Faculty Bibliography

Several tau antibody therapies are now in clinical trials and numerous other tau antibodies are in various stages of preclinical development to treat Alzheimer's disease and related tauopathies. This involves long-term studies in mouse models that are necessary but time consuming and typically provide only a limited mechanistic understanding of how the antibodies work and why some are not effective. Live cellular imaging with fluorescently tagged pathological tau proteins and tau antibodies provides a valuable insight into their dynamic interaction outside or within the cell. Furthermore, this acute technique may have predictive validity to assess the potential efficacy of different tau antibodies in neutralizing and/or clearing tau aggregates, and can likely be applied to other amyloid diseases. Overall, it should facilitate identifying candidate antibodies for more detailed long-term validation. Due to the human origin of the model, it may be particularly useful to characterize humanized antibodies that utilize receptor-mediated uptake to reach their intracellular target.

Cortical mechanisms that regulate acute or chronic pain remain poorly understood. The prefrontal cortex (PFC) exerts crucial control of sensory and affective behaviors. Recent studies show that activation of the projections from the PFC to the nucleus accumbens (NAc), an important pathway in the brain's reward circuitry, can produce inhibition of both sensory and affective components of pain. However, it is unclear whether this circuit is endogenously engaged in pain regulation. To answer this question, we disrupted this circuit using an optogenetic strategy. We expressed halorhodopsin in pyramidal neurons from the PFC, and then selectively inhibited the axonal projection from these neurons to neurons in the NAc core. Our results reveal that inhibition of the PFC or its projection to the NAc, heightens both sensory and affective symptoms of acute pain in naïve rats. Inhibition of this corticostriatal pathway also increased nociceptive sensitivity and the aversive response in a chronic neuropathic pain model. Finally, corticostriatal inhibition resulted in a similar aversive phenotype as chronic pain. These results strongly suggest that the projection from the PFC to the NAc plays an important role in endogenous pain regulation, and its impairment contributes to the pathology of chronic pain.

Oxytocin is a hypothalamic neuropeptide first recognized as a regulator of parturition and lactation which has recently gained attention for its ability to modulate social behaviors. In this chapter, we review several aspects of the oxytocinergic system, focusing on evidence for release of oxytocin and its receptor distribution in the cortex as the foundation for important networks that control social behavior. We examine the developmental timeline of the cortical oxytocin system as demonstrated by RNA, autoradiographic binding, and protein immunohistochemical studies, and describe how that might shape brain development and behavior. Many recent studies have implicated oxytocin in cognitive processes such as processing of sensory stimuli, social recognition, social memory, and fear. We review these studies and discuss the function of oxytocin in the young and adult cortex as a neuromodulator of central synaptic transmission and mediator of plasticity.

Optogenetics allows for optical manipulation of neuronal activity and has been increasingly combined with intra- and extra-cellular electrophysiological recordings. Genetically-identified classes of neurons are optically manipulated, though the versatility of optogenetics would be increased if independent control of distinct neural populations could be achieved on a sufficient spatial and temporal resolution. We report a scalable multi-site optoelectrode design that allows simultaneous optogenetic control of two spatially intermingled neuronal populations in vivo. We describe the design, fabrication, and assembly of low-noise, multi-site/multi-color optoelectrodes. Each shank of the four-shank assembly is monolithically integrated with 8 recording sites and a dual-color waveguide mixer with a 7 × 30 μm cross-section, coupled to 405 nm and 635 nm injection laser diodes (ILDs) via gradient-index (GRIN) lenses to meet optical and thermal design requirements. To better understand noise on the recording channels generated during diode-based activation, we developed a lumped-circuit modeling approach for EMI coupling mechanisms and used it to limit artifacts to amplitudes under 100 μV upto an optical output power of 450 μW. We implanted the packaged devices into the CA1 pyramidal layer of awake mice, expressing Channelrhodopsin-2 in pyramidal cells and ChrimsonR in paravalbumin-expressing interneurons, and achieved optical excitation of each cell type using sub-mW illumination. We highlight the potential use of this technology for functional dissection of neural circuits.

A fundamental problem in the field of obstructive sleep apnea (OSA) and memory is that it has historically minimized the basic neurobiology of sleep's role in memory. Memory formation has been classically divided into phases of encoding, processing/consolidation, and retrieval. An abundance of evidence suggests that sleep plays a critical role specifically in the processing/consolidation phase, but may do so differentially for memories that were encoded using particular brain circuits. In this review, we discuss some of the more established evidence for sleep's function in the processing of declarative, spatial navigational, emotional, and motor/procedural memories and more emerging evidence highlighting sleep's importance in higher order functions such as probabilistic learning, transitive inference, and category/gist learning. Furthermore, we discuss sleep's capacity for memory augmentation through targeted/cued memory reactivation. OSA - by virtue of its associated sleep fragmentation, intermittent hypoxia, and potential brain structural effects - is well positioned to specifically impact the processing/consolidation phase, but testing this possibility requires experimental paradigms in which memory encoding and retrieval are separated by a period of sleep with and without the presence of OSA. We argue that such paradigms should focus on the specific types of memory tasks for which sleep has been shown to have a significant effect. We discuss the small number of studies in which this has been done, in which OSA nearly uniformly negatively impacts offline memory processing. When periods of offline processing are minimal or absent and do not contain sleep, as is the case in the broad literature on OSA and memory, the effects of OSA on memory are far less consistent.

