Mechanisms regulating the maturation of prefrontal top-down circuity in control of attentional behavior

Abstract for Alzheimer's-focused administrative supplement for R01MH119523 Cognitive decline is one of frequent challenges accompanying Alzheimer's disease (AD). The goal of this study is to examine to what extent a PFC cognitive control circuit identified in the ongoing R01 project is vulnerable to AD risk gene manipulation and also responsible for cognitive control behavior to establish pre-clinical strategy for ameliorating cognitive deficits in AD. As a part of our R01 project, we recently demonstrated that PFC top-down frontal-sensory projections from anterior cingulate area (ACA) to visual cortex (VIS) (ACAvis projection) plays an essential causal role in cognitive control by linking error monitoring and attention adjustment in mice (Norman et al Neuron 2021). Further, we found that this circuit is disrupted in a mouse model of Fragile X syndrome, but this circuit deficit can be targeted to prevent attention deficits (Falk et al Science Advances 2021). Of note, Aβ is over-expressed in the brain of Fmr1KO mice, suggesting seemingly disparate neurologic diseases (FXS and AD) may share a common pathology. Consistently, our preliminary study using APP knock-in (KI) mouse, which contains humanized sequences and mutations in the endogenous mouse APP gene, showed reduced correct performance selective after error trials, suggesting that AD-risk gene is associated with deficits in post-error attention adjustment, a key aspect of cognitive control. As functional cortical imaging around the onset of AD shows accelerated posterior-anterior shift in aging (PASA), we hypothesize that AD-related APP mutations disrupt top-down frontal-sensory projection and associated network contributing to cognitive control deficit. We will test this hypothesis by applying the techniques all established by the parent R01. Aim 1 will examine the impact of AD related APP mutations on frontal-sensory network by studying synaptic inputs onto ACAvis projection neuron in APP KI mice through patch-clamp recording. Aim2 will study the recruitment of frontal-sensory projection during cognitive control behavior in APP KI mice by in vivo fiber photometry calcium imaging. Aim3 aims to ameliorate cognitive control deficits through the optogenetic modulation of frontal-sensory projection in APP KI mice. Given that Aβ is over-expressed in Fmr1KO brain, the proposed study using APP KI model fits within the scope of parent R01 which studies attention deficits in Fmr1KO mice using the same circuit techniques. This project will be conducted in collaboration with Dr. Joseph Castellano (co-I: Ronald M. Loeb Center for Alzheimer’s disease at Mt. Sinai) who has an extensive expertise and working knowledge of APP KI mouse model and AD pathology. Successful completion of the proposed experiments will set a stage for future R01 project with more in depth network analysis combining spike/LFP recordings from frontal and sensory cortical areas in behaving animals, and also exploration of long-lasting cognitive deficit rescue strategies.