The overall goal of this research is to elucidate, using functional magnetic resonance imaging (fMRI), how aging in humans affects neural systems critical for eyeblink conditioning, including the cerebellum and the medial temporal lobe (MTL). While the cerebellum is essential for conditioned eyeblink responses, the MTL is also necessary for a specific type of learning referred to as """"""""trace"""""""" conditioning, in which there is a gap in time between the offset of the conditioned stimulus (CS) and the onset of the unconditioned stimulus (US). Trace conditioning is also impaired in older subjects, and in both older and younger subjects who do not acquire awareness of the stimulus contingencies during the conditioning training. Our hypothesis is that in trace conditioning differences in MTL activation, along with differences in patterns of functional connectivity among neocortical and subcortical structures, will account for differences in trace conditioning behavioral performance in both older and unaware subjects. We predict that when the gap in time is absent (i.e., """"""""delay"""""""" conditioning), awareness will have less effect on either performance or cerebellar activations, age group differences in cerebellar activation will account for more of the age differences in conditioned eyeblink performance than will MTL activation differences, and age group differences in patterns of functional connectivity will differ from those observed in trace conditioning. We plan to first characterize age-related changes in CS and US pathways using unpaired CS and US presentations, and hypothesize that any age differences will be observed in the cerebellum for short CSs and in the MTL during the trace period. We will investigate age-related changes in brain activation during delay and trace conditioning protocols, and hypothesize differential importance of cerebellar and MTL activations, respectively, for age-related changes in performance of delay and trace conditioning. Finally, we will investigate the role of awareness in age-related changes in brain activation underlying eyeblink conditioning by (a) disrupting the acquisition of awareness and observing its effect on conditioning and brain activation and (b) measuring the concurrent development of awareness, eyeblink conditioning, and brain activation. We predict that in trace conditioning, subjects that acquire awareness will condition better and exhibit greater MTL activation than unaware subjects, age differences in conditioning and MTL activation will be reduced or eliminated after equating for awareness, age-related changes in functional connectivity will differ between delay and trace conditioning, patterns of functional connectivity will change as a function of awareness for trace conditioning, and left prefrontal cortex will be a critical node in awareness-related functional circuits. Finally, we will examine the link between age-related differences in trace conditioning and other types of age-related cognitive decline, and we will test a model of MTL/neocortical involvement in trace conditioning and awareness using transcranial magnetic stimulation.
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