Peripheral withdrawal recruits distinct central nuclei in morphine-dependent rats

This study examined if brain pathways in morphine-dependent rats are activated by opioid withdrawal precipitated outside the central nervous system. Withdrawal precipitated with a peripherally acting quaternary opioid antagonist (naloxone methiodide) increased Fos expression but caused a more restricted pattern of neuronal activation than systemic withdrawal (precipitated with naloxone which enters the brain). There was no effect on locus coeruleus and significantly smaller increases in Fos neurons were produced in most other areas. However in the ventrolateral medulla (A1/C1 catecholamine neurons), nucleus of the solitary tract (A2/C2 catecholamine neurons), lateral parabrachial nucleus, supramamillary nucleus, bed nucleus of the stria terminalis. accumbens core and medial prefrontal cortex no differences in the withdrawal treatments were detected. We have shown that peripheral opioid withdrawal can affect central nervous system pathways. Crown Copyright (C) 2001 Published by Elsevier Science Ltd. All rights reserved.

Cervical mobilisation: concurrent effects on pain, sympathetic nervous system activity and motor activity

Recent findings that spinal manual therapy (SMT) produces concurrent hypoalgesic and sympathoexcitatory effects have led to the proposal that SMT may exert its initial effects by activating descending inhibitory pathways from the dorsal periaqueductal gray area of the midbrain (dPAG). In addition to hypoalgesic and sympathoexcitatory effects, stimulation of the dPAG in animals has been shown to hal e a facilitatory effect on motor activity. This study sought to further investigate the proposal regarding SMT and the FAG by including a test of motor function in addition to the variables previously investigated, Using a condition randomised, placebo-controlled, double blind, repeated measures design, 30 subjects with mid to lon er cervical spine pain of insidious onset participated in the study. The results indicated that the cervical mobilisation technique produced a hypoalgesic effect as revealed by increased pressure pain thresholds on the side of treatment (P = 0.0001) and decreased resting visual analogue scale scores (P = 0.049). The treatment technique also produced a sympathoexcitatory effect with an increase in skin conductance (P < 0.002) and a decrease in skin temperature (P = < 0.02). There was a decrease in superficial neck flexor muscle activity (P < 0.0002) at the lower levels of a staged cranio-cervical flexion test. This could imply facilitation of the deep neck flexor muscles with a decreased need for co-activation of the superficial neck flexors, The combination of all findings,would support the proposal that SMT may, at least initially, exert part of its influence via activation of the PAG, (C) 2000 Harcourt Publishers Ltd.

Embryonic development of the nervous system of the temnocephalid flatworm Craspedella pedum

The nervous system of temnocephalid flatworms consists of the brain and three pairs of longitudinal connectives extending into the trunk and tail. The connectives are crosslinked by an invariant number of regularly spaced commissures. Branches of the connectives innervate the tentacles of the head and the sucker organ in the tail. A set of nerve rings encircling the pharynx and connected to the brain and connectives constitute the pharyngeal nervous system. The nervous system is formed during early embryogenesis when the embryo represents a multilayered mesenchymal mass of cells. Gastrulation and the formation of separate epithelial germ layers that characterize most other animal groups are absent. The brain arises as a bilaterally symmetric condensation of postmitotic cells in the deep layers of the anterior region of the embryonic mesenchyme. The pattern of axon outgrowth, visualized by labeling with anti-acetylated tubulin (acTub) antibody, shows marked differences from the pattern observed in other flatworm taxa. in regard to the number of neurons that express the acTub epitope. Acetylated tubulin is only expressed in neurons that form long axon tracts. In other flatworm species, such as the typhloplanoid Mesostoma and the polyclad Imogine, which were investigated by us with the acTub antibody (Hartenstein and Ehlers [2000] Dev. Genes Evol. 210:399-415; Younossi-Hartenstein and Hartenstein [2000] Dev. Genes Evol. 210:383-398), only a small number of pioneer neurons become acTub positive during the embryonic period. By contrast, in temnocephalids, most, if not all, neurons express acTub and form long, large-diameter axons. Initially, the brain commissure, pharyngeal nerve ring, and the connectives are laid down. Commissural tracts and tentacle nerves branching off the connectives appear later. We speculate that the precocious differentiation of the nervous system may be related to the fact that temnocephalids move by muscle action, and possess a massive and complex muscular system when they hatch. In addition, they have muscular specializations such as the anterior tentacles and the posterior sucker that are used as soon as they hatch. By contrast, juveniles of Mesostoma and larvae of polyclads move predominantly by ciliary action that may not require a complex neural circuitry for coordination. (C) 2001 Wiley-Liss, Inc.

