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A method for 3D differentiation of human pluripotent stem cells yields brain cortical spheroids with functional neurons and astrocytes. The spheroids can be sliced for imaging and electrophysiological studies. The human cerebral cortex develops through an elaborate succession of cellular events that, when disrupted, can lead to neuropsychiatric disease. The ability to reprogram somatic cells into pluripotent cells that can be differentiated in vitro provides a unique opportunity to study normal and abnormal corticogenesis. Here, we present a simple and reproducible 3D culture approach for generating a laminated cerebral cortex–like structure, named human cortical spheroids (hCSs), from pluripotent stem cells. hCSs contain neurons from both deep and superficial cortical layers and map transcriptionally to in vivo fetal development. These neurons are electrophysiologically mature, display spontaneous activity, are surrounded by nonreactive astrocytes and form functional synapses. Experiments in acute hCS slices demonstrate that cortical neurons participate in network activity and produce complex synaptic events. These 3D cultures should allow a detailed interrogation of human cortical development, function and disease, and may prove a versatile platform for generating other neuronal and glial subtypes in vitro .

Key Points Synapses of the mammalian CNS are highly complex structures composed of thousands of distinct proteins. Synaptic proteins are often expressed in variable patterns across different brain regions and neuronal populations, suggesting a high degree of molecular diversity in synapses. Synapse types have long been discriminated on the basis of neurotransmitter molecules, but it is now necessary to recognize much deeper diversity of both synaptic protein composition and function within each traditional neurotransmitter type. Intra-type synapse diversity reflects many factors, including diversity of presynaptic and postsynaptic parent neurons, activity histories and influences of third-party neurons and glial cells. Intra-type functional diversity is reflected in strength, kinetics, voltage-dependence and plasticity of synaptic transmission. Improving knowledge of the relationships between molecular and functional aspects of diversity is sure to illuminate principals of synaptic circuit function. Proteins identifiable at mature synapses include adhesion molecules that guide selective synaptogenesis during development. Such molecules may encode circuit context and connectivity in the mature brain and aid circuit reconstruction efforts. Many mental and neurological disorders reflect mutations in synaptic proteins expressed in subsets of synapses. A better grasp of synapse molecular diversity is certain to contribute to our understanding of specific brain disorders. New techniques that probe the combinatorial expression of proteins at the level of individual synapses within the brain are bolstering our efforts to link intra-type diversity to distinct physiological and structural properties of synaptic connections and brain circuits. The use of sophisticated molecular and genetic techniques has revealed the complexity and diversity of the protein composition of different synapses. Smith and colleagues describe methods for investigating synaptic diversity and show how knowledge gained from these studies can advance our understanding of neural circuit organization and function. Pioneering studies in the middle of the twentieth century revealed substantial diversity among mammalian chemical synapses and led to a widely accepted classification of synapse type on the basis of neurotransmitter molecule identity. Subsequently, powerful new physiological, genetic and structural methods have enabled the discovery of much deeper functional and molecular diversity within each traditional neurotransmitter type. Today, this deep diversity continues to pose both daunting challenges and exciting new opportunities for neuroscience. Our growing understanding of deep synapse diversity may transform how we think about and study neural circuit development, structure and function.

The development of the nervous system involves a coordinated succession of events including the migration of GABAergic (γ-aminobutyric-acid-releasing) neurons from ventral to dorsal forebrain and their integration into cortical circuits. However, these interregional interactions have not yet been modelled with human cells. Here we generate three-dimensional spheroids from human pluripotent stem cells that resemble either the dorsal or ventral forebrain and contain cortical glutamatergic or GABAergic neurons. These subdomain-specific forebrain spheroids can be assembled in vitro to recapitulate the saltatory migration of interneurons observed in the fetal forebrain. Using this system, we find that in Timothy syndrome—a neurodevelopmental disorder that is caused by mutations in the Ca V 1.2 calcium channel—interneurons display abnormal migratory saltations. We also show that after migration, interneurons functionally integrate with glutamatergic neurons to form a microphysiological system. We anticipate that this approach will be useful for studying neural development and disease, and for deriving spheroids that resemble other brain regions to assemble circuits in vitro . Human pluripotent stem cells were used to develop dorsal and ventral forebrain 3D spheroids, which can be assembled to study interneuron migration and to derive a functionally integrated forebrain system with cortical interneurons and glutamatergic neurons. Modelling forebrains in a dish GABAergic neurons play important roles in brain function and are implicated in numerous psychiatric disorders. They migrate long distances from the ventral to the dorsal forebrain before integrating to cortical circuits. In vitro modelling of GABAergic neuronal differentiation during this interaction would allow us to investigate the cause of human brain disorders associated with defects in neuronal migration, but this has so far been difficult. Sergiu Paşca and colleagues have developed an approach for generating neural three-dimensional spheroids resembling either the ventral or dorsal forebrain. They show that assembling the two types of spheroids separately in vitro allows the saltatory migration of human interneurons into the cortex, as seen in human development, and the formation of functional synapses with the dorsally derived cortical glutamatergic neurons. In this context, they find that interneurons from Timothy syndrome patients exhibit perturbation in migration patterns. Elsewhere in this issue, Paola Arlotta and colleagues carried out single cell expression analysis on cells from human brain organoids to investigate the nature of cells generated by these three-dimensional models.

