Inhibitory control, the ability to suppress a planned action when it suddenly becomes inappropriate, is essential for survival in an ever-changing environment. Aging is associated with decline in inhibitory control but the underlying mechanisms remain unclear. A powerful and widely used paradigm to study inhibitory control in both basic and clinical research is the Stop Signal Task (SST). In the SST, subjects are required to rapidly respond to an imperative go signal and cancel the preparation of this response following an infrequent stop signal. Recently, our lab has developed and validated a rodent-appropriate SST and characterized both reactive (e.g., rapid stimulus-driven responses) and proactive (e.g., preparation to stop prior to stimulus onset based on trial history and expectation) control strategies in young adult rats (Mayse et al, Front. in Neurosci. 2014). During the current reporting period, our research effort focused on two main areas: (1) determine the role of BF neuronal activity in inhibitory control; and (2) characterize whether aged rats show deficient inhibitory control. In the first research direction, we investigated the role of BF neuronal activity in rapid behavioral stopping using the SST (Mayse et al, Nature Neuroscience, 2015). Cognitive inhibitory control, the ability to rapidly suppress responses inappropriate for the context, is essential for flexible and adaptive behavior. Although most studies on inhibitory control have focused on the fronto-basal-ganglia circuit, we found that rapid behavioral stopping is enabled by neuronal inhibition in the basal forebrain (BF). In rats performing the stop signal task, putative noncholinergic BF neurons with phasic bursting responses to the go signal were nearly completely inhibited by the stop signal. The onset of BF neuronal inhibition was tightly coupled with and temporally preceded the latency to stop, the stop signal reaction time. Artificial inhibition of BF activity in the absence of the stop signal was sufficient to reproduce rapid behavioral stopping. These results reveal a previously unknown subcortical mechanism of rapid inhibitory control by the BF, which provides bidirectional control over the speed of response generation and inhibition. In the second research direction, we investigate whether, like monkeys and humans, aged rats show SST impairments. We found that, compared to young adults at 9 months of age, 24-month-old Long-Evans rats were slower in their covert latency of reactive inhibition, i.e., the stop signal reaction time (SSRT). Aged rats also displayed increased population variability in the SSRT: some aged rats had SSRTs on par with young rats whereas others were impaired compared to controls. For proactive inhibitory control, we found that aged rats adjust both their reaction time and the ability to stop following stop trials to a greater extent than young controls. In addition, we found that slower SSRTs were not correlated with either slower go reaction times, or hippocampus-dependent spatial learning ability as assessed by a Morris Water Maze (MWM) task. Together, these results indicate that inhibitory control is impaired in aged rats, and that these deficits emerge independent of other prominent features of cognitive aging. Such a demonstration establishes the rat as a valid model for identifying the neural mechanisms underlying age-related decline in inhibitory control.
