{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,11]],"date-time":"2026-07-11T14:19:49Z","timestamp":1783779589290,"version":"3.55.0"},"reference-count":128,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,3,11]],"date-time":"2022-03-11T00:00:00Z","timestamp":1646956800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R37AG008796"],"award-info":[{"award-number":["R37AG008796"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["RF1AG017139"],"award-info":[{"award-number":["RF1AG017139"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["F31AG055331"],"award-info":[{"award-number":["F31AG055331"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Aging Neurosci."],"abstract":"<jats:p>With aging comes a myriad of different disorders, and cognitive decline is one of them. Studies have consistently shown a decline amongst aged subjects in their ability to acquire and maintain temporal associative memory. Defined as the memory of the association between two objects that are separated in time, temporal associative memory is dependent on neocortical structures such as the prefrontal cortex and temporal lobe structures. For this memory to be acquired, a mental trace of the first stimulus is necessary to bridge the temporal gap so the two stimuli can be properly associated. Persistent firing, the ability of the neuron to continue to fire action potentials even after the termination of a triggering stimulus, is one mechanism that is posited to support this mental trace. A recent study demonstrated a decline in persistent firing ability in pyramidal neurons of layer III of the lateral entorhinal cortex with aging, contributing to learning impairments in temporal associative memory acquisition. In this work, we explore the potential ways persistent firing in lateral entorhinal cortex (LEC) III supports temporal associative memory, and how aging may disrupt this mechanism within the temporal lobe system, resulting in impairment in this crucial behavior.<\/jats:p>","DOI":"10.3389\/fnagi.2022.838513","type":"journal-article","created":{"date-parts":[[2022,3,11]],"date-time":"2022-03-11T10:34:27Z","timestamp":1646994867000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Aging-Related Alterations to Persistent Firing in the Lateral Entorhinal Cortex Contribute to Deficits in Temporal Associative Memory"],"prefix":"10.3389","volume":"14","author":[{"given":"Carmen","family":"Lin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. Matthew","family":"Oh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John F.","family":"Disterhoft","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,3,11]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"e13243","DOI":"10.1111\/acel.13243","article-title":"Age-related impairment of declarative memory: linking memorization of temporal associations to GluN2B redistribution in dorsal CA1.","volume":"19","author":"Al Abed","year":"2020","journal-title":"Aging Cell"},{"key":"B2","doi-asserted-by":"publisher","first-page":"2538","DOI":"10.1073\/pnas.82.8.2538","article-title":"Protein Kinase C regulates ionic conductance in hippocampal pyramidal neurons: electrophysiological effects of phorbol esters.","volume":"82","author":"Baraban","year":"1985","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1874","DOI":"10.1016\/j.neurobiolaging.2007.04.024","article-title":"Aging elevates metabolic gene expression in brain cholinergic neurons.","volume":"29","author":"Baskerville","year":"2008","journal-title":"Neurobiol. Aging"},{"key":"B4","doi-asserted-by":"publisher","first-page":"e45333","DOI":"10.7554\/eLife.45333","article-title":"Mapping sequence structure in the human lateral entorhinal cortex.","volume":"8","author":"Bellmund","year":"2019","journal-title":"Elife"},{"key":"B5","doi-asserted-by":"publisher","first-page":"5301","DOI":"10.1523\/JNEUROSCI.0182-04.2004","article-title":"Small conductance Ca2+-activated K+ channel knock-out mice reveal the identity of calcium-dependent afterhyperpolarization currents.","volume":"24","author":"Bond","year":"2004","journal-title":"J. Neurosci."},{"key":"B6","doi-asserted-by":"publisher","first-page":"701","DOI":"10.1038\/s41583-018-0068-2","article-title":"Maintenance, reserve and compensation: the cognitive neuroscience of healthy ageing.","volume":"19","author":"Cabeza","year":"2018","journal-title":"Nat. Rev. Neurosci."},{"key":"B7","doi-asserted-by":"publisher","first-page":"1394","DOI":"10.1006\/nimg.2002.1280","article-title":"Aging gracefully: compensatory brain activity in high-performing older adults.","volume":"17","author":"Cabeza","year":"2002","journal-title":"Neuroimage"},{"key":"B8","doi-asserted-by":"publisher","first-page":"6286","DOI":"10.1523\/JNEUROSCI.16-19-06286.1996","article-title":"Aging changes in voltage-gated calcium currents in hippocampal CA1 neurons.","volume":"16","author":"Campbell","year":"1996","journal-title":"J. Neurosci."