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  • Role of Circular RNAs in Brain Development and CNS Diseases
    Prog. Neurobiol. (IF 10.658) Pub Date : 2020-01-10
    Suresh L. Mehta; Robert J. Dempsey; Raghu Vemuganti
  • Reelin reverts biochemical, physiological and cognitive alterations in mouse models of Tauopathy
    Prog. Neurobiol. (IF 10.658) Pub Date : 2019-12-20
    Daniela Rossi; Agnès Gruart; Gerardo Contreras-Murillo; Ashraf Muhaisen; Jesús Ávila; José María Delgado-García; Lluís Pujadas; Eduardo Soriano

    Reelin is an extracellular protein crucial for adult brain plasticity. Moreover, Reelin is protective against amyloid-β (Aβ) pathology in Alzheimer’s Disease (AD), reducing plaque deposition, synaptic loss and cognitive decline. Given that Tau protein plays a key role in AD pathogenesis, and that the Reelin pathway modulates Tau phosphorylation, here we explored the involvement of Reelin in AD-related Tau pathology. We found that Reelin overexpression modulates the levels of Tau phosphorylation in AD-related epitopes in VLW mice expressing human mutant Tau. In vitro, Reelin reduced the Aβ-induced missorting of axonal Tau and neurofilament proteins to dendrites. Reelin also reverted in vivo the toxic somatodendritic localization of phosphorylated Tau. Finally, overexpression of Reelin in VLW mice improved long-term potentiation and long-term memory cognitive performance thus masking the cognitive and physiological deficits in VLW mice. These data suggest that the Reelin pathway, which is also protective against Aβ pathology, modulates fundamental traits of Tau pathology, strengthening the potential of Reelin as a therapeutic target in AD.

  • Regional iron distribution and soluble ferroprotein profiles in the healthy human brain
    Prog. Neurobiol. (IF 10.658) Pub Date : 2019-12-20
    Erin J. McAllum; Dominic J. Hare; Irene Volitakis; Catriona A. McLean; Ashley I. Bush; David I. Finkelstein; Blaine R. Roberts
  • Deciphering midbrain mechanisms underlying prepulse inhibition of startle
    Prog. Neurobiol. (IF 10.658) Pub Date : 2019-12-19
    Niveen Fulcher; Erin Azzopardi; Cleusa De Oliveira; Roger Hudson; Ashley L. Schormans; Tariq Zaman; Brian L. Allman; Steven R. Laviolette; Susanne Schmid

    Prepulse inhibition (PPI) is an operational measure of sensorimotor gating. Deficits of PPI are a hallmark of schizophrenia and associated with several other psychiatric illnesses such as e.g. autism spectrum disorder, yet the mechanisms underlying PPI are still not fully understood. There is growing evidence contradicting the long-standing hypothesis that PPI is mediated by a short feed-forward midbrain circuitry including inhibitory cholinergic projections from the pedunculopontine tegmental nucleus (PPTg) to the startle pathway. Here, we employed a chemogenetic approach to explore the involvement of the PPTg in general, and cholinergic neurons specifically, in PPI. Activation of inhibitory DREADDs (designer receptors exclusively activated by designer drugs) in the PPTg by systemic administration of clozapine-N-oxide (CNO) disrupted PPI, confirming the involvement of the PPTg in PPI. In contrast, chemogenetic inhibition of specifically cholinergic PPTg neurons had no effect on PPI, but inhibited morphine-induced conditioned place preference (CPP) in the same animals, showing that the DREADDs were effective in modulating behavior. These findings support a functional role of the PPTg and/or neighboring structures in PPI in accordance with previous lesion studies, but also provide strong evidence against the hypothesis that specifically cholinergic PPTg neurons are involved in mediating PPI, implicating rather non-cholinergic midbrain neurons.

  • A multi-faceted genotoxic network of alpha-synuclein in the nucleus and mitochondria of dopaminergic neurons in Parkinson’s disease: Emerging concepts and challenges
    Prog. Neurobiol. (IF 10.658) Pub Date : 2019-12-18
    Velmarini Vasquez; Joy Mitra; Haibo Wang; Pavana M. Hegde; K.S. Rao; Muralidhar L. Hegde

    α-Synuclein is a hallmark amyloidogenic protein component of the Lewy bodies (LBs) that are found in dopaminergic neurons affected by Parkinson’s disease (PD). Despite an enormous increase in emerging knowledge, the mechanism(s) of α-synuclein neurobiology and crosstalk among pathological events that are critical for PD progression remains enigmatic, creating a roadblock for effective intervention strategies. One confounding question is about the potential link between α-synuclein toxicity and genome instability in PD. We previously reported that pro-oxidant metal ions, together with reactive oxygen species (ROS), act as a “double whammy” in dopaminergic neurons by not only inducing genome damage but also inhibiting their repair. Our recent studies identified a direct role for chromatin-bound, oxidized α-synuclein in the induction of DNA strand breaks, which raised the question of a paradoxical role for α-synuclein’s DNA binding in neuroprotection versus neurotoxicity. Furthermore, recent advances in our understanding of α-synuclein mediated mitochondrial dysfunction, warrants revisiting the topics of α-synuclein pathophysiology in order to devise and assess the efficacy of α-synuclein-targeted interventions. In this review article, we discuss the multi-faceted neurotoxic role of α-synuclein in the nucleus and mitochondria with a particular emphasis on the role of α-synuclein in DNA damage/repair defects. We utilized a protein-DNA binding simulation to identify potential residues in α-synuclein that could mediate its binding to DNA and may be critical for its genotoxic functions. We also discuss the crosstalk of α-synuclein toxicity with the RNA binding protein, TDP-43. These emerging insights and paradigms may guide new drug targets and therapeutic modalities.

  • Conserved and divergent expression dynamics during early patterning of the telencephalon in mouse and chick embryos
    Prog. Neurobiol. (IF 10.658) Pub Date : 2019-12-14
    Vijaykumar Yogesh Muley; Carlos Javier López-Victorio; Jorge Tonatiuh Ayala-Sumuano; Adriana González-Gallardo; Leopoldo González-Santos; Carlos Lozano-Flores; Gregory Wray; Maribel Hernández; Alfredo Varela-Echavarría

    The mammalian and the avian telencephalon are nearly indistinguishable at early embryonic vesicle stages but differ substantially in form and function at their adult stage. We sequenced and analyzed RNA populations present in mouse and chick during the early stages of embryonic telencephalon to understand conserved and lineage-specific developmental differences. We found approximately 3,000 genes that orchestrate telencephalon development. Many chromatin-associated epigenetic and transcription regulators were highly expressed in both species and some showed species-specific expression dynamics. Interestingly, previous studies associated them to autism, intellectual disabilities, and mental retardation supporting a causal link between their impaired functions during telencephalon development and brain dysfunction. Most striking was the finding that conserved up-regulated genes were differentially enriched in ontologies related to development or functions of the adult brain. Moreover, a differential enrichment of distinct repertoires of transcription factor binding motifs in their upstream promoter regions suggest a species-specific regulation of the various gene groups identified. Overall, our results reveal that the ontogenetic divergences between the mouse and chick telencephalon result from subtle differences in the regulation of common patterning signaling cascades and regulatory networks unique to each species at their very early stages of development.

  • Identifying neuronal correlates of dying and resuscitation in a model of reversible brain anoxia
    Prog. Neurobiol. (IF 10.658) Pub Date : 2019-12-10
    Adrien E. Schramm, Antoine Carton-Leclercq, Shana Diallo, Vincent Navarro, Mario Chavez, Séverine Mahon, Stéphane Charpier

    We developed a new rodent model of reversible brain anoxia and performed continuous electrocorticographic (ECoG) and intracellular recordings of neocortical neurons to identify in real-time the cellular and network dynamics that successively emerge throughout the dying-to-recovery process. Along with a global decrease in ECoG amplitude, deprivation of oxygen supply resulted in an early surge of beta-gamma activities, accompanied by rhythmic membrane depolarizations and regular firing in pyramidal neurons. ECoG and intracellular signals were then dominated by low-frequency activities which progressively declined towards isoelectric levels. Cortical neurons during the isoelectric state underwent a massive membrane potential depolarizing shift, captured in the ECoG as a large amplitude triphasic wave known as the “wave-of-death” (WoD). This neuronal anoxic depolarization, associated with a block of action potentials and a loss of cell integrative properties, could however be reversed if brain re-oxygenation was rapidly restored (within 23.5 min). The subsequent slow repolarization of neocortical neurons resulted in a second identifiable ECoG wave we termed “wave-of-resuscitation” since it inaugurated the progressive regaining of pre-anoxic synaptic and firing activities. These results demonstrate that the WoD is not a biomarker of an irremediable death and unveil the cellular correlates of a novel ECoG wave that may be predictive of a successful recovery. The identification of real-time biomarkers of onset and termination of cell anoxic insult could benefit research on interventional strategies to optimize resuscitation procedures.

  • Circulating microRNAs as potential biomarkers for psychiatric and neurodegenerative disorders
    Prog. Neurobiol. (IF 10.658) Pub Date : 2019-12-07
    M.M.J. van den Berg, J. Krauskopf, J.G. Ramaekers, J.C.S. Kleinjans, J. Prickaerts, J.J. Briedé

    Circulating microRNAs (cimiRNAs) are a class of non-encoding RNAs found in bodily fluids such as blood, cerebrospinal fluid (CSF) and tears. CimiRNAs have been implicated as promising biomarkers for central nervous system (CNS) disorders because they are actively secreted as messengers and are profoundly involved in fine-tuning of developmental and differentiation processes. Furthermore, they are attractive biomarkers because they are extremely stable, tissue enriched and can be determined in a quantitative manner. This review aims to provide a comprehensive assessment on the current progress regarding the potential value of cimiRNAs as CNS biomarkers. Within this framework five CNS disorders are explored which share a common pathological hallmark namely cognitive impairment. The CNS disorders include Major depression disorder (MDD), Bipolar disorder (BD), Schizophrenia (SZ), Alzheimer’s disease (AD) and Parkinson disease (PD). The similarities and differences between altered cimiRNAs in the different disorders are described. The miR-29 family, miR-34a-5p and miR-132-3p are discussed as common dysregulated cimiRNAs found in the CNS disorders. Furthermore, it is shown that the type of bodily fluid used for measuring cimiRNAs is important as inconsistencies in cimiRNAs expression directions are found when comparing CSF, blood cell-free and blood cell-bound samples.

  • Dissecting beta-state changes during timed movement preparation in Parkinson’s disease
    Prog. Neurobiol. (IF 10.658) Pub Date : 2019-11-25
    Simone G. Heideman, Andrew J. Quinn, Mark W. Woolrich, Freek van Ede, Anna C. Nobre

    An emerging perspective describes beta-band (15-28 Hz) activity as consisting of short-lived high-amplitude events that only appear sustained in conventional measures of trial-average power. This has important implications for characterising abnormalities observed in beta-band activity in disorders like Parkinson’s disease. Measuring parameters associated with beta-event dynamics may yield more sensitive measures, provide more selective diagnostic neural markers, and provide greater mechanistic insight into the breakdown of brain dynamics in this disease. Here, we used magnetoencephalography in eighteen Parkinson’s disease participants off dopaminergic medication and eighteen healthy control participants to investigate beta-event dynamics during timed movement preparation. We used the Hidden Markov Model to classify event dynamics in a data-driven manner and derived three parameters of beta events: (1) beta-state amplitude, (2) beta-state lifetime, and (3) beta-state interval time. Of these, changes in beta-state interval time explained the overall decreases in beta power during timed movement preparation and uniquely captured the impairment in such preparation in patients with Parkinson’s disease. Thus, the increased granularity of the Hidden Markov Model analysis (compared with conventional analysis of power) provides increased sensitivity and suggests a possible reason for impairments of timed movement preparation in Parkinson’s disease.

