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Sensory Experience and Cortical Rewiring

Barnes, S. J., Finnerty, G. T. — Thu, 01 Oct 2009 19:19:04 PDT

Adult primary sensory cortex is not hard wired, but adapts to sensory experience. The cellular basis for cortical plasticity involves a combination of functional and structural changes in cortical neurons and the connections between them. Functional changes such as synaptic strengthening have been the focus of many investigations. However, structural modifications to the connections between neurons play an important role in cortical plasticity. In this review, the authors focus on structural remodeling that leads to rewiring of cortical circuits. Recent work has identified axonal remodeling, growth of new dendritic spines, and synapse turnover as important structural mechanisms for experience dependent plasticity in mature cortex. These findings have begun to unravel how rewiring occurs in adult neocortex and offer new insights into the cellular mechanisms for learning and memory.

PET Studies of Cerebral Levodopa Metabolism: A Review of Clinical Findings and Modeling Approaches

Kumakura, Y., Cumming, P. — Tue, 29 Sep 2009 21:17:40 PDT

[¹⁸F]Fluoro-3,4-dihydroxyphenyl-l-alanine (FDOPA) was one of the first successful tracers for molecular imaging by positron emission tomography (PET), and has proven immensely valuable for studies of Parkinson’s disease. Following intravenous FDOPA injection, the decarboxylated metabolite [¹⁸F] fluorodopamine is formed and trapped within terminals of the nigrostriatal dopamine neurons; reduction in the simple ratio between striatum and cerebellum is indicative of nigrostriatal degeneration. However, the kinetic analysis of dynamic FDOPA-PET recordings is formidably complex due to the entry into brain of the plasma metabolite O-methyl-FDOPA and due to the eventual washout of decarboxylated metabolites. Linear graphical analysis relative to a reference tissue input function is popular and convenient for routine clinical studies in which serial arterial blood samples are unavailable. This simplified approach has facilitated longitudinal studies in large patient cohorts. Linear graphical analysis relative to the metabolite-corrected arterial FDOPA input yields a more physiological index of FDOPA utilization, the net blood-brain clearance. Using a constrained compartmental model, FDOPA-PET recordings can be used to calculate the relative activity of the enzyme DOPA decarboxylase in living brain. We have extended this approach so as to obtain an index of steady-state trapping of [¹⁸F]fluorodopamine in synaptic vesicles. Although simple methods of image analysis are sufficient for the purposes of routine clinical studies, the more complex approaches have revealed hidden aspects of brain dopamine in personality, healthy aging, and in the pathophysiologies of Parkinson’s disease and schizophrenia.

Sex Hormones: Modulators of Interhemispheric Inhibition in the Human Brain

Weis, S., Hausmann, M. — Wed, 02 Sep 2009 19:08:05 PDT

Functional cerebral asymmetries (FCAs),which constitute a basic principle of human brain organization,are supposedly generated by interhemispheric inhibition of the dominant on the nondominant hemisphere. It has repeatedly been shown that FCAs are sex specific:While they are relatively stable in men, they change during the menstrual cycle in women, indicating that sex hormones might play an important role in modulating functional brain organization and brain asymmetries in particular. Modern brain imaging techniques like functional magnetic resonance imaging (fMRI) allow for the noninvasive study of the mechanisms underlying changing FCAs. Imaging data show that in women the inhibitory influence of the dominant on the nondominant hemisphere is reduced with rising levels of sex hormones in the course of the menstrual cycle.Apart from modulating interhemispheric inhibition,sex hormones also seem to change functional organization within hemispheres. These results reveal a powerful neuromodulatory action of sex hormones on the dynamics of functional brain organization in the female brain.They may further contribute to the ongoing discussion of sex differences in brain function in that they help explain the dynamic part of functional brain organization in which the female differs from the male brain.

The Two Faces of Estradiol: Effects on the Developing Brain

McCarthy, M. M. — Fri, 21 Aug 2009 17:44:25 PDT

Estradiol is a potent steroid of both gonadal and neuronal origin that exerts profound and enduring effects on the brain as it develops.Differences in estradiol production in males and females underlie the establishment of many sexually dimorphic brain characteristics.Two paradigm shifts in the understanding of estradiol and its actions have expanded the view from one of slow narrowly controlled nuclear transcription to include rapid effects initiated at the membrane and inducible by locally synthesized steroid.A survey of estradiol actions reveals regional specificity underlying opposing effects such that estradiol induces cell death in one region but prevents it in another or promotes synaptogenesis in one region but retards it in the other. Similarly, estradiol is neuroprotective or neurodamaging and enhances excitation or dampens excitation, depending on the model and neurotransmitter under study. Understanding the diverse actions of estradiol in different brain regions under differing conditions is essential to harnessing the tremendous therapeutic potential of this endogenous naturally occurring and efficacious neural modulator.