},{"key":"B9","doi-asserted-by":"publisher","first-page":"381243","DOI":"10.1155\/2008\/381243","article-title":"What does the anatomical organization of the entorhinal cortex tell us?","volume":"2008","author":"Canto","year":"2008","journal-title":"Neural Plast."},{"key":"B10","doi-asserted-by":"publisher","first-page":"118","DOI":"10.1016\/j.nlm.2010.12.003","article-title":"Eyeblink conditioning and systems consolidation: an ironic yet powerful pairing.","volume":"95","author":"Clark","year":"2011","journal-title":"Neurobiol. Learn. Mem."},{"key":"B11","doi-asserted-by":"publisher","first-page":"7020","DOI":"10.1523\/JNEUROSCI.2486-17.2018","article-title":"Persistent spiking activity underlies working memory.","volume":"38","author":"Constantinidis","year":"2018","journal-title":"J. Neurosci."},{"key":"B12","doi-asserted-by":"publisher","first-page":"5987","DOI":"10.1002\/hbm.23803","article-title":"Frequency-specific neuromodulation of local and distant connectivity in aging and episodic memory function.","volume":"38","author":"Davis","year":"2017","journal-title":"Hum. Brain Mapp."},{"key":"B13","doi-asserted-by":"publisher","first-page":"8410","DOI":"10.1523\/JNEUROSCI.20-22-08410.2000","article-title":"Corticolimbic interactions associated with performance on a short-term memory task are modified by age.","volume":"20","author":"Della-Maggiore","year":"2000","journal-title":"J. Neurosci."},{"key":"B14","doi-asserted-by":"publisher","first-page":"69","DOI":"10.3389\/fnbeh.2011.00069","article-title":"Representation of non-spatial and spatial information in the lateral entorhinal cortex.","volume":"5","author":"Deshmukh","year":"2011","journal-title":"Front. Behav. Neurosci."},{"key":"B15","doi-asserted-by":"publisher","first-page":"809","DOI":"10.1126\/science.2916127","article-title":"Nimpodipine facilitates associative learning in aging rabbits.","volume":"243","author":"Deyo","year":"1989","journal-title":"Science"},{"key":"B16","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1016\/j.nlm.2003.08.004","article-title":"Modulation of cholinergic transmission enhances excitability of hippocampal pyramidal neurons and ameliorates learning impairments in aging animals.","volume":"80","author":"Disterhoft","year":"2003","journal-title":"Neurobiol. Learn. Mem."},{"key":"B17","doi-asserted-by":"publisher","first-page":"587","DOI":"10.1016\/j.tins.2006.08.005","article-title":"Learning, aging and intrinsic neuronal plasticity.","volume":"29","author":"Disterhoft","year":"2006","journal-title":"Trends Neurosci."},{"key":"B18","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1038\/nature01030","article-title":"Graded persistent activity in entorhinal cortex neurons.","volume":"420","author":"Egorov","year":"2002","journal-title":"Nature"},{"key":"B19","doi-asserted-by":"publisher","first-page":"732","DOI":"10.1038\/nrn3827","article-title":"Time cells in the hippocampus: a new dimension for mapping memories.","volume":"15","author":"Eichenbaum","year":"2014","journal-title":"Nat. Rev. Neurosci."},{"key":"B20","doi-asserted-by":"publisher","first-page":"8087","DOI":"10.1523\/JNEUROSCI.0543-09.2009","article-title":"A cholinergic-dependent role for the entorhinal cortex in trace fear conditioning.","volume":"29","author":"Esclassan","year":"2009","journal-title":"J. Neurosci."},{"key":"B21","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1038\/nrn1607","article-title":"The organization of recent and remote memories.","volume":"6","author":"Frankland","year":"2005","journal-title":"Nat. Rev. Neurosci."},{"key":"B22","doi-asserted-by":"publisher","first-page":"4113","DOI":"10.1523\/JNEUROSCI.16-13-04113.1996","article-title":"Cholinergic-dependent plateau potential in hippocampal CA1 pyramidal neurons.","volume":"16","author":"Fraser","year":"1996","journal-title":"J. Neurosci."},{"key":"B23","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1152\/jn.1973.36.1.61","article-title":"Unit activity in prefrontal cortex during delayed-response performance: neuronal correlates of transient memory.","volume":"36","author":"Fuster","year":"1972","journal-title":"J. Physiol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"1915","DOI":"10.1016\/j.neurobiolaging.2009.11.014","article-title":"Age-related deficits in a forebrain-dependent task, trace-eyeblink conditioning.","volume":"32","author":"Galvez","year":"2011","journal-title":"Neurobiol. Aging"},{"key":"B25","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1002\/hipo.20728","article-title":"Deletion of the L-type calcium channel Ca(V) 1.3 but not Ca(V) 1.2 results in a diminished sAHP in mouse CA1 pyramidal neurons.","volume":"21","author":"Gamelli","year":"2011","journal-title":"Hippocampus"},{"key":"B26","doi-asserted-by":"publisher","first-page":"10878","DOI":"10.1523\/JNEUROSCI.1248-15.2015","article-title":"Reversal of aging-related neuronal Ca2+ dysregulation and cognitive impairment by delivery of a transgene encoding FK506-binding protein 12.6\/1b to the hippocampus.","volume":"35","author":"Gant","year":"2015","journal-title":"J. Neurosci."