Ctip2 Controls the Differentiation of Medium Spiny Neurons and the Establishment of the Cellular Architecture of the Striatum

Striatal medium spiny neurons (MSN) are critically involved in motor control, and their degeneration is a principal component of Huntington's disease. We find that the transcription factor Ctip2 (also known as Bcl11b) is central to MSN differentiation and striatal development. Within the striatum, it is expressed by all MSN, although it is excluded from essentially all striatal interneurons. In the absence of Ctip2, MSN do not fully differentiate, as demonstrated by dramatically reduced expression of a large number of MSN markers, including DARPP-32, FOXP1, Chrm4, Reelin, MOR1 (mu-opioid receptor 1), glutamate receptor 1, and Plexin-D1. Furthermore, MSN fail to aggregate into patches, resulting in severely disrupted patch-matrix organization within the striatum. Finally, heterotopic cellular aggregates invade the Ctip2-/- striatum, suggesting a failure by MSN to repel these cells in the absence of Ctip2. This is associated with abnormal dopaminergic innervation of the mutant striatum and dramatic changes in gene expression, including dysregulation of molecules involved in cellular repulsion. Together, these data indicate that Ctip2 is a critical regulator of MSN differentiation, striatal patch development, and the establishment of the cellular architecture of the striatum.Stem Cell and Regenerative Biolog

Developmental emergence of cortical neurogliaform cell diversity

GABAergic interneurons are key regulators of cortical circuit function. Among the dozens of reported transcriptionally distinct subtypes of cortical interneurons, neurogliaform cells (NGCs) are unique: they are recruited by long-range excitatory inputs, are a source of slow cortical inhibition and are able to modulate the activity of large neuronal populations. Despite their functional relevance, the developmental emergence and diversity of NGCs remains unclear. Here, by combining single-cell transcriptomics, genetic fate mapping, and electrophysiological and morphological characterization, we reveal that discrete molecular subtypes of NGCs, with distinctive anatomical and molecular profiles, populate the mouse neocortex. Furthermore, we show that NGC subtypes emerge gradually through development, as incipient discriminant molecular signatures are apparent in preoptic area (POA)-born NGC precursors. By identifying NGC developmentally conserved transcriptional programs, we report that the transcription factor Tox2 constitutes an identity hallmark across NGC subtypes. Using CRISPR-Cas9-mediated genetic loss of function, we show that Tox2 is essential for NGC development: POA-born cells lacking Tox2 fail to differentiate into NGCs. Together, these results reveal that NGCs are born from a spatially restricted pool of Tox2+ POA precursors, after which intra-type diverging molecular programs are gradually acquired post-mitotically and result in functionally and molecularly discrete NGC cortical subtypes

RORβ Induces Barrel-like Neuronal Clusters in the Developing Neocortex

Neurons in layer IV of the rodent whisker somatosensory cortex are tangentially organized in periodic clusters called barrels, each of which is innervated by thalamocortical axons transmitting sensory information from a single principal whisker, together forming a somatotopic map of the whisker pad. Proper thalamocortical innervation is critical for barrel formation during development, but the molecular mechanisms controlling layer IV neuron clustering are unknown. Here, we investigate the role in this mapping of the nuclear orphan receptor RORβ, which is expressed in neurons in layer IV during corticogenesis. We find that RORβ protein expression specifically increases in the whisker barrel cortex during barrel formation and that in vivo overexpression of RORβ is sufficient to induce periodic barrel-like clustering of cortical neurons. Remarkably, this clustering can be induced as early as E18, prior to innervation by thalamocortical afferents and whisker derived-input. At later developmental stages, these ectopic neuronal clusters are specifically innervated by thalamocortical axons, demonstrated by anterograde labeling from the thalamus and by expression of thalamocortical-specific synaptic markers. Together, these data indicate that RORβ expression levels control cytoarchitectural patterning of neocortical neurons during development, a critical process for the topographical mapping of whisker input onto the cortical surfac

Central venous O2 saturation and venous-to-arterial CO2 difference as complementary tools for goal-directed therapy during high-risk surgery

International audienceIntroduction: Central venous oxygen saturation (ScvO 2) is a useful therapeutic target in septic shock and high-risk surgery. We tested the hypothesis that central venous-to-arterial carbon dioxide difference (P(cv-a)CO 2), a global index of tissue perfusion, could be used as a complementary tool to ScvO 2 for goal-directed fluid therapy (GDT) to identify persistent low flow after optimization of preload has been achieved by fluid loading during high-risk surgery. Methods: This is a secondary analysis of results obtained in a study involving 70 adult patients (ASA I to III), undergoing major abdominal surgery, and treated with an individualized goal-directed fluid replacement therapy. All patients were managed to maintain a respiratory variation in peak aortic flow velocity below 13%. Cardiac index (CI), oxygen delivery index (DO 2 i), ScvO 2 , P(cv-a)CO 2 and postoperative complications were recorded blindly for all patients. Results: A total of 34% of patients developed postoperative complications. At baseline, there was no difference in demographic or haemodynamic variables between patients who developed complications and those who did not. In patients with complications, during surgery, both mean ScvO 2 (78 ± 4 versus 81 ± 4%, P = 0.017) and minimal ScvO 2 (minScvO 2) (67 ± 6 versus 72 ± 6%, P = 0.0017) were lower than in patients without complications, despite perfusion of similar volumes of fluids and comparable CI and DO 2 i values. The optimal ScvO 2 cutoff value was 70.6% and minScvO 2 < 70% was independently associated with the development of postoperative complications (OR = 4.2 (95% CI: 1.1 to 14.4), P = 0.025). P(cv-a)CO 2 was larger in patients with complications (7.8 ± 2 versus 5.6 ± 2 mmHg, P < 10-6). In patients with complications and ScvO 2 ≥71%, P(cv-a)CO 2 was also significantly larger (7.7 ± 2 versus 5.5 ± 2 mmHg, P < 10-6) than in patients without complications. The area under the receiver operating characteristic (ROC) curve was 0.785 (95% CI: 0.74 to 0.83) for discrimination of patients with ScvO 2 ≥71% who did and did not develop complications, with 5 mmHg as the most predictive threshold value