From Guidance Signals to Movement: Signaling Molecules Governing Growth Cone Turning

Hong, K., Nishiyama, M. — Fri, 21 Aug 2009 17:44:24 PDT

Directed growth cone movements in response to external guidance signals are required for the establishment of functional neuronal connections during development, adult nerve regeneration, and adult neurogenesis. Growth cone intrinsic properties permit different growth cone responses (e.g., attraction or repulsion) to a guidance signal, and alterations to these intrinsic properties often result in opposite growth cone responses.This article reviews the current knowledge of growth cone signaling, emphasizing the dependency of Ca²⁺ signaling on membrane potential shifts, and cyclic nucleotide and phosphoinositide signaling pathways during growth cone turning in response to guidance signals.We also discuss how asymmetrical growth cone signaling is achieved for the fine-tuned growth cone movement.

The Making of Synaptic Ribbons: How They Are Built and What They Do

Schmitz, F. — Fri, 21 Aug 2009 17:44:25 PDT

Ribbon synapses in the retina and inner ear maintain tonic neurotransmitter release at high rates to transduce a broad bandwidth of stimulus intensities. In ribbon synapses, synaptic vesicles can be released by a slow, sustained mode and by fast, synchronous mechanisms. The high release rates require structural and functional specializations. The synaptic ribbon is the key structural specialization of ribbon synapses. Synaptic ribbons are large, electron-dense structures that immobilize numerous synaptic vesicles next to presynaptic release sites. A main component of synaptic ribbons is the protein RIBEYE that has the capability to build the scaffold of the synaptic ribbon via multiple RIBEYE-RIBEYE interactions. A modular assembly model of synaptic ribbons has been proposed in which synaptic ribbons are formed from individual RIBEYE subunits. The scaffold of the synaptic ribbon provides a docking site for RIBEYE-associated proteins that could execute specific synaptic ribbon functions. Multiple functions have been assigned to synaptic ribbons including roles in exocytosis, endocytosis, and synaptic membrane trafficking. Recent studies demonstrated the importance of synaptic ribbons for fast, synchronous release and emphasized the need of a tight and efficient coupling between presynaptic Ca²⁺ signaling and exocytosis. The present review summarizes recent advances on structure and function of synaptic ribbons.

The Medial Prefrontal Cortex and Integration in Autism

Ben Shalom, D. — Mon, 17 Aug 2009 13:08:21 PDT

This article offers a unifying theoretical interpretation of known abnormalities in people with autism spectrum disorders (ASDs) in four psychological domains, namely emotion, memory, sensation-perception, and motor skills. It proposes that in all four domains three levels of processing can be identified: a basic level, an integrative level, and a "logical" or higher-order level. It also notes that in typically developing people, there is evidence that the integrative level is subserved by subregions of the medial prefrontal cortex. The major argument of the article is to propose and argue that the integrative level in all four domains is responsible for common atypicalities in people with ASDs.

Disruption of Normal Cytoskeletal Dynamics May Play a Key Role in the Pathogenesis of Epilepsy

Gardiner, J., Marc, J. — Fri, 08 May 2009 18:20:24 PDT

Epilepsy, a common disease affecting 1% to 2% of the population, is characterized by seizures, hyperexcitability at synapses, and aberrant extension of neurons following seizures. Much work has been done on the role of synaptic components in the pathogenesis of epilepsy, but relatively little attention has been given to the potential role of the cytoskeleton. The neuronal cytoskeleton consists of microtubules, actin filaments, intermediate filaments, and associated proteins. a number of mutations in both microtubule-associated proteins (MaPs) and actin-binding proteins, as well as altered expression levels of several cytoskeletal proteins, are known to be involved in epilepsy. These changes will affect the dynamics of the neuronal cytoskeleton and therefore are likely to contribute to the pathogenesis of epilepsy through mechanisms such as increased neurotrophic support to neurons and increased sprouting of mossy fibers. These changes may also contribute to hyperexcitability of neurons through an as yet unidentified mechanism.

