Suicide spectrum among young people during the COVID-19 pandemic: A systematic review and meta-analysis.

Background: There are concerns that suicidal behaviors are arising among adolescents. The COVID-19 pandemic could have worsened the picture, however, studies on this topic reported contrasting results. This work aimed to summarise findings from the worldwide emerging literature on the rates of suicidality among young people during the COVID-19 pandemic. Methods: A systematic review and meta-analysis were performed, searching five electronic databases for studies published from January 1, 2020 until July 27, 2022. Studies reporting rates for each of the three considered outcomes (suicide, suicidal behaviors, and suicidal ideation) among young people under 19 years old during the COVID-19 pandemic were included. Random-effects meta-analyses were conducted, and the intra-study risk of bias was assessed. When pre-COVID-19 data were available, incidence rate ratio (IRR) and prevalence ratio (PR) estimates were calculated between the two periods. All the analyses were performed according to the setting explored: general population, emergency department (ED), and psychiatric services. The review protocol was registered on PROSPERO (CRD42022308014). Findings: Forty-seven observational studies were selected for more than 65 million subjects. The results of the meta-analysis showed a pooled annual incidence rate of suicides of 4.9 cases/100,000 during 2020, accounting for a non-statistically significant increase of 10% compared to 2019 (IRR 1.10, 95% CI: 0.94-1.29). The suicidal behaviors pooled prevalence during the COVID-19 pandemic was higher in the psychiatric setting (25%; 95% CI: 17-36%) than in the general population (3%; 1-13%) and ED (1%; 0-9%). The pooled rate of suicidal ideation was 17% in the general population (11-25%), 36% in psychiatric setting (20-56%) and 2% in ED (0-12%). The heterogeneity level was over 97% for both outcomes in all settings considered. The comparison between before and during COVID-19 periods highlighted a non-statistically significant upward trend in suicidal behaviors among the general population and in ED setting. The only significant increase was found for suicidal ideation in psychiatric setting among studies conducted in 2021 (PR 1.15; 95% CI: 1.04-1.27), not observed exploring 2020 alone. Interpretation: During the pandemic, suicide spectrum issues seemed to follow the known pattern described in previous studies, with higher rates of suicidal ideation than of suicidal behaviors and suicide events. Governments and other stakeholders should be mindful that youth may have unique risks at the outset of large disasters like the COVID-19 pandemic and proactive steps are necessary to address the needs of youth to mitigate those risks. Funding: The present study was funded by the University of Torino (CHAL_RILO_21_01).

Multisystemic Manifestations in Rare Diseases: The Experience of Dyskeratosis Congenita.

Dyskeratosis congenital (DC) is the first genetic syndrome described among telomeropathies. Its classical phenotype is characterized by the mucocutaneous triad of reticulated pigmentation of skin lace, nail dystrophy and oral leukoplakia. The clinical presentation, however, is heterogeneous and serious clinical complications include bone marrow failure, hematological and solid tumors. It may also involve immunodeficiencies, dental, pulmonary and liver disorders, and other minor complication. Dyskeratosis congenita shows marked genetic heterogeneity, as at least 14 genes are responsible for the shortening of telomeres characteristic of this disease. This review discusses clinical characteristics, molecular genetics, disease evolution, available therapeutic options and differential diagnosis of dyskeratosis congenita to provide an interdisciplinary and personalized medical assessment that includes family genetic counseling.

Clinical and Genetic Aspects of Phelan-McDermid Syndrome: An Interdisciplinary Approach to Management.

Phelan-McDermid syndrome (PMS) is a rare, heterogeneous, and complex neurodevelopmental disorder. It is generally caused by a heterozygous microdeletion of contiguous genes located in the distal portion of the long arm of chromosome 22, including the SHANK3 gene. Sequence variants of SHANK3, including frameshift, nonsense mutations, small indels and splice site mutations also result in PMS. Furthermore, haploinsufficiency in SHANK3 has been suggested as the main cause of PMS. SHANK3 is also associated with intellectual disability, autism spectrum disorder and schizophrenia. The phenotype of PMS is variable, and lacks a distinctive phenotypic characteristic, so the clinical diagnosis should be confirmed by genetic analysis. PMS is a multi-system disorder, and clinical care must encompass various specialties and therapists. The role of risperidone, intranasal insulin, insulin growth factor 1, and oxytocin as potential therapeutic options in PMS will be discussed in this review. The diagnosis of PMS is important to provide an appropriate clinical evaluation, treatment, and genetic counseling.

