Effect of aging on neurogenesis in the canine brain (original) (raw)
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Neurogenesis decreases with age in the canine hippocampus and correlates with cognitive function
Neurobiology of Learning and Memory, 2007
New neurons are continually produced in the adult mammalian brain from progenitor cells located in specific brain regions, including the subgranular zone (SGZ) of the dentate gyrus of the hippocampus. We hypothesized that neurogenesis occurs in the canine brain and is reduced with age. We examined neurogenesis in the hippocampus of five young and five aged animals using doublecortin (DCX) and bromodeoxyuridine (BrdU) immunostaining. The total unilateral number of new neurons in the canine SGZ and granule cell layer (GCL) was estimated using stereological techniques based upon unbiased principles of systematic uniformly random sampling. Animals received 25mg/kg of BrdU once a day for 5 days and were euthanized 9 days after the last injection. We found evidence of neurogenesis in the canine brain and that cell genesis and neurogenesis are greatly reduced in the SGZ/GCL of aged animals compared to young. We further tested the hypothesis that an antioxidant fortified food or behavioral enrichment would improve neurogenesis in the aged canine brain and neurogenesis may correlate with cognitive function. Aged animals were treated for 2.8 years and tissue was available for six that received the antioxidant food, five that received the enrichment and six receiving both treatments. There were no significant differences in the absolute number of DCX or DCX-BrdU neurons or BrdU nuclei between the treatment groups compared to control animals. The number of DCX-positive neurons and double-labeled DCX-BrdU-positive neurons, but not BrdU-positive nuclei alone, significantly correlated with performance on several cognitive tasks including spatial memory and discrimination learning. These results suggest that new neurons in the aged canine dentate gyrus may participate in modulating cognitive functions.
Hippocampal neurogenesis during normal and pathological aging
Psychoneuroendocrinology, 2007
It is now widely accepted that new neurons continue to be added to the brain throughout life including during normal aging. The finding of adult neurogenesis in the hippocampus, a structure involved in the processing of memories, has favored the idea that newborn neurons might subserve cognitive functions. Recent work on human post-mortem tissues and mice models of Alzheimer's disease (AD) has reported persistent hippocampal proliferative capacity during pathological aging. Although it is not yet clear whether neurogenesis leads to the production of fully functional mature neurons in AD brains, these findings open prospects for cell-replacement therapies. Strategies aimed at promoting neurogenesis may also contribute to improve cognitive deficits caused by normal or pathological aging.
Age-related effects on hippocampal precursor cell subpopulations and neurogenesis
Neurobiology of Aging, 2011
Hippocampal neurogenesis continuously declines in the aging brain but only little is known about age-related alterations in the subgranular zone (SGZ) of the dentate gyrus which accommodates different subpopulations of precursor cells. Here, we examined the age-related effects on total number and proliferation rate of distinct precursor cell populations in the dentate gyrus of 3 and 16 months old transgenic pNestin-GFP mice. Following a single injection of bromodeoxyuridine (BrdU) we observed a significant reduction of all proliferating precursor subtypes in aged mice compared to young controls. Stereological analysis further revealed that this decreased proliferation was not only caused by a general reduction in total number of precursor subtypes but also by a subtype-specific alteration of the proliferation rate. Whereas radial glia-like and early neuronal precursor cells demonstrate decreased proliferation rates, no difference was found for doublecortin-positive precursors. Additional long-term experiments further revealed that these age-related alterations in the proliferative zone were accompanied by a strongly decreased neurogenesis while hippocampal function was not impaired.
Acta Neuropathologica, 2008
Stimulation of endogenous neurogenesis and transplantation of neuronal progenitors (NPs) are considered in therapy of neuronal loss associated with ageing and in neurodegenerative diseases with amyloidosis-, for example, Alzheimer's disease and Down syndrome. However, the inXuence of brain environment altered by ageing and deposits of amyloid-on proliferation of endogenous and transplanted NPs and their maturation into neurons is not understood. We studied the eVect of ageing and development of amyloidosis-on proliferation of NPs (1) in the granular layer of dentate gyrus in the hippocampi of APP-transgenic mice (Tg9291) before and after development of amyloidosis-, that is, in mice aged 2-4 months and 9-12 months, respectively, and in age-matched controls; and (2) in culture of NPs isolated from brains of control and Tg9291 mice, aged 3 and 9 months. We found that the number of proliferating NPs was reduced in 9-12months-old mice, in both control and Tg9291, as compared to 2-4-months-old mice. However, the 9-12-months-old Tg9291 mice with amyloid-deposits had signiWcantly more proliferating NPs than the age-matched controls. NPs proliferation in culture did not depend on the age, presence of APP-transgene, and amyloidosis-in donors. The results indicate that the local brain environment inXuences proliferation of NPs, and development of amyloidosisin the neurogenic regions attenuates the age-associated reduction of proliferation of NPs. IdentiWcation of the responsible mechanisms may be important for development of a successful therapy of neurodegeneration caused by amyloidosis-.