Acquired central diabetes insipidus in children: A 12 year Brisbane experience

Objective: To study the clinical, endocrine and radiological features and progress of children presenting with acquired diabetes insipidus (CDI). Methodology: Chart review of children presenting because of CDI to Brisbane paediatric endocrine clinics between 1987 and 1999. Results: Thirty-nine children (female/male ratio 21/18) aged 0.1-15.4 years (mean age 6.7 years) were identified. Aetiologies were head trauma or familial in eight cases (20.5%) each, central nervous system (CNS) tumours in five cases (12.8%), CNS malformations in four cases (10.2%), histiocytosis in three cases (7%) and hypoxia and infection in two cases (5.1%) each. Seven cases (17.9%) remain undiagnosed. Of the 32 (82%) cases with isolated anti-diuretic hormone deficiency at presentation, 24 cases (61.5%) experienced no further endocrine deficit. Additional endocrine deficits occurred mainly in the tumour or undiagnosed groups. On follow-up brain magnetic resonance imaging (MRI) scans in the seven undiagnosed cases, six patients bad mild or no change and one patient had marked improvement of MRI findings. These changes occurred 10-48 months (mean 18 months) after presentation. Conclusions: Children without an aetiological diagnosis for the uncommon condition of acquired CDI require careful follow-up. More intensive investigation at presentation (e.g. estimation of cerebrospinal fluid human chorionic gonadotrophin) promises to lessen the number of such cases. Pituitary stalk biopsies should be reserved for those patients with progressive MRI changes. If these changes do not occur early, our experience suggests that follow-up MRI scans may need to be performed only yearly.

ATM, a central controller of cellular responses to DNA damage

Mutations in the ATM gene lead to the genetic disorder ataxia-telangiectasia. ATM encodes a protein kinase that is mainly distributed in the nucleus of proliferating cells. Recent studies reveal that ATM regulates multiple cell cycle checkpoints by phosphorylating different targets at different stages of the cell cycle. ATM also functions in the regulation of DNA repair and apoptosis, suggesting that it is a central regulator of responses to DNA double-strand breaks.

Systemic administration of interleukin-1 beta activates select populations of central amygdala afferents

The central nucleus of the amygdala (CeA) is activated robustly by an immune challenge such as the systemic administration of the proinflammatory cytokine interleukin-1beta (IL-1beta). Because IL-1beta is not believed to cross the blood-brain barrier in any significant amount, it is likely that IL-1beta elicits CeA cell recruitment by means of activation of afferents to the CeA. However, although many studies have investigated the origins of afferent inputs to the CeA, we do not know which of these also respond to IL-1beta. Therefore, to identify candidate neurons responsible for the recruitment of CeA cells by an immune challenge, we iontophoretically deposited a retrograde tracer, cholera toxin b-subunit (CTb), into the CeA of rats 7 days before systemic delivery of IL-1beta (1 mug/kg, i.a.). By using combined immunohistochemistry, we then quantified the number of Fos-positive CTb cells in six major regions known to innervate the CeA. These included the medial prefrontal cortex, paraventricular thalamus (PVT), ventral tegmental area, parabrachial nucleus (PB), nucleus tractus solitarius, and ventrolateral medulla. Our results show that after deposit of CTb into the CeA, the majority of double-labeled cells were located in the PB and the PVT, suggesting that CeA cell activation by systemic IL-1beta is likely to arise predominantly from cell bodies located in these regions. These findings may have significant implications in determining the central pathways involved in generating acute central responses to a systemic immune challenge. J. Comp. Neurol. 452:288-296, 2002. (C) 2002 Wiley-Liss, Inc.

