Abdul H. Mohammed

Long-term environmental enrichment leads to regional increases in neurotrophin levels in rat brain

A number of studies have demonstrated that both morphological and biochemical indices in the brain undergo alterations in response to environmental influences. In previous work we have shown that rats raised in an enriched environmental condition (EC) perform better on a spatial memory task than rats raised in isolated conditions (IC). We have also found that EC rats have a higher density of immunoreactivity than IC rats for both low and high affinity nerve growth factor (NGF) receptors in the basal forebrain. In order to determine if these alterations were coupled with altered levels of neurotrophins in other brain regions as well, we measured neurotrophin levels in rats that were raised in EC or IC conditions. Rats were placed in the different environments at 2 months of age and 12 months later brain regions were dissected and analyzed for NGF, brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3) levels using Promega ELISA kits. We found that NGF and BDNF levels were increased in the cerebral cortex, hippocampal formation, basal forebrain, and hindbrain in EC animals compared to age-matched IC animals. NT-3 was found to be increased in the basal forebrain and cerebral cortex of EC animals as well. These findings demonstrate significant alterations in NGF, BDNF, and NT-3 protein levels in several brain regions as a result of an enriched versus an isolated environment and thus provide a possible biochemical basis for behavioral and morphological alterations that have been found to occur with a shifting environmental stimulus.

Changes in brain nerve growth factor levels and nerve growth factor receptors in rats exposed to environmental enrichment for one year

This study examined the effects of long-term differential rearing on levels of brain nerve growth factor, its receptors, and their relationships to cognitive function. Adult rats (two months old) were placed into either enriched or standard housing conditions where they remained for 12 months. Animals from the enriched condition group had significantly higher levels of nerve growth factor in hippocampus, visual and entorhinal cortices compared with animals housed in isolated condition. Immunohistochemical analysis of brain tissue from the medial septal area revealed higher staining intensity and fibre density with both the low-affinity and the high-affinity nerve growth factor receptors. Enriched rats performed better than isolated rats in acquisition of spatial learning and had lower locomotion scores in the open field. These results provide further evidence that experimental stimulation results in increased production of trophic factors and structural reorganization in specific brain regions known to be involved in cognitive function.

Environmental influences on the central nervous system and their implications for the aging rat

Two methods of providing environmental stimulation that were introduced in the 1950s have guided much research on neurobehavioural plasticity. These are neonatal handling and environmental enrichment. Neonatal handling has been shown to permanently affect behaviour and endocrine responses. Recently this manipulation has been shown to have important influences on the aging individual, protecting the hippocampus from age-related dysfunction and neuronal loss. These effects are mediated, in part, by keeping glucocorticoid levels low. This has been characterised by, among other things, elevated expression of glucocorticoid receptors in the hippocampus. Earlier studies have failed to present convincing evidence for differences in hormonal variables between animals housed in enriched and impoverished environments, and have not consistently reported changes in the hippocampus. Recent data from our laboratories have shown that adult animals housed in enriched environments had, like neonatally-handled rats, higher expression of the gene encoding glucocorticoid receptors in the hippocampus. Taken together with the induction of NGF and NGFIA gene expression in the hippocampus of enriched animals, these results implicate genes encoding transcription factors and glucocorticoid receptors in the cascade of events leading to environmentally induced cerebral changes. In addition, these results suggest that environmental enrichment in adulthood, like neonatal handling, may have the potential to protect the aging hippocampus from glucocorticoid neurotoxicity.

Environmental enrichment and the brain.

An intriguing capacity of the adult nervous system for structural and functional modification in response to external stimuli (plasticity) has been the focus of research efforts for decades. This review shows history of ideas about brain changes in relation to experiential factors and surveys experimental studies of the impact of enriched environment on the brain and behaviour, in adult, aged and injured nervous system.

Environmental enrichment results in higher levels of nerve growth factor mRNA in the rat visual cortex and hippocampus

Evidence for structural modifications in the brain following environmental changes have been provided during the last decades. The most pronounced alterations following environmental manipulations have been found in the visual cortex. These plastic changes are supposed to reflect reorganization of neuronal connections involved in postnatal development and adult adjustments of connections involved in sensori-perceptual processing and learning. Potential candidates to mediate these changes are neurotrophins. Nerve growth factor (NGF) has been associated with cognitive functions and shown to improve the performance of aged rats in spatial learning and memory task. In the central nervous system, NGF is of importance for development and maintenance of cholinergic neurons and atrophy of cholinergic neurons is strongly correlated with learning and memory impairments. Exposure to enriched environmental conditions improves learning and problem-solving ability and results in plastic changes in the brain. This study examined the effect of environmental enrichment on expression of NGF mRNA in the rat visual cortex and hippocampus. Rats housed in groups in a stimulus-rich environment for 30 days had significantly higher levels of NGF mRNA than rats housed individually in single cages without stimulus-enrichment. We have recently presented results showing higher levels of neurotrophin-3 (NT-3) mRNA and improved spatial learning following environmental enrichment, and suggest that an interplay involving the neurotrophins NGF and NT-3 may be mediating experience-induced structural changes.

