Retrosplenial cortex microglia and perineuronal net densities are associated with memory impairment in aged rhesus macaques.

Synapse loss and altered plasticity are significant contributors to memory loss in aged individuals. Microglia, the innate immune cells of the brain, play critical roles in maintaining synapse function, including through a recently identified role in regulating the brain extracellular matrix. This study sought to determine the relationship between age, microglia, and extracellular matrix structure densities in the macaque retrosplenial cortex. Twenty-nine macaques ranging in age from young adult to aged were behaviorally characterized on 3 distinct memory tasks. Microglia, parvalbumin (PV)-expressing interneurons and extracellular matrix structures, known as perineuronal nets (PNNs), were immuno- and histochemically labeled. Our results indicate that microglia densities increase in the retrosplenial cortex of aged monkeys, while the proportion of PV neurons surrounded by PNNs decreases. Aged monkeys with more microglia had fewer PNN-associated PV neurons and displayed slower learning and poorer performance on an object recognition task. Stepwise regression models using age and the total density of aggrecan, a chondroitin sulfate proteoglycan of PNNs, better predicted memory performance than did age alone. Together, these findings indicate that elevated microglial activity in aged brains negatively impacts cognition in part through mechanisms that alter PNN assembly in memory-associated brain regions.

Aged Rats Exhibit Altered Behavior-Induced Oscillatory Activity, Place Cell Firing Rates, and Spatial Information Content in the CA1 Region of the Hippocampus.

Hippocampal gamma and theta oscillations are associated with mnemonic and navigational processes and adapt to changes in the behavioral state of an animal to optimize spatial information processing. It has been shown that locomotor activity modulates gamma and theta frequencies in rats, although how age alters this modulation has not been well studied. Here, we examine gamma and theta local-field potential and place cell activity in the hippocampus CA1 region of young and old male rats as they performed a spatial eye-blink conditioning task across 31 d. Although mean gamma frequency was similar in both groups, gamma frequency increased with running speed at a slower rate in old animals. By contrast, theta frequencies scaled with speed similarly in both groups but were lower across speeds in old animals. Although these frequencies scaled equally well with deceleration and speed, acceleration was less correlated with gamma frequency in both age groups. Additionally, spike phase-locking to gamma, but not theta, was greater in older animals. Finally, aged rats had reduced within-field firing rates but greater spatial information per spike within the field. These data support a strong relationship between locomotor behavior and local-field potential activity and suggest that age significantly affects this relationship. Furthermore, observed changes in CA1 place cell firing rates and information content lend support to the hypothesis that age may result in more general and context-invariant hippocampal representations over more detailed information. These results may explain the observation that older adults tend to recall the gist of an experience rather than the details.SIGNIFICANCE STATEMENT Hippocampal oscillations and place cell activity are sensitive to sensorimotor input generated from active locomotion, yet studies of aged hippocampal function often do not account for this. By considering locomotion and spatial location, we identify novel age-associated differences in the scaling of oscillatory activity with speed, spike-field coherence, spatial information content, and within-field firing rates of CA1 place cells. These results indicate that age has an impact on the relationship between locomotion and hippocampal oscillatory activity, perhaps indicative of alterations to afferent input. These data also support the hypothesis that aged hippocampal place cells, compared with young, may more often represent more general spatial information. If true, these results may help explain why older humans tend to recall less specific and more gist-like information.

Microglia Drive Pockets of Neuroinflammation in Middle Age.