  • Traumatic Brain Injury Triggers APP and Tau Cleavage by Delta-secretase, Mediating Alzheimer’s Disease Pathology
    Prog. Neurobiol. (IF 10.658) Pub Date : 2019-11-25
    Zhourui Wu, Zhi-Hao Wang, Xia Liu, Zhentao Zhang, Shan Ping Yu, C. Dirk Keene, Liming Cheng, Keqiang Ye

    Traumatic brain injury (TBI) is associated in some studies with clinical dementia, and neuropathological features, including amyloid plaque deposition and Tau neurofibrillary degeneration commonly identified in Alzheimer’s disease (AD). However, the molecular mechanisms linking TBI to AD remain unclear. Here we show that TBI activates transcription factor CCAAT/Enhancer Binding Protein Beta (C/EBPβ), increasing delta-secretase (AEP) expression. Activated AEP cleaves both APP and Tau at APP N585 and Tau N368 sites, respectively, which mediate AD pathogenesis by promoting Aβ production and Tau hyperphosphorylation and inducing neuroinflammation and neurotoxicity. Knockout of AEP or C/EBPβ diminishes TBI-induced AD-like pathology and cognitive impairment in the 3xTg AD mouse model. Remarkably, viral expression of AEP-resistant Tau N368A in the hippocampus of 3xTg mice also ameliorates the pathological and cognitive consequences of TBI. Finally, clinical TBI activates C/EBPβ and escalates AEP expression, leading to APP N585 and Tau N368 proteolytic cleavage in TBI patient brains. Hence, our findings support a potential role for AEP in linking TBI exposure with AD pathogenesis.

  • Imaging in mice and men: Pathophysiological insights into multiple sclerosis from conventional and advanced MRI techniques
    Prog. Neurobiol. (IF 10.658) Pub Date : 2019-07-30
    Julia Krämer, Wolfgang Brück, Frauke Zipp, Manuela Cerina, Sergiu Groppa, Sven G. Meuth

    Magnetic resonance imaging (MRI) is the most important tool for diagnosing multiple sclerosis (MS). However, MRI is still unable to precisely quantify the specific pathophysiological processes that underlie imaging findings in MS. Because autopsy and biopsy samples of MS patients are rare and biased towards a chronic burnt-out end or fulminant acute early stage, the only available methods to identify human disease pathology are to apply MRI techniques in combination with subsequent histopathological examination to small animal models of MS and to transfer these insights to MS patients. This review summarizes the existing combined imaging and histopathological studies performed in MS mouse models and humans with MS (in vivo and ex vivo), to promote a better understanding of the pathophysiology that underlies conventional MRI, diffusion tensor and magnetization transfer imaging findings in MS patients. Moreover, it provides a critical view on imaging capabilities and results in MS patients and mouse models and for future studies recommends how to combine those particular MR sequences and parameters whose underlying pathophysiological basis could be partly clarified. Further combined longitudinal in vivo imaging and histopathological studies on rationally selected, appropriate mouse models are required.

  • Exosomal miRNAs in central nervous system diseases: biomarkers, pathological mediators, protective factors and therapeutic agents
    Prog. Neurobiol. (IF 10.658) Pub Date : 2019-09-19
    Xiaohuan Xia, Yi Wang, Yunlong Huang, Han Zhang, Hongfang Lu, Jialin C. Zheng

    Exosomes are small bilipid layer-enclosed extracellular vesicles that can be found in tissues and biological fluids. As a key cell-to-cell and distant communication mediator, exosomes are involved in various central nervous system (CNS) diseases, potentially through transferring their contents such as proteins, lipids and nucleic acids to the target cells. Exosomal miRNAs, which are small non-coding RNAs in the exosomes, are known to be more stable than free miRNAs and therefore have lasting effects on disease-related gene expressions. There are distinct profiles of exosomal miRNAs in different types of CNS diseases even before the onset of irreversible neurological damages, indicating that exosomal miRNAs within tissues and biological fluids could serve as promising biomarkers. Emerging evidence has also demonstrated the pathological effects of several exosomal miRNAs in CNS diseases via specific modulation of disease-related factors. Moreover, exosomes carry therapeutically beneficial miRNAs across the blood-brain-barrier, which can be exploited as a powerful drug delivery tool to help alleviating multiple CNS diseases. In this review, we summarize the recent progress made in understanding the biological roles of exosomal miRNAs as potential diagnostic biomarkers, pathological regulators, and therapeutic targets/drugs for CNS diseases. A comprehensive discussion of the main concerns and challenges for the applications of exosomal miRNAs in the clinical setting is also provided.

  • microRNA dysregulation in neurodegenerative diseases: A systematic review
    Prog. Neurobiol. (IF 10.658) Pub Date : 2019-07-26
    Camille A. Juźwik, Sienna S. Drake, Yang Zhang, Nicolas Paradis-Isler, Alexandra Sylvester, Alexandre Amar-Zifkin, Chelsea Douglas, Barbara Morquette, Craig S. Moore, Alyson E. Fournier
  • N-acetylaspartylglutamate (NAAG) and Glutamate Carboxypeptidase II: An abundant peptide neurotransmitter-enzyme system with multiple clinical applications
    Prog. Neurobiol. (IF 10.658) Pub Date : 2019-11-12
    Joseph H. Neale, Tatsuo Yamamoto

    N-Acetylaspartylglutamate (NAAG) is the third most prevalent neurotransmitter in the mammalian nervous system, yet its therapeutic potential is only now being fully recognized. Drugs that inhibit the inactivation of NAAG by glutamate carboxypeptidase II (GCPII) increase its extracellular concentration and its activation of its receptor, mGluR3. These drugs warrant attention, as they are effective in animal models of several clinical disorders including stroke, traumatic brain injury and schizophrenia. In inflammatory and neuropathic pain studies, GCPII inhibitors moderated both the primary and secondary pain responses when given systemically, locally or in brain regions associated with the pain perception pathway. The finding that GCPII inhibition also moderated the motor and cognitive effects of ethanol intoxication led to the discovery of their procognitive efficacy in long-term memory tests in control mice and in short-term memory in a mouse model of Alzheimer’s disease. NAAG and GCPII inhibitors respectively reduce cocaine self-administration and the rewarding effects of a synthetic stimulant. Most recently, GCPII inhibition also has been reported to be efficacious in a model of inflammatory bowel disease. GCPII was first discovered as a protein expressed by and released from metastatic prostate cells where it is known as prostate specific membrane antigen (PSMA). GCPII inhibitors with high affinity for this protein have been developed as prostate imaging and radiochemical therapies for prostate cancer. Taken together, these data militate in favor of the development and application of GCPII inhibitors in more advanced preclinical research as a prelude to clinical trials.

  • Microglia, neurodegeneration and loss of neuroendocrine control
    Prog. Neurobiol. (IF 10.658) Pub Date : 2019-11-09
    Julie A. Chowen, Luis M. Garcia-Segura

    Microglia, the primary regulators of inflammatory responses in the brain, suffer deterioration during aging culminating in their inability to generate adequate adaptive responses to maintain physiological homeostasis in brain tissue. Microglia affect the function of other glial cells and neurons, including those involved in the hypothalamic control of body homeostasis. Microglial dysfunction with aging in cognitive areas such as the hippocampus is known to associate with cognitive decline; more recently, microglial alterations in the hypothalamus during midlife was suggested to participate in changes in the endocrine and metabolic control exerted by this brain region. Consequently, the feed-back loops between endocrine glands and the hypothalamus are altered. This generates a vicious circle in which the plasma levels of key neuroprotective hormones, such as gonadal hormones, insulin-like growth factor-1, growth hormone and leptin and their hypothalamic signaling are decreased, which further enhances microglial alterations and deterioration of hypothalamic function. Hypothalamic dysfunction is a risk factor for neurodegenerative diseases and these diseases in turn promote additional alterations in hypothalamic microglial cells, which are unable to cope with the neurodegenerative process, resulting in permanent damage of the neuronal-glial circuits controlling endocrine homeostasis, food intake and body metabolism. Thus, a “vicious cycle” may such be initiated.

  • Can the emerging field of immunometabolism provide insights into neuroinflammation?
    Prog. Neurobiol. (IF 10.658) Pub Date : 2019-11-06
    Marina A. Lynch

    In the past few years it has become increasingly clear that an understanding of the interaction between metabolism and immune function can provide an insight into cellular responses to challenges. Significant progress has been made in terms of how macrophages are metabolically re-programmed in response to inflammatory stimuli but, to date, little emphasis has been placed on evaluating equivalent changes in microglia. The need to make progress is driven by the fact that, while microglial activation and the cell’s ability to adopt an inflammatory phenotype is necessary to fulfil the neuroprotective function of the cell, persistent activation of microglia and the associated neuroinflammation is at the heart of several neurodegenerative diseases. Understanding the metabolic changes that accompany microglial responses may broaden our perspective on how dysfunction might arise and be tempered. This review will evaluate the current literature that addresses the interplay between inflammation and metabolic reprogramming in microglia, reflecting on the parallels that exist with macrophages. It will consider the changes that take place with age including those that have been reported in neurons and astrocytes with the development of non-invasive imaging techniques, and reflect on the literature that is currently available relating to metabolic reprogramming of microglia with age and in neurodegeneration. Finally it will consider the possibility that manipulating microglial metabolism may provide a valuable approach to modulating neuroinflammation.

  • Nerve growth factor against PTSD symptoms: preventing the impaired hippocampal cytoarchitectures
    Prog. Neurobiol. (IF 10.658) Pub Date : 2019-11-05
    Da-Yun Feng, Bao-Lin Guo, Gao-Hua Liu, Ke Xu, Jing Yang, Kai Tao, Jing Huang, Li-Ying Wang, Wen Wang, Sheng-Xi Wu

    Although exogenous nerve growth factor demonstrated great potential for post-traumatic stress disorder (PTSD) treatment, its therapeutic effect and underlying cytological mechanism were not fully elucidated so far. We employed a controlled, prospectively designed modified single prolonged stress mice model to investigate the role of exogenous nerve growth factor on the modified single prolonged stress induced PTSD-like symptoms and hippocampal cytoarchitecture impairment, as well as the potential neuronal signaling modulation. We discovered that the modified single prolonged stress-exposure induced significant PTSD-like symptoms as well as mildly impaired hippocampal Cornu Ammonis 1 (CA1) subregion cytoarchitecture, but not dentate gyrus neurogenesis, together with a gradual inhibition of TrkA-CREB-ERK signalings in hippocampal CA1 subregion. Nerve growth factor (NGF) treatment dose-dependently ameliorated the modified single prolonged stress induced PTSD-like symptoms. NGF increased the cytoplasm/nucleus ratio and improved the neuronal plasticity, mainly via the TrkA-CREB-ERK pathway. Our study offered the translational evidence for the potential application of exogenous NGF for treating or early preventing PTSD after stress exposure.