Tuned inhibition in perceptual decision-making circuits can explain seemingly suboptimal confidence behavior.

Current dominant views hold that perceptual confidence reflects the probability that a decision is correct. Although these views have enjoyed some empirical support, recent behavioral results indicate that confidence and the probability of being correct can be dissociated. An alternative hypothesis suggests that confidence instead reflects the magnitude of evidence in favor of a decision while being relatively insensitive to the evidence opposing the decision. We considered how this alternative hypothesis might be biologically instantiated by developing a simple neural network model incorporating a known property of sensory neurons: tuned inhibition. The key idea of the model is that the level of inhibition that each accumulator unit receives from units with the opposite tuning preference, i.e. its inhibition 'tuning', dictates its contribution to perceptual decisions versus confidence judgments, such that units with higher tuned inhibition (computing relative evidence for different perceptual interpretations) determine perceptual discrimination decisions, and units with lower tuned inhibition (computing absolute evidence) determine confidence. We demonstrate that this biologically plausible model can account for several counterintuitive findings reported in the literature where confidence and decision accuracy dissociate. By comparing model fits, we further demonstrate that a full complement of behavioral data across several previously published experimental results-including accuracy, reaction time, mean confidence, and metacognitive sensitivity-is best accounted for when confidence is computed from units without, rather than units with, tuned inhibition. Finally, we discuss predictions of our results and model for future neurobiological studies. These findings suggest that the brain has developed and implements this alternative, heuristic theory of perceptual confidence computation by relying on the diversity of neural resources available.

Variable Statistical Structure of Neuronal Spike Trains in Monkey Superior Colliculus.

Popular models of decision-making propose that noisy sensory evidence accumulates until reaching a bound. Behavioral evidence as well as trial-averaged ramping of neuronal activity in sensorimotor regions of the brain support this idea. However, averaging activity across trials can mask other processes, such as rapid shifts in decision commitment, calling into question the hypothesis that evidence accumulation is encoded by delay period activity of individual neurons. We mined two sets of data from experiments in four monkeys in which we recorded from superior colliculus neurons during two different decision-making tasks and a delayed saccade task. We applied second-order statistical measures and spike train simulations to determine whether spiking statistics were similar or different in the different tasks and monkeys, despite similar trial-averaged activity across tasks and monkeys. During a motion direction discrimination task, single-trial delay period activity behaved statistically consistent with accumulation. During an orientation detection task, the activity behaved superficially like accumulation, but statistically consistent with stepping. Simulations confirmed both findings. Importantly, during a simple saccade task, with similar trial-averaged activity, neither process explained spiking activity, ruling out interpretations based on differences in attention, reward, or motor planning. These results highlight the need for exploring single-trial spiking dynamics to understand cognitive processing and raise the interesting hypothesis that the superior colliculus participates in different aspects of decision-making depending on task differences.SIGNIFICANCE STATEMENT How are decisions based on sensory information transformed into actions? We report that single-trial neuronal activity dynamics in the superior colliculus of monkeys show differences in decision-making tasks depending on task idiosyncrasies and requirements and despite similar trial-averaged ramping activity. These results highlight the importance of exploring single-trial spiking dynamics to understand cognitive processing and raise the interesting hypothesis that the superior colliculus participates in different aspects of decision-making depending on task requirements.

Using rAAV2-retro in rhesus macaques: Promise and caveats for circuit manipulation.

BACKGROUND: Recent genetic technologies such as opto- and chemogenetics allow for the manipulation of brain circuits with unprecedented precision. Most studies employing these techniques have been undertaken in rodents, but a more human-homologous model for studying the brain is the nonhuman primate (NHP). Optimizing viral delivery of transgenes encoding actuator proteins could revolutionize the way we study neuronal circuits in NHPs. NEW METHOD: rAAV2-retro, a popular new capsid variant, produces robust retrograde labeling in rodents. Whether rAAV2-retro's highly efficient retrograde transport would translate to NHPs was unknown. Here, we characterized the anatomical distribution of labeling following injections of rAAV2-retro encoding opsins or DREADDs in the cortico-basal ganglia and oculomotor circuits of rhesus macaques. RESULTS: rAAV2-retro injections in striatum, frontal eye field, and superior colliculus produced local labeling at injection sites and robust retrograde labeling in many afferent regions. In every case, however, a few brain regions with well-established projections to the injected structure lacked retrogradely labeled cells. We also observed robust terminal field labeling in downstream structures. COMPARISON WITH EXISTING METHOD(S): Patterns of labeling were similar to those obtained with traditional tract-tracers, except for some afferent labeling that was noticeably absent. CONCLUSIONS: rAAV2-retro promises to be useful for circuit manipulation via retrograde transduction in NHPs, but caveats were revealed by our findings. Some afferently connected regions lacked retrogradely labeled cells, showed robust axon terminal labeling, or both. This highlights the importance of anatomically characterizing rAAV2-retro's expression in target circuits in NHPs before moving to manipulation studies.