},{"key":"B27","doi-asserted-by":"publisher","first-page":"477","DOI":"10.1016\/0896-6273(95)90304-6","article-title":"Cellular basis of working memory.","volume":"14","author":"Goldman-Rakic","year":"1995","journal-title":"Neuron"},{"key":"B28","doi-asserted-by":"publisher","first-page":"491","DOI":"10.1038\/nrn3256","article-title":"The cognitive neuroscience of ageing.","volume":"13","author":"Grady","year":"2012","journal-title":"Nat. Rev. Neurosci."},{"key":"B29","doi-asserted-by":"publisher","first-page":"575","DOI":"10.1016\/j.pbb.2005.04.010","article-title":"Muscarinic and nicotinic receptor modulation of object and spatial n-back working memory in humans.","volume":"81","author":"Green","year":"2005","journal-title":"Pharmacol. Biochem. Behav."},{"key":"B30","doi-asserted-by":"publisher","first-page":"1077","DOI":"10.1523\/JNEUROSCI.2834-05.2006","article-title":"Involvement of the CA3-CA1 synapse in the acquisition of associative learning in behaving mice.","volume":"26","author":"Gruart","year":"2006","journal-title":"J. Neurosci."},{"key":"B31","doi-asserted-by":"publisher","first-page":"1164","DOI":"10.1016\/j.neuron.2019.06.024","article-title":"The cholinergic basal forebrain links auditory stimuli with delayed reinforcement to support learning.","volume":"103","author":"Guo","year":"2019","journal-title":"Neuron"},{"key":"B32","doi-asserted-by":"publisher","first-page":"1844","DOI":"10.1523\/JNEUROSCI.4106-05.2006","article-title":"Small-conductance Ca2+-activated K+ channel type 2 (SK2) modulates hippocampal learning, memory, and synaptic plasticity.","volume":"26","author":"Hammond","year":"2006","journal-title":"J. Neurosci."},{"key":"B33","doi-asserted-by":"publisher","first-page":"710","DOI":"10.1016\/j.conb.2006.09.002","article-title":"The role of acetylcholine in learning and memory.","volume":"16","author":"Hasselmo","year":"2006","journal-title":"Curr. Opin. Neurobiol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"1432","DOI":"10.1523\/JNEUROSCI.4428-13.2014","article-title":"Functional reorganization of a prefrontal cortical network mediating consolidation of trace eyeblink conditioning.","volume":"34","author":"Hattori","year":"2014","journal-title":"J. Neurosci."},{"key":"B35","doi-asserted-by":"publisher","first-page":"32","DOI":"10.3389\/fnbeh.2012.00032","article-title":"Effects of acetylcholine on neuronal properties in entorhinal cortex.","volume":"6","author":"Heys","year":"2012","journal-title":"Front. Behav. Neurosci."},{"key":"B36","doi-asserted-by":"publisher","first-page":"146","DOI":"10.1002\/(SICI)1098-1063(1997)7:2<146::AID-HIPO4>3.0.CO;2-L","article-title":"Entorhinal cortex of the rat: cytoarchitectonic subdivisions and the origin and distribution of cortical efferents.","volume":"7","author":"Insausti","year":"1997","journal-title":"Hippocampus"},{"key":"B37","doi-asserted-by":"publisher","first-page":"2250","DOI":"10.1111\/ejn.12236","article-title":"Persistent firing supported by an intrinsic cellular mechanism in hippocampal CA3 pyramidal cells.","volume":"38","author":"Jochems","year":"2013","journal-title":"Eur. J. Neurosci."},{"key":"B38","doi-asserted-by":"publisher","first-page":"9","DOI":"10.3389\/fnagi.2011.00009","article-title":"Age sensitivity of behavioral tests and brain substrates of normal aging in mice.","volume":"3","author":"Kennard","year":"2011","journal-title":"Front. Aging Neurosci."},{"key":"B39","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1007\/BF03323872","article-title":"The role of calcium regulation in brain aging: reexamination of a hypothesis.","volume":"1","author":"Khachaturian","year":"1989","journal-title":"Aging"},{"key":"B40","doi-asserted-by":"publisher","first-page":"675","DOI":"10.1126\/science.1585183","article-title":"Modality-specific retrograde amnesia of fear.","volume":"256","author":"Kim","year":"1992","journal-title":"Science"},{"key":"B41","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1037\/\/0735-7044.109.2.195","article-title":"Hippocampectomy impairs the memory of recently, but not remotely, acquired trace eyeblink conditioned responses.","volume":"109","author":"Kim","year":"1995","journal-title":"Behav. Neurosci."},{"key":"B42","doi-asserted-by":"publisher","first-page":"1317","DOI":"10.1016\/j.neuron.2015.08.036","article-title":"Entorhinal cortical ocean cells encode specific contexts and drive context-specific fear memory.","volume":"87","author":"Kitamura","year":"2015","journal-title":"Neuron"},{"key":"B43","doi-asserted-by":"publisher","first-page":"820","DOI":"10.1002\/hipo.22136","article-title":"Long-lasting intrinsic persistent firing in rat CA1 pyramidal cells: a possible mechanism for active maintenance of memory.","volume":"23","author":"Knauer","year":"2013","journal-title":"Hippocampus"},{"key":"B44","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/s0197-4580(00)00194-9","article-title":"Age-related effects on eyeblink conditioning in the F344xBN F1 hybrid rat.","volume":"22","author":"Knuttinen","year":"","journal-title":"Neurobiol. Aging"},{"key":"B45","doi-asserted-by":"publisher","first-page":"747","DOI":"10.1037\/0735-7044.115.4.747","article-title":"Awareness in classical differential eyeblink conditioning in young and aging humans.","volume":"115","author":"Knuttinen","year":"","journal-title":"Behav. Neurosci."