During aging, microglia produce inflammatory factors, show reduced tissue surveillance, altered interactions with synapses, and prolonged responses to CNS insults, positioning these cells to have profound impact on the function of nearby neurons. We and others recently showed that microglial attributes differ significantly across brain regions in young adult mice. However, the degree to which microglial properties vary during aging is largely unexplored. Here, we analyze and manipulate microglial aging within the basal ganglia, brain circuits that exhibit prominent regional microglial heterogeneity and where neurons are vulnerable to functional decline and neurodegenerative disease. In male and female mice, we demonstrate that VTA and SNc microglia exhibit unique and premature responses to aging, compared with cortex and NAc microglia. This is associated with localized VTA/SNc neuroinflammation that may compromise synaptic function as early as middle age. Surprisingly, systemic inflammation, local neuron death, and astrocyte aging do not appear to underlie these early aging responses of VTA and SNc microglia. Instead, we found that microglial lysosome status was tightly linked to early aging of VTA microglia. Microglial ablation/repopulation normalized VTA microglial lysosome swelling and suppressed increases in VTA microglial density during aging. In contrast, CX3CR1 receptor KO exacerbated VTA microglial lysosome rearrangements and VTA microglial proliferation during aging. Our findings reveal a previously unappreciated regional variation in onset and magnitude of microglial proliferation and inflammatory factor production during aging and highlight critical links between microglial lysosome status and local microglial responses to aging.SIGNIFICANCE STATEMENT Microglia are CNS cells that are equipped to regulate neuronal health and function throughout the lifespan. We reveal that microglia in select brain regions begin to proliferate and produce inflammatory factors in late middle age, months before microglia in other brain regions. These findings demonstrate that CNS neuroinflammation during aging is not uniform. Moreover, they raise the possibility that local microglial responses to aging play a critical role in determining which populations of neurons are most vulnerable to functional decline and neurodegenerative disease.

Experiments in macaque monkeys provide critical insights into age-associated changes in cognitive and sensory function.

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.

Auditory and Visual System White Matter Is Differentially Impacted by Normative Aging in Macaques.

Deficits in auditory and visual processing are commonly encountered by older individuals. In addition to the relatively well described age-associated pathologies that reduce sensory processing at the level of the cochlea and eye, multiple changes occur along the ascending auditory and visual pathways that further reduce sensory function in each domain. One fundamental question that remains to be directly addressed is whether the structure and function of the central auditory and visual systems follow similar trajectories across the lifespan or sustain the impacts of brain aging independently. The present study used diffusion magnetic resonance imaging and electrophysiological assessments of auditory and visual system function in adult and aged macaques to better understand how age-related changes in white matter connectivity at multiple levels of each sensory system might impact auditory and visual function. In particular, the fractional anisotropy (FA) of auditory and visual system thalamocortical and interhemispheric corticocortical connections was estimated using probabilistic tractography analyses. Sensory processing and sensory system FA were both reduced in older animals compared with younger adults. Corticocortical FA was significantly reduced only in white matter of the auditory system of aged monkeys, while thalamocortical FA was lower only in visual system white matter of the same animals. Importantly, these structural alterations were significantly associated with sensory function within each domain. Together, these results indicate that age-associated deficits in auditory and visual processing emerge in part from microstructural alterations to specific sensory white matter tracts, and not from general differences in white matter condition across the aging brain.SIGNIFICANCE STATEMENT Age-associated deficits in sensory processing arise from structural and functional alterations to both peripheral sensory organs and central brain regions. It remains unclear whether different sensory systems undergo similar or distinct trajectories in function across the lifespan. To provide novel insights into this question, this study combines electrophysiological assessments of auditory and visual function with diffusion MRI in aged macaques. The results suggest that age-related sensory processing deficits in part result from factors that impact the condition of specific white matter tracts, and not from general decreases in connectivity between sensory brain regions. Such anatomic specificity argues for a framework aimed at understanding vulnerabilities with relatively local influence and brain region specificity.

Auditory Processing Deficits Are Selectively Associated with Medial Temporal Lobe Mnemonic Function and White Matter Integrity in Aging Macaques.

Deficits in auditory function and cognition are hallmarks of normative aging. Recent evidence suggests that hearing-impaired individuals have greater risks of developing cognitive impairment and dementia compared to people with intact auditory function, although the neurobiological bases underlying these associations are poorly understood. Here, a colony of aging macaques completed a battery of behavioral tests designed to probe frontal and temporal lobe-dependent cognition. Auditory brainstem responses (ABRs) and visual evoked potentials were measured to assess auditory and visual system function. Structural and diffusion magnetic resonance imaging were then performed to evaluate the microstructural condition of multiple white matter tracts associated with cognition. Animals showing higher cognitive function had significantly better auditory processing capacities, and these associations were selectively observed with tasks that primarily depend on temporal lobe brain structures. Tractography analyses revealed that the fractional anisotropy (FA) of the fimbria-fornix and hippocampal commissure were associated with temporal lobe-dependent visual discrimination performance and auditory sensory function. Conversely, FA of frontal cortex-associated white matter was not associated with auditory processing. Visual sensory function was not associated with frontal or temporal lobe FA, nor with behavior. This study demonstrates significant and selective relationships between ABRs, white matter connectivity, and higher-order cognitive ability.

