bims-medebr 2021-11-14 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2021–11–14
seven papers selected by
Regina F. Fernández, Johns Hopkins University

Voxel-Based Analysis of [18F]-FDG Brain PET in Rats Using Data-Driven Normalization.
Cholesterol in Brain Development and Perinatal Brain Injury: more than a Building Block.
Maternal vitamin D deficiency reduces docosahexaenoic acid, placental growth factor and peroxisome proliferator activated receptor gamma levels in the pup brain in a rat model of preeclampsia.
Chronic Hypoxia Inhibits Respiratory Complex IV Activity and Disrupts Mitochondrial Dynamics in the Fetal Guinea Pig Forebrain.
Membrane Cholesterol Is a Critical Determinant for Hippocampal Neuronal Polarity.
Fetal Neuroprotective Mechanism of Maternal Magnesium Sulfate: Proteomic Analysis.
Endocannabinoid System Unlocks the Puzzle of Autism Treatment via Microglia.

Front Med (Lausanne). 2021 ;8 744157

Voxel-Based Analysis of [18F]-FDG Brain PET in Rats Using Data-Driven Normalization.

Silke Proesmans, Robrecht Raedt, Charlotte Germonpré, Emma Christiaen, Benedicte Descamps, Paul Boon, Veerle De Herdt, Christian Vanhove.

  Introduction: [18F]-FDG PET is a widely used imaging modality that visualizes cellular glucose uptake and provides functional information on the metabolic state of different tissues in vivo. Various quantification methods can be used to evaluate glucose metabolism in the brain, including the cerebral metabolic rate of glucose (CMRglc) and standard uptake values (SUVs). Especially in the brain, these (semi-)quantitative measures can be affected by several physiological factors, such as blood glucose level, age, gender, and stress. Next to this inter- and intra-subject variability, the use of different PET acquisition protocols across studies has created a need for the standardization and harmonization of brain PET evaluation. In this study we present a framework for statistical voxel-based analysis of glucose uptake in the rat brain using histogram-based intensity normalization. Methods: [18F]-FDG PET images of 28 normal rat brains were coregistered and voxel-wisely averaged. Ratio images were generated by voxel-wisely dividing each of these images with the group average. The most prevalent value in the ratio image was used as normalization factor. The normalized PET images were voxel-wisely averaged to generate a normal rat brain atlas. The variability of voxel intensities across the normalized PET images was compared to images that were either normalized by whole brain normalization, or not normalized. To illustrate the added value of this normal rat brain atlas, 9 animals with a striatal hemorrhagic lesion and 9 control animals were intravenously injected with [18F]-FDG and the PET images of these animals were voxel-wisely compared to the normal atlas by group- and individual analyses. Results: The average coefficient of variation of the voxel intensities in the brain across normal [18F]-FDG PET images was 6.7% for the histogram-based normalized images, 11.6% for whole brain normalized images, and 31.2% when no normalization was applied. Statistical voxel-based analysis, using the normal template, indicated regions of significantly decreased glucose uptake at the site of the ICH lesion in the ICH animals, but not in control animals. Conclusion: In summary, histogram-based intensity normalization of [18F]-FDG uptake in the brain is a suitable data-driven approach for standardized voxel-based comparison of brain PET images.

Keywords:  PET; [18F]-FDG; intensity normalization; rat brain; voxel-based analysis

DOI:  https://doi.org/10.3389/fmed.2021.744157
Curr Neuropharmacol. 2021 Nov 11.

Cholesterol in Brain Development and Perinatal Brain Injury: more than a Building Block.

Fuxin Lu, Donna M Ferriero, Xiangning Jiang.

  The central nervous system (CNS) is enriched with important classes of lipids, in which cholesterol is known to make up a major portion of myelin sheaths, besides being a structural and functional unit of CNS cell membranes. Unlike in the adult brain where the cholesterol pool is relatively stable, cholesterol is synthesized and accumulated at the highest rate in the developing brain to meet the needs of rapid brain growth at this stage, which is also a critical period for neuroplasticity. In addition to its biophysical role in membrane organization, cholesterol is crucial for brain development due to its involvement in brain patterning, myelination, neuronal differentiation and synaptogenesis. Thus any injuries to the immature brain that affect cholesterol homeostasis may have long-term adverse neurological consequences. In this review, we describe the unique features of brain cholesterol biosynthesis and metabolism, cholesterol trafficking between different cell types, and highlight cholesterol-dependent biological processes during brain maturation. We also discuss the association of impaired cholesterol homeostasis with several forms of perinatal brain disorders in term and preterm newborns, including hypoxic-ischemic encephalopathy. Strategies targeting the cholesterol pathways may open new avenues for diagnosis and treatment of developmental brain injury.

Keywords:  brain development; brain injury; cholesterol

DOI:  https://doi.org/10.2174/1570159X19666211111122311
Prostaglandins Leukot Essent Fatty Acids. 2021 Nov 04. pii: S0952-3278(21)00126-5. [Epub ahead of print]175 102364

Maternal vitamin D deficiency reduces docosahexaenoic acid, placental growth factor and peroxisome proliferator activated receptor gamma levels in the pup brain in a rat model of preeclampsia.

