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Diffuse intrinsic pontine glioma (DIPG) is the most severe paediatric solid tumour, with no significant therapeutic progress made in the past 50 years. Recent studies suggest that diffuse midline glioma, H3 - K27M mutant, may comprise more than one biological entity. The aim of the study was to determine the clinical and biological variables that most impact their prognosis. Ninety-one patients with classically defined DIPG underwent a systematic stereotactic biopsy and were included in this observational retrospective study. Histone H3 genes mutations were assessed by immunochemistry and direct sequencing, whilst global gene expression profiling and chromosomal imbalances were determined by microarrays. A full description of the MRI findings at diagnosis and at relapse was integrated with the molecular profiling data and clinical outcome. All DIPG but one were found to harbour either a somatic H3-K27M mutation and/or loss of H3K27 trimethylation. We also discovered a novel K27M mutation in HIST2H3C , and a lysine-to-isoleucine substitution (K27I) in H3F3A , also creating a loss of trimethylation. Patients with tumours harbouring a K27M mutation in H3.3 ( H3F3A ) did not respond clinically to radiotherapy as well, relapsed significantly earlier and exhibited more metastatic recurrences than those in H3.1 ( HIST1H3B/C ). H3.3-K27M-mutated DIPG have a proneural/oligodendroglial phenotype and a pro-metastatic gene expression signature with PDGFRA activation, while H3.1-K27M-mutated tumours exhibit a mesenchymal/astrocytic phenotype and a pro-angiogenic/hypoxic signature supported by expression profiling and radiological findings. H3K27 alterations appear as the founding event in DIPG and the mutations in the two main histone H3 variants drive two distinct oncogenic programmes with potential specific therapeutic targets.

A neural circuit from the parabrachial nucleus to the central nucleus of the amygdala mediates appetite suppression. Neural circuitry closely linked to appetite modulation The parabrachial nucleus (PBN) is an area of the brainstem containing subpopulations of neurons associated with taste, sodium intake, respiration, pain, thermosensation and appetite suppression. Partly because of the heterogeneous mix of cells making up this structure, it has proved difficult to identify the specific pathways driving appetite suppression. Now, using a variety of tools including optogenetic and pharmacogenetic analysis, Richard Palmiter and colleagues identify active calcitonin gene-related peptide-expressing neurons, projecting from the PBN to the central nucleus of the amygdala as a critical circuit driving appetite suppression. By contrast, inhibition of these neurons leads to increased feeding, suggesting that this neural circuit may provide targets for therapeutic intervention to both suppress and promote appetite. Appetite suppression occurs after a meal and in conditions when it is unfavourable to eat, such as during illness or exposure to toxins. A brain region proposed to play a role in appetite suppression is the parabrachial nucleus 1 , 2 , 3 , a heterogeneous population of neurons surrounding the superior cerebellar peduncle in the brainstem. The parabrachial nucleus is thought to mediate the suppression of appetite induced by the anorectic hormones amylin and cholecystokinin 2 , as well as by lithium chloride and lipopolysaccharide, compounds that mimic the effects of toxic foods and bacterial infections, respectively 4 , 5 , 6 . Hyperactivity of the parabrachial nucleus is also thought to cause starvation after ablation of orexigenic agouti-related peptide neurons in adult mice 1 , 7 . However, the identities of neurons in the parabrachial nucleus that regulate feeding are unknown, as are the functionally relevant downstream projections. Here we identify calcitonin gene-related peptide-expressing neurons in the outer external lateral subdivision of the parabrachial nucleus that project to the laterocapsular division of the central nucleus of the amygdala as forming a functionally important circuit for suppressing appetite. Using genetically encoded anatomical, optogenetic 8 and pharmacogenetic 9 tools, we demonstrate that activation of these neurons projecting to the central nucleus of the amygdala suppresses appetite. In contrast, inhibition of these neurons increases food intake in circumstances when mice do not normally eat and prevents starvation in adult mice whose agouti-related peptide neurons are ablated. Taken together, our data demonstrate that this neural circuit from the parabrachial nucleus to the central nucleus of the amygdala mediates appetite suppression in conditions when it is unfavourable to eat. This neural circuit may provide targets for therapeutic intervention to overcome or promote appetite.

