Metabolic Regulation of Neocortical Expansion in Development and Evolution

The neocortex, the seat of our higher cognitive abilities, has expanded in size during the evolution of certain mammals such as primates, including humans. This expansion occurs during development and is linked to the proliferative capacity of neural stem and progenitor cells (NPCs) in the neocortex. A number of cellintrinsic and cell-extrinsic factors have been implicated in increasing NPC proliferative capacity. However, NPC metabolism has only recently emerged as major regulator of NPC proliferation. In this Perspective, we summarize recent insights into the role of NPC metabolism in neocortical development and neurodevelopmental disorders and its relevance for neocortex evolution. We discuss certain human-specific genes and microcephaly-implicated genes that operate in, or at, the mitochondria of NPCs and stimulate their proliferation by promoting glutaminolysis. We also discuss other metabolic pathways and develop a perspective on how metabolism mechanistically regulates NPC proliferation in neocortical development and how this contributed to neocortex evolution.Peer reviewe

Lipopolysaccharide-induced alteration of mitochondrial morphology induces a metabolic shift in microglia modulating the inflammatory response in vitro and in vivo

Accumulating evidence suggests that changes in the metabolic signature of microglia underlie their response to inflammation. We sought to increase our knowledge of how pro‐inflammatory stimuli induce metabolic changes. Primary microglia exposed to lipopolysaccharide (LPS)‐expressed excessive fission leading to more fragmented mitochondria than tubular mitochondria. LPS‐mediated Toll‐like receptor 4 (TLR4) activation also resulted in metabolic reprogramming from oxidative phosphorylation to glycolysis. Blockade of mitochondrial fission by Mdivi‐1, a putative mitochondrial division inhibitor led to the reversal of the metabolic shift. Mdivi‐1 treatment also normalized the changes caused by LPS exposure, namely an increase in mitochondrial reactive oxygen species production and mitochondrial membrane potential as well as accumulation of key metabolic intermediate of TCA cycle succinate. Moreover, Mdivi‐1 treatment substantially reduced LPS induced cytokine and chemokine production. Finally, we showed that Mdivi‐1 treatment attenuated expression of genes related to cytotoxic, repair, and immunomodulatory microglia phenotypes in an in vivo neuroinflammation paradigm. Collectively, our data show that the activation of microglia to a classically pro‐inflammatory state is associated with a switch to glycolysis that is mediated by mitochondrial fission, a process which may be a pharmacological target for immunomodulation

Expression of GPR17 receptor in a murine model of perinatal brain neuroinflammation and its possible interaction with Wnt pathway

Oligodendrocyte precursor cells (OPCs) are generated in specific germinal regions and progressively maturate to myelinating cells. Oligodendrocytes (OLs) differentiation is regulated by a complex interplay of intrinsic, epigenetic and extrinsic factors, including Wnt and the G protein-coupled receptor referred to as GPR17 (Mitew et al., 2014). This receptor responds to both extracellular nucleotides (UDP, UDP-glucose) and cysteinyl-leukotrienes (Ciana et al., 2006), endogenous signaling molecules involved in inflammatory response and in the repair of brain lesions. GPR17 is highly expressed in OPCs during the transition to immature OLs, but it is down-regulated in mature cells. Accordingly, GPR17-expressing OPCs are already present in mice at birth, increase over time, reach a peak at P10, before the peak of myelination, and then decline in the adult brain (Boda et al., 2011). Of note, in cultured OPCs, early GPR17 silencing has been shown to profoundly affect their ability to generate mature OLs (Fumagalli et al., 2011, 2015). Myelination defects characterize many brain disorders, including perinatal brain injury caused by systemic inflammation (Favrais et al., 2011), which is a leading cause of preterm birth. It has already been suggested that an imbalance in the Wnt/\u3b2-catenin/TCF4 pathway could be involved in the maturation arrest of OLs that is observed in premature infants (Yuen et al., 2014). No data are currently available on GPR17 in perinatal brain injury and on its possible interaction with Wnt pathway. Based on these premises, the aim of this work was to assess if the maturational blockade of OLs due to mild systemic perinatal inflammation, induced by intraperitoneal injections of interleukin-1\u3b2 (IL- 1\u3b2), is accompanied by defects in GPR17 expression and whether the Wnt pathway is involved in the regulation of GPR17. Data showed that in newborn mice exposed to IL-1\u3b2, which induces a blockade of oligodendrocyte maturation, GPR17 expression is not affected at early time point (P5), but it is downregulated at P10, when its expression should be maximal. Moreover, in vitro studies revealed that the maturation blockade of the oligodendroglial cell line Oli-Neu, after treatment with a Wnt Agonist II, is accompanied by a severe inhibition of GPR17 expression. In conclusion, our data have shown that myelination defects observed in perinatal brain injury are associated with defects in GPR17 expression; further studies are needed to characterize the molecular link between Wnt pathway and GPR17 receptor