Environmental influences on brain neurotrophins in rats

Environmental factors can have profound influences on the brain. Enriching environments with physical, social and sensory stimuli are now established to be beneficial to brain development and ageing. A multitude of responses from cellular and molecular mechanisms to macroscopic changes in neural morphology and neurogenesis have been considered in the context for evidences that environmental inputs can regulate brain plasticity in the rat at all stages of life. Data from our laboratory have revealed that enriched environment increased nerve growth factor (NGF) gene expression and protein levels in the hippocampus, and this may contribute to events underlying environmentally induced neural plasticity. Because neurotrophic factors are essential for neural development and survival, they are likely to be involved in the cerebral consequences modified by enriched experiences.

Psychological stress and environmental adaptation in enriched vs. impoverished housed rats.

In this study, we report differential behavioural and cognitive effects, as assessed in the open-field and the Morris water maze, following psychological stress in enriched vs. impoverished housed rats. Three stress conditions were evaluated: nonstress, mild stress and powerful stress. Mild stress consisted of exposure to an avoidance box but without shock, while in the powerful stress condition animals were exposed to an electric shock. The results revealed distinct effects in the differentially housed animals. Prior exposure to a mild stress enhanced escape performance in the water maze in enriched but not impoverished animals. However, preexposure to powerful stress negatively affected animals from both housing conditions in the water maze task, but with the enriched animals less affected than impoverished animals. In the open-field test, stress preexposure reduced locomotion counts in both the differentially housed animals. In addition, the results showed that the enrichment effect on emotional reactivity in the open-field is long-lasting and persists even after extensive training and housing in standard laboratory conditions. The results are discussed in relation to the nature of the behavioural and learning differences between the differentially housed animals.

Effects of environmental enrichment on cognitive function and hippocampal NGF in the non-handled rats

In this study we examine whether exposure to differential housing after weaning would counteract the effects of postnatal handling (H) or nonhandling (NH) treatment by affecting learning and memory processes in young rats. In addition, we seek to determine if experience in enriched environment would alter hippocampal nerve growth factor (NGF) levels which is one of the factors known to be involved in the regulation of the survival and differentiation of developing basal forebrain neurones. Rats were either exposed to handling treatment, or left undisturbed starting day 1 after birth through day 21. After weaning on day 22, we exposed half of the H rats and half of the NH rats to environmental enrichment for 60 days. The other respective half of the rats was housed in isolated environmental condition (IC). Behavioural measures were taken in open field test, and spatial water maze test. Exposure to enriched environment following postnatal handling and nonhandling increased hippocampal NGF levels, and improved cognitive function in the both groups, with NH rats being more responsive to the effects of enrichment. Our results suggest that environmental enrichment has the potential to prevent or reduce the cognitive and neurochemical deficits in the adult animals associated with nonhandling.

Environmental enrichment selectively increases 5-HT1A receptor mRNA expression and binding in the rat hippocampus

Environmental enrichment augments neuronal plasticity and cognitive function and possible mediators of these changes are of considerable interest. In this study, male rats were exposed to environmental enrichment or single housing for 30 days. Rats from the enriched group had significantly higher 5-HT1A receptor mRNA expression in the dorsal hippocampus (62%, 59% and 44% increase in the CA1, CA2 and CA3 subfields, respectively). This was associated with significantly higher [3H]8-OH-DPAT binding in the inferior part of CA1. No changes were seen for 5-HT2A or 5-HT2C receptor mRNAs. The neuronal plasticity detected after environmental change may be mediated, in part, through 5-HT1A receptors.

Glucocorticoid receptor and NGFI-A gene expression are induced in the hippocampus after environmental enrichment in adult rats ☆

Environmental manipulation alters hippocampal glucocorticoid receptor (GR) expression in neonatal rats, but effects in adults have not been documented. Chronic environmental enrichment (EE) increases nerve-growth factor (NGF) concentrations in the adult rat hippocampus. Here we demonstrate that EE induces GR, but not mineralocorticoid receptor (MR) gene expression in specific hippocampal subfields (CA1 and CA2). This is accompanied by increased expression of mRNA encoding the (NGF-induced) immediate early gene NGFI-A in CA2, whereas expression of NGFI-B mRNA decreased in CA1 and CA2. The nature of any relationship between NGF, the transcription factors and GR remains to be determined, but the results demonstrate that chronic environmental manipulations alter hippocampal GR gene expression in adult rats.