},{"key":"B46","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1016\/s0091-3057(96)00164-5","article-title":"Metrifonate treatment enhances acquisition of eyeblink conditioning in aging rabbits.","volume":"56","author":"Kronforst-Collins","year":"1997","journal-title":"Pharmacol. Biochem. Behav."},{"key":"B47","doi-asserted-by":"publisher","first-page":"998","DOI":"10.1002\/psc.1034","article-title":"Peptide fragment of the m3 muscarinic acetylcholine receptor activates G(q) but not G(i2).","volume":"14","author":"Kubota","year":"2008","journal-title":"J. Pept. Sci."},{"key":"B48","doi-asserted-by":"publisher","first-page":"2437","DOI":"10.1152\/jn.01148.2003","article-title":"Enhanced long-term potentiation during aging is masked by processes involving intraceullular calcium stores.","volume":"91","author":"Kumar","year":"2004","journal-title":"J. Neurophysiol."},{"key":"B49","doi-asserted-by":"publisher","first-page":"2","DOI":"10.3389\/neuro.24.002.2009","article-title":"Susceptibility to calcium dysregulation during brain aging.","volume":"1","author":"Kumar","year":"2009","journal-title":"Front. Aging Neurosci."},{"key":"B50","doi-asserted-by":"publisher","first-page":"346","DOI":"10.1016\/0197-4580(87)90074-1","article-title":"\u2018Increased calcium-current\u2019 hypothesis of brain aging.","volume":"8","author":"Landfield","year":"1987","journal-title":"Neurobiol. Aging"},{"key":"B51","author":"Lin","year":"2020","journal-title":"Mechanisms Underlying Associative Learning: Classical Conditioning Paradigms and the Functional Neuronal Changes that Support Acquisition."},{"key":"B52","doi-asserted-by":"publisher","first-page":"e56816","DOI":"10.7554\/eLife.56816","article-title":"Persistent firing in LEC III neurons is differentially modulated by learning and aging.","volume":"9","author":"Lin","year":"2020","journal-title":"Elife"},{"key":"B53","doi-asserted-by":"publisher","first-page":"458","DOI":"10.1126\/science.1256573","article-title":"Medial prefrontal activity during delay period contributes to learning of a working memory task.","volume":"346","author":"Liu","year":"2014","journal-title":"Science"},{"key":"B54","doi-asserted-by":"publisher","first-page":"7013","DOI":"10.1523\/JNEUROSCI.2485-17.2018","article-title":"Working memory: delay activity, yes! persistent activity? maybe not.","volume":"38","author":"Lundqvist","year":"2018","journal-title":"J. Neurosci."},{"key":"B55","doi-asserted-by":"publisher","first-page":"14607","DOI":"10.1523\/JNEUROSCI.1537-13.2013","article-title":"Distinct hippocampal time cell sequences represent odor memories in immobilized rats.","volume":"33","author":"MacDonald","year":"2013","journal-title":"J. Neurosci."},{"key":"B56","doi-asserted-by":"publisher","first-page":"737","DOI":"10.1016\/j.neuron.2011.07.012","article-title":"Hippocampal \u201ctime cells\u201d bridge the gap in memory for discontiguous events.","volume":"71","author":"MacDonald","year":"2011","journal-title":"Neuron"},{"key":"B57","doi-asserted-by":"publisher","first-page":"4750","DOI":"10.1523\/JNEUROSCI.0384-09.2009","article-title":"The fast and slow afterhyperpolarizations are differentially modulated in hippocampal neurons by aging and learning.","volume":"29","author":"Matthews","year":"2009","journal-title":"J. Neurosci."},{"key":"B58","doi-asserted-by":"publisher","first-page":"1030","DOI":"10.1152\/jn.1997.78.2.1030","article-title":"Sequence of single neuron changes in CA1 hippocampus of rabbits during acquisition of trace eyeblink conditioned responses.","volume":"78","author":"McEchron","year":"1997","journal-title":"J. Neurophysiol."},{"key":"B59","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1002\/(SICI)1098-1063(1999)9:4<385::AID-HIPO5>3.0.CO;2-K","article-title":"Hippocampal encoding of non-spatial trace conditioning.","volume":"9","author":"McEchron","year":"1999","journal-title":"Hippocampus"},{"key":"B60","doi-asserted-by":"publisher","first-page":"1839","DOI":"10.1152\/jn.2001.86.4.1839","article-title":"Aging and learning-specific changes in single-neuron activity in CA1 hippocampus during rabbit trace eyeblink conditioning.","volume":"86","author":"McEchron","year":"2001","journal-title":"J. Neurophysiol."},{"key":"B61","doi-asserted-by":"publisher","first-page":"863","DOI":"10.1152\/jn.00025.2012","article-title":"Increasing SK2 channel activity impairs associative learning.","volume":"108","author":"McKay","year":"2012","journal-title":"J. Neurophysiol."},{"key":"B62","doi-asserted-by":"publisher","first-page":"1115","DOI":"10.1016\/j.bcp.2005.05.019","article-title":"Brain cholinergic vulnerability: relevance to behavior and disease.","volume":"70","author":"McKinney","year":"2005","journal-title":"Biochem. Pharmacol."