Opposing roles for medial and central amygdala in the initiation of noradrenergic cell responses to a psychological stressor

Psychological stressors trigger the activation of medullary noradrenergic cells, an effect that has been shown to depend upon yet-to-be-identified structures located higher in the brain. To test whether the amygdala is important in this regard, we examined the effects of amygdala lesions on noradrenergic cell responses to restraint, and also looked at whether any amygdala cells that respond to restraint project directly to the medulla. Ibotenic acid lesions of the medial amygdala completely abolished restraint-induced Fos expression in A1 and A2 noradrenergic cells. In contrast, lesions of the central amygdala actually facilitated noradrenergic cell responses to restraint. Tracer deposits in the dorsomedial (but not ventrolateral) medulla retrogradely labelled many cells in the central nucleus of the amygdala, but none of these cells expressed Fos in response to restraint. These data suggest for the first time that the medial amygdala is critical to the activation of medullary noradrenergic cells by a psychological stressor whereas the central nucleus exerts an opposing, inhibitory influence upon noradrenergic cell recruitment. The initiation of noradrenergic cell responses by the medial amygdala does not involve a direct projection to the medulla. Accordingly, a relay through some other structure, such as the hypothalamic paraventricular nucleus, warrants careful consideration.

The embryonic development of the bodywall and nervous system of the cestode flatworm Hymenolepis diminuta

Cestodes (tapeworms) are a derived, parasitic clade of the phylum Platyhelminthes (flatworms). The cestode body wall represents an adaptation to its endoparasitic lifestyle. The epidermis forms a nonciliated syncytium, and both muscular and nervous system are reduced. Morphological differences between cestodes and free-living flatworms become apparent already during early embryogenesis. Cestodes have a complex life cycle that begins with an infectious larva, called the oncosphere. In regard to cell number, cestode oncospheres are among the simplest multicellular organisms, containing in the order of 50-100 cells. As part of our continuing effort to analyze embryonic development in flatworms, we describe here the staining pattern obtained with acTub in embryos and larvae of the cestode Hymenolepis diminuta and, briefly, the monogenean Neoheterocotyle rhinobatidis. In addition, we labeled the embryonic musculature of Hymenolepis with phalloidin. In Hymenolepis embryos, two different cell types that we interpret as neurons and epidermal gland cells express acTub. There exist only two neurons that develop close to the midline at the anterior pole of the embryo. The axons of these two neurons project posteriorly into the center of the oncosphere, where they innervate the complex of muscles that is attached to the booklets. In addition to neurons, acTub labels a small and invariant set of epidermal gland cells that develop at superficial positions, anteriorly adjacent to the neurons, in the dorsal midline, and around the posteriorly located hooklets. During late stages of embryogenesis they spread and form a complete covering of the embryo. We discuss these data in the broader context of platyhelminth embryology.

Analysis of the mouse transcriptome for genes involved in the function of the nervous system

We analyzed the mouse Representative Transcript and Protein Set for molecules involved in brain function. We found full-length cDNAs of many known brain genes and discovered new members of known brain gene families, including Family 3 G-protein coupled receptors, voltage-gated channels, and connexins. We also identified previously unknown candidates for secreted neuroactive molecules. The existence of a large number of unique brain ESTs suggests an additional molecular complexity that remains to be explored. A list of genes containing CAG stretches in the coding region represents a first step in the potential identification of candidates for hereditary neurological disorders.

