The amazing brain

It is in the human nature to be curious about how we feel pain, see the world, hear bird`s songs, remember, forget, reason. We want to understand the nature of love, anger, satisfaction, desire and madness. This is a short story about the evolution of the science on the human brain and about major brain discoveries. It gives a concise historic perspective of the understanding of the nervous system - from ancient Egypt to the birth of Renaissance, with the works of Vesalius and his esteemed contemporaries. The contributions of 17th century neuroanatomists such as Tomas Willis followed by the pre-modern neuroscience researchers Camillo Golgi and especially Santiago Ramon y Cajal are highlighted. The contribution of transgenic mouse models and the application of modern noninvasive imaging methods such as positron emission tomography (PET) and magnetic resonance imaging (MRI) for ground braking functional studies on the human brain are briefly reviewed. Important 21st century projects such as the Human and Mouse Connectome projects and the White House Brain Initiative are also presented. Biomed Rev 2015; 26: 1-12.Key words: psychikon pneuma, census communis, NGF, PET, fMRI, connectom

Electron microscopist's view of the Alzheimer's plaque

Alzheimer's disease (AD) is characterized by extracellular aggregation and deposition of Amyloid-beta peptide in the form of diffuse and fibrillar plaques. More than 50 years ago electron microscopic studies in humans have characterized the structure of the amyloid plaque and neurofibrillary tangles. More recently animal models of AD-type amyloidosis have provided excellent opportunities to study plaque structure during the development and expression of AD-type pathology. Ultrastructural data from a variety of transgenic mice overexpressing mutant amyloid precursor proteins, mutant presenilins, with or without human ApoE knock-in isoforms, are highly comparable to classical electron microscopic findings in AD. This review is an attempt to evaluate, from an electron microscopist`s point of view, the structural identity of AD type pathology, and the mature amyloid plaque in particular.Biomedical Reviews 2012; 23: 9-17

Modeling traumatic brain injury: mechanisms of early neuronal and axon degeneration in the infant rodent brain

Traumatic brain injury (TBI) remains a major health challenge and affects the young disproportionately. Accidental and non-accidental TBI in children is a major contributor to morbidity, disability, and death. TBI in this critical period leads to profound neuronal and axonal degeneration followed by cognitive, psychological and memory impairment, altered processing speed, impaired executive functions, emotional liability as well as word finding difficulties. Cognitive and behavioral changes may remain unrecognized for periods even after sustaining mild injury. Although accidental and non-accidental inflicted injury (blunt force or violent shaking-inflicting brain injury or “Shaken baby” syndrome) posits a major clinical and sociological problem, mechanisms of tissue degeneration might be largely similar. The scope of this review will be the experimental research related to modeling blunt (concussive) head trauma specifically to the infant rodent brain resulting in acute (early) and protracted (late) degenerative changes such as axonal degeneration and apoptotic neuronal cell death. Similarly, discussion will be limited to therapeutic windows and potentials for ameliorating the development of early brain injury

Apoptosis in the mammalian nervous system: developmental and clinical implications

Among the many regulatory steps in brain development is the process of elimination of differentiating neurons at certain stages of maturation through an intrinsic suicide program now widely known as apoptosis. Apoptosis may thus describe a cell death pathway utilized by many developing cells in the nervous system, but may also be activated as a consequence of acute or chronic pathological impulses. Such pathological impulses may include brain injury, cerebral hypoxia-ischemia and the potentials of selected drugs such as N-methyl D-aspartate (NMDA) receptor antagonists, GABA mimetics and ethanol. In recent years, there has been a great interest in mechanisms of cell death in the nervous system and apoptotic cell death has been implicated in many neuro degenerative diseases such as Alzheimer's disease, amiotrophic lateral sclerosis, Parkinson's disease and other central and peripheral nervous system disorders. Recent findings have evaluated the contribution of programmed cell death and specific gene products involved in each of these cases. A deeper understanding of these processes may lead to the discovery of strategies for slowing, reducing or arresting neuronal and glial cell death induced by injury, aging or disease.Biomedical Reviews 2002; 13: 49-61

NGF-PC-AD connection

In an elegant manner Viviana Triaca presented in this volume of Adipobiology her Homage to Rita Levi-Montalcini highlighting the significance of nerve growth factor (NGF) in the molecular mechanisms of Alzheimer's disease (AD). This remarkable review generates a completely new direction in understanding some of the new and specific aspect of AD pathology, focusing on the NGF modulation of amyloid precursor protein (APP) processing and metabolism. Dr Triaca provides a paradigm shift from "classical" cholinergic to NGF-centered approach showing that the dysregulation of NGF-TrkA (receptor tyrosine kinase A) and proNGF-p75NTR signaling systems is a good candidate for being primus movens in the pathogenesis of AD.Adipobiology 2013; 5: 19-22

