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 (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 proactive and reactive inhibitory control;and (2) characterize whether aged rats show deficient inhibitory control. In the first research direction, we examined whether proactive and reactive adjustments of RT in rats performing the rodent SST are mediated by the BF activity. We have previously found that reactive inhibitory control in response to the Stop Signal is likely mediated by the rapid inhibitory response of a subset of neurons in the basal forebrain (BF) (Mayse et. al, Society for Neuroscience, 2013). Based on our recent report that the bursting activity of salience-encoding BF neurons controls the speed of response generation (Avila &Lin, PLoS Bio., 2014), we further hypothesize that proactive adjustments of RT may be mediated by modulating BF bursting amplitude in response to the Go signal. We found that response speed on Go trials varied as a function of the outcome of the previous trials: rats tended to speed up following a Go trial and slow down following Stop trials. In addition, we found that response speed varied as a function of the local trial history: response speed tended to be slower as the number of stop trials in the previous block increased. These proactive adjustments of RT are correlated with the modulation BF bursting amplitudes. These data provide further support for the role of BF bursting neurons in control of response speed and provide evidence that these neurons contribute to both reactive and proactive control in the SST. 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.