Age-associated changes in waking hippocampal sharp-wave ripples.

Hippocampal sharp-wave ripples are brief high-frequency (120-250 Hz) oscillatory events that support mnemonic processes during sleep and awake behavior. Although ripples occurring during sleep are believed to facilitate memory consolidation, waking ripples may also be involved in planning and memory retrieval. Recent work from our group determined that normal aging results in a significant reduction in the peak oscillatory frequency and rate-of-occurrence of ripples during sleep that may contribute to age-associated memory decline. It is unknown, however, how aging alters waking ripples. We investigated whether characteristics of waking ripples undergo age-dependent changes. Sharp-wave ripple events were recorded from the CA1 region of the hippocampus in old (n = 5) and young (n = 6) F344 male rats as they performed a place-dependent eyeblink conditioning task. Several novel observations emerged from this analysis. First, although aged rats expressed more waking ripples than young rats during track running and reward consumption, this effect was eliminated, and, in the case of track-running, reversed when time spent in each location was accounted for. Thus, aged rats emit more ripples, but young rats express a higher ripple rate. This likely results from reduced locomotor activity in aged animals. Furthermore, although ripple rates increased as young rats approached rewards, rates did not increase in aged rats, and rates in aged and young animals were not affected by eyeblink conditioning. Finally, although the oscillatory frequency of ripples was lower in aged animals during rest, frequencies in aged rats increased during behavior to levels indistinguishable from young rats. Given the involvement of waking ripples in memory retrieval, a possible consequence of slower movement speeds of aged animals is to provide more opportunity to replay task-relevant information and compensate for age-related declines in ripple rate during task performance.

Age Is Associated with Reduced Sharp-Wave Ripple Frequency and Altered Patterns of Neuronal Variability.

UNLABELLED: Spatial and episodic memory performance declines with age, and the neural basis for this decline is not well understood. Sharp-wave ripples are brief (∼70 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 = 5) and young (n = 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. SIGNIFICANCE STATEMENT: The hippocampus is a structure that is critical for the formation of episodic memories. Sharp-wave ripple events generated in the hippocampus have been implicated in memory consolidation processes critical to memory stabilization. We examine here whether these ripple oscillations are altered over the course of the life span, which could contribute to hippocampus-dependent memory deficits that occur during aging. This experiment used young and aged memory-impaired rats to examine age-related changes in ripple architecture, ripple-triggered spike variance, and spike-phase coherence. We found that there are, indeed, significant changes in characteristics of ripples in older animals that could impact consolidation processes and memory stabilization in the aged brain.

Extracellular matrix proteoglycans support aged hippocampus networks: a potential cellular-level mechanism of brain reserve.

One hallmark of normative brain aging is vast heterogeneity in whether older people succumb to or resist cognitive decline. Resilience describes a brain's capacity to maintain cognition in the face of aging and disease. One factor influencing resilience is brain reserve-the status of neurobiological resources available to support neuronal circuits as dysfunction accumulates. This study uses a cohort of behaviorally characterized adult, middle-aged, and aged rats to test whether neurobiological factors that protect inhibitory neurotransmission and synapse function represent key components of brain reserve. Histochemical analysis of extracellular matrix proteoglycans, which play critical roles in stabilizing synapses and modulating inhibitory neuron excitability, was conducted alongside analyses of lipofuscin-associated autofluorescence. The findings indicate that aging results in lower proteoglycan density and more lipofuscin in CA3. Aged rats with higher proteoglycan density exhibited better performance on the Morris watermaze, whereas lipofuscin abundance was not related to spatial memory. These data suggest that the local environment around neurons may protect against synapse dysfunction or hyperexcitability and could contribute to brain reserve mechanisms.