Superior colliculus signals decisions rather than confidence: analysis of single neurons.

Recent findings indicate that monkeys can report their confidence in perceptual decisions and that this information is encoded in neurons involved in making decisions, including the lateral intraparietal area (LIP) and the supplementary eye field (SEF). A key issue to consider when studying confidence is that decision accuracy often correlates with confidence reports; when we are performing well, we generally feel more confident. Expanding on work performed in humans, we designed a novel task for monkeys that dissociates perceptual information leading to decisions from perceptual information leading to confidence reports. Using this task, we recently showed that decoded ensemble activity recorded from the superior colliculus (SC) reflected decisions rather than confidence reports. However, our previous population level analysis collapsed over multiple SC neuronal types and therefore left open the possibility that first, individual discharge rates might encode information related to decision confidence, and second, different neuronal cell types within the SC might signal decision confidence independently of decision accuracy. We found that when decision accuracy and decision confidence covaried, modulation occurred primarily in neurons with prelude activity (buildup neurons). However, isolating decision confidence from decision accuracy uncovered that only a few, primarily buildup neurons showed signals correlating uniquely with decision confidence and the effect sizes were very small. Based on this work and our previous work using decoding methods, we conclude that neuronal signals for decision confidence, independent of decision accuracy, are unlikely to exist at the level of single or populations of neurons in the SC. Our results together with other recent work call into question normative models of confidence based on the optimal readout of decision signals. NEW & NOTEWORTHY Models of decision confidence suggest that our sense of confidence is an optimal readout of perceptual decision signals. Here, we report that a subcortical area, the superior colliculus (SC), contains neurons with activity that signal decisions and confidence in a task in which decision accuracy and confidence covary, similar to area lateral intraparietal area in cortex. The signals from SC occur primarily in the neurons with prelude activity (buildup neurons). However, in a task that dissociates decision accuracy from decision confidence, we find that only a few individual neurons express unique signals of confidence. These results call into question normative models of confidence based on optimal readout of perceptual decision signals.

Superior colliculus neuronal ensemble activity signals optimal rather than subjective confidence.

Recent studies suggest that neurons in sensorimotor circuits involved in perceptual decision-making also play a role in decision confidence. In these studies, confidence is often considered to be an optimal readout of the probability that a decision is correct. However, the information leading to decision accuracy and the report of confidence often covaried, leaving open the possibility that there are actually two dissociable signal types in the brain: signals that correlate with decision accuracy (optimal confidence) and signals that correlate with subjects' behavioral reports of confidence (subjective confidence). We recorded neuronal activity from a sensorimotor decision area, the superior colliculus (SC) of monkeys, while they performed two different tasks. In our first task, decision accuracy and confidence covaried, as in previous studies. In our second task, we implemented a motion discrimination task with stimuli that were matched for decision accuracy but produced different levels of confidence, as reflected by behavioral reports. We used a multivariate decoder to predict monkeys' choices from neuronal population activity. As in previous studies on perceptual decision-making mechanisms, we found that neuronal decoding performance increased as decision accuracy increased. However, when decision accuracy was matched, performance of the decoder was similar between high and low subjective confidence conditions. These results show that the SC likely signals optimal decision confidence similar to previously reported cortical mechanisms, but is unlikely to play a critical role in subjective confidence. The results also motivate future investigations to determine where in the brain signals related to subjective confidence reside.

Measuring away an attentional confound?