During early development of the mammalian cerebral cortex, young neurons migrate outward from the site of their final mitosis in the ventricular zone into the cortical plate, where they form the adult cortex. Time-lapse confocal microscopy was used to observe directly the dynamic behaviors of migrating cells in living slices of developing cortex. The majority of cells migrated along a radial pathway, consistent with the view that cortical neurons migrate along radial glial fibers. A fraction of cells, however, turned within the intermediate zone and migrated orthogonal to the radial fibers. This orthogonal migration may contribute to the tangential dispersion of clonally related cortical neurons.

During early development of the mammalian cerebral cortex, young neurons migrate outward from the site of their final mitosis in the ventricular zone into the cortical plate, where they form the adult cortex. Time-lapse confocal microscopy was used to observe directly the dynamic behaviors of migrating cells in living slices of developing cortex. The majority of cells migrated along a radial pathway, consistent with the view that cortical neurons migrate along radial glial fibers. A fraction of cells, however, turned within the intermediate zone and migrated orthogonal to the radial fibers. This orthogonal migration may contribute to the tangential dispersion of clonally related cortical neurons.

A group of medical ethicists and pediatricians asks for reconsideration of the recent Office for Human Research Protections decision about informed consent in SUPPORT. To the Editor: We are a group of scholars and leaders in bioethics and pediatrics with extensive experience in ethical and regulatory issues in pediatrics and human subjects research. We urge the Office for Human Research Protections (OHRP) to withdraw its notification to the institutions involved in the Surfactant, Positive Pressure, and Oxygenation Randomized Trial (SUPPORT) that they failed to meet regulatory informed-consent requirements, in particular regarding reasonably foreseeable risks of enrollment in the study. We believe that this conclusion was a substantive error and will have adverse implications for future research. SUPPORT was undertaken, in part, because neonatologists lacked . . .

Despite decades of study, conservation biocontrol via manipulation of landscape elements has not become a mainstream strategy for pest control. Meanwhile, conservation groups and governments rarely consider the impacts of land management on pest control, and growers can even fear that conservation biocontrol strategies may exacerbate pest problems. By finding leverage points among these actors, there may be opportunities to align them to promote more widespread adoption of conservation biological control at the landscape-scale. But are ecologists measuring the right things and presenting the right evidence to enable such alignment? We articulate key concerns of growers, conservation groups, and governments with regards to implementing conservation biological control at the landscape scale and argue that if ecologists want to gain more traction, we need to reconsider what we measure, for what goals, and for which audiences. A wider set of landscape objectives that ecologists should consider in our measurements include risk management for growers and co-benefits of multifunctional landscapes for public actors. Ecologists need to shift our paradigm toward longer-term, dynamic measurements, and build cross-disciplinary understanding with socioeconomic and behavioral sciences, to enable better integration of the objectives of these diverse actors that will be necessary for landscape management for conservation biocontrol to achieve its full potential.

According to the American Association of Nurse Practitioners, NP malpractice claim rates continue to be low, and only 2% of NPs have been named as primary defendants. Caring for more complex chronically ill patients also increases the likelihood of liability and malpractice claims. Since the implementation of the Patient Protection and Affordable Care Act, more NPs are becoming primary care providers of choice and are caring for patients with more complex medical problems.

In this study, we replicated and extended the work of Williams et al. (2020) by finding that most individuals believe the Freudian perspective on dreams, regardless of whether or not the theory description contained Freud's name in a citation. Also consistent with prior work, we found participants' attribution of meaning to celebrity dreams to be higher when the dream about the celebrity was cast in a positive rather than negative light. In a key extension we documented more specificity of the relationships among dream perspective support, dream scenario valence, and celebrity attachment and admiration by examining all subscales of the Celebrity Attitude Scale (CAS). We found participants who supported the Freudian perspective tended to score higher on the Intense-Personal (IP) subscale than participants who supported a non-Freudian perspective. Also, those who experienced a positive dream scenario about their favorite celebrity tended to score higher on the Entertainment-Social (ES) subscale than participants who experienced a negative dream scenario. Through this replication and extension, we proposed multiple avenues for future research.

A web-based survey was conducted by the Federation of Veterinarians of Europe with the support of the European Medicines Agency to gain a better insight into the adverse event reporting habits of veterinary practitioners and the level of information on reported adverse events that flows back to them. It was completed by 3545 veterinarians. The findings indicate marked under-reporting and that the system is poorly equipped to deal with lack of expected efficacy, with few cases reported and most found to be inconclusive. It was also found that feedback systems are greatly lacking. In order to increase spontaneous reporting, there is a need to make reporting easier (eg, by developing mobile apps, to incorporate the reporting into the practice management system software) and to make veterinarians better aware of the importance of reporting and the added value it may bring. Feedback systems should be improved. The best way to motivate reporters is to demonstrate that the reports they submit are indeed useful and contribute to the improved use of veterinary medicinal products. The major role veterinarians can play in improving animal health, welfare and public health by reporting adverse events needs to be further promoted.