Deficits in attention are a major feature of many neurodegenerative and neuropsychiatric diseases. Thus, understanding the brain circuitry underlying attention is important to develop novel treatments. Dysfunction and degeneration of basal forebrain (BF) neurons are early features of these diseases. Previous studies have suggested that cholinergic BF neurons are important in attention and their loss contributes to attention deficits. However, the majority of BF neurons are non-cholinergic and little is known about their role in cognition. Here, we use state-of-the-art optogenetic techniques in combination with cortical local field potential (LFP) recordings and behavioral paradigms in mice to test the role of one non-cholinergic subtype, basal forebrain parvalbumin neurons (BF PV), in attention for the first time. Our group and others have shown that BF PV neurons control fast cortical oscillations. These oscillations are associated with increased levels of arousal, alertness, and attention, but direct behavioral tests implicating BF PV for functions in attention are lacking. This proposal will address that gap in our knowledge by demonstrating that regulation of cortical oscillations by BF PV neurons is important for two domains of attention (Aim 1. Attention for Action;
Aim 2. Attention for Learning).
The first aim will assess the role of BF PV neurons in promoting levels of sustained attention needed for optimal performance in signal detection tasks. We predict that BF PV optogenetic excitation with specific parameters (tonic vs patterned frequency) and during specific task epochs (prior to vs coincident with signals) will entrain cortical oscillations to enhance performance in attentional challenges and ameliorate vigilance decrements incurred either by sleep deprivation or time-on- task. Furthermore, we predict that BF PV optogenetic inhibition will impair maintenance of attention and mimic the effects of sleep deprivation.
The second aim will show that BF PV neurons modulate learning by altering the attentional salience of sensory stimuli. Research under this aim will use classical conditioning procedures to show that BF PV activity underlies cortical processing of prediction error, the discrepancy between predicted events and actual events, and that bidirectional optogenetic modulation of BF PV activity can promote with excitation or disrupt with inhibition the allocation of attention to cues for the purposes of learning. The training plan for this award includes mentorship from an expert team of Harvard Medical School professors specializing in BF mechanisms in arousal, attention, and cortical oscillations. Indeed, the proposed training on advanced signal processing and electrophysiological analysis techniques will prove invaluable for an independent research career studying systems level neural mechanisms of attention.
This research will expand our understanding of basal forebrain mechanisms in attention by studying the role of a subgroup of non-cholinergic parvalbumin-expressing neurons for the first time. This work will inform novel therapeutic targets for disorders of attention that are common to many neurodegenerative and neuropsychiatric diseases, including Alzheimer's.