Acute pericarditis due to pegylated interferon alpha therapy for chronic HCV hepatitis - Case report

<p>Abstract</p> <p>Background</p> <p>Cardio toxicity due to interferon therapy was reported only in small case series or case reports. The most frequent cardiac adverse effects related to interferon are arrhythmias and ischemic manifestations. The cardiomyopathy and pericarditis are rare but can be life threatening. The predisposing factors for interferon cardio toxicity were described only for ischemic manifestations and arrhythmias.</p> <p>Case presentation</p> <p>The authors report a case of pericarditis due to alpha interferon therapy for chronic hepatitis C, in a young woman without previous cardiac pathology. The clinical manifestations started during the 7-th month of interferon treatment. The cessation of interferon was necessary. After interferon discontinuation the patient recovered, with complete resolution of pericarditis. The patient scored 9 points on the Naranjo ADR probability scale, indicating a very probable association between pericarditis and interferon administration.</p> <p>Conclusion</p> <p>If a patient receiving interferon therapy complains of chest pain of sudden onset, a cardiac ultrasound should be performed in order to rule out pericarditis. We point out the possibility of an infrequent but severe adverse effect of interferon therapy.</p

Inhaled 45-50% argon augments hypothermic brain protection in a piglet model of perinatal asphyxia

Cooling to 33.5 °C in babies with neonatal encephalopathy significantly reduces death and disability, however additional therapies are needed to maximize brain protection. Following hypoxia–ischemia we assessed whether inhaled 45–50% Argon from 2–26 h augmented hypothermia neuroprotection in a neonatal piglet model, using MRS and aEEG, which predict outcome in babies with neonatal encephalopathy, and immunohistochemistry. Following cerebral hypoxia–ischemia, 20 Newborn male Large White piglets < 40 h were randomized to: (i) Cooling (33 °C) from 2–26 h (n = 10); or (ii) Cooling and inhaled 45–50% Argon (Cooling + Argon) from 2–26 h (n = 8). Whole-brain phosphorus-31 and regional proton MRS were acquired at baseline, 24 and 48 h after hypoxia–ischemia. EEG was monitored. At 48 h after hypoxia–ischemia, cell death (TUNEL) was evaluated over 7 brain regions. There were no differences in body weight, duration of hypoxia–ischemia or insult severity; throughout the study there were no differences in heart rate, arterial blood pressure, blood biochemistry and inotrope support. Two piglets in the Cooling + Argon group were excluded. Comparing Cooling + Argon with Cooling there was preservation of whole-brain MRS ATP and PCr/Pi at 48 h after hypoxia–ischemia (p < 0.001 for both) and lower 1H MRS lactate/N acetyl aspartate in white (p = 0.03 and 0.04) but not gray matter at 24 and 48 h. EEG background recovery was faster (p < 0.01) with Cooling + Argon. An overall difference between average cell-death of Cooling versus Cooling + Argon was observed (p < 0.01); estimated cells per mm2 were 23.9 points lower (95% C.I. 7.3–40.5) for the Cooling + Argon versus Cooling. Inhaled 45–50% Argon from 2–26 h augmented hypothermic protection at 48 h after hypoxia–ischemia shown by improved brain energy metabolism on MRS, faster EEG recovery and reduced cell death on TUNEL. Argon may provide a cheap and practical therapy to augment cooling for neonatal encephalopathy

Effects of Preterm Birth on Cortical Thickness Measured in Adolescence

Despite the extensive research into brain development after preterm birth, few studies have investigated its long-term effects on cortical thickness. The Stockholm Neonatal Project included infants between 1988 and 1993 with birth weight (BW) ≤1500 g. Using a previously published method, cortical thickness was estimated on T1-weighted 3D anatomical images acquired from 74 ex-preterm and 69 term-born adolescents (mean age 14.92 years). The cortex was significantly thinner in ex-preterm individuals in focal regions of the temporal and parietal cortices as indicated by voxel-wise t-tests. In addition, large regions around the central sulcus and temporal lobe as well as parts of the frontal and occipital lobes tended also to be thinner in the ex-preterm group. Although these results were not significant on voxel-wise tests, the spatially coherent arrangement of the thinning in ex-preterm individuals made it notable. When the group of ex-preterm individuals was divided by gestational age or BW, the thinning tended to be more pronounced in the anterior and posterior poles in those born nearer term or with a BW closer to 1500 g. These results support the notion that preterm birth is a risk factor for long-term development of cortical thickness

