Biomedical subjects

W Mayo

Publications and source records attributed to W Mayo.

At least 19 recordsLinked to original sources

PubMed1999

Ciliary neurotrophic factor is a regulator of muscular strength in aging.

Ciliary neurotrophic factor (CNTF) participates in the survival of motor neurons and reduces the denervation-induced atrophy of skeletal muscles. Experiments performed in rats show a decrease in peripheral CNTF synthesis during aging, associated with an overexpression of its alpha-binding receptor component by skeletal muscles. Measurement of sciatic nerve CNTF production and of the muscular performance developed by the animals revealed a strong correlation between the two studied parameters (r = 0.8; p < 0.0003). Furthermore, the twitch and tetanic tensions measured in the isolated soleus skeletal muscle in 24-month-old animals increased 2. 5-fold by continuous in vivo administration of CNTF. Analyses of the activation level of leukemia inhibitory factor receptor beta- and signal transducer and activator of transcription 3-signaling molecules in response to exogenous CNTF revealed an increased tyrosine phosphorylation positively correlated with the twitch tension developed by the soleus muscle of the animals.

Aging↗

PubMed1999

The promnesic neurosteroid pregnenolone sulfate increases paradoxical sleep in rats.

The effect of systemic administration of the neurosteroid pregnenolone sulfate (PREG-S) on sleep-wakefulness cycle and on spatial memory performances was investigated in male Sprague-Dawley rats. In the first experiment, the effect of PREG-S administration (saline, 4.75, 47.5 mg/kg, i.p.) on 24 h EEG recording was evaluated. In the second experiment, spatial memory performance in a two-trial memory task was evaluated after post-acquisition administration of similar doses of PREG-S as in the first experiment. Results show that PREG-S increases paradoxical sleep and improves the performance on the memory task yielding similar dose response curves. Starting 4 h after administration of 47.5 mg/kg PREG-S, paradoxical sleep is increased for 10 h. The PREG-S effect on spatial memory lasts for at least 24 h after injection. These results suggest that an enhancement of paradoxical sleep may be involved in the promnesic effects of this neurosteroid.

Animals↗

PubMed1999

Infusion of neurosteroids into the rat nucleus basalis affects paradoxical sleep in accordance with their memory modulating properties.

The neurosteroids pregnenolone sulfate and allopregnanolone affect memory processes in an opposite manner, pregnenolone sulfate acts as a potent memory-enhancer whereas allopregnanolone impairs memory performance. The mechanisms underlying these memory modulating properties have yet to be elucidated. We have previously reported that infusions of either neurosteroid into the nucleus basalis magnocellularis, one of the main forebrain cholinergic nuclei, differentially affect spatial memory in rats. The relationships between memory performance and paradoxical sleep are well documented, therefore we investigated whether neurosteroids infused into the nucleus basalis magnocellularis affected the sleep-wakefulness cycle in rats, measured by electroencephalographic recordings. Results show that pregnenolone sulfate (5 ng) increased by 12%, whereas allopregnanolone (2 ng) decreased by 24%, the duration of paradoxical sleep in the 24 h interval following injection compared to control recordings. Pregnenolone sulfate inhibits GABA(A) receptors whereas allopregnanolone stimulates them. Since cholinergic neurons of the nucleus basalis magnocellularis are GABA-modulated, it may be postulated that these neurosteroids modify paradoxical sleep by acting on the cholinergic transmission. This may account, at least in part, for the memory modulating properties of these compounds.

Animals↗

PubMed1998

Reaction of sleep-wakefulness cycle to stress is related to differences in hypothalamo-pituitary-adrenal axis reactivity in rat.

Acute stress is known to modify sleep-wakefulness cycle, although with considerable interindividual differences. The origin of these individual differences remains unknown. One possibility is an involvement of the hypothalamo-pituitary-adrenal axis (HPA), as its reactivity is correlated with an individual's behavioral reactivity to stress, and it is known to influence the sleep-wakefulness cycle. The present study was designed to analyze relationships between natural differences in behavioral reactivity to stress associated with differential HPA reactivity and stress-induced changes in sleep-wakefulness. Adult rats were classified into two sub-groups according to their locomotor reactivity to a mild stress (novel environment): the 'low responders (LR)' and the 'high responders (HR)' animals exhibited different glucocorticoid secretion in response to stress. We show that immobilization stress induced an increase in wakefulness in LR animals and a decrease in wakefulness in HR animals. On the other hand, paradoxical sleep was increased in both LR and HR animals. Moreover, we observed that LR animals slept more than the HR animals, whereas the two groups had similar levels of paradoxical sleep. These results indicate that the response of the sleep-wakefulness cycle to stress is related to the behavioral reactivity to stress, in turn governed by the individual's reactivity of the HPA axis. The involvement of dopaminergic mechanisms is discussed.

