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Summary The human brain has undergone rapid expansion since humans diverged from other great apes, but the mechanism of this human-specific enlargement is still unknown. Here, we use cerebral organoids derived from human, gorilla, and chimpanzee cells to study developmental mechanisms driving evolutionary brain expansion. We find that neuroepithelial differentiation is a protracted process in apes, involving a previously unrecognized transition state characterized by a change in cell shape. Furthermore, we show that human organoids are larger due to a delay in this transition, associated with differences in interkinetic nuclear migration and cell cycle length. Comparative RNA sequencing (RNA-seq) reveals differences in expression dynamics of cell morphogenesis factors, including ZEB2, a known epithelial-mesenchymal transition regulator. We show that ZEB2 promotes neuroepithelial transition, and its manipulation and downstream signaling leads to acquisition of nonhuman ape architecture in the human context and vice versa, establishing an important role for neuroepithelial cell shape in human brain expansion., Graphical abstract, Highlights • Human brain organoids are expanded relative to nonhuman apes prior to neurogenesis • Ape neural progenitors go through a newly identified transition morphotype state • Delayed morphological transition with shorter cell cycles underlie human expansion • ZEB2 is as an evolutionary regulator of this transition, Cerebral organoid models reveal that differences in the duration of a developmental transitional state driven by the factor ZEB2 underlie the basis of brain expansion in humans in comparison to great apes.

Purpose This article investigates the possible connections between the level of chronic stress and success of steroid therapy in patients with sudden sensorineural hearing loss (SSNHL). Method A single-center, retrospective, longitudinal cohort study on 55 patients in a tertiary referral otology center was examined. Patients diagnosed with SSNHL between 2014 and 2017 were asked to complete a Measure of Perceived Stress (Brajac, Tkalcic, Dragojević, & Gruber, 2003 ) questionnaire. Inclusion criteria were patients > 18 years of age, SSNHL diagnosed within 4 previous weeks, completed steroid treatment, and complete documentation. Results There were 30 patients (55%) that showed significant improvement in their pure-tone audiogram (PTA) hearing threshold average (≥ 15 dB) after steroid treatment. Two-step cluster analysis identified 3 clusters based on average PTA hearing threshold recovery and average Measure of Perceived Stress scores. The difference between pretreatment and posttreatment hearing levels was significantly higher in the cluster with moderate stress compared to clusters with mild and high stress levels (Kruskal–Wallis test, Friedman test, p < .001). There were no significant differences in average PTA hearing threshold recovery after steroid therapy between groups of patients with mild and severe stress. Conclusion Patients with moderate stress levels show significantly better results after steroid treatment for SSNHL than patients with low or high stress levels.

Subventricular zone (SVZ) progenitors are a hallmark of the developing neocortex. Recent studies described a novel type of SVZ progenitor that retains a basal process at mitosis, sustains expression of radial glial markers, and is capable of self-renewal. These progenitors, referred to here as basal radial glia (bRG), occur at high relative abundance in the SVZ of gyrencephalic primates (human) and nonprimates (ferret) but not lissencephalic rodents (mouse). Here, we analyzed the occurrence of bRG cells in the embryonic neocortex of the common marmoset Callithrix jacchus, a near-lissencephalic primate. bRG cells, expressing Pax6, Sox2 (but not Tbr2), glutamate aspartate transporter, and glial fibrillary acidic protein and retaining a basal process at mitosis, occur at similar relative abundance in the marmoset SVZ as in human and ferret. The proportion of progenitors in M-phase was lower in embryonic marmoset than developing ferret neocortex, raising the possibility of a longer cell cycle. Fitting the gyrification indices of 26 anthropoid species to an evolutionary model suggested that the marmoset evolved from a gyrencephalic ancestor. Our results suggest that a high relative abundance of bRG cells may be necessary, but is not sufficient, for gyrencephaly and that the marmoset's lissencephaly evolved secondarily by changing progenitor parameters other than progenitor type. © The Author 2011., This work was supported by the Strategic Research Program for Brain Sciences from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan to E.S. and H.O. and by ‘‘Funding Program for World-leading Innovative R&D on Science and Technology’’ to E.S. and H.O. W.B.H. was supported by grants from the Deutsche Forschungsgemeinschaft (DFG) (SFB 655, A2; TRR 83, Tp6) and the European Research Council (250197), by the DFG-funded Center for Regenerative Therapies Dresden, and by the Fonds der Chemischen Industrie. V.B. was supported by grants from the International Human Frontier Science Program Organization (CDA0027/2007-C), MICINN (SAF2009-07367), and CONSOLIDER (CSD2007-00023).

Recent breakthroughs in pluripotent stem cell technologies have enabled a new class of in vitro systems for functional modeling of human brain development. These advances, in combination with improvements in neural differentiation methods, allow the generation of in vitro systems that reproduce many in vivo features of the brain with remarkable similarity. Here, we describe advances in the development of these methods, focusing on neural rosette and organoid approaches, and compare their relative capabilities and limitations. We also discuss current technical hurdles for recreating the cell-type complexity and spatial architecture of the brain in culture and offer potential solutions.

Cnidarians, the sister group to bilaterians, have a simple diffuse nervous system. This morphological simplicity and their phylogenetic position make them a crucial group in the study of the evolution of the nervous system. The development of their nervous systems is of particular interest, as by uncovering the genetic programme that underlies it, and comparing it with the bilaterian developmental programme, it is possible to make assumptions about the genes and processes involved in the development of ancestral nervous systems. Recent advances in sequencing methods, genetic interference techniques and transgenic technology have enabled us to get a first glimpse into the molecular network underlying the development of a cnidarian nervous system—in particular the nervous system of the anthozoanNematostella vectensis. It appears that much of the genetic network of the nervous system development is partly conserved between cnidarians and bilaterians, with Wnt and bone morphogenetic protein (BMP) signalling, andSoxgenes playing a crucial part in the differentiation of neurons. However, cnidarians possess some specific characteristics, and further studies are necessary to elucidate the full regulatory network. The work on cnidarian neurogenesis further accentuates the need to study non-model organisms in order to gain insights into processes that shaped present-day lineages during the course of evolution.

Expansion of the neocortex is a hallmark of human evolution. However, it remains an open question what adaptive mechanisms facilitated its expansion. Here we show, using gyrencephaly index (GI) and other physiological and life-history data for 102 mammalian species, that gyrencephaly is an ancestral mammalian trait. We provide evidence that the evolution of a highly folded neocortex, as observed in humans, requires the traversal of a threshold of 10^9 neurons, and that species above and below the threshold exhibit a bimodal distribution of physiological and life-history traits, establishing two phenotypic groups. We identify, using discrete mathematical models, proliferative divisions of progenitors in the basal compartment of the developing neocortex as evolutionarily necessary and sufficient for generating a fourteen-fold increase in daily prenatal neuron production and thus traversal of the neuronal threshold. We demonstrate that length of neurogenic period, rather than any novel progenitor-type, is sufficient to distinguish cortical neuron number between species within the same phenotypic group., Comment: Currently under review; 38 pages, 5 Figures, 13 Supplementary Figures, 2 Tables

Mota and Herculano-Houzel (Reports, 3 July 2015, p. 74) assign power functions to neuroanatomical data and present a model to account for evolutionary patterns of cortical folding in the mammalian brain. We detail how the model assumptions are in conflict with experimental and observational work and show that the model itself does not accurately fit the data.