bluuebunny/crossref_metadata_2025 huggingface dataset:
Is There an Amygdala and How Far Does It Extend?
Authors: McDONALD ALEXANDER J.
Published: July 2010

Abstract:Burdach is credited with first using the term ‘amygdala’ to describe an almond‐shaped mass of gray matter in the anterior portion of the human temporal lobe. With the subsequent development of histological techniques in the latter part of the nineteenth century it became readily apparent that there were areas dorsal and medial to Burdach's amygdala that seemed to be anatomically related to it. These regions include the nuclei that are now called the central, medial, and cortical amygdalar nuclei. Johnston considered the amygdala to have two major portions: (1) the centromedial nuclei, which are closely associated with the striatum, and (2) the cortical and basolateral nuclei, which are closely associated with the cerebral cortex. Johnston also importantly observed that the centromedial nuclei appear to have extensions that project rostralward to become continuous with the bed nucleus of the stria terminalis. Johnston's concept of a multicompartmental amygdala, with striatal‐like and cortical‐like components, dominated thought about the structure and function of the amygdala for most of the twentieth century. Recently, it was suggested that the amygdala is not a single neurobiological entity, but is better conceived as a region where several distinct structures, each with affiliations with different systems, are in close proximity to each other. These current concepts and issues concerning the configuration of the amygdala are discussed in light of recent cytological, immunohistochemical, and connectional studies.
Intrinsic Synaptic Circuitry of the Amygdala
Authors: PITKÄNEN ASLA , SAVANDER MIA , NURMINEN NINA , YLINEN AARNE
Published: July 2010

Abstract:The present study is part of an ongoing project aimed at understanding the electrophysiologic properties of single amygdaloid neurons and their correlations with the morphology of the somata as well as axonal and dendritic trees. The axonal morphology of 14 three‐dimensional, reconstructed spiny neurons (4 in the lateral and 10 in the basal nucleus) that were filledin vivowith intracellular injections of biocytin is described. Three‐dimensional reconstruction was performed using Neurolucida software (MicroBrightField). Sholl analysis was used to assess the axonal length as well as the number of axonal varicosities and endings within concentric spherical shells placed at 50‐μm intervals from the soma. These data indicate that the same neuron can innervate several amygdaloid nuclear divisions or nuclei and extra‐amygdaloid regions. This finding suggests that the same neuron can modulate various brain areas in parallel. Both the presumed intra‐amygdaloid (all axonal branches within the amygdala) and extra‐amygdaloid (axons also outside the amygdala) projection neurons have dense perisomatic axonal arborizations, and consequently, the intra‐amygdaloid and extra‐amygdaloid projection neurons are difficult to differentiate based on the analysis of perisomatic axonal morphology. Furthermore, the same extra‐amygdaloid neuron can drive many neurons both locally as well as at extra‐amygdaloid projection areas within a relatively short time. Finally, the axonal morphology of spiny neurons located in the lateral or basal nuclei was similar. These data provide baseline quantitative information about the axonal dimensions of amygdaloid neurons and can form the anatomic basis for modeling amygdaloid neuronal circuits when more quantitative data regarding neuronal numbers, size, and dendritic morphology become available.
Excitatory Synaptic Transmission in the Lateral and Central Amygdala
Authors: SAH P. , DE ARMENTIA MIKEL LOPEZ
Published: July 2010

Abstract: The amygdala plays a major role in the acquisition and expression of fear conditioning. NMDA receptor‐dependent synaptic plasticity within the basolateral amygdala has been proposed to underlie the acquisition and possible storage of fear memories. Here the properties of fast glutamatergic transmission in the lateral and central nuclei of the amygdala are presented. In the lateral amygdala, two types of neurons, interneurons and projection neurons, could be distinguished by their different firing properties. Glutamatergic inputs to interneurons activated AMPA receptors with inwardly rectifying current‐voltage relations (I‐Vs), whereas inputs to projection neurons activated receptors that had linear I‐Vs, indicating that receptors on interneurons lack GluR2 subunits. Inputs to projection neurons formed dual component synapses with both AMPA and NMDA components, whereas at inputs to interneurons, the contribution of NMDA receptors was very small. Neurons in the central amygdala received dual component glutamatergic inputs that activated AMPA receptors with linear I‐Vs. NMDA receptor‐mediated EPSCs had slow decay time constants in the central nucleus. Application of NR2B selective blockers ifenprodil or CP‐101,606 blocked NMDA EPSCs by 70% in the central nucleus, but only by 30% in the lateral nucleus. These data show that the distribution of glutamatergic receptors on amygdalar neurons is not uniform. In the lateral amygdala, interneurons and pyramidal neurons express AMPA receptors with different subunit compositions. Synapses in the central nucleus activate NMDA receptors that contain NR1 and NR2B subunits, whereas synapses in the lateral nucleus contain receptors with both NR2A and NR2B subunits.
The Amygdala, Synaptic Plasticity, and Fear Memory
Authors: MAREN STEPHEN
Published: July 2010