Area-specific temporal control of corticospinal motor neuron differentiation by COUP-TFI

Transcription factors with gradients of expression in neocortical progenitors give rise to distinct motor and sensory cortical areas by controlling the area-specific differentiation of distinct neuronal subtypes. However, the molecular mechanisms underlying this area-restricted control are still unclear. Here, we show that COUP-TFI controls the timing of birth and specification of corticospinal motor neurons (CSMN) in somatosensory cortex via repression of a CSMN differentiation program. Loss of COUP-TFI function causes an area-specific premature generation of neurons with cardinal features of CSMN, which project to subcerebral structures, including the spinal cord. Concurrently, genuine CSMN differentiate imprecisely and do not project beyond the pons, together resulting in impaired skilled motor function in adult mice with cortical COUP-TFI loss-of-function. Our findings indicate that COUP-TFI exerts critical areal and temporal control over the precise differentiation of CSMN during corticogenesis, thereby enabling the area-specific functional features of motor and sensory areas to arise.Stem Cell and Regenerative Biolog

Non-cell-autonomous regulation of interneuron specification mediated by extracellular vesicles

Disruption in neurogenesis and neuronal migration can influence the assembly of cortical circuits, affecting the excitatory-inhibitory balance and resulting in neurodevelopmental and neuropsychiatric disorders. Using ventral cerebral organoids and dorsoventral cerebral assembloids with mutations in the extracellular matrix gene LGALS3BP, we show that extracellular vesicles released into the extracellular environment regulate the molecular differentiation of neurons, resulting in alterations in migratory dynamics. To investigate how extracellular vesicles affect neuronal specification and migration dynamics, we collected extracellular vesicles from ventral cerebral organoids carrying a mutation in LGALS3BP, previously identified in individuals with cortical malformations and neuropsychiatric disorders. These results revealed differences in protein composition and changes in dorsoventral patterning. Proteins associated with cell fate decision, neuronal migration, and extracellular matrix composition were altered in mutant extracellular vesicles. Moreover, we show that treatment with extracellular vesicles changes the transcriptomic profile in neural progenitor cells. Our results indicate that neuronal molecular differentiation can be influenced by extracellular vesicles

A fluorescent perilipin 2 knock-in mouse model visualizes lipid droplets in the developing and adult brain

Lipid droplets (LDs) are dynamic lipid storage organelles. They are tightly linked to metabolism and can exert protective functions, making them important players in health and disease. Most LD studies in vivo rely on staining methods, providing only a snapshot. We therefore developed a LD-reporter mouse by endogenously labelling the LD coat protein perilipin 2 (PLIN2) with tdTomato, enabling staining-free fluorescent LD visualisation in living and fixed tissues and cells. Here we validate this model under standard and high-fat diet conditions and demonstrate that LDs are present in various cells in the healthy brain, including neurons, astrocytes, ependymal cells, neural stem/progenitor cells and microglia. Furthermore, we show that LDs are abundant during brain development and can be visualized using live-imaging of embryonic slices. Taken together, our tdTom-Plin2 mouse serves as a novel tool to study LDs and their dynamics under both physiological and diseased conditions in all tissues expressing Plin2

Stress-induced cardiomyopathy after negative pressure pulmonary edema during emergence from anesthesia -A case report-

Stress-induced cardiomyopathy (SICM) presenting as an acute myocardial dysfunction is characterized by transient left ventricular wall motion abnormality, which has been known to be associated with excessive catecholamine production caused due to various types of stress. Sympathetic hyperactivity is common during the perioperative period, and reports of SICM occurring during this period have actually increased. We present a case of SICM following negative pressure pulmonary edema due to upper airway obstruction during emergence from anesthesia. Excessive catecholamine release in response to respiratory difficulty could have been the underlying inciting factor

Preattentive interference between touch and audition: a case study on multisensory alloesthesia

Alloesthesia is a rare clinical condition that corresponds to a spatial disorder of stimulus localization, in which patients experience a given stimulus on the side opposite to the side of stimulation. Whereas it has been mostly described for unisensory stimulations, evidence of multisensory alloesthesia is only anecdotal. Here, we investigated a case of multisensory auditory-tactile alloesthesia. Our data suggest that auditory-tactile integration and multisensory alloesthesia not only depend on attentional mechanisms, but also on somatotopic preattentive mechanisms

A recruitment maneuver increases oxygenation after intubation of hypoxemic intensive care unit patients: a randomized controlled study

International audienc