Motherhood-induced memory improvement persists across lifespan in rats but is abolished by a gestational stress.

Motherhood modifies the biology and behavior of the female, a process which prepares the mother's cognitive systems that are needed for nurturance. It has recently been shown that motherhood enhances hippocampal-mediated spatial learning and synaptic plasticity. Deleterious and long-term effects of a stress experienced during gestation have been demonstrated on progeny. Surprisingly little is known about the effect of such stress on mothers. Here, we investigated the effect of gestational stress on the adaptive changes due to motherhood. Female rats were mated and stressed during the last week of gestation. Two weeks after weaning, they were submitted to behavioral tests or electrophysiological study. A group of females were then kept for 16 months after motherhood experience to study the long-term effect of gestational stress and motherhood on memory when they were 22 months old. We confirm that a single motherhood experience selectively increases hippocampal-mediated spatial memory during the entire lifespan of female rats and protects them from age-associated memory impairments. However, we demonstrate that a stressful experience during gestation totally abolishes the positive effects of motherhood both on spatial memory and on hippocampal synaptic plasticity (long-term potentiation). Environmental factors that induce biological vulnerability have negative effects even for fundamental biological behaviors.

Chronic exposure of rats to noise: relationship between long-term memory deficits and slow wave sleep disturbances.

Noise is now recognized as a serious health problem in our modern societies. Although its deleterious and direct effects on cognitive tasks (long-term memory, mental arithmetic activity, visual tasks, etc.) are clearly admitted, no studies have determined a delayed indirect effect of noise on cognitive processes. Furthermore, the link between sleep disturbances related to environmental noise (EN) exposure and these indirect deteriorations of human performances has never been demonstrated. This could be due to inappropriate evaluation of sleep as well as to uncontrolled and confounding factors such as sex, age, and also inter-individual vulnerability. Based on a recently validated animal model [Rabat A, Bouyer JJ, Aran JM, Le Moal M, Mayo W. Chronic exposure to an environmental noise permanently disturbs sleep in rats: inter-individual vulnerability. Brain Res 2005;1059:72-82], aims of the present study were (i) to determine long-term memory (LTM) deficits following a chronic exposure to EN and (ii) to link these behavioral problems to sleep disturbances related to EN. For this purpose in a first experiment, LTM performances were evaluated before and following 9 days of EN. Results show LTM deficits following a chronic exposure to EN with inter-individual vulnerability. Vulnerability profile was related to the psychobiological profile of rats. Results of the second experiment show LTM deficits correlated to both debt of slow wave sleep (SWS) and to daily decrease of SWS bout duration. Our results demonstrate that chronic exposure to noise indirectly disturbs LTM possibly through SWS disturbances and suggest a possible role of the stress hormonal axis in these biological effects of noise.

Smad-dependent alterations of PPT cholinergic neurons as a pathophysiological mechanism of age-related sleep-dependent memory impairments.

In humans, memory impairments are highly prevalent in the aged population, but their functional and structural origins are still unknown. We hypothesized that circadian rhythm alterations may predict spatial memory impairment in aged rats. We demonstrate an association between sleep/wake circadian rhythm disturbances (non-REM sleep fragmentation) and spatial memory impairments in aged rats. We show by light and electron microscopy that these age-related disruptions in circadian rhythm and spatial memory are also associated with degeneration of cholinergic neurons of the pedunculopontine nucleus (PPT), a structure known to be involved in sleep and cognitive functions and which is altered during aging. Finally, we demonstrate that a trophic deregulation of the PPT occur in aged impaired rats, involving an over activation of the TGFbeta-Smad cascade, a signalling pathway involved in neurodegeneration. In conclusion these results provide a new pathophysiological mechanism for age-related sleep-dependent memory impairments opening the ground for the development of new therapeutic approaches of these pathologies.

Educational and health services innovation to improve care for rural Hispanic communities in the USA.