Abstract: The nature and mechanisms of synaptic plasticity in the amygdala and the relation of amygdaloid plasticity to behavior are exciting new areas of study in neuroscience. These issues were at the heart of presentations by Paul Chapman, Michael Fanselow, Patricia Shinnick‐Gallagher, and Michael Rogawski in a session entitled “Long‐Term Plasticity in Amygdala Synaptic Transmission” that was held at the conference featured in this volume. In this chapter, I briefly summarize these talks and give my perspective on the presentations as the session chair. I argue that we must first understand the role of the amygdala in learning and memory in order to understand the contribution of amygdaloid synaptic plasticity to behavior. Although it is generally agreed that the amygdala is involved in several forms of emotional learning and memory such as pavlovian fear conditioning, a recent debate has emerged concerning the precise role of the amygdala in learning versus performing fear responses. I discuss data from my laboratory that unravel this issue. I argue that the basolateral complex of the amygdala (BLA) normally plays an essential role in associative processes in fear conditioning. Nonetheless, rats with BLA lesions acquire and express conditional fear under some conditions. A neuroanatomical model that accounts for these data is presented.
The Amygdala and Its Place in the Cerebral Hemisphere
Authors: SWANSON LARRY W.
Published: July 2010

Abstract:Developmental, gene expression, connectional, and neuron morphology evidence converges to suggest that cell groups of the amygdalar region participate in at least four distinct, though interrelated, functional systems associated with differentiated corticostriatopallidal projections. The amygdala is neither a structural nor a functional unit; instead, it is a collection of adjacent cell groups in the medial temporal lobe and adjacent regions of the caudal piriform lobe that was defined on gross anatomic terms.
Appetitive Behavior
Authors: EVERITT BARRY J. , CARDINAL RUDOLF N. , PARKINSON JOHN A. , ROBBINS TREVOR W.
Published: July 2010

Abstract:In this chapter, we review data from studies involving appetitive conditioning using measures of pavlovian approach behavior and the effects of pavlovian conditioned stimuli on instrumental behavior, including the pavlovian‐to‐instrumental transfer effect and conditioned reinforcement. These studies consistently demonstrate double dissociations of function between the basolateral area and the central nucleus of the amygdala. Moreover, the data show marked parallels with data derived from aversive (fear) conditioning studies and are consistent with the idea that these subsystems of the amygdala mediate different kinds of associative representation formed during pavlovian conditioning. We hypothesize that the basolateral amygdala is required for a conditioned stimulus to gain access to the current affective value of its specific unconditioned stimulus, whereas the central nucleus mediates stimulus‐response representations and conditioned motivational influences on behavior. Although these systems normally operate together, they can also modulate behavior in distinct ways. In many circumstances, then, emotional behavior can be seen as a coordinated combination of processing by these amygdaloid sub‐nuclei, reflecting the superimposition of a phylogenetically recent basolateral amygdala subsystem that encodes and retrieves the affective value of environmental stimuli and thereby directs complex, adaptive behavioral responses onto a phylogenetically older central amygdala subsystem that enables cortical structures (including the basolateral amygdala) to recruit incentive motivational processes and thereby invigorate emotional responding.
Amygdala Automaticity in Emotional Processing
Authors: DOLAN R. J. , VUILLEUMIER PATRICK
Published: July 2010

Abstract: The question addressed in this paper is whether the human amygdala processes threat‐related stimuli independent of selective attention. This is considered from a functional neuroimaging perspective, describing studies in normal volunteers and patients with brain lesions. The conclusion is that the evidence for such automaticity is strong, indicating that important distinctions exist between emotion and other forms of cognition.
The Amygdala and Alzheimer's Disease
Authors: SHINOTOH H. , FUKUSHI K. , NAGATSUKA S. , TANAKA N. , AOTSUKA A. , OTA T. , NAMBA H. , TANADA S. , IRIE T.
Published: July 2010

Abstract: The primary transmitter deficit is cholinergic in Alzheimer's disease (AD), and the amygdala receives a major cholinergic projection from the nucleus basalis of Meynert (Ch4), which may play an important role in the retention of affective conditioning and/or memory consolidation. We measured brain acetylcholinesterase (AChE) activity in 54 patients with AD and in 22 normal controls by positron emission tomography and N‐[11C]methylpiperidin‐4‐yl acetate to characterize the cholinergic pathology in AD. The k3 values were calculated as an index of AChE activity in a three‐compartment model analysis using the metabolite‐corrected arterial input function. The k3 values were highly significantly reduced by 20% in the cerebral neocortex (P <0.0001 in the two‐tailed t test), 14% in the hippocampus (P <0.001), and 33% in the amygdala (P <0.0001) in AD patients compared with normal controls. The k3 values were significantly correlated with the Mini‐Mental State Examination scores in both the cerebral cortex (P <0.001) and the amygdala (P <0.05) in AD patients, supporting the cholinergic hypothesis of cognitive dysfuncion in AD. Further studies are required, however, to elucidate the specific role of the cholinergic deficit in the amygdala in the emotional and behavioral symptoms in AD.
Sexual Behavior Problems in Preteen Children
Authors: FRIEDRICH W. N. , DAVIES W. HOBART , FEHER ELEONORA , WRIGHT JOHN
Published: July 2010

Abstract: A large sample of 2–12 year old children (N= 2311) was studied to determine the relationship between three sexually intrusive behavior items (SIBs) measured by the Child Sexual Behavior Inventory (CSBI) and a range of developmental, ecological, and behavioral correlates. The variables studied included age, gender, race, family income, single parent status, maternal education, family sexual behaviors, physical abuse, sexual abuse, domestic violence, social competence of the child, and three scales from the CBCL (Internalizing, Externalizing, and PTSD). Sexual abuse was not the primary predictor of SIB, but a model incorporating family adversity, modeling of coercive behavior, child behavior, and modeling of sexuality predicted a significant amount of variance.
Principles of Forensic Mental Health Assessment
Authors: HEILBRUN KIRK
Published: July 2010