},{"key":"B63","doi-asserted-by":"publisher","first-page":"4002","DOI":"10.1073\/pnas.062057099","article-title":"Induction of behavioral associative memory by stimulation of the nucleus basalis.","volume":"99","author":"McLin","year":"2002","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B64","doi-asserted-by":"publisher","first-page":"607685","DOI":"10.3389\/fnagi.2020.607685","article-title":"Cognitive reserve in model systems for mechanistic discovery: the importance of longitudinal studies.","volume":"12","author":"McQuail","year":"2021","journal-title":"Front. Aging Neurosci."},{"key":"B65","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1016\/j.neuron.2018.09.023","article-title":"Working memory 2.0","volume":"100","author":"Miller","year":"2018","journal-title":"Neuron"},{"key":"B66","doi-asserted-by":"publisher","first-page":"e01982","DOI":"10.7554\/eLife.01982","article-title":"CA1 cell activity sequences emerge after reorganization of network correlation structure during associative learning.","volume":"3","author":"Modi","year":"2014","journal-title":"Elife"},{"key":"B67","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1038\/s41593-018-0303-1","article-title":"Precise temporal memories are supported by the lateral entorhinal cortex in humans.","volume":"22","author":"Montchal","year":"2019","journal-title":"Nat. Neurosci."},{"key":"B68","doi-asserted-by":"publisher","first-page":"5356","DOI":"10.1523\/JNEUROSCI.5227-11.2012","article-title":"Functional dissociation within the entorhinal cortex for memory retrieval of an association between temporally discontiguous stimuli.","volume":"32","author":"Morrissey","year":"2012","journal-title":"J. Neurosci."},{"key":"B69","doi-asserted-by":"publisher","first-page":"5476","DOI":"10.1523\/JNEUROSCI.20-14-05476.2000","article-title":"Increased excitability of aged rabbit CA1 neurons after trace eyeblink conditioning.","volume":"20","author":"Moyer","year":"2000","journal-title":"J. Neurosci."},{"key":"B70","doi-asserted-by":"publisher","first-page":"2100","DOI":"10.1152\/jn.1992.68.6.2100","article-title":"Nimodipine increases excitability of rabbit CA1 pyramidal neurons in an age- and concentration-dependent manner.","volume":"68","author":"Moyer","year":"1992","journal-title":"J. Neurophysiol."},{"key":"B71","doi-asserted-by":"crossref","first-page":"5536","DOI":"10.1523\/JNEUROSCI.16-17-05536.1996","article-title":"Trace eyeblink conditioning increases CA1 excitability in a transient and learning-specific manner","volume":"16","author":"Moyer","year":"1996","journal-title":"J. Neurosci"},{"key":"B72","doi-asserted-by":"publisher","first-page":"1392","DOI":"10.1002\/hipo.20975","article-title":"Muscarinic receptor activation enables persistent firing in pyramidal neurons from superficial layers of dorsal perirhinal cortex.","volume":"22","author":"Navaroli","year":"2012","journal-title":"Hippocampus"},{"key":"B73","doi-asserted-by":"publisher","first-page":"7905","DOI":"10.1523\/JNEUROSCI.5457-12.2013","article-title":"Altered calcium metabolism in aging CA1 hippocampal pyramidal neurons.","volume":"33","author":"Oh","year":"2013","journal-title":"J. Neurosci."},{"key":"B74","doi-asserted-by":"publisher","first-page":"1814","DOI":"10.1523\/JNEUROSCI.19-05-01814.1999","article-title":"Metrifonate increases neuronal excitability in CA1 pyramidal neurons from both young and aging rabbit hippocampus.","volume":"19","author":"Oh","year":"1999","journal-title":"J. Neurosci."},{"key":"B75","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1016\/j.celrep.2018.06.014","article-title":"Intrinsic projections of layer Vb neurons to layers Va, III, and II in the lateral and medial entorhinal cortex of the rat.","volume":"24","author":"Ohara","year":"2018","journal-title":"Cell Rep."},{"key":"B76","doi-asserted-by":"publisher","first-page":"116","DOI":"10.1016\/j.neuron.2012.08.036","article-title":"Acetylcholine as a neuromodulator: cholinergic signaling shapes nervous system function and behavior.","volume":"76","author":"Picciotto","year":"2012","journal-title":"Neuron"},{"key":"B77","doi-asserted-by":"publisher","first-page":"735","DOI":"10.1016\/j.biopsych.2015.07.017","article-title":"Temporal memory and its enhancement by estradiol requires surface dynamics of hippocampal CA1 N-Methyl-D-Aspartate receptors.","volume":"79","author":"Potier","year":"2016","journal-title":"Biol. Psychiatry"},{"key":"B78","doi-asserted-by":"publisher","first-page":"1184","DOI":"10.1152\/jn.1997.78.2.1184","article-title":"Enhanced synaptic transmission in CA1 hippocampus after eyeblink conditioning.","volume":"78","author":"Power","year":"1997","journal-title":"J. Physiol."},{"key":"B79","doi-asserted-by":"publisher","first-page":"7234","DOI":"10.1523\/JNEUROSCI.22-16-07234.2002","article-title":"Age-Related enhancement of the slow outward calcium-activated potassium current in hippocampal CA1 pyramidal neurons in Vitro.","volume":"22","author":"Power","year":"2002","journal-title":"J. Neurosci."