  • Can data repositories help find effective treatments for complex diseases?
    Prog. Neurobiol. (IF 10.658) Pub Date : 2016-03-29
    Gregory K Farber

    There are many challenges to developing treatments for complex diseases. This review explores the question of whether it is possible to imagine a data repository that would increase the pace of understanding complex diseases sufficiently well to facilitate the development of effective treatments. First, consideration is given to the amount of data that might be needed for such a data repository and whether the existing data storage infrastructure is enough. Several successful data repositories are then examined to see if they have common characteristics. An area of science where unsuccessful attempts to develop a data infrastructure is then described to see what lessons could be learned for a data repository devoted to complex disease. Then, a variety of issues related to sharing data are discussed. In some of these areas, it is reasonably clear how to move forward. In other areas, there are significant open questions that need to be addressed by all data repositories. Using that baseline information, the question of whether data archives can be effective in understanding a complex disease is explored. The major goal of such a data archive is likely to be identifying biomarkers that define sub-populations of the disease.

  • New targets for rapid antidepressant action.
    Prog. Neurobiol. (IF 10.658) Pub Date : 2016-01-03
    Rodrigo Machado-Vieira,Ioline D Henter,Carlos A Zarate

    Current therapeutic options for major depressive disorder (MDD) and bipolar disorder (BD) are associated with a lag of onset that can prolong distress and impairment for patients, and their antidepressant efficacy is often limited. All currently approved antidepressant medications for MDD act primarily through monoaminergic mechanisms. Glutamate is the major excitatory neurotransmitter in the central nervous system, and glutamate and its cognate receptors are implicated in the pathophysiology of MDD, and in the development of novel therapeutics for this disorder. The rapid and robust antidepressant effects of the N-methyl-d-aspartate (NMDA) antagonist ketamine were first observed in 2000. Since then, other NMDA receptor antagonists have been studied in MDD. Most have demonstrated relatively modest antidepressant effects compared to ketamine, but some have shown more favorable characteristics. This article reviews the clinical evidence supporting the use of novel glutamate receptor modulators with direct affinity for cognate receptors: (1) non-competitive NMDA receptor antagonists (ketamine, memantine, dextromethorphan, AZD6765); (2) subunit (GluN2B)-specific NMDA receptor antagonists (CP-101,606/traxoprodil, MK-0657); (3) NMDA receptor glycine-site partial agonists (GLYX-13); and (4) metabotropic glutamate receptor (mGluR) modulators (AZD2066, RO4917523/basimglurant). We also briefly discuss several other theoretical glutamate receptor targets with preclinical antidepressant-like efficacy that have yet to be studied clinically; these include α-amino-3-hydroxyl-5-methyl-4-isoxazoleproprionic acid (AMPA) agonists and mGluR2/3 negative allosteric modulators. The review also discusses other promising, non-glutamatergic targets for potential rapid antidepressant effects, including the cholinergic system (scopolamine), the opioid system (ALKS-5461), corticotropin releasing factor (CRF) receptor antagonists (CP-316,311), and others.

  • 5-HT(1A) receptor function in major depressive disorder.
    Prog. Neurobiol. (IF 10.658) Pub Date : 2009-05-12
    Jonathan Savitz,Irwin Lucki,Wayne C Drevets

    Dysfunction of the serotonin 1A receptor (5-HT(1A)) may play a role in the genesis of major depressive disorder (MDD). Here we review the pharmacological, post-mortem, positron emission tomography (PET), and genetic evidence in support of this statement. We also touch briefly on two MDD-associated phenotypes, cognitive impairment and somatic pain. The results of pharmacological challenge studies with 5-HT(1A) receptor agonists are indicative of blunted endocrine responses in depressed patients. Lithium, valproate, selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), and other treatment, such as electroconvulsive shock therapy (ECT), all increase post-synaptic 5-HT(1A) receptor signaling through either direct or indirect effects. Reduced somatodendritic and postsynaptic 5-HT(1A) receptor numbers or affinity have been reported in some post-mortem studies of suicide victims, a result consistent with well-replicated PET analyses demonstrating reduced 5-HT(1A) receptor binding potential in diverse regions such as the dorsal raphe, medial prefrontal cortex (mPFC), amygdala and hippocampus. 5-HT(1A) receptor knockout (KO) mice display increased anxiety-related behavior, which, unlike in their wild-type counterparts, cannot be rescued with antidepressant drug (AD) treatment. In humans, the G allele of a single nucleotide polymorphism (SNP) in the 5-HT(1A) receptor gene (HTR1A; rs6295), which abrogates a transcription factor binding site for deformed epidermal autoregulatory factor-1 (Deaf-1) and Hes5, has been reported to be over-represented in MDD cases. Conversely, the C allele has been associated with better response to AD drugs. We raise the possibility that 5-HT(1A) receptor dysfunction represents one potential mechanism underpinning MDD and other stress-related disorders.

  • Priming for l-dopa-induced dyskinesia in Parkinson's disease: a feature inherent to the treatment or the disease?
    Prog. Neurobiol. (IF 10.658) Pub Date : 2008-10-22
    Agnès Nadjar,Charles R Gerfen,Erwan Bezard

    Involuntary movements, or dyskinesia, represent a debilitating complication of levodopa therapy for Parkinson's disease ultimately experienced by the vast majority of patients. This article does not review the increased understanding of dyskinesia pathophysiology we have seen during the past few years but, instead, specifically focuses upon the very first molecular events thought to be responsible for the establishment of dyskinesia and generally grouped under the term of "priming". Priming is classically defined as the process by which the brain becomes sensitized such that administration of a dopaminergic therapy modifies the response to subsequent dopaminergic treatments. In this way, over time, with repeated treatment, the chance of dopaminergic stimulation eliciting dyskinesia is increased and once dyskinesia has been established, the severity of dyskinesia increases. In this opinion review, however, we aim at strongly opposing the common view of priming. We propose, and hopefully will demonstrate, that priming does not exist per se but is the direct and intrinsic consequence of the loss of dopamine innervation of the striatum (and other target structures), meaning that the first injections of dopaminergic drugs only exacerbate those mechanisms (sensitization) but do not induce them. Chronicity and pulsatility of subsequent dopaminergic treatment only exacerbates the likelihood of developing dyskinesia.

  • Epigenetic regulation of nervous system development by DNA methylation and histone deacetylation.
    Prog. Neurobiol. (IF 10.658) Pub Date : 2009-06-26
    Jessica L MacDonald,A Jane Roskams

    Alterations in the epigenetic modulation of gene expression have been implicated in several developmental disorders, cancer, and recently, in a variety of mental retardation and complex psychiatric disorders. A great deal of effort is now being focused on why the nervous system may be susceptible to shifts in activity of epigenetic modifiers. The answer may simply be that the mammalian nervous system must first produce the most complex degree of developmental patterning in biology and hardwire cells functionally in place postnatally, while still allowing for significant plasticity in order for the brain to respond to a rapidly changing environment. DNA methylation and histone deacetylation are two major epigenetic modifications that contribute to the stability of gene expression states. Perturbing DNA methylation, or disrupting the downstream response to DNA methylation - methyl-CpG-binding domain proteins (MBDs) and histone deacetylases (HDACs) - by genetic or pharmacological means, has revealed a critical requirement for epigenetic regulation in brain development, learning, and mature nervous system stability, and has identified the first distinct gene sets that are epigenetically regulated within the nervous system. Epigenetically modifying chromatin structure in response to different stimuli appears to be an ideal mechanism to generate continuous cellular diversity and coordinate shifts in gene expression at successive stages of brain development - all the way from deciding which kind of a neuron to generate, through to how many synapses a neuron can support. Here, we review the evidence supporting a role for DNA methylation and histone deacetylation in nervous system development and mature function, and present a basis from which to understand how the clinical use of HDAC inhibitors may impact nervous system function.

  • Inflammation in Alzheimer's disease: amyloid-beta oligomers trigger innate immunity defence via pattern recognition receptors.
    Prog. Neurobiol. (IF 10.658) Pub Date : 2009-04-25
    Antero Salminen,Johanna Ojala,Anu Kauppinen,Kai Kaarniranta,Tiina Suuronen

    The inflammatory process has a fundamental role in the pathogenesis of Alzheimer's disease (AD). Recent studies indicate that inflammation is not merely a bystander in neurodegeneration but a powerful pathogenetic force in the disease process. Increased production of amyloid-beta peptide species can activate the innate immunity system via pattern recognition receptors (PRRs) and evoke Alzheimer's pathology. We will focus on the role of innate immunity system of brain in the initiation and the propagation of inflammatory process in AD. We examine here in detail the significance of amyloid-beta oligomers and fibrils as danger-associated molecular patterns (DAMPs) in the activation of a wide array of PRRs in glial cells and neurons, such as Toll-like, NOD-like, formyl peptide, RAGE and scavenger receptors along with complement and pentraxin systems. We also characterize the signaling pathways triggered by different PRRs in evoking inflammatory responses. In addition, we will discuss whether AD pathology could be the outcome of chronic activation of the innate immunity defence in the brain of AD patients.

  • Calcium-permeable acid-sensing ion channel in nociceptive plasticity: a new target for pain control.
    Prog. Neurobiol. (IF 10.658) Pub Date : 2009-04-25
    Tian-Le Xu,Bo Duan

    The development of chronic pain involves increased sensitivity of peripheral nociceptors and elevated neuronal activity in many regions of the central nervous system. Much of these changes are caused by the amplification of nociceptive signals resulting from the modulation and altered expression of specific ion channels and receptors in the central and peripheral nervous system. Understanding the processes by which these ion channels and receptors are regulated and how these mechanisms malfunction may lead to new treatments for chronic pain. Here we review the contribution of the Ca2+-permeable acid-sensing ion channel (ASIC(Ca)) in the development and persistence of chronic pain, and the potential underlying mechanisms. Accumulating evidence suggests that ASIC(Ca) represents an attractive new target for developing effective therapies for chronic pain.

  • Neurodegeneration in familial amyloid polyneuropathy: from pathology to molecular signaling.
    Prog. Neurobiol. (IF 10.658) Pub Date : 2004-02-06
    Mónica Mendes Sousa,Maria João Saraiva

    Familial amyloid polyneuropathy (FAP) is an autosomal dominant neurodegenerative disorder related to the systemic deposition of mutated transthyretin (TTR) amyloid fibrils, particularly in peripheral nervous system (PNS). TTR fibrils are diffusely distributed in the PNS of FAP patients, involving nerve trunks, plexuses and ganglia. In peripheral nerves, amyloid deposits are prominent in the endoneurium, near blood vessels, Schwann cells and collagen fibrils. Fiber degeneration is axonal, beginning in the unmyelinated and low diameter myelinated fibers. Several hypotheses have been raised to explain axonal and neuronal loss: (i) compression of the nervous tissue by amyloid; however, a cause-effect relationship between amyloid deposition, structural nerve changes and degeneration was never clearly made; (ii) role of nerve ischemia secondary to lesions caused by perivascular amyloid, which is also doubtful as compromised blood flow was never demonstrated; (iii) lesions in the dorsal root ganglia neurons or Schwann cells. Recently, evidence for the presence of toxic non-fibrillar TTR aggregates early in FAP nerves constituted a first step to unravel molecular signaling related to neurodegeneration in FAP. The toxic nature of TTR non-fibrillar aggregates, and not mature TTR fibrils, was evidenced by their ability to induce the expression of oxidative stress and inflammation-related molecules in neuronal cells, driving them into apoptotic pathways. How these TTR aggregates exert their effects is debatable; interaction with cellular receptors, namely, the receptor for advanced glycation endproducts (RAGE), is a probable candidate mechanism. The pathology and the yet unknown molecular signaling mechanisms responsible for neurodegeneration in FAP are discussed.