Abstract: Risk assessment with sexual offenders is generally performed for two purposes: to assist the court in deciding on a relevant legal question (in a legal context), or to plan treatment interventions (in a clinical context). Failure to make this distinction, and to accurately identify the context and purpose for which the assessment is being conducted, can result in significant problems. This chapter will begin by making this distinction. Then, focusing on evaluations done for legal decision making purposes, it will describe 29 recently derived broad principles of forensic mental health assessment and their application to evaluations done to assist legal decision making.
After Hendricks: Defining Constitutional Treatment for Washington State's Civil Commitment Program
Authors: LIEB ROXANNE
Published: July 2010

Abstract: Washington State's law for sexually violent predators was enacted in 1990; since then, 14 other states have passed similar laws authorizing civil commitment for dangerous sexual offenders following their prison terms. Although the law has survived constitutional challenges at both the state and in the U.S. Supreme Court, a related set of court actions has addressed whether the treatment program is adequate. In 1994, the federal district court placed Washington's program under injunction and appointed a special master to ensure that the state improve deficiencies in the program. As of 2003, the federal court continues to oversee the state's program, with a threat of fines totaling several million dollars if the injunction terms are not met. Over an eight‐year period, the special master delivered 19 reports to the court, documenting the program's deficiencies as well as its successes in meeting the court's orders. This article reviews these reports and court orders, detailing the court's requirements for an adequate treatment program.
Sexual Offender Commitment in the United States
Authors: FITCH W. LAWRENCE
Published: July 2010

Abstract: Fifteen states and the District of Columbia have laws for the special civil commitment of convicted sexual offenders who are about to be released from penal confinement and do not meet criteria for ordinary psychiatric civil commitment. As of summer 2002, nearly 2500 sexual offenders were hospitalized pursuant to one of these laws. An American Psychiatric Association task force declared that ‘sexual predator commitment laws establish a non‐medical definition of what purports to be a clinical condition without regard for scientific and clinical knowledge,’ and thus ‘distort the traditional meaning of civil commitment, misallocate psychiatric facilities and resources, and constitute an abuse of psychiatry.’ It remains unclear how legislatures in states with these laws will respond to the U.S. Supreme Court's 2002 decision in Kansas v. Crane indicating that, absent a finding that an offender has ‘serious difficulty controlling behavior’ (not an explicit commitment criterion in any state), commitment is invalid.
Emerging Issues, Policy Changes, and the Future of Treating Children with Sexual Behavior Problems
Authors: LONGO ROBERT E.
Published: July 2010

Abstract: Children and adolescents with sexual behavior problems are a growing national concern. While the field continues to make advances, we have much more work to do. We are working in a difficult and trying period for juvenile justice. It is a time when many are willing to give up on adolescents or punish them as we do adults. We have reached a point where many in our society do not know about, or care to understand, the complex issues that are the roots of violence and sexual violence in youth. Certainly their faith in the resiliency of youth has been tarnished. Nine critical areas that need to be taken into account when working with youth with sexual behavior problems are addressed. These areas include the unfortunate but continued trickle‐down and use of adult‐based treatment models to treat youth with sexual behavior problems, changes in juvenile law that have an impact on our ability to treat these youths effectively, the need for continued research in developing typologies for youths with sexual behavior problems and valid and reliable risk assessment scales, continued work with understanding and developing dynamic risk factors for sexually abusive youth, the need to develop better treatments for special populations of youth with sexual behavior problems, the need for a continuum of care, what constitutes best practice in treating youths with sexual behavior problems, the need for developing and refining standards of care, and the need for continued public education that supports prevention efforts to reduce sexual abuse by youth.
Parkin and Endoplasmic Reticulum Stress
Authors: TAKAHASHI RYOSUKE , IMAI YUZURU , HATTORI NOBUTAKA , MIZUNO YOSHIKUNI
Published: July 2010

Abstract: Autosomal‐recessive juvenile parkinsonism (AR‐JP) is caused by mutations in the parkin gene. Parkin protein is characterized by a ubiquitin‐like domain at its NH2 terminus and by two RING finger motifs and one IBR (in between RING finger) motif at its COOH‐terminus (RING‐IBR‐RING). We showed that the parkin protein is an E3 ubiquitin ligase, which binds to ubiquitin‐conjugating enzymes (E2s) through its RING‐IBR‐RING motif. The pathogenesis of AR‐JP, therefore, was hypothesized to be accumulation of unidentified neurotoxic protein (a substrate of parkin). On the basis of this hypothesis, the substrate of parkin was sought using a yeast two‐hybrid system. A putative G protein‐coupled transmembrane polypeptide, named Pael (parkin‐associated endothelin receptor‐like) receptor, was identified as a parkin binding protein. When overexpressed in cells, this receptor tends to become unfolded, insoluble, and ubiquitinated. The insoluble Pael receptor leads to endoplasmic reticulum (ER) stress‐induced cell death. Parkin specifically ubiquitinates this receptor in the presence of ER‐resident E2s and promotes the degradation of unfolded Pael receptor, resulting in suppression of the cell death induced by the accumulation of unfolded Pael receptor in the ER. Moreover, the insoluble form of Pael receptor accumulates in the brain of AR‐JP patients. This protein is highly expressed in the dopaminergic neurons in the substantia nigra, which is specifically affected in Parkinson's disease; although it is also widely expressed in oligodendroglias in the fiber tract. In conclusion, we showed that the accumulation of unfolded Pael receptor (a substrate of parkin) may cause selective death of dopaminergic neurons in AR‐JP.
Convergent Pathobiologic Model of Parkinson's Disease
Authors: MAGUIRE‐ZEISS KATHLEEN A. , FEDEROFF HOWARD J.
Published: July 2010

