Cognition, mood disorders, and sex hormones

Macaques (Macaca spp.) are useful models to evaluate effects of ovarian sex steroids and selective estrogen receptor modulators (SERMs) on mood and cognitive function due to similarities to women in their reproductive and central nervous systems. The results of nonhuman primate studies support the hypothesis that estrogen mediates specific aspects of attention and memory, yet much work is needed to understand which cognitive processes are affected, whether natural versus surgical menopause effects are different, and the interaction of age and ovarian senescence on cognitive function. This knowledge is necessary to determine whether to support the cognitive function of women in the menopausal phase of life and, if so, to determine efficacious therapeutic interventions. Mood disorders are prevalent in women and are associated with reproductive function in women and macaques. Exogenous steroid therapies, including oral contraceptives and postmenopausal hormone replacement therapies, have behavioral effects in women and appear to affect the behavior and underlying neural substrates of monkeys. Additional research is necessary to confirm and extend these observations. Ovarian steroids have multiple effects on serotonin synthesis, reuptake, and degradation, on neural activity that drives serotonin release, and on receptor activation in primates. This system modulates cognitive function and mood and is the target of a broad class of antidepressant therapies. Understanding the effects of ovarian steroids on the neural serotonergic system is necessary to understand depression in women. These studies are best carried out in primate models, which are more similar to humans in neural serotonergic function than other animal models.     

Listeria monocytogenes: epidemiology, human disease, and mechanisms of brain invasion

Listeria monocytogenes is a facultative intracellular bacterium that has predilection for causing central nervous systemic infections in humans and domesticated animals. This pathogen can be found worldwide in the food supply and most L. monocytogenes infections are acquired through ingestion of contaminated food. The main clinical syndromes caused by L. monocytogenes include febrile gastroenteritis, perinatal infection, and systemic infections marked by central nervous system infections with or without bacteremia. Experimental infection of mice has been used for over 50 years as a model system to study the pathogenesis of this organism including the mechanisms by which it invades the brain. Data from this model indicate that a specific subset of monocytes, distinguished in part by high expression of the Ly-6C antigen, become parasitized in the bone marrow and have a key role in transporting intracellular bacteria across the blood-brain barriers and into the central nervous system. This Minireview will summarize recent epidemiologic and clinical information regarding L. monocytogenes as a human pathogen and will discuss current in vitro and in vivo data relevant to the role of parasitized monocytes and the pathogenetic mechanisms that underlie its formidable ability to invade the central nervous system.     

Gold nanograin microelectrodes for neuroelectronic interfaces

Neuroelectronic interfaces are imperative in investigating neural tissues as electrical signals are the main information carriers in the nervous system and metal microelectrodes have been widely used for recording and stimulation of nerve cells. For high performance microelectrodes, low tissue-electrode interfacial impedance and high charge injection limits are essential and nanoscale surface engineering has been utilized to meet the requirements for microelectrodes. We report a single-cell sized microelectrode, which has unique gold nanograin structures, using a simple electrochemical deposition method. The fabricated microelectrode had a sunflower shape with 1–5 (m of micropetals along the circumference of the microelectrode and 500 nm nanograins at the center. The nanograin electrodes had 69-fold decrease of impedance and 10-fold increase in electrical stimulation capability compared to unmodified flat gold microelectrodes. The recording and stimulation performance of nanograin electrodes was tested using dissociated rat hippocampal neuronal cultures. Noise levels were extremely low (2.89 μV_rms) resulting in high signal-to-noise ratio for low-amplitude action potentials (18.6–315 μV). Small biphasic current pulses (20–60 μA) could evoke action potentials from neurons nearby electrodes. This new nanostructured neural electrode may be applicable for the development of cell-based biosensors or clinical neural prosthetic devices.     

Diet, central nervous system, and aging.

A variety of morphological, structural, and chemical changes have been described in the central nervous systems of aging humans and animals. Brain size and volume decline during senescence, and the brain atrophy is accompanied by changes in the number, size, and ultrastructural characteristics of nerve and glial cells. Moreover, recent evidence suggests that the ability of central nervous system cells to communicate with one another via the release of neurotransmitter compounds might be impaired in the elderly. Nutritional factors may play important roles in the aging process of the central nervous system by influencing brain neurotransmission, or by accelerating or retarding geriatric changes in central nervous system structure.     

