There has been considerable progress in identifying signaling pathways directing the differentiation of human pluripotent stem cells (hPSCs) into specialized cell types including neurons. However, extrinsic factor-based differentiation of hPSCs is a slow, step-wise process mimicking the protracted timing of normal human development. Using a small molecule screen we identified a combination of five small molecule pathway inhibitors sufficient to yield hPSC-derived neurons at >75% efficiency within 10 days of differentiation. The resulting neurons express canonical markers and functional properties of human nociceptors including TTX-resistant, SCN10A-dependent sodium currents and response to nociceptive stimuli including ATP and capsaicin. Neuronal fate acquisition occurs three-fold faster than during in vivo1 development suggesting that use of small molecule pathway inhibitors could develop into a general strategy for accelerating developmental timing in vitro. The quick and high efficiency derivation of nociceptors offers unprecedented access to this medically relevant cell type for studies of human pain.

The neocortex contains excitatory neurons and inhibitory interneurons. Clones of neocortical excitatory neurons originating from the same progenitor cell are spatially organized and contribute to the formation of functional microcircuits. In contrast, relatively little is known about the production and organization of neocortical inhibitory interneurons. We found that neocortical inhibitory interneurons were produced as spatially organized clonal units in the developing ventral telencephalon. Furthermore, clonally related interneurons did not randomly disperse but formed spatially isolated clusters in the neocortex. Individual clonal clusters consisting of interneurons expressing the same or distinct neurochemical markers exhibited clear vertical or horizontal organization. These results suggest that the lineage relationship plays a pivotal role in the organization of inhibitory interneurons in the neocortex.

This is the first study of the genetic diversity and structure of the big tree rhododendron, Rhododendron protistum var. giganteum, which is a highly endangered species with only two known endemic populations in a small area in the southern part of Yunnan Province in China. We detected moderate to high genetic diversity at the species level, but low genetic differentiation between the two extant populations. These results suggest that some rare and endangered species are able to maintain high levels of genetic diversity even at small population sizes.

The neocortex plays a key role in higher-order brain functions, such as perception, language and decision-making. Since the groundbreaking work of Ramón y Cajal over a century ago, defining the neural circuits underlying brain functions has been a field of intense study. Here, we review recent findings on the formation of neocortical circuits, which have taken advantage of improvements to mouse genetics and circuit-mapping tools. These findings are beginning to reveal how individual components of circuits are generated and assembled during development, and how early developmental processes, such as neurogenesis and neuronal migration, guide precise circuit assembly. Key words: Lineage, Neuronal circuits, Neocortex IntroductionThe mammalian cerebral cortex is composed of the archicortex (hippocampal region), the paleocortex (olfactory cortex) and the neocortex, with the last being the evolutionarily youngest region. The neocortex is composed of two major classes of neurons: glutamatergic projection neurons (see Glossary, Box 1), which elicit excitation in postsynaptic neurons and generate circuit output; and GABA (γ-aminobutyric acid)-ergic interneurons (see Glossary, Box 1), which typically trigger inhibition in postsynaptic neurons and are essential for shaping circuit output. It is generally accepted that two defining structural and functional features of the neocortex are lamination and radial columns (Douglas and Martin, 2004). Together, these features provide the basic framework on which neocortical circuits are built. Interestingly, both of these features are tightly linked to early developmental events, including neurogenesis and neuronal migration. In this Review, we discuss recent findings on the generation, migration and organization of excitatory and inhibitory neurons in the neocortex, with a focus on how the lineage history of neurons influences the assembly of functional circuits. Lamination: a hallmark of the neocortexThe neocortex is a continuous six-layered structure. All components of neocortical circuits, including afferents, excitatory cells, inhibitory cells and efferents, are organized with respect to the laminae (Douglas and Martin, 2004). Cortical lamination is generated as a result of radial migration of newborn excitatory neurons during development (Hatten, 1999;Rakic, 1971;Rakic, 1972). Glutamatergic excitatory neurons are produced from progenitor cells (Fig. 1A) that reside in the proliferative zone of the dorsal telencephalon (see Glossary, Box 1). In the earliest stages, the neural tube is composed of a single layer of neuroepithelial (NE) cells that proliferate rapidly (Breunig et al., 2011). A small fraction of NE cells undergoes asymmetric division to generate the first wave of postmitotic neurons, which migrate out radially and form a transient structure called the preplate (see Glossary, Box 1) (Del Río et al., 2000;Marin-Padilla, 1970;Marin-Padilla, 1971;Marin-Padilla, 1978). As development proceeds, NE cells transform into a more fate-restricted progenitor type: radial glial ...

Melatonin is involved in regulation of a variety of physiological functions through activation of specific G-protein coupled receptors. However, the neuromodulatory role of melatonin, released from photoreceptors in the retina, is poorly understood. Here we show that melatonin enhances the sensitivity of the rod signal pathway by potentiating signal transfer from rod photoreceptors to ON bipolar cells (Rod-ON-BCs). Whole-cell patch-clamp recordings showed that melatonin induced a sustained inward current from Rod-ON-BCs, through activation of the melatonin MT2 receptor, which was identified as one mediated by a cGMP-dependent cation channel. Consistent with this, melatonin was found, using immunocytochemistry, to increase intracellular cGMP levels, which was identified due to an inhibition of phosphodiesterase. Physiologically, melatonin potentiated responses of Rod-ON-BCs to simulated light flashes (brief puffs of CPPG, an mGluR6 antagonist, in the presence of L-AP4, an mGluR6 agonist), which was mediated by cGMP-dependent kinase, and increased the amplitude of the scotopic electroretinographic b-wave, a reflection of Rod-ON-BC activity. These results suggest that melatonin, being at a higher level at night, may improve the signal/noise ratio for rod signals in the outer retina by enhancing signal transfer from rods to BCs.