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Many cells, including neuronal and glial progenitor cells, stem cells and microglial cells, have the capacity to move through the extracellular spaces of the developing and mature brain. This is particularly pronounced in astrocyte-derived tumors, gliomas, which diffusely infiltrate the normal brain. Although a significant body of literature exists regarding signals that are involved in the guidance of cells and their processes, little attention has been paid to cell-shape and cell-volume changes of migratory cells. However, extracellular spaces in the brain are very narrow and represent a major obstacle that requires cells to dynamically regulate their volume. Recent studies in glioma cells show that this involves the secretion of Cl− and K+ with water. Pharmacological inhibition of Cl− channels impairs their ability to migrate and limits tumor progression in experimental tumor models. One Cl−-channel inhibitor, chlorotoxin, is currently in Phase II clinical trials to treat malignant glioma. This article reviews our current knowledge of cell-volume changes and the role of ion channels during the migration of glioma cells. It also discusses evidence that supports the importance of channel-mediated cell-volume changes in the migration of immature neurons and progenitor cells during development. New unpublished data is presented, which demonstrates that Cl− and K+ channels involved in cell shrinkage localize to lipid-raft domains on the invadipodia of glioma cells and that their presence might be regulated by trafficking of these proteins in and out of lipid rafts.
The development and maintenance of myelinated nerves in the PNS requires constant and reciprocal communication between Schwann cells and their associated axons. However, little is known about the nature of the cell-surface molecules that mediate axon–glial interactions at the onset of myelination and during maintenance of the myelin sheath in the adult. Based on the rationale that such molecules contain a signal sequence in order to be presented on the cell surface, we have employed a eukaryotic-based, signal-sequence-trap approach to identify novel secreted and membrane-bound molecules that are expressed in myelinating and non-myelinating Schwann cells. Using cDNA libraries derived from dbcAMP-stimulated primary Schwann cells and 3-day-old rat sciatic nerve mRNAs, we generated an extensive list of novel molecules expressed in myelinating nerves in the PNS. Many of the identified proteins are cell-adhesion molecules (CAMs) and extracellular matrix (ECM) components, most of which have not been described previously in Schwann cells. In addition, we have identified several signaling receptors, growth and differentiation factors, ecto-enzymes and proteins that are associated with the endoplasmic reticulum and the Golgi network. We further examined the expression of several of the novel molecules in Schwann cells in culture and in rat sciatic nerve by primer-specific, real-time PCR and in situ hybridization. Our results indicate that myelinating Schwann cells express a battery of novel CAMs that might mediate their interactions with the underlying axons.
Myelin formation and maintenance depends on the establishment of two structurally and biochemically discernible domains: (a) compact myelin, that is multilamellar stacks of plasma membrane sheets; and (b) cytoplasmic channels that border the compact myelin domains, attach them to the cell body and anchor the myelin sheath to the axonal membrane. To identify proteins involved in the organization of these domains we took advantage of the high lipid content of compact myelin to separate it cleanly from other neural membranes and then used reverse-phase HPLC coupled to Electro-Spray Double Mass Spectrometry (‘MudPIT’) to characterize the proteome of this sample. MudPIT allowed us to sidestep the bias of 2D-PAGE against either highly charged or transmembrane proteins. Thus, of 97 proteins that presented at least two, fully tryptic peptides (a stringent threshold), seven were well known myelin markers, including the mayor CNS myelin proteins: proteolipid protein and myelin basic protein, which are not resolvable by 2D-PAGE. Furthermore, we have confirmed and extended the known compact myelin proteome by 22 proteins and confirmed that CNS and PNS myelinated tracts present Sirtuin 2, a tubulin deacetylase, and Septin 7, a small GTPase that is likely to be involved in membrane and cytoplasm partitioning.
Recent advances in the field of neuron–glia interactions were presented at the 27th International Symposium of the University of Montreal Center de Recherche en Sciences Neruologiques. Topics included synaptogenesis, regulation of synaptic strength by glia at the neuromuscular junction and hippocampus; myelin formation, structure, and maintenance; involvement of glia in nervous-system response to injury, hypoxia, and ischemia; neurogenesis and apoptosis, and microglial involvement in chronic pain.