SOS for SOC: the renaissance of a seemingly ubiquitous organelle

In this volume of Biomedical Reviews Denys Wheatley presents a short review "Rediscovery" of a forgotten organelle, the primary cilium: the root cause of a plethora of disorders. Dr Wheatley has extensively published cilium-related research papers, reviews and book chapters. Quite naturally has been an advocate for attracting scientific interest to this beautiful biological structure for decades. Therefore he is well suited to provide a world-class view on this scientific problem. He does that in an elegant manner in his review, and states the future direction of research into the ubiquitous nature and involvement of this organelle in health and disease.Biomedical Reviews 2013; 24: 9-10

Alcohol-induced apoptosis of oligodendrocytes in the fetal macaque brain

BACKGROUND: In utero exposure of the fetal non-human primate (NHP) brain to alcohol on a single occasion during early or late third-trimester gestation triggers widespread acute apoptotic death of cells in both gray and white matter (WM) regions of the fetal brain. In a prior publication, we documented that the dying gray matter cells are neurons, and described the regional distribution and magnitude of this cell death response. Here, we present new findings regarding the magnitude, identity and maturational status of the dying WM cells in these alcohol-exposed fetal NHP brains. RESULTS: Our findings document that the dying WM cells belong to the oligodendrocyte (OL) lineage. OLs become vulnerable when they are just beginning to generate myelin basic protein in preparation for myelinating axons, and they remain vulnerable throughout later stages of myelination. We found no evidence linking astrocytes, microglia or OL progenitors to this WM cell death response. The mean density (profiles per mm(3)) of dying WM cells in alcohol-exposed brains was 12.7 times higher than the mean density of WM cells dying by natural apoptosis in drug-naive control brains. CONCLUSIONS: In utero exposure of the fetal NHP brain to alcohol on a single occasion triggers widespread acute apoptotic death of neurons (previous study) and of OLs (present study) throughout WM regions of the developing brain. The rate of OL apoptosis in alcohol-exposed brains was 12.7 times higher than the natural OL apoptosis rate. OLs become sensitive to the apoptogenic action of alcohol when they are just beginning to generate constituents of myelin in their cytoplasm, and they remain vulnerable throughout later stages of myelination. There is growing evidence for a similar apoptotic response of both neurons and OLs following exposure of the developing brain to anesthetic and anticonvulsant drugs. Collectively, this body of evidence raises important questions regarding the role that neuro and oligo apoptosis may play in the human condition known as fetal alcohol spectrum disorder (FASD), and also poses a question whether other apoptogenic drugs, although long considered safe for pediatric/obstetric use, may have the potential to cause iatrogenic FASD-like developmental disability syndromes

Mitochondrial structure and function are not different between nonfailing donor and end‐stage failing human hearts

During human heart failure, the balance of cardiac energy use switches from predominantly fatty acids (FAs) to glucose. We hypothesized that this substrate shift was the result of mitochondrial degeneration; therefore, we examined mitochondrial oxidation and ultrastructure in the failing human heart by using respirometry, transmission electron microscopy, and gene expression studies of demographically matched donor and failing human heart left ventricular (LV) tissues. Surprisingly, respiratory capacities for failing LV isolated mitochondria (n = 9) were not significantly diminished compared with donor LV isolated mitochondria (n = 7) for glycolysis (pyruvate + malate)‐ or FA (palmitoylcarnitine)‐derived substrates, and mitochondrial densities, assessed via citrate synthase activity, were consistent between groups. Transmission electron microscopy images also showed no ultrastructural remodeling for failing vs. donor mitochondria; however, the fraction of lipid droplets (LDs) in direct contact with a mitochondrion was reduced, and the average distance between an LD and its nearest neighboring mitochondrion was increased. Analysis of FA processing gene expression between donor and failing LVs revealed 0.64‐fold reduced transcript levels for the mitochondrial‐LD tether, perilipin 5, in the failing myocardium (P = 0.003). Thus, reduced FA use in heart failure may result from improper delivery, potentially via decreased perilipin 5 expression and mitochondrial‐LD tethering, and not from intrinsic mitochondrial dysfunction.—Holzem, K. M., Vinnakota, K. C., Ravikumar, V. K., Madden, E. J., Ewald, G. A., Dikranian, K., Beard, D. A., Efimov, I. R. Mitochondrial structure and function are not different between nonfailing donor and end‐stage failing human hearts. FASEB J. 30, 2698‐2707 (2016). www.fasebj.orgPeer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154292/1/fsb2fj201500118r.pd

Zika virus infection in the developing mouse produces dramatically different neuropathology dependent on viral strain

Zika virus (ZIKV) infection during pregnancy has been causally linked to a constellation of neurodevelopmental deformities in the fetus resulting in a disease termed congenital Zika syndrome (CZS). Here we detail how ZIKV infection produces extensive neuropathology in the developing mouse brain and spinal cord of both sexes. Surprisingly, neuropathology differs depending on viral strain with a French Polynesian isolate producing primarily excitotoxicity and a Brazilian isolate being almost exclusively apoptotic but occurring over a prolonged period that is more likely to produce severe hypoplasia. We also show exposure can produce a characteristic pattern of infection that mirrors neuropathology and ultimately results in gross morphological deformities strikingly similar to CZS. This research provides a valuable mouse model mirroring the clinical course of disease that can be used to test potential therapies to improve treatment and gain a better understanding of the disabilities associated with CZS