Animals↗

PubMed1998

An experimental model of acute encephalopathy after total body irradiation in the rat: effect of liposome-entrapped Cu/Zn superoxide dismutase.

PURPOSE: To develop an experimental model of acute encephalopathy following total body irradiation in rats and to define the therapeutic effect of liposome-entrapped Cu/Zn superoxide dismutase. METHODS AND MATERIALS: A total of 120 4-month-old rats received 4.5 Gy total body irradiation (TBI) while 120 rats received sham irradiation. A behavioral study based on a conditioning test of negative reinforcement, the one-way avoidance test, was performed 5 hours before irradiation and repeated the following days. Subcutaneous treatment was started 1 hour after irradiation and repeated daily for 2 weeks. In both the irradiated and sham group, three subgroups were defined according to the treatment received: liposome-entrapped Cu/Zn superoxide dismutase (0.5 mg/kg), liposomes only, normal saline. RESULTS: This work comprised two consecutive studies. In study A (90 rats) the one-way avoidance test was administered daily from day 0 to day 4 with a recall session at day 14. In study B (validation phase in 150 rats) the behavioral test was performed only from day 0 to day 6. Before irradiation, all rats showed a similar behavioral response. Study A (6 groups of 15 rats): Following TBI, irradiated rats treated with liposomes only or saline demonstrated a significant delay in learning the one-way avoidance test in comparison with sham-irradiated rats (0.05 < p <0.001 depending upon the day of evaluation and the subgroup type). In contrast, irradiated rats treated with liposome-entrapped Cu/Zn superoxide dismutase did not differ from sham-irradiated rats. Study B (6 groups of 25 rats): The results were the same as those in study A, demonstrating a significant delay in the learning of the test in the liposome and saline-treated irradiated rats in comparison with sham-irradiated rats (0.02 < p < 0.001). The irradiated rats, treated with liposome-entrapped Cu/Zn superoxide dismutase did not differ from the sham-irradiated controls. CONCLUSION: This study indicates that a relatively low dose of total body irradiation induces a substantial acute learning dysfunction in the rat. This effect is prevented by the administration of liposome-entrapped Cu/Zn superoxide dismutase.

Animals↗

PubMed1998

The neurosteroid pregnenolone sulfate infused into the nucleus basalis increases both acetylcholine release in the frontal cortex or amygdala and spatial memory.

The effects of an infusion (5 ng) of the neurosteroid pregnenolone sulfate into the nucleus basalis magnocellularis on acetylcholine release in the frontoparietal cortex and basolateral amygdala were evaluated during the 130 min post-injection in male Sprague-Dawley rats using in vivo microdialysis coupled "on line" with high performance liquid chromatography detection. One week later, the same animals were tested for spatial memory after another infusion of pregnenolone sulfate (5 ng) into the nucleus basalis. Results show that pregnenolone sulfate enhanced acetylcholine release by more than 50% of baseline concentrations in the two structures relative to a control injection. The duration of this effect was longer in cortex (130 min) than in amygdala (30 min). Furthermore, pregnenolone sulfate improved memory performance in a task based upon spatial recognition of a familiar environment. A significant positive correlation (r=0.49) was found between the recognition score in the spatial memory test and the levels of acetylcholine release in the frontoparietal cortex but not in the basolateral amygdala. Therefore, our results suggest that the nucleus basalis magnocellularis-cortical pathway could be in part responsible for the promnesic effect of pregnenolone sulfate. This neurosteroid acts as a negative modulator of the GABA(A) receptor complex and positively modulates the N-methyl-D-aspartate receptor, possibly resulting in a global stimulatory effect on central cholinergic neurotransmission.

Acetylcholine↗

PubMed1998

The neurosteroid pregnenolone sulfate increases cortical acetylcholine release: a microdialysis study in freely moving rats.