Juhi Nema, Karuna Randhir, Nisha Wadhwani, Deepali Sundrani, Sadhana Joshi.

   BACKGROUND: Preeclampsia is a pregnancy disorder characterized with abnormal placental angiogenesis. Vitamin D and long chain polyunsaturated fatty acids (LCPUFA) play a crucial role in pregnancy and are required for normal placental and fetal growth and development. This study reports the effect of maternal vitamin D on LCPUFA levels in the mother and offspring brain fatty acid levels and angiogenic markers in a rat model of preeclampsia.
METHODS: Female rats were divided into four groups from pre-pregnancy to pregnancy, viz Control; Preeclampsia (PE); Vitamin D deficient with PE (VDD-PE) and Vitamin D supplemented with PE (VDS-PE). Preeclampsia was induced by administering l-nitroarginine methyl ester (L-NAME) at the dose of 50 mg/kg body weight/day from day 14 to day 19 of gestation. Dams were sacrificed at d20 of gestation to collect dam blood, placenta and pup brain. LCPUFA levels from dam plasma, erythrocytes and placenta and its transcription factor peroxisome proliferator activated receptor gamma (PPAR-g) from placenta were estimated. Pup brain LCPUFA levels, angiogenic factors vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) and transcription factor hypoxia inducible factor (Hif-1α) and PPAR-g were also estimated.
RESULTS: Maternal vitamin D status influences fatty acid levels. Placental PPAR-g levels were lower in the VDD-PE group as compared to the VDS-PE groups (p < 0.01). In the offspring brain, both PE and VDD-PE group showed lower levels of DHA (p < 0.05 for both) while saturated fatty acids (SFA) levels in the VDD-PE group were higher as compared to the control group (p < 0.05). VDD-PE group also showed lower levels of PlGF and PPAR-g (p < 0.01 and p < 0.05, respectively) in the pup brain while vitamin D supplementation demonstrated levels similar to control.
CONCLUSION: This study for the first time demonstrates that maternal vitamin D status influences LCPUFA metabolism and angiogenesis in the offspring brain.

Keywords:  Docosahexaenoic acid; Long chain polyunsaturated fatty acids; Peroxisome proliferator activated receptor gamma; Preeclampsia; Vascular endothelial growth factor; Vitamin d

DOI:  https://doi.org/10.1016/j.plefa.2021.102364
Reprod Sci. 2021 Nov 08.

Chronic Hypoxia Inhibits Respiratory Complex IV Activity and Disrupts Mitochondrial Dynamics in the Fetal Guinea Pig Forebrain.

Tabitha M Quebedeaux, Hong Song, Jamiu Giwa-Otusajo, Loren P Thompson.

  Mitochondrial dysfunction is an underlying cause of childhood neurological disease secondary to the crucial role of mitochondria in proper neurodevelopment. We hypothesized that chronic intrauterine hypoxia (HPX) induces mitochondrial deficits by altering mitochondrial biogenesis and dynamics in the fetal brain. Pregnant guinea pigs were exposed to either normoxia (NMX, 21%O2) or HPX (10.5%O2) starting at 28-day (early onset, EO-HPX) or 50-day (late onset, LO-HPX) gestation until term (65 days). Near-term male and female fetuses were extracted from anesthetized sows, and mitochondria were isolated from excised fetal forebrains (n = 6/group). Expression of mitochondrial complex subunits I-V (CI-CV), fission (Drp-1), and fusion (Mfn-2) proteins was measured by Western blot. CI and CIV enzyme activities were measured by colorimetric assays. Chronic HPX reduced fetal body wts and increased (P < 0.05) brain/body wt ratios of both sexes. CV subunit levels were increased in EO-HPX males only and CII levels increased in LO-HPX females only compared to NMX. Both EO- and LO-HPX decreased CIV activity in both sexes but had no effect on CI activity. EO-HPX increased Drp1 and decreased Mfn2 levels in males, while LO-HPX had no effect on either protein levels. In females, both EO-HPX and LO-HPX increased Drp1 but had no effect on Mfn2 levels. Chronic HPX alters abundance and activity of select complex subunits and shifts mitochondrial dynamics toward fission in a sex-dependent manner in the fetal guinea pig brain. This may be an underlying mechanism of reduced respiratory efficiency leading to disrupted metabolism and increased vulnerability to a second neurological injury at the time of birth in HPX fetal brains.

Keywords:  Brain; Dynamics; Fetal; Hypoxia; Mitochondria; Respiratory complex

DOI:  https://doi.org/10.1007/s43032-021-00779-w
Front Mol Neurosci. 2021 ;14 746211

Membrane Cholesterol Is a Critical Determinant for Hippocampal Neuronal Polarity.

Mini Jose, Aiswarya Sivanand, Chaitra Channakeshava.

