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Diminished trk A receptor signaling reveals cholinergic‐attentional vulnerability of aging
dc.contributor.authorParikh, Vinayen_US
dc.contributor.authorHowe, William M.en_US
dc.contributor.authorWelchko, Ryan M.en_US
dc.contributor.authorNaughton, Sean X.en_US
dc.contributor.authorD'Amore, Drew E.en_US
dc.contributor.authorHan, Daniel H.en_US
dc.contributor.authorDeo, Monikaen_US
dc.contributor.authorTurner, David L.en_US
dc.contributor.authorSarter, Martinen_US
dc.date.accessioned2013-02-12T19:01:04Z
dc.date.available2014-03-03T15:09:25Zen_US
dc.date.issued2013-01en_US
dc.identifier.citationParikh, Vinay; Howe, William M.; Welchko, Ryan M.; Naughton, Sean X.; D'Amore, Drew E.; Han, Daniel H.; Deo, Monika; Turner, David L.; Sarter, Martin (2013). "Diminished trk A receptor signaling reveals cholinergic‐attentional vulnerability of aging." European Journal of Neuroscience (2): 278-293. <http://hdl.handle.net/2027.42/96365>en_US
dc.identifier.issn0953-816Xen_US
dc.identifier.issn1460-9568en_US
dc.identifier.urihttps://hdl.handle.net/2027.42/96365
dc.description.abstractThe cellular mechanisms underlying the exceptional vulnerability of the basal forebrain ( BF ) cholinergic neurons during pathological aging have remained elusive. Here we employed an adeno‐associated viral vector‐based RNA interference ( AAV ‐ RNA i) strategy to suppress the expression of tropomyosin‐related kinase A (trk A ) receptors by cholinergic neurons in the nucleus basalis of M eynert/substantia innominata ( nMB / SI ) of adult and aged rats. Suppression of trk A receptor expression impaired attentional performance selectively in aged rats. Performance correlated with trk A levels in the nMB / SI . trk A knockdown neither affected nMB / SI cholinergic cell counts nor the decrease in cholinergic cell size observed in aged rats. However, trk A suppression augmented an age‐related decrease in the density of cortical cholinergic processes and attenuated the capacity of cholinergic neurons to release acetylcholine ( AC h). The capacity of cortical synapses to release AC h in vivo was also lower in aged/trk A ‐ AAV ‐infused rats than in aged or young controls, and it correlated with their attentional performance. Furthermore, age‐related increases in cortical pro NGF and p75 receptor levels interacted with the vector‐induced loss of trk A receptors to shift NGF signaling toward p75‐mediated suppression of the cholinergic phenotype, thereby attenuating cholinergic function and impairing attentional performance. These effects model the abnormal trophic regulation of cholinergic neurons and cognitive impairments in patients with early A lzheimer's disease. This rat model is useful for identifying the mechanisms rendering aging cholinergic neurons vulnerable as well as for studying the neuropathological mechanisms that are triggered by disrupted trophic signaling. The cellular mechanisms underlying the exceptional vulnerability of the basal forebrain ( BF ) cholinergic neurons during pathological aging have remained elusive. Here we employed an adeno‐associated viral vector‐based RNA interference ( AAV ‐ RNA i) strategy to suppress the expression of trk A receptors by cholinergic neurons in the nucleus basalis of M eynert/substantia innominata (n MB / SI ) of adult and aged rats. This study provides novel evidence that reduced trkA receptors is not sufficient to trigger cholinergic dysfunction. Rather, aging interacts with disrupted trkA signaling to escalate the vulnerability of BF cholinergic neurons and the manifestation of age‐related attentional impairments.en_US
dc.publisherElsevieren_US
dc.publisherWiley Periodicals, Inc.en_US
dc.subject.otherAcetylcholineen_US
dc.subject.otherRatsen_US
dc.subject.otherRNA Ien_US
dc.subject.otherTrophicen_US
dc.subject.otherCognitionen_US
dc.titleDiminished trk A receptor signaling reveals cholinergic‐attentional vulnerability of agingen_US
dc.typeArticleen_US
dc.rights.robotsIndexNoFollowen_US
dc.subject.hlbsecondlevelNeurosciencesen_US
dc.subject.hlbtoplevelHealth Sciencesen_US
dc.description.peerreviewedPeer Revieweden_US
dc.identifier.pmid23228124en_US
dc.description.bitstreamurlhttp://deepblue.lib.umich.edu/bitstream/2027.42/96365/1/ejn12090-sup-0001-SupportingInformation.pdf
dc.description.bitstreamurlhttp://deepblue.lib.umich.edu/bitstream/2027.42/96365/2/ejn12090.pdf
dc.identifier.doi10.1111/ejn.12090en_US
dc.identifier.sourceEuropean Journal of Neuroscienceen_US
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