Early regeneration of injured peripheral nerves involves a series of events that are important in the success of eventual reconnection. In many nerve injuries, such as transections with gaps, axons and Schwann cells (SCs) penetrate into new microenvironments de novo, not involving zones of Wallerian degeneration. We studied unexplored axon–SC interactions by sampling of newly forming connections through a silicone conduit across transected rat sciatic peripheral nerve gaps. Axon and SC participation in bridge formation was addressed by light microscopy, electron microscopy and by double-labeling immunohistochemistry, including confocal imaging, and several, less appreciated aspects of early regrowth were identified. There are limitations to early and widespread regeneration of axons and SCs into bridges initially formed from connective tissue and blood vessels. Regrowth is ‘staggered’ such that only a small percentage of parent axons sampled the early bridge. There is an intimate, almost invariable relationship between SCs and extension of axons, which challenges the concept that axons lead and SCs follow. ‘Naked’ axons were infrequent and limited in scope. Axons did not seek out and adhere to vascular laminin but intimately followed laminin deposits associated with apposed SCs. Growth cones identified by labeling of β III tubulin, PGP 9.5 and GAP43/B50 were complex, implying a pause in their regrowth, and were most prominent at the proximal stump–regenerative bridge interface. There is surprising and substantial hostility to local regrowth of axons into newly forming peripheral nerve bridges. Early axon outgrowth, associated with apposed Schwann cell processes, is highly constrained even when not exposed to adjacent myelin and products of Wallerian degeneration.
We provide both molecular and pharmacological evidence that the metabotropic, purinergic, P2Y6, P2Y12 and P2Y13 receptors and the ionotropic P2X4 receptor contribute strongly to the rapid calcium response caused by ATP and its analogues in mouse microglia. Real-time PCR demonstrates that the most prevalent P2 receptor in microglia is P2Y6 followed, in order, by P2X4, P2Y12, and P2X7 = P2Y13. Only very small quantities of mRNA for P2Y1, P2Y2, P2Y4, P2Y14, P2X3 and P2X5 were found. Dose-response curves of the rapid calcium response gave a potency order of: 2MeSADP>ADP=UDP=IDP=UTP>ATP>BzATP, whereas A2P4 had little effect. Pertussis toxin partially blocked responses to 2MeSADP, ADP and UDP. The P2X4 antagonist suramin, but not PPADS, significantly blocked responses to ATP. These data indicate that P2Y6, P2Y12, P2Y13 and P2X receptors mediate much of the rapid calcium responses and shape changes in microglia to low concentrations of ATP, presumably at least partly because ATP is rapidly hydrolyzed to ADP. Expression of P2Y6, P2Y12 and P2Y13 receptors appears to be largely glial in the brain, so that peripheral immune cells and CNS microglia share these receptors. Thus, purinergic, metabotropic, P2Y6, P2Y12, P2Y13 and P2X4 receptors might share a role in the activation and recruitment of microglia in the brain and spinal cord by widely varying stimuli that cause the release of ATP, including infection, injury and degeneration in the CNS, and peripheral tissue injury and inflammation which is signaled via nerve signaling to the spinal cord.
This chapter tests and refines a developmental taxonomy of antisocial behavior, which proposed two primary hypothetical prototypes: life-course persistent offenders whose antisocial behavior begins in childhood and continues worsening thereafter, versus adolescence-limited offenders whose antisocial behavior begins in adolescence and desists in young adulthood (Moffitt, 1993). Two of our previous reports have described clinically defined groups of childhood-onset and adolescence-onset antisocial youths in the Dunedin birth cohort during childhood (Moffitt & Caspi, 2001) and at age 18 (Moffitt, Caspi, Dickson, Silva, & Stanton, 1996). Recently we followed up the cohort at age 26, and here we describe how the two groups of males fared in adulthood. In so doing we test a hypothesis critical to the theory: that childhood-onset, but not adolescent-onset, antisocial behavior is associated in adulthood with antisocial personality, violence, and continued serious antisocial behavior that expands into maladjustment in work life and victimization of partners and children (Moffitt, 1993).
THE TWO PROTOTYPES AND THEIR PREDICTED ADULT OUTCOMES
According to the theory, life-course persistent antisocials are few, persistent, and pathological. Adolescence-limited antisocials are common, relatively temporary, and near normative. The developmental typology hypothesized that childhood-onset versus adolescent-onset conduct problems have different etiologies. In addition, the typology differed from other developmental crime theories by predicting different outcome pathways for the two types across the adult life-course (Caspi & Moffitt, 1995; Moffitt, 1993, 1994, 1997).
By
Elizabeth J. Susman, Jean Phillips Shibley Professor of Biobehavioral Health The Pennsylvania State University,
David M. Stoff, Chief of the extramural research programs National Institute of Mental Health
Edited by
David M. Stoff, National Institute of Mental Health, Bethesda, Maryland,Elizabeth J. Susman, Pennsylvania State University
The expression that time changes everything could be no more true than in the case of the integration of human biology and aggressive behavior. Earlier perspectives concerning the integration of biology and behavior were riddled with ideas of determinism and the preponderance of nature over nurture. Biological processes were viewed as causal agents in behavior. Current perspectives view biology and behavior as evolving in dynamic interaction throughout ontogeny (Lerner, 2002; Magnusson, 1999; Magnusson & Stattin, 1998; Susman, Dorn, & Schiefelbein, 2003; Susman & Rogol, 2004). These perspectives suggest that levels of existence, from the molecular and genetic to the macro social levels, co-dependently produce the uniqueness of individuals.
