Abstract
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 non-human 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 the hippocampal region CA3 is negatively correlated with the density of somatostatin-expressing inhibitory interneurons in the vicinity of the recording electrodes in the 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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Plassman BL, Langa KM, Fisher GG, Heeringa SG, Weir DR, Ofstedal MB et al. Prevalence of dementia in the United States: the aging, demographics, and memory study. Neuroepidemiology 2007; 29: 125–132.
Luo L, Craik F . Aging and memory: a cognitive approach. Can J Psychiatry Rev Can Psychiatr 2008; 53: 346–353.
Burke SN, Ryan L, Barnes CA . Characterizing cognitive aging of recognition memory and related processes in animal models and in humans. Front Aging Neurosci 2012; 4: 15.
Moscovitch M, Nadel L, Winocur G, Gilboa A, Rosenbaum RS . The cognitive neuroscience of remote episodic, semantic and spatial memory. Curr Opin Neurobiol 2006; 16: 179–190.
Rapp PR, Amaral DG . Evidence for task-dependent memory dysfunction in the aged monkey. J Neurosci Off J Soc Neurosci 1989; 9: 3568–3576.
West MJ, Coleman PD, Flood DG, Troncoso JC . Differences in the pattern of hippocampal neuronal loss in normal ageing and Alzheimer’s disease. Lancet 1994; 344: 769–772.
Keuker JIH, Luiten PGM, Fuchs E . Preservation of hippocampal neuron numbers in aged rhesus monkeys. Neurobiol Aging 2003; 24: 157–165.
Wilson IA, Ikonen S, Gallagher M, Eichenbaum H, Tanila H . Age-associated alterations of hippocampal place cells are subregion specific. J Neurosci 2005; 25: 6877–6886.
Spiegel AM, Koh MT, Vogt NM, Rapp PR, Gallagher M . Hilar interneuron vulnerability distinguishes aged rats with memory impairment. J Comp Neurol 2013; 521: 3508–3523.
Mitchell KJ, Johnson MK, Raye CL, D’Esposito M . fMRI evidence of age-related hippocampal dysfunction in feature binding in working memory. Brain Res Cogn Brain Res 2000; 10: 197–206.
Tigges J, Gordon TP, McClure HM, Hall EC, Peters A . Survival rate and life span of rhesus monkeys at the Yerkes Regional Primate Research Center. Am J Primatol 1988; 15: 263–273.
Harlow H, Bromer J . A test apparatus for monkeys. Psychol Rec 1938; 2: 434–436.
Moss MB, Rosene DL, Peters A . Effects of aging on visual recognition memory in the rhesus monkey. Neurobiol Aging 1988; 9: 495–502.
Herndon JG, Moss MB, Rosene DL, Killiany RJ . Patterns of cognitive decline in aged rhesus monkeys. Behav Brain Res 1997; 87: 25–34.
Alexander GE, Chen K, Aschenbrenner M, Merkley TL, Santerre-Lemmon LE, Shamy JL et al. Age-related regional network of magnetic resonance imaging gray matter in the rhesus macaque. J Neurosci 2008; 28: 2710–2718.
Mishkin M . Memory in monkeys severely impaired by combined but not by separate removal of amygdala and hippocampus. Nature 1978; 273: 297–298.
Murray EA, Mishkin M . Severe tactual as well as visual memory deficits follow combined removal of the amygdala and hippocampus in monkeys. J Neurosci Off J Soc Neurosci 1984; 4: 2565–2580.
Saunders RC, Murray EA, Mishkin M . Further evidence that amygdala and hippocampus contribute equally to recognition memory. Neuropsychologia 1984; 22: 785–796.
Buffalo EA, Ramus SJ, Squire LR, Zola SM . Perception and recognition memory in monkeys following lesions of area TE and perirhinal cortex. Learn Mem 2000; 7: 375–382.
Zola SM, Squire LR, Teng E, Stefanacci L, Buffalo EA, Clark RE . Impaired recognition memory in monkeys after damage limited to the hippocampal region. J Neurosci 2000; 20: 451–463.
Baxter MG, Murray EA . Opposite relationship of hippocampal and rhinal cortex damage to delayed nonmatching-to-sample deficits in monkeys. Hippocampus 2001; 11: 61–71.
Barker GRI, Warburton EC . When is the hippocampus involved in recognition memory? J Neurosci 2011; 31: 10721–10731.
Skaggs WE, McNaughton BL, Permenter M, Archibeque M, Vogt J, Amaral DG et al. EEG sharp waves and sparse ensemble unit activity in the macaque hippocampus. J Neurophysiol 2007; 98: 898.
Thome A, Erickson CA, Lipa P, Barnes CA . Differential effects of experience on tuning properties of macaque MTL neurons in a passive viewing task. Hippocampus 2012; 22: 2000–2011.
Paxinos G, Huang X-F, Toga AW . The Rhesus Monkey Brain in Stereotaxic Coordinates. 1st edn. Academic Press: San Diego, 1999.
Mouton PR, Gokhale AM, Ward NL, West MJ . Stereological length estimation using spherical probes. J Microsc 2002; 206: 54–64.
Squire LR, Zola-Morgan S . The medial temporal lobe memory system. Science 1991; 253: 1380.
Bartho P, Hirase H, Monconduit L, Zugaro M, Harris KD, Buzsaki G . Characterization of neocortical principal cells and interneurons by network interactions and extracellular features. J Neurophysiol 2004; 92: 600.
