Accumulation of hyperphosphorylated tau within subcortical nuclei and subsequent dysfunction of these neurons is a nearly ubiquitous feature along Alzheimer's disease (AD) progression (Ehrenberg et al., 2017; Theofilas et al., 2015). A seminal report from Braak and colleagues (Braak et al., 2011), independently replicated by other groups (Elobeid et al., 2012; Pletnikova et al., 2018; Theofilas et al., 2017), positions the noradrenergic locus coeruleus (LC) as the earliest site of pathological tau deposition, well before cortical β-amyloid (Aβ) plaque accumulation or the onset of diagnostic cognitive deficits. During prodromal phases of AD, non-cognitive symptoms consistent with noradrenergic hyperactivity, including sleep disturbances, agitation, and anxiety, emerge coincident with the appearance of hyperphosphorylated tau in the LC (Ehrenberg et al., 2018; Johansson et al., 2021; Kelberman et al., 2022; Pentkowski et al., 2018; Weinshenker, 2018). Cerebrospinal fluid norepinephrine (NE) levels and its turnover are elevated in early AD (Elrod et al., 1997; Henjum et al., 2022; Hoogendijk et al., 1999; Palmer et al., 1987), and a recent neuroimaging study demonstrated that higher LC signal on a neuromelanin-sensitive MRI was predictive of neuropsychiatric symptom severity in AD patients (Cassidy et al., 2022), further supporting the theory of LC hyperactivity during initial stages of disease. At the same time, numerous studies have linked the deterioration of LC integrity to cognitive and structural decline in aging and AD (Bachman et al., 2021; Jacobs et al., 2021; Kelly et al., 2017; Prokopiou et al., 2022; van Hooren et al., 2021; Wilson et al., 2013), suggestive of reduced LC-NE transmission during later stages of the disease.

While neurochemical, neuropathological, and behavioral results are consistent with disease stage-specific alterations in LC activity, direct evidence for changes in LC firing is mostly lacking. Aβ pathology often induces neural hyperactivity (Busche and Hyman, 2020), including in the LC (Kelly et al., 2021), whereas tau pathology typically induces neuronal hypoactivity (Busche et al., 2019). However, there are other reports of tau-mediated hyperactivity (Holth et al., 2013; Huijbers et al., 2019; Shimojo et al., 2020), suggesting region and/or cell-type specific effects. Given that Aβ only accumulates in the LC during late stages of AD (Cole et al., 1993; Kelly et al., 2021), the dysregulation of LC circuits at the level of the cell bodies is likely dominated by the early accumulation of hyperphosphorylated tau. Therefore, understanding the impact of aberrant tau on LC neural activity is critical for determining the neurobiological underpinnings of prodromal AD symptoms and progression to cognitive impairment. This information could then inform rational development of early biomarkers and therapeutic interventions at various disease stages.

The objective of this study was to delineate the effects of AD-like hyperphosphorylated tau on LC firing rates. Though some studies have begun to track LC activity in humans using functional MRI (Prokopiou et al., 2022), these techniques lack spatial and target specificity for small regions like the LC (Kelberman et al., 2020). We therefore employed the TgF344-AD rat model, which expresses mutant human amyloid precursor protein and presenilin-1 (APP/PS1) that cause autosomal dominant, early-onset AD (Cohen et al., 2013). This model possesses several benefits for our study. These rats demonstrate many of the same behavioral phenotypes that are observed in AD that are influenced by LC activity. These include early anxiety-like behaviors followed later by cognitive impairment that can be reversed by LC activation (Cohen et al., 2013; Kelberman et al., 2022; Pentkowski et al., 2018; Rorabaugh et al., 2017). In addition, TgF344-AD rats, unlike their APP/PS1 transgenic mouse counterparts, develop endogenous tau pathology that first appears in the LC (Rorabaugh et al., 2017). This tau deposition is coincident with the appearance of non-cognitive behavioral abnormalities but prior to tau or Aβ pathology elsewhere in the brain, reminiscent of human disease progression. In the current study, we recorded single unit LC activity from anesthetized TgF344-AD rats and wild-type (WT) littermates at baseline and in response to footshock at 6 months, an age when anxiety-like behavior emerges and hyperphosphorylated tau in the LC is the only detectable AD-like neuropathology, as well as 15 months, when brain-wide tau and Aβ pathology are evident in combination with deficits in learning and memory.