Abstract: The etiology of Parkinson's disease (PD) has yet to be delineated. Human genetic studies as well as neurotoxicant and transgenic animal models of PD suggest that multiple events trigger the initiation of this progressive age‐related neurodegenerative disorder. In addition, we propose that despite disparate disease triggers a convergent pathobiologic pathway exists leading to cell death. The common pathway model posits that both familial and sporadic forms of Parkinson's disease obligately share a common pathophysiological substrate. Herein we discuss the evidence for a common pathway model of Parkinson's disease through a review of synuclein transgenic models and outline an approach for the idenfication of shared therapeutic targets. We end with a discussion of a potential alternative therapy for Parkinson's disease.
Induction of Adult Neurogenesis
Authors: ARLOTTA PAOLA , MAGAVI SANJAY S. , MACKLIS JEFFREY D.
Published: July 2010

Abstract: Over most of the past century, it was thought that the adult brain was completely incapable of generating new neurons. However, in the last decade, the development of new techniques has resulted in an explosion of new research showing that (i) neurogenesis, the birth of new neurons, is not restricted to embryonic development, but normally also occurs in two limited regions of the adult mammalian brain (the olfactory bulb and the dentate gyrus of the hippocampus); (ii) that there are significant numbers of multipotent neural precursors in many parts of the adult mammalian brain; and (iii) that it is possible to induce neurogenesis even in regions of the adult mammalian brain, like the neocortex, where it does not normally occur, via manipulation of endogenous multipotent precursors in situ. In the neocortex, recruitment of small numbers of new neurons can be induced in a region‐specific, layer‐specific, and neuronal type‐specific manner, and newly recruited neurons can form long‐distance connections to appropriate targets. This suggests that elucidation of the relevant molecular controls over adult neurogenesis from endogenous neural precursors/stem cells may allow the development of neuronal replacement therapies for neurodegenerative disease and other central nervous system injuries that may not require transplantation of exogenous cells.
Mechanisms of Ischemic Neuroprotection by Acetyl‐l‐carnitine
Authors: ZANELLI SANTINA A. , SOLENSKI NINA J. , ROSENTHAL ROBERT E. , FISKUM GARY
Published: July 2010

Abstract: Acetyl‐l‐carnitine is a naturally occurring substance that, when administered at supraphysiologic concentrations, is neuroprotective in several animal models of global and focal cerebral ischemia. Three primary mechanisms of action are supported by neurochemical outcome measures performed with these models and with in vitro models of acute neuronal cell death. The metabolic hypothesis is based on the oxidative metabolism of the acetyl component of acetyl‐l‐carnitine and is a simple explanation for the reduction in postischemic brain lactate levels and elevation of ATP seen with drug administration. The antioxidant mechanism is supported by reduction of oxidative stress markers, for example, protein oxidation, in both brain tissue and cerebrospinal fluid. The relatively uncharacterized mechanism of inhibiting excitotoxicity could be extremely important in both acute brain injury and chronic neurodegenerative disorders. New experiments performed with primary cultures of rat cortical neurons indicate that the presence of acetyl‐l‐carnitine significantly inhibits both acute and delayed cell death following exposure to NMDA, an excitotoxic glutamate antagonist. Finally, several other mechanisms of action are possible, including a neurotrophic effect of acetyl‐l‐carnitine and inhibition of mitochondrial permeability transition. While the multiple potential mechanisms of neuroprotection by acetyl‐l‐carnitine limit an accurate designation of the most important mode of action, they are compatible with the concept that several brain injury pathways must be inhibited to optimize therapeutic efficacy.
Circulatory Arrest as a Model for Studies of Global Ischemic Injury and Neuroprotection
Authors: WIKLUND LARS , SHARMA HARI SHANKER , BASU SAMAR
Published: July 2010

Abstract: Despite many programs aimed at better immediate care of cardiac arrest victims, the subsequent mortality rate is high, with myocardial and central nervous system (CNS) injuries as the most common causes of death. Preclinical research is badly needed to produce a sound base for future clinical trials and possible improvements in clinical outcome. In our laboratory, we use piglets weighing approximately 25 kg. Ventricular fibrillation is produced by an AC current and left without treatment for 8‐12 min, after which cardiopulmonary resuscitation according to current human guidelines is undertaken. The heart is then defibrillated and restoration of spontaneous circulation induced. During the procedure, blood pressure and flow measurements are obtained in the systemic, pulmonary, and cerebral circulation. Peroxidation and inflammation are monitored by systemic and cerebral venous plasma concentrations of isoprostane (8‐iso‐PGF2α), an indicator of oxidative damage, and prostaglandin F2α metabolite (15‐keto‐dihydro‐PGF2α), an indicator of cyclooxygenase‐2 activity, respectively. Neurocellular damage is monitored by the jugular plasma concentration of protein S‐100β. Neurological outcome is assessed at >24 h after the incident. Our results show that plasma concentrations of 8‐iso‐PGF2α are greater after more extended periods of ischemia. PBN (α‐phenyl‐N‐tert‐butyl nitrone), a so‐called spin‐trap scavenger, has a neuroprotective effect since neurological outcome is enhanced, and the 8‐iso‐PGF2α concentration is decreased during reperfusion. Use of water‐soluble sulfonated PBN (S‐PBN) results in better autoregulation of cerebral cortical blood flow and less peroxidation of CNS lipids during reperfusion. These observations suggest that our model can be used to explore neuroprotective effects of potential therapeutic agents.
Potentially Neuroprotective and Therapeutic Properties of Nitrous Oxide and Xenon
Authors: ABRAINI JACQUES H. , DAVID HÉLÈNE N. , LEMAIRE MARC
Published: July 2010

