Hippocampal interneuron populations are reportedly vulnerable to normal aging. The relationship between interneuron network integrity and age-related memory impairment, however, has not been tested directly. That question was addressed in the present study using a well-characterized model in which outbred, aged, male Long-Evans rats exhibit a spectrum of individual differences in hippocampal-dependent memory. Selected interneuron populations in the hippocampus were visualized for stereological quantification with a panel of immunocytochemical markers, including glutamic acid decarboxylase-67 (GAD67), somatostatin, and neuropeptide Y. The overall pattern of results was that, although the numbers of GAD67- and somatostatin-positive interneurons declined with age across multiple fields of the hippocampus, alterations specifically related to the cognitive outcome of aging were observed exclusively in the hilus of the dentate gyrus. Because the total number of NeuN-immunoreactive hilar neurons was unaffected, the decline observed with other markers likely reflects a loss of target protein rather than neuron death. In support of that interpretation, treatment with the atypical antiepileptic levetiracetam at a low dose shown previously to improve behavioral performance fully restored hilar SOM expression in aged, memory-impaired rats. Age-related decreases in GAD67- and somatostatin-immunoreactive neuron number beyond the hilus were regionally selective and spared the CA1 field of the hippocampus entirely. Together these findings confirm the vulnerability of hippocampal interneurons to normal aging and highlight that the integrity of a specific subpopulation in the hilus is coupled with age-related memory impairment.

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.

Episodic memory impairment due to aging has been linked to hippocampal dysfunction. Evidence exists for alterations in specific circuits within the hippocampal system that are closely coupled to individual differences in the presence and severity of such memory loss. Here, we used the newly developed Diversity Outbred (DO) mouse that was designed to model the genetic diversity in human populations. Young and aged DO mice were tested in a hippocampal-dependent water maze task. Young mice showed higher proficiency and more robust memory compared to the overall performance of aged mice. A substantial number of the older mice, however, performed on par with the normative performance of the younger mice. Stereological quantification of somatostatin-immunoreactive neurons in the dentate hilus showed that high-performing young and unimpaired aged mice had similar numbers of somatostatin-positive interneurons, while aged mice that were impaired in the spatial task had significantly fewer such neurons. These data in the DO model tie loss of hilar inhibitory network integrity to age-related memory impairment, paralleling data in other rodent models.

Epigenetic modifications of chromatin structure provide a mechanistic interface for gene-environment interactions that impact the individualization of health trajectories across the lifespan. A growing body of research indicates that dysfunctional epigenetic regulation contributes to poor cognitive outcomes among aged populations. Here we review neuroepigenetic research as it relates to cognitive aging, focusing specifically on memory function mediated by the hippocampal system. Recent work that differentiates epigenetic contributions to chronological aging from influences on mindspan, or the preservation of normal cognitive abilities across the lifespan, is also highlighted. Together, current evidence indicates that while age-related memory impairment is associated with dysfunction in the coordinated regulation of chromatin modification, animal models that show individual differences in cognitive outcome underscore the enormous mechanistic complexity that surrounds epigenetic dynamics in the aged hippocampus.Cognitive decline, especially memory loss, is one of the most prevalent and feared consequences of growing older. In the United States it is expected that by 2050, 12% of people over the age of 65 will suffer from moderate-to-severe memory impairment (Federal Interagency Forum on Aging-Related Statistics: Older Americans Update 2004). Understanding the neural basis of cognitive decline is all the more pressing in light of national demographic trends highlighting the rapidly expanding elderly population, with the number of people aged 65 and older projected to increase from 43 million to more than 83 million over the next four decades (Ortman et al. 2014). Alongside a focus on negative outcomes, there is increasing recognition that memory decline is not an inevitable consequence of aging as some older adults maintain normal memory abilities across the lifespan. Identifying the neurobiological mechanisms that impact differential cognitive outcomes with age is critical. In this context, research exploring the biological substrates that drive individual healthspan trajectories from early development through old age can provide valuable insight into the brain mechanisms that influence mindspan.A life course perspective emphasizes that environmental and experiential factors operate throughout life to potently influence the biological mechanisms that dictate the arc of an individual's health trajectory (for review, see Halfon et al. 2014). An emerging theme is that age alone is only a coarse predictor of health outcome, and current efforts are focused on disentangling chronological age effects from other determinants of functional outcomes in the elderly. Epigenetic modifications of the genome have gained attention in this context since they allow for genomic plasticity in post-mitotic cells and provide a means by which environment and experience interface with gene transcription to impact biological functions across the lifespan. This plasticity is crucial for adaptation and resilience in the face of environmenta...

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