The effects of pregnenolone sulfate (Preg-S) administrations (0, 12, 48, 96, and 192 nmol intracerebroventricularly) on acetylcholine (ACh) release in the frontal cortex and dorsal striatum were investigated by on-line microdialysis in freely moving rats. Following Preg-S administration, extracellular ACh levels in the frontal cortex increased in a dose-dependent manner, whereas no change was observed in the striatum. The highest doses (96 and 192 nmol) induced a threefold increase above control values of ACh release, the intermediate dose of 48 nmol led to a twofold increase, whereas after the dose of 12 nmol, the levels of ACh were not different from those observed after vehicle injection. The increase in cortical ACh reached a maximum 30 min after administration for all the active doses. Taken together, these results suggest that Preg-S interacts with the cortical cholinergic system, which may account, at least in part, for the promnesic and/or antiamnesic properties of this neurosteroid.

Acetylcholine↗

PubMed1997

Neurosteroids: deficient cognitive performance in aged rats depends on low pregnenolone sulfate levels in the hippocampus.

Pregnenolone sulfate (PREG S) is synthesized in the nervous system and is a major neurosteroid in the rat brain. Its concentrations were measured in the hippocampus and other brain areas of single adult and aged (22-24 month-old) male Sprague-Dawley rats. Significantly lower levels were found in aged rats, although the values were widely scattered and reached, in about half the animals, the same range as those of young ones. The spatial memory performances of aged rats were investigated in two different spatial memory tasks, the Morris water maze and Y-maze. Performances in both tests were significantly correlated and, accompanied by appropriate controls, likely evaluated genuine memory function. Importantly, individual hippocampal PREG S and distance to reach the platform in the water maze were linked by a significant correlation, i.e., those rats with lower memory deficit had the highest PREG S levels, whereas no relationship was found with the PREG S content in other brain areas (amygdala, prefrontal cortex, parietal cortex, striatum). Moreover, the memory deficit of cognitively impaired aged rats was transiently corrected after either intraperitoneal or bilateral intrahippocampal injection of PREG S. PREG S is both a gamma-aminobutyric acid antagonist and a positive allosteric modulator at the N-methyl-D-aspartate receptor, and may reinforce neurotransmitter system(s) that decline with age. Indeed, intracerebroventricular injection of PREG S was shown to stimulate acetylcholine release in the adult rat hippocampus. In conclusion, it is proposed that the hippocampal content of PREG S plays a physiological role in preserving and/or enhancing cognitive abilities in old animals, possibly via an interaction with central cholinergic systems. Thus, neurosteroids should be further studied in the context of prevention and/or treatment of age-related memory disorders.

Aging↗

PubMed1997

Inter-individual differences in the effects of acute stress on the sleep-wakefulness cycle in the rat.

It has been described that an acute immobilization stress (IS) modifies subsequent paradoxical sleep (PS). However, its effects are complex because some subjects remain unaffected. This discrepancy might result from constitutive inter-individual psychobiological differences. In order to test this hypothesis, an inter-individual analysis of sleep patterns and their modifications after 60 min IS has been performed. Even though global analysis showed a PS increase after IS, inter-individual analysis evidenced different PS reactivity; subjects which had the least PS during control recordings were those with the largest PS increase. Unlike global analysis, an inter-individual study evidenced different modifications of wakefulness and slow wave sleep according to individuals. Subjects presenting the highest amount of wakefulness in control conditions (the lowest amount of slow wave sleep) decreased their wakefulness amount, while subjects with the lowest amount of wakefulness increased it. Thus, individual characteristics of the sleep-wakefulness cycle should be considered while studying its modifications induced by different treatments.

Animals↗

PubMed1997

Prenatal stress induces high anxiety and postnatal handling induces low anxiety in adult offspring: correlation with stress-induced corticosterone secretion.