BACKGROUND: Access to comprehensive and quality healthcare services is difficult for socioeonomically disadvantaged groups in rural regions. Barriers to health care for rural Latinos include lack of insurance, language barriers and cultural differences. For the Latino immigrant population in rural areas, barriers to access are compounded. HEALTH NEEDS OF RURAL AREAS: THE CASE OF WALHALLA, SC: The town of Walhalla, South Carolina, USA, is a rural community located in Oconee County, the northwest corner of the state. Disparities exist between rural and urban residents in several health categories, and these disparities illustrate the need to provide competent, appropriate and affordable healthcare to rural populations. The Hispanic population of Oconee has dramatically increased in the past decade, and the majority of these immigrants have no health insurance and have limited access to health services. DESIGNING A PROGRAM TO FIT THE COMMUNITY--THE "WALHALLA EXPERIENCE": The purpose of the Accessible and Culturally Competent Health Care Project (ACCHCP) is to provide care for underserved populations, in Oconee County, South Carolina while providing rural educational opportunities for health services students. Funded by the Health Resources and Services Administration of DHHS, the program is designed to offer culturally appropriate, sensitive, accessible, affordable and compassionate care in a mobile clinic setting. In this interdisplinary program, nurse practitioners, health educators, bilingual interpreters, medical residents and Clemson University students and professors all played key roles. Women in the community also serve as promotoras or lay health advisors. The program is unique in using educational initiatives and innovative strategies for bringing health care to this underserved community and offers important information for rural healthcare initiatives targeting minority groups. This article reports on the challenges and successes in the development and implementation of the ACCHCP program in Walhalla, South Carolina.

Chronic exposure to an environmental noise permanently disturbs sleep in rats: inter-individual vulnerability.

Chronic exposure to an environmental noise (EN) induces sleep disturbances. However, discrepancies exist in the literature since many contradictory conclusions have been reported. These disagreements are largely due to inappropriate evaluation of sleep and also to uncontrolled and confounding factors such as sex, age and also inter-individual vulnerability. Based on a recently validated animal model, aims of the present study were (i) to determine the effects of a chronic exposure to EN on sleep and (ii) to evaluate the inter-individual vulnerability of sleep to EN. For this purpose, rats were exposed during 9 days to EN. Results show that a chronic exposure to EN restricts continually amounts of slow wave sleep (SWS) and paradoxical sleep (PS) and fragments these two sleep stages with no habituation effect. Results also evidence the existence of subpopulations of rats that are either resistant or vulnerable to these deleterious effects of EN on sleep and especially on SWS amounts, bouts number and bout duration. Furthermore, importance of SWS debt and daily decrease of SWS bout duration are correlated to each others and both correlate to the amplitude of the locomotor reactivity to novelty, a behavioral measure of reactivity to stress. This last result suggests that this psychobiological profile of subjects, known to induce profound differences in neural and endocrine systems, could be responsible for their SWS vulnerability under a chronic EN exposure.

Pregnenolone sulfate enhances neurogenesis and PSA-NCAM in young and aged hippocampus.

Age-dependent cognitive impairments have been correlated with functional and structural modifications in the hippocampal formation. In particular, the brain endogenous steroid pregnenolone-sulfate (Preg-S) is a cognitive enhancer whose hippocampal levels have been linked physiologically to cognitive performance in senescent animals. However, the mechanism of its actions remains unknown. Because neurogenesis is sensitive to hormonal influences, we examined the effect of Preg-S on neurogenesis, a novel form of plasticity, in young and old rats. We demonstrate that in vivo infusion of Preg-S stimulates neurogenesis and the expression of the polysialylated forms of NCAM, PSA-NCAM, in the dentate gyrus of 3- and 20-month-old rats. These influences on hippocampal plasticity are mediated by the modulation of the gamma-aminobutyric acid receptor complex A (GABA(A)) receptors present on hippocampal neuroblasts. In vitro, Preg-S stimulates the division of adult-derived spheres suggesting a direct influence on progenitors. These data provide evidence that neurosteroids represent one of the local secreted signals controlling hippocampal neurogenesis. Thus, therapies which stimulate neurosteroidogenesis could preserve hippocampal plasticity and prevent the appearance of age-related cognitive disturbances.

New insights into the role of neuroactive steroids in cognitive aging.

