Explore the vast range of titles available.

Huntington’s disease (HD) causes selective degeneration of striatal and cortical neurons, resulting in cell mosaicism of coexisting still functional and dysfunctional cells. The impact of non-cell autonomous mechanisms between these cellular states is poorly understood. Here we generated telencephalic organoids with healthy or HD cells, grown separately or as mosaics of the two genotypes. Single-cell RNA sequencing revealed neurodevelopmental abnormalities in the ventral fate acquisition of HD organoids, confirmed by cytoarchitectural and transcriptional defects leading to fewer GABAergic neurons, while dorsal populations showed milder phenotypes mainly in maturation trajectory. Healthy cells in mosaic organoids restored HD cell identity, trajectories, synaptic density, and communication pathways upon cell-cell contact, while showing no significant alterations when grown with HD cells. These findings highlight cell-type-specific alterations in HD and beneficial non-cell autonomous effects of healthy cells, emphasizing the therapeutic potential of modulating cell-cell communication in disease progression and treatment. Mosaic organoids where pathological and healthy cells are grown together, reveal the rescue of phenotypes in pathological cells due to communication with healthy cells without harming them, as demonstrated by single-cell RNA-sequencing data.

Systematic analyses of spatiotemporal gene expression trajectories during organogenesis have been challenging because diverse cell types at different stages of maturation and differentiation coexist in the emerging tissues. We identified discrete cell types as well as temporally and spatially restricted trajectories of radial glia maturation and neurogenesis in developing human telencephalon. These lineage-specific trajectories reveal the expression of neurogenic transcription factors in early radial glia and enriched activation of mammalian target of rapamycin signaling in outer radial glia. Across cortical areas, modest transcriptional differences among radial glia cascade into robust typological distinctions among maturing neurons. Together, our results support a mixed model of topographical, typological, and temporal hierarchies governing cell-type diversity in the developing human telencephalon, including distinct excitatory lineages emerging in rostral and caudal cerebral cortex.

Dorsoventral patterning of the telencephalon is established early in forebrain development and underlies many of the regional subdivisions that are critical to the later organization of neural circuits in the cerebral cortex and basal ganglia. Sonic hedgehog (Shh) is involved in the generation of the ventral-most telencephalic cells, but the identity of the extrinsic signal(s) that induce dorsal character in telencephalic cells is not known. Here we show in chick embryos that sequential Wnt and fibroblast growth factor (FGF) signaling specifies cells of dorsal telencephalic character.

The basic helix-loop-helix transcription factors Ascl1/Mash1, Hes1, and Olig2 regulate fate choice of neurons, astrocytes, and oligodendrocytes, respectively. These same factors are coexpressed by neural progenitor cells. Here, we found by time-lapse imaging that these factors are expressed in an oscillatory manner by mouse neural progenitor cells. In each differentiation lineage, one of the factors becomes dominant. We used optogenetics to control expression of Ascl1 and found that, although sustained Ascl1 expression promotes neuronal fate determination, oscillatory Ascl1 expression maintains proliferating neural progenitor cells. Thus, the multipotent state correlates with oscillatory expression of several fate-determination factors, whereas the differentiated state correlates with sustained expression of a single factor.

The mechanisms governing the expansion of neuron number in specific brain regions are still poorly understood. Enlarged neuron numbers in different species are often anticipated by increased numbers of progenitors dividing in the subventricular zone. Here we present live imaging analysis of radial glial cells and their progeny in the ventral telencephalon, the region with the largest subventricular zone in the murine brain during neurogenesis. We observe lineage amplification by a new type of progenitor, including bipolar radial glial cells dividing at subapical positions and generating further proliferating progeny. The frequency of this new type of progenitor is increased not only in larger clones of the mouse lateral ganglionic eminence but also in cerebral cortices of gyrated species, and upon inducing gyrification in the murine cerebral cortex. This implies key roles of this new type of radial glia in ontogeny and phylogeny. Amplification of neural progenitor cells mediates expansion of brain regions. Using imaging of progenitor cell amplification in the mouse ventral forebrain, the authors identify a new progenitor type with high frequency, which they also show to be present in expanded brain regions of other species.

Exposure to predator scents triggers an instinctive fear response in mice, including a surge in blood levels of stress hormones; here, the amygdalo-piriform transition area is identified as provoking these hormonal responses. Neural circuits responsive to predator odours Exposure to volatile predator scents triggers an instinctive fear response in mice, including a surge in the stress hormones corticotrophin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH) and corticosterone. Such stereotyped responses are likely to be mediated by hard-wired neural circuits, but the olfactory areas involved have so far remain unknown. Here Linda Buck and colleagues identify the amygdalo-piriform transition area as the only olfactory area upstream of hypothalamic CRH neurons that is activated by volatile predator odours, and show that this area mediates hormonal but not behavioural fear responses to these odours. Instinctive reactions to danger are critical to the perpetuation of species and are observed throughout the animal kingdom. The scent of predators induces an instinctive fear response in mice that includes behavioural changes, as well as a surge in blood stress hormones that mobilizes multiple body systems to escape impending danger 1 , 2 . How the olfactory system routes predator signals detected in the nose to achieve these effects is unknown. Here we identify a specific area of the olfactory cortex in mice that induces stress hormone responses to volatile predator odours. Using monosynaptic and polysynaptic viral tracers, we found that multiple olfactory cortical areas transmit signals to hypothalamic corticotropin-releasing hormone (CRH) neurons, which control stress hormone levels. However, only one minor cortical area, the amygdalo-piriform transition area (AmPir), contained neurons upstream of CRH neurons that were activated by volatile predator odours. Chemogenetic stimulation of AmPir activated CRH neurons and induced an increase in blood stress hormones, mimicking an instinctive fear response. Moreover, chemogenetic silencing of AmPir markedly reduced the stress hormone response to predator odours without affecting a fear behaviour. These findings suggest that AmPir, a small area comprising <5% of the olfactory cortex, plays a key part in the hormonal component of the instinctive fear response to volatile predator scents.