It is well known that the hypothalamo-pituitary-adrenal (HPA) axis is altered by early environmental experiences, particularly in the perinatal period. This may be one mechanism by which the environment changes the physiology of the animal such that individual differences in adult adaptative capabilities, such as behavioral reactivity and memory performance, are observable. To determine the origin of these behavioral individual differences, we have investigated whether the long-term influence of prenatal and postnatal experiences on emotional and cognitive behaviors in adult rats are correlated with changes in HPA activity. To this end, prenatal stress of rat dams during the last week of gestation and postnatal daily handling of rat pups during the first 3 weeks of life were used as two environmental manipulations. The behavioral reactivity of the adult offspring in response to novelty was evaluated using four different parameters: the number of visits to different arms in a Y-maze, the distance covered in an open field, the time spent in the corners of the open field, and the time spent in the open arms of an elevated plus-maze. Cognitive performance was assessed using a water maze and a two-trial memory test. Adult prenatally stressed rats showed high anxiety-like behavior, expressed as an escape behavior to novelty correlated with high secretion of corticosterone in response to stress, whereas adult handled rats exhibited low anxiety-like behavior, expressed as high exploratory behavior correlated with low secretion of corticosterone in response to stress. On the other hand, neither prenatal stress nor handling changed spatial learning or memory performance. Taken together, these results suggest that individual differences in adult emotional status may be governed by early environmental factors; however, perinatal experiences are not effective in influencing adult memory capacity.

Analysis of Variance↗

PubMed1997

Decrease in highly polysialylated neuronal cell adhesion molecules and in spatial learning during ageing are not correlated.

Age-dependent spatial memory impairments have been related to a decline in hippocampal plasticity. Highly polysialylated neuronal cell adhesion molecules (PSA-NCAM) show a strong expression during adulthood within regions associated with neuroplastic events. Furthermore, NCAM molecules have been proposed to mediate neuronal plasticity during learning and memory. The aim of the present study was to examine the effect of ageing on the expression of PSA-NCAM within the hippocampus. To investigate whether age-dependent changes in expression of PSA-NCAM were accentuated in aged rats with learning impairment, animals were in a first step assessed for their cognitive abilities using a Morris water maze. Seven-month-old and 24-month-old-rats were tested for their performance in the Morris water maze. The animals were sacrificed and brain sections were processed for PSA-NCAM immunohistochemistry. Ageing was accompanied by an overall decrease in PSA-NCAM-immunoreactivity (-IR) within the forebrain, presenting a important decrease of the number of PSA-NCAM-IR perikarya within the hippocampus. These results were confirmed by Western blot analysis. No difference in PSA-NCAM immunoreactivity was observed in aged rats with or without spatial learning impairment. It is concluded that although changes in PSA-NCAM accompanied the decrease in cognitive abilities, our data did not evidence a causal relationship between these two parameters.

Aging↗

PubMed1997

Facilitation of cognitive performance in aged rats by past experience depends on the type of information processing involved: a combined cross-sectional and longitudinal study.

The impact of past history on behavior across the life span is largely unknown. This is why the role of previous experience in subsequent memory performances has been studied in a combined longitudinal (animals repeatedly tested) and cross-sectional (animals tested once at various ages) study, in male Sprague-Dawley rats. Different types of memory (reference and working memory) and/or information processing (route or place learning) were assessed in three different tasks (T-maze, Morris water maze, and eight-arm radial maze). Our results indicate that experience prevents age-related impairments in the learning phase of the T-maze and the Morris water maze, in both middle-aged and old rats. Nonexperienced animals of the same age were found to present age-related memory deficits. However, previous experience did not have any effect on the learning of the radial maze or on the reversal performance. It is suggested that controlled processes (intentional and attentional) are impaired by aging and cannot be improved by training, whereas automated processes appear to benefit from it. These data underline the heterogeneity of cognitive aging and indicate that aging is not inevitably accompanied by a decline in performance.

Aging↗

PubMed1996

Early and later adoptions have different long-term effects on male rat offspring.

