The overall objective of this research project is to elucidate the roles of basal forebrain (BF) neurons as potential neural mechanisms for attention. During the current reporting period, our research effort focused on two main questions: (1) how does BF neuronal activity facilitate response speed through the encoding of motivational salience of the stimulus;and (2) how does BF activity mediate the influence of attention on enhancing cortical neural activity, especially in terms of event-related potential (ERP) responses. Given that aging is associated with reduced processing speed as well as changes in ERP responses, these investigations will help to better understand the neural mechanisms of cognitive aging. The survival of animals depends critically on prioritizing responses to motivationally salient stimuli. While it is generally accepted that motivational salience is coupled with faster decision speed and shorter reaction time (RT), their quantitative coupling relationship remains unclear. To understand how the encoding of motivational salience signal in the BF influences decision speed, we recorded neuronal activity in the BF while rats performed a reward-biased simple RT task. Our study shows that the neural correlate of motivational salience in the BF, defined independently of RT, is coupled with faster and also more precise decision speed. Faster RTs were correlated with stronger BF motivational salience signals and were elicited by BF electrical stimulation that augmented the motivational salience signal. Furthermore, the fraction of RT variability reflecting the contribution of intrinsic noise in the decision making process was actively suppressed in faster RT distributions with stronger BF motivational salience signals. These results suggest that the BF motivational salience signal influences an early and previously unrecognized step in the decision making process to modulate both the speed and variability of RT. The coupling with faster and more precise decision speed demonstrated in this study adds to the functional significance of this previously neglected neuronal population in the BF. Dissecting the neural circuit level mechanisms of the BF motivational salience signal will have important translational implications. Dysregulation of motivational salience coupled with decreased decision speed are well documented in schizophrenia and depression. Significant decreases in decision speed also represent a key feature in dementia and cognitive aging. We therefore propose that the functional impairment of the BF motivational salience system represents a novel candidate mechanism that may underlie the decline of decision speed in some of these conditions. To further understand whether the influence of attention on enhancing cortical neural activity may be mediated by BF neuronal activity, we studied the relationship between the activity of non-cholinergic BF neurons and ERP responses in the cortex. The brain processes behaviorally relevant information using highly stereotypical and large-scale activity patterns reflected in ERPs. ERPs have been widely used in both healthy and neuropsychiatric conditions as robust physiological indices of attention and other cognitive functions, but the underlying neural circuit mechanisms that generate cognitive ERPs remain unclear. Our study shows that a performance-related ERP response in the frontal cortex is correlated with, and likely generated by, subcortical inputs from the BF. In rats performing an auditory oddball task, the frontal ERP was tightly coupled with the phasic bursting response of BF neurons in single trials, both in terms of amplitude and timing. BF bursting was similarly coupled with local field potential (LFP) activity in frontal cortical regions that concentrated in the zone of BF inputs in deep cortical layers. Furthermore, electrical stimulation of the BF was sufficient to trigger the layer-specific LFP responses in the oddball task with a short delay of 5-10 msec. Together, these results link a key component of cognitive ERPs to the activity of a well-defined neuronal population in the BF and highlight the important and previously unrecognized role of subcortical inputs in generating cortical ERPs. These results suggest that the motivational salience information encoded by BF bursting activity is transformed into the frontal ERP response with a minimum delay, which will likely provide powerful modulation on the early stages of information processing and lead to faster and better decision making. These results also raise the hypothesis that the decline of frontal ERP amplitude in neuropsychiatric conditions may be mediated by the functional impairment of the BF bursting mechanism or a dysfunctional BF-cortical interaction.

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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Whitmore, Nathan W; Lin, Shih-Chieh (2016) Unmasking local activity within local field potentials (LFPs) by removing distal electrical signals using independent component analysis. Neuroimage 132:79-92
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
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
Mayse, Jeffrey D; Nelson, Geoffrey M; Park, Pul et al. (2014) Proactive and reactive inhibitory control in rats. Front Neurosci 8:104
Nguyen, David P; Lin, Shih-Chieh (2014) A frontal cortex event-related potential driven by the basal forebrain. Elife 3:e02148
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