Abstract: Despite the beneficial effects of prototypical glutamatergic receptor antagonists in animal models, the pharmacological attempts by the use of such agents have met with very limited clinical success because these compounds produce adverse side effects and possess an intrinsic neurotoxicity at neuroprotective and therapeutic concentrations. Interestingly, nitrous oxide and xenon, which are anesthetic gases with a remarkably safe clinical profile, have been shown to be effective inhibitors of the NMDA receptor. We briefly review accumulating evidence that nitrous oxide and xenon at subanesthetic concentrations may have potentially neuroprotective and therapeutic properties, with a particular focus on their beneficial effects on ischemia‐induced neuronal death and amphetamine‐induced sensitization. Nitrous oxide at 75‐vol% and xenon up to 70‐vol% reduce ischemia‐induced neuronal death induced by occlusion of the middle cerebral artery in rodents, and decrease NMDA‐induced Ca2+ influx in neuronal cell cultures, a critical event involved in excitotoxicity. Nitrous oxide at 75‐vol% and xenon at 50‐vol% further reduced amphetamine‐induced locomotor sensitization in rodents. However, at a higher concentration of 75‐vol%, xenon shows potentially neurotoxic properties and adverse side effects. Because both agents are rapidly eliminated from the body, it is plausible that their administration at appropriate subanesthetic neuroprotective and therapeutic concentrations may not be associated, in contrast with prototypical NMDA receptor antagonists, with adverse side effects and potentially neurotoxicity. Finally, the possible therapeutic implications in humans are discussed.
Novel Neuroprotective Mechanism of Action of Rasagiline Is Associated with Its Propargyl Moiety: Interaction of Bcl‐2 Family Members with PKC Pathway
Authors: WEINREB ORLY , AMIT TAMAR , BAR‐AM ORIT , CHILLAG‐TALMOR ORLY , YOUDIM MOUSSA B. H.
Published: July 2010

Abstract: Our studies have provided new insights into the biological mechanism of neuroprotection of the anti‐Parkinson drug, rasagiline [N‐propargyl‐(1R)‐aminoindan], involving the association of Bcl‐2 family proteins with protein kinase C (PKC) pathway. In a model of serum withdrawal‐induced apoptosis of rat pheochromocytoma PC12 cells, rasagiline and its propargyl moiety, N‐propargylamine, decreased cell death via multiple neuroprotective pathways that include the stimulation of PKC phosphorylation; upregulation of PKCε mRNA; induction of Bcl‐XL, Bcl‐w, and brain‐derived neurotrophic factor (BDNF) mRNAs; and downregulation of PKCγ, Bad, and Bax mRNAs. Moreover, these drugs inhibited the cleavage and activation of pro‐caspase‐3 and poly(ADP‐ribose) polymerase (PARP), while PKC inhibitor, GF109203X, reversed these actions. In addition, rasagiline decreased serum‐free‐induced levels of the important regulator of cell death, Bad, which was also blocked by GF109203X, indicating the involvement of PKC‐dependent cell survival activity of rasagiline. Structure activity studies have established that N‐propargylamine is essential for the novel neuroprotective and the neuronal cell survival activity of rasagiline since this moiety itself revealed similar protective effects and mechanisms of action. These results have led us to develop several multifunctional neuroprotective drugs containing the propargyl moiety and iron‐chelating property for the treatment and/or prevention of neurodegenerative diseases.
Gene Expression Profiling of Sporadic Parkinson's Disease Substantia Nigra Pars Compacta Reveals Impairment of Ubiquitin‐Proteasome Subunits, SKP1A, Aldehyde Dehydrogenase, and Chaperone HSC‐70
Authors: MANDEL SILVIA , GRUNBLATT EDNA , RIEDERER PETER , AMARIGLIO NINETTE , HIRSCH JASMINE JACOB , RECHAVI GIDEON , YOUDIM MOUSSA B. H.
Published: July 2010

Abstract: Sporadic Parkinson's disease (PD) constitutes 99% of the disorder, while the remaining 1% of the cases is of familial (genetic) origin. The mutations reported to be associated with familial PD indicate impairment in protein processing and misfolding, as is handled by the ubiquitin‐proteasome system (UPS), and in mitochondrial function. For these reasons, we have recently applied, for the first time, Affymetrix oligonucleotide microarray technique in the substantia nigra pars compacta of sporadic parkinsonian patients for studying global gene expression analysis and comparison to the alterations identified in inherited PD. This study identified decreased expression of 68 genes and elevation of 69 genes. Classification into functional groups revealed that the downregulated genes are related to signal transduction, protein degradation (e.g., ubiquitin‐proteasome subunits), dopaminergic transmission/metabolism, iron transport, protein modification/phosphorylation, and energy pathways/glycolysis functional classes. A major finding is the decreased expressions of 5 subunits of the UPS, SKP1A, a member of the SCF (E3) ubiquitin ligase complex, and chaperone HSC‐70, which can lead to a wide impairment in the function of an entire repertoire of proteins. The upregulated genes are clustered in cell adhesion/cytoskeleton, extracellular matrix components, cell cycle, protein modification/phosphorylation, protein metabolism and transcription, and inflammation/hypoxia (e.g., key iron and oxygen sensor EGLN1) classes. The study shows, for the first time, a convergence in the pathogenic processes that are observed in hereditary (familial) and sporadic PD, where abnormal iron metabolism, oxidative stress, and aggregation of proteins occur. An additional breakthrough in this research is the identification of a number of previously unsuspected crucial gene players that are also involved in the process of neurodegeneration, which can serve as specific biomarkers for PD and novel drug development.
Neuronal Growth‐Promoting and Inhibitory Cues in Neuroprotection and Neuroregeneration
Authors: SKAPER STEPHEN D.
Published: July 2010

