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

Abstract

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.

Keywords: cognitive aging; nonhuman primates; presbycusis.

Fig. 1.

Comparison of human, macaque, and mouse brains. (A) Images of the dorsal surface of a human brain, macaque brain, and mouse brain. Notice the striking differences in the size and convolution complexity of the cerebral cortex across the 3 species. (B) Coronal Nissl-stained sections of hippocampus-containing tissue in the 3 species. Reproduced with permission from ref. .

Fig. 2.

Macaques with object recognition memory deficits display hyperactivity in the CA3 region of the hippocampus that is associated with fewer somatostatin(SOM)-positive inhibitory interneurons. (A) Proportion of correct responses made by adult and aged rhesus macaques performing a delayed nonmatching-to-sample task at different delays. Aged animals were significantly impaired relative to adult animals at the 600-s delay condition. (B) Boxplots of pyramidal neuron baseline firing rates recorded from the perirhinal cortex (PRC) and CA3 in adult and aged monkeys. Baseline firing rates were significantly greater in the CA3 of aged animals relative to the adults. PRC firing rates were not different between age groups. (C) Magnified images of CA3 and PRC SOM inhibitory neurons. SOM interneuron densities were reduced in the stratum oriens layer of CA3 in aged animals, but not in the stratum radiatum or in the PRC. Parvalbumin-positive neuron density was not different between age groups in either region. (D) CA3 SOM neuron densities were significantly negatively correlated with CA3 baseline firing rates. (E) CA3 SOM neuron density and CA3 firing rates showed weak associations with object recognition performance. DNMS, delayed nonmatching-to-sample. *P < 0.05. Reproduced with permission from ref. .

Fig. 3.

Greater numbers of neurons expressing CaBPs in the central auditory system of aging macaques is associated with poorer peripheral auditory function. (A) Photomicrographs of parvalbumin-expressing neurons in an adult and aged macaque auditory brainstem. Note the qualitatively greater density of parvalbumin-positive cells in the older animal. Reprinted with permission from ref. . (B) Age is significantly associated with greater numbers of auditory neurons expressing parvalbumin in the core of the inferior colliculus (IC). Reprinted with permission from ref. , which is published under CC BY 3.0. (C) Animals with more parvalbumin-positive cells in the IC had higher auditory brainstem response pure-tone average thresholds. (D) Remarkably, animals with fewer outer hair cells (OHCs) in the cochlea had more neurons expressing parvalbumin (PV) in the dorsal cochlear nucleus of the auditory brainstem. Note that both auditory brainstem response thresholds and hair cell numbers reflect cochlear function. Together, these data indicate that chemical expression patterns of CaBPs in the central auditory system are associated with peripheral auditory dysfunction. (Scale bar, 100 μm.) Reprinted with permission from refs. ; and , which is published under CC BY 3.0.

Fig. 4.

Schematic depiction of the relative size of auditory nuclei within the SOC of humans, macaques, and rats. (Top) Human SOC is characterized by a relatively small LSO nucleus (light blue) and an elongated MSO nucleus that is surrounded by other olivary nuclei (gray). (Middle) Organization of the macaque SOC follows very similar organizational principles, with a slightly larger LSO and slightly smaller MSO than humans. (Bottom) Rats, on the other hand, have a drastically expanded LSO relative to humans and macaques, as well as a significantly reduced MSO. Additionally, the shape and organization of the other olivary nuclei are very different in the rat compared with monkeys and humans. These anatomical differences between species are thought to reflect the drastically different acoustic sensitivities of primates and rodents. D, dorsal; L, lateral; M, medial; V, ventral. Adapted by permission from ref. (Springer Nature: The Mammalian Auditory Pathway: Neuroanatomy, Copyright 1992).

Fig. 5.

Animals with greater hippocampus-associated white matter integrity have better auditory processing capacities and lower auditory thresholds. (A) Representative probability map of the right hemisphere fimbria-fornix overlaid upon T1-weighted MRI (Top) and a fractional anisotropy (FA) map pseudocolored in copper (Bottom). (B) Animals with higher right hemisphere fimbria-fornix FA had better auditory processing abilities. (C) Similarly, animals with higher right hemisphere fimbria-fornix FA had lower auditory brainstem response (ABR) thresholds. Note that lower values indicate better function for both auditory measures. (D) Representative probability map of the right hemisphere frontal thalamic radiation overlaid upon T1-weighted MRI (Top) and an FA map pseudocolored in copper (Bottom). (E) Frontal radiation FA was not associated with auditory processing. (F) Frontal radiation FA was also not associated with ABR thresholds. Together, these findings indicate that auditory function is specifically associated with the structural composition of medial temporal lobe-associated, but not frontal lobe-associated, white matter.