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Light-sheet microscopy is an ideal technique for imaging large cleared samples; however, the community is still lacking instruments capable of producing volumetric images of centimeter-sized cleared samples with near-isotropic resolution within minutes. Here, we introduce the mesoscale selective plane-illumination microscopy initiative, an open-hardware project for building and operating a light-sheet microscope that addresses these challenges and is compatible with any type of cleared or expanded sample (www.mesospim.org).

In this Tools of the Trade article, Daniel Kirschenbaum describes the development of Zman-seq and its utility for capturing dynamic changes in cellular state within single-cell RNA sequencing data.

A hallmark of Alzheimer’s disease (AD) is the extracellular aggregation of toxic amyloid-beta (Aβ) peptides in form of plaques. Here, we identify netoglitazone, an antidiabetic compound previously tested in humans, as an Aβ aggregation antagonist. Netoglitazone improved cognition and reduced microglia activity in a mouse model of AD. Using quantitative whole-brain three-dimensional histology (Q3D), we precisely identified brain regions where netoglitazone reduced the number and size of Aβ plaques. We demonstrate the utility of Q3D in preclinical drug evaluation for AD by providing a high-resolution brain-wide view of drug efficacy. Applying Q3D has the potential to improve pre-clinical drug evaluation by providing information that can help identify mechanisms leading to brain region-specific drug efficacy.

Vasocative-intestinal-peptide (VIP + ) and somatostatin (SST + ) interneurons are involved in modulating barrel cortex activity and perception during active whisking. Here we identify a developmental transition point of structural and functional rearrangements onto these interneurons around the start of active sensation at P14. Using in vivo two-photon Ca 2+ imaging, we find that before P14, both interneuron types respond stronger to a multi-whisker stimulus, whereas after P14 their responses diverge, with VIP + cells losing their multi-whisker preference and SST + neurons enhancing theirs. Additionally, we find that Ca 2+ signaling dynamics increase in precision as the cells and network mature. Rabies virus tracings followed by tissue clearing, as well as photostimulation-coupled electrophysiology reveal that SST + cells receive higher cross-barrel inputs compared to VIP + neurons at both time points. In addition, whereas prior to P14 both cell types receive direct input from the sensory thalamus, after P14 VIP + cells show reduced inputs and SST + cells largely shift to motor-related thalamic nuclei. Sensory neuronal circuits adapt during maturation when animals start to actively interact with the external world. The authors reveal structural and functional rearrangements of the input cortical interneurons receive around the time the animals start active sensation.

Many efforts targeting amyloid‐β (Aβ) plaques for the treatment of Alzheimer's Disease thus far have resulted in failures during clinical trials. Regional and temporal heterogeneity of efficacy and dependence on plaque maturity may have contributed to these disappointing outcomes. In this study, we mapped the regional and temporal specificity of various anti‐Aβ treatments through high‐resolution light‐sheet imaging of electrophoretically cleared brains. We assessed the effect on amyloid plaque formation and growth in Thy1‐APP/PS1 mice subjected to β‐secretase inhibitors, polythiophenes, or anti‐Aβ antibodies. Each treatment showed unique spatiotemporal Aβ clearance, with polythiophenes emerging as a potent anti‐Aβ compound. Furthermore, aligning with a spatial‐transcriptomic atlas revealed transcripts that correlate with the efficacy of each Aβ therapy. As observed in this study, there is a striking dependence of specific treatments on the location and maturity of Aβ plaques. This may also contribute to the clinical trial failures of Aβ‐therapies, suggesting that combinatorial regimens may be significantly more effective in clearing amyloid deposition. Synopsis The brain is highly compartmentalized with many distinct regions. It is unknown how drugs for treating Alzheimer's Disease (AD) work across brain regions and disease stages. We developed a technology to quantify the effects of different AD drugs throughout the brain at different time points. A novel technology was developed for high‐throughput optical mouse brain clarification and staining of Aβ plaques, followed by lightsheet imaging, brain atlas registration, and plaque morphology quantification. Mice were treated with either a BACE1 inhibitor, a polythiophene for stabilizing amyloid fibrils, or an anti‐Aβ antibody. Quantitative results show distinct Aβ plaque modification and removal across brain regions and disease stage. Spatial efficacy profiles of anti‐Aβ therapies were correlated with gene expression maps using a spatial transcriptomics brain atlas. Graphical Abstract The brain is highly compartmentalized with many distinct regions. It is unknown how drugs for treating Alzheimer's Disease (AD) work across brain regions and disease stages. We developed a technology to quantify the effects of different AD drugs throughout the brain at different time points.