Abstract: During development of the nervous system, neurons extend axons over considerable distances in a highly stereospecific fashion in order to innervate their targets in an appropriate manner. This involves the recognition, by the axonal growth cone, of guidance cues that determine the pathway taken by the axons. These guidance cues can act to promote and/or repel growth cone advance. The directed growth of axons is partly governed by cell adhesion molecules (CAMs) on the neuronal growth cone that bind to CAMs on the surface of other axons or nonneuronal cells. In vitro assays have established the importance of the CAMs (NCAM, N‐cadherin, and L1) in promoting axonal growth over cells. Compelling evidence implicates the fibroblast growth factor receptor tyrosine kinase as the primary signal transduction molecule in the CAM pathway. CAMs are important constituents of synapses, and they appear to play important and diverse roles in regulating synaptic plasticity associated with learning and memory. Synthetic NCAM peptide mimetics corresponding to the binding site of NCAM for the fibroblast growth factor receptor promote synaptogenesis, enhance presynaptic function, and facilitate memory consolidation. Dimeric versions of functional binding motifs of N‐cadherin behave as N‐cadherin agonists, promoting both neuritogenesis and neuronal cell survival. Negative extracellular signals that physically direct neurite growth have also been described. The latter include the myelin inhibitory proteins, Nogo, myelin‐associated glycoprotein, and oligodendrocyte‐myelin glycoprotein. Potentiation of outgrowth‐promoting signals, together with antagonism of myelin proteins or their convergent receptor, NgR, and its second messenger pathways, may provide new opportunities in the rational design of treatments for acute brain injury and neurodegenerative disorders.
Neuroprotective Effects of Nitric Oxide Synthase Inhibitors in Spinal Cord Injury‐Induced Pathophysiology and Motor Functions
Authors: SHARMA HARI SHANKER , BADGAIYAN RAJENDRA D. , ALM PER , MOHANTY S , WIKLUND LARS
Published: July 2010

Abstract: The role of nitric oxide (NO) in spinal cord injury (SCI)‐induced motor dysfunction, breakdown of the blood‐spinal cord barrier (BSCB), edema formation, and cell injury was examined using a pharmacological approach. We used three types of nitric oxide synthase (NOS) inhibitors: a nonselective blocker, L‐NAME; an irreversible inhibitor of all isoforms of NOS, L‐NMMA; and a long‐term competitive inhibitor of neuronal NOS with equal potency to inhibit endothelial NOS, L‐NNA. The compounds were administered once daily in separate groups of rats for 7 days. On the 8th day, SCI was performed by making a longitudinal incision into the right dorsal horn of the t10 segments, and the rats were allowed to survive 5 h after injury. Long‐term treatment with L‐NNA attenuated SCI‐induced NOS upregulation, BSCB breakdown, edema formation, and cell injury, whereas comparatively less neuroprotection is offered by L‐NMMA. The magnitude of neuroprotection is much less evident in injured animals that received L‐NAME. Interestingly, SCI‐induced motor dysfunction measured according to the Tarlov scale showed close correlation with the magnitude of neuroprotection. Thus, an improvement in motor function was seen in animals pretreated with L‐NNA, whereas rats treated with L‐NAME or L‐NMMA did not show any influence on motor dysfunction after SCI. This observation suggests that inhibition of neuronal NOS is important for neuroprotection, and the disturbances in motor function following SCI are associated with the state of spinal cord pathology.
Age at Onset: An Essential Variable for the Definition of Genetic Risk Factors for Sporadic Alzheimer's Disease
Authors: BEYER KATRIN , LAO JOSÉ I. , LATORRE PILAR , ARIZA AURELIO
Published: July 2010

The aim of our work was to detect minor loci acting as Alzheimer's disease (AD) genetic markers. We divided 206 AD patients and 186 individuals as controls into six age at onset/age‐dependent groups. We studied polymorphisms of the genes of apolipoprotein E (APOE) and its promoter, cathepsin D, butyrylcholinesterase, cystatin C, methionine synthase, and cystathionine beta‐synthase. Our results demonstrated that data analysis according to age at onset allows the detection of minor genetic risk factors for AD. Thus, the Th1/E47cs‐G allele was an independent AD risk factor after 80 years, whereas the catD‐T, BChE‐K, CBS‐844ins68, and CBS‐VNTR 19 alleles are independent AD risk factors after 75 years. On the other hand, the CST3‐A allele was an independent AD risk factor before 60 years while the CBS‐VNTR allele 21 was an independent AD risk factor before 64 years. In contrast, the MS‐AA genotype was an AD risk factor unrelated to age at onset. In conclusion, two main tasks remain to be accomplished to facilitate early detection of people at risk of developing AD: (1) the establishment of common criteria to carry out association studies for different genetic markers, including the introduction of AD age at onset as a crucial variable in each study, and (2) the definition of global and population‐specific genetic markers for each age at onset AD subgroup.
Mind‐Body Medicine: Stress and Its Impact on Overall Health and Longevity
Authors: VITETTA L , ANTON B , CORTIZO F , SALI A
Published: July 2010