Oligodendrocytes: Facilitating Axonal Conduction by More Than Myelination

Yamazaki, Y., Hozumi, Y., Kaneko, K., Fujii, S., Goto, K., Kato, H. — Fri, 08 May 2009 18:20:24 PDT

Oligodendrocytes have received much attention in relation to neurological and psychiatric disorders. The involvement of oligodendrocytes and their myelin in normal brain functions has been suggested by many lines of evidence. The conduction velocity of action potentials along axons is dramatically increased by myelination, that is, the formation of a passive insulator. There is a growing understanding of the functional roles of ion channels and neurotransmitter receptors on oligodendrocytes, and the activity-dependent facilitative effect of oligodendrocytes on conduction velocity has been demonstrated. In this article, we summarize evidence for the ability of oligodendrocytes to monitor neuronal activity and for the facilitation of axonal conduction by oligodendrocytes by mechanisms other than myelination. We suggest the underlying mechanisms for this facilitation in relation to the morphological dynamics of myelinating processes and discuss the physiological roles of the facilitation in information processing.

Posttraumatic Epilepsy: The Roles of Synaptic Plasticity

Timofeev, I., Bazhenov, M., Avramescu, S., Nita, D. A. — Thu, 09 Apr 2009 14:59:32 PDT

Acute cerebral cortical trauma often leads to paroxysmal activities that terminate in a few hours, but several months later, patients can develop epilepsy. The process occurring between the initial acute triggered seizures and the onset of spontaneous unprovoked seizures is termed epileptogenesis. Here the authors summarize recent morphological, electrophysiological, and computational studies demonstrating that partial cortical isolation increases the number and duration of silent states in the cortical network, boosting neuronal connectivity and network excitability. These changes develop progressively, and after several weeks their synergetic action leads to epilepsy.

The Janus-Faced Effects of Hypoxia on Astrocyte Function

Vangeison, G., Rempe, D. A. — Thu, 09 Apr 2009 14:59:33 PDT

Astrocytes are increasingly recognized for their impact on neuronal function and viability in health and disease. Hypoxia has Janus-faced influences on astrocytes and their ability to support neuronal viability. For example, hypoxia induces astrocyte-dependent protection of neurons following hypoxia preconditioning. Yet, hypoxia induces processes in astrocytes that augment neuronal death in other situations, such as the coincidence of hypoxia with inflammatory signaling. A complex array of gene expression is induced by hypoxia within astrocytes and neurons through multiple transcription factors and intracellular molecular pathways. The hypoxia inducible factors (HIFs) are transcription factors that are likely instrumental in orchestrating adaptive and pathological functions of astrocytes. As such, the HIFs are postulated to mediate both adaptive and pathological functions during hypoxia/ ischemia. Identifying the conditions under which hypoxia induces signaling in astrocytes that alters autonomous or neuronal survival will undoubtedly have important implications regarding the development of new strategies for stroke treatment.

Cortical Up and Activated States: Implications for Sensory Information Processing

Castro-Alamancos, M. A. — Tue, 24 Mar 2009 21:25:37 PDT

The neocortex generates spontaneous slow oscillations that consist of up and down states during quiescence. Up states are short epochs of persistent activity that resemble the state of cortical activation during arousal and cognition. The excitability of cortical cells and synaptic networks is impacted by up states. This review describes the characteristics and putative functional role of up states and their similarity with activated states.

The Dichotomy of NMDA Receptor Signaling

Papadia, S., Hardingham, G. E. — Tue, 02 Oct 2007 08:10:08 PDT

The N-methyl-D-aspartate (NMDA) subtype of ionotropic glutamate receptors plays a Jekyll and Hyde role in the mammalian central nervous system. In pathological scenarios such as ischemia, Ca^²⁺ influx through the NMDA receptor is a key mediator of cell death. However, physiological levels of NMDA-receptor activity can promote neuronal survival and resistance to trauma and play important roles in synaptic plasticity and transmission. This dichotomy may explain the poor tolerance and efficacy of NMDA-receptor antagonists in clinical trials for excitotoxic trauma. There is a growing understanding of the signaling events that mediate the opposing effects of NMDA-receptor activity and the factors that determine whether an episode of NMDA-receptor activity will promote survival or death. This knowledge may lead to therapeutic strategies that enable the selective blockade of prodeath signaling cassettes while sparing physiological signaling to survival and plasticity. DOI: 10.1177/1073858407305833