A recent fMRI study by Webb et al. (Cortical networks involved in visual awareness independent of visual attention, Proc Natl Acad Sci U S A 2016;113:13923-28) proposes a new method for finding the neural correlates of awareness by matching attention across awareness conditions. The experimental design, however, seems at odds with known features of attention. We highlight logical and methodological points that are critical when trying to disentangle attention and awareness.

Anatomical Connections of the Functionally Defined "Face Patches" in the Macaque Monkey.

The neural circuits underlying face recognition provide a model for understanding visual object representation, social cognition, and hierarchical information processing. A fundamental piece of information lacking to date is the detailed anatomical connections of the face patches. Here, we injected retrograde tracers into four different face patches (PL, ML, AL, AM) to characterize their anatomical connectivity. We found that the patches are strongly and specifically connected to each other, and individual patches receive inputs from extrastriate cortex, the medial temporal lobe, and three subcortical structures (the pulvinar, claustrum, and amygdala). Inputs from prefrontal cortex were surprisingly weak. Patches were densely interconnected to one another in both feedforward and feedback directions, inconsistent with a serial hierarchy. These results provide the first direct anatomical evidence that the face patches constitute a highly specialized system and suggest that subcortical regions may play a vital role in routing face-related information to subsequent processing stages.

There are things that we know that we know, and there are things that we do not know we do not know: Confidence in decision-making.

Metacognition, the ability to think about our own thoughts, is a fundamental component of our mental life and is involved in memory, learning, planning and decision-making. Here we focus on one aspect of metacognition, namely confidence in perceptual decisions. We review the literature in psychophysics, neuropsychology and neuroscience. Although still a very new field, several recent studies suggest there are specific brain circuits devoted to monitoring and reporting confidence, whereas others suggest that confidence information is encoded within decision-making circuits. We provide suggestions, based on interdisciplinary research, to disentangle these disparate results.

Saccade modulation by optical and electrical stimulation in the macaque frontal eye field.

Recent studies have demonstrated that strong neural modulations can be evoked with optogenetic stimulation in macaque motor cortex without observing any evoked movements (Han et al., 2009, 2011; Diester et al., 2011). It remains unclear why such perturbations do not generate movements and if conditions exist under which they may evoke movements. In this study, we examine the effects of five optogenetic constructs in the macaque frontal eye field and use electrical microstimulation to assess whether optical perturbation of the local network leads to observable motor changes during optical, electrical, and combined stimulation. We report a significant increase in the probability of evoking saccadic eye movements when low current electrical stimulation is coupled to optical stimulation compared with when electrical stimulation is used alone. Experiments combining channelrhodopsin 2 (ChR2) and electrical stimulation with simultaneous fMRI revealed no discernible fMRI activity at the electrode tip with optical stimulation but strong activity with electrical stimulation. Our findings suggest that stimulation with current ChR2 optogenetic constructs generates subthreshold activity that contributes to the initiation of movements but, in most cases, is not sufficient to evoke a motor response.

Origins and control of the differentiation of inhibitory interneurons and glia in the cerebellum.

Cerebellar GABAergic interneurons and glia originate from progenitors that delaminate from the ventricular neuroepithelium and proliferate in the prospective white matter. Even though this population of progenitor cells is multipotent as a whole, clonal analysis indicates that different lineages are already separated during postnatal development and little is known about the mechanisms that regulate the specification and differentiation of these cerebellar types at earlier stages. Here, we investigate the role of Ascl1 in the development of inhibitory interneurons and glial cells in the cerebellum. This gene is expressed by maturing oligodendrocytes and GABAergic interneurons and is required for the production of appropriate quantities of these cells, which are severely reduced in Ascl1(-/-) mouse cerebella. Nevertheless, the two lineages are not related and the majority of oligodendrocytes populating the developing cerebellum actually derive from extracerebellar sources. Targeted electroporation of Ascl1-expression vectors to ventricular neuroepithelium progenitors enhances the production of interneurons and completely suppresses astrocytic differentiation, whereas loss of Ascl1 function has opposite effects on both cell types. Our results indicate that Ascl1 directs ventricular neuroepithelium progenitors towards inhibitory interneuron fate and restricts their ability to differentiate along the astroglial lineage.

Induction and survival of binucleated Purkinje neurons by selective damage and aging.

Fusion of bone marrow-derived cells with adult Purkinje cells in the cerebellum gives rise to binucleated Purkinje cells. Whether fusion can be modulated by epigenetic factors and whether fused neurons are stable has remained unclear. Here, we show that in mice and rats, partial ablation of Purkinje cells and local microglial activation in the absence of structural damage to the cerebellum increase the rate of fusion. Moreover, mouse Purkinje cells once fused with bone marrow-derived cells are viable for at least 7 months. We also show that cerebellar irradiation is unnecessary for the generation of binucleated Purkinje cells after bone marrow grafting. Moreover, binucleated Purkinje cells can be found in aged mice that did not receive any treatment, suggesting that fusion events occasionally occur throughout the whole lifespan of healthy, unmanipulated individuals. However, in aged chimeric mice that, after bone marrow transplant, have the majority of their nucleated blood cells fluorescent, the number of binucleated fluorescent Purkinje cells is two orders of magnitude less than the total number of binucleated Purkinje cells. This suggests that, in the majority of heterokaryons, either the incoming nucleus is quickly inactivated or fusion is not the only way to generate a binucleated Purkinje cell.

Lack of neurogenesis in the adult rat cerebellum after Purkinje cell degeneration and growth factor infusion.

Although constitutive neurogenesis exclusively occurs in restricted regions of the adult mammalian brain, resident progenitors can be isolated from many different CNS sites, and neuronal neogeneration can be stimulated in vivo by injury or infusion of growth factors. To ask whether latent compensatory mechanisms, which may be exploited to promote repair processes, are present throughout the CNS, we examined the neurogenic potentialities of the adult rat cerebellum in normal conditions, following injury, and after infusion of growth factors. Degeneration of Purkinje cells was induced by intracerebroventricular administration of the toxin saporin, conjugated to anti-p75 antibodies. In addition, epidermal growth factor and basic fibroblast growth factor, or FGF8, were infused for 2 weeks to either intact or injured animals. In all conditions, proliferating cells were identified from bromodeoxyuridine (BrdU) incorporation. In the unmanipulated cerebellum there were rare dividing cells, mainly represented by NG2-positive presumptive oligodendrocyte precursors. Mitotic activity was strongly enhanced in cortical areas with Purkinje cell degeneration, being mostly sustained by microglia, plus minor fractions of NG2-expressing cells, astrocytes and oligodendrocytes. In contrast, growth factor infusion had a weak effect on both intact and injured cerebella. In all experimental conditions, we never found any BrdU-positive cells coexpressing distinctive markers for immature or differentiated cerebellar neurons. Therefore, although some progenitor cells reside in the adult cerebellum, the local environment, either intact or injured, does not provide efficient cues to direct their differentiation towards neuronal phenotypes. In addition, neurogenic potentialities cannot be induced or boosted by the application of growth factors which are effective in other CNS regions.

Neuronal replacement and integration in the rewiring of cerebellar circuits.

Repair of CNS injury or degeneration by cell replacement may lead to significant functional recovery only through faithful reconstruction of the original anatomical architecture. This is particularly relevant for point-to-point systems, where precisely patterned connections have to be re-established to regain adaptive function. Despite the major interest recently drawn on cell therapies, little is known about the mechanisms and the potentialities for specific integration of new neurons in the mature CNS. Major findings and concepts about this issue will be reviewed here, with special focus on work dealing with the Purkinje cell transplantation in the rodent cerebellum. These studies show that the adult CNS may provide some efficient information to direct cell engraftment and process outgrowth. On their side, immature cells may be able to induce adaptive changes in their adult partners to facilitate their incorporation in the recipient network. Despite the rather high degree of specific integration achieved in several different CNS regions, these processes are usually defective and long-distance connections are not rewired. Thus, although some potentialities for cell replacement exist in the mature CNS, full incorporation of new neurons in adult circuits is rarely observed. Indeed, intrinsic mechanisms for growth control as well as injury-induced changes in the properties and architecture of the nervous tissue contribute to hamper repair processes. As a consequence, crucial to obtain successful cell replacement and integration in the mature CNS is a deep understanding of the basic biological mechanisms that regulate the interactions between newly added elements and the recipient environment.

Fate restriction and developmental potential of cerebellar progenitors. Transplantation studies in the developing CNS.