Dissection of peripheral and central endogenous opioid modulation of systemic interleukin-1 beta responses using c-fos expression in the rat brain

In opiate addicts or patients receiving morphine treatment, it has been reported that the immune system is often compromised. The mechanisms responsible for the adverse effects of opioids on responses to infection are not clear but it is possible that central and/or peripheral opioid receptors may be important. We have utilised an experimental immune challenge model in rats, the systemic administration of the human pro-inflammatory cytokine interleukin-1 beta (IL-1 beta) to study the effects of selectively blocking peripheral opioid receptors only (using naloxone methiodide) or after blocking both central and peripheral opioid receptors (using naloxone). Pre-treatment with naloxone methiodide decreased (15%) IL-1 beta-induced Fos-immunoreactivity (Fos-IR) in medial parvocellular paraventricular nucleus (mPVN) corticotropin-releasing hormone (CRH) neurons but increased responses in the ventrolateral medulla (VLM) C1 (65%) and nucleus tractus solitarius (NTS) A2 (110%) catecholamine cell groups and area postrema (136%). However no effect of blocking peripheral opioid receptors was detected in the central nucleus of the amygdala (CeA) or dorsal bed nucleus of the stria terminalis (BNST). We next determined the effect of blocking both central and peripheral opioid receptors with naloxone and, when compared to the naloxone methiodide pre-treated group, a further 60% decrease in Fos-IR mPVN CRH neurons induced by IL-1 beta was detected, which was attributed to block of central opioid receptors. Similar comparisons also detected decreases in Fos-IR neurons induced by IL-1 beta in the VLM A1, VLM C1 and NTS A2 catecholamine cell groups, area postrema, and parabrachial nucleus. In contrast, pre-treatment with naloxone increased Fos-IR neurons in CeA (98%) and dorsal BNST (72%). These results provide novel evidence that endogenous opioids can influence central neural responses to systemic IL-1 beta and also suggest that the differential patterns of activation may arise because of actions at central and/or peripheral opioid receptors that might be important in regulating behavioural, hypothalamic-pituitary-adrenal axis and sympathetic nervous system responses during an immune challenge. (c) 2005 Elsevier Ltd. All rights reserved.

Immunocytochemistry and metamorphic fate of the larval nervous system of Triphyllozoon mucronatum (Ectoprocta : Gymnolaemata : Cheilostomata)

The development of gymnolaemate Ectoprocta includes a larval stage of either the coronate or the cyphonautes type. Herein, we provide the first description of the larval neural anatomy of a coronate larva using immunocytochemical methods. We used antibodies against the neurotransmitters serotonin and FMRFamide and followed the fate of immunoreactive cells through metamorphosis. The larval serotonergic nervous system of Triphyllozoon mucronatum consists of an apical commissure, one pair of lateral axons, a coronate nerve net, an internal nerve mesh, and one pair of axons innervating the frontal organ. FMRFamide is only found in the larval commissure and in the lateral axons. The entire serotonergic and FMRFamidergic nervous system is lost during metamorphosis and the adult neural structures form independent of the larval ones. In the postlarval zooid, both neurotransmitters are detected in the cerebral commissure, in cell bodies located at the base of the lophophore, and in neurites connecting these somata to the cerebral commissure. These findings differ significantly from that observed in other lophotrochozoans, where certain larval neural features are either incorporated in the adult nervous system and/or have inductive functions during its ontogeny. The occurrence of a larval commissure and the lack of a serotonergic or FMRFamidergic apical organ in T. mucronatum are unique among lophotrochozoan larvae, which usually have a distinct apical organ containing serotonergic cells. Our data show that the larval neuroanatomy and the processes that underlie the reorganization of larval organ systems during metamorphosis may vary much more among lophotrochozoan taxa than previously thought.

Non-coding RNAs in the nervous system

Increasing evidence suggests that the development and function of the nervous system is heavily dependent on RNA editing and the intricate spatiotemporal expression of a wide repertoire of non-coding RNAs, including micro RNAs, small nucleolar RNAs and longer non-coding RNAs. Non-coding RNAs may provide the key to understanding the multi-tiered links between neural development, nervous system function, and neurological diseases.

The roles of exercise-induced immune system disturbances in the pathology of heat stroke - The dual pathway model of heat stroke

Heat stroke is a life-threatening condition that can be fatal if not appropriately managed. Although heat stroke has been recognised as a medical condition for centuries, a universally accepted definition of heat stroke is lacking and the pathology of heat stroke is not fully understood. Information derived from autopsy reports and the clinical presentation of patients with heat stroke indