Environmental enrichment promotes neurogenesis and changes the extracellular concentrations of glutamate and GABA in the hippocampus of aged rats

The aim of the present study was to investigate the effects of environmental enrichment on the neurogenesis and the extracellular concentrations of glutamate and GABA in the hippocampus of freely moving young and aged rats. Male Wistar rats of 2 (young) and 25 (old) months of age were housed during 8 weeks in an enriched environment; control rats were kept in individual plastic cages during that same period of time. Rats were injected intraperitoneally with bromodeoxyuridine (BrdU; 40 mg/kg; 7 days) during the fourth week of the housing period to detect neurogenesis in the dentate gyrus (DG) of the hippocampus. Rats were sacrified 6 weeks after the last injection of BrdU. During the last week of housing, rats were tested in the water maze for the evaluation of spatial learning. After the housing period, rats were stereotaxically implanted with guide-cannulas to accommodate microdialysis probes in the CA3 area of the hippocampus and the extracellular concentrations of glutamate and GABA were determined. Aged rats showed a decrease in the number of BrdU positive cells in the dentate gyrus compared to young rats. However, neurogenesis in the dentate gyrus of both young and old rats was increased in animals housed in an enriched environment. Microdialysis experiments in the CA3 area of the hippocampus showed that enriched housing conditions increased basal extracellular concentrations of glutamate in aged rats. Perfusion of KCl 100 mM produced a higher increase of extracellular glutamate and GABA in aged rats but not in young rats housed in an enriched environment compared to control rats. These results suggest that enriched housing conditions change both neurogenesis in the dentate gyrus and glutamate and GABA levels in the CA3 area of the hippocampus of aged rats.     

Glutamate–dopamine–GABA interactions in the aging basal ganglia

The study of neurotransmitter interactions gives a better understanding of the physiology of specific circuits in the brain. In this review we focus mostly on our own results on the interaction of the neurotransmitters glutamate, dopamine and GABA in the basal ganglia during the normal process of aging. We review first the studies on the action of endogenous glutamate on the extracellular concentrations of dopamine and GABA in the neostriatum and nucleus accumbens during aging. It was found that there exists an age-related change in the interaction of glutamate, dopamine and GABA and that these effects of aging exhibit a dorsal-to-ventral pattern of effects with no changes in the dorsal parts (dorsal striatum) and changes in the most ventral parts (nucleus accumbens). Second we reviewed the data on the effects of different ionotropic and metabotropic glutamate receptor agonists on the extracellular concentrations of dopamine and GABA in the nucleus accumbens. The results obtained clearly show the different contribution of each glutamate receptor subtype in the age-related changes produced on the interaction of glutamate, dopamine and GABA in this area of the brain. Third the effects of an enriched environment on the action of AMPA and NMDA-receptor agonists in the nucleus accumbens of rats during aging are also evaluated. Finally, and since the nucleus accumbens has been suggested to play a role in emotion and motivation and also motor behaviour, we speculated on the possibility of a specific contribution for the different glutamatergic pathways terminating in the nucleus accumbens and their interaction with a decreased dopamine playing a relevant role in motor behaviour during aging.     

Environmental impoverishment and aging alter object recognition,spatial learning,and dentate gyrus astrocytes

Environmental and age‐related effects on learning and memory were analysed and compared with changes observed in astrocyte laminar distribution in the dentate gyrus. Aged (20 months) and young (6 months) adult female albino Swiss mice were housed from weaning either in impoverished conditions or in enriched conditions, and tested for episodic‐like and water maze spatial memories. After these behavioral tests, brain hippocampal sections were immunolabeled for glial fibrillary acid protein to identify astrocytes. The effects of environmental enrichment on episodic‐like memory were not dependent on age, and may protect water maze spatial learning and memory from declines induced by aging or impoverished environment. In the dentate gyrus, the number of astrocytes increased with both aging and enriched environment in the molecular layer, increased only with aging in the polymorphic layer, and was unchanged in the granular layer. We suggest that long‐term experience‐induced glial plasticity by enriched environment may represent at least part of the circuitry groundwork for improvements in behavioral performance in the aged mice brain.     