  • Functional organisation of central cardiovascular pathways: studies using c-fos gene expression.
    Prog. Neurobiol. (IF 10.658) Pub Date : 2004-02-06
    R A L Dampney,J Horiuchi

    Until about 10 years ago, knowledge of the functional organisation of the central pathways that subserve cardiovascular responses to homeostatic challenges and other stressors was based almost entirely on studies in anaesthetised animals. More recently, however, many studies have used the method of the expression of immediate early genes, particularly the c-fos gene, to identify populations of central neurons that are activated by such challenges in conscious animals. In this review we first consider the advantages and limitations of this method. Then, we discuss how the application of the method of immediate early gene expression, when used alone or in combination with other methods, has contributed to our understanding of the central mechanisms that regulate the autonomic and neuroendocrine response to various cardiovascular challenges (e.g., hypotension, hypoxia, hypovolemia, and other stressors) as they operate in the conscious state. In general, the results of studies of central cardiovascular pathways using immediate early gene expression are consistent with previous studies in anaesthetised animals, but in addition have revealed other previously unrecognised pathways that also contribute to cardiovascular regulation. Finally, we briefly consider recent evidence indicating that immediate early gene expression can modify the functional properties of central cardiovascular neurons, and the possible significance of this in producing long-term changes in the regulation of the cardiovascular system both in normal and pathological conditions.

  • The GABAergic phenotype of the "glutamatergic" granule cells of the dentate gyrus.
    Prog. Neurobiol. (IF 10.658) Pub Date : 2004-02-06
    Rafael Gutiérrez

    The granule cells of the dentate gyrus (DG), origin of the mossy fibers (MFs), have been considered to be glutamatergic. However, data obtained with different experimental approaches in recent years may be calling for a redefinition of their phenotype. Although they indeed release glutamate for fast neurotransmission, immunohistological and molecular biology evidence has revealed that these glutamatergic cells also express GABAergic markers. The granule cell expression of a GABAergic phenotype is developmentally regulated. Electrophysiological studies reveal that during the first 3 weeks of age, mossy fiber stimulation provokes monosynaptic fast inhibitory transmission mediated by GABA, besides the monosynaptic excitatory glutamatergic transmission, onto their targets in CA3. After this age, mossy fiber GABAergic transmission abruptly disappears and the GABAergic markers are undetected. In the adult, the GABAergic markers are upregulated and GABA-mediated transmission emerges after induction of hyperexcitability. The simultaneous glutamate- and GABA-mediated signals share the same plastic and pharmacological characteristics that correspond to neurotransmission of mossy fiber origin. This intriguing evidence gives rise to two fundamental points of discussion. The first is the plausible fact that glutamate and GABA, two neurotransmitters of opposing actions, are coreleased from the mossy fibers. The second relates to its functional implications that can be immediately inferred, as the dentate gyrus can exert direct GABA-mediated excitatory actions early in life and inhibitory actions in young and adult hippocampus. This evidence poses the need to reevaluate and reinterpret some aspects of the physiology of the mossy fiber pathway under normal and pathological conditions. This work reviews the recent evidence that supports the assumption that glutamate and GABA can be coreleased from a single pathway, the mossy fibers, and makes some considerations about its functional implications.

  • Paying attention to consciousness.
    Prog. Neurobiol. (IF 10.658) Pub Date : 2003-12-31
    John G Taylor

    An engineering control approach is developed for the movement of attention, based on several features: experimental data indicating separate sites for attention modulation and for the creation of that modulation; the resulting analogy with motor control, to which an engineering approach has been applied; simulation and qualitative results supporting the presence of several of the necessary modules. These features are reviewed in the paper and a control model developed for the movement of attention. The engineering control framework is extended to the attended learning of motor control, again with description of support arising from simulations and qualitative analysis of several paradigms. The framework is even further extended to analyze how consciousness could arise during attentive processing, using the COrollary Discharge of Attention Movement (CODAM) model. This model is extended to encompass the temporal development of activity in various brain sites. Particular signals of the CODAM model are described and related to paradigms such as the attentional blink (AB) and features of simultaneous experience in neglect. A program of future explorations of the CODAM model and a set of open questions conclude the paper.

  • Loading and recycling of synaptic vesicles in the Torpedo electric organ and the vertebrate neuromuscular junction.
    Prog. Neurobiol. (IF 10.658) Pub Date : 2003-12-31
    William Van der Kloot

    In vertebrate motor nerve terminals and in the electromotor nerve terminals of Torpedo there are two major pools of synaptic vesicles: readily releasable and reserve. The electromotor terminals differ in that the reserve vesicles are twice the diameter of the readily releasable vesicles. The vesicles contain high concentrations of ACh and ATP. Part of the ACh is brought into the vesicle by the vesicular ACh transporter, VAChT, which exchanges two protons for each ACh, but a fraction of the ACh seems to be accumulated by different, unexplored mechanisms. Most of the vesicles in the terminals do not exchange ACh or ATP with the axoplasm, although ACh and ATP are free in the vesicle interior. The VAChT is controlled by a multifaceted regulatory complex, which includes the proteoglycans that characterize the cholinergic vesicles. The drug (-)-vesamicol binds to a site on the complex and blocks ACh exchange. Only 10-20% of the vesicles are in the readily releasable pool, which therefore is turned over fairly rapidly by spontaneous quantal release. The turnover can be followed by the incorporation of false transmitters into the recycling vesicles, and by the rate of uptake of FM dyes, which have some selectivity for the two recycling pathways. The amount of ACh loaded into recycling vesicles in the readily releasable pool decreases during stimulation. The ACh content of the vesicles can be varied over eight-fold range without changing vesicle size.

  • Role of semaphorins in the adult nervous system.
    Prog. Neurobiol. (IF 10.658) Pub Date : 2003-12-23
    Joris de Wit,Joost Verhaagen

    In the developing nervous system, extending axons are directed towards their appropriate targets by a myriad of attractive and repulsive guidance cues. Work in the past decade has significantly advanced our understanding of these molecules and has made it increasingly clear that their function is not limited to the guidance of growing axons during embryogenesis. Axon guidance cues fulfill additional roles in angiogenesis, cell migration and the immune system, and often display sustained expression in adulthood. Here we focus on the semaphorin (Sema) family and review their proposed functions in the adult nervous system. Several semaphorin family members continue to be expressed in the adult brain and spinal cord, and increasing evidence indicates that their expression is regulated upon nervous system injury in rodents and in neuropathology in humans. The available evidence suggests that semaphorins might significantly contribute to the maintenance and stability of neuronal networks. Furthermore, semaphorins could play important roles in the regeneration, or failure thereof, of neuronal connections. In the future, genetic manipulation of semaphorins and their receptors in the adult intact and injured nervous system should provide a deeper insight into the mechanisms by which semaphorin signaling contributes to structural plasticity and regeneration in the adult brain.

  • Synaptic plasticity and cell cycle activation in neurons are alternative effector pathways: the 'Dr. Jekyll and Mr. Hyde concept' of Alzheimer's disease or the yin and yang of neuroplasticity.
    Prog. Neurobiol. (IF 10.658) Pub Date : 2003-12-23
    Thomas Arendt

    Mental actions are based on the dynamic organization of neuronal networks. In particular, phylogenetically young brain areas (e.g., cortical associative circuits) involved in the realization of higher brain functions are continuously re-adjusted to meet environmental demands. The mechanisms of synaptic plasticity, i.e., of structural stabilization and labilization underlying a life-long synaptic remodelling, are largely based on external morphoregulatory cues and internal signalling pathways that non-neuronal cells have phylogenetically acquired to sense their relationship to the local neighbourhood and to control after development is completed proliferation and differentiation in the process of tissue repair and regeneration. After having withdrawn from the cell cycle, differentiated neurons are, thus, able to use molecular mechanisms primarily developed to control proliferation alternatively to control synaptic plasticity. The existence of these alternative effector pathways within a neuron puts it at risk to erroneously convert signals derived from plastic synaptic changes into positional cues that will activate the cell cycle. This cell cycle activation potentially links synaptic plasticity to cell death. Preventing cell cycle activation by locking neurons in a differentiated but still highly plastic phenotype will, thus, be crucial to prevent neurodegeneration.

  • Neurosteroid modulation of GABAA receptors.
    Prog. Neurobiol. (IF 10.658) Pub Date : 2003-11-13
    Jeremy J Lambert,Delia Belelli,Dianne R Peden,Audrey W Vardy,John A Peters

    Certain metabolites of progesterone and deoxycorticosterone are established as potent and selective positive allosteric modulators of the gamma-aminobutyric acid type A (GABA(A)) receptor. Upon administration these steroids exhibit clear behavioural effects that include anxiolysis, sedation and analgesia, they are anticonvulsant and at high doses induce a state of general anaesthesia, a profile consistent with an action to enhance neuronal inhibition. Physiologically, peripherally synthesised pregnane steroids derived from endocrine glands such as the adrenals and ovaries function as hormones by crossing the blood brain barrier to influence neuronal signalling. However, the demonstration that certain neurons and glial cells within the central nervous system (CNS) can synthesize these steroids either de novo, or from peripherally derived progesterone, has led to the proposal that these steroids (neurosteroids) can additionally function in a paracrine manner, to locally influence GABAergic transmission. Steroid levels are known to change dynamically, for example in stress and during pregnancy. Given that GABA(A) receptors are ubiquitously expressed throughout the central nervous system, such changes in steroid levels would be predicted to cause a global enhancement of inhibitory neurotransmission throughout the brain, a scenario that would seem incompatible with a physiological role as a selective neuromodulator. Here, we will review emerging evidence that the GABA-modulatory actions of the pregnane steroids are highly selective, with their actions being brain region and indeed neuron dependent. Furthermore, the sensitivity of GABA(A) receptors is not static but can dynamically change. The molecular mechanisms underpinning this neuronal specificity will be discussed with particular emphasis being given to the role of GABA(A) receptor isoforms, protein phosphorylation and local steroid metabolism and synthesis.

