Cellular anatomy of the mouse primary motor cortex.

An essential step toward understanding brain function is to establish a structural framework with cellular resolution on which multi-scale datasets spanning molecules, cells, circuits and systems can be integrated and interpreted1. Here, as part of the collaborative Brain Initiative Cell Census Network (BICCN), we derive a comprehensive cell type-based anatomical description of one exemplar brain structure, the mouse primary motor cortex, upper limb area (MOp-ul). Using genetic and viral labelling, barcoded anatomy resolved by sequencing, single-neuron reconstruction, whole-brain imaging and cloud-based neuroinformatics tools, we delineated the MOp-ul in 3D and refined its sublaminar organization. We defined around two dozen projection neuron types in the MOp-ul and derived an input-output wiring diagram, which will facilitate future analyses of motor control circuitry across molecular, cellular and system levels. This work provides a roadmap towards a comprehensive cellular-resolution description of mammalian brain architecture

Development and regeneration of neuronal circuits in the vertebrate retina

Thesis (Ph.D.)--University of Washington, 2016-08Like in other parts of the central nervous system (CNS), information processing in the retina depends upon the exquisite organization of synaptic connectivity amongst diverse neuronal cell types. Assembly of neuronal circuits during retinal development is highly orchestrated. Recapitulating the precision of this process presents a major challenge for therapeutic efforts to repair the retina after injury or disease in mammals. Whereas mammals cannot replenish lost neurons in their retinas, zebrafish show an innate ability to regenerate their retinas. In this work, I sought to advance our understanding of the restorative potential of retinal regeneration. I capitalized on the native regenerative capacity of the zebrafish to provide some of the first insights into the fidelity of neuronal replacement and integration in the retina. In Chapter 1, I review the factors and mechanisms that shape organized circuitry during retinal development, as well as summarize the current state of the field in teleost and mammalian retinal regeneration research. In Chapters 2 and 3, I investigate bipolar cells, interneurons that convey light signals from photoreceptors to the retinal output neurons. In Chapter 2, I explore the cellular strategies that functionally distinct bipolar cell types undertake during retinal development to attain their characteristic morphologies and dendritic wiring patterns. I use this knowledge in Chapter 3 as a framework to assess the ability of regenerated circuits to engage developmental mechanisms to re-establish their original patterning. I utilize a genetically targeted cell ablation technique to trigger regeneration of bipolar cells in situ, and investigate the precision with which regenerated cells integrate into a mature retinal network. In Chapter 4, I examine the specificity of endogenous neuronal replacement by comparing the composition of regenerated cone photoreceptor populations after ablation of distinct cone types. Lastly, in Chapter 5 I summarize my findings and discuss future directions to address questions raised by this work

Conditional and biased regeneration of cone photoreceptor types in the zebrafish retina

A major challenge in regenerative medicine is replacing cells lost through injury or disease. While significant progress has been made, much remains unknown about the accuracy of native regenerative programs in cell replacement. Here, we capitalized on the regenerative capacity and stereotypic retinal organization of zebrafish to determine the specificity with which retinal Müller glial cells replace lost neuronal cell types. By utilizing a targeted genetic ablation technique, we restricted death to all or to distinct cone photoreceptor types (red, blue or UV‐sensitive cones), enabling us to compare the composition of cones that are regenerated. We found that Müller glia produce cones of all types upon non‐discriminate ablation of these photoreceptors, or upon selective ablation of red or UV cones. Pan‐ablation of cones led to regeneration of the various cone types in relative abundances that resembled those of non‐ablated controls, i.e. red>green>UV ~ blue cones. Moreover, selective loss of red or UV cones biased production toward the cone type that was ablated. In contrast, ablation of blue cones alone largely failed to induce cone production at all, although it did induce cell division in Müller glia. The failure to produce cones upon selective elimination of blue cones may be due to their low abundance compared to other cone types. Alternatively, it may be that blue cone death alone does not trigger a change in progenitor competency to support cone genesis. Our findings add to the growing notion that cell replacement during regeneration does not perfectly mimic programs of cell generation during development

