Attenuated NMDAR signaling on fast-spiking interneurons in prefrontal cortex contributes to age-related decline of cognitive flexibility
Introduction
Executive functions encompass higher-order cognitive processes that guide goal-directed behavior. Cognitive flexibility, the ability to modify behavioral strategies in accord with shifting contingencies, is an integral aspect of executive function that normally attains its maximal capacity in early adulthood, contemporaneous with the maturation of the prefrontal cortex (PFC; reviewed in Diamond, 2013). Advanced aging is characterized by a decline in cognitive flexibility, which can be assessed across species via “set-shifting” tasks (Barense et al., 2002; Beas et al., 2013; Boone et al., 1993; Floresco et al., 2008; Hernandez et al., 2017; Lacreuse et al., 2018; Moore et al., 2003; Nieves-Martinez et al., 2012; Rhodes, 2004; Ridderinkhof et al., 2002; Tomm et al., 2018; and reviewed in Bizon et al., 2012; McQuail et al., 2018). Attenuated N-methyl-d-aspartate receptor (NMDAR) signaling in aging may be one contributor to age-related cognitive deficits as acutely blocking NMDARs with MK-801, phencyclidine or ketamine reliably impairs set-shifting in young adult rats (Blot et al., 2015; Darrah et al., 2008; Egerton et al., 2005; Jett et al., 2017; Nikiforuk et al., 2010; Stefani et al., 2003; Stefani and Moghaddam, 2005, 2010). Consistent with this view, NMDARs are known to decline in PFC aging across humans and rats (Dickstein et al., 2013; Dyall et al., 2007; Hellström-Lindahl and Court, 2000; Magnusson, 1998; Magnusson et al., 2005, Magnusson et al., 2007; Magnusson and Cotman, 1993; McQuail et al., 2016; Migani et al., 2000; Mitchell and Anderson, 1998; Piggott et al., 1992; Wenk et al., 1991). Critically, activation of PFC NMDARs during cognitively demanding tasks depends on permissive contributions from α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs), which may also diminish with age and are implicated in cognitive flexibility (Jett et al., 2017; Magnusson and Cotman, 1993; McQuail et al., 2016; Stefani et al., 2003; Wang et al., 2013). While these data make a compelling case that age-related changes in glutamatergic NMDARs and AMPARs contribute to cognitive dysfunction, relatively little is known about whether such changes are localized to specific types of neurons.
Non-competitive NMDAR antagonists that produce set-shifting deficits in rodent models are known to suppress activity of GABAergic interneurons in medial PFC (mPFC), resulting in increased, but desynchronized, activity of pyramidal neurons (Homayoun and Moghaddam, 2007; Kargieman et al., 2007; Hervig et al., 2016). In particular, fast-spiking interneurons (FSIs) target and potently inhibit somatic compartments of pyramidal neurons, contributing to feedforward inhibition, gain control, and the generation of gamma oscillations (Bartos et al., 2007, Cardin et al., 2009, Cruikshank et al., 2012, Delevich et al., 2015, Doischer et al., 2008, Ferguson and Gao, 2018, Isaacson and Scanziani, 2011, Mann and Paulsen, 2007, Sohal et al., 2009). Consistent with a vital role for inhibitory regulation of PFC-dependent cognitive flexibility, blocking GABAARs with their selective antagonist bicuculline impairs set-shifting whereas the GABABR agonist baclofen improves set-shifting in young adult rats (Enomoto et al., 2011; Beas et al., 2016). This relationship is conserved in the aging brain as intra-mPFC infusion of baclofen effectively reverses impaired set-shifting in aged rats (Beas et al., 2017). These cellular and behavioral pharmacology data are suggestive that diminished NMDAR signaling on aging FSIs may be particularly consequential to impaired cognitive flexibility. The goals of the present study were two-fold. Our first goal was to determine the relationship between individual differences in cognitive flexibility of aging rats and PFC protein levels of ionotropic glutamate receptor (iGluR) subunits. The second goal was to determine whether the relevant age-associated changes were specific to either PFC pyramidal neurons or FSIs.