Furutachi et al . identified a slowly dividing subpopulation of embryonic progenitors that later gives rise to most adult neural stem cells (NSCs) in the subependymal zone. Moreover, they found that p57 is responsible for the slow cell cycle of this embryonic population and acts causally in the emergence of adult NSCs. The mechanism by which adult neural stem cells (NSCs) are established during development is unclear. In this study, analysis of cell cycle progression by examining retention of a histone 2B (H2B)-GFP fusion protein revealed that, in a subset of mouse embryonic neural progenitor cells (NPCs), the cell cycle slows between embryonic day (E) 13.5 and E15.5 while other embryonic NPCs continue to divide rapidly. By allowing H2B-GFP expressed at E9.5 to become diluted in dividing cells until the young adult stage, we determined that a majority of NSCs in the young adult subependymal zone (SEZ) originated from these slowly dividing embryonic NPCs. The cyclin-dependent kinase inhibitor p57 is highly expressed in this embryonic subpopulation, and the deletion of p57 impairs the emergence of adult NSCs. Our results suggest that a substantial fraction of adult SEZ NSCs is derived from a slowly dividing subpopulation of embryonic NPCs and identify p57 as a key factor in generating this embryonic origin of adult SEZ NSCs.

Spatial learning in teleost fish requires an intact telencephalon 1 , a brain region that contains putative analogues to components of the mammalian limbic system (for example, hippocampus) 2 – 4 . However, cells fundamental to spatial cognition in mammals—for example, place cells (PCs) 5 , 6 —have yet to be established in any fish species. In this study, using tracking microscopy to record brain-wide calcium activity in freely swimming larval zebrafish 7 , we compute the spatial information content 8 of each neuron across the brain. Strikingly, in every recorded animal, cells with the highest spatial specificity were enriched in the zebrafish telencephalon. These PCs form a population code of space from which we can decode the animal’s spatial location across time. By continuous recording of population-level activity, we found that the activity manifold of PCs refines and untangles over time. Through systematic manipulation of allothetic and idiothetic cues, we demonstrate that zebrafish PCs integrate multiple sources of information and can flexibly remap to form distinct spatial maps. Using analysis of neighbourhood distance between PCs across environments, we found evidence for a weakly preconfigured network in the telencephalon. The discovery of zebrafish PCs represents a step forward in our understanding of spatial cognition across species and the functional role of the early vertebrate telencephalon. Using a tracking microscope for freely moving animals, the authors discover a population of place cells in the zebrafish brain and demonstrate that a non-amniote brain is capable of integrating allothetic and idiothetic information to create a neural map of space.

Background Fear conditioning is a form of learning essential for animal survival and used as a behavioral paradigm to study the mechanisms of learning and memory. In mammals, the amygdala plays a crucial role in fear conditioning. In teleost, the medial zone of the dorsal telencephalon (Dm) has been postulated to be a homolog of the mammalian amygdala by anatomical and ablation studies, showing a role in conditioned avoidance response. However, the neuronal populations required for a conditioned avoidance response via the Dm have not been functionally or genetically defined. Results We aimed to identify the neuronal population essential for fear conditioning through a genetic approach in zebrafish. First, we performed large-scale gene trap and enhancer trap screens, and created transgenic fish lines that expressed Gal4FF, an engineered version of the Gal4 transcription activator, in specific regions in the brain. We then crossed these Gal4FF-expressing fish with the effector line carrying the botulinum neurotoxin gene downstream of the Gal4 binding sequence UAS, and analyzed the double transgenic fish for active avoidance fear conditioning. We identified 16 transgenic lines with Gal4FF expression in various brain areas showing reduced performance in avoidance responses. Two of them had Gal4 expression in populations of neurons located in subregions of the Dm, which we named 120A-Dm neurons. Inhibition of the 120A-Dm neurons also caused reduced performance in Pavlovian fear conditioning. The 120A-Dm neurons were mostly glutamatergic and had projections to other brain regions, including the hypothalamus and ventral telencephalon. Conclusions Herein, we identified a subpopulation of neurons in the zebrafish Dm essential for fear conditioning. We propose that these are functional equivalents of neurons in the mammalian pallial amygdala, mediating the conditioned stimulus–unconditioned stimulus association. Thus, the study establishes a basis for understanding the evolutionary conservation and diversification of functional neural circuits mediating fear conditioning in vertebrates.

Increasing evidence suggests that early neurodevelopmental defects in Huntington’s disease (HD) patients could contribute to the later adult neurodegenerative phenotype. Here, by using HD-derived induced pluripotent stem cell lines, we report that early telencephalic induction and late neural identity are affected in cortical and striatal populations. We show that a large CAG expansion causes complete failure of the neuro-ectodermal acquisition, while cells carrying shorter CAGs repeats show gross abnormalities in neural rosette formation as well as disrupted cytoarchitecture in cortical organoids. Gene-expression analysis showed that control organoid overlapped with mature human fetal cortical areas, while HD organoids correlated with the immature ventricular zone/subventricular zone. We also report that defects in neuroectoderm and rosette formation could be rescued by molecular and pharmacological approaches leading to a recovery of striatal identity. These results show that mutant huntingtin precludes normal neuronal fate acquisition and highlights a possible connection between mutant huntingtin and abnormal neural development in HD.