104. It seems like the definition of inhumanity,…. The study was conducted in macaque monkeys. Macaque Monkey is a YouTube channel that upload everyday about MONKEY. Alternatively, if it allowed one to stay awake for longer periods of time before reaching exhaustion by continuously stimulating that region, that’d be pretty great too. This work was supported by NIH Grants R01 AG050548 (to C.A.B.) The technology could one day make artificial eyesight possible in humans. 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. A strong argument can be made that, despite the measures taken, the animals did suffer during this experiment and that monkeys should never be used for experiments such as this. (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). In neuroimaging analysis of macaques, brain extraction or skull stripping of magnetic resonance imaging (MRI) is a crucial step for following processing. and C.A.B. 2018-06: Visualize your own data inside a brain atlas with SBA Composer. This similarity in cortical function between humans and old-world monkeys suggests that brain networks supporting volitional communication have a common evolutionary origin that arose well prior to the hominin radiation. 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. The data discussed here do not focus on age-associated changes in the cochlea, but rather on the central auditory system’s response to a weakened drive from the periphery. 2E). This circuitry is described here in the context of a two-level model that distinguishes between feedforward and feedback connections. Additionally, axospinous, axosomatic, and axodendritic spine sizes appear to increase with age in the prefrontal cortex, and the extent of these structural changes in superficial cortical layers was significantly associated with performance measures on an object recognition task (36, 37). Lesion and functional imaging studies in humans indicate that the integrity of medial temporal lobe brain structures, including the hippocampus, is critical for episodic memory formation (13, 14). “This study is significant,” said Earl Miller, a professor of neuroscience from the Department of Brain and Cognitive Sciences at the Massachusetts Institute of Technology, in an email to Gizmodo. Recent work utilizing aging macaques provides a perspective on the association between auditory and cognitive function across the lifespan ( 90 ). Since most CaBPs operate as intracellular calcium buffers (67), the greater expression of these proteins in the auditory system of older animals has been proposed to reflect cellular response mechanisms to the potentially pathophysiological environment associated with greater calcium levels. The June 2018 release is out. The ability to uncover the neurobiological changes responsible for dementing neurodegenerative disease requires knowledge of the “normal” trajectory that brain function takes across the lifespan. With respect specifically to a calcium homeostasis approach, there is evidence that CaBP expression differs considerably between the auditory systems of primates and rodents. Perhaps the most important interspecies difference between rodents and primates with respect to presbycusis research is their vastly different hearing ranges. 5B) and lower acoustic thresholds (Fig. Numerous studies, first in rodents (both rats and mice) and then in macaques, have demonstrated that the number of neurons expressing CaBPs changes across the lifespan at multiple levels of the ascending auditory pathway (58⇓⇓⇓⇓⇓⇓⇓–66). Once the stimulation was turned off, the macaques returned to an unconscious state. Unfortunately, public awareness of the importance of nonhuman primates in neuroscience research as a whole, and their importance in aging research in particular, is limited. Electrophysiological evidence from studies utilizing in vitro slice preparations further indicate that frontal cortical and medial temporal lobe networks are differentially impacted by normative aging. 58. As societies worldwide continue to achieve longer life expectancies, it is becoming more critical to devise strategies to maintain sensory and cognitive health to reduce the burden of declines in function for older individuals themselves, as well as the impact that this has on their families. We present evidence for continuous generation of neurons, oligodendrocytes, and astrocytes in the hippocampal dentate gyrus of adult macaque monkeys, using immunohistochemical double labeling for bromodeoxyuridine and cell-type-specific markers. Based on acoustic sensitivity, the auditory system of mice should utilize calculations of interaural intensity differences in the LSO more so than the primate auditory system, which should utilize interaural time difference calculations in the MSO to a greater extent. Experiments in macaque monkeys provide critical insights into age-associated changes