Expansion of a stretch of polyglutamine in huntingtin (htt), the protein product of the IT15 gene, causes Huntington's disease (HD). Previous investigations into the role of the polyglutamine stretch ...(polyQ) in htt function have suggested that its length may modulate a normal htt function involved in regulating energy homeostasis. Here we show that expression of full-length htt lacking its polyglutamine stretch (DeltaQ-htt) in a knockin mouse model for HD (Hdh(140Q/DeltaQ)), reduces significantly neuropil mutant htt aggregates, ameliorates motor/behavioral deficits, and extends lifespan in comparison to the HD model mice (Hdh(140Q/+)). The rescue of HD model phenotypes is accompanied by the normalization of lipofuscin levels in the brain and an increase in the steady-state levels of the mammalian autophagy marker microtubule-associate protein 1 light chain 3-II (LC3-II). We also find that DeltaQ-htt expression in vitro increases autophagosome synthesis and stimulates the Atg5-dependent clearance of truncated N-terminal htt aggregates. DeltaQ-htt's effect on autophagy most likely represents a gain-of-function, as overexpression of full-length wild-type htt in vitro does not increase autophagosome synthesis. Moreover, Hdh(DeltaQ/DeltaQ) mice live significantly longer than wild-type mice, suggesting that autophagy upregulation may be beneficial both in diseases caused by toxic intracellular aggregate-prone proteins and also as a lifespan extender in normal mammals.
Current understanding of sea turtle nesting, hatching, and emergence events has been largely limited to observable events on the surface of the sand, though recent approaches using audio or visual ...equipment have allowed scientists to better understand some underground nest phenomena. We used a technology-based approach to define motion-related Caretta caretta hatching and emergence nest events. We describe a novel low-cost, accelerometer-based system called TurtleSense that can detect movement and temperature within sea turtle nests remotely. TurtleSense is successfully able to specifically detect motion within sea turtle nests over the entire course of incubation. This system allows for the identification of infertile nests and the detection of four predictable sequential developmental activity patterns in viable nests, including a hatch and posthatch period, the timing of which can be used to tightly predict hatchling emergence events almost to the day. TurtleSense provides a much better understanding about what is happening in the nest before emergence and allows for the generation of a theory of the mechanism that triggers mass emergence. Our results suggest that motion plays a large role in hatchling communication and that the timing of emergence events may be related to the cessation of movement within the nest. Current management of sea turtle nesting events is primarily driven by counting the number of days since the nest was laid, with further safeguards placed at the nest upon subsequent visual observation of depression or emergence events. Use of TurtleSense technology can impact nest management and conservation efforts, allowing organizations to use this motion data to more tightly predict emergence dates for sea turtle hatchlings and to use viability data to inform nest management decisions.
Retinal vasculopathies, including diabetic retinopathy (DR), threaten the vision of over 100 million people. Retinal pericytes are critical for microvascular control, supporting retinal endothelial ...cells via direct contact and paracrine mechanisms. With pericyte death or loss, endothelial dysfunction ensues, resulting in hypoxic insult, pathologic angiogenesis, and ultimately blindness. Adipose-derived stem cells (ASCs) differentiate into pericytes, suggesting they may be useful as a protective and regenerative cellular therapy for retinal vascular disease. In this study, we examine the ability of ASCs to differentiate into pericytes that can stabilize retinal vessels in multiple pre-clinical models of retinal vasculopathy.
We found that ASCs express pericyte-specific markers in vitro. When injected intravitreally into the murine eye subjected to oxygen-induced retinopathy (OIR), ASCs were capable of migrating to and integrating with the retinal vasculature. Integrated ASCs maintained marker expression and pericyte-like morphology in vivo for at least 2 months. ASCs injected after OIR vessel destabilization and ablation enhanced vessel regrowth (16% reduction in avascular area). ASCs injected intravitreally before OIR vessel destabilization prevented retinal capillary dropout (53% reduction). Treatment of ASCs with transforming growth factor beta (TGF-β1) enhanced hASC pericyte function, in a manner similar to native retinal pericytes, with increased marker expression of smooth muscle actin, cellular contractility, endothelial stabilization, and microvascular protection in OIR. Finally, injected ASCs prevented capillary loss in the diabetic retinopathic Akimba mouse (79% reduction 2 months after injection).
ASC-derived pericytes can integrate with retinal vasculature, adopting both pericyte morphology and marker expression, and provide functional vascular protection in multiple murine models of retinal vasculopathy. The pericyte phenotype demonstrated by ASCs is enhanced with TGF-β1 treatment, as seen with native retinal pericytes. ASCs may represent an innovative cellular therapy for protection against and repair of DR and other retinal vascular diseases.
Objective
Prenatal alcohol exposure can result in neurological changes in affected individuals and may result in the emergence of a broad spectrum of neurobehavioral abnormalities termed fetal ...alcohol spectrum disorders (FASD). The effects of ethanol exposure during development are both time and dose dependent. Although many animal models of FASD use more chronic ethanol exposure, acute developmental alcohol exposure may also cause long‐lasting neuronal changes. Our research employed behavioral measures to assess the effects of a single early postnatal ethanol intoxication event in mice.
Materials and Methods
Mice were dosed at postnatal day 6 (a 2.5 g/kg dose of ethanol or a saline control administered twice, 2 hr apart) as a model of third trimester binge drinking in humans. This exposure was followed by behavioral assessment in male mice at 1 month (1M) and at 4 months of age (4M), using the Barnes maze (for learning/memory retrieval), exploratory behavior, and a social responsiveness task.
