Expectations of longevity have increased two-fold in the last century and it is estimated that upwards of 25% of people over age 65 exhibit some form of cognitive deficit. The term mild cognitive impairment (MCI) has been adopted to describe cognitive dysfunction that precedes or occurs in the absence of profound memory loss associated with devastating age-related conditions such as Alzheimer's disease (AD), but that can nevertheless severely compromise one's quality of life. Importantly, however, such cognitive decline is not an inevitable consequence of the aging process, as many people maintain mnemonic function on par with young adults well into advanced age. Among aged human and rodent populations, measures of basal forebrain cholinergic projection neuron integrity correlate with cognitive impairment, particularly in explicit/spatial memory. However, co-distributed GABAergic neurons, that comprise at least half of the projection from basal forebrain to cortical targets and that are implicated in the same mnemonic processes as cholinergic neurons, remain largely unstudied within the context of aging. Moreover, the mechanisms and timing of basal forebrain neuronal dysfunction as it relates to emergence of cognitive deficits across the lifespan is still unclear. In part, absence of such data has been due to a limited ability to detect cognitive deficits in rodents at ages preceding the latest stages of their lifespan. However, we have developed a novel rodent model of cognitive aging that reliably detects cognitive decline in some middle-aged and aged Fischer 344 rats while other rats at both ages perform as well as young cohorts. We hypothesize that combined deficiencies in cholinergic and GABAergic basal forebrain projection systems contribute to the emergence of age-related cognitive deficits. To test this hypothesis, we will evaluate the following measures in behaviorally-characterized young, middle-aged and aged rats: (i) integrity of cholinergic and GABAergic neuronal number, morphology, and phenotypic expression (using combined stereology/confocal microscopy) (ii) synaptic properties of cholinergic and GABAergic neurons in recordings from slices taken through basal forebrain, and (iii) muscarinic cholinergic and GABA(B) receptor expression and function in basal forebrain and its cortical target fields. Finally, we will treat middle-aged and aged rats with cholinergic and GABAergic drugs, both separately and in concert, to reverse age-related cognitive impairments. ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG029421-01A1
Application #
7320325
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Wagster, Molly V
Project Start
2007-08-01
Project End
2012-05-31
Budget Start
2007-08-01
Budget End
2008-05-31
Support Year
1
Fiscal Year
2007
Total Cost
$304,662
Indirect Cost
Name
Texas A&M University
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
078592789
City
College Station
State
TX
Country
United States
Zip Code
77845
McQuail, Joseph A; Krause, Eric G; Setlow, Barry et al. (2018) Stress-induced corticosterone secretion covaries with working memory in aging. Neurobiol Aging 71:156-160
Burke, Sara N; Gaynor, Leslie S; Barnes, Carol A et al. (2018) Shared Functions of Perirhinal and Parahippocampal Cortices: Implications for Cognitive Aging. Trends Neurosci 41:349-359
Orsini, Caitlin A; Hernandez, Caesar M; Bizon, Jennifer L et al. (2018) Deconstructing value-based decision making via temporally selective manipulation of neural activity: Insights from rodent models. Cogn Affect Behav Neurosci :
Yoder, Wendy M; Gaynor, Leslie S; Burke, Sara N et al. (2017) Interaction between age and perceptual similarity in olfactory discrimination learning in F344 rats: relationships with spatial learning. Neurobiol Aging 53:122-137
Beas, B S; McQuail, J A; Ban Uelos, C et al. (2017) Prefrontal cortical GABAergic signaling and impaired behavioral flexibility in aged F344 rats. Neuroscience 345:274-286
Hernandez, Abbi R; Reasor, Jordan E; Truckenbrod, Leah M et al. (2017) Medial prefrontal-perirhinal cortical communication is necessary for flexible response selection. Neurobiol Learn Mem 137:36-47
Hernandez, Caesar M; Vetere, Lauren M; Orsini, Caitlin A et al. (2017) Decline of prefrontal cortical-mediated executive functions but attenuated delay discounting in aged Fischer 344 × brown Norway hybrid rats. Neurobiol Aging 60:141-152
Carpenter, Haley E; Kelly, Kyle B; Bizon, Jennifer L et al. (2016) Age-related changes in tonic activation of presynaptic versus extrasynaptic ?-amniobutyric acid type B receptors in rat medial prefrontal cortex. Neurobiol Aging 45:88-97
Beas, B Sofia; Setlow, Barry; Bizon, Jennifer L (2016) Effects of acute administration of the GABA(B) receptor agonist baclofen on behavioral flexibility in rats. Psychopharmacology (Berl) 233:2787-97
McQuail, Joseph A; Beas, B Sofia; Kelly, Kyle B et al. (2016) NR2A-Containing NMDARs in the Prefrontal Cortex Are Required for Working Memory and Associated with Age-Related Cognitive Decline. J Neurosci 36:12537-12548

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