in cognitive and sensory function. The animals with better discrimination abilities and measures of medial temporal lobe tract fractional anisotropy also had higher auditory processing capacities (Fig. The complete program and video recordings of most presentations are available on the NAS website at http://www.nasonline.org/using-monkey-models. Critically, these hypotheses are not necessarily mutually exclusive, and each remains to be verified or ruled out. “This would pave the way for a similar stimulation paradigm to be used in the clinic,” said Redinbaugh. Hearing impairment and incident dementia and cognitive decline in older adults: The health ABC study, Hearing loss and cognition among older adults in the United States, Hearing loss in older adults affects neural systems supporting speech comprehension, Neural processing during older adults’ comprehension of spoken sentences: age differences in resource allocation and connectivity, Functional changes in the human auditory cortex in ageing, Language and the aging brain: Patterns of neural compensation revealed by functional brain imaging. Little Dog claims that the brain of a macaque monkey is closer to a human brain than any other living mammal, and he claims that the macaques are capable of critical thought and problem solving, and that they have the ability to recall past events. Monkeys with greater fractional anisotropy in the fimbria-fornix (Fig. Because MCPH1 is a key gene for neurogenesis, one of the expected phenotypic outcomes in the transgenic monkeys would be a larger brain, which was not the case in this study. (D) CA3 SOM neuron densities were significantly negatively correlated with CA3 baseline firing rates. Human neuroimaging has revealed a specific network of brain regions—the default-mode network (DMN)—that reduces its activity during goal-directed behavior. Under this hypothesis, the efficacy of neural circuits in relatively close proximity might become similarly impacted by vascular aging. That said, the scientists used a dozen ceramic skull screws and dental acrylic to “affix head implants” on the monkeys, among other severely invasive measures required for the experiment, some of which were designed to immobilize the heads of the monkeys during EEG readings. Because cognitive problems arise relatively late in the progression of these diseases, some participants considered to be aging normally may actually have undetected pathophysiological brain markers during the period when behavioral testing is conducted (5). (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). The SOC is the first site of binaural integration in the auditory system, and is critical in computing the interaural time, intensity, and phase differences necessary for sound source localization in azimuth (72, 73). Michelle Redinbaugh, the first author of the new study and a graduate student at the University of Wisconsin-Madison, said the primary goal of the experiment was to locate NCCs in the brain. 58; and 59, which is published under CC BY 3.0. Furthermore, these electrophysiological changes were significantly associated with performance on an object recognition task (41). Studies using electrophysiological and neuroanatomical techniques in aging rats have provided a critical, yet incomplete, window into the neurobiological processes that might result in CA3/dentate gyrus hyperactivity in older people. Copyright © 2021 National Academy of Sciences. The authors declare no conflict of interest. These profound discrepancies in acoustic sensitivity between mice and primates are reflected by interspecies differences in auditory system anatomy. 5A) and hippocampal commissure, both fiber tracts associated with hippocampus connectivity, were better able to discriminate stimuli with overlapping features, a cognitive process known to require medial temporal lobe circuits. Additionally, both within and between brain regions, aged neurons can exhibit striking differences in excitability. There will be a particular emphasis on conceptualizing the critical bridge that nonhuman primates provide between behavioral, neuroanatomical, and electrophysiological data obtained in aged rodents and cognitive, psychophysical, and functional imaging data from older humans. This observation highlights a major challenge in cognitive aging research of understanding each individual’s unique behavioral and neurobiological profile. Health 3 December 2020 By Michael Le Page. Baseline firing rates were significantly greater in the CA3 of aged animals relative to the adults. Notice the striking differences in the size and convolution complexity of the cerebral cortex across the 3 species. Using genetically encoded indicators including GCaMP5 and GCaMP6s delivered by In fact, the density of CaBP-expressing neurons has been found to be significantly associated with higher acoustic thresholds and