Age-related deficits in episodic memory result, in part, from declines in the integrity of medial temporal lobe structures, such as the hippocampus, but are not thought to be due to widespread loss of principal neurons. Studies in rodents suggest, however, that inhibitory interneurons may be particularly vulnerable in advanced age. Optimal encoding and retrieval of information depend on a balance of excitatory and inhibitory transmission. It is not known whether a disruption of this balance is observed in aging nonhuman primates, and whether such changes affect network function and behavior. To examine this question we combine large scale electrophysiological recordings with cell type-specific imaging in the medial temporal lobe of cognitively-assessed, aged rhesus macaques. We found that neuron excitability in hippocampal region CA3 is negatively correlated with the density of the somatostatin-expressing inhibitory interneurons in the vicinity of the recording electrodes in stratum oriens. By contrast, no hyperexcitability or interneuron loss was observed in the perirhinal cortex of these aged, memory-impaired monkeys. These data provide a link, for the first time, between selective increases in principal cell excitability and declines in a molecularly-defined population of interneurons that regulate network inhibition.

Positive immunoreactivity to the calcium-binding protein parvalbumin (PV) and nitric oxide synthase NADPH-diaphorase (NADPHd) is well documented within neurons of the central auditory system of both rodents and primates. These proteins are thought to play roles in the regulation of auditory processing. Studies examining the age-related changes in expression of these proteins have been conducted primarily in rodents but are sparse in primate models. In the brainstem, the superior olivary complex (SOC) is crucial for the computation of sound source localization in azimuth, and one hallmark of age-related hearing deficits is a reduced ability to localize sounds. To investigate how these histochemical markers change as a function of age and hearing loss, we studied eight rhesus macaques ranging in age from 12 to 35 years. Auditory brainstem responses (ABRs) were obtained in anesthetized animals for click and tone stimuli. The brainstems of these same animals were then stained for PV and NADPHd reactivity. Reactive neurons in the three nuclei of the SOC were counted, and the densities of each cell type were calculated. We found that PV and NADPHd expression increased with both age and ABR thresholds in the medial superior olive but not in either the medial nucleus of the trapezoid body or the lateral superior olive. Together these results suggest that the changes in protein expression employed by the SOC may compensate for the loss of efficacy of auditory sensitivity in the aged primate.

Spatial and episodic memory performance declines with age, and the neural basis for this decline is not well understood. Sharp-wave ripples are brief (ϳ70 ms) high-frequency oscillatory events generated in the hippocampus and are associated with the consolidation of spatial memories. Given the connection between ripple oscillations and memory consolidation, we investigated whether the structure of ripple oscillations and ripple-triggered patterns of single-unit activity are altered in aged rats. Local field and single-unit activity surrounding sharp-wave ripple events were examined in the CA1 region of the hippocampus of old (n ϭ 5) and young (n ϭ 6) F344 rats during periods of rest preceding and following performance on a place-dependent eyeblink-conditioning task. Neural responses in aged rats differed from responses in young rats in several ways. First, compared with young rats, the rate of ripple occurrence (ripple density) is reduced in aged rats during postbehavior rest. Second, mean ripple frequency during prebehavior and postbehavior rest is lower in aged animals (aged: 132 Hz; young: 146 Hz). Third, single neurons in aged animals responded more consistently from ripple to ripple. Fourth, variability in interspike intervals was greater in aged rats. Finally, neurons were tuned to a narrower range of phases of the ripple oscillation relative to young animals. Together, these results suggest that the CA1 network in aged animals has a reduced "vocabulary" of available representational states.

Hippocampal circuits are among the best described networks in the mammalian brain, particularly with regard to the alterations that arise during normal aging. Decades of research indicate multiple points of vulnerability in aging neural circuits, and it has been proposed that each of these changes make a contribution to observed age-related cognitive deficits. Another view has been relatively overlooked - namely that some of these changes arise in adaptive response to protect network function in aged animals. This possibility leads to a rather different view on the biological variation of function in the brain of older individuals. Using the hippocampus as a model neural circuit we discuss how, in normally aged animals, some age-related changes may arise through processes of neural plasticity that serve to enhance network function rather than to hinder it. Conceptually disentangling the initial age-related vulnerabilities from changes that result in adaptive responses will be a major challenge for the future research on brain aging. We suggest that a reformulation of how normal aging could be understood from an adaptive perspective will lead to a deeper understanding of the secrets behind successful brain aging and our recent cultural successes in facilitating these processes.

The use of animal models in brain aging research has led to numerous fundamental insights into the neurobiological processes that underlie changes in brain function associated with normative aging. Macaque monkeys have become the predominant nonhuman primate model system in brain aging research due to their striking similarities to humans in their behavioral capacities, sensory processing abilities, and brain architecture. Recent public concern about nonhuman primate research has made it imperative to attempt to clearly articulate the potential benefits to human health that this model enables. The present review will highlight how nonhuman primates provide a critical bridge between experiments conducted in rodents and development of therapeutics for humans. Several studies discussed here exemplify how nonhuman primate research has enriched our understanding of cognitive and sensory decline in the aging brain, as well as how this work has been important for translating mechanistic implications derived from experiments conducted in rodents to human brain aging research.