Results
Ethanol‐exposed mice appeared to be less motivated to complete the Barnes maze at 1M, but were able to successfully learn the maze. However, deficits in long‐term spatial memory retrieval were observed in ethanol‐exposed mice when the Barnes maze recall was measured at 4M. No significant differences were found in open field behavior or social responsiveness at 1M or 4M of age.
Conclusions
Acute ethanol exposure at P6 in mice leads to mild but long‐lasting deficits in long‐term spatial memory. Results suggest that even brief acute exposure to high ethanol levels during the third trimester equivalent of human pregnancy may have a permanent negative impact on the neurological functioning of the offspring.
We assessed the effects of a single early postnatal ethanol intoxication event on several behavioral measures in mice. We conclude that acute ethanol exposure at P6 in mice leads to a deficits in long‐term spatial memory, but found no changes in social responsiveness in adolescence or adulthood.
Traditional large lecture classes can be passive experiences for students. Instead, imagine that several of those learners work at a sleep laboratory and admit four new patients. Within hours, the ...entire facility is on lockdown, and a mysterious voice on the intercom proclaims that all researchers will lose their ability to sleep within the next hour. This story is the plot of an interactive educational escape room (EER) where students work together and apply concepts related to the history of sleep research, circadian rhythms, and neurological concepts of sleep to solve puzzles. Conventionally, escape rooms are an entertainment experience that requires participants to escape a room in a limited timeframe. We have created a neuroscience EER designed to educate students about the neural basis of sleep, while providing small groups of students with an immersive and interactive experience. Students follow a specially designed digital escape room framework to review sleep pathways, researchers, and brain regions involved with sleep. Unlike conventional escape rooms that can accommodate a limited number of participants, this sleep lab EER is scalable to hundreds of students without the need for a specialized room. Puzzles are enhanced by digital technology that allows instructors to track the progress of every team and note how the entire classroom is doing. Students and teaching assistants had very positive experiences with this EER activity, reporting that the EER solidified course concepts while using creativity, collaboration, and critical thinking skills. We find that EERs are an easy, useful tool to increase engagement and boost inclusivity within large classroom settings, with potential to also be used as an assessment tool.
Huntingtin (htt), the protein encoded by the Huntington's disease (HD) gene, contains a polymorphic stretch of glutamines (polyQ) near its N-terminus. When the polyQ stretch is expanded beyond 37Q, ...HD results. However, the role of the normal polyQ stretch in the function of htt is still unknown. To determine the contribution of the polyQ stretch to normal htt function, we have generated mice with a precise deletion of the short CAG triplet repeat encoding 7Q in the mouse HD gene (HdhΔQ). Hdh(ΔQ/ΔQ) mice are born with normal Mendelian frequency and exhibit no gross phenotypic differences in comparison to control littermates, suggesting that the polyQ stretch is not essential for htt's functions during embryonic development. Adult mice, however, commit more errors initially in the Barnes circular maze learning and memory test and perform slightly better than wild-type controls in the accelerating rotarod test for motor coordination. To determine whether these phenotypes may reflect an altered cellular physiology in the HdhΔQ mice, we characterized the growth and energy status of primary embryonic and adult Hdh(ΔQ/ΔQ) fibroblasts in culture. The HdhΔQ fibroblasts exhibited elevated levels of ATP, but senesced prematurely in comparison with wild-type fibroblasts. Taken altogether, these results suggest that htt's polyQ stretch is required for modulating longevity in culture and support the hypothesis that the polyQ stretch may also modulate a htt function involved in regulating energy homeostasis.
Huntington's disease (HD) is an autosomal dominant genetic disorder that specifically causes neurodegeneration of striatal neurons, resulting in a triad of symptoms that includes emotional, ...cognitive, and motor disturbances. The HD mutation causes a polyglutamine repeat expansion within the N-terminal of the huntingtin (Htt) protein. This expansion causes aggregate formation within the cytosol and nucleus due to the presence of misfolded mutant Htt, as well as altered interactions with Htt's multiple binding partners, and changes in post-translational Htt modifications. The present review charts efforts toward a therapy that delays age of onset or slows symptom progression in patients affected by HD, as there is currently no effective treatment. Although silencing Htt expression appears promising as a disease modifying treatment, it should be attempted with caution in light of Htt's essential roles in neural maintenance and development. Other therapeutic targets include those that boost aggregate dissolution, target excitotoxicity and metabolic issues, and supplement growth factors.
Scientific writing is an important communication and learning tool in neuroscience, yet it is a skill not adequately cultivated in introductory undergraduate science courses. Proficient, confident ...scientific writers are produced by providing specific knowledge about the writing process, combined with a clear student understanding about how to think about writing (also known as metacognition). We developed a rubric for evaluating scientific papers and assessed different methods of using the rubric in inquiry-based introductory biology classrooms. Students were either 1) given the rubric alone, 2) given the rubric, but also required to visit a biology subject tutor for paper assistance, or 3) asked to self-grade paper components using the rubric. Students who were required to use a peer tutor had more negative attitudes towards scientific writing, while students who used the rubric alone reported more confidence in their science writing skills by the conclusion of the semester. Overall, students rated the use of an example paper or grading rubric as the most effective ways of teaching scientific writing, while rating peer review as ineffective. Our paper describes a concrete, simple method of infusing scientific writing into inquiry-based science classes, and provides clear avenues to enhance communication and scientific writing skills in entry-level classes through the use of a rubric or example paper, with the goal of producing students capable of performing at a higher level in upper level neuroscience classes and independent research.
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