Mammalian sleep consists of distinct rapid eye movement (REM) and non-REM (NREM) states. The midbrain region ventrolateral periaqueductal gray (vlPAG) is known to be important for gating REM sleep, but the underlying neuronal mechanism is not well understood. Here, we show that activating vlPAG GABAergic neurons in mice suppresses the initiation and maintenance of REM sleep while consolidating NREM sleep, partly through their projection to the dorsolateral pons. Cell-type-specific recording and calcium imaging reveal that most vlPAG GABAergic neurons are strongly suppressed at REM sleep onset and activated at its termination. In addition to the rapid changes at brain state transitions, their activity decreases gradually between REM sleep and is reset by each REM episode in a duration-dependent manner, mirroring the accumulation and dissipation of REM sleep pressure. Thus, vlPAG GABAergic neurons powerfully gate REM sleep, and their firing rate modulation may contribute to the ultradian rhythm of REM/NREM alternation. The vlPAG in the midbrain is known to suppress REM sleep, but the precise neural correlates are not known. Here, the authors record the activity of vlPAG GABAergic neurons during the sleep–wake cycle and report fast changes at REM sleep transitions and slower changes that correlate with REM sleep pressure.

The cerebellum’s involvement in a range of cognitive, emotional, and motor processes has become increasingly evident. Given the uniformity of the cerebellar cortex’s cellular architecture its contributions to varied processes are thought be partially mediated by its patterns of reciprocal connectivity with the rest of the brain. A better understanding of these connections is therefore fundamental to disentangling the cerebellum’s contribution to cognition and behavior. While these connections have been studied extensively in non-human animals using invasive methods, we have limited knowledge of these connections in humans. The current work reconstructed the corticopontine projection, the first segment of downstream connections between the cerebral and cerebellar cortices, with diffusion MRI tractography in human in-vivo whole brain data and an independent higher resolution postmortem brainstem dataset. Dimensionality reduction was used to characterize the pattern of connectivity of cerebral cortical projections to the pons as two overlapping gradients that were consistent across participants and datasets: medial to lateral and core to belt. Our findings align with invasive work done in animals and advance our understanding of this connection in humans – providing valuable context to a growing body of cerebellar research, offering insights into impacts of damage along the pathway, and informing clinical interventions.

Mammalian sleep comprises rapid eye movement (REM) sleep and non-REM (NREM) sleep. To functionally isolate from the complex mixture of neurons populating the brainstem pons those involved in switching between REM and NREM sleep, we chemogenetically manipulated neurons of a specific embryonic cell lineage in mice. We identified excitatory glutamatergic neurons that inhibit REM sleep and promote NREM sleep. These neurons shared a common developmental origin with neurons promoting wakefulness; both derived from a pool of proneural hindbrain cells expressing Atoh1 at embryonic day 10.5. We also identified inhibitory γ-aminobutyric acid–releasing neurons that act downstream to inhibit REM sleep. Artificial reduction or prolongation of REM sleep in turn affected slow-wave activity during subsequent NREM sleep, implicating REM sleep in the regulation of NREM sleep.

Drug delivery in diffuse intrinsic pontine glioma is significantly limited by the blood-brain barrier (BBB). Focused ultrasound (FUS), when combined with the administration of microbubbles can effectively open the BBB permitting the entry of drugs across the cerebrovasculature into the brainstem. Given that the utility of FUS in brainstem malignancies remains unknown, the purpose of our study was to determine the safety and feasibility of this technique in a murine pontine glioma model. A syngeneic orthotopic model was developed by stereotactic injection of PDGF-B + PTEN −/− p53 −/− murine glioma cells into the pons of B6 mice. A single-element, spherical-segment 1.5 MHz ultrasound transducer driven by a function generator through a power amplifier was used with concurrent intravenous microbubble injection for tumor sonication. Mice were randomly assigned to control, FUS and double-FUS groups. Pulse and respiratory rates were continuously monitored during treatment. BBB opening was confirmed with gadolinium-enhanced MRI and Evans blue. Kondziela inverted screen testing and sequential weight lifting measured motor function before and after sonication. A subset of animals were treated with etoposide following ultrasound. Mice were either sacrificed for tissue analysis or serially monitored for survival with daily weights. FUS successfully caused BBB opening while preserving normal cardiorespiratory and motor function. Furthermore, the degree of intra-tumoral hemorrhage and inflammation on H&E in control and treated mice was similar. There was also no difference in weight loss and survival between the groups ( p  > 0.05). Lastly, FUS increased intra-tumoral etoposide concentration by more than fivefold. FUS is a safe and feasible technique for repeated BBB opening and etoposide delivery in a preclinical pontine glioma model.