Peripheral Nervous System Neuropathology and Progressive Sensory Impairments in a Mouse Model of Mucopolysaccharidosis IIIB

The lysosomal storage pathology in Mucopolysaccharidosis (MPS) IIIB manifests in cells of virtually all organs. However, it is the profound role of the neurological pathology that leads to morbidity and mortality in this disease, and has been the major challenge to developing therapies. To date, MPS IIIB neuropathologic and therapeutic studies have focused predominantly on changes in the central nervous system (CNS), especially in the brain, and little is known about the disease pathology in the peripheral nervous system (PNS). This study demonstrates characteristic lysosomal storage pathology in dorsal root ganglia affecting neurons, satellite cells (glia) and Schwann cells. Lysosomal storage lesions were also observed in the myoenteric plexus and submucosal plexus, involving enteric neurons with enteric glial activation. Further, MPS IIIB mice developed progressive impairments in sensory functions, with significantly reduced response to pain stimulation that became detectable at 4–5 months of age as the disease progressed. These data demonstrate that MPS IIIB neuropathology manifests not only in the entire CNS but also the PNS, likely affecting both afferent and efferent neural signal transduction. This study also suggests that therapeutic development for MPS IIIB may benefit from targeting the entire nervous system.     

Ghrelin and appetite control in humans--potential application in the treatment of obesity

Ghrelin is a peptide hormone secreted into circulation from the stomach. It has been postulated to act as a signal of hunger. Ghrelin administration acutely increases energy intake in lean and obese humans and chronically induces weight gain and adiposity in rodents. Circulating ghrelin levels are elevated by fasting and suppressed following a meal. Inhibiting ghrelin signaling therefore appears an attractive target for anti-obesity therapies. A number of different approaches to inhibiting the ghrelin system to treat obesity have been explored. Despite this, over a decade after its discovery, no ghrelin based anti-obesity therapies are close to reaching the market. This article discusses the role of ghrelin in appetite control in humans, examines different approaches to inhibiting the ghrelin system and assesses their potential as anti-obesity therapies.     

Brain-computer interfaces for control of neuroprostheses: from synchronous to asynchronous mode of operation.

Transferring a brain-computer interface (BCI) from the laboratory environment into real world applications is directly related to the problem of identifying user intentions from brain signals without any additional information in real time. From the perspective of signal processing, the BCI has to have an uncued or asynchronous design. Based on the results of two clinical applications, where 'thought' control of neuroprostheses based on movement imagery in tetraplegic patients with a high spinal cord injury has been established, the general steps from a synchronous or cue-guided BCI to an internally driven asynchronous brain-switch are discussed. The future potential of BCI methods for various control purposes, especially for functional rehabilitation of tetraplegics using neuroprosthetics, is outlined.     

Gene therapy for diseases of the nervous system.

Advances in molecular biology and recombinant DNA technologies have contributed to our understanding of the molecular basis of many diseases. Now the possibility of gene transfer into normal cells to produce a gene product of therapeutic potential, or into diseased cells to correct the pathologic alteration, promises to revolutionize medical practice. In contemporary medicine, many therapeutic strategies focus on the link between a biochemical deficiency and the ensuing disorder. The treatment of noninfectious disease is often based on replacement therapy; medication is given to compensate for biochemical defects and to prevent or reverse the progression of disease. Although conventional therapies seldom alter the fundamental cause of a disease, gene therapy potentially could correct, at a molecular level, the genetic abnormalities contributing to its pathogenesis. Treatment directed at specific molecular alterations associated with the development of neurologic disease provides expectations of more effective and less toxic therapy. The development of gene therapy for nervous system tumors has progressed rapidly and may be prototypical in the development of therapies for inherited and acquired disorders of the nervous system. We describe possible strategies for using gene therapy to treat nervous system disorders, and we review recent advances in gene therapy for nervous system tumors.     

Human thermogenic adipocytes: a reflection on types of adipocyte,developmental origin,and potential application

Obesity is a leading health problem facing the modern world; however, no effective therapy for this health issue has yet been developed. A promising research direction to identify novel therapies to prevent obesity has emerged from discoveries on development and function of brown/brite adipocytes in mammals. Importantly, there is evidence for the presence and function of active thermogenic brown adipocytes in both infants and adult humans. Several new investigations have shown that thermogenic adipocytes are beneficial to maintain glucose homeostasis, insulin sensitivity, and a healthy body fat content. Such thermogenic adipocytes have been considered as targets to develop a therapy for preventing obesity. This short review seeks to highlight recent findings on the development and function of brown/brite adipocytes in humans and to discuss potential treatments based on these adipocytes to reduce obesity and its related disorders.     

Derivation, characterization, and stable transfection of induced pluripotent stem cells from Fischer344 rats

The rat represents an important animal model that, in many respects, is superior to the mouse for dissecting behavioral, cardiovascular and other physiological pathologies relevant to humans. Derivation of induced pluripotent stem cells from rats (riPS) opens the opportunity for gene targeting in specific rat strains, as well as for the development of new protocols for the treatment of different degenerative diseases. Here, we report an improved lentivirus-based hit-and-run riPS derivation protocol that makes use of small inhibitors of MEK and GSK3. We demonstrate that the excision of proviruses does not affect either the karyotype or the differentiation ability of these cells. We show that the established riPS cells are readily amenable to genetic manipulations such as stable electroporation. Finally, we propose a genetic tool for an improvement of riPS cell quality in culture. These data may prompt iPS cell-based gene targeting in rat as well as the development of iPS cell-based therapies using disease models established in this species.     

