PROJECT SUMMARY Alzheimer’s disease (AD) is the most common form of dementia world-wide, afflicting nearly 46 million people. The two hallmark AD pathologies are extracellular β-amyloid (Aβ) plaques and intracellular aggregated tau, termed neurofibrillary tangles. Many treatments that target amyloid deposition in mid to late stages of disease are effective in animal models but have failed in clinical trials. However, recent evidence indicates that hyperphosphorylated “pre-tangle” tau in the noradrenergic locus coeruleus (LC) appears decades prior to cognitive symptoms and Aβ deposition, offering fresh insight into the potential cause and progression of AD. The LC coordinates distinct brain states through norepinephrine release at target sites, and many LC-modulated behaviors go awry in AD, but few studies have directly investigated the consequences of aberrant tau on LC function. Aberrant tau expression causes hypoactivity in neurons, and tau load is associated with blunted novelty response, a key behavior influenced by LC activity. Furthermore, the LC does not exhibit frank neuronal loss until late stages of disease when cognitive decline is evident, but neuron morphology is altered, and innervation density is decreased at early stages of disease. Despite these potentially pathogenic changes, our data indicates that activation of the LC has the potential to restore normal cognition. In TgF344-AD transgenic rats, similar to humans, hyperphosphorylated tau appears in the LC prior to tau or Aβ pathology in the forebrain. Importantly, chemogenetic activation of the LC is effective at rescuing spatial learning deficits in aged TgF344-AD rats, indicating that LC stimulation enhances cognition even in the presence of AD-like neuropathology in the LC and forebrain. However, there is no information regarding the effects of tau on LC physiology or LC-induced changes in brain-wide functional connectivity. In this proposed project, I will use TgF344-AD rats to assess both tau-mediated LC neuron dysfunction and the therapeutic potential of LC stimulation to correct functional connectome deterioration. In Aim 1, I will use in vivo electrophysiology to determine whether hyperphosphorylated tau in the LC can alter neuron firing rates in an age-dependent manner. In Aim 2, I will combine optogenetic stimulation of the LC with simultaneous functional magnetic resonance imaging to assess whether LC stimulation can rescue brain-wide network functional connectivity deficits. I hypothesize that aberrant tau will decrease neuron firing rates in an age- dependent manner that will be paralleled by gradual, brain-wide hypoconnectivity, which will be corrected by optogenetic LC stimulation. Completion of these aims will determine the functional consequences of the earliest known AD pathology, hyperphosphorylated tau in the LC, and facilitate development of LC-NE based therapeutic interventions to retard progression.