Showing papers by "Michela Gallagher published in 2012"

Age-related memory impairment is associated with disrupted multivariate epigenetic coordination in the hippocampus.

Abstract: Mounting evidence linking epigenetic regulation to memory-related synaptic plasticity raises the possibility that altered chromatin modification dynamics might contribute to age-dependent cognitive decline. Here we show that the coordinated orchestration of both baseline and experience-dependent epigenetic regulation seen in the young adult hippocampus is lost in association with cognitive aging. Using a well-characterized rat model that reliably distinguishes aged individuals with significant memory impairment from others with normal memory, no single epigenetic mark or experience-dependent modification in the hippocampus uniquely predicted differences in the cognitive outcome of aging. The results instead point to a multivariate pattern in which modification-specific, bidirectional chromatin regulation is dependent on recent behavioral experience, chronological age, cognitive status, and hippocampal region. Whereas many epigenetic signatures were coupled with memory capacity among young adults and aged rats with preserved cognitive function, such associations were absent among aged rats with deficits in hippocampal memory. By comparison with the emphasis in current preclinical translational research on promoting chromatin modifications permissive for gene expression, our findings suggest that optimally successful hippocampal aging may hinge instead on enabling coordinated control across the epigenetic landscape.

Aging Reduces Total Neuron Number in the Dorsal Component of the Rodent Prefrontal Cortex

Abstract: For many years, aging was thought to be accompanied by significant decreases in total neuron number across multiple brain regions. However, this view was revised with the advent of modern quantification methods, and it is now widely accepted that the hippocampus and many regions of the cortex show substantially preserved numbers of neurons during normal aging. Nonetheless, age-related changes in neuron number do occur in focal regions of the primate prefrontal cortex (PFC), but the question of whether age-related neuron loss is an exclusive characteristic of the PFC in primates remains relatively unexplored. To investigate the loss of neurons with normal aging in rodents, we used unbiased stereological methods to quantify the number of principal neurons and interneurons in the PFC of young and aged rats. We observed a significant age-related decline in the number of principal neurons in the dorsal PFC. The number of interneurons positively stained with antibodies to glutamic acid decarboxylase 67 was also reduced in the dorsal PFC of aged rats. These observations indicate that the dorsal PFC is susceptible to neuron loss with aging in rodent brain and suggest some common basis for vulnerability in cortical circuits across species.

Characterization of CpG island DNA methylation of impairment-related genes in a rat model of cognitive aging.

Abstract: Cognitive abilities, particularly memory formation, vary substantially in the elderly, with some individuals exhibiting dramatic decline with age while others maintain function well into late life. Epigenetic modifications suggest an intriguing mechanism to account for the range of cognitive outcomes in aging as they are responsive to environmental influences and affect gene transcription in cognitively relevant brain regions. Leveraging a well-characterized rat model of neurocognitive aging that recapitulates the range of outcomes seen in humans, we previously identified gene expression profiles in the CA3 subregion of the hippocampus that distinguish between young and aged subjects as well as between impaired and preserved spatial memory function. To investigate the influence of epigenetics on these profiles, we examined genomic CpG DNA methylation in the promoter regions of three neurophysiologically relevant genes (Gabra5, Hspa5 and Syn1) whose expression levels decrease with age and correlate with spatial memory performance. Consistent with mRNA decreases, DNA methylation increased in aged rats relative to young in CpG dense regions of all target promoters examined. However, no correlation with cognition was found. Focused analysis of the Gabra5 gene found that methylation changes were limited to the CpG island and varied substantially across individual CpGs. Methylation at one CpG correlated with learning and demonstrated a significant difference between memory impaired aged rats and those with intact learning. These data provide evidence that broad age-dependent DNA methylation changes occur in CpG dense promoter regions of cognitively relevant genes but suggest that methylation at single CpGs may be more pertinent to individual cognitive differences.

Clinical Trials: New Opportunities

Abstract: Human cognitive aging has been too long neglected and underappreciated for its critical importance to quality of life in old age. The articles in this session present novel approaches to improving cognitive function in normal aging persons with drugs and interventions that are based on findings in epidemiology, studies in aged animals, and in vitro research. In addition, since aging is the primary risk factor for Alzheimer's disease, these studies also have implications as interventions for prevention and treatment. As a field of research, new knowledge regarding the causes and mechanisms of cognitive aging are ripe for translation into human studies, with the application of this knowledge leading the development of interventions and therapeutics for the prevention of cognitive decline in old age and Alzheimer's disease.