The belief that adverse life stressors and the emotional states that can lead to major negative impacts on an individual's body functions and hence health has been held since antiquity. Adverse health outcomes such as coronary heart disease, gastrointestinal distress, and cancer have been linked to unresolved lifestyle stresses that can be expressed as a negative impact on human survival and ultimately a decrease of the human life span. Psychological modulation of immune function is now a well‐established phenomenon, with much of the relevant literature published within the last 50 years. Psychoneuroimmunology and psychoneuroendocrinology embrace the scientific evidence of research of the mind with that of endocrinology, neurology and immunology, whereby the brain and body communicate with each other in a multidirectional flow of information that consists of hormones, neurotransmitters/neuropeptides, and cytokines. Advances in mind‐body medicine research together with healthy nutrition and lifestyle choices can have a significant impact on health maintenance and disease prevention and hence the prolongation of the human life span.
Role of autophagy in diabetes and mitochondria
Authors: Jung Hye Seung , Lee Myung‐Shik
Published: July 2010

Type 2 diabetes mellitus is characterized by insulin resistance and failure of pancreatic β‐cells producing insulin. Mitochondrial dysfunction may play a role in both processes of diabetes. Autophagy maintains cellular homeostasis through degradation and recycling of organelles such as mitochondria. As dysfunctional mitochondria are the main organelles removed by autophagy, we studied the role of autophagy in diabetes using mice with β‐cell–specific deletion of the Atg7 gene. Atg7‐mutant mice showed reduction in β‐cell mass and pancreatic insulin content. Electron microscopy showed swollen mitochondria and other ultrastructural changes in autophagy‐deficient β‐cells. Insulin secretory function ex vivo was also impaired. As a result, Atg7‐mutant mice showed hypoinsulinemia and hyperglycemia. These results suggest that autophagy is necessary to maintain structure, mass, and function of β‐cells. Besides its effect on β‐cells, autophagy may affect insulin sensitivity because mitochondrial dysfunction has been implicated in insulin resistance and autophagy is involved in the maintenance of the organelles. Furthermore, since aging is associated with impaired glucose tolerance, decline of autophagic activity may be involved in age‐associated reduction of glucose tolerance.
Functional effects of cancer mitochondria on energy metabolism and tumorigenesis: utility of transmitochondrial cybrids
Authors: Kaipparettu Benny Abraham , Ma Yewei , Wong Lee‐Jun C.
Published: July 2010

Reprogramming of energy metabolism is one of the hallmarks of cancer. In normal conditions, cells rely on mitochondrial oxidative phosphorylation to provide energy for cellular activities. Cancer cells are characterized by increased glycolysis and reduced mitochondrial respiratory function. In the past decade, somatic mitochondrial DNA alterations are found to be common in all types of cancers. However, the functional significance of the altered cancer mitochondria is largely unknown. This is because the bulk of cancer properties are regulated by nuclear encoded genes. To overcome this problem, the transmitochondrial cybrid system, which allows the study of the effect of cancer mitochondria in a common nuclear background, has been used. Here we review the accumulating evidence that altered cancer mitochondria affect the respiratory chain function and oncogenic properties in vitro and in vivo using cybrid technologies.
Persistent organic pollutants, mitochondrial dysfunction, and metabolic syndrome
Authors: Lim Soo , Cho Young Min , Park Kyong Soo , Lee Hong Kyu
Published: July 2010

The number of individuals with metabolic syndrome is increasing worldwide, constituting a major social problem in many countries. Recently, epidemiological and experimental studies have associated insulin resistance or type 2 diabetes with elevated body burdens of persistent organic pollutants (POPs). It has been proposed that mitochondrial dysfunction plays a key role in this association. Mitochondrial DNA abnormalities are known to cause pancreas beta cell damage, insulin resistance, and diabetes mellitus. Recently, much evidence has emerged showing that environmental toxins, including POPs, affect mitochondrial function and subsequently induce insulin resistance. In this review, we present a novel concept in which metabolic syndrome is the result of mitochondrial dysfunction, which in turn is caused by exposure to POPs. The potential mechanism including POPs for mitochondrial dysfunction on metabolic syndrome is also discussed. We propose that the mitochondrial paradigm for the etiology of metabolic syndrome will facilitate the prevention and treatment of this major health problem.
Potential therapeutic applications of tetrahydrobiopterin: from inherited hyperphenylalaninemia to mitochondrial diseases
Authors: Kim Hyoung K. , Ha Seung H. , Han Jin
Published: July 2010