Glutamate-dopamine-GABA interactions in the aging basal ganglia

The study of neurotransmitter interactions gives a better understanding of the physiology of specific circuits in the brain. In this review we focus mostly on our own results on the interaction of the neurotransmitters glutamate, dopamine and GABA in the basal ganglia during the normal process of aging. We review first the studies on the action of endogenous glutamate on the extracellular concentrations of dopamine and GABA in the neostriatum and nucleus accumbens during aging. It was found that there exists an age-related change in the interaction of glutamate, dopamine and GABA and that these effects of aging exhibit a dorsal-to-ventral pattern of effects with no changes in the dorsal parts (dorsal striatum) and changes in the most ventral parts (nucleus accumbens). Second we reviewed the data on the effects of different ionotropic and metabotropic glutamate receptor agonists on the extracellular concentrations of dopamine and GABA in the nucleus accumbens. The results obtained clearly show the different contribution of each glutamate receptor subtype in the age-related changes produced on the interaction of glutamate, dopamine and GABA in this area of the brain. Third the effects of an enriched environment on the action of AMPA and NMDA-receptor agonists in the nucleus accumbens of rats during aging are also evaluated. Finally, and since the nucleus accumbens has been suggested to play a role in emotion and motivation and also motor behaviour, we speculated on the possibility of a specific contribution for the different glutamatergic pathways terminating in the nucleus accumbens and their interaction with a decreased dopamine playing a relevant role in motor behaviour during aging.     

Environmental enrichment,prefrontal cortex,stress, and aging of the brain

As a result of living in an enriched environment, the brain of animals undergoes molecular and morphological changes leading to improvements in learning and memory. These improvements correlate well with increase in neurogenesis, synaptic density, or neurotrophic factors. We review here, in the context of the literature, the experiments performed in our own laboratory on the effects of environmental enrichment on the dynamics of dopamine and acetylcholine in the prefrontal cortex under a situation of acute mild stress. In these last studies we found that the release of dopamine and acetylcholine under stress is reduced in animals housed in an enriched environment. We also reported that the stress-induced release of dopamine but not acetylcholine is lower in aged rats compared with young rats. These results suggest that environmental enrichment reduces the reactivity to stress of the prefrontal dopaminergic and cholinergic systems in the rat. We further hypothesize that the positive effects on stress coping behaviors of housing animals in an enriched environment are associated with reductions, rather than increases, in the release of dopamine and acetylcholine in the prefrontal cortex. Finally we propose that a reduction in the stress-induced release of dopamine observed during aging in control animals might be an index of a better adaptation to stressful stimuli. Dedicated to the special issue on Brain Plasticity, Prof. Fuxe.     

Environmental enrichment promotes fiber sprouting after deafferentation of the superior colliculus in the adult rat brain

Exposure to an enriched environment has proven to be beneficial in the recovery of function after brain lesions, but the underlying mechanisms remain only partly understood. One possibility is that environmental enrichment stimulates the reorganization of areas and fiber tracts that have been spared by the injury. Here we evaluate the effects of enriched environment on the sprouting of undamaged retinal afferents into the deafferented superior colliculus (SC) after a partial retinal lesion in adult rats. Anterograde tracing of retinal axons demonstrated a significant increase in fiber sprouting in the denervated SC of animals reared in enriched environment compared to animals reared in standard conditions. Environmental enrichment also promoted a substantial recovery of synaptic sites within the deafferented SC as shown by both synapsin I and vesicular glutamate transporter 2 immunostaining. These data provide evidence that environmental enrichment stimulates axonal plasticity and synaptic reorganization following brain injury.     

Effects of enriched environments with different durations and starting times on learning capacity during aging in rats assessed by a refined procedure of the Hebb-Williams maze task