The chapters in this volume attest to how the decline in the perennial debate about nature and nurture has facilitated the acceptance of new theoretical and empirical developments on biological parameters of aggressive behavior. First, the chapters show that explaining a complex human behavior, such as aggression, now is not the purview of any one disciplinary perspective. Throughout the history of the study of development, philosophers and scientists have been devotees of either a biological or a social perspective on the causes of aggressive and criminal behavior. In the past few decades, a clear distinction existed between biological, behavioral, and social science perspectives on aggression. The prevailing view was that biologists search for universals to explain human behavior and differences among species. In contrast, behavioral and social scientists focus on social processes and search for individual differences among persons.
New Guinea, early 1930s: “Malikindjin killed her [with sorcery]…. That is Malikindjin's way.” “But later Malikindjin fell sick [with spirit revenge]. That is because everybody wants vengeance upon him. All who know anything …, they are all agreed.”
(narrated case from Bateson, 1958, pp. 64, 67)
Nigeria, early 1940s: “You shouldn't encourage him too much dear. He is too argumentative.”
(Soyinka, 1981, p. 55)
Tahiti, early 1960's: “[Shy, mamahu, people] can't look you in the eye. They don't seem to get mad easily, but you have to watch out, because if they finally do get mad they are very violent.”
(Levy, 1973, p. 286)
Botswana, 1971: “That Besa, something was wrong with his brain! I thought, ‘No, this man is a bad one.’” “I thought about how he had hit me and how I didn't like being with a man like that.” “Besa was always jealous….”
(Shostak, 1981, p. 226, 225, 309)
INTRODUCTION
Over 50 years ago, Bateson argued strenuously that the concept of individual behavior is vacuous because people act in the context of others' behavior, concluding that social psychology properly should study “the reactions of individuals to the reactions of other individuals” (Bateson, 1958, p. 175). Nonetheless, as the above quotes from his and others' ethnographies suggest, individual differences in behavior are ubiquitous and universally attributed to temperamental differences even as socialization practices are predicated on an equally universal assumption of nurture's role in behavior development.
This volume is an outgrowth of a memorial conference to honor the scientific contributions and accomplishments of Robert B. Cairns, internationally recognized for his pioneering efforts as an interdisciplinary developmental scientist. His theories and research in humans and animals provided a template and direction for future research in the developmental sciences and the psychobiology of aggression. This perspective integrated biology with psychological development, emphasizing the dynamic interactions among biological, psychological, and environmental influences on development and behavior. Cairns described a conception of human developmental processes, characterized by biobehavioral organization and involving reciprocal interactions of bidirectionality, plasticity, and gene–environment relationships. This conceptual framework provided an expanded array of multiple biological and behavioral levels as it applied to aggression, offering a refreshing departure from the very limited unidimensional belief in the deterministic role that unfolding biology exerts on behavior (see Figure 1.1; Cairns, 1996).
In earlier volumes, we presented various research approaches to the biology of aggression (Stoff & Cairns, 1996) and provided a comprehensive review of research on many aspects of antisocial behavior (Stoff, Breiling, & Maser, 1997). This volume updates those works, principally from a developmental psychobiological viewpoint of aggression, emphasizing modern neuroscience approaches that focus not only on “bottom-up” causality (e.g., molecular processes involving genes, cells, and synapses) but also on “top-down” causality (e.g., more molar processes mediated by experiences).
In the last quarter of the 20th century, Robert Cairns helped to transform psychology. In doing so, he rescued it from a virulent susceptibility to reductionism. Standing on the shoulders of great psychologists of the first half of that century (James Baldwin and Kurt Lewin most readily come to mind), he created a truly interdisciplinary environment at Chapel Hill. The Carolina Consortium on Human Development became an international crossroad for the establishment of a new synthesis termed developmental science. A legion of graduate students, postdoctoral Fellows, young faculty, and many senior investigators emerged from this oasis with a deeper, more nuanced understanding of human development. By formulating sound theory and exacting the highest standards for basic research, Cairns and his colleagues moved the field into a realm in which social behavior was not reducible: not to motivations or environmental contingencies any more than to neurons or molecules. Behavior was not sacrificed to biology, nor was it glorified to the environment. Rather, a coherence of behavior and biology was refined in a manner that was intellectually robust and scientifically challenging. Evolution, genetics, ontogeny, and social relationships were interwoven with honesty and with appropriate appreciation for the subtleties involved.
In this volume a group of accomplished protégés and admirers of Cairns explore the nature of aggression, an area of social behavior that most intrigued him. How is it that a social species tolerates aggression?