The GJ 504 system revisited. Combining interferometric, radial velocity, and high contrast imaging data

International audienceContext. The G-type star GJ504A is known to host a 3-35 M<SUB>Jup</SUB> companion whose temperature, mass, and projected separation all contribute to making it a test case for planet formation theories and atmospheric models of giant planets and light brown dwarfs. <BR /> Aims: We aim at revisiting the system age, architecture, and companion physical and chemical properties using new complementary interferometric, radial-velocity, and high-contrast imaging data. <BR /> Methods: We used the CHARA interferometer to measure GJ504A's angular diameter and obtained an estimation of its radius in combinationwith the HIPPARCOS parallax. The radius was compared to evolutionary tracks to infer a new independent age range for the system. We collected dual imaging data with IRDIS on VLT/SPHERE to sample the near-infrared (1.02-2.25 mum) spectral energy distribution (SED) of the companion. The SED was compared to five independent grids of atmospheric models (petitCODE,Exo-REM, BT-SETTL, Morley et al., and ATMO) to infer the atmospheric parameters of GJ 504b and evaluate model-to-model systematic errors. In addition, we used a specific model grid exploring the effect of different C/O ratios. Contrast limits from 2011 to 2017 were combined with radial velocity data of the host star through the MESS2 tool to define upper limits on the mass of additional companions in the system from 0.01 to 100 au. We used an MCMC fitting tool to constrain the companion'sorbital parameters based on the measured astrometry, and dedicated formation models to investigate its origin. <BR /> Results: We report a radius of 1.35 ± 0.04 R<SUB>&sun;</SUB> for GJ504A. The radius yields isochronal ages of 21 ± 2 Myr or 4.0 ± 1.8 Gyr for the system and line-of-sight stellar rotation axis inclination of 162.4<SUB>-4.3</SUB><SUP> 3.8</SUP> degrees or 186.6<SUB>-3.8</SUB><SUP> 4.3</SUP> degrees. We re-detect the companion in the Y2, Y3, J3, H2, and K1 dual-band images. The complete 1-4 mum SED shape of GJ504b is best reproduced by T8-T9.5 objects with intermediate ages (<= 1.5Gyr), and/or unusual dusty atmospheres and/or super-solar metallicities. All atmospheric models yield T<SUB>eff</SUB> = 550 ± 50 K for GJ504b and point toward a low surface gravity (3.5-4.0 dex). The accuracy on the metallicity value is limited by model-to-model systematics; it is not degenerate with the C/O ratio. We derive log L/L<SUB>&sun;</SUB> = -6.15 ± 0.15 dex for the companion from the empirical analysis and spectral synthesis. The luminosity and T<SUB>eff</SUB> yield masses of M = 1.3<SUB>-0.3</SUB><SUP> 0.6</SUP> M<SUB>Jup</SUB> and M = 23<SUB>-9</SUB><SUP> 10</SUP> M<SUB>Jup</SUB> for the young and old age ranges, respectively. The semi-major axis (sma) is above 27.8 au and the eccentricity is lower than 0.55. The posterior on GJ 504b's orbital inclination suggests a misalignment with the rotation axis of GJ 504A. We exclude additional objects (90% prob.) more massive than 2.5 and 30 M<SUB>Jup</SUB> with semi-major axes in the range 0.01-80 au for the young and old isochronal ages, respectively. <BR /> Conclusions: The mass and semi-major axis of GJ 504b are marginally compatible with a formation by disk-instability if the system is 4 Gyr old. The companion is in the envelope of the population of planets synthesized with our core-accretion model. Additional deep imaging and spectroscopic data with SPHERE and JWST should help to confirm the possible spin-orbit misalignment and refine the estimates on the companion temperature, luminosity, and atmospheric composition