The aim of this article is to describe neuroactive steroid research that has been focused on their physiological role in cognitive aging, an attractive new field in experimental gerontology. Neuroactive steroids have been recently proposed as biomarkers of cognitive aging, however, their specific functions have not yet been fully established. For instance, data emerging from human and animal studies suggest a complex relationship between neuroactive steroids and/or metabolites and cognitive processes during aging. Thus, a better knowledge of neuroactive steroid brain distribution and function could broaden our understanding of their physiological roles and lead to novel and more effective treatments for the management of age-related brain disorders. To this end, newly developed sensitive, specific, and accurate mass spectrometry assays may allow the quantification of neuroactive steroids in discrete brain regions and greatly contribute to unravel their role in age-related cognitive deficits.

Deleterious effects of an environmental noise on sleep and contribution of its physical components in a rat model.

Sleep disturbances induced by environmental noise (EN) exposure are now well admitted. However, many contradictory conclusions and discrepancies have been reported, resulting from uncontrolled human factors or the use of artificial noises (pure tone). Thus, the development of an animal model appears to be a useful strategy for determining whether EN is deleterious to sleep. The aims of this study were: (i) to confirm the effects of noise on sleep in a rat model; and (ii) to determine the most deleterious physical component of noise regarding sleep structure. For this purpose, rats were exposed during 24 h either to EN or to artificial broad-band noises [either continuous broad-band noise (CBBN) or intermittent broad-band noise (IBBN)]. All the noises decrease both slow wave sleep (SWS) and paradoxical sleep (PS) amounts during the first hours of exposure. However, CBBN acts indirectly on PS through a reduction of SWS bout duration, whereas IBBN and EN disturb directly and more strongly both SWS and PS. Finally, EN fragments SWS and decreases PS amount during the dark period, whereas IBBN only fragments PS. These results demonstrate the validity and suitability of a rodent model for studying the effects of noise on sleep and definitively show that sleep is disturbed by EN exposure. Two physical factors seem to be implicated: the intermittency and the frequency spectrum of the noise events, which both induce long-lasting sleep disturbances. An additive effect of frequency spectrum to intermittency tends to abolish all possible adaptations to EN exposure. Since sleep is involved in cognitive processes, such disturbances could lead to cognitive deficits.

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

Without medical progress, dementing diseases such as Alzheimer's 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 Alzheimer's disease patients and aged non-demented controls by GC/MS, providing reference values. In Alzheimer's 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 Alzheimer's 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 Alzheimer's patients and controls. The formation of these metabolites within distinct brain regions negatively correlated with the density of beta-amyloid deposits.

The effect of restraint stress on paradoxical sleep is influenced by the circadian cycle.

It is well known that the physiological impact imposed by events or behaviors displayed during the waking period determines the way organisms sleep. Among the situations known to affect sleep both in its duration and quality, stress has been widely studied and it is now admitted that its effects on sleep architecture depend on several factors specific to the stressor or the individual itself. Although numerous reports have highlighted the prominent role of the circadian cycle in the physiological, endocrine and behavioral consequences of restraint stress, a possible circadian influence in the effects of stress on the sleep-wake cycle has never been studied. Thus the present study was designed to compare the effects on sleep of a 1 h-lasting restraint stress applied at light onset to those observed after the same stressor was applied at light offset. We report that in both conditions stress induced a marked paradoxical sleep increase, whereas wakefulness displayed a moderate decrease and slow wave sleep a moderate augmentation. Although the effects of stress at lights on were of similar magnitude than those of stress at lights off, important differences in the sleep rebound latencies were observed: whatever the time of day the stress was applied, its effects on sleep always occurred during the dark period. This result thus shows that restraint stress could be efficiently used to study the interaction between the circadian and homeostatic components of sleep regulation.

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 Alzheimer's disease.

Neurosteroids in learning and memory processes.