  • Neuroactive steroids influence peripheral myelination: a promising opportunity for preventing or treating age-dependent dysfunctions of peripheral nerves.
    Prog. Neurobiol. (IF 10.658) Pub Date : 2003-11-13
    R C Melcangi,I Azcoitia,M Ballabio,I Cavarretta,L C Gonzalez,E Leonelli,V Magnaghi,S Veiga,L M Garcia-Segura

    The process of aging deeply influences morphological and functional parameters of peripheral nerves. The observations summarized here indicate that the deterioration of myelin occurring in the peripheral nerves during aging may be explained by the fall of the levels of the major peripheral myelin proteins [e.g., glycoprotein Po (Po) and peripheral myelin protein 22 (PMP22)]. Neuroactive steroids, such as progesterone (PROG), dihydroprogesterone (5alpha-DH PROG), and tetrahydroprogesterone (3alpha,5alpha-TH PROG), are able to stimulate the low expression of these two myelin proteins present in the sciatic nerve of aged male rats. Since Po and PMP22 play an important physiological role in the maintenance of the multilamellar structure of PNS myelin, we have evaluated the effect of PROG and its neuroactive derivatives, 5alpha-DH PROG and 3alpha,5alpha-TH PROG, on the morphological alterations of myelinated fibers in the sciatic nerve of 22-24-month-old male rats. Data obtained clearly indicate that neuroactive steroids are able to reduce aging-associated morphological abnormalities of myelin and aging-associated myelin fiber loss in the sciatic nerve.

  • Steroids and the reversal of age-associated changes in myelination and remyelination.
    Prog. Neurobiol. (IF 10.658) Pub Date : 2003-11-13
    C Ibanez,S A Shields,M El-Etr,E Leonelli,V Magnaghi,W-W Li,F J Sim,E-E Baulieu,R C Melcangi,M Schumacher,R J M Franklin

    The myelin sheaths that surround all but the smallest diameter axons within the mammalian central nervous system (CNS) must maintain their structural integrity for many years. Like many tissues, however, this function is prone to the effects of ageing, and various structural anomalies become apparent in the aged CNS. Similarly, the regenerative process by which myelin sheaths, lost as a consequence of exposure to a demyelinating insult, are restored (remyelination) is also affected by age. As animals grow older, the efficiency of remyelination progressively declines. In this article, we review both phenomena and describe how both can be partially reversed by steroid hormones and their derivatives.

  • Individual differences in cognitive aging: implication of pregnenolone sulfate.
    Prog. Neurobiol. (IF 10.658) Pub Date : 2003-11-13
    Willy Mayo,Olivier George,Sonia Darbra,Jean-Jacques Bouyer,Monique Vallée,Muriel Darnaudéry,Marc Pallarès,Valérie Lemaire-Mayo,Michel Le Moal,Pier-Vincenzo Piazza,Nora Abrous

    In humans and animals, individual differences in aging of cognitive functions are classically reported. Some old individuals exhibit performances similar to those of young subjects while others are severely impaired. In senescent animals, we have previously demonstrated a significant correlation between the cognitive performance and the cerebral concentration of a neurosteroid, the pregnenolone sulfate (PREG-S). Neurotransmitter systems modulated by this neurosteroid were unknown until our recent report of an enhancement of acetylcholine (ACh) release in basolateral amygdala, cortex and hippocampus induced by intracerebroventricular (i.c.v.) or intracerebral administrations of PREG-S. Central ACh neurotransmission is known to be involved in the regulation of memory processes and is affected in normal aging and severely altered in human neurodegenerative pathologies like Alzheimer's disease. In the central nervous system, ACh neurotransmission is also involved in the modulation of sleep-wakefulness cycle, and particularly the paradoxical sleep (PS). Relationships between paradoxical sleep and memory are documented in the literature in old animals in which the spatial memory performance positively correlates with the basal amounts of paradoxical sleep. PREG-S infused at the level of ACh cell bodies (nucleus basalis magnocellularis, NBM, or pedunculopontine nucleus, PPT) increases paradoxical sleep in young animals.Finally, aging related cognitive dysfunctions, particularly those observed in Alzheimer's disease, have also been related to alterations of mechanisms underlying cerebral plasticity. Amongst these mechanisms, neurogenesis has been extensively studied recently. Our data demonstrate that PREG-S central infusions dramatically increase neurogenesis, this effect could be related to the negative modulator properties of this steroid at the GABA(A) receptor level. Taken together these data suggest that neurosteroids can influence cognitive processes, particularly in senescent subjects, through a modulation of ACh neurotransmission associated with paradoxical sleep modifications; furthermore, our recent data suggest a critical role for neurosteroids in the modulation of cerebral plasticity, mainly on hippocampal neurogenesis.

  • Aromatase: a neuroprotective enzyme.
    Prog. Neurobiol. (IF 10.658) Pub Date : 2003-11-13
    Luis M Garcia-Segura,Sergio Veiga,Amanda Sierra,Roberto C Melcangi,Iñigo Azcoitia

    Estradiol, in addition to its participation in neuroendocrine regulation and sexual behavior, has neuroprotective properties. Different types of brain injury induce the expression of the enzyme aromatase in reactive astroglia. This enzyme catalyzes the conversion of testosterone and other C19 steroids to estradiol. Genetic or pharmacological inhibition of brain aromatase results in marked neurodegeneration after different forms of mild neurodegenerative stimuli that do not compromise neuronal survival under control conditions. Furthermore, aromatase mediates neuroprotective effects of precursors of estradiol such as pregnenolone, dehydroepiandrosterone (DHEA) and testosterone. These findings strongly suggest that local formation of estradiol in the brain is neuroprotective and that the induction of aromatase and the consecutive increase in the local production of estradiol are part of the program triggered by the neural tissue to cope with neurodegenerative insults. Aromatase may thus represent an important pharmacological target for therapies conducted to prevent aging-associated neurodegenerative disorders.

  • Steroid hormones and neurosteroids in normal and pathological aging of the nervous system.
    Prog. Neurobiol. (IF 10.658) Pub Date : 2003-11-13
    M Schumacher,S Weill-Engerer,P Liere,F Robert,R J M Franklin,L M Garcia-Segura,J J Lambert,W Mayo,R C Melcangi,A Parducz,U Suter,C Carelli,E E Baulieu,Y Akwa

    Without medical progress, dementing diseases such as Alzheimer's disease will become one of the main causes of disability. Preventing or delaying them has thus become a real challenge for biomedical research. Steroids offer interesting therapeutical opportunities for promoting successful aging because of their pleiotropic effects in the nervous system: they regulate main neurotransmitter systems, promote the viability of neurons, play an important role in myelination and influence cognitive processes, in particular learning and memory. Preclinical research has provided evidence that the normally aging nervous system maintains some capacity for regeneration and that age-dependent changes in the nervous system and cognitive dysfunctions can be reversed to some extent by the administration of steroids. The aging nervous system also remains sensitive to the neuroprotective effects of steroids. In contrast to the large number of studies documenting beneficial effects of steroids on the nervous system in young and aged animals, the results from hormone replacement studies in the elderly are so far not conclusive. There is also little information concerning changes of steroid levels in the aging human brain. As steroids present in nervous tissues originate from the endocrine glands (steroid hormones) and from local synthesis (neurosteroids), changes in blood levels of steroids with age do not necessarily reflect changes in their brain levels. There is indeed strong evidence that neurosteroids are also synthesized in human brain and peripheral nerves. The development of a very sensitive and precise method for the analysis of steroids by gas chromatography/mass spectrometry (GC/MS) offers new possibilities for the study of neurosteroids. The concentrations of a range of neurosteroids have recently been measured in various brain regions of aged Alzheimer's disease patients and aged non-demented controls by GC/MS, providing reference values. In Alzheimer's patients, there was a general trend toward lower levels of neurosteroids in different brain regions, and neurosteroid levels were negatively correlated with two biochemical markers of Alzheimer's disease, the phosphorylated tau protein and the beta-amyloid peptides. The metabolism of dehydroepiandrosterone has also been analyzed for the first time in the aging brain from Alzheimer patients and non-demented controls. The conversion of dehydroepiandrosterone to Delta5-androstene-3beta,17beta-diol and to 7alpha-OH-dehydroepiandrosterone occurred in frontal cortex, hippocampus, amygdala, cerebellum and striatum of both Alzheimer's patients and controls. The formation of these metabolites within distinct brain regions negatively correlated with the density of beta-amyloid deposits.

  • Patterned Purkinje cell death in the cerebellum.
    Prog. Neurobiol. (IF 10.658) Pub Date : 2003-10-22
    Justyna R Sarna,Richard Hawkes

    The object of this review is to assemble much of the literature concerning Purkinje cell death in cerebellar pathology and to relate this to what is now known about the complex topography of the cerebellar cortex. A brief introduction to Purkinje cells, and their regionalization is provided, and then the data on Purkinje cell death in mouse models and, where appropriate, their human counterparts, have been arranged according to several broad categories--naturally-occurring and targeted mutations leading to Purkinje cell death, Purkinje cell death due to toxins, Purkinje cell death in ischemia, Purkinje cell death in infection and in inherited disorders, etc. The data reveal that cerebellar Purkinje cell death is much more topographically complex than is usually appreciated.

  • Yin and Yang: complement activation and regulation in Alzheimer's disease.
    Prog. Neurobiol. (IF 10.658) Pub Date : 2003-10-22
    Yong Shen,Seppo Meri

    The spectrum of inflammatory diseases is nowadays considered to include diverse diseases of the central nervous system (CNS). Current evidence suggests that syndromes such as Alzheimer's disease (AD) have important inflammatory and immune components and may be amenable to treatment by anti-inflammatory and immunotherapeutic approaches. Compelling evidence has been reported that complement activation occurs in the brain with Alzheimer's disease, and that this contributes to the development of a local inflammatory state that is correlated with cognitive dysfunction. The complement system is a critical element of the innate immune system recognizing and killing, or targeting for destruction, otherwise pathogenic organisms. In addition to triggering the generation of a membranolytic complex, complement proteins interact with cell surface receptors to promote a local inflammatory response that contributes to the protection and healing of the host. Complement activation causes inflammation and cell damage, yet it is an essential component in trying to eliminate cell debris and potentially toxic protein aggregates. It is the balance of these seemingly competing events--the "Yin" and the "Yang"--that influences the ultimate state of neuronal function. Knowledge of the unique molecular interactions that occur in the development of Alzheimer's disease, the functional consequences of those interactions, and the proportional contribution of each element to this disorder, should facilitate the design of effective therapeutic strategies for this disease.

  • Insulin-like growth factor-1 and post-ischemic brain injury.
    Prog. Neurobiol. (IF 10.658) Pub Date : 2003-10-22
    J Guan,L Bennet,P D Gluckman,A J Gunn

    Insulin-like growth factor-1 (IGF-1) is a naturally occurring neurotrophic factor that plays an important role in promoting cell proliferation and differentiation during normal brain development and maturation. The present review examines recent evidence that endogenous IGF-1 also plays a significant role in recovery from insults such as hypoxia-ischemia and that giving additional exogenous IGF-1 can actively ameliorate damage. It is now well established that neurons and other cell types die many hours or even days after initial injury due to activation of programmed cell death pathways. IGF-1 and its binding proteins and receptors are intensely induced within damaged brain regions following brain injury, suggesting a possible a role for IGF-1 in brain recovery. Exogenous administration of IGF-1 within a few hours after brain injury is now known to be protective in both gray and white matter and leads to improved somatic function. In contrast, pre-treatment is ineffective, likely reflecting limited intracerebral penetration of IGF-1 into the uninjured brain. The neuroprotective effects of IGF-1 are mediated by IGF-1 receptors and its binding proteins and are specific to particular cellular phenotypes and brain regions. The window of opportunity for treatment with IGF-1 is limited to a few hours after normothermic brain injury, reflecting its specific actions on early, intracellular events in the apoptotic cascade. However, injury-associated mild post-hypoxic hypothermia, which delays the development of cell death, can shift and dramatically extend the window of opportunity for delayed treatment with IGF-1. Such a combined approach is likely to be essential for any clinical treatment.

