; indeed, circulating glucocorticoids levels of prenatally stressed middle‐aged animals are similar to old control ones, and also induced cognitive impairments. In contrast, postnatal handling protected from the age‐related neuroendocrine and behavioural alterations. These results show that the altered glucocorticoid secretion induced by early environmental manipulations is primary to the cognitive alterations observed only later in life and could be one cause of age‐related memory deficits.

A two-trial memory task with automated recording: study in young and aged rats

A two-trial recognition task, based on place or object exploration in a Y-maze, was developed to study memory in adult and aged rats. This paradigm avoids the use of electric shocks or deprivation that may have non-specific influences on the responses, and the task does not require learning of a rule. A number of behavioral parameters in several animals could be recorded automatically. These behavioral parameters were found to be differently influenced both by the type of recognition (place vs. object) and by the inter-trial interval (recognition retention time). Impaired recognition was also detected in 18-months-old rats. This recognition task which combines simplicity, sensitivity and high specificity may thus be a useful adjunct to our current battery of memory tasks.

Steroid hormones and neurosteroids in normal and pathological aging of the nervous system

Without medical progress, dementing diseases such as Alzheimers disease will become one of the main causes of disability. Preventing or delaying them has thus become a real challenge for biomedical research. Steroids offer interesting therapeutical opportunities for promoting successful aging because of their pleiotropic effects in the nervous system: they regulate main neurotransmitter systems, promote the viability of neurons, play an important role in myelination and influence cognitive processes, in particular learning and memory. Preclinical research has provided evidence that the normally aging nervous system maintains some capacity for regeneration and that age-dependent changes in the nervous system and cognitive dysfunctions can be reversed to some extent by the administration of steroids. The aging nervous system also remains sensitive to the neuroprotective effects of steroids. In contrast to the large number of studies documenting beneficial effects of steroids on the nervous system in young and aged animals, the results from hormone replacement studies in the elderly are so far not conclusive. There is also little information concerning changes of steroid levels in the aging human brain. As steroids present in nervous tissues originate from the endocrine glands (steroid hormones) and from local synthesis (neurosteroids), changes in blood levels of steroids with age do not necessarily reflect changes in their brain levels. There is indeed strong evidence that neurosteroids are also synthesized in human brain and peripheral nerves. The development of a very sensitive and precise method for the analysis of steroids by gas chromatography/mass spectrometry (GC/MS) offers new possibilities for the study of neurosteroids. The concentrations of a range of neurosteroids have recently been measured in various brain regions of aged Alzheimers disease patients and aged non-demented controls by GC/MS, providing reference values. In Alzheimers patients, there was a general trend toward lower levels of neurosteroids in different brain regions, and neurosteroid levels were negatively correlated with two biochemical markers of Alzheimers disease, the phosphorylated tau protein and the beta-amyloid peptides. The metabolism of dehydroepiandrosterone has also been analyzed for the first time in the aging brain from Alzheimer patients and non-demented controls. The conversion of dehydroepiandrosterone to Delta5-androstene-3beta,17beta-diol and to 7alpha-OH-dehydroepiandrosterone occurred in frontal cortex, hippocampus, amygdala, cerebellum and striatum of both Alzheimers patients and controls. The formation of these metabolites within distinct brain regions negatively correlated with the density of beta-amyloid deposits.

Infusion of neurosteroids into the nucleus basalis magnocellularis affects cognitive processes in the rat

The neurosteroids, pregnenolone sulfate (PREG-S) and tetrahydroprogesterone (TH-PROG), act on the GABAA receptor with antagonist or agonist-like properties, respectively. In this study the effect of the infusion of PREG-S and TH-PROG into the nucleus basalis magnocellularis (NBM) of the rat was examined in a two-trial memory task. The results show that PREG-S (5 ng in 0.5 microliter) enhances memory performance when injected after an acquisition trial; conversely TH-PROG (2 ng in 0.5 microliter) disrupts performance when injected before an acquisition trial. A role for neurosteroids in memory processes subserved by the nucleus basalis magnocellularis is of interest in view of the implication of this structure and these substances in neurodegenerative processes.