The discovery that neurosteroids could be synthesized de novo in the brain independent from the periphery and display neuronal actions led to great enthusiasm for the study of their physiological role. Pharmacological studies suggest that neurosteroids may be involved in several physiological processes, such as learning and memory. This chapter summarizes the effects of the administration of neurosteroids on learning and memory capabilities in rodents and in models of amnesia. We address the central mechanisms involved in mediating the modulation of learning and memory processes by neurosteroids. In this regard, the neurosteroid-modulated neurotransmitter systems, such as gamma-aminobutyric acid type A, N-methyl-D-aspartate, and cholinergic and sigma opioid systems, appear to be potential targets for the rapid memory alteration actions of neurosteroids. Moreover, given that some neurosteroids affect neuronal plasticity, this neuronal change could be involved in the long-term modulation of learning and memory processes. To understand the role of endogeneous neurosteroids in learning and memory processes, we present some physiological studies in rodents and humans. However, the latter do not successfully prove a role of endogenous neurosteroids in age-related memory impairments. Finally, we discuss the relative implication of a given neurosteroid vs its metabolites. For this question, a new approach using the quantitative determination of traces of neurosteroids by mass spectrometry seems to have potential for examining the role of each neurosteroid in discrete brain areas in learning and memory alterations, as observed during aging.

Pregnenolone sulfate and aging of cognitive functions: behavioral, neurochemical, and morphological investigations.

Neurosteroids are a subclass of steroids that can be synthesized in the central nervous system independently of peripheral sources. Several neurosteroids influence cognitive functions. Indeed, in senescent animals we have previously demonstrated a significant correlation between the cerebral concentration of pregnenolone sulfate (PREG-S) and cognitive performance. Indeed, rats with memory impairments exhibited low PREG-S concentrations compared to animals with correct memory performance. Furthermore, these memory deficits can be reversed by intracerebral infusions of PREG-S. Neurotransmitter systems modulated by this neurosteroid were unknown until our recent report of an enhancement of acetylcholine (ACh) release in basolateral amygdala, cortex, and hippocampus induced by central administrations of PREG-S. Central ACh neurotransmission is involved in the regulation of memory processes and is affected in normal aging and in human neurodegenerative pathologies like Alzheimer's disease. ACh neurotransmission is also involved in the modulation of sleep-wakefulness cycle and relationships between paradoxical sleep and memory are well documented in the literature. PREG-S infused at the level of ACh cell bodies induces a dramatic increase of paradoxical sleep in young animals. Cognitive dysfunctions, particularly those observed in Alzheimer's disease, have also been related to alterations of cerebral plasticity. Among these mechanisms, neurogenesis has been recently studied. Preliminary data suggest that PREG-S central infusions dramatically increase neurogenesis. Taken together these data suggest that PREG-S can influence cognitive processes, particularly in senescent subjects, through a modulation of ACh neurotransmission associated with paradoxical sleep modifications; furthermore our recent data suggest a role for neurosteroids in the modulation of hippocampal neurogenesis.

[Early experience, stressful dysregulation of the hormonal axis and age-related vulnerability to neurodegenerative processus: a longitudinal study in the rat]. / Expériences précoces, dérèglement de l'axe hormonal du stress, vulnérabilité aux processus neurodégénératifs liés à l'âge.

The deleterious effects of particular environmental situations have been suspected to augment the repercussions of cerebral injuries leading to increased vulnerability during ageing. The relationship between the hormones of the hypothalamo-pituitary-adrenal axis, mainly glucocorticosteroids, and cerebral structures like the hippocampus has been the subject of intense investigation in the recent years. Data suggest that long-term elevated blood levels of these hormones can induce neuronal alterations leading to cognitive dysfunction. This hypothesis has been tested with relevant animal models of normal/abnormal ageing. The models are based on the existence of considerable inter-individual differences in the degree of age-related cognitive impairments observed in rodents. Results show that long-term glucocorticosteroid exposure induces cerebral changes related to the action of these hormones on their central receptors. Experimental data are in accordance with clinical investigations suggesting that hormonal changes, and chronic life events, could be considered as a predictive factor of future cognitive dysfunction.

Infrared microscopic imaging of bone: spatial distribution of CO3(2-).

