Basal Forebrain Non-cholinergic Circuit Mechanisms of Sustained Attention

ABSTRACT The long-term goal is to understand how basal forebrain (BF) circuits underlie cognitive functions like sustained attention. Traditionally, BF was thought to mediate attention through its cholinergic neurons and cortical acetylcholine release. However, recent recordings suggest that cholinergic signaling reflects arousal and reinforcement learning instead. If not cholinergic neurons, what alternative BF circuits support attention? The objective of this proposal is to determine the circuit and behavioral roles of an understudied BF population: parvalbumin-expressing GABAergic neurons (BF-PV) that project to the cortex. Our previous work using a sustained attention-demanding auditory detection task revealed that BF cholinergic neurons respond to reinforcement surprises, independent of temporal fluctuations of attention. This discovery prompted an investigation into alternative BF neuron types. Our preliminary studies suggest that BF-PV neurons have key attributes relevant for sustained attention: their activity predicts detection accuracy and reaction time on a trial-by-trial basis, and their optogenetic stimulation enhances performance. Using quantitative behavior, cell-type-specific recordings and manipulations, viral tracing, and computational modeling, we aim to explore the link between BF-PV neurons and sustained attention. Aim 1 will map BF-PV cortical projections and investigate whether they produce cortical gain control through disinhibition. Aim 2 will record BF-PV neuron activity to assess how its dynamics predict momentary attention levels during sustained attention tasks and use optogenetics to evaluate their necessity and sufficiency. Aim 3 seeks to determine if BF-PV neurons convey motivational salience signals that guide attention allocation. This work will elucidate how long-range, cortex-projecting BF-PV neurons support sustained attention, distinguishing their contributions from known cholinergic effects. Defining the computations and connectivity underlying sustained attention will provide fundamental insights into basal forebrain circuits for normal cognition. Illuminating this poorly understood pathway may also reveal new therapeutic targets for attention disorders and BF-related dementias like Alzheimer's and Parkinson's disease.