The term Pontocerebellar Hypoplasia (PCH) was initially used to designate a heterogeneous group of fetal-onset genetic neurodegenerative disorders. As a descriptive term, PCH refers to pons and cerebellum of reduced volume. In addition to the classic PCH types described in OMIM, many other disorders can result in a similar imaging appearance. This study aims to review imaging, clinical and genetic features and underlying etiologies of a cohort of children with PCH on imaging. We systematically reviewed brain images and clinical charts of 38 patients with radiologic evidence of PCH. Our cohort included 21 males and 17 females, with ages ranging between 8 days to 15 years. All individuals had pons and cerebellar vermis hypoplasia, and 63% had cerebellar hemisphere hypoplasia. Supratentorial anomalies were found in 71%. An underlying etiology was identified in 68% and included chromosomal (21%), monogenic (34%) and acquired (13%) causes. Only one patient had pathogenic variants in an OMIM listed PCH gene. Outcomes were poor regardless of etiology, though no one had regression. Approximately one third of patients deceased at a median age of 8 months. All individuals had global developmental delay, 50% were non-verbal, 64% were non-ambulatory and 45% required gastrostomy feeding. This cohort demonstrates that radiologic PCH has heterogenous etiologies and the “classic” OMIM-listed PCH genes underlie only a minority of cases. Broad genetic testing, including chromosomal microarray and exome or multigene panels, is recommended in individuals with PCH-like imaging appearance. Our results strongly suggest that the term PCH should be used to designate radiologic findings, and not to imply neurogenerative disorders.

To determine whether multiple repeated administrations of gadolinium-based macrocyclic ionic MR contrast agent (MICA) are associated with intracranial gadolinium deposition and identify the predisposing factors for deposition in various clinical situations. In this institutional review board-approved retrospective study, 385 consecutive patients who underwent MICA-enhanced MR imaging were enrolled. The dentate nucleus-to-pons (DN/P) and globus pallidus-to-thalamus (GP/Th) signal intensity (SI) ratios on unenhanced T1-weighted images were recorded by 2 independent readers and averaged. The mean DN/P and GP/Th SI ratio difference between the last and the first examinations were tested using the one-sample t-test. Student's t-test and stepwise regression analysis were used to identify the predisposing factors for deposition based on the number of administrations, time interval, hepatic and renal function, magnetic field strength, and chemo- or radiation therapy. The mean DN/P SI ratio difference was not different from zero (P = .697), even in patients with ≥20 administrations (n = 33). Only patients with abnormal renal function showed an increase in the mean DN/P SI ratio difference (P = .019). The mean DN/P SI ratio difference was not associated with any predisposing factors. However, the mean GP/Th SI ratio difference showed decrease (P < .001), which was associated with age (P = .007), number of administrations (P = .01) and number of radiation therapy sessions (P = .022) on multivariate analysis. Multiple repeated administrations of MICA were not associated with increased T1 signal intensity in deep brain nuclei suggestive of Gd deposition in patients with normal renal function.