fewer inner and outer hair cells at the level of the cochlea in macaques (58, 59, 65) (Fig. These findings exemplify how basic research in animal models of brain aging can reveal neurobiological mechanisms contributing to age-related cognitive impairments that are clinically targetable to maintain cognitive health later in life. Importantly, auditory processing abilities were not associated with the microstructural condition of white matter in the frontal thalamic radiations (Fig. From February 2001 through May 2019 colloquia were supported by a generous gift from The Dame Jillian and Dr. Arthur M. Sackler Foundation for the Arts, Sciences, & Humanities, in memory of Dame Sackler's husband, Arthur M. Sackler. Animals with greater hippocampus-associated white matter integrity have better auditory processing capacities and lower auditory thresholds. Scientists genetically modified rhesus macaque monkeys with a human gene thought to play a role in the development of our big brains. Together, these data indicate that chemical expression patterns of CaBPs in the central auditory system are associated with peripheral auditory dysfunction. Comparison of human, macaque, and mouse brains. These findings indicate that aging can lead to a disruption in the activity of circuits within the hippocampus that negatively impacts mnemonic processing. “I hope many studies will follow that will try to better understand the role of thalamus not only in the state of consciousness, but also in perceptual processes.”. Compared with other types of memory, episodic memory is particularly vulnerable to the effects of normative brain aging, and a hallmark of Alzheimer’s disease is a drastic reduction in the capacity to form these representations (12). This fascinating result is providing new clues about the brain and how it produces conscious awareness—insights that could potentially lead to therapies for patients trapped in a coma. The cortices were cut in 50-μm thick … When the tetrodes were advanced further into the brain, perirhinal cortical cells were also recorded. Neuroscientists had previously pegged the central lateral thalamus as an NCC, but this latest research adds more credence to the claim. Aged animals were significantly impaired relative to adult animals at the 600-s delay condition. Hippocampal synapse density has also been carefully examined across the macaque lifespan, with the bulk of this work focusing on synapses formed by perforant path input from the superficial layers of the entorhinal cortex to the inner and outer molecular layers of the dentate gyrus (38). Nonhuman primates provide the animal model that is closest to humans and remain an important bridge for testing the veracity of discoveries effective in rodents when clinical applications of these are being considered for human testing. (C) Similarly, animals with higher right hemisphere fimbria-fornix FA had lower auditory brainstem response (ABR) thresholds. 105 (Springer Nature: The Mammalian Auditory Pathway: Neuroanatomy, Copyright 1992). These observations indicate that the brains of older people functionally reorganize themselves to preserve auditory perception. Furthermore, given the rich literature base on cognitive and sensory aging in the macaque that does not yet exist in the marmoset, combined with major advances in fast gene-editing technologies such as the CRISPR/Cas9 system (103), a parallel approach may be to expand the suite of tools available in the marmoset to macaques in order to take advantage of these past advances. Interspecies differences in the chemical composition of different brain regions highlight that not all aspects of brain physiology are the same across species. We estimate that the relative rate of neurogenesis is approximately 10 times less than that reported in the adult rodent dentate gyrus. The rhesus monkey brain in stereotaxic coordinates (2000) Google Scholar 28. Some species, such as the crab-eating macaque, subsist on a diet of invertebrates and occasionally small vertebrates. Shapeshifting designs could have wide-ranging pharmaceutical and biomedical applications in coming years. (B) Boxplots of pyramidal neuron baseline firing rates recorded from the perirhinal cortex (PRC) and CA3 in adult and aged monkeys. Stimulating this brain region at 50 Hertz while the monkeys were under anesthesia caused them to wake up. These characteristics allow different aspects of brain function to be tested with similar or even identical tests as those used in humans. In macaques, 2 parallel ascending pathways that can be distinguished by immunohistochemical labeling of the CaBPs parvalbumin and calbindin traverse through the auditory system. Second, differential patterns of age-related neurovascular dysfunction between different brain regions also could bias circuits contained within a lobe to experience comparable physiological consequences associated with poorer vascular health. These observations indicate that neurochemical changes occur within the central auditory system in response to a reduced acoustic drive from the periphery. Edited by Elizabeth A. Buffalo, University of Washington, Seattle, WA, and accepted by Editorial Board Member Tony Movshon July 5, 2019 (received for review March 19, 2019). This is largely due to evidence from large longitudinal studies that individuals with poorer acoustic function are at a higher risk of developing age-related cognitive decline and dementia (83, 84). D, dorsal; L, lateral; M, medial; V, ventral. (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). 