},{"key":"B80","doi-asserted-by":"publisher","first-page":"1187","DOI":"10.1016\/j.neuron.2018.01.039","article-title":"Functional imbalance of anterolateral entorhinal cortex and hippocampal dentate\/CA3 underlies age-related object pattern separation deficits.","volume":"97","author":"Reagh","year":"2018","journal-title":"Neuron"},{"key":"B81","doi-asserted-by":"publisher","first-page":"736","DOI":"10.1038\/416736a","article-title":"Direct cortical input modulates plasticity and spiking in CA1 pyramidal neurons.","volume":"416","author":"Remondes","year":"2002","journal-title":"Lett. Nat."},{"key":"B82","doi-asserted-by":"publisher","first-page":"699","DOI":"10.1038\/nature02965","article-title":"Role for a cortical input to hippocampal area CA1 in the consolidation of a long-term memory.","volume":"431","author":"Remondes","year":"2004","journal-title":"Nature"},{"key":"B83","doi-asserted-by":"publisher","first-page":"4325","DOI":"10.1523\/JNEUROSCI.19-11-04325.1999","article-title":"Calcium-induced calcium release contributes to action potential-evoked calcium transients in hippocampal CA1 pyramidal neurons.","volume":"19","author":"Sandler","year":"1999","journal-title":"J. Neurosci."},{"key":"B84","doi-asserted-by":"publisher","first-page":"10010","DOI":"10.1523\/JNEUROSCI.3307-05.2005","article-title":"Tracking the fear engram: the lateral amygdala is an essential locus of fear memory storage.","volume":"25","author":"Schafe","year":"2005","journal-title":"J. Neurosci."},{"key":"B85","doi-asserted-by":"publisher","first-page":"555","DOI":"10.1016\/j.bbr.2010.11.058","article-title":"The cholinergic system in aging and neuronal degeneration.","volume":"221","author":"Schliebs","year":"2011","journal-title":"Behav. Brain Res."},{"key":"B86","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1136\/jnnp.20.1.11","article-title":"Loss of recent memory after bilateral hippocampal lesions.","volume":"20","author":"Scoville","year":"1957","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"B87","doi-asserted-by":"publisher","first-page":"10262","DOI":"10.1073\/pnas.1619657114","article-title":"Temporal binding function of dorsal CA1 is critical for declarative memory formation.","volume":"114","author":"Sellami","year":"2017","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B88","doi-asserted-by":"publisher","first-page":"729","DOI":"10.1037\/0735-7044.100.5.729","article-title":"Hippocampus and trace conditioning of the rabbit\u2019s classically conditioned nictitating membrane response.","volume":"100","author":"Solomon","year":"1986","journal-title":"Behav. Neurosci."},{"key":"B89","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1146\/annurev.neuro.27.070203.144130","article-title":"The medial temporal lobe.","volume":"27","author":"Squire","year":"2004","journal-title":"Annu. Rev. Neurosci."},{"key":"B90","doi-asserted-by":"publisher","first-page":"1503","DOI":"10.1038\/s41467-019-09558-3","article-title":"Recollection in the human hippocampal-entorhinal cell circuitry.","volume":"10","author":"Staresina","year":"2019","journal-title":"Nat. Commun."},{"key":"B91","doi-asserted-by":"publisher","first-page":"1305","DOI":"10.1016\/j.jalz.2018.07.219","article-title":"Whitepaper: defining and investigating cognitive reserve, brain reserve, and brain maintenance.","volume":"16","author":"Stern","year":"2020","journal-title":"Alzheimers Dement."},{"key":"B92","doi-asserted-by":"publisher","first-page":"1415","DOI":"10.1126\/science.1210125","article-title":"Entorhinal cortex layer III input to the hippocampus is crucial for temporal associative memory.","volume":"334","author":"Suh","year":"2011","journal-title":"Science"},{"key":"B93","doi-asserted-by":"publisher","first-page":"511","DOI":"10.1002\/hipo.23041","article-title":"Differential responsivity of neurons in perirhinal cortex, lateral entorhinal cortex, and dentate gyrus during time-bridging learning.","volume":"29","author":"Suter","year":"2019","journal-title":"Hippocampus"},{"key":"B94","doi-asserted-by":"publisher","first-page":"1062","DOI":"10.1152\/jn.1997.78.2.1062","article-title":"Object and place memory in the macaque entorhinal cortex.","volume":"78","author":"Suzuki","year":"1997","journal-title":"J. Neurophysiol."},{"key":"B95","doi-asserted-by":"publisher","first-page":"2006","DOI":"10.1152\/jn.00911.2007","article-title":"Ionic basis of ON and OFF persistent activity in layer III lateral entorhinal cortical principal neurons.","volume":"99","author":"Tahvildari","year":"2008","journal-title":"J. Neurophysiol."},{"key":"B96","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1002\/hipo.20270","article-title":"Switching between \u201cOn\u201d and \u201cOff\u201d states of persistent activity in lateral entorhinal layer III neurons.","volume":"17","author":"Tahvildari","year":"2007","journal-title":"Hippocampus"},{"key":"B97","doi-asserted-by":"publisher","first-page":"9897","DOI":"10.1523\/JNEUROSCI.23-30-09897.2003","article-title":"Time-dependent reorganization of the brain components underlying memory retention in trace eyeblink conditioning.","volume":"23","author":"Takehara","year":"2003","journal-title":"J. Neurosci."