Environmental enrichment restores neurogenesis and rapid acquisition in aged rats
Neurobiology of Aging, 2013
Strategies combatting cognitive decline among the growing aging population are vital. We tested whether environmental enrichment could reverse age-impaired rapid spatial search strategy acquisition concomitantly with hippocampal neurogenesis in rats. Young (5-8 months) and aged (20 -22 months) male Fischer 344 rats were pair-housed and exposed to environmental enrichment (n ϭ 7 young, 9 aged) or housed individually (n ϭ 7 young, 7 aged) for 10 weeks. After 5 weeks, hidden platform trials (5 blocks of 3 trials; 15 m inter-block interval), a probe trial, and then visible platform trials (5 blocks of 3 trials; 15 m inter-block interval) commenced in the water maze. One week after testing, rats were given 5 daily intraperitoneal bromodeoxyuridine (50 mg/kg) injections and perfused 4 weeks later to quantify neurogenesis. Although young rats outperformed aged rats, aged enriched rats outperformed aged individually housed rats on all behavioral measures. Neurogenesis decreased with age but enrichment enhanced new cell survival, regardless of age. The novel correlation between new neuron number and behavioral measures obtained in a rapid water maze task among aged rats, suggests that environmental enrichment increases their ability to rapidly acquire and flexibly use spatial information along with neurogenesis.
Adult hippocampal neurogenesis and aging
European Archives of Psychiatry and Clinical Neuroscience, 2007
The demographic changes in the foreseeable future stress the need for research on successful cognitive aging. Advancing age constitutes a primary risk factor for disease of the central nervous system most notably neurodegenerative disorders. The hippocampus is one of the brain regions that is prominently affected by neurodegeneration and functional decline even in what is still considered "normal aging". Plasticity is the basis for how the brain adapts to changes over time. The discovery of adult hippocampal neurogenesis has added a whole new dimension to research on structural plasticity in the adult and aging hippocampus. In this article, we briefly summarize and discuss recent findings on the regulation of adult neurogenesis with relevance to aging. Aging is an important co-variable for many regulatory mechanisms affecting adult neurogenesis but so far, only few studies have specifically addressed this interaction. We hypothesize that adult neurogenesis contributes to a neural reserve, i.e. the maintained potential for structural plasticity that allows compensation in situations of functional losses with aging. As such we propose that adult neurogenesis might contribute to the structural correlates of successful aging.
Diminished adult neurogenesis in the marmoset brain precedes old age
Proceedings of the National Academy of Sciences, 2007
With aging there is a decline in the number of newly generated neurons in the dentate gyrus of the hippocampus. In rodents and tree shrews, this age-related decrease in neurogenesis is evident long before the animals become aged. No previous studies have investigated whether primates exhibit a similar decline in hippocampal neurogenesis with aging. To investigate this possibility, young to middle aged adult common marmosets (Callithrix jacchus) were injected with BrdU and perfused 3 weeks later. The number of newly generated cells in the subgranular zone/granule cell layer of the dentate gyrus was significantly lower in older animals and decreased linearly with age. A similar age-related decline in new cells was observed in the subventricular zone but not in the hilar region of the dentate gyrus. These data demonstrate that a substantial decrease in neurogenesis occurs before the onset of old age in the adult marmoset brain, suggesting the possibility that similar alterations occur in the human brain.
Changes in neurogenesis in dementia and Alzheimer mouse models: are they functionally relevant?
European Archives of Psychiatry and Clinical Neuroscience, 2007
Alzheimer's disease and related dementias are devastating disorders that lead to the progressive decline of cognitive functions. Characteristic features are severe brain atrophy, paralleled by accumulation of beta amyloid and neurofibrillary tangles. With the discovery of neurogenesis in the adult brain, the hopes have risen that these neurodegenerative conditions could be overcome, or at least ameliorated, by the generation of new neurons. The location of the adult neurogenic zones in the hippocampus and the lateral ventricle wall, close to corpus callosum and neocortex, indicates strategic positions for potential repair processes. However, we also need to consider that the generation of new neurons is possibly involved in cognitive functions and could, therefore, be influenced by disease pathology. Moreover, aberrant neurogenic mechanisms could even be a part of the pathological events of neurodegenerative diseases. It is the scope of this review to summarize and analyze the recent data from neurogenesis research with respect to Alzheimer's disease and its animal models.
Proceedings of The National Academy of Sciences, 2003
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. Agedependent 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-2deoxyuridine (BrdUrd, 50 or 150 mg͞kg) 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 agedrelated cognitive alterations.
Neurobiology of Disease, 2006
Adult proliferation and hippocampal neurogenesis are stimulated by injury. In agreement, aberrant cell-cycle-related protein expression has been reported in senile Alzheimer's disease (AD), where the hippocampus is particularly affected. Recently, increased expression of doublecortin (DCX), a neurogenesis marker, was reported in senile AD. Here, we addressed whether proliferative and neurogenic responses also occur in younger, i.e., presenile AD cases, using immunohistochemistry for Ki-67, GFAP and DCX. Increased numbers of Ki-67+ cells with a healthy, non-mature appearance were found in CA1-3. These were mainly due to glial and vasculature-associated changes, while DCX immunostaining appeared sensitive to postmortem breakdown. We found no indications for altered dentate gyrus neurogenesis. Our data obtained using validated methodology in a well-characterized, presenile cohort thus differ from previous data obtained in senile AD. They reflect clear differences in proliferative responsivity, particularly in the glia and vascular components, and suggest different underlying mechanisms in these groups.