AMPA Receptors Exist in Tunable Mobile and Immobile Synaptic Fractions In Vivo.

Highlighted Research Paper: AMPA Receptors Exist in Tunable Mobile and Immobile Synaptic Fractions In Vivo, by Haiwen Chen, Richard H. Roth, Elena Lopez-Ortega, Han L. Tan, and Richard L. Huganir.

An Alternative to Dye-Based Approaches to Remove Background Autofluorescence From Primate Brain Tissue.

Brain tissue contains autofluorescing elements that potentially impede accurate identification of neurons when visualized with fluorescent microscopy. Age-related accumulation of molecules with autofluorescent properties, such as lipofuscin, can possess spectral profiles that invade the typical emission range of fluorophores commonly utilized in fluorescent microscopy. The traditional method for accounting for this native fluorescence is to apply lipophilic dyes that are able to sequester these unwanted signals. While effective, such dyes can present a range of problems including the obstruction of fluorescent probe emissions. The present study utilizes aged primate midbrain tissue stained for tyrosine hydroxylase and calbindin to investigate an image processing approach for removing autofluorescence utilizing spectral imaging and linear unmixing. This technique is then compared against the traditional, dye-based autofluorescence sequestration method using Sudan Black B (SBB). Spectral imaging and linear unmixing yielded significantly higher cell numbers than SBB treatment. This finding suggests that computational approaches for removing autofluorescence in neural tissue are both viable and preferential to dye-based approaches for estimation of cell body numbers.

Different macaque models of cognitive aging exhibit task-dependent behavioral disparities.

Deficits in cognitive functions that rely on the integrity of the frontal and temporal lobes are characteristic of normative human aging. Due to similar aging phenotypes and homologous cortical organization between nonhuman primates and humans, several species of macaque monkeys are used as models to explore brain senescence. These macaque species are typically regarded as equivalent models of cognitive aging, yet no direct comparisons have been made to support this assumption. Here we used adult and aged rhesus and bonnet macaques (Macaca mulatta and Macaca radiata) to characterize the effect of age on acquisition and retention of information across delays in a battery of behavioral tasks that rely on prefrontal cortex and medial temporal lobe networks. The cognitive functions that were tested include visuospatial short-term memory, object recognition memory, and object-reward association memory. In general, bonnet macaques at all ages outperformed rhesus macaques on tasks thought to rely primarily on the prefrontal cortex, and were more resilient to age-related deficits in these behaviors. On the other hand, both species were comparably impaired by age on tasks thought to preferentially engage the medial temporal lobe. Together, these results suggest that rhesus and bonnet macaques are not equivalent models of cognitive aging and highlight the value of cross-species comparisons. These observations should enable improved design and interpretation of future experiments aimed at understanding changes in cognition across the lifespan.

Tract-Specific White Matter Correlates of Age-Related Reward Devaluation Deficits in Macaque Monkeys.

AIM: Cognitive aging is known to alter reward-guided behaviors that require interactions between the orbitofrontal cortex (OFC) and amygdala. In macaques, OFC, but not amygdala volumes decline with age and correlate with performance on a reward devaluation (RD) task. The present study used diffusion magnetic resonance imaging (dMRI) methods to investigate whether the condition of the white matter associated with amygdala-OFC connectivity changes with age and relates to reward devaluation. METHODS: Diffusion-, T1- and T2-weighted MRIs were acquired from adult and aged bonnet macaques. Using probabilistic tractography, fractional anisotropy (FA) estimates from two separate white matter tracts associated with amygdala-OFC connectivity, the uncinate fasciculus (UF) and amygdalofugal (AF) pathways, were obtained. Performance measures on RD and reversal learning (RL) tasks were also acquired and related to FA indices from each anatomical tract. RESULTS: Aged monkeys were impaired on both the RD and RL tasks and had lower FA indices in the AF pathway. Higher FA indices from the right hemisphere UF pathway correlated with better performance on an object-based RD task, whereas higher FA indices from the right hemisphere AF were associated with better performance on an object-free version of the task. FA measures from neither tract correlated with RL performance. CONCLUSIONS: These results suggest that the condition of the white matter connecting the amygdala and OFC may impact reward devaluation behaviors. Furthermore, the observation that FA indices from the UF and AF differentially relate to reward devaluation suggests that the amygdala-OFC interactions that occur via these separate tracts are partially independent.