},{"key":"B98","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1016\/s0006-8993(02)03159-1","article-title":"Time-limited role of the hippocampus in the memory for trace eyeblink conditioning in mice.","volume":"951","author":"Takehara","year":"2002","journal-title":"Brain Res."},{"key":"B99","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/j.neures.2014.02.012","article-title":"Entorhinal cortex and consolidated memory.","volume":"84","author":"Takehara-Nishiuchi","year":"2014","journal-title":"Neurosci. Res."},{"key":"B100","doi-asserted-by":"publisher","first-page":"2398212820925580","DOI":"10.1177\/2398212820925580","article-title":"Prefrontal-hippocampal interaction during the encoding of new memories.","volume":"4","author":"Takehara-Nishiuchi","year":"2020","journal-title":"Brain Neurosci. Adv."},{"key":"B101","doi-asserted-by":"publisher","first-page":"960","DOI":"10.1126\/science.1161299","article-title":"Spontaneous changes of neocortical code for associative memory during consolidation.","volume":"322","author":"Takehara-Nishiuchi","year":"2008","journal-title":"Science"},{"key":"B102","doi-asserted-by":"publisher","first-page":"90","DOI":"10.3389\/fnbeh.2011.00090","article-title":"Increased entorhinal-prefrontal theta synchronization parallels decreased entorhinal-hippocampal theta synchronization during learning and consolidation of associative memory.","volume":"5","author":"Takehara-Nishiuchi","year":"2011","journal-title":"Front. Behav. Neurosci."},{"key":"B103","doi-asserted-by":"publisher","first-page":"1456","DOI":"10.1002\/hipo.22466","article-title":"Cholinergic, but not NMDA, receptors in the lateral entorhinal cortex mediate acquisition in trace eyeblink conditioning.","volume":"25","author":"Tanninen","year":"2015","journal-title":"Hippocampus"},{"key":"B104","doi-asserted-by":"publisher","first-page":"1017","DOI":"10.1126\/science.272.5264.1017","article-title":"Increase in single L-type calcium channels in hippocampal neurons during aging.","volume":"272","author":"Thibault","year":"1996","journal-title":"Science"},{"key":"B105","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1111\/j.1474-9726.2007.00295","article-title":"Expansion of the calcium hypothesis of brain aging and Alzheimer\u2019s disease: minding the store.","volume":"6","author":"Thibault","year":"2007","journal-title":"Aging Cell"},{"key":"B106","doi-asserted-by":"publisher","first-page":"9744","DOI":"10.1523\/jneurosci.21-24-09744.2001","article-title":"Elevated Postsynaptic [Ca2+] and L-Type calcium channel activity in aged hippocampal neurons: relationship to impaired synaptic plasticity.","volume":"21","author":"Thibault","year":"2001","journal-title":"J. Neurosci."},{"key":"B107","doi-asserted-by":"publisher","first-page":"619","DOI":"10.1016\/0197-4580(96)00026-7","article-title":"Trace eyeblink conditioning in rabbits demonstrates heterogeneity of learning ability both between and within age groups.","volume":"17","author":"Thompson","year":"","journal-title":"Neurobiol. Aging"},{"key":"B108","doi-asserted-by":"publisher","first-page":"1836","DOI":"10.1152\/jn.1996.76.3.1836","article-title":"Transient changes in excitability of rabbit CA1 neurons with a time course appropriate to support memory consolidation.","volume":"76","author":"Thompson","year":"","journal-title":"J. Neurophys."},{"key":"B109","doi-asserted-by":"publisher","first-page":"2609","DOI":"10.1523\/JNEUROSCI.5023-04.2005","article-title":"The slow afterhyperpolarization in hippocampal CA1 neurons covaries with spatial learning ability in aged Fisher 344 rats.","volume":"25","author":"Tombaugh","year":"2005","journal-title":"J. Neurosci."},{"key":"B110","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1038\/s41586-018-0459-6","article-title":"Integrating time from experience in the lateral entorhinal cortex.","volume":"561","author":"Tsao","year":"2018","journal-title":"Nature"},{"key":"B111","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1002\/hipo.10037","article-title":"The entorhinal cortex of the mouse: organization of the projection to the hippocampal formation.","volume":"13","author":"van Groen","year":"2003","journal-title":"Hippocampus"},{"key":"B112","doi-asserted-by":"publisher","first-page":"2400","DOI":"10.1016\/j.celrep.2016.05.021","article-title":"Enhancing prefrontal neuron activity enables associative learning of temporally disparate events.","volume":"15","author":"Volle","year":"2016","journal-title":"Cell Rep."},{"key":"B113","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1101\/lm.69804","article-title":"Galantamine facilitates acquisition of hippocampus-dependent trace eyeblink conditioning in aged rabbits.","volume":"11","author":"Weible","year":"2004","journal-title":"Learn. Mem."