This article describes a novel technology for quantitative determination of the spatial distribution of CO3(2-) substitution in bone mineral using infrared (IR) imaging at approximately 6 microm spatial resolution. This novel technology consists of an IR array detector of 64 x 64 elements mapped to a 400 microm x 400 microm spot at the focal plane of an IR microscope. During each scan, a complete IR spectrum is acquired from each element in the array. The variation of any IR parameter across the array may be mapped. In the current study, a linear relationship was observed between the band area or the peak height ratio of the CO3(2-) v3 contour at 1415 cm(-1) to the PO4(3-) v1,v3 contour in a series of synthetic carbonated apatites. The correlation coefficient between the spectroscopically and analytically determined ratios (R2 = 0.989) attests to the practical utility of this IR area ratio for determination of bone CO3(2-) levels. The relationship forms the basis for the determination of CO3(2-) in tissue sections using IR imaging. In four images of trabecular bone the average CO3(2-) levels were 5.95 wt% (2298 data points), 6.67% (2040 data points), 6.66% (1176 data points), and 6.73% (2256 data points) with an overall average of 6.38+/-0.14% (7770 data points). The highest levels of CO3(2-) were found at the edge of the trabeculae and immediately adjacent to the Haversian canal. Examination of parameters derived from the phosphate v1,v3 contour of the synthetic apatites revealed that the crystallinity/perfection of the hydroxyapatite (HA) crystals was diminished as CO3(2-) levels increased. The methodology described will permit evaluation of the spatial distribution of CO3(2-) levels in diseased and normal mineralized tissues.

Long term neurodevelopmental and behavioral effects of perinatal life events in rats.

Modern neurosciences are now able to open new avenues concerning an experimental approach to clinical neurosciences and psychiatry. Detection and prediction of potential vulnerabilities such as behavioral disturbances and neurodegenerative diseases, are urgent tasks leading to prevention that must be encouraged in parallel to the enormous efforts displayed for treatments. Besides possible genetic origins of diseases, environmental factors are now coming under scrutiny, and especially deleterious and challenging life events and stress occurring during prenatal and postnatal critical periods may orient brain functions towards deleterious developments. The hypothesis that will be examined is that early events might be at the origin of pathological transformations and symptoms after long periods of apparent normal abilities and behavioral homeostasis. We used models of prenatal stress and postnatal manipulations such as cross-fostering. It will be demonstrated that such events induce long-term changes, cognitive and emotional modifications appearing first, when offspring are adults, followed by cognitive defects later in life. Increased sensitivity of the hypothalamic pituitary-adrenal axis (HPA), the endocrine system controlling the secretion of stress hormones (corticoids), appears to be a major element of pathogenesis. HPA axis dysfunction appears very early after birth (3 days) and lasts for months. Cumulative exposure to high levels of hormones seems to be detrimental for some brain regions, especially the hippocampus and major neurotransmitter systems such as dopamine neurons. We evidenced that neuronal modifications in hippocampal region are correlated with behavioral and cognitive defects, relating environment, stress in early life, hormonal changes, long-term neuropathological processes and impaired cognition in aging. Moreover appears in offspring, when adults, a proneness to engage in drug dependence. These data emphasize the need to consider early environmental life events as etiological factors for delayed neuropsychiatric disturbances, neurodegenerative defects included. Moreover, they strengthen the interest for a longitudinal approach to promote experimental psychopathology.

PSA-NCAM: an important regulator of hippocampal plasticity.

The Neural Cell Adhesion Molecule (NCAM) serves as a temporally and spatially regulated modulator of a variety of cell-cell interactions. This review summarizes recent results of studies aimed at understanding its regulation of expression and biological function, thereby focussing on its polysialylated isoforms (PSA-NCAM). The detailed analysis of the expression of PSA and NCAM in the hippocampal mossy fiber system and the morphological consequences of PSA-NCAM deficiency in mice support the notion that the levels of expression of NCAM are important not only for the regulation and maintenance of structural changes, such as migration, axonal growth and fasciculation, but also for activity-induced plasticity. There is evidence that PSA-NCAM can specifically contribute to a presynaptic form of plasticity, namely long-term potentiation at hippocampal mossy fiber synapses. This is consistent with previous observations that NCAM-deficient mice show deficits in spatial learning and exploratory behavior. Furthermore, our data points to an important role of the hypothalamic-pituitary-adrenal axis, which is the principle adaptive response of the organism to environmental challenges, in the control of PSA-NCAM expression in the hippocampal formation. In particular, we evidence an inhibitory influence of corticosterone on PSA-NCAM expression.