Abstract Food addiction has become a popular notion in the media and scientific community, with many proposing that an addiction to food causes obesity. An article published in this journal in December 2017 by Tompkins et al. asserted that food addiction poses a barrier to the treatment of adolescent obesity. This review questions some of the methods, results, and perspectives offered by Tompkins et al. It also considers the extant evidence overall about this construct. The data about food addiction provide minimal support for the discriminant validity of this conceptualization relative to depressed binge eating. We believe that the evidence suggests that the potential harm outweighs the benefits of encouraging researchers, clinicians, and especially obese people to view food addiction as a cause of obesity or a barrier to effective weight management. Ultimately, this review concludes that the construct of food addiction does not serve the interests of those striving to lose weight permanently (i.e., weight controllers) nearly as well as an alternative perspective: weight controllers are athletes, not food addicts.

Transmissible spongiform encephalopathies (TSEs) are caused by the prion, which consists essentially of PrPSc, an aggregated, conformationally modified form of the cellular prion protein (PrPC). Although TSEs can be experimentally transmitted by intracerebral inoculation, most instances of infection in the field occur through extracerebral routes. The epidemics of kuru and variant Creutzfeldt-Jakob disease were caused by dietary exposure to prions, and parenteral administration of prion-contaminated hormones has caused hundreds of iatrogenic TSEs. In all these instances, the development of postexposure prophylaxis relies on understanding of how prions propagate from the site of entry to the brain. While much evidence points to lymphoreticular invasion followed by retrograde transfer through peripheral nerves, prions are present in the blood and may conceivably cross the blood-brain barrier directly. Here we have addressed the role of the blood-brain barrier (BBB) in prion disease propagation using Pdgfbret/ret mice which possess a highly permeable BBB. We found that Pdgfbret/ret mice have a similar prion disease incubation time as their littermate controls regardless of the route of prion transmission. These surprising results indicate that BBB permeability is irrelevant to the initiation of prion disease, even when prions are administered parenterally.

Abstract Background: Pediatric obesity is recognized as a worldwide epidemic. Treatment of this problem has proven difficult, but many promising interventions exist, including immersion treatment. The purpose of this study is to examine the potential influence of psychotropic medications on immersion treatment outcomes in a real-world treatment setting. Methods: This study examines the prescription rates of psychotropic medications and treatment process and outcomes of 642 adolescents in ten different cognitive behavioral therapeutic immersion weight-loss camps in the United States and in the United Kingdom. Results: The US participants received psychotropic medications at drastically varying rates by geographical location and overall at almost ten times the rate of UK participants. Those taking psychotropic medications engaged in treatment and decreased percentage overweight at similar rates as their nonmedicated peers. The medication group reported higher initial and final rates of distress, but both groups improved their moods during camp and exhibited smaller differences in mood ratings by the end of camp. Conclusions: Significantly higher prescription rates of psychotropic medication, especially evident comparing the United States to the United Kingdom, were unrelated to immersion obesity treatment process and outcomes for youth. Immersion treatment for obese adolescents appears effective regardless of psychotropic medication status of the participant. This finding supports the use of cognitive behavioral immersion treatments for adolescent obesity and leads to several possible conclusions and directions for future study.

Abstract Background: Various organizations published five sets of expert recommendations recently: 2007 Healthcare Organizations' Four Stage Model; 2006 Canadian Clinical Practice Guidelines; 2008 The Endocrine Society Recommendations; 2009 Seven Step Model; and 2010 US Preventive Task Force Recommendations. Methods: We compared the recommendations' approaches and conclusions pertaining to four treatments (self-help groups, outpatient cognitive-behavior therapy [CBT], immersion CBT, and surgery). Results: All of the expert committees supported using intensive dietary, physical activity, and cognitive-behavioral counseling; two of the five groups discouraged reliance on educational interventions alone, and two of the groups explicitly promoted a stepped-care approach. Conclusions: Greatest benefits may accrue by encouraging healthcare providers and parents to view medical management and education as foundations to change, but to pursue increasingly intensive viable options until overweight and obese children make clinically significant progress toward improved health and happiness.