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Accumulation of hyperphosphorylated tau in the locus coeruleus (LC) is a ubiquitous feature of prodromal Alzheimers disease (AD), and LC neurons degenerate as AD progresses. Tau-mediated LC dysfunction may contribute to early neuropsychiatric symptoms, while loss of LC integrity is associated with conversion to cognitive impairment. Hyperphosphorylated tau alters firing rates in other brain regions, but its effects on LC neurons have not been described. The purpose of this study was to characterize changes in firing properties of LC neurons when they are the only cells containing hyperphosphorylated tau, as well as later in disease when β-amyloid (Aβ) and tau pathology is abundant in the forebrain. Single unit LC activity was recorded from anesthetized wild-type (WT) and TgF344-AD rats, which carry the APP/PS1 transgene. Similar to human AD, these rats develop hyperphosphorylated tau in the LC (at 6 months) prior to Aβ or tau pathology in forebrain regions (at 12-15 months). At baseline, LC neurons from TgF344-AD rats were hypoactive at both ages compared to WT littermates, but showed elevated spontaneous bursting properties, particularly in younger animals. Differences in footshock-evoked LC firing depended on age, with 6-month TgF344-AD rats demonstrating aspects of hyperactivity, and aged transgenic rats showing hypoactivity relative to WT. Tau-induced alterations in LC firing rates may contribute to the pathophysiology of AD, with early hyperactivity associated with prodromal symptoms, followed by hypoactivity contributing to cognitive impairment. These results support further investigation into disease stage-dependent noradrenergic interventions for AD.

Due to the uncontrollable generators, islanded microgrids powered only by renewable energy require costly energy storage systems. Energy storage needs are amplified when load and generation are misaligned on hourly, monthly, or seasonal timescales. Diversification of both loads and generation can smooth out such mismatches. However, the ideal type of battery to smooth out remaining generation deficits will depend on the duration(s) that energy is stored. This study presents a controls co-design approach to design an islanded microgrid, showing the benefit of hybridizing tidal and solar generation and hybridizing lithium-ion and flow battery energy storage. The optimization of the microgrid’s levelized cost of energy is initially studied in grid-search slices to understand convexity and smoothness. Then, a particle swarm optimization is proposed and used to study the sensitivity of the hybrid system configuration to variations in component costs. The study highlights the benefits of controls co-design, the need to model premature battery failure, and the importance of using battery cost models that are applicable across orders of magnitude variations in energy storage durations. The results indicate that such a hybrid microgrid would currently produce energy at five times the cost of diesel generation, but flow battery innovations could bring this closer to only twice the cost while using 100% renewable energy.

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BackgroundFunctional connectivity of the brain as measured by the blood oxygen level dependent (BOLD) signal in fMRI is altered during Alzheimer’s disease (AD) progression. Common practice during preprocessing of fMRI data is removal of the global signal, defined as the averaged brain signal, by regression, removing major sources of noise while risking loss of neural activity. The locus coeruleus (LC), one of the first brain regions to accumulate hyperphosphorylated tau, contributes to brainwide neuromodulatory regulation. Therefore, we combined optogenetics and fMRI to study how LC activity affects the global signal in the TgF344‐AD rat model of AD, which overexpresses mutant human amyloid precursor protein and presenilin‐1.MethodsAt 2 months of age, TgF344‐AD rats and WT littermates received intra‐LC infusions of a ChR2‐mCherry virus under the noradrenergic specific PRSx8 promoter. 2‐4 weeks prior to fMRI, rats were implanted with an optic ferrule targeting the LC. Functional ChR2 expression and LC activation were confirmed by pupil dilation following optogenetic LC stimulation. At ∼6 months of age, rats underwent 10‐minute fMRI scans at baseline and during 2 Hz optogenetic stimulation. During scanning, rats were anesthetized with 1.3% isoflurane, intubated, and administered pancuronium (1.5 mg/kg*hr, s.c.). fMRI scans were gradient echo EPI (TR = 1.25 s) and obtained using a 9.4T Bruker Animal MRI scanner. Data were preprocessed using a customized pipeline. The voxel‐wise analysis was performed by correlating each voxel timecourse with the global signal via Pearson’s linear correlation.ResultsIn general, there were levels of slightly higher correlation to the global signal in the anterior medial region of the brain and bilaterally in the posterior region of the brain (Figure 1). The highest levels of correlation to the global signal were observed in the WT rats at baseline, but differences between groups were negligible.ConclusionNeither genotype nor optogenetic simulation profoundly affected global signal. These negative results may be explained by (1) the lack of profound forebrain AD‐like neuropathology in 6‐month TgF344‐AD rats, and (2) the 2 Hz optogenetic stimulation being insufficient to drive changes in global signal above the 1‐2 Hz baseline activity of LC neurons.