Mutant alpha-synuclein-induced degeneration is reduced by parkin in a fly model of Parkinson's disease.

Parkinson's disease (PD) patients show a characteristic loss of motor control caused by the degeneration of dopaminergic neurons. Mutations in the genes that encode alpha-synuclein and parkin have been linked to inherited forms of this disease. The parkin protein functions as a ubiquitin ligase that targets proteins for degradation. Expression of isoforms of human alpha-synuclein in the Drosophila melanogaster nervous system forms the basis of an excellent genetic model that recapitulates phenotypic and behavioural features of PD. Using this model, we analysed the effect of parkin co-expression on the climbing ability of aging flies, their life span, and their retinal degeneration. We have determined that co-expression of parkin can suppress phenotypes caused by expression of mutant alpha-synuclein. In the developing eye, parkin reduces retinal degeneration. When co-expressed in the dopaminergic neurons, the ability to climb is extended over time. If conserved in humans, we suggest that upregulation of parkin may prove a method of suppression for PD induced by mutant forms of alpha-synuclein.     

The functional anatomy of cerebral reorganisation after focal brain injury

Stroke is a major cause of disability in all age groups. Although the value of specific rehabilitative therapies is now acknowledged, the mechanisms of impairment and recovery are not well understood. There is growing interest in the role that central nervous system reorganisation might play in the recovery process, and in particular whether this reorganisation can be manipulated to provide clinical benefits for patients. The careful use of non-invasive techniques such as functional magnetic resonance imaging and transcranial magnetic stimulation allows the study of the working human brain, and studies in humans suggest that functionally relevant adaptive changes occur in cerebral networks following stroke. An understanding of how these changes influence the recovery process will facilitate the development of novel therapeutic techniques that are based on neurobiological principles and will allow the delivery of specific therapies to appropriately targeted patients suffering from stroke.     

RIC, a calmodulin-binding Ras-like GTPase.

Neuronal activity dramatically increases the concentration of cytosolic Ca2+, which then serves as a second messenger to direct diverse cellular responses. Calmodulin is a primary mediator of Ca2+ signals in the nervous system. In a screen for calmodulin-binding proteins, we identified RIC, a protein related to the Ras subfamily of small GTPases. In addition to the ability to bind calmodulin, a number of unique features distinguished RIC from other Ras-like GTPases, including the absence of a signal for prenylation and a distinct effector (G2) domain. Furthermore, we describe two human proteins, RIN and RIT, which were 71% and 66% identical to RIC respectively, shared related G2 domains with RIC, and lacked prenylation signals, suggesting that the RIC family is conserved from flies to humans. While Ric and RIT were widely expressed, expression of RIN was confined to the neuron system.     

Measles virus infection in a transgenic model: virus-induced immunosuppression and central nervous system disease.

Measles virus (MV) infects 40 million persons and kills one million per year primarily by suppressing the immune system and afflicting the central nervous system (CNS). The lack of a suitable small animal model has impeded progress of understanding how MV causes disease and the development of novel therapies and improved vaccines. We tested a transgenic mouse line in which expression of the MV receptor CD46 closely mimicked the location and amount of CD46 found in humans. Virus replicated in and was recovered from these animals' immune systems and was associated with suppression of humoral and cellular immune responses. Infectious virus was recovered from the CNS, replicated primarily in neurons, and spread to distal sites presumably by fast axonal transport. Thus, a small animal model is available for analysis of MV pathogenesis.     

Model Systems: transgenic mouse models for measles pathogenesis

Studies of the diseases caused by measles virus (MV) in humans have been restricted owing to the lack of suitable animal models. The discovery of cellular receptors for MV entry has facilitated the development of transgenic mice that are susceptible to MV infection, and that mimic certain aspects of the central nervous system diseases and immunosuppression that can occur in infected humans. Moreover, such mouse models have allowed a clearer understanding of the contributions of the innate and adaptive immune response following infection, and will no doubt be important tools in the future for the development of new antiviral and vaccine reagents.     

Neural regulation of drug resistance in cancer treatment

The treatment of cancer has made great progress. However, drug resistance remains problematic. Multiple physiologic processes of tumor development can be dominated by central and sympathetic nervous systems. The interactions between the nervous system, immune system, and tumor occur consistently and dynamically. Recent evidence suggests that nerves and neural signals are intimately involved in the development of resistance to cancer therapies. In this review, we will provide an overview of the recent progress in this rapidly growing area and discuss the potential new strategies for targeting the neural signaling pathway to improve the effectiveness of chemotherapies, targeted therapies, and immunotherapies.     