Both prenatal and postnatal environmental factors exert complex influences on the development of an organism. Previous studies have demonstrated that intervening events during the prenatal period can have different and even opposite effects than similar intervening events occurring in the postnatal period. We have reported previously that early postnatal adoption prevents prenatal stress-induced long-term impairments in glucocorticoid feedback. To characterize further the effects of adoptions during the postnatal period, adoptions have been performed at different times, and the effect on the postnatal ontogeny of the hypothalamo-pituitary-adrenal axis has been investigated. Adoptions were performed during the first hour after birth (A1) and on the fifth (A5) and twelfth (A12) days after birth. At each of these times, other litters (S1, S5, S12) underwent a "separation" controlling for the 1 min maternal separation necessary for the adoptions. Locomotor behavior, cognition, and stress-induced corticosterone secretion in the adult male offspring have been examined, along with maternal behavior. Early adoption (A1) was found to prevent the prolonged stress-induced secretion of corticosterone evident in early separated (S1) offspring. Similarly, A1 rats demonstrated lower novelty-induced locomotion and improved recognition performance in a Y-maze compared to S1 offspring. However, later adoption (A5, A12) prolonged stress-induced corticosterone secretion, increased the locomotor response to novelty, and disrupted cognitive performance in the offspring. Only the early adoption increased maternal licking behavior, a factor that may have a protective effect on the pups. Taken together, these results suggest that the same postnatal manipulation realized at different times can induce different, or even opposite, effects on the behavioral and neuroendocrine characteristics of the adult offspring.

Aging↗

PubMed1996

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.

Animals↗

PubMed1996

Behavioral reactivity to novelty during youth as a predictive factor of stress-induced corticosterone secretion in the elderly--a life-span study in rats.

Inter- and intra-individual differences in hypothalamo-pituitary adrenal (HPA) axis activity and behavioral reactivity to novelty between young and old rats were evidenced in this longitudinal life-span study. Higher responders to novelty (HR) had a higher corticosterone secretion which showed a quicker increase with age than did the others (LR); the differences in response to novelty observed in youth were no longer apparent in the old rats. Response to novelty in youth is a predictive factor of accelerated aging of the HPA axis. These early changes, which precede the appearance of the memory deficits, may be a causal factor. Disappearance of behavioral and endocrinological inter-individual differences at 21 months highlights the importance of not restricting aging studies to old subjects.

Aging↗

PubMed1996

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.

Animals↗

PubMed1995

Biosynthesis and assay of neurosteroids in rats and mice: functional correlates.

Pregnenolone (PREG), synthesized de novo in rodent brain, is the precursor of PREG sulfate (S) and progesterone (PROG). PROG is further converted to 5 alpha-pregnane 3, 20-dione (DH PROG) and to 3 alpha-hydroxy-5 alpha-pregnan-20-one (TH PROG). PROG, DH PROG and TH PROG have been measured in the brain of male and female rats. Neither PROG nor DH PROG disappeared from brain, contrary to plasma, after combined adrenalectomy (ADX) and gonadectomy (CX). Trilostane decreased PROG and increased PREG in the brain of CX+ADX rats and mice, in accordance with a precursor to product relationship. As previously described in CX male mice, the neurosteroid DHEA and its analog 3 beta-methyl-androst-5-en-17-one (CH3-DHEA) inhibited the aggressive behavior of female mice towards lactating female intruders. The decrease of biting attacks by DHEA was definitely more prominent in females neonatally imprinted with testosterone. The degree of inhibition of aggressive behavior was related to the decrease of PREG S concentrations in brain. The memory-enhancing effects of DHEA S and PREG S in male mice have been previously documented. Infusion of PREG S (12 fmol) into the nucleus basalis magnocellularis (NBM) of the rat after the acquisition trial enhanced memory performance in a two-trial recognition task (TTRT). Conversely, TH PROG (6 fmol), which potentiates GABAergic neurotransmission, disrupted performance when injected before the acquisition trial. Accordingly, we have found a positive correlation between the performances of 2-year-old rats in the TTRT and the concentrations of PREG S in the hippocampus, namely animals which performed best had the highest steroid levels.

Adrenalectomy↗

PubMed1994

Reactivity to novelty during youth as a predictive factor of cognitive impairment in the elderly: a longitudinal study in rats.

A life-span study of certain behavioral traits was conducted in rats. Animals were repeatedly tested in a circular corridor for reactivity to novelty and in a recognition memory task for cognitive abilities. These measures revealed important inter-individual differences in young as well as in old subjects. Some of these differences appear with aging (memory deficits) and others disappear (high reactivity to novelty). Moreover, a relationship between high reactivity to novelty in youth and deficits in memory recognition in elderly was found. Rats that are high-responders to novelty had age-related memory impairments whereas the low-responder rats did not. While the biological mechanism linking these two behavioral traits remains to be demonstrated, this study shows that age-related impairments can be predicted by factors detectable early in life.

Aging↗