By
David M. Stoff, Chief of the extramural research programs on HIV/AIDS Neuropsychiatry and HIV/AIDS Health Disparities and Director of AIDS Research Training Center for Mental Health Research on AIDS of the National Institute of Mental Health (NIMH),
Elizabeth J. Susman, Jean Phillips Shibley Professor of Biobehavioral Health in the Department of Biobehavioral Health The Pennsylvania State University
Edited by
David M. Stoff, National Institute of Mental Health, Bethesda, Maryland,Elizabeth J. Susman, Pennsylvania State University
“The reader who wants to study the best work on aggression in the second half of the 20th century will find most of it in the works of Bob Cairns.”
Tremblay 2000 p. 138
Toward an integrative understanding of behavioral development, one sufficient to address how complex behaviors emerge over the course of development, the field of developmental psychobiology has advanced in recent years to transcend dichotomous views of cause and effect or nature versus nurture. Beyond parsing the stuff of life into genetic or environmental sources, contemporary theorists are likely to envision three-dimensional interactive webs, lifelines or fabrics of intertwined strands, recursive fractal forms, and dialectical transformations across levels of organization as conceptual models for aspects of developmental processes (Cairns, 1996; Gottlieb, 1998; Hood, 1995; Lerner, 1998; Michel & Moore, 1995; Thelen & Smith, 1998). Whether these models are generative in revealing new properties of specific developmental domains is an active question. For present purposes, they bring an expanding range of issues to the research agenda for a multidisciplinary approach to the study of development. A consideration of aggressive behavior as enfolded within a dynamic developmental manifold may contribute to the goal of a fully integrative account. This is the present project.
A critical issue for proceeding is how to construe the ubiquitous and continuous bidirectional flow of actions that comprise social interchanges. Social environments affect individual development even as individuals choose and shape their changing social environments.
By
David M. Stoff, Chief of the extramural research programs on HIV/AIDS Neuropsychiatry and HIV/AIDS Health Disparities and Director of AIDS Research Training Center for Mental Health Research on AIDS of the National Institute of Mental Health (NIMH),
Elizabeth J. Susman, Jean Phillips Shibley Professor of Biobehavioral Health in the Department of Biobehavioral Health The Pennsylvania State University
Edited by
David M. Stoff, National Institute of Mental Health, Bethesda, Maryland,Elizabeth J. Susman, Pennsylvania State University
By
David M. Stoff, Chief of the extramural research programs on HIV/AIDS Neuropsychiatry and HIV/AIDS Health Disparities and Director of AIDS Research Training Center for Mental Health Research on AIDS of the National Institute of Mental Health (NIMH),
Elizabeth J. Susman, Jean Phillips Shibley Professor of Biobehavioral Health in the Department of Biobehavioral Health The Pennsylvania State University
Edited by
David M. Stoff, National Institute of Mental Health, Bethesda, Maryland,Elizabeth J. Susman, Pennsylvania State University
By
David M. Stoff, Chief of the extramural research programs on HIV/AIDS Neuropsychiatry and HIV/AIDS Health Disparities and Director of AIDS Research Training Center for Mental Health Research on AIDS of the National Institute of Mental Health (NIMH),
Elizabeth J. Susman, Jean Phillips Shibley Professor of Biobehavioral Health in the Department of Biobehavioral Health The Pennsylvania State University
Edited by
David M. Stoff, National Institute of Mental Health, Bethesda, Maryland,Elizabeth J. Susman, Pennsylvania State University
The notion of plasticity in relation to biological and behavioral development is not a new one. Even when very little was known about brain structure and function and long before the advent of modern molecular and neuroanatomical techniques, scientists recognized that the brain had the capacity to adapt and change in response to environmental input. Already in 1892, William James stressed the importance of brain plasticity in the organization of habits:
Plasticity, then, in the wide sense of the word, means the possession of a structure weak enough to yield to an influence, but strong enough not to yield all at once. Each relatively stable phase of equilibrium in such a structure is marked by what we call a new set of habits. Organic matter, especially nervous tissue, seems endowed with a very extraordinary degree of plasticity of this sort; so that we may without hesitation lay down as our first proposition the following: that the phenomena of habit in living beings are due to plasticity of the organic materials of which their bodies are composed.
(p. 2, italic original (James, 1892)
James's intuition was confirmed in the 1960s when a group of scientists provided the first empirical evidence of environmentally induced alterations in brain chemistry and structure (Diamond, Krech, & Rozenzweig,1964; Krech, Rozenzweig, & Bennett, 1960; Rozenzweig, Krech, Bennett, & Diamond, 1962). Importantly, it was shown that these neurobiological alterations were associated with enhanced behavioral and particularly cognitive functions.