Cyclic GMP is not involved in neural induction inXenopus laevis

Summary Recent evidence indicates an important role for cell-surface mediated signal transduction in embryonic induction. We, therefore, started a systematic search to identify signal transduction pathways which are activated during embryonic induction and specifically during neural induction. We showed previously that the protein kinase C and cAMP pathways mediate neural induction inXenopus laevis. Here, we investigated whether cGMP is also involved in the early development of the nervous system. We measured the cGMP content of whole embryos at embryonic stages which mark important events in the early development of the nervous system, as well as in the developing neural tissue itself, after this was induced from ectoderm by dorsal mesoderm. No changes in cGMP content were found, either in whole embryos at different developmental stages, or in developing neural tissue from these stages. We also found no evidence for the presence of nitroprusside stimulatable guanylate cyclase in these developmental stages. A cGMP analogue, 8-Br-cGMP, was not able to induce neural tissue, either alone or in combination with known neural inducers, the phorbol ester TPA and 8-Br-cAMP. 8-Br-cGMP also had no negative influence on the neural inducing ability of dorsal mesoderm or TPA, alone or in combination with 8-Br-cAMP. We conclude that cGMP has no role in the early development of the central nervous system inXenopus laevis. This conclusion underlines the specificity of the signal transduction pathways (PKC and cAMP pathways) that do mediate neural induction.     

Neurodegenerative Erkrankungen des Kindesalters

The understanding of neurodegenerative diseases of childhood has been changing rapidly in recent times: not only is the number of different diseases and underlying genetic defects steadily increasing, approaches to diagnosis and treatment have also developed because of recent technological and therapeutic advances relating to this group of disorders. New gene defects have been identified that provide a basis for understanding the molecular mechanisms underlying this group of diseases, and for the development of targeted therapies. This review focuses predominantly on one of the most common groups of diseases leading to degeneration of the central nervous system, neuronal ceroid lipofuscinosis (NCL). The number of NCL-causing genes and knowledge about genotype–phenotype correlations has been growing over the past few years and the first therapies have been developed. Hence, this group of diseases represents the rapid scientific development in the field of rare neurodegenerative diseases in childhood very well.     

A role for leptin in sexual maturation and puberty?

Leptin, the ob gene product, is involved in the regulation of body weight in rodents, primates and humans. It provides a molecular basis for the lipostatic theory of the regulation of energy balance. White adipose tissue and placenta are the main sites of leptin synthesis. There is also evidence of ob gene expression in brown fat. Leptin seems to play a key role in the control of body fat stores by coordinated regulation of feeding behaviour, metabolic rate, autonomic nervous system regulation and body energy balance. Apart from the function of leptin in the central nervous system on the regulation of energy balance, it may well be one of the hormonal factors that signal to the brain the body's readiness for sexual maturation and reproduction. During late pregnancy and at birth when maternal fat stores have been developed, leptin levels are high. During these developmental stages leptin could be a messenger molecule signalling the adequacy of the fat stores for reproduction and maintenance of pregnancy. At later stages of gestation leptin could signal the expansion of fat stores in order to prepare the expectant mother for the energy requirements of full-term gestation, labour and lactation. Leptin serum concentrations change during pubertal development in rodents, primates and humans. In girls, leptin serum concentrations increase dramatically as pubertal development proceeds. The pubertal rise in leptin levels parallels the increase in body fat mass. In contrast, leptin levels increase shortly before and during the early stages of puberty in boys and decline thereafter. Testosterone has been found to suppress leptin synthesis by adipocytes both in vivo and in vitro. The decline of leptin levels in late puberty in boys accompanies increased androgen production during that time and most likely reflects suppression of leptin by testosterone and a decrease in fat mass and relative increase in muscle mass during late puberty in males. This overview focuses on those topics of leptin research which are of particular interest in reproductive and adolescent medicine.     

DNA vaccines: progress and challenges

In the years following the publication of the initial in vivo demonstration of the ability of plasmid DNA to generate protective immune responses, DNA vaccines have entered into a variety of human clinical trials for vaccines against various infectious diseases and for therapies against cancer, and are in development for therapies against autoimmune diseases and allergy. They also have become a widely used laboratory tool for a variety of applications ranging from proteomics to understanding Ag presentation and cross-priming. Despite their rapid and widespread development and the commonplace usage of the term "DNA vaccines," however, the disappointing potency of the DNA vaccines in humans underscores the challenges encountered in the efforts to translate efficacy in preclinical models into clinical realities. This review will provide a brief background of DNA vaccines including the insights gained about the varied immunological mechanisms that play a role in their ability to generate immune responses.