Mitchell JF, Sundberg KA, Reynolds JH . Differential attention-dependent response modulation across cell classes in Macaque visual area V4. Neuron 2007; 55: 131–141.
Stanley DP, Shetty AK . Aging in the rat hippocampus is associated with widespread reductions in the number of glutamate decarboxylase-67 positive interneurons but not interneuron degeneration. J Neurochem 2004; 89: 204–216.
McNaughton BL, Morris RGM . Hippocampal synaptic enhancement and information storage within a distributed memory system. Trends Neurosci 1987; 10: 408–415.
Freund TF, Buzsáki G . Interneurons of the hippocampus. Hippocampus 1996; 6: 347–470.
Lavenex P, Amaral DG . Hippocampal–neocortical interaction: a hierarchy of associativity. Hippocampus 2000; 10: 420–430.
Yassa MA, Lacy JW, Stark SM, Albert MS, Gallagher M, Stark CEL . Pattern separation deficits associated with increased hippocampal CA3 and dentate gyrus activity in nondemented older adults. Hippocampus 2011; 21: 968–979.
Bakker A, Krauss GL, Albert MS, Speck CL, Jones LR, Stark CE et al. Reduction of hippocampal hyperactivity improves cognition in amnestic mild cognitive impairment. Neuron 2012; 74: 467–474.
Landfield PW, Pitler TA . Prolonged Ca2+-dependent afterhyperpolarizations in hippocampal neurons of aged rats. Science 1984; 226: 1089–1092.
Luebke JI, Amatrudo JM . Age-related increase of sI(AHP) in prefrontal pyramidal cells of monkeys: relationship to cognition. Neurobiol Aging 2012; 33: 1085–1095.
Geinisman Y, de Toledo-Morrell L, Morrell F, Persina IS, Rossi M . Age-related loss of axospinous synapses formed by two afferent systems in the rat dentate gyrus as revealed by the unbiased stereological dissector technique. Hippocampus 1992; 2: 437–444.
Barnes CA . Memory deficits associated with senescence: a neurophysiological and behavioral study in the rat. J Comp Physiol Psychol 1979; 93: 74–104.
Bartus RT, Dean RL, Beer B, Lippa AS . The cholinergic hypothesis of geriatric memory dysfunction. Science 1982; 217: 408–414.
Shen J, Barnes CA . Age-related decrease in cholinergic synaptic transmission in three hippocampal subfields. Neurobiol Aging 1996; 17: 439–451.
Penner MR, Roth TL, Chawla MK, Hoang LT, Roth ED, Lubin FD et al. Age-related changes in Arc transcription and DNA methylation within the hippocampus. Neurobiol Aging 2011; 32: 2198–2210.
Berchtold NC, Coleman PD, Cribbs DH, Rogers J, Gillen DL, Cotman CW . Synaptic genes are extensively downregulated across multiple brain regions in normal human aging and Alzheimer’s disease. Neurobiol Aging 2013; 34: 1653–1661.
Juarez-Salinas DL, Engle JR, Navarro XO, Recanzone GH . Hierarchical and serial processing in the spatial auditory cortical pathway is degraded by natural aging. J Neurosci Off J Soc Neurosci 2010; 30: 14795–14804.
Wang M, Gamo NJ, Yang Y, Jin LE, Wang X-J, Laubach M et al. Neuronal basis of age-related working memory decline. Nature 2011; 476: 210–213.
Koh MT, Rosenzweig-Lipson S, Gallagher M . Selective GABA(A) α5 positive allosteric modulators improve cognitive function in aged rats with memory impairment. Neuropharmacology 2013; 64: 145–152.
Acknowledgements
This work was supported by RO1 AG003376, P51 RR000169, and the McKnight Brain Research Foundation. We thank Bruce McNaughton for help with the design of the primate hyperdrive and participation in the implant surgeries. We also thank Katalin Gothard for participation in all headpost surgeries for the animals, Bill Skaggs, Michele Permenter, Julie Vogt and Matthew Archibeque for acquisition of the single-unit data, Jie Wang for cell separation and processing the single-unit data. We are grateful to Alison Comrie and Chelsea Takamatsu for help with the immunohistochemistry image processing, and also to Rachel Samson for consultation on statistical analyses. AT is currently at the Department of Brain and Cognitive Sciences, University of Rochester (Rochester, NY, USA).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Rights and permissions
About this article
Cite this article
Thomé, A., Gray, D., Erickson, C. et al. Memory impairment in aged primates is associated with region-specific network dysfunction. Mol Psychiatry 21, 1257–1262 (2016). https://doi.org/10.1038/mp.2015.160
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/mp.2015.160
This article is cited by
-
Genetic Ablation of Dentate Hilar Somatostatin-Positive GABAergic Interneurons is Sufficient to Induce Cognitive Impairment
Molecular Neurobiology (2024)
-
Prevention of age-associated neuronal hyperexcitability with improved learning and attention upon knockout or antagonism of LPAR2
Cellular and Molecular Life Sciences (2021)
-
Dentate granule cell recruitment of feedforward inhibition governs engram maintenance and remote memory generalization
Nature Medicine (2018)
-
Targeting Adult Neurogenesis to Optimize Hippocampal Circuits in Aging
Neurotherapeutics (2017)
-
Targeting Neural Hyperactivity as a Treatment to Stem Progression of Late-Onset Alzheimer's Disease
Neurotherapeutics (2017)