Tetrahydrobiopterin (BH4) is an essential enzymatic cofactor in the formation of key neurotransmitters and nitric oxide (NO). It also has a cellular protective role as an antioxidant and scavenger of reactive nitrogen or oxygen species. Inherited hyperphenylalaninemia, which is caused by mutations in converting enzymes responsible for BH4 synthesis, was the first reported disease implicating BH4. Oxidative stress can also cause decreased BH4 levels, leading to uncoupling of BH4–nitric oxide synthase (NOS) and diminished NO, further aggravating numerous pathologies. BH4 deficiency is found in cardiovascular, neurodegenerative, and metabolic diseases and is also involved in aging and mitochondrial dysfunction. BH4 supplementation successfully prevents the development or progression of these diseases and thus has valuable clinical potential.
Advantages and considerations in the confirmation of mitochondrial DNA mutations by denaturing HPLC and pyrosequencing
Authors: Yen Hsiu‐Chuan , Hsu Wei‐Chien , Lin Chih‐Lung , Chen Guang‐Wu , Huang Yu‐Hsiang
Published: July 2010

Human mitochondrial DNA (mtDNA) encodes 13 polypeptides essential for oxidative phosphorylation. Because of the unique features of “replicative segregation” and “threshold expression” of mtDNA genetics, identification of homoplasmy versus heteroplasmy status is critical. Results from various detection methods may lead to different interpretations on formation or outcome of mtDNA mutations, such as the conclusion of somatic mutation versus genetic drift in cancers. Denaturing high‐performance liquid chromatography (DHPLC) and pyrosequencing (PSQ) have recently been employed to confirm the presence of heteroplasmy of mtDNA because of their high sensitivity in detecting heteroplasmic mutations compared with direct sequencing. Moreover, PSQ has superior ability in quantifying percentage of heteroplasmy. However, there could be disagreement between these two techniques and several issues specific for mtDNA should be taken into consideration. Particularly, DHPLC analysis should be more prone to be interfered by nuclear mitochondrial sequences (Numts), if it is coamplified with mtDNA, than PSQ analysis.
Dynamic regulation of mitochondrial fission through modification of the dynamin‐related protein Drp1
Authors: Chang Chuang‐Rung , Blackstone Craig
Published: July 2010

Mitochondria in cells comprise a tubulovesicular network shaped continuously by complementary fission and fusion events. The mammalian Drp1 protein plays a key role in fission, while Mfn1, Mfn2, and OPA1 are required for fusion. Shifts in the balance between these opposing processes can occur rapidly, indicating that modifications to these proteins may regulate mitochondrial membrane dynamics. We highlight posttranslational modifications of the mitochondrial fission protein Drp1, for which these regulatory mechanisms are best characterized. This dynamin‐related GTPase undergoes a number of steps to mediate mitochondrial fission, including translocation from cytoplasm to the mitochondrial outer membrane, higher‐order assembly into spirals, GTP hydrolysis associated with a conformational change and membrane deformation, and ultimately disassembly. Many of these steps may be influenced by covalent modification of Drp1. We discuss the dynamic nature of Drp1 modifications and how they contribute not only to the normal regulation of mitochondrial division, but also to neuropathologic processes.
Glycoxidative stress–induced mitophagy modulates mitochondrial fates
Authors: Lo Mei‐Chen , Lu Chin‐I , Chen Ming‐Hong , Chen Chun‐Da , Lee Horng‐Mo , Kao Shu‐Huei
Published: July 2010

Diabetes mellitus (DM), a state of chronic hyperglycemia, is associated with a variety of serious complications. Hyperglycemia‐induced advanced glycation end products (AGEs) play an important role in the development of diabetic complications. In vivo, we demonstrated that disrupted mitochondria and autophagy was elevated in type II DM db/db mice. Mitophagy was evidenced by increased autophagosome formation in the β‐islet cells. The adducts of Nɛ‐(carboxymethyl) lysine (CML), a major AGE, and bovine serum albumin (CML‐BSA) stimulated the conversion of microtubule‐associated protein 1 light chain 3‐I (LC3‐I) to LC3‐II in rat insulinoma cells (RIN‐m5F). CML‐BSA increased ROS generation as demonstrated in a time‐dependent manner. Experiments with mitochondrial targeted enhanced yellow fluorescent protein transfected RIN‐m5F cells, massive fragmented mitochondria were visualized in the CML‐BSA treated cells. Taken together, these data suggested that AGEs may cause mitochondrial dysfunction and mitophagosome formation, and AGEs‐induced glycoxidative stress may trigger mitophagic process to modulate mitochondrial fates leading to either cell survival or cell death.
Mitochondrial respiratory dysfunction‐elicited oxidative stress and posttranslational protein modification in mitochondrial diseases
Authors: Wu Yu‐Ting , Wu Shi‐Bei , Lee Wan‐Yu , Wei Yau‐Huei
Published: July 2010

Pathogenic mutation in mtDNA and mitochondrial dysfunction are associated with mitochondrial diseases. In this review, we discuss the oxidative stress‐elicited mitochondrial protein modifications that may contribute to the pathophysiology of mitochondrial diseases. We demonstrated that excess ROS produced by defective mitochondria could increase the acetylation of microtubule proteins through the suppression of Sirt2, which results in perinuclear distribution of mitochondria in skin fibroblasts of patients with CPEO syndrome. Our recent work showed that mitochondrial dysfunction‐induced oxidative stress can disrupt protein degradation system by inhibiting the ubiquitin‐proteasome pathway and protease activity in human cells harboring mutant mtDNA. This in turn causes accumulation of aberrant proteins in mitochondria and renders the mutant cells more susceptible to apoptosis induced by oxidative stress. Furthermore, oxidative stress can modulate phosphorylation of mitochondrial proteins, which can affect metabolism in a number of diseases. Taken together, we suggest that oxidative stress‐triggered protein modifications and defects in protein turnover play an important role in the pathogenesis and progression of mitochondrial diseases.