  Maintaining a normal cholesterol balance is crucial for the functioning of a healthy brain. Dysregulation in cholesterol metabolism and homeostasis in the brain have been correlated to various neurological disorders. The majority of previous studies in primary cultures focus on the role of cholesterol balance in neuronal development after polarity has been established. Here we have investigated how transient alteration of membrane lipids, specifically cholesterol, affects neuronal development and polarity in developing hippocampal neurons prior to polarity establishment, soon after initiation of neurite outgrowth. We observed that temporary cholesterol perturbation affects axonal and dendritic development differentially in an opposing manner. Transient membrane cholesterol deficiency increased neuronal population with a single neurite, simultaneously generating a second population of neurons with supernumerary axons. Brief replenishment of cholesterol immediately after cholesterol sequestering rescued neuronal development defects and restored polarity. The results showed a small window of cholesterol concentration to be complementing neurite outgrowth, polarity reestablishment, and in determining the normal neuronal morphology, emphasizing the critical role of precise membrane lipid balance in defining the neuronal architecture. Membrane cholesterol enhancement modified neurite outgrowth but did not significantly alter polarity. Cholesterol sequestering at later stages of development has shown to enhance neurite outgrowth, whereas distinct effects for neurite development and polarity were observed at early developmental stages, signifying the relevance of precise membrane cholesterol balance in altering neuronal physiology. Our results confirm cholesterol to be a key determinant for axo-dendritic specification and neuronal architecture and emphasize the possibility to reverse neuronal developmental defects caused by cholesterol deficiency by modulating membrane cholesterol during the early developmental stages.

Keywords:  axo-dendritic specification; cholesterol labeling; hippocampal neuronal development; lipid homeostasis; membrane cholesterol; neurite outgrowth; neuronal polarity

DOI:  https://doi.org/10.3389/fnmol.2021.746211
J Mol Neurosci. 2021 Nov 10.

Fetal Neuroprotective Mechanism of Maternal Magnesium Sulfate: Proteomic Analysis.

Lee Reicher, Hanin Dabaja, Yuval Ginsberg, Nizar Khatib, Yuval Fouks, Emmanuel Attali, Michael G Ross, Zeev Weiner, Ron Beloosesky.

  Mg supplementation has been shown to protect preterm fetuses from white and gray matter damage, but the mechanism is unclear. The purpose of this study was to study the effect of maternal inflammation on the overall protein panel of the fetal rat brain, as well as the neuroprotective effect of magnesium-sulfate (MG). Pregnant rats at e20 (n = 6, 18 total) received injections of i.p. lipopolysaccharide (LPS) 500 ug/kg or control saline (SAL) at time 0. Dams were randomized to treatment with s.c. MG (270 mg/kg loading followed by 27 mg/kg q20 min) or saline (SAL) from -2 to +2 h, followed by an additional injection of MG (270 mg/kg) at +2 h. At 4 h after LPS administration, fetal brains were collected from the 3 treatment groups (LPS/SAL, LPS/MG, SAL/SAL) and analyzed by proteomic technique. LPS significantly decreased fetal brain complement C3, alpha-1-antiproteinase, metallothionein-3, alpha-2-macroglobulin, neurosecretory protein VGF, glutathione S-transferase mu 2, fam91a1, cnot7, mitogen-activated protein kinase levels, and significantly increased fetal brain Hbg1, while MG treatment normalized these measures to normal values. Maternal inflammation may cause brain injury via pathways other than the activation of neurotoxic cytokines; this effect could be due to increased/decreased production of certain proteins associated with securing oligodendrocytes, encouraging neuronal growth in the brain, or protecting against cerebral ischemia. MG's neuroprotective activity may be achieved by modifying the effect of LPS on proteins involved in early brain development.

Keywords:  Asphyxia; Infection; Magnesium sulfate; Neuroprotection; Preterm

DOI:  https://doi.org/10.1007/s12031-021-01939-y
Front Psychiatry. 2021 ;12 734837

Endocannabinoid System Unlocks the Puzzle of Autism Treatment via Microglia.

Tangfeng Su, Yu Yan, Qiang Li, Jiacai Ye, Lei Pei.

  Autism spectrum disorder (ASD) is a serious neurodevelopmental disorder and characterized by early childhood-onset impairments in social interaction and communication, restricted and repetitive patterns of behavior or interests. So far there is no effective treatment for ASD, and the pathogenesis of ASD remains unclear. Genetic and epigenetic factors have been considered to be the main cause of ASD. It is known that endocannabinoid and its receptors are widely distributed in the central nervous system, and provide a positive and irreversible change toward a more physiological neurodevelopment. Recently, the endocannabinoid system (ECS) has been found to participate in the regulation of social reward behavior, which has attracted considerable attention from neuroscientists and neurologists. Both animal models and clinical studies have shown that the ECS is a potential target for the treatment of autism, but the mechanism is still unknown. In the brain, microglia express a complete ECS signaling system. Studies also have shown that modulating ECS signaling can regulate the functions of microglia. By comprehensively reviewing previous studies and combining with our recent work, this review addresses the effects of targeting ECS on microglia, and how this can contribute to maintain the positivity of the central nervous system, and thus improve the symptoms of autism. This will provide insights for revealing the mechanism and developing new treatment strategies for autism.

Keywords:  autism spectrum disorder; endocannabinoid system; immune; microglia; neurodevelopmental disorders

DOI:  https://doi.org/10.3389/fpsyt.2021.734837