},{"key":"B114","doi-asserted-by":"publisher","first-page":"318","DOI":"10.1037\/a0023520","article-title":"Exploring prefrontal cortical memory mechanisms with eyeblink conditioning.","volume":"125","author":"Weiss","year":"2011","journal-title":"Behav. Neurosci."},{"key":"B115","doi-asserted-by":"publisher","first-page":"352","DOI":"10.1002\/hipo.22095","article-title":"Lateral entorhinal cortex is critical for novel object-context recognition.","volume":"23","author":"Wilson","year":"","journal-title":"Hippocampus"},{"key":"B116","doi-asserted-by":"publisher","first-page":"1280","DOI":"10.1002\/hipo.22165","article-title":"Lateral entorhinal cortex is necessary for associative but not nonassociative recognition memory.","volume":"23","author":"Wilson","year":"","journal-title":"Hippocampus"},{"key":"B117","doi-asserted-by":"publisher","first-page":"484","DOI":"10.1038\/375484a0","article-title":"Essential role of neocortical acetylcholine in spatial memory.","volume":"375","author":"Winkler","year":"1995","journal-title":"Lett. Nat."},{"key":"B118","doi-asserted-by":"publisher","first-page":"46","DOI":"10.3389\/fnsys.2017.00046","article-title":"Architecture of the entorhinal cortex A review of entorhinal anatomy in rodents with some comparative notes.","volume":"11","author":"Witter","year":"2017","journal-title":"Front. Syst. Neurosci."},{"key":"B119","doi-asserted-by":"publisher","first-page":"2346","DOI":"10.1152\/jn.00977.2003","article-title":"Slow afterhyperpolarization governs the development of NMDA receptor-dependent afterdepolarization in CA1 pyramidal neurons during synaptic stimulation.","volume":"92","author":"Wu","year":"2004","journal-title":"J. Neurophysiol."},{"key":"B120","doi-asserted-by":"publisher","first-page":"10038","DOI":"10.1523\/JNEUROSCI.1042-09.2009","article-title":"TRPC channels mediate a muscarinic receptor-induced afterdepolarization in cerebral cortex.","volume":"29","author":"Yan","year":"2009","journal-title":"J. Neurosci."},{"key":"B121","doi-asserted-by":"publisher","first-page":"8873","DOI":"10.1073\/pnas.1101567108","article-title":"Age-related memory deficits linked to circuit-specific disruptions in the hippocampus.","volume":"108","author":"Yassa","year":"2011","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B122","doi-asserted-by":"publisher","first-page":"722","DOI":"10.1016\/j.neuron.2014.07.017","article-title":"Neurons are recruited to a memory trace based on relative neuronal excitability immediately before training.","volume":"83","author":"Yiu","year":"2014","journal-title":"Neuron"},{"key":"B123","doi-asserted-by":"publisher","first-page":"1116","DOI":"10.1111\/j.1460-9568.2008.06409.x","article-title":"mGluR-dependent persistent firing in entorhinal cortex layer III neurons.","volume":"28","author":"Yoshida","year":"2008","journal-title":"Eur. J. Neurosci."},{"key":"B124","doi-asserted-by":"publisher","first-page":"5183","DOI":"10.1523\/JNEUROSCI.17-13-05183.1997","article-title":"Memory representation within the parahippocampal region.","volume":"17","author":"Young","year":"1997","journal-title":"J. Neurosci."},{"key":"B125","doi-asserted-by":"publisher","first-page":"e19358","DOI":"10.7554\/eLife.19358","article-title":"CREB overexpression in dorsal CA1 ameliorates long-term memory deficits in aged rats.","volume":"6","author":"Yu","year":"2017","journal-title":"Elife"},{"key":"B126","doi-asserted-by":"publisher","first-page":"2999","DOI":"10.1152\/jn.1997.78.6.2999","article-title":"Kinetics of muscarinic reduction of IsAHP in hippocampal neurons: effects of acetylcholinesterase inhibitors.","volume":"78","author":"Zhang","year":"1997","journal-title":"J. Neurophysiol."},{"key":"B127","doi-asserted-by":"publisher","first-page":"386","DOI":"10.1002\/hipo.20755","article-title":"TRPC channels underlie cholinergic plateau potentials and persistent activity in entorhinal cortex.","volume":"21","author":"Zhang","year":"2011","journal-title":"Hippocampus"},{"key":"B128","doi-asserted-by":"publisher","first-page":"603","DOI":"10.1146\/annurev-neuro-","article-title":"Mechanisms of persistent activity in cortical circuits: possible neural substrates for working memory.","volume":"40","author":"Zylberberg","year":"2017","journal-title":"Ann. Rev. Neurosci."}],"container-title":["Frontiers in Aging Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnagi.2022.838513\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,3,11]],"date-time":"2022-03-11T10:34:32Z","timestamp":1646994872000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnagi.2022.838513\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,11]]},"references-count":128,"alternative-id":["10.3389\/fnagi.2022.838513"],"URL":"https:\/\/doi.org\/10.3389\/fnagi.2022.838513","relation":{},"ISSN":["1663-4365"],"issn-type":[{"value":"1663-4365","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,11]]},"article-number":"838513"}}