27. The 23 species of macaques inhabit ranges throughout Asia, North Africa, and Gibraltar. We present a quadrature volume coil designed for brain imaging of a macaque monkey fixed in a sphinx position (facing down the bore) within a stereotactic frame at 3 T, where the position of the monkey and presence of the frame preclude use of existing coils. “Essentially, we were looking for increases in behaviors that you would normally see in an animal—or human—that was waking up from anesthesia.”. 2017-10: New 3d viewer: in addition to the wholebrain surface viewer, a per-region mesh viewer is under way. These anatomical differences between species are thought to reflect the drastically different acoustic sensitivities of primates and rodents. We do not capture any email address. So far, evidence for a similar network in monkeys is mainly indirect, since, except for one positron emission tomography study, it is all based on functional connectivity analysis rather than activity increases during passive task states. PRC firing rates were not different between age groups. Since the 2000s, however, neuroscientists have focused primarily on the cortex to find the mechanisms of consciousness, he said. We thank Michelle Albert for assistance with the graphics. (A) Proportion of correct responses made by adult and aged rhesus macaques performing a delayed nonmatching-to-sample task at different delays. wrote the paper. (Bottom) Rats, on the other hand, have a drastically expanded LSO relative to humans and macaques, as well as a significantly reduced MSO. When this happened, the primates behaved just as they would when awake. Reproduced with permission from ref. These observations indicate that, like cognitive function, not all aspects of sensory function are equivalently impacted by the aging process in macaques. Note that lower values indicate better function for both auditory measures. Sensory functioning and intelligence in old age: A strong connection, The strong connection between sensory and cognitive performance in old age: Not due to sensory acuity reductions operating during cognitive assessment. First, monkeys possess cognitive and sensory repertoires that more closely resemble those of humans compared with other animal models (7). Thank you for your interest in spreading the word on PNAS. Image credit: Acacia Dishman/Medical College of Wisconsin. New research suggests monkeys, like this Japanese macaque, have vocal tracts anatomically capable of humanlike speech, but they lack the necessary brain wiring to produce it. Nonhuman primates, in particular, have been central and arguably irreplaceable to cognitive aging research due to several critical features unique to these animals. Image credit: Shutterstock/greenbutterfly. A rhesus macaque. The calcium hypothesis suggests that rebalancing intracellular calcium levels, and perhaps hyperexcitability, by increasing inhibition to control excess neural activity may rebalance circuit activity and help preserve memory function in aging. Animal models of cognitive and sensory aging have enriched our understanding of the mechanisms that contribute to different aspects of healthy brain aging. Nonhuman primates will be a critical component to the future of brain aging research since many aspects of cognitive aging simply cannot be properly modeled in other laboratory animals. Critically, there was a selective decrease in somatostatin-positive interneuron density in the stratum oriens layer of CA3 (Fig. 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. 2018-05: After 9 years of operation, ran broken link detector on the Scalable Brain Atlas ecosystem and fixed 40 issues. (C) Magnified images of CA3 and PRC SOM inhibitory neurons. First, it might be the case that embryological and developmental differences between the frontal and temporal lobes predispose each region to succumb to distinct risk factors associated with brain aging. NAS colloquia began in 1991 and have been published in PNAS since 1995. Parvalbumin-positive neuron density was not different between age groups in either region. The same monkeys underwent electrophysiological assessments of auditory thresholds, auditory system temporal information processing, and visual system temporal information processing. (B) Coronal Nissl-stained sections of hippocampus-containing tissue in the 3 species. Nonhuman animals also do not spontaneously develop dementing neurodegenerative diseases, which eliminates a major confound often encountered in human brain aging research. Evidence from an animal model of normal aging, Hilar interneuron vulnerability distinguishes aged rats with memory impairment, Reduction of hippocampal hyperactivity improves cognition in amnestic mild cognitive impairment, Memory impairment in aged primates is associated with region-specific network dysfunction, Neurobiological bases of age-related cognitive decline in the rhesus monkey, The effects of aging on area 46 of the frontal cortex of the rhesus monkey, The effects of age on the cells in layer 1 of primate cerebral cortex, Morphological analyses of the brains of behaviorally characterized aged nonhuman primates, Preserved number of entorhinal cortex layer II neurons in aged macaque monkeys, Preservation of hippocampal neuron numbers in aged rhesus monkeys, Age-related changes in prefrontal cortex of Macaca mulatta: Synaptic density, Synapses are lost during aging in the primate prefrontal cortex, Selective changes in thin spine density and morphology in monkey prefrontal cortex correlate with aging-related cognitive impairment, Effects of age on axon terminals forming axosomatic and axodendritic inhibitory synapses in prefrontal cortex, Topographical organization of the entorhinal projection to the dentate gyrus of the monkey, Preservation into old age of synaptic number and size in the supragranular layer of the dentate gyrus in rhesus monkeys, Synaptic correlates of memory and menopause in the hippocampal dentate gyrus in rhesus monkeys, Increased action potential firing rates of layer 2/3 pyramidal cells in the prefrontal cortex are significantly related to cognitive performance in aged monkeys, Neuronal basis of age-related working memory decline, Aging alters dendritic morphology, input resistance, and inhibitory signaling in dentate granule cells of the rhesus monkey, Protection of auditory receptors and neurons: Evidence for interactive damage, The Aging Auditory System, Springer Handbook of Auditory Research, Further observations on the pathology of presbycusis, Age-related changes in the response properties of cartwheel cells in rat dorsal cochlear nucleus, Age-related changes in the inhibitory response properties of dorsal cochlear nucleus output neurons: Role of inhibitory inputs, Inhibitory neurotransmission, plasticity and aging in the mammalian central auditory system, Alterations of GABAA receptor subunit mRNA levels in the aging Fischer 344 rat inferior colliculus, GABAA receptor binding in the aging rat inferior colliculus, Responses of young and aged rat inferior colliculus neurons to sinusoidally amplitude modulated stimuli, Reduced GABA(A) receptor-mediated tonic inhibition in aged rat auditory thalamus, Stimulus-specific adaptation in auditory thalamus of young and aged awake rats, Diminished cortical inhibition in an aging mouse model of chronic tinnitus, Hierarchical and serial processing in the spatial auditory cortical pathway is degraded by natural aging, Age-related neurochemical changes in the rhesus macaque inferior colliculus, Age-related neurochemical changes in the rhesus macaque superior olivary complex, Auditory peripheral influences on calcium binding protein immunoreactivity in the cochlear nucleus during aging in the C57BL/6J mouse, Age-related increases in calcium-binding protein immunoreactivity in the cochlear nucleus of hearing impaired C57BL/6J mice, Presbyacusis and calcium-binding protein immunoreactivity in the cochlear nucleus of BALB/c mice, Age-related changes in calbindin and calretinin immunoreactivity in the central auditory system of the rat, Changes in parvalbumin immunoreactivity with aging in the central auditory system of the rat, Age-related neurochemical changes in the rhesus macaque cochlear nucleus, Parvalbumin increases in the medial and lateral geniculate nuclei of aged rhesus macaques, Calcium-binding proteins in the nervous system, Viewpoint: The core and matrix of thalamic organization, Calbindin D-28k and parvalbumin in the rat nervous system, Introduction to the superior olivary complex, The lateral superior olive: A functional role in sound source localization, Neural mechanisms of encoding binaural localization cues in the auditory brainstem, Integrative Functions in the Mammalian Auditory Pathway, Springer Handbook of Auditory Research, Interaural time sensitivity in medial superior olive of cat, Microelectrode study of superior olivary nuclei, Topographic organization of the olivocochlear projections from the lateral and medial zones of the superior olivary complex. 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