Section snippets
Subjects
Young adult (4 months, n = 23) and aged (22 months, n = 27) male Fischer 344 (F344) rats were obtained from the National Institute on Aging's Aging Rodent Colony maintained by Charles River Laboratories. All animals were housed in the Association for Assessment and Accreditation of Laboratory Animal Care International-accredited vivarium facility in the McKnight Brain Institute at the University of Florida. The facility was maintained at a consistent temperature of 25 °C with a 12-h light/dark
Age-related deficits in cognitive flexibility associated with lower level of NR1 in medial prefrontal cortex
Young adult and aged rats did not differ in number of trials to acquire the initial discrimination (see Methods) compared to young adults (t (21) = −0.392, p = 0.699; Fig. 1B). In contrast, aged rats were impaired relative to young adults in their ability to modify learned behavior as revealed by the greater number of trials needed to reliably shift their response strategy to conform to a new rule (t (21) = -3.075, p = 0.006; Fig. 1C). In this same cohort of rats, mPFC expression of the
Discussion
Cognitive flexibility, or the ability to update behavioral strategies in relation to shifting contingencies in the environment, complements other aspects of executive function, such as attentional control, behavioral inhibition and working memory, to coordinate goal-directed behaviors, which critically depend on the PFC. The present study selectively links age-related deficits in cognitive flexibility to loss of NMDARs from the PFC and, further, reveals an age-related increase in AMPA/NMDA
Conclusions
These new, descriptive data strongly suggest that diminished NMDAR signaling specific to FSIs contributes to later-life decline of PFC-dependent cognition. The apparent specificity of this deficit may explain why non-selective NMDAR potentiators produce modest-to-mixed effects on cognition in aging (Baxter et al., 1994; Billard and Rouaud, 2007; Burgdorf et al., 2011; McQuail et al., 2016; Panizzutti et al., 2014). Consequently, new studies of NMDAR signaling on FSIs may inform the development
CRediT authorship contribution statement
Joseph A. McQuail: Conceptualization, Investigation, Visualization, Formal analysis, Writing – original draft, Writing – review & editing. B. Sofia Beas: Investigation, Visualization, Writing – review & editing. Kyle B. Kelly: Investigation, Visualization, Writing – review & editing. Caesar M. Hernandez: Investigation, Writing – review & editing. Jennifer L. Bizon: Conceptualization, Funding acquisition, Supervision, Writing – review & editing. Charles J. Frazier: Conceptualization,
Declaration of competing interest
The authors declare no competing financial interests.
Acknowledgements
We thank Miranda Schwabe, Kailey Simpson, Shannon Wall, and Lauren Vetere for assistance with behavioral testing, and Brandon Hellbusch for assistance with Western blotting. This work was supported by NIH grants F32AG051371 (JAM), K01AG061263 (JAM), P20GM109091 (JAM), P20GM103641 (JAM), NSF Graduate Research Fellowship Program DGE-0802270 (BSB), NIH/NICHD 2T32HD071866-06 (CMH), a McKnight Predoctoral Fellowship and the Pat Tillman Foundation (CMH), R01AG029421 (JLB), and the McKnight Brain
References (92)
- et al.
D-cycloserine, a novel cognitive enhancer, improves spatial memory in aged rats
Neurobiol. Aging
(1994) - et al.
Distinct manifestations of executive dysfunction in aged rats
Neurobiol. Aging
(2013) - et al.
Prefrontal cortical GABAergic signaling and impaired behavioral flexibility in aged F344 rats
Neuroscience
(2017) - et al.
Spatial reference and working memory across the lifespan of male Fischer 344 rats
Neurobiol. Aging
(2009) - et al.
The N-methyl-d-aspartate receptor modulator GLYX-13 enhances learning and memory, in young adult and learning impaired aging rats
Neurobiol. Aging
(2011) - et al.
Age-related changes in tonic activation of presynaptic versus extrasynaptic γ-amniobutyric acid type B receptors in rat medial prefrontal cortex
Neurobiol. Aging
(2016) - et al.
Dendritic spine changes associated with normal aging
Neuroscience
(2013) - et al.
Dietary enrichment with omega-3 polyunsaturated fatty acids reverses age-related decreases in the GluR2 and NR2B glutamate receptor subunits in rat forebrain
Neurobiol. Aging
(2007) - et al.
Reducing prefrontal gamma-aminobutyric acid activity induces cognitive, behavioral, and dopaminergic abnormalities that resemble schizophrenia
Biol. Psychiatry, Schizophrenia: From Circuit Dysfunction to Treatment?
(2011) - et al.
Inactivation of the medial prefrontal cortex of the rat impairs strategy set-shifting, but not reversal learning, using a novel, automated procedure
Behav. Brain Res.
(2008)
Nicotinic acetylcholine receptors during prenatal development and brain pathology in human aging
Behav. Brain Res.
Decline of prefrontal cortical-mediated executive functions but attenuated delay discounting in aged Fischer 344 × brown Norway hybrid rats
Neurobiol. Aging
Acute phencyclidine administration induces c-Fos-immunoreactivity in interneurons in cortical and subcortical regions
Neuroscience
Age-related changes in GluR2 and NMDAR1 glutamate receptor subunit protein immunoreactivity in corticocortically projecting neurons in macaque and patas monkeys
Brain Res.
How inhibition shapes cortical activity
Neuron
Deficits in cognitive flexibility induced by chronic unpredictable stress are associated with impaired glutamate neurotransmission in the rat medial prefrontal cortex
Neuroscience
Age-related decline in cognitive flexibility in female chimpanzees
Neurobiol. Aging
Age-related increase of sIAHP in prefrontal pyramidal cells of monkeys: relationship to cognition
Neurobiol. Aging
Normal aging results in decreased synaptic excitation and increased synaptic inhibition of layer 2/3 pyramidal cells in the monkey prefrontal cortex
Neuroscience
Aging of glutamate receptors: correlations between binding and spatial memory performance in mice
Mech. Ageing Dev.
The effects of aging on different C-terminal splice forms of the zeta1(NR1) subunit of the N-methyl-d-aspartate receptor in mice
Brain Res. Mol. Brain Res.
Age-related changes in excitatory amino acid receptors in two mouse strains
Neurobiol. Aging
Role of GABAergic inhibition in hippocampal network oscillations
Trends Neurosci.
Molecular aspects of age-related cognitive decline: the role of GABA signaling
Trends Mol. Med.
Chapter 17 - rat models of cognitive aging
Spatial reference memory in normal aging Fischer 344 × Brown Norway F1 hybrid rats
Neurobiol. Aging
Excitatory amino acid receptors in the prefrontal cortex of aging mice
Neurobiol. Aging
Age-related changes in [3H]MK-801 binding in the Fischer 344 rat brain
Neurobiol. Aging
Impairment in abstraction and set shifting in aged rhesus monkeys
Neurobiol. Aging
Muscarinic receptor/G-protein coupling is reduced in the dorsomedial striatum of cognitively impaired aged rats
Behav. Brain Res.
Mazindol attenuates ketamine-induced cognitive deficit in the attentional set shifting task in rats
Eur. Neuropsychopharmacol
Comparison of set-shifting ability in patients with chronic schizophrenia and frontal lobe damage
Schizophr. Res.
Synapses are lost during aging in the primate prefrontal cortex
Neuroscience
[3H]MK-801 binding to the NMDA receptor complex, and its modulation in human frontal cortex during development and aging
Brain Res.
Perseverative behavior and adaptive control in older adults: performance monitoring, rule induction, and set shifting
Brain Cognit.
Activation of type 5 metabotropic glutamate receptors attenuates deficits in cognitive flexibility induced by NMDA receptor blockade
Eur. J. Pharmacol.
Effects of aging on executive functioning and mesocorticolimbic dopamine markers in male Fischer 344 × brown Norway rats
Neurobiol. Aging
NMDA receptors subserve persistent neuronal firing during working memory in dorsolateral prefrontal cortex
Neuron
Loss of NMDA, but not GABA-A, binding in the brains of aged rats and monkeys
Neurobiol. Aging
Regional variability in age-related loss of neurons from the primary visual cortex and medial prefrontal cortex of male and female rats
Brain Res.
Exploring age-related decline on the Wisconsin card sorting test
Clin. Neuropsychol.
Prefrontal cortical GABAergic dysfunction contributes to age-related working memory impairment
J. Neurosci.
Aged rats are impaired on an attentional set-shifting task sensitive to medial frontal cortex damage in young rats
Learn. Mem. Cold Spring Harb. N
Multistability of cognitive maps in the hippocampus of old rats
Nature
Synaptic mechanisms of synchronized gamma oscillations in inhibitory interneuron networks
Nat. Rev. Neurosci.
Effects of acute administration of the GABA(B) receptor agonist baclofen on behavioral flexibility in rats
Psychopharmacology
Cited by (12)
D-cycloserine rescues scopolamine-induced deficits in cognitive flexibility in rats measured by the attentional set-shifting task
2022, Behavioural Brain ResearchCitation Excerpt :However, we found robust scopolamine effects on all reversal phases and the EDS phase, as already reported by Chen and colleagues. The working hypothesis of our study that DCS may be able to rescue scopolamine-induced deficits in cognitive flexibility was based on studies showing that (a) the NMDA receptor is crucial for cognitive flexibility [33–35,38], (b) the partial NMDA receptor agonist DCS is able to improve cognitive flexibility [39], and (c) DCS is able to rescue scopolamine-induced cognitive deficits measured by place and object recognition [7], odor discrimination learning [40], and spatial learning [41]. Of note, the latter studies investigated DCS effects on scopolamine-induced deficits in basal learning processes.
GABA<inf>B</inf> receptors in prelimbic cortex and basolateral amygdala differentially influence intertemporal decision making and decline with age
2022, NeuropharmacologyCitation Excerpt :Therefore, it will be important for future work to determine whether aging merely leads to a diminished contribution of mPFC GABABRs to time-based decision making and to what degree other mechanisms within the aged mPFC guide decision-making. Indeed, our lab and others have documented age-related loss of NMDARs from mPFC (Dyall et al., 2007; McQuail et al., 2016b, 2021; Mitchell and Anderson, 1998; Wenk et al., 1991) that normally contribute to intertemporal choice in young adult rats (Isherwood et al., 2015; Yates et al., 2015, 2017, 2018a, 2018b). The present findings and existing data suggest that further study of the age-related imbalance of excitatory-inhibitory signaling is needed to fully understand how mPFC aging contributes to changes in choice behavior across the lifespan.
Aging or chronic stress impairs working memory and modulates GABA and glutamate gene expression in prelimbic cortex
2023, Frontiers in Aging Neuroscience