  • Thinking globally, acting locally: steroid hormone regulation of the dendritic architecture, synaptic connectivity and death of an individual neuron.
    Prog. Neurobiol. (IF 10.658) Pub Date : 2003-09-27
    Janis C Weeks

    Steroid hormones act via evolutionarily conserved nuclear receptors to regulate neuronal phenotype during development, maturity and disease. Steroid hormones exert 'global' effects in organisms to produce coordinated physiological responses whereas, at the 'local' level, individual neurons can respond to a steroidal signal in highly specific ways. This review focuses on two phenomena-the loss of dendritic processes and the programmed cell death (PCD) of neurons-that can be regulated by steroid hormones (e.g. during sexual differentiation in vertebrates). In insects such as the moth, Manduca sexta, and fruit fly, Drosophila melanogaster, ecdysteroids orchestrate a reorganization of neural circuits during metamorphosis. In Manduca, accessory planta retractor (APR) motoneurons undergo dendritic loss at the end of larval life in response to a rise in 20-hydroxyecdysone (20E). Dendritic regression is associated with a decrease in the strength of monosynaptic inputs, a decrease in the number of contacts from pre-synaptic neurons, and the loss of a behavior mediated by these synapses. The APRs in different abdominal segments undergo segment-specific PCD at pupation and adult emergence that is triggered directly and cell-autonomously by a genomic action of 20E, as demonstrated in cell culture. The post-emergence death of APRs provides a model for steroid-mediated neuroprotection. APR death occurs by autophagy, not apoptosis, and involves caspase activation and the aggregation and ultracondensation of mitochondria. Manduca genes involved in segmental identity, 20E signaling and PCD are being sought by suppressive subtractive hybridization (SSH) and cDNA microarrays. Experiments utilizing Drosophila as a complementary system have been initiated. These insect model systems contribute toward understanding the causes and functional consequences of dendritic loss and neurodegeneration in human neurological disorders.

  • Role of the basolateral amygdala in memory consolidation.
    Prog. Neurobiol. (IF 10.658) Pub Date : 2003-09-27
    Denis Paré

    Typically, emotionally charged events are better remembered than neutral ones. This paper reviews data indicating that the amygdala is responsible for this facilitation of memory by emotional arousal. Pharmacological and behavioral studies have shown that the release of adrenal stress hormones facilitates memory consolidation. The available evidence suggests that this effect depends on a central action of stress hormones involving the release of the neuromodulators noradrenaline (NA) and acetylcholine in the basolateral complex of the amygdala (BLA). Indeed, BLA lesions block the memory modulating effects of stress hormones. Moreover, microdialysis studies have revealed that BLA concentrations of NA and acetylcholine are transiently (2h) elevated following emotionally arousing learning episodes. Last, post-learning intra-BLA injections of beta-adrenergic or muscarinic receptor antagonists reduce retention. These results have led to the hypothesis that NA and acetylcholine increase the activity of BLA neurons in the hours after the learning episode. In turn, the BLA would facilitate synaptic plasticity in other brain structures, believed to constitute the storage sites for different types of memory. Consistent with this, post-learning treatments that reduce or enhance the excitability of BLA neurons respectively decrease or improve long-term retention on various emotionally charged learning tasks. However, a number of issues remain unresolved. Chief among them is how the BLA facilitates synaptic plasticity elsewhere in the brain. The present review concludes with a consideration of this issue based on recent advances in our understanding of the BLA. Among other possibilities, it is suggested that rhythmic BLA activity at the theta frequency during arousal as well as the uniform conduction times of BLA axons to distributed rhinal sites may promote plasticity in co-active structures of the temporal lobe.

  • Kainate receptors and synaptic transmission.
    Prog. Neurobiol. (IF 10.658) Pub Date : 2003-09-27
    James E Huettner

    Excitatory glutamatergic transmission involves a variety of different receptor types, each with distinct properties and functions. Physiological studies have identified both post- and presynaptic roles for kainate receptors, which are a subtype of the ionotropic glutamate receptors. Kainate receptors contribute to excitatory postsynaptic currents in many regions of the central nervous system including hippocampus, cortex, spinal cord and retina. In some cases, postsynaptic kainate receptors are co-distributed with alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors, but there are also synapses where transmission is mediated exclusively by postsynaptic kainate receptors: for example, in the retina at connections made by cones onto off bipolar cells. Modulation of transmitter release by presynaptic kainate receptors can occur at both excitatory and inhibitory synapses. The depolarization of nerve terminals by current flow through ionotropic kainate receptors appears sufficient to account for most examples of presynaptic regulation; however, a number of studies have provided evidence for metabotropic effects on transmitter release that can be initiated by activation of kainate receptors. Recent analysis of knockout mice lacking one or more of the subunits that contribute to kainate receptors, as well as studies with subunit-selective agonists and antagonists, have revealed the important roles that kainate receptors play in short- and long-term synaptic plasticity. This review briefly addresses the properties of kainate receptors and considers in greater detail the physiological analysis of their contributions to synaptic transmission.

  • Regulation and critical role of potassium homeostasis in apoptosis.
    Prog. Neurobiol. (IF 10.658) Pub Date : 2003-09-10
    Shan Ping Yu

    Programmed cell death or apoptosis is broadly responsible for the normal homeostatic removal of cells and has been increasingly implicated in mediating pathological cell loss in many disease states. As the molecular mechanisms of apoptosis have been extensively investigated a critical role for ionic homeostasis in apoptosis has been recently endorsed. In contrast to the ionic mechanism of necrosis that involves Ca(2+) influx and intracellular Ca(2+) accumulation, compelling evidence now indicates that excessive K(+) efflux and intracellular K(+) depletion are key early steps in apoptosis. Physiological concentration of intracellular K(+) acts as a repressor of apoptotic effectors. A huge loss of cellular K(+), likely a common event in apoptosis of many cell types, may serve as a disaster signal allowing the execution of the suicide program by activating key events in the apoptotic cascade including caspase cleavage, cytochrome c release, and endonuclease activation. The pro-apoptotic disruption of K(+) homeostasis can be mediated by over-activated K(+) channels or ionotropic glutamate receptor channels, and most likely, accompanied by reduced K(+) uptake due to dysfunction of Na(+), K(+)-ATPase. Recent studies indicate that, in addition to the K(+) channels in the plasma membrane, mitochondrial K(+) channels and K(+) homeostasis also play important roles in apoptosis. Investigations on the K(+) regulation of apoptosis have provided a more comprehensive understanding of the apoptotic mechanism and may afford novel therapeutic strategies for apoptosis-related diseases.

  • Physiological, anatomical and genetic identification of CPG neurons in the developing mammalian spinal cord.
    Prog. Neurobiol. (IF 10.658) Pub Date : 2003-09-10
    Ole Kiehn,Simon J B Butt

    The basic motor patterns underlying rhythmic limb movements during locomotion are generated by neuronal networks located within the spinal cord. These networks are called Central Pattern Generators (CPGs). Isolated spinal cord preparations from newborn rats and mice have become increasingly important for understanding the organization of the CPG in the mammalian spinal cord. Early studies using these preparations have focused on the overall network structure and the localization of the CPG. In this review we concentrate on recent experiments aimed at identifying and characterizing CPG-interneurons in the rodent. These experiments include the organization and function of descending commissural interneurons (dCINs) in the hindlimb CPG of the neonatal rat, as well as the role of Ephrin receptor A4 (EphA4) and its Ephrin ligand B3 (EphrinB3), in the construction of the mammalian locomotor network. These latter experiments have defined EphA4 as a molecular marker for mammalian excitatory hindlimb CPG neurons. We also review genetic approaches that can be applied to the mouse spinal cord. These include methods for identifying sub-populations of neurons by genetically encoded reporters, techniques to trace network connectivity with cell-specific genetically encoded tracers, and ways to selectively ablate or eliminate neuron populations from the CPG. We propose that by applying a multidisciplinary approach it will be possible to understand the network structure of the mammalian locomotor CPG. Such an understanding will be instrumental in devising new therapeutic strategies for patients with spinal cord injury.

  • Hippocampal modulation of sensorimotor processes.
    Prog. Neurobiol. (IF 10.658) Pub Date : 2003-09-10
    Tobias Bast,Joram Feldon

    While the hippocampus makes unique contributions to memory, it has also long been associated with sensorimotor processes, i.e. innate processes involving control of motor responses to sensory stimuli. Moreover, hippocampal dysfunction has been implicated in neuropsychiatric diseases, such as schizophrenia and anxiety disorders, primarily characterized by non-mnemonic deficits in the processing of and responding to sensory information. This review is concerned with the hippocampal modulation of three sensorimotor processes in rats-locomotor activity, prepulse inhibition (PPI) of the startle reflex, and the startle reflex itself-whose alterations are related to human psychosis or anxiety disorders. Its main purpose is to present and discuss the picture emerging from studies examining the effects of pharmacological manipulations of the dorsal and ventral hippocampus by local drug microinfusions. While a role of the hippocampus in regulating locomotor activity, PPI, and startle reactivity has also been suggested based on the effects of hippocampal lesions, the microinfusion studies have revealed additional important details of this role and suggest modifications of notions based on lesion studies. In summary, the microinfusion studies corroborate that hippocampal mechanisms can directly influence locomotor activity, PPI, and startle reactivity, and that aberrant hippocampal function may contribute to neuropsychiatric diseases, in particular psychosis. The relation between different sensorimotor processes and hippocampal neurotransmission, the role of ventral and dorsal hippocampus, and the extrahippocampal mechanisms mediating the hippocampal modulation of different sensorimotor processes can partly be dissociated. Thus, the hippocampal modulation of these sensorimotor processes appears to reflect multiple operations, rather than one unitary operation.

  • Structure and function of the vomeronasal system: an update.
    Prog. Neurobiol. (IF 10.658) Pub Date : 2003-09-03
    Mimi Halpern,Alino Martínez-Marcos

    Several developments during the past 15 years have profoundly affected our understanding of the vomeronasal system (VNS) of vertebrates. In the mid 1990s, the vomeronasal epithelium of mammals was found to contain two populations of receptor cells, based on their expression of G-proteins. These two populations of neurons were subsequently found to project their axons to different parts of the accessory olfactory bulb (AOB), forming the basis of segregated pathways with possibly heterogeneous functions. A related discovery was the cloning of members of at least two gene families of putative vomeronasal G-protein-coupled receptors (GPRs) in the vomeronasal epithelium. Ligand binding to these receptors was found to activate a phospholipase C (PLC)-dependent signal transduction pathway that primarily involves an increase in intracellular inositol-tris-phosphate and intracellular calcium. In contrast to what was previously believed, neuron replacement in the vomeronasal epithelium appears to occur through a process of vertical migration in most mammals. New anatomical studies of the central pathways of the olfactory and vomeronasal systems indicated that these two systems converge on neurons in the telencephalon, providing an anatomical substrate for functional interactions. Combined anatomical, physiological and behavioral studies in mice provided new information that furthered our understanding of one of the most striking pheromonal phenomena, the Bruce effect. Finally, contrary to prior observations, new anatomical studies indicated that a vomeronasal organ (VNO) was present in human adults and reports were published indicating that this system might be functional. These latter observations are still controversial and require confirmation from independent laboratories.