The generation of cell diversity from undifferentiated progenitors is regulated by interdependent mechanisms, including cell intrinsic programs and environmental cues. This interaction can be investigated by means of heterochronic/heterotopic transplantation, which allows to examine the behaviour of precursor cells in an unusual environment. The cerebellum provides an ideal model to study cell specification, because its neurons originate according to a well-defined timetable and they can be are readily recognised by morphological features and specific markers. Cerebellar progenitors transplanted to the embryonic cerebellum develop fully mature cerebellar neurons, which often integrate in the host circuitry in a highly specific manner. In extracerebellar locations, cerebellar progenitors preferentially settle in caudal CNS regions where they exclusively acquire cerebellar identities. By contrast, neocortical precursors preferentially settle in rostral regions and fail to develop hindbrain phenotypes. The phenotypic repertoire generated by transplanted cerebellar progenitors is strictly dependent on their age. Embryonic progenitors originate all mature cerebellar cells, whereas postnatal ones exclusively generate later-born types, such as molecular layer interneurons and granule cells. Together, these observations foster the hypothesis that neural progenitors are first specified towards region-specific phenotypes along the rostro-caudal axis of the neural tube. Thereafter, the developmental potential of progenitor cells is progressively restricted towards later generated types. Such a progressive specification of precursor cells in space and time is stably transmitted to their progeny and it cannot be modified by local cues, when these cells are confronted with heterotopic and/or heterochronic environments.

Engraftment and differentiation of neocortical progenitor cells transplanted to the embryonic brain in utero.

Transplantation of neural progenitors or stem cells is a most useful tool to investigate the relative contribution of cell-autonomous mechanisms and environmental cues in the regulation of cell specification and differentiation during CNS development. To assess the capability of neocortical progenitor cells to integrate into foreign brain regions, here we examined the fate of precursor cells isolated from the dorsal telencephalon of E12 ss-actin-EGFP transgenic mouse embryos after heterotopic/heterochronic transplantation to the E16 rat brain in utero. Our observations show that donor cells were able to penetrate, survive and produce mature cell types into wide regions of the host CNS. Namely, EGFP-positive cells acquired site-specific neuronal identities in many telencephalic regions, including neocortex, hippocampus, olfactory bulb and corpus striatum. In contrast, incorporation into more caudal sites was much less efficient. A fraction of donor cells formed large aggregates that remained segregated from the host milieu. Such aggregates contained mature neurons and glia, including some EGFP-negative elements of host origin, and developed the complex organization of the mature nervous tissue. On the other hand, transplanted cells that engrafted in the parenchyma of extratelencephalic regions predominantly generated glial types. The few neurons failed to acquire obvious site-specific phenotypic traits and did not integrate into the local host architecture. Altogether, our observations indicate that E12 neocortical progenitors are already committed towards regional identities and are unable to modify their phenotypic choices when exposed to heterotopic environmental conditions along different rostro-caudal domains of the embryonic CNS.

Specification of cerebellar progenitors after heterotopic-heterochronic transplantation to the embryonic CNS in vivo and in vitro.

The different cerebellar phenotypes are generated according to a precise time schedule during embryonic and postnatal development. To assess whether the differentiative potential of cerebellar progenitors is progressively restricted in space and time we examined the fate of embryonic day 12 (E12) or postnatal day 4 (P4) cerebellar cells after heterotopic-heterochronic transplantation into the embryonic rat brain in utero or into organotypic CNS explants in vitro. Donor cells, isolated from transgenic mice overexpressing the enhanced-green fluorescent protein under the control of the beta-actin-promoter, engrafted throughout the host brainstem and diencephalon, whereas they rarely incorporated into specific telencephalic structures. In any recipient site, the vast majority of transplanted cells could be recognized as cerebellar phenotypes, and we did not obtain clear evidence that ectopically located cells adopted host-specific identities. Nevertheless, the two donor populations displayed different developmental potentialities. P4 progenitors exclusively generated granule cells and molecular layer interneurons, indicating that they are committed to late-generated cerebellar identities and not responsive to heterotopic-heterochronic environmental cues. In contrast, E12 precursors had the potential to produce all major cerebellar neurons, but the repertoire of adult phenotypes generated by these cells was different in distinct host regions, suggesting that they require instructive environmental information to acquire mature identities. Thus, cerebellar precursors are able to integrate into different foreign brain regions, where they develop mature phenotypes that survive long after transplantation, but they are committed to cerebellar fates at E12. Embryonic progenitors are initially capable, although likely not competent, to generate all cerebellar identities, but their potential is gradually restricted toward late-generated phenotypes.