Peer review is the driving force of journal development, and reviewers are gatekeepers who ensure that Inorganics maintains its standards for the high quality of its published papers. Thanks to the cooperation of our reviewers, in 2020, the median time to first decision was 13 days and the median time to publication was 32 days. Czujko, Tomasz Pistidda, Claudio De León, A. S. Pointillart, Fabrice De Salas, Felipe Pons, Josefina Djuran, Miloš I. Pop, Flavia Enemark, John Popat, Amirali Escudero, Daniel Potapov, Andrei Florindo, Pedro R. Py, Beatrice Förster, Christoph Remhof, Arndt Fourmigué, Marc Reyes-Gasga, José Franczyk, Adrian Roberto, Dominique Frontera, Antonio Robertson, Stuart D. Garino, Claudio Rončević, Sanda Gheju, Marius Rose, Michael Gil-Kowalczyk, Malgorzta Rossin, Andrea Gillan, Edward G. Ruta, Lavinia L. Glover, T. Grant Sadykov, Vladislav Gościańska, Joanna Samia, Benmansour Granado Castro, María Dolores Sanhueza, Luis Grigorova, Eli Santoni, Marie-Pierre Guo, Lei Sargent, Frank Guo, Yisong Shen, Fengyu Hawes, Chris S. Sheong, Fu Kit Heck, Jürgen Shomura, Yasuhito Higgins, Khadine Silvestru, Cristian Hirva, Pipsa Skvortsov, Alexey N. Hix, Gary Song, Jong-Won Holynska, Malgorzata Sour, Angélique Hong, Liang Stripp, Sven T. Horchidan, Nadejda Suaud, Nicolas Humphries, Terry Sukhikh, Taisiya Iatrou, Hermis Takahashi, Kazuyuki Ioannides, Theophilos Takao, Toshiro Isaeva, Vera I. Tayade, Rajesh Ito, Jun-ichi Topoglidis, Emmanuel Jensen, Torben Tsukuda, Toshiaki Jurkschat, Klaus Varga, Richard A. Kalska-Szostko, Beata Vasic, Vesna Kamecka, Anna Vassilyeva, Olga Yu.

Activation of GABAergic neurons in the ventral medulla can reliably induce REM sleep and prolong the duration of REM episodes in mice. Control of REM sleep Previous attempts to understand the contribution of specific brain regions to the promotion and maintenance of rapid eye movement (REM) sleep, the type of sleep during which most instances of dreaming occur, have mainly relied on transection or lesion-based studies. Here, Yang Dan and colleagues use optogenetics to demonstrate that activation of GABAergic neurons in the ventral medulla can reliably induce REM sleep and prolong the duration of REM episodes in mice. The ability to control REM sleep at a high temporal precision, as demonstrated in this study, should provide a useful tool for the study of its functions. Rapid eye movement (REM) sleep is a distinct brain state characterized by activated electroencephalogram and complete skeletal muscle paralysis, and is associated with vivid dreams 1 , 2 , 3 . Transection studies by Jouvet first demonstrated that the brainstem is both necessary and sufficient for REM sleep generation 2 , and the neural circuits in the pons have since been studied extensively 4 , 5 , 6 , 7 , 8 . The medulla also contains neurons that are active during REM sleep 9 , 10 , 11 , 12 , 13 , but whether they play a causal role in REM sleep generation remains unclear. Here we show that a GABAergic (γ-aminobutyric-acid-releasing) pathway originating from the ventral medulla powerfully promotes REM sleep in mice. Optogenetic activation of ventral medulla GABAergic neurons rapidly and reliably initiated REM sleep episodes and prolonged their durations, whereas inactivating these neurons had the opposite effects. Optrode recordings from channelrhodopsin-2-tagged ventral medulla GABAergic neurons showed that they were most active during REM sleep (REM max ), and during wakefulness they were preferentially active during eating and grooming. Furthermore, dual retrograde tracing showed that the rostral projections to the pons and midbrain and caudal projections to the spinal cord originate from separate ventral medulla neuron populations. Activating the rostral GABAergic projections was sufficient for both the induction and maintenance of REM sleep, which are probably mediated in part by inhibition of REM-suppressing GABAergic neurons in the ventrolateral periaqueductal grey. These results identify a key component of the pontomedullary network controlling REM sleep. The capability to induce REM sleep on command may offer a powerful tool for investigating its functions.