The overall goal of this project is to test the hypothesis that the slowing of processing speed and the decline of cognitive inhibitory control in the aging process are mediated by an impaired cortical-basal forebrain (BF) interaction involving non-cholinergic BF neurons. During the current reporting period, our research effort focused on two main areas: (1) determine the role of BF neuronal activity in cognitive inhibitory control;and (2) characterize whether aged rats show deficient inhibitory control. Cognitive inhibitory control, or the ability to suppress responses inappropriate for the context, is essential for flexible and adaptive behavior. Normal aging is commonly accompanied by declining cognitive inhibitory control. The stop-signal task, which estimates the latency to suppress a response as the stop-signal reaction time (SSRT), is a powerful paradigm for studying inhibitory control. Our study showed that inhibition of non-cholinergic BF neurons provides a novel neural correlate of the SSRT. In rats performing a stop-signal task with multiple stop-signal delays, non-cholinergic BF neurons that showed a bursting response to the go-signal were completely inhibited by the stop-signal. The onset of BF neuronal inhibition was tightly coupled to, and slightly preceded, the behaviorally estimated SSRT. Consistent with a causal interpretation, precisely timed direct manipulation of BF activity in place of the stop-signal was sufficient to reproduce the stopping behavior. Together, these results reveal a novel subcortical mechanism of inhibitory control by non-cholinergic BF neurons. These observations provide strong support that non-cholinergic BF neurons constitute a rapid and powerful mechanism by which the stop-signal can affect ongoing information processing, likely mediated by the prominent disinhibitory circuit non-cholinergic BF neurons form with pyramidal cells across the entire cortical mantle. A poster presentation describing these findings has been selected as one of the hot topics for news release at the Society for Neuroscience 2012 annual meeting. To gain further insight on whether aged rats show deficient inhibitory control, we trained both aged and young rats on an auditory Go/Nogo task and its reversal with detailed measures of their reaction time (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, in addition to a moderate but statistically significant slowing of their RT in Go-trials. Detailed analysis of RT data showed that, while the asymptotic performance level in terms of Go/Nogo accuracy was similar between aged and young rats in both the acquisition and the reversal phase, aged rats demonstrated a persistent processing impairment throughout all phases of the task. Specifically, aged rats showed a diminished difference in RT between Go and Nogo trials, being slower in Go trials but faster in Nogo trials compared with young rats. This age-related deficit was specific to the earliest component of RT as rats exited the nosepoke port after hearing the Go/Nogo tones. This finding supports that aged rats failed to quickly process the Nogo-cue in order to promptly inhibit their fast Go responses, a processing deficit likely resulting from deficient inhibitory control. Furthermore, the contrast between the initial processing deficit and the subsequent intact Go/Nogo performance suggests that the age-related inhibitory deficit can be compensated for when given a longer response window. Future experiments will seek to determine whether the age-related impairment of inhibitory control may result from impairments of non-cholinergic BF neuronal activity and/or impairments in their modulation of cortical activity.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Investigator-Initiated Intramural Research Projects (ZIA)
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National Institute on Aging
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Raver, Sylvina M; Lin, Shih-Chieh (2015) Basal forebrain motivational salience signal enhances cortical processing and decision speed. Front Behav Neurosci 9:277
Mayse, Jeffrey D; Nelson, Geoffrey M; Avila, Irene et al. (2015) Basal forebrain neuronal inhibition enables rapid behavioral stopping. Nat Neurosci 18:1501-8
Nguyen, David P; Lin, Shih-Chieh (2014) A frontal cortex event-related potential driven by the basal forebrain. Elife 3:e02148
Mayse, Jeffrey D; Nelson, Geoffrey M; Park, Pul et al. (2014) Proactive and reactive inhibitory control in rats. Front Neurosci 8:104
Avila, Irene; Lin, Shih-Chieh (2014) Motivational salience signal in the basal forebrain is coupled with faster and more precise decision speed. PLoS Biol 12:e1001811
Avila, Irene; Lin, Shih-Chieh (2014) Distinct neuronal populations in the basal forebrain encode motivational salience and movement. Front Behav Neurosci 8:421
Zhang, Hao; Lin, Shih-Chieh; Nicolelis, Miguel A L (2011) A distinctive subpopulation of medial septal slow-firing neurons promote hippocampal activation and theta oscillations. J Neurophysiol 106:2749-63
Lin, Shih-Chieh (2010) The dynamics of striatum circuitry. Front Integr Neurosci 4:3
Zhang, Hao; Lin, Shih-Chieh; Nicolelis, Miguel A L (2010) Spatiotemporal coupling between hippocampal acetylcholine release and theta oscillations in vivo. J Neurosci 30:13431-40