Background: Behavioral methods enhance the effectiveness of lifestyle interventions, but are often resource intensive. Although mobile health (mHealth) technology can help create lower input interventions, their feasibility, acceptability and efficacy have not been adequately evaluated in hemodialysis (HD) patients.
Method(s): Maintenance HD patients with persistent hyperphosphatemia (n=40) were randomized to receive: (1) educational (Edu) videos (EDU), (2) Edu + mobile selfmonitoring (SM) with MyNetDiary (MON), or (3) Edu + SM + social cognitive theory (SCT)-based behavioral counseling videos (SCT) over a 12-week period with videos for each group delivered using iPads. Serum phosphorus concentrations (sPO4) were measured at baseline, 12 and 24 weeks, and a 5-point Likert scale survey on the mHealth technology was completed at 24-weeks. Two participants in the EDU group with no follow-up sPO4 measurements were excluded; missing sPO4 measurements at 12-and 24-weeks were imputed by carrying forward the most recent sPO4 values.
Result(s): At the end of the intervention phase (12-weeks), there was a non-significant trend towards greater decreases in sPO4 in the MON (-0.5+/-1.6 mg/dL, p=0.32) and SCT (-0.3+/-2.1 mg/dL, p=0.56) groups compared to the EDU group (+0.2+/-1.4 mg/dL), but these differences had mostly disappeared by the end of the monitoring phase (24-weeks) (EDU +0.1+/-1.2 mg/dL, MON -0.1+/-1.9 mg/dL, SCT -0.1+/-2.1 mg/dL). Most participants agreed or strongly agreed that the iPads were convenient (64%), and SM helped them stay motivated (68%), take binders (61%), and limit phosphorus intake (68%). Relatively few participants reported that they agreed or strongly agreed that they sometimes "got lost" maneuvering the iPad programs (24%), felt that SM wasn't worthwhile (16%), or would have preferred face-to-face meetings offsite (4%).
Conclusion(s): Many HD patients are willing, able and report benefits of engaging in technology-supported behavioral interventions involving SM and SCT. Although these programs are easy to disseminate with limited resources once developed, any benefits for phosphorus management in HD patients may last only as long as the intervention is active

Tau immunotherapies have now advanced from proof-of-concept studies to Phase II clinical trials. This review briefly outlines developments in the field and discusses how these therapies may work, which involves multiple variables that are connected in complex ways. These various factors are likely to define therapeutic success in humans and have not been thoroughly investigated, at least based on published reports.

Objective-To study transfection efficiency of folate-modified chitosan (FA-CS) nanoparticles as a non-viral vector delivering pEGFP-C3plasmid (FA-CS/P) to 293T cells with or without the combination of ultrasound and microbubble. Method-pEGFP-C3 was used as reporter gene and FA-CS nanoparticles, which prepared by complex coagulation method were used as biological carriers. Transfection efficiency to 293T cells mediated by FA-CS/P nanoparticles, ultrasound (US) and microbubble (MB) was assessed by fluorescence microscopy and flow cytometry. Result-FA-CS/P nanoparticles have a particle size of 355.1 nm and zeta potential of 10.4 mV. Significant green fluorescence could be observed in CS/P group, FA-CS/P group, US+MB/P group, US+FA-CS/P group, Liposome 2000 (L) group under inverted fluorescence microscope, while US+MB+FA-CS/P group only scattered fluorescence observed. Result of flow cytometry showed that transfection rate of US+MB+FA-CS/P group was (2.0 ± 0.2)%, which was significantly lower than other groups (P＜0.05). CCK-8 experiments showed that cell vitality of US+MB+FA-CS/P was (64.1±4.6)%, which was also lower than other groups (P＜0.05). Conclusion-In this study, FA-CS was successfully synthesized. FA-CS could combine with pEGFP-C3 effectively forming nanoparticles with nanoparticle size, well dispersion, high encapsulation efficiency and no significant toxicity to cells. The application of ultrasound increased the transfection rate of FA-CS/P. However, while exposed to ultrasound and microbubble, the transfection rate of FA-CS/P decreased obviously, may indicating that there was no synergistic effect for gene transfection by the combination of ultrasound, folate modified chitosan and microbubbles.