Abstracts from the 50th European Society of Human Genetics Conference: Posters

International audienc

A systems-level framework for drug discovery identifies Csf1R as an anti-epileptic drug target

The identification of drug targets is highly challenging, particularly for diseases of the brain. To address this problem, we developed and experimentally validated a general computational framework for drug target discovery that combines gene regulatory information with causal reasoning (“Causal Reasoning Analytical Framework for Target discovery”—CRAFT). Using a systems genetics approach and starting from gene expression data from the target tissue, CRAFT provides a predictive framework for identifying cell membrane receptors with a direction-specified influence over disease-related gene expression profiles. As proof of concept, we applied CRAFT to epilepsy and predicted the tyrosine kinase receptor Csf1R as a potential therapeutic target. The predicted effect of Csf1R blockade in attenuating epilepsy seizures was validated in three pre-clinical models of epilepsy. These results highlight CRAFT as a systems-level framework for target discovery and suggest Csf1R blockade as a novel therapeutic strategy in epilepsy. CRAFT is applicable to disease settings other than epilepsy

Loss of the Wnt/β-catenin pathway in microglia of the developing brain drives pro-inflammatory activation leading to white matter injury

Microglia-mediated neuroinflammation is key in numerous brain diseases including encephalopathy of the preterm born infant. Microglia of the still-developing brain have unique properties but little is known of how they regulate their inflammatory activation. This is important information as every year 9 million preterm born infants acquire persisting neurological injuries associated with encephalopathy and we lack strategies to prevent and treat these injuries. Our study of activation state regulators in immature brain microglia found a robust down-regulation of Wnt/β-catenin pathway receptors, ligands and intracellular signalling members in pro-inflammatory microglia. We undertook our studies initially in a mouse model of microglia-mediated encephalopathy including the clinical hallmarks of oligodendrocyte injury and hypomyelination. We purified microglia from this model and applied a genome-wide transcriptomics analysis validated with quantitative profiling. We then verified that down-regulation of the Wnt/β-catenin signalling cascade is sufficient and necessary to drive microglia into an oligodendrocyte-damaging phenotype using multiple pharmacological and genetic approaches in vitro and in vivo in mice and in humans and zebrafish. We also demonstrated that genomic variance in the WNT/β-catenin pathway is associated with the anatomical connectivity phenotype of the human preterm born infant. This integrated analysis of genomics and connectivity, as a surrogate for oligodendrocyte function/myelination, is agnostic to cell type. However, this data indicates that the WNT pathway is relevant to human brain injury and specifically that WNT variants may be useful clinically for injury stratification and prognosis. Finally, we performed a translational experiment using a BBB penetrant microglia-specific targeting 3DNA nanocarrier to deliver a Wnt agonist specifically and directly to microglia in vivo. Increasing the activity of the Wnt/β-catenin pathway specifically in microglia in our model of microglia-mediated encephalopathy was able to reduce microglial pro-inflammatory activation, prevent the typical hypomyelination and also prevent the long-term memory deficit associated with this hypomyelination. In summary, the canonical Wnt/β-catenin pathway regulates microglial activation and up-regulation of this pathway could be a viable neurotherapeutic strategy

Acute LPS sensitization and continuous infusion exacerbates hypoxic brain injury in a piglet model of neonatal encephalopathy

Co-existing infection/inflammation and birth asphyxia potentiate the risk of developing neonatal encephalopathy (NE) and adverse outcome. In a newborn piglet model we assessed the effect of E. coli lipopolysaccharide (LPS) infusion started 4 h prior to and continued for 48 h after hypoxia on brain cell death and systemic haematological changes compared to LPS and hypoxia alone. LPS sensitized hypoxia resulted in an increase in mortality and in brain cell death (TUNEL positive cells) throughout the whole brain, and in the internal capsule, periventricular white matter and sensorimotor cortex. LPS alone did not increase brain cell death at 48 h, despite evidence of neuroinflammation, including the greatest increases in microglial proliferation, reactive astrocytosis and cleavage of caspase-3. LPS exposure caused splenic hypertrophy and platelet count suppression. The combination of LPS and hypoxia resulted in the highest and most sustained systemic white cell count increase. These findings highlight the significant contribution of acute inflammation sensitization prior to an asphyxial insult on NE illness severity