Shih-Chieh Lin, M.D.,Ph.D. - US grants

The overall goal of this project is to test the hypothesis that the slowing of processing speed and the decline of executive functions in the aging process are mediated by an impairment in cortical-basal forebrain (BF) interaction, especially involving non-cholinergic (non-ACh) BF neurons. Reaction time (RT) is a widely used behavioral measure that reflects the speed of information processing and decision making. To gain insights into the neural control of RT, we recorded neuronal activity in the BF while rats perform a reward-guided RT task in which two distinct tone cues signal a large or small reward. We hypothesized that the encoding of motivational salience by ensemble bursting of non-ACh BF neurons may systematically influence RT via its fast modulation of cortical activity. We first replicated a well-established feature of human RT distribution in the nosepoke exit RT of the rat: the reciprocal of the RT obeys a Gaussian distribution, a central feature of the LATER (Linear Approach to Threshold with Ergodic Rate) model. Non-ACh BF neurons showed stronger bursting responses to the cue associated with the large reward (and faster RT) compared to the cue for the small reward. Preliminary data suggest that the session-by-session fluctuation of the BF bursting strength to the two cues is correlated with the modulation of RT to the two cues across sessions. However, the strength of BF bursting does not correlate with the variability of RT to the same cue at single trials. Overall, these data support our hypothesis that stronger BF bursting response may lead to faster RT. These data also suggest that this BF motivational salience signal may formally represent the rate parameter of the LATER model at the level of the entire RT distribution. To gain insights on the processing speed and RT in aged animals, we trained both aged and young rats on an auditory Go/NoGo paradigm and its reversal with detailed measures of their RT. Consistent with prior literature, aged rats demonstrated a mild impairment to acquire the Go/Nogo task and a substantial learning deficit during contingency reversal. The asymptotic performance level, however, was similar between aged and young rats in both the acquisition and the reversal phase. Despite their similar levels of asymptotic performance, we found that, in both the acquisition and the reversal phase, aged rats demonstrated a diminished difference in RT between Go and Nogo trials. This age-related deficit is specific to the earliest component of RT as rats exit the nosepoke port after hearing the Go/Nogo tones. Our finding suggests that aged rats were slower at processing and differentiating rewarded from non-reward cues. Future experiments seek to determine whether the the selective impairment of fast behavioral discrimination in aged rats may result from impairments of non-ACh BF neuronal activity and/or impairments in their modulation of cortical activity.