A separable two-dimensional random field model of binary response data from multi-day behavioral experiments.

BACKGROUND: The study of learning in populations of subjects can provide insights into the changes that occur in the brain with aging, drug intervention, and psychiatric disease. NEW METHOD: We introduce a separable two-dimensional (2D) random field (RF) model for analyzing binary response data acquired during the learning of object-reward associations across multiple days. The method can quantify the variability of performance within a day and across days, and can capture abrupt changes in learning. RESULTS: We apply the method to data from young and aged macaque monkeys performing a reversal-learning task. The method provides an estimate of performance within a day for each age group, and a learning rate across days for each monkey. We find that, as a group, the older monkeys require more trials to learn the object discriminations than do the young monkeys, and that the cognitive flexibility of the younger group is higher. We also use the model estimates of performance as features for clustering the monkeys into two groups. The clustering results in two groups that, for the most part, coincide with those formed by the age groups. Simulation studies suggest that clustering captures inter-individual differences in performance levels. COMPARISON WITH EXISTING METHOD(S): In comparison with generalized linear models, this method is better able to capture the inherent two-dimensional nature of the data and find between group differences. CONCLUSIONS: Applied to binary response data from groups of individuals performing multi-day behavioral experiments, the model discriminates between-group differences and identifies subgroups.

Seizure-Induced Arc mRNA Expression Thresholds in Rat Hippocampus and Perirhinal Cortex.

Immediate-early genes (IEGs) are rapidly and transiently induced following excitatory neuronal activity including maximal electroconvulsive shock treatment (ECT). The rapid RNA response can be blocked by the sodium channel antagonist tetrodotoxin (TTX), without blocking seizures, indicating a role for electrical stimulation in electroconvulsive shock-induced mRNA responses. In behaving animals, Arc mRNA is selectively transcribed following patterned neuronal activity and rapidly trafficked to dendrites where it preferentially accumulates at active synapses for local translation. Here we examined whether there is a relationship between the current intensities that elicit seizures and the threshold for Arc mRNA transcription in the rat hippocampus and perirhinal cortex (PRC). Animals received ECT of varying current intensities (0, 20, 40 65, 77 and 85 mA) and were sacrificed 5 min later. While significantly more CA1, CA3 and perirhinal pyramidal cells expressed Arc at the lowest stimulus intensity compared to granule cells, there was an abrupt threshold transition that occurred in all four regions at 77 mA. This precise threshold for Arc expression in all temporal lobe neurons examined may involve regulation of the calcium-dependent mechanisms that are upstream to activity-dependent IEG transcription.

Attentional updating and monitoring and affective shifting are impacted independently by aging in macaque monkeys.

One hallmark of the normal cognitive aging process involves alterations in executive function. Executive function can be divided into at least three separable components, including set shifting, attentional updating and monitoring, and inhibition of prepotent responses. The ability to study the neural basis of cognitive aging has been enriched by the use of animal models such as the macaque monkey. In aged macaques, changes in attentional updating and monitoring systems are poorly understood compared to changes in shifting and inhibition. A partial explanation for this is the fact that the tasks designed to study executive function in aged monkeys, to date, primarily have probed shifting and inhibition processes. Here we examine how aging impacts attentional updating and monitoring processes in monkeys using an interference task designed after a paradigm used to examine multi-tasking in older humans. Young and aged macaque monkeys were tested on this interference task as well as on an object reversal learning task to study these processes in the same animals. Relative to the young monkeys, aged animals were impaired on both tasks. Proactive and retroactive interference did not differ between age groups on an array of 40 object pairs presented each day in the object reversal learning task. The levels of performance on the interference task were not correlated with levels of performance in the object reversal task. These results suggest that attentional updating and monitoring and affective shifting are separable functions in the macaque, and that normal aging affects these mental operations independently.