Role of pregnenolone, dehydroepiandrosterone and their sulfate esters on learning and memory in cognitive aging

Aging is a general process of functional decline which involves in particular a decline of cognitive abilities. However, the severity of this decline differs from one subject to another and inter-individual differences have been reported in humans and animals. These differences are of great interest especially as concerns investigation of the neurobiological factors involved in cognitive aging. Intensive pharmacological studies suggest that neurosteroids, which are steroids synthesized in the brain in an independent manner from peripheral steroid sources, could be involved in learning and memory processes. This review summarizes data in animals and humans in favor of a role of neurosteroids in cognitive aging. Studies in animals demonstrated that the neurosteroids pregnenolone (PREG) and dehydroepiandrosterone (DHEA), as sulfate derivatives (PREGS and DHEAS, respectively), display memory-enhancing properties in aged rodents. Moreover, it was recently shown that memory performance was correlated with PREGS levels in the hippocampus of 24-month-old rats. Human studies, however, have reported contradictory results. First, improvement of learning and memory dysfunction was found after DHEA administration to individuals with low DHEAS levels, but other studies failed to detect significant cognitive effects after DHEA administration. Second, cognitive dysfunctions have been associated with low DHEAS levels, high DHEAS levels, or high DHEA levels; while in other studies, no relationship was found. As future research perspectives, we propose the use of new methods of quantification of neurosteroids as a useful tool for understanding their respective role in improving learning and memory impairments associated with normal aging and/or with pathological aging, such as Alzheimers disease.

The effect of education on cognitive performances and its implication for the constitution of the cognitive reserve.

Some studies have suggested that people with a high educational level have a lower risk of developing dementia compared to people with a low educational level. This protective effect of education has been explained by the constitution of a cognitive reserve which might delay the cognitive and functional expression of neurodegenerative illnesses. The aim of this study is, on the one hand, to evaluate the impact of education on cognitive functioning, which is thought to support the cognitive reserve capacity, and on the other, to determine the extent to which cognitive functioning is affected by other explanatory variables. The analysis was conducted on 1,022 individuals without physical or neurological disorders in the Personnes Agées Quid study. These participants were aged 66 and over and had completed a neuropsychological battery. The effect of some demographic and socioeconomic variables on cognitive performance was also analyzed. Multivariate analysis showed a significant effect of education on most neuropsychological performances, independently of the other variables, and more particularly, in the high-attention-demanding tests. A principal component analysis demonstrated that education specifically increases 2 cognitive components: controlled processes and conceptualization ability. Moreover, mental stimulation occurring after the education years, such as high-complex activity occupations, seems to increase the controlled component. All these results suggest that the effect of education on cognitive reserve may be explained by an increase in controlled processes and conceptualization abilities. These 2 cognitive components might delay the clinical expression of neurodegenerative illnesses by maintaining global cognitive efficiency. Of these 2 components, controlled processes were also influenced by high attention-demanding occupations.

Profound disturbances of spontaneous and learned behaviors following lesions of the nucleus basalis magnocellularis in the rat

It has been shown that a marked decline in the cortical activity of the cholinergic synthesizing enzyme choline-acetyltransferase (ChAT), accompanied by a severe neuronal loss in the nucleus basalis magnocellularis of Meynert occurs in the brains of patients with senile dementia of the Alzheimer type. However, the functional role of these neurons is largely unknown. In fact, very few studies have been done in animals. In this paper we report the behavioral effects of the lesion of the nucleus basalis magnocellularis in the rat either by radiofrequency current or by ibotenic acid injection at the level of the cell bodies. The two kinds of lesion lead to a profound disturbance of spontaneous and learned behaviors. There is a complete disorganization of behavior which is evidenced by an enhanced locomotor activity, an alteration in alimentary and hoarding behavior. In addition, we observed a deterioration of spatial memory and an incapacity to reverse a previously learned response. Biochemical assay showed that radiofrequency and ibotenic acid lesions produced a decrease of ChAT activity in the prefrontal and sensorimotor cortices and in amygdala without affecting the hippocampus or striatum. Ibotenic acid lesions seem to specifically destroy the cell bodies of the nucleus basalis magnocellularis since the dopaminergic and noradrenergic fibers of passage remained intact as measured by the unchanged level of endogenous catecholamine concentration in the terminal region in the prefrontal cortex. Presently, it cannot be said that the behavioral syndrome results solely from the lesion of the cholinergic neurons. Also, it is likely that the lesion of the nucleus basalis magnocellularis in the rat does not exactly reproduce the behavioral syndrome observed in Alzheimers disease in man. However, this experimental approach in leading to a better knowledge of the functioning of these neurones could improve our understanding of this disease.

Long-term effects of prenatal stress and handling on metabolic parameters: relationship to corticosterone secretion response

The prenatal and postnatal environment exerts a long-term influence on the stress-response of the hypothalamic-pituitary-adrenal (HPA) axis. In this study, the long-term effects of prenatal and postnatal manipulations and their related changes on glucocorticoid secretion were examined on metabolic parameters in adult rats. Plasma glucose levels, body weight and basal feeding behavior were measured. We show that modifications of the prenatal and postnatal environment have opposite long-term effects on these parameters, except for blood glucose, which was increased in prenatally stressed animals. Although the mechanisms underlying these phenomena remain to be elucidated, the observations show that perinatal manipulations have long-term effects on metabolic functions related to HPA activity.