Age-related Changes in GABA: Effects on Neural Distinctiveness and Variability

Abstract

Tens of millions of otherwise healthy people experience age-related cognitive and sensory impairments. Nevertheless, there are large individual differences in these declines and understanding the neural bases of individual differences during aging is imperative in designing future interventions to slow age-related cognitive impairments. The objective of this dissertation is to investigate the neurochemical bases of three such neural factors that may play a role, namely age-related changes in the distinctiveness of neural representations, age-related changes in the variability of neural signals, and age-related changes in the modulation of this variability in response to different visual stimuli. Previous work in humans using functional Magnetic Resonance Imaging (fMRI) has found that neural distinctiveness in the ventral visual cortex in response to different stimulus categories (face vs. houses) is reduced in older adults compared to young adults (Park et.al.,2004), a phenomenon known as neural dedifferentiation that is also associated with poorer cognitive performance (Park et.al.,2010). In first study of the dissertation, I showed that this age-related neural dedifferentiation, measured using fMRI, extends to the auditory cortex and that individual differences in the brain’s major inhibitory neurotransmitter (gamma-aminobutyric acid (GABA)), measured using MR Spectroscopy, are associated with individual differences in neural distinctiveness in older adults. In a second study, I replicated previous research findings showing that neural variability (measured as standard-deviation in the fMRI BOLD signal, SDBOLD) declines with age in most cortical regions of the brain. I also found that pharmacologically potentiating the activity of GABA using lorazepam led to an increase in SDBOLD particularly for older, poorer cognitive performers. These results provide the first evidence that GABA activity plays a causal role in individual differences in SDBOLD and that in older adults it can be restored by targeting the GABAergic system. In the third and final study, I examined the modulation of SDBOLD (SDBOLD) during a visual task (viewing houses vs. faces). Previous research has found that SDBOLD differs by cognitive states and that individuals who modulate SDBOLD more in response to different task conditions perform better on a range of fluid processing tasks. Furthermore, variability seems to be upregulated to match the richness and complexity of perceptual inputs. I found that SDBOLD and ventrovisual GABA levels are significantly lower in older adults and lower GABA levels are associated with lower SDBOLD in both young and older adults. However, GABA-agonism can change SDBOLD: Older adults with lower baseline GABA levels experience a boost in SDBOLD on drug while those with higher GABA levels experience a reduction, consistent with an inverted-U account. Finally, I also found that individual differences in visual GABA levels and SDBOLD are both associated with individual differences in visual sensory function. These results are consistent with the hypothesis that age-related declines in GABA levels lead to a reduction in SDBOLD, which in turn is associated with visual function. Across the three studies, this dissertation provides novel evidence that age-related differences in GABA play an important role in age-related changes in three different measures of neural function, all of which are linked to individual differences in behavior. This research suggests the promise of interventions targeting the brain’s inhibitory systems to slow cognitive declines associated with aging.