Age-related neurochemical changes in the rhesus macaque cochlear nucleus.

Neurochemical changes in the expression of various proteins within the central auditory system have been associated with natural aging. These changes may compensate in part for the loss of auditory sensitivity arising from two phenomena of the aging auditory system: cochlear histopathologies and increased excitability of central auditory neurons. Recent studies in the macaque monkey have revealed age-related changes in the density of nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase (NADPHd) and parvalbumin (PV)-positive cells within the inferior colliculus and superior olivary complex. The cochlear nucleus (CN), which is the first central auditory nucleus, remains unstudied. Since the CN participates in the generation of the auditory brainstem response (ABR) and receives direct innervation from the cochlea, it serves as an ideal nucleus to compare the relationship between these neurochemical changes and the physiological and peripheral changes of the aging auditory system. We used stereological sampling to calculate the densities of NADPHd and PV reactive neurons within the three subdivisions of the CN in middle-aged and aged rhesus macaques. Regression analyses of these values with ABR properties and cochlear histopathologies revealed relationships between these cell types and the changing characteristics of the aging auditory system. Our results indicate that NADPHd expression does change with age in a specific subdivision of the CN, but PV does not. Conversely, PV expression correlated with ABR amplitudes and outer hair cell loss in the cochlea, but NADPHd did not. These results indicate that NADPHd and PV may take part in distinct compensatory efforts of the aging auditory system.

Age-related neurochemical changes in the rhesus macaque inferior colliculus.

Age-related hearing loss (ARHL) is marked by audiometric hearing deficits that propagate along the auditory pathway. Neurochemical changes as a function of aging have also been identified in neurons along the auditory pathway in both rodents and carnivores, however, very little is known about how these neurochemicals change in the non-human primate. To examine how these compensatory neurochemical changes relate to normal aging and audiometric sensitivity along the auditory pathway, we collected auditory brainstem responses (ABRs) and brain specimens from seven rhesus monkeys spanning in age from 15 to 35 years old, and examined the relationship between click evoked ABR thresholds and the ABR evoked pure tone average (PTA) and changes in the number of parvalbumin and NADPH-diaphorase positive cells in the auditory midbrain. We found that the number of parvalbumin positive cells in the central nucleus and the surrounding cortex regions of the inferior colliculus were strongly correlated with advancing age and ABR PTA. We also found that the numbers of NADPHd positive cells in these same regions were not associated with normal aging or changes in the ABR thresholds. These findings suggest that the auditory midbrain undergoes an up-regulation of parvalbumin expressing neurons with aging that is related to changes in the processing of frequencies across the audiometric range.

Age-related neurochemical changes in the rhesus macaque superior olivary complex.

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 the sesame 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.

Parvalbumin increases in the medial and lateral geniculate nuclei of aged rhesus macaques.

Subcortical auditory structures in the macaque auditory system increase their densities of neurons expressing the calcium binding protein parvalbumin (PV) with age. However, it is unknown whether these increases occur in the thalamic division of the auditory system, the medial geniculate nucleus (MGN). Furthermore, it is also unclear whether these age-related changes are specific to the macaque auditory system or are generalized to other sensory systems. To address these questions, the PV immunoreactivity of the medial and lateral geniculate nuclei (LGN) from seven rhesus macaques ranging in age from 15 to 35 was assessed. Densities of PV expressing neurons in the three subdivisions of the MGN and the six layers of the LGN were calculated separately using unbiased stereological sampling techniques. We found that the ventral and magnocellular subdivisions of the MGN and all six layers of the LGN increased their expressions of PV with age, although increases in the MGN were greater in magnitude than in the LGN. Together, these results suggest that the MGN shows age-related increases in PV expression as is seen throughout the macaque ascending auditory system, and that the analogous region of the visual system shows smaller increases. We conclude that, while there are some similarities between sensory systems, the age-related neurochemical changes seen throughout the macaque auditory system cannot be fully generalized to other sensory systems.