Abstract
The prefrontal cortex (PFC) governs top–down control of attention and is known to be vulnerable in aging. Cortical reorganization with increased PFC recruitment is suggested to account for functional compensation. Here, we hypothesized that reduced PFC output would exert differential effects on attentional capacities in young and aged rats, with the latter exhibiting a more robust decline in performance. A chemogenetic approach involving designer receptors exclusively activated by designer drugs was utilized to determine the impact of silencing PFC projection neurons in rats performing an operant attention task. Visual distractors were presented in all behavioral testing sessions to tax attentional resources. Under control conditions, aged rats exhibited impairments in discriminating signals with the shortest duration from non-signal events. Surprisingly, chemogenetic inhibition of PFC output neurons did not worsen performance amongst aged animals. Conversely, significant impairments in attentional capacities were observed in young subjects following such manipulation. Given the involvement of PFC-projecting basal forebrain cholinergic neurons in top–down regulation of attention, amperometric recordings were conducted to measure alterations in prefrontal cholinergic transmission in a separate cohort of young and aged rats. While PFC silencing resulted in a robust attenuation of tonic cholinergic signaling across age groups, the capacity to generate phasic cholinergic transients was impaired only amongst young animals. Collectively, our findings suggest a reduced efficiency of PFC-mediated top–down control of attention and cholinergic system in aging, and that activity of PFC output neurons does not reflect compensation in aged rats, at least in the attention domain.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data availability
All data generated and analyzed during this study are included in this published article.
References
Ansado J, Monchi O, Ennabil N, Faure S, Joanette Y (2012) Load-dependent posterior-anterior shift in aging in complex visual selective attention situations. Brain Res 1454:14–22. https://doi.org/10.1016/j.brainres.2012.02.061
Bloem B, Schoppink L, Rotaru DC, Faiz A, Hendriks P, Mansvelder H, Wouterlood F (2014) Topographic mapping between basal forebrain cholinergic neurons and the medial prefrontal cortex in mice. J Neurosci 34:16234–16246. https://doi.org/10.1523/JNEUROSCI.3011-14.2014
Broussard JI, Karelina K, Sarter M, Givens B (2009) Cholinergic optimization of cue-evoked parietal activity during challenged attentional performance. Eur J Neurosci 29(8):1711–1722. https://doi.org/10.1111/j.1460-9568.2009.06713.x
Burk JA, Herzog CD, Porter MC, Sarter M (2002) Interactions between aging and cortical cholinergic deafferentation on attention. Neurobiol Aging 23(3):467–477. https://doi.org/10.1016/s0197-4580(01)00315-3
Cabeza R, Daselaar SM, Dolcos F, Prince SE, Budde M, Nyberg L (2004) Task-independent and task-specific age effects on brain activity during working memory, visual attention and episodic retrieval. Cereb Cortex 14(4):364–375. https://doi.org/10.1093/cercor/bhg133
Cabeza R, Dennis NA (2012) Frontal lobes and aging. In: Knight DTSRT (ed) Principles of frontal lobe function, 2nd edn. Oxford University Press, New York, pp 628–652
Chao LL, Knight RT (1995) Human prefrontal lesions increase distractibility to irrelevant sensory inputs. NeuroReport 6(12):1605–1610. https://doi.org/10.1097/00001756-199508000-00005
Chudasama Y, Muir JL (2001) Visual attention in the rat: a role for the prelimbic cortex and thalamic nuclei? Behav Neurosci 115(2):417–428. https://doi.org/10.1037/0735-7044.115.2.417
Dalley JW, Cardinal RN, Robbins TW (2004a) Prefrontal executive and cognitive functions in rodents: neural and neurochemical substrates. Neurosci Biobehav Rev 28(7):771–784. https://doi.org/10.1016/j.neubiorev.2004.09.006
Dalley JW, Theobald DE, Bouger P, Chudasama Y, Cardinal RN, Robbins TW (2004b) Cortical cholinergic function and deficits in visual attentional performance in rats following 192 IgG-saporin-induced lesions of the medial prefrontal cortex. Cereb Cortex 14(8):922–932. https://doi.org/10.1093/cercor/bhh052
Davis SW, Dennis NA, Daselaar SM, Fleck MS, Cabeza R (2008) Que PASA? The posterior-anterior shift in aging. Cereb Cortex 18(5):1201–1209. https://doi.org/10.1093/cercor/bhm155
Demeter E, Sarter M, Lustig C (2008) Rats and humans paying attention: cross-species task development for translational research. Neuropsych 22(6):787–799. https://doi.org/10.1037/a0013712
Dennis NA, Cabeza R (2011) Age-related dedifferentiation of learning systems: an fMRI study of implicit and explicit learning. Neurobiol Aging 32(12):2318.e2317-2330. https://doi.org/10.1016/j.neurobiolaging.2010.04.004
Everitt BJ, Robbins TW (1997) Central cholinergic systems and cognition. Annu Rev Psychol 48:649–684. https://doi.org/10.1146/annurev.psych.48.1.649
Fadel J (2011) Regulation of cortical acetylcholine release: insights from in vivo microdialysis studies. Behav Brain Res 221(2):527–536. https://doi.org/10.1016/j.bbr.2010.02.022
Fadel J, Sarter M, Bruno JP (2001) Basal forebrain glutamatergic modulation of cortical acetylcholine release. Synapse 39(3):201–212. https://doi.org/10.1002/1098-2396(20010301)39:3%3c201::Aid-syn1001%3e3.0.Co;2-3
Fortenbaugh FC, DeGutis J, Germine L, Wilmer JB, Grosso M, Russo K, Esterman M (2015) Sustained attention across the life span in a sample of 10,000: dissociating ability and strategy. Psychol Sci 26(9):1497–1510. https://doi.org/10.1177/0956797615594896
Gallagher M, Rapp PR (1997) The use of animal models to study the effects of aging on cognition. Annu Rev Psychol 48:339–370. https://doi.org/10.1146/annurev.psych.48.1.339
Gazzaley A, Rissman J, Cooney J, Rutman A, Seibert T, Clapp W, D’Esposito M (2007) Functional interactions between prefrontal and visual association cortex contribute to top–down modulation of visual processing. Cereb Cortex 17(0 1):i125-135. https://doi.org/10.1093/cercor/bhm113 (Suppl 1)
Ge F, Wang N, Cui C, Li Y, Liu Y, Ma Y, Sun X (2017) Glutamatergic projections from the entorhinal cortex to dorsal dentate gyrus mediate context-induced reinstatement of heroin seeking. Neuropsychopharmacology 42(9):1860–1870. https://doi.org/10.1038/npp.2017.14
Gielow MR, Zaborszky L (2017) The input–output relationship of the cholinergic basal forebrain. Cell Rep 18(7):1817–1830. https://doi.org/10.1016/j.celrep.2017.01.060
Glasper ER, Gould E (2013) Sexual experience restores age-related decline in adult neurogenesis and hippocampal function. Hippocampus 23(4):303–312. https://doi.org/10.1002/hipo.22090
Grady CL, Maisog JM, Horwitz B, Ungerleider LG, Mentis MJ, Salerno JA, Haxby JV (1994) Age-related changes in cortical blood flow activation during visual processing of faces and location. J Neurosci 14(3):1450. https://doi.org/10.1523/JNEUROSCI.14-03-01450.1994
Gritton HJ, Howe WM, Mallory CS, Hetrick VL, Berke JD, Sarter M (2016) Cortical cholinergic signaling controls the detection of cues. Proc Natl Acad Sci USA 113(8):E1089. https://doi.org/10.1073/pnas.1516134113
Gu L, Chen J, Gao L, Shu H, Wang Z, Liu D, Zhang Z (2018) Cognitive reserve modulates attention processes in healthy elderly and amnestic mild cognitive impairment: an event-related potential study. Clin Neurophysiol 129(1):198–207. https://doi.org/10.1016/j.clinph.2017.10.030
Hasselmo ME, Sarter M (2011) Modes and models of forebrain cholinergic neuromodulation of cognition. Neuropsychopharmacology 36(1):52–73. https://doi.org/10.1038/npp.2010.104
Howe WM, Ji J, Parikh V, Williams S, Mocaer E, Trocme-Thibierge C, Sarter M (2010) Enhancement of attentional performance by selective stimulation of alpha4beta2(*) nAChRs: underlying cholinergic mechanisms. Neuropsychopharmacology 35(6):1391–1401. https://doi.org/10.1038/npp.2010.9
Howe WM, Berry A, Francois J, Gilmour G, Carp J, Tricklebank M, Sarter M (2013) Prefrontal cholinergic mechanisms instigating shifts from monitoring for cues to cue-guided performance: converging electrochemical and fMRI evidence from rats and humans. J Neurosci 33(20):8742. https://doi.org/10.1523/JNEUROSCI.5809-12.2013
Ingram DK, Spangler EL, Vincent GP (1983) Behavioral comparison of aged virgin and retired breeder mice. Exp Aging Res 9(2):111–113. https://doi.org/10.1080/03610738308258436
Jendryka M, Palchaudhuri M, Ursu D, van der Veen B, Liss B, Kätzel D, Pekcec A (2019) Pharmacokinetic and pharmacodynamic actions of clozapine-N-oxide, clozapine, and compound 21 in DREADD-based chemogenetics in mice. Sci Rep 9(1):4522. https://doi.org/10.1038/s41598-019-41088-2
Kahn JB, Ward RD, Kahn LW, Rudy NM, Kandel ER, Balsam PD, Simpson EH (2012) Medial prefrontal lesions in mice impair sustained attention but spare maintenance of information in working memory. Learn Mem 19(11):513–517. https://doi.org/10.1101/lm.026302.112
Katsuki F, Constantinidis C (2013) Bottom–up and top–down attention: different processes and overlapping neural systems. Neuroscientist 20(5):509–521. https://doi.org/10.1177/1073858413514136
Khateb A, Fort P, Serafin M, Jones BE, Mühlethaler M (1995) Rhythmical bursts induced by NMDA in Guinea-pig cholinergic nucleus basalis neurones in vitro. J Physiol 487:623–638. https://doi.org/10.1113/jphysiol.1995.sp020905 (Pt 3)
Kim J, Wasserman EA, Castro L, Freeman JH (2016) Anterior cingulate cortex inactivation impairs rodent visual selective attention and prospective memory. Behav Neurosci 130(1):75–90. https://doi.org/10.1037/bne0000117
Koen JD, Rugg MD (2019) Neural dedifferentiation in the aging brain. Trends Cogn Sci 23(7):547–559. https://doi.org/10.1016/j.tics.2019.04.012
Laszlovszky T, Schlingloff D, Hegedüs P, Freund TF, Gulyás A, Kepecs A, Hangya B (2020) Distinct synchronization, cortical coupling and behavioral function of two basal forebrain cholinergic neuron types. Nat Neurosci 23(8):992–1003. https://doi.org/10.1038/s41593-020-0648-0
Lee TG, D’Esposito M (2012) The dynamic nature of top–down signals originating from prefrontal cortex: a combined fMRI-TMS study. J Neurosci 32(44):15458–15466. https://doi.org/10.1523/JNEUROSCI.0627-12.2012
Lichtenberg NT, Pennington ZT, Holley SM, Greenfield VY, Cepeda C, Levine MS, Wassum KM (2017) Basolateral amygdala to orbitofrontal cortex projections enable cue-triggered reward expectations. J Neurosci 37(35):8374. https://doi.org/10.1523/JNEUROSCI.0486-17.2017
Luchicchi A, Mnie-Filali O, Terra H, Bruinsma B, de Kloet SF, Obermayer J, Mansvelder HD (2016) Sustained attentional states require distinct temporal involvement of the dorsal and ventral medial prefrontal cortex. Front Neural Circuits 10:70. https://doi.org/10.3389/fncir.2016.00070
Madden DJ (2007) Aging and visual attention. Curr Directions Psychol Sci 16(2):70–74. https://doi.org/10.1111/j.1467-8721.2007.00478.x
Maddux JM, Kerfoot EC, Chatterjee S, Holland PC (2007) Dissociation of attention in learning and action: effects of lesions of the amygdala central nucleus, medial prefrontal cortex, and posterior parietal cortex. Behav Neurosci 121(1):63–79. https://doi.org/10.1037/0735-7044.121.1.63
Mahler SV, Aston-Jones G (2018) CNO evil? Considerations for the use of DREADDs in behavioral neuroscience. Neuropsychopharmacology 43(5):934–936. https://doi.org/10.1038/npp.2017.299
Mahler SV, Vazey EM, Beckley JT, Keistler CR, McGlinchey EM, Kaufling J, Aston-Jones G (2014) Designer receptors show role for ventral pallidum input to ventral tegmental area in cocaine seeking. Nat Neurosci 17(4):577–585. https://doi.org/10.1038/nn.3664
McDonough IM, Wood MM, Miller WS Jr (2019) A review on the trajectory of attentional mechanisms in aging and the Alzheimer’s disease continuum through the attention network test. Yale J Biol Med 92(1):37–51. https://doi.org/10.1186/s13195-017-0262-x
McGaughy J, Sarter M (1995) Behavioral vigilance in rats: task validation and effects of age, amphetamine, and benzodiazepine receptor ligands. Psychopharmacology 117(3):340–357. https://doi.org/10.1007/bf02246109
McMurtray A, Clark DG, Christine D, Mendez MF (2006) Early-onset dementia: frequency and causes compared to late-onset dementia. Dement Geriatr Cogn Disord 21(2):59. https://doi.org/10.1159/000089546
Mesulam MM (1981) A cortical network for directed attention and unilateral neglect. Ann Neurol 10(4):309–325. https://doi.org/10.1002/ana.410100402
Morcom AM, Henson RNA (2018) Increased prefrontal activity with aging reflects nonspecific neural responses rather than compensation. J Neurosci 38(33):7303. https://doi.org/10.1523/JNEUROSCI.1701-17.2018
Nelson CL, Sarter M, Bruno JP (2005) Prefrontal cortical modulation of acetylcholine release in posterior parietal cortex. Neuroscience 132(2):347–359. https://doi.org/10.1016/j.neuroscience.2004.12.007
Newman LA, McGaughy J (2008) Cholinergic deafferentation of prefrontal cortex increases sensitivity to cross-modal distractors during a sustained attention task. J Neurosci 28(10):2642. https://doi.org/10.1523/JNEUROSCI.5112-07.2008
Newman LA, McGaughy J (2011) Attentional effects of lesions to the anterior cingulate cortex: how prior reinforcement influences distractibility. Behav Neurosci 125(3):360–371. https://doi.org/10.1037/a0023250
Nuechterlein KH, Luck SJ, Lustig C, Sarter M (2009) CNTRICS final task selection: control of attention. Schizophr Bull 35(1):182–196. https://doi.org/10.1093/schbul/sbn158
Paneri S, Gregoriou GG (2017) Top–down control of visual attention by the prefrontal cortex functional specialization and long-range interactions. Front Neurosci 11:545. https://doi.org/10.3389/fnins.2017.00545
Parikh V, Sarter M (2008) Cholinergic mediation of attention. Ann NY Acad Sci 1129:225–235. https://doi.org/10.1196/annals.1417.021
Parikh V, Kozak R, Martinez V, Sarter M (2007) Prefrontal acetylcholine release controls cue detection on multiple timescales. Neuron 56(1):141–154. https://doi.org/10.1016/j.neuron.2007.08.025
Parikh V, Ji J, Decker MW, Sarter M (2010) Prefrontal beta2 subunit-containing and alpha7 nicotinic acetylcholine receptors differentially control glutamatergic and cholinergic signaling. J Neurosci 30(9):3518–3530. https://doi.org/10.1523/JNEUROSCI.5712-09.2010
Parikh V, Howe WM, Welchko RM, Naughton SX, D’Amore DE, Han DH, Sarter M (2013) Diminished trkA receptor signaling reveals cholinergic-attentional vulnerability of aging. Eur J Neurosci 37(2):278–293. https://doi.org/10.1111/ejn.12090
Parikh V, Bernard CS, Naughton SX, Yegla B (2014) Interactions between Abeta oligomers and presynaptic cholinergic signaling: age-dependent effects on attentional capacities. Behav Brain Res 274:30–42. https://doi.org/10.1016/j.bbr.2014.07.046
Passetti F, Chudasama Y, Robbins TW (2002) The frontal cortex of the rat and visual attentional performance: dissociable functions of distinct medial prefrontal subregions. Cereb Cortex 12(12):1254–1268. https://doi.org/10.1093/cercor/12.12.1254
Perry RJ, Hodges JR (1999) Attention and executive deficits in Alzheimer’s disease—a critical review. Brain 122:383–404. https://doi.org/10.1093/brain/122.3.383
Quigley C, Müller MM (2014) Feature-selective attention in healthy old age: a selective decline in selective attention? J Neurosci 34(7):2471–2476. https://doi.org/10.1523/JNEUROSCI.2718-13.2014
Reuter-Lorenz P, Cappell K (2008) Neurocognitive aging and the compensation hypothesis. Curr Directions Psychol Sci 17(3):177–182. https://doi.org/10.1111/j.1467-8721.2008.00570.x
Reuter-Lorenz P, Lustig C (2005) Brain aging: reorganizing discoveries about the aging mind. Curr Opin Neurobiol 15(2):245–251. https://doi.org/10.1016/j.conb.2005.03.016
Roldan-Tapia L, Garcia J, Canovas R, Leon I (2012) Cognitive reserve, age, and their relation to attentional and executive functions. Appl Neuropsychol Adult 19(1):2–8. https://doi.org/10.1080/09084282.2011.595458
Rossi AF, Pessoa L, Desimone R, Ungerleider LG (2009) The prefrontal cortex and the executive control of attention. Exp Brain Res 192(3):489–497. https://doi.org/10.1007/s00221-008-1642-z
Rypma B, Eldreth DA, Rebbechi D (2007) Age-related differences in activation-performance relations in delayed-response tasks: a multiple component analysis. Cortex 43(1):65–76. https://doi.org/10.1016/S0010-9452(08)70446-5
Samson RD, Barnes CA (2013) Impact of aging brain circuits on cognition. Eur J Neurosci 37(12):1903–1915. https://doi.org/10.1111/ejn.12183
Sarter M, Parikh V (2005) Choline transporters, cholinergic transmission and cognition. Nat Rev Neurosci 6(1):48–56. https://doi.org/10.1038/nrn1588
Sarter M, Bruno J, Givens B (2003) Attentional functions of cortical cholinergic inputs: what does it mean for learning and memory? Neurobiol Learn Mem 80(3):245–256. https://doi.org/10.1016/S1074-7427(03)00070-4
Sarter M, Hasselmo ME, Bruno JP, Givens B (2005) Unraveling the attentional functions of cortical cholinergic inputs: interactions between signal-driven and cognitive modulation of signal detection. Brain Res Rev 48(1):98–111. https://doi.org/10.1016/j.brainresrev.2004.08.006
Sarter M, Gehring WJ, Kozak R (2006) More attention must be paid: the neurobiology of attentional effort. Brain Res Rev 51(2):145–160. https://doi.org/10.1016/j.brainresrev.2005.11.002
Smith KS, Bucci DJ, Luikart BW, Mahler SV (2016) DREADDS: use and application in behavioral neuroscience. Behav Neurosci 130(2):137–155. https://doi.org/10.1037/bne0000135
St Peters M, Demeter E, Lustig C, Bruno JP, Sarter M (2011) Enhanced control of attention by stimulating mesolimbic-corticopetal cholinergic circuitry. J Neurosci 31(26):9760–9771. https://doi.org/10.1523/JNEUROSCI.1902-11.2011
Stern Y (2012) Cognitive reserve in ageing and Alzheimer’s disease. Lancet Neurol 11(11):1006–1012. https://doi.org/10.1016/S1474-4422(12)70191-6
Stevens WD, Hasher L, Chiew KS, Grady CL (2008) A neural mechanism underlying memory failure in older adults. J Neurosci 28(48):12820–12824. https://doi.org/10.1523/JNEUROSCI.2622-08.2008
Suzuki M, Gottlieb J (2013) Distinct neural mechanisms of distractor suppression in the frontal and parietal lobe. Nat Neurosci 16(1):98–104. https://doi.org/10.1038/nn.3282
Unal CT, Golowasch JP, Zaborszky L (2012) Adult mouse basal forebrain harbors two distinct cholinergic populations defined by their electrophysiology. Front Behav Neurosci 6:21. https://doi.org/10.3389/fnbeh.2012.00021
Vazey EM, Aston-Jones G (2014) Designer receptor manipulations reveal a role of the locus coeruleus noradrenergic system in isoflurane general anesthesia. Proc Natl Acad Sci USA 111(10):3859–3864. https://doi.org/10.1073/pnas.1310025111
Verhaeghen P, Cerella J (2002) Aging, executive control, and attention: a review of meta-analyses. Neurosci Biobehav Rev 26(7):849–857. https://doi.org/10.1016/s0149-7634(02)00071-4
Wang W, Rein B, Zhang F, Tan T, Zhong P, Qin L, Yan Z (2018) Chemogenetic activation of prefrontal cortex rescues synaptic and behavioral deficits in a mouse model of 16p11.2 deletion syndrome. J Neurosci 38(26):5939–5948. https://doi.org/10.1523/JNEUROSCI.0149-18.2018
Yegla B, Parikh V (2017) Developmental suppression of forebrain trkA receptors and attentional capacities in aging rats: a longitudinal study. Behav Brain Res 335:111–121. https://doi.org/10.1016/j.bbr.2017.08.017
Yegla B, Joshi S, Strupp J, Parikh V (2021) Dynamic interplay of frontoparietal cholinergic innervation and cortical reorganization in the regulation of attentional capacities in aging. Neurobiol Aging. https://doi.org/10.1016/j.neurobiolaging.2021.04.027
Zaborszky L, Gaykema RP, Swanson DJ, Cullinan WE (1997) Cortical input to the basal forebrain. Neuroscience 79(4):1051–1078. https://doi.org/10.1016/S0306-4522(97)00049-3
Zaborszky L, Duque A, Gielow M, Gombkoto P, Nadasdy Z, Somogyi J (2015) Organization of the basal forebrain cholinergic projection system: specific or diffuse? In: Paxinos G (ed) The rat nervous system, 4th edn. Academic Press, San Diego, pp 491–507
Zanto TP, Rubens MT, Thangavel A, Gazzaley A (2011) Causal role of the prefrontal cortex in top–down modulation of visual processing and working memory. Nat Neurosci 14(5):656–661. https://doi.org/10.1038/nn.2773
Zarahn E, Rakitin B, Abela D, Flynn J, Stern Y (2007) Age-related changes in brain activation during a delayed item recognition task. Neurobiol Aging 28(5):784–798. https://doi.org/10.1016/j.neurobiolaging.2006.03.002
Acknowledgements
The authors thank Munir Gunes Kutlu and Brittney Yegla for assistance with DREADD validation studies, and Alyssa Kniffin and Miranda Targum for help with some of the behavioral data collection and immunohistochemistry. The authors also gratefully acknowledge the support from Dr. Anna Moore (Department of Biology, Temple University) with Confocal Microscopy.
Funding
This research was supported by the National Institute of Health (grant number AG046580).
Author information
Authors and Affiliations
Contributions
VP conceived the original idea and designed research. MD and SJ conducted behavioral and amperometric recording experiments and analyzed all data. JS conducted immunohistochemical analysis. VP and MD prepared the manuscript.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare no competing interests.
Ethical approval
All experiments were conducted in accordance with National Institute of Health guidelines and were approved by the Institutional Animal Care and Use Committee, as well as the Institutional Biosafety Committee at Temple University.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Duggan, M.R., Joshi, S., Strupp, J. et al. Chemogenetic inhibition of prefrontal projection neurons constrains top–down control of attention in young but not aged rats. Brain Struct Funct 226, 2357–2373 (2021). https://doi.org/10.1007/s00429-021-02336-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00429-021-02336-2