  • The neurobiology and control of anxious states.
    Prog. Neurobiol. (IF 10.658) Pub Date : 2003-08-21
    Mark J Millan

    Fear is an adaptive component of the acute "stress" response to potentially-dangerous (external and internal) stimuli which threaten to perturb homeostasis. However, when disproportional in intensity, chronic and/or irreversible, or not associated with any genuine risk, it may be symptomatic of a debilitating anxious state: for example, social phobia, panic attacks or generalized anxiety disorder. In view of the importance of guaranteeing an appropriate emotional response to aversive events, it is not surprising that a diversity of mechanisms are involved in the induction and inhibition of anxious states. Apart from conventional neurotransmitters, such as monoamines, gamma-amino-butyric acid (GABA) and glutamate, many other modulators have been implicated, including: adenosine, cannabinoids, numerous neuropeptides, hormones, neurotrophins, cytokines and several cellular mediators. Accordingly, though benzodiazepines (which reinforce transmission at GABA(A) receptors), serotonin (5-HT)(1A) receptor agonists and 5-HT reuptake inhibitors are currently the principle drugs employed in the management of anxiety disorders, there is considerable scope for the development of alternative therapies. In addition to cellular, anatomical and neurochemical strategies, behavioral models are indispensable for the characterization of anxious states and their modulation. Amongst diverse paradigms, conflict procedures--in which subjects experience opposing impulses of desire and fear--are of especial conceptual and therapeutic pertinence. For example, in the Vogel Conflict Test (VCT), the ability of drugs to release punishment-suppressed drinking behavior is evaluated. In reviewing the neurobiology of anxious states, the present article focuses in particular upon: the multifarious and complex roles of individual modulators, often as a function of the specific receptor type and neuronal substrate involved in their actions; novel targets for the management of anxiety disorders; the influence of neurotransmitters and other agents upon performance in the VCT; data acquired from complementary pharmacological and genetic strategies and, finally, several open questions likely to orientate future experimental- and clinical-research. In view of the recent proliferation of mechanisms implicated in the pathogenesis, modulation and, potentially, treatment of anxiety disorders, this is an opportune moment to survey their functional and pathophysiological significance, and to assess their influence upon performance in the VCT and other models of potential anxiolytic properties.

  • Neuroimaging studies of priming.
    Prog. Neurobiol. (IF 10.658) Pub Date : 2003-08-21
    R N A Henson

    This article reviews functional neuroimaging studies of priming, a behavioural change associated with the repeated processing of a stimulus. Using the haemodynamic techniques of functional magnetic resonance imaging (fMRI) and positron emission tomography (PET), priming-related effects have been observed in numerous regions of the human brain, with the specific regions depending on the type of stimulus and the manner in which it is processed. The most common finding is a decreased haemodynamic response for primed versus unprimed stimuli, though priming-related response increases have been observed. Attempts have been made to relate these effects to a form of implicit or "unconscious" memory. The priming-related decrease has also been used as a tool to map the brain regions associated with different stages of stimulus-processing, a method claimed to offer superior spatial resolution. This decrease has a potential analogue in the stimulus repetition effects measured with single-cell recording in the non-human primate. The paradigms reviewed include word-stem completion, masked priming, repetition priming of visual objects and semantic priming. An attempt is made to relate the findings within a "component process" framework, and the relationship between behavioural, haemodynamic and neurophysiological data is discussed. Interpretation of the findings is not always clear-cut, however, given potential confounding factors such as explicit memory, and several recommendations are made for future neuroimaging studies of priming.

  • Nature versus nurture revisited: an old idea with a new twist.
    Prog. Neurobiol. (IF 10.658) Pub Date : 2003-08-21
    Leah Krubitzer,Dianna M Kahn

    The nature versus nurture debate has recently resurfaced with the emergence of the field of developmental molecular neurobiology. The questions associated with "nature" have crystallized into testable hypotheses regarding patterns of gene expression during development, and those associated with "nurture" have given over to activity-dependent cellular mechanisms that give rise to variable phenotypes in developing nervous systems. This review focuses on some of the features associated with complex brains and discusses the evolutionary and activity-dependent mechanisms that generate these features. These include increases in the size of the cortical sheet, changes in cortical domain and cortical field specification, and the activity-dependent intracellular mechanisms that regulate the structure and function of neurons during development. We discuss which features are likely to be genetically mediated, which features are likely to be regulated by activity, and how these two mechanisms act in concert to produce the wide variety of phenotypes observed for the mammalian neocortex. For example, the size of the cortical sheet is likely to be under genetic control, and regulation of cell-cycle kinetics through upregulation of genes such as beta-catenin can account for increases in the size of the cortical sheet. Similarly, intrinsic signaling genes or gene products such as Wnt, Shh, Fgf2, Fgf8 and BMP may set up a combinatorial coordinate system that guides thalamic afferents. Changes in peripheral morphology that regulate patterned activity are also likely to be under genetic control. Finally, the intracellular machinery that allows for activity-dependent plasticity in the developing CNS may be genetically regulated, although the specific phenotype they generate are not. On the other hand, aspects of neocortical organization such as sensory domain assignment, the size and shape of cortical fields, some aspects of connectivity, and details of functional organization are likely to be activity-dependent. Furthermore, the role of genes versus activity, and their interactions, may be different for primary fields versus non-primary fields.

  • Roles of amyloid precursor protein and its fragments in regulating neural activity, plasticity and memory.
    Prog. Neurobiol. (IF 10.658) Pub Date : 2003-08-21
    Paul R Turner,Kate O'Connor,Warren P Tate,Wickliffe C Abraham

    Amyloid-beta precursor protein (APP) is a membrane-spanning protein with a large extracellular domain and a much smaller intracellular domain. It is the source of the amyloid-beta (Abeta) peptide found in neuritic plaques of Alzheimer's disease (AD) patients. Because Abeta shows neurotoxic properties, and because familial forms of AD promote Abeta accumulation, a massive international research effort has been aimed at understanding the mechanisms of Abeta generation, catabolism and toxicity. APP, however, is an extremely complex molecule that may be a functionally important molecule in its full-length configuration, as well as being the source of numerous fragments with varying effects on neural function. For example, one fragment derived from the non-amyloidogenic processing pathway, secreted APPalpha (sAPPalpha), is neuroprotective, neurotrophic and regulates cell excitability and synaptic plasticity, while Abeta appears to exert opposing effects. Less is known about the neural functions of other fragments, but there is a growing interest in understanding the basic biology of APP as it has become recognized that alterations in the functional activity of the APP fragments during disease states will have complex effects on cell function. Indeed, it has been proposed that reductions in the level or activity of certain APP fragments, in addition to accumulation of Abeta, may play a critical role in the cognitive dysfunction associated with AD, particularly early in the course of the disease. To test and modify this hypothesis, it is important to understand the roles that full-length APP and its fragments normally play in neuronal structure and function. Here we review evidence addressing these fundamental questions, paying particular attention to the contributions that APP fragments play in synaptic transmission and neural plasticity, as these may be key to understanding their effects on learning and memory. It is clear from this literature that APP fragments, including Abeta, can exert a powerful regulation of key neural functions including cell excitability, synaptic transmission and long-term potentiation, both acutely and over the long-term. Furthermore, there is a small but growing literature confirming that these fragments correspondingly regulate behavioral learning and memory. These data indicate that a full account of cognitive dysfunction in AD will need to incorporate the actions of the full complement of APP fragments. To this end, there is an urgent need for a dedicated research effort aimed at understanding the behavioral consequences of altered levels and activity of the different APP fragments as a result of experience and disease.

  • From cells to circuits: development of the zebrafish spinal cord.
    Prog. Neurobiol. (IF 10.658) Pub Date : 2003-07-26
    Katharine E Lewis,Judith S Eisen

    The ability of an animal to carry out its normal behavioral repertoire requires generation of an enormous diversity of neurons and glia. The relative simplicity of the spinal cord makes this an especially attractive part of the nervous system for addressing questions about the development of vertebrate neural specification and function. The last decade has witnessed an explosion in our understanding of spinal cord development and the functional interactions among spinal cord neurons and glia. Cellular, genetic, molecular, physiological and behavioral studies in zebrafish have all been important in providing insights into questions that remained unanswered by studies from other vertebrate model organisms. This is the case because many zebrafish spinal neurons can be individually identified and followed over time in living embryos and larvae. In this review, we discuss what is currently known about the cellular, genetic and molecular mechanisms involved in specifying distinct cell types in the zebrafish spinal cord and how these cells establish the functional circuitry that mediates particular behaviors. We start by describing the early signals and morphogenetic movements that form the nervous system, and in particular, the spinal cord. We then provide an overview of the cell types within the spinal cord and describe how they are specified and patterned. We begin ventrally with floor plate and proceed dorsally, through motoneurons and oligodendrocytes, interneurons, astrocytes and radial glia, spinal sensory neurons and neural crest. We next describe axon pathfinding of spinal neurons. Finally, we discuss the roles of particular spinal cord neurons in specific behaviors.

  • Presence and functional significance of presynaptic ryanodine receptors.
    Prog. Neurobiol. (IF 10.658) Pub Date : 2003-07-26
    Ron Bouchard,Roberto Pattarini,Jonathan D Geiger

    Ca(2+)-induced Ca(2+) release (CICR) mediated by sarcoplasmic reticulum resident ryanodine receptors (RyRs) has been well described in cardiac, skeletal and smooth muscle. In brain, RyRs are localised primarily to endoplasmic reticulum (ER) and have been demonstrated in postsynaptic entities, astrocytes and oligodendrocytes where they regulate intracellular Ca(2+) concentration ([Ca(2+)](i)), membrane potential and the activity of a variety of second messenger systems. Recently, the contribution of presynaptic RyRs and CICR to functions of central and peripheral presynaptic terminals, including neurotransmitter release, has received increased attention. However, there is no general agreement that RyRs are localised to presynaptic terminals, nor is it clear that RyRs regulate a large enough pool of intracellular Ca(2+) to be physiologically significant. Here, we review direct and indirect evidence that on balance favours the notion that ER and RyRs are found in presynaptic terminals and are physiologically significant. In so doing, it became obvious that some of the controversy originates from issues related to (i) the ability to demonstrate conclusively the physical presence of ER and RyRs, (ii) whether the biophysical properties of RyRs are such that they can contribute physiologically to regulation of presynaptic [Ca(2+)](i), (iii) how ER Ca(2+) load and feedback gain of CICR contributes to the ability to detect functionally relevant RyRs, (iv) the distance that Ca(2+) diffuses from plasma membranes to RyRs to trigger CICR and from RyRs to the Active Zone to enhance vesicle release, and (v) the experimental conditions used. The recognition that ER Ca(2+) stores are able to modulate local Ca(2+) levels and neurotransmitter release in presynaptic terminals will aid in the understanding of the cellular mechanisms controlling neuronal function.

