ABSTRACT
Whole-brain intrinsic activity as detected by resting-state fMRI can be summarized by three primary spatiotemporal patterns. These patterns have been shown to change with different brain states, especially arousal. The noradrenergic locus coeruleus (LC) is a key node in arousal circuits and has extensive projections throughout the brain, giving it neuromodulatory influence over the coordinated activity of structurally separated regions. In this study, we used optogenetic-fMRI in rats to investigate the impact of LC stimulation on the global signal and three primary spatiotemporal patterns. We report small, spatially specific changes in global signal distribution as a result of tonic LC stimulation, as well as regional changes in spatiotemporal patterns of activity at 5 Hz tonic and 15 Hz phasic stimulation. We also found that LC stimulation had little to no effect on the spatiotemporal patterns detected by complex principal component analysis. These results show that the effects of LC activity on the BOLD signal in rats may be small and regionally concentrated, as opposed to widespread and globally acting.
ABSTRACT
Hyperphosphorylated tau in the locus coeruleus (LC) is ubiquitous in prodromal Alzheimer's disease (AD), and LC neurons degenerate as AD progresses. Hyperphosphorylated tau alters firing rates in other brain regions, but its effects on LC neurons are unknown. We assessed single unit LC activity in anesthetized wild-type (WT) and TgF344-AD rats at 6 months, which represents a prodromal stage when LC neurons are the only cells containing hyperphosphorylated tau in TgF344-AD animals, and at 15 months when amyloid-ß (Aß) and tau pathology are both abundant in the forebrain. At baseline, LC neurons from TgF344-AD rats were hypoactive at both ages compared to WT littermates but showed elevated spontaneous bursting properties. Differences in footshock-evoked LC firing depended on age, with 6-month TgF344-AD rats demonstrating aspects of hyperactivity, and 15-month transgenic rats showing hypoactivity. Early LC hyperactivity is consistent with appearance of prodromal neuropsychiatric symptoms and is followed by LC hypoactivity which contributes to cognitive impairment. These results support further investigation into disease stage-dependent noradrenergic interventions for AD.
