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 #
5R01AG029421-06
Application #
8231356
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Wagster, Molly V
Project Start
2007-08-01
Project End
2013-05-31
Budget Start
2011-06-15
Budget End
2013-05-31
Support Year
6
Fiscal Year
2011
Total Cost
$277,501
Indirect Cost
Name
University of Florida
Department
Neurosciences
Type
Schools of Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
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
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
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, 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
McQuail, Joseph A; Frazier, Charles J; Bizon, Jennifer L (2015) Molecular aspects of age-related cognitive decline: the role of GABA signaling. Trends Mol Med 21:450-60
Bañuelos, Cristina; Beas, B Sofia; McQuail, Joseph A et al. (2014) Prefrontal cortical GABAergic dysfunction contributes to age-related working memory impairment. J Neurosci 34:3457-66
Griffith, William H; Dubois, Dustin W; Fincher, Annette et al. (2014) Characterization of age-related changes in synaptic transmission onto F344 rat basal forebrain cholinergic neurons using a reduced synaptic preparation. J Neurophysiol 111:273-86

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