  • Dopamine: a potential substrate for synaptic plasticity and memory mechanisms.
    Prog. Neurobiol. (IF 10.658) Pub Date : 2003-07-26
    Thérèse M Jay

    It is only recently that a number of studies on synaptic plasticity in the hippocampus and other brain areas have considered that a heterosynaptic modulatory input could be recruited as well as the coincident firing of pre- and post-synaptic neurons. So far, the strongest evidence for such a regulation has been attributed to dopaminergic (DA) systems but other modulatory pathways have also been considered to influence synaptic plasticity. This review will focus on dopamine contribution to synaptic plasticity in different brain areas (hippocampus, striatum and prefrontal cortex) with, for each region, a few lines on the distribution of DA projections and receptors. New insights into the possible mechanisms underlying these plastic changes will be considered. The contribution of various DA systems in certain forms of learning and memory will be reviewed with recent advances supporting the hypothesis of similar cellular mechanisms underlying DA regulation of synaptic plasticity and memory processes in which the cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) pathway has a potential role. To summarize, endogenous DA, which depends on the activity patterns of DA midbrain neurons in freely moving animals, appears as a key regulator in specific synaptic changes observed at certain stages of learning and memory and of synaptic plasticity.

  • Neurotrophin secretion: current facts and future prospects.
    Prog. Neurobiol. (IF 10.658) Pub Date : 2003-06-06
    Volkmar Lessmann,Kurt Gottmann,Marzia Malcangio

    The proteins of the mammalian neurotrophin family (nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and neurotrophin-4/5 (NT-4/5)) were originally identified as neuronal survival factors. During the last decade, evidence has accumulated implicating them (especially BDNF) in addition in the regulation of synaptic transmission and synaptogenesis in the CNS. However, a detailed understanding of the secretion of neurotrophins from neurons is required to delineate their role in regulating synaptic function. Some crucial questions that need to be addressed include the sites of neurotrophin secretion (i.e. axonal versus dendritic; synaptic versus extrasynaptic) and the neuronal and synaptic activity patterns that trigger the release of neurotrophins. In this article, we review the current knowledge in the field of neurotrophin secretion, focussing on activity-dependent synaptic release of BDNF. The modality and the site of neurotrophin secretion are dependent on the processing and subsequent targeting of the neurotrophin precursor molecules. Therefore, the available data regarding formation and trafficking of neurotrophins in the secreting neurons are critically reviewed. In addition, we discuss existing evidence that the characteristics of neurotrophin secretion are similar (but not identical) to those of other neuropeptides. Finally, since BDNF has been proposed to play a critical role as an intercellular synaptic messenger in long-term potentiation (LTP) in the hippocampus, we try to reconcile this possible role of BDNF in LTP with the recently described features of synaptic BDNF secretion.

  • Adenosine in the spinal cord and periphery: release and regulation of pain.
    Prog. Neurobiol. (IF 10.658) Pub Date : 2003-06-06
    Jana Sawynok,Xue Jun Liu

    In the central nervous system (CNS), adenosine is an important neuromodulator and regulates neuronal and non-neuronal cellular function (e.g. microglia) by actions on extracellular adenosine A(1), A(2A), A(2B) and A(3) receptors. Extracellular levels of adenosine are regulated by synthesis, metabolism, release and uptake of adenosine. Adenosine also regulates pain transmission in the spinal cord and in the periphery, and a number of agents can alter the extracellular availability of adenosine and subsequently modulate pain transmission, particularly by activation of adenosine A(1) receptors. The use of capsaicin (which activates receptors selectively expressed on C-fibre afferent neurons and produces neurotoxic actions in certain paradigms) allows for an interpretation of C-fibre involvement in such processes. In the spinal cord, adenosine availability/release is enhanced by depolarization (K(+), capsaicin, substance P, N-methyl-D-aspartate (NMDA)), by inhibition of metabolism or uptake (inhibitors of adenosine kinase (AK), adenosine deaminase (AD), equilibrative transporters), and by receptor-operated mechanisms (opioids, 5-hydroxytryptamine (5-HT), noradrenaline (NA)). Some of these agents release adenosine via an equilibrative transporter indicating production of adenosine inside the cell (K(+), morphine), while others release nucleotide which is converted extracellularly to adenosine by ecto-5'-nucleotidase (capsaicin, 5-HT). Release can be capsaicin-sensitive, Ca(2+)-dependent and involve G-proteins, and this suggests that within C-fibres, Ca(2+)-dependent intracellular processes regulate production and release of adenosine. In the periphery, adenosine is released from both neuronal and non-neuronal sources. Neuronal release from capsaicin-sensitive afferents is induced by glutamate and by neurogenic inflammation (capsaicin, low concentration of formalin), while that from sympathetic postganglionic neurons (probably as adenosine 5'-triphosphate (ATP) with NA) occurs following more generalized inflammation. Such release is modified differentially by inhibitors of AK and AD. Following nerve injury, there is an alteration in capsaicin-sensitive adenosine release, as spinal release now is less responsive to opioids, while peripheral release is less responsive to inhibitors of metabolism. Following inflammation, adenosine is released from a variety of cell types in addition to neurons (e.g. endothelial cells, neutrophils, mast cells, fibroblasts). ATP is released both spinally and peripherally following inflammation or injury, and may be converted to adenosine by ecto-5'-nucleotidase contributing an additional source of adenosine. Release of adenosine from both spinal and peripheral compartments has inhibitory effects on pain transmission, as methylxanthine adenosine receptor antagonists reduce analgesia produced by agents which augment extracellular levels of adenosine spinally (morphine, 5-HT, substance P, AK inhibitors) and peripherally (AK inhibitors, AD inhibitors). Increases in extracellular adenosine availability also may contribute to antiinflammatory effects of certain agents (methotrexate, sulfasalazine, salicylates, AK inhibitors), and this could have secondary effects on pain signalling in chronic inflammation. The purpose of the present review is to consider: (a). the factors that regulate the extracellular availability of adenosine in the spinal cord and at peripheral sites; and (b). the extent to which this adenosine affects pain signalling in these two distinct compartments.

  • In vivo cellular and molecular mechanisms of neuronal apoptosis in the mammalian CNS.
    Prog. Neurobiol. (IF 10.658) Pub Date : 2003-06-06
    L Lossi,A Merighi

    Apoptosis has been recognized to be an essential process during neural development. It is generally assumed that about half of the neurons produced during neurogenesis die before completion of the central nervous system (CNS) maturation, and this process affects nearly all classes of neurons. In this review, we discuss the experimental data in vivo on naturally occurring neuronal death in normal, transgenic and mutant animals, with special attention to the cerebellum as a study model. The emerging picture is that of a dual wave of apoptotic cell death affecting central neurons at different stages of their life. The first wave consists of an early neuronal death of proliferating precursors and young postmitotic neuroblasts, and appears to be closely linked to cell cycle regulation. The second wave affects postmitotic neurons at later stages, and is much better understood in functional terms, mainly on the basis of the neurotrophic concept in its broader definition. The molecular machinery of late apoptotic death of postmitotic neurons more commonly follows the mitochondrial pathway of intracellular signal transduction, but the death receptor pathway may also be involved.Undoubtedly, analysis of naturally occurring neuronal death (NOND) in vivo will offer a basis for parallel and future studies aiming to elucidate the mechanisms of pathologic neuronal loss occurring as the result of conditions such as neurodegenerative disorders, trauma or ischemia.

  • Proteomics in brain research: potentials and limitations.
    Prog. Neurobiol. (IF 10.658) Pub Date : 2003-05-22
    Gert Lubec,Kurt Krapfenbauer,Michael Fountoulakis

    The advent of proteomics techniques has been enthusiastically accepted in most areas of biology and medicine. In neuroscience, a host of applications was proposed ranging from neurotoxicology, neurometabolism, determination of the proteome of the individual brain areas in health and disease, to name a few. Only recently, the limitations of the method have been shown, hampering the rapid spreading of the technology, which in principle consists of two-dimensional gel electrophoresis with in-gel protein digestion of protein spots and identification by mass-spectrometrical approaches or microsequencing. The identification, including quantification using specific software, of brain protein classes, like enzymes, cytoskeleton proteins, heat shock proteins/chaperones, proteins of the transcription and translation machinery, synaptosomal proteins, antioxidant proteins, is a clear domain of proteomics. Furthermore, the concomitant detection of several hundred proteins on a gel allows the demonstration of an expressional pattern, rather generated by a reliable, protein-chemical method than by immunoreactivity, proposed by protein-arrays. An additional advantage is that hitherto unknown proteins, so far only proposed from their nucleic acid structure, designated as hypothetical proteins, can be identified as brain proteins. As to shortcomings and disadvantages of the method we would point to the major problem, the failure to separate hydrophobic proteins. There is so far no way to analyse the vast majority of these proteins in gels. Several other analytical problems need to be overcome, but once the latter problem can be solved, there is nothing to stop the method for a large scale analysis of membrane proteins in neuroscience.

  • Estrogens: protective or risk factors in brain function?
    Prog. Neurobiol. (IF 10.658) Pub Date : 2003-05-22
    Phyllis M Wise

    Over the past century, the average lifespan of women has increased from 50 to over 80 years, but the age of the menopause has remained fixed at 51 years. This "change of life" is marked by a dramatic and permanent decrease in circulating levels of ovarian estrogens. Therefore, more women will live a greater proportion of their lives in a chronic hypoestrogenic state. Ovarian steroid hormones are pleiotropic and have multiple, diverse, and possibly opposing actions in different contexts. In light of recent reports of the possible health risks of hormone replacement therapy (HRT) on several different physiological systems, the question of whether estrogens are protective or risk factors must be carefully re-evaluated.

  • Impact of aging on hippocampal function: plasticity, network dynamics, and cognition.
    Prog. Neurobiol. (IF 10.658) Pub Date : 2003-05-22
    Ephron S Rosenzweig,Carol A Barnes

    Aging is associated with specific impairments of learning and memory, some of which are similar to those caused by hippocampal damage. Studies of the effects of aging on hippocampal anatomy, physiology, plasticity, and network dynamics may lead to a better understanding of age-related cognitive deficits. Anatomical and electrophysiological studies indicate that the hippocampus of the aged rat sustains a loss of synapses in the dentate gyrus, a loss of functional synapses in area CA1, a decrease in the NMDA-receptor-mediated response at perforant path synapses onto dentate gyrus granule cells, and an alteration of Ca(2+) regulation in area CA1. These changes may contribute to the observed age-related impairments of synaptic plasticity, which include deficits in the induction and maintenance of long-term potentiation (LTP) and lower thresholds for depotentiation and long-term depression (LTD). This shift in the balance of LTP and LTD could, in turn, impair the encoding of memories and enhance the erasure of memories, and therefore contribute to cognitive deficits experienced by many aged mammals. Altered synaptic plasticity may also change the dynamic interactions among cells in hippocampal networks, causing deficits in the storage and retrieval of information about the spatial organization of the environment. Further studies of the aged hippocampus will not only lead to treatments for age-related cognitive impairments, but may also clarify the mechanisms of learning in adult mammals.

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上海纽约大学William Glover