Cognitive function as measured by the Hebb-Williams maze task was examined in Fischer 344 male rats that had been exposed to an enriched environment for periods of variable duration and at different starting ages. In one experiment, rats were exposed to environmental enrichment from weaning until the age of 2.5, 15, or 25 months. The results of 12 problems of the Hebb-Williams maze task showed that the enriched rearing condition improved the learning ability in all the age groups; however, factor analysis and ANOVA demonstrated that four of the 12 maze problems were not suitable for detecting the effect of age under different environmental conditions. Reanalysis of the results obtained with the other eight maze problems more clearly revealed both the effects of rearing condition and aging. The latter analysis demonstrated that the learning rate of rats reared under enriched conditions was faster than that of rats reared under standard social conditions. Short-term (3-month) exposure also had positive effects on cognitive function in both adult (11-month-old) and aged (22-month-old) animals. The effect of long-term exposure to an enriched environment starting at weaning was much greater than that of short-term exposure in aged rats, whereas the effects of both long-term and short-term exposure were almost the same in adult rats. These results show that aged animals still have appreciable plasticity in cognitive function, and suggest that environmental stimulation could benefit aging humans as well.     

Amperometric measures of age-related changes in glutamate regulation in the cortex of rhesus monkeys

l-glutamate (glutamate) is the principal excitatory neurotransmitter of the central nervous system and is involved in altered neural function during aging and in neurodegenerative diseases. Relatively little is known about the mechanisms of glutamate signaling in the primate brain, in part, because there is an absence of a method capable of rapidly measuring glutamate in either a non-clinical or a clinical setting. We have addressed this paucity of information by measuring extracellular glutamate at 1 Hz in the pre-motor and motor cortices of young, middle-aged, and aged monkeys using a minimally invasive amperometric recording method. In the motor cortex, mean resting glutamate levels were five times higher in the aged group compared to the young group while the pre-motor cortex showed an increasing trend in resting glutamate levels that was not statistically significant. In addition, we measured rapid, phasic glutamate release after local pressure-ejection of nanoliter volumes of either isotonic 70 mM potassium (to stimulate glutamate release) or 1 mM glutamate (to study glutamate uptake) into the pre-motor and motor cortex. In the pre-motor cortex, we measured reproducible glutamate uptake signals that had a significantly decreased (47%) rate of glutamate uptake in aged animals compared to young animals. However, following a 70 mM potassium delivery, we did not observe any consistent changes in evoked release between young versus aged animals. Using these non-clinical microelectrodes to measure glutamate signaling in the brain, our results support the hypothesis that the glutamatergic system undergoes reorganization with aging of the central nervous system.     

Tonic activity and GABA responsiveness of medial vestibular nucleus neurons in aged rats.

The tonic discharge of rat medial vestibular nucleus (MVN) neurons, and their responsiveness to GABA receptor agonists were investigated in slices prepared from aged rats (24 months old). Aged MVN neurons showed regular spontaneous activity similar to that seen in slices from young adults. However the inhibitory effects of the GABA(A) agonist muscimol on the spontaneous activity of aged MVN neurons were significantly greater than in young MVN neurons. Inhibitory responses to the GABA(B) agonist baclofen also tended to be greater in slices from aged animals, but this difference was not statistically significant. The regular discharge of aged MVN neurons at firing rates similar to those in young animals suggests that the intrinsic excitability of MVN cells is maintained with age. The up-regulation of GABA(A) receptor efficacy in aged MVN neurons may compensate for changes in inhibitory inputs from vestibular commissures and cerebellum that may occur with neuronal loss in the aged brain.     

Age-related changes in GABA and benzodiazepine receptor binding in rat brain are influenced by sampling time

1. This study examined the saturation binding of tritiated gamma-aminobutyric acid [( 3H]GABA) and [3H]diazepam in brain membranes from young (3 month-old) and aged (21-23 month-old) Long Evans male rats killed at two time points in the 24-hour cycle. 2. The daytime density of low-affinity GABA binding sites was significantly (p less than 0.05) lower in cortical membranes from aged animals. There were no differences between young and old rats in low-affinity GABA binding at night, or in high-affinity GABA binding at either time point. 3. Diazepam binding was significantly lower in the brains of aged animals killed during the daytime. There was no differences at night, when diazepam binding in young animals declined to match that of aged animals. 4. There were no differences in the affinities of either GABA or diazepam binding sites. 5. These findings indicate that sampling time significantly influences age-associated changes in the densities of low-affinity GABA and diazepam binding sites. Therefore, the effects of age on brain receptor binding parameters should be measured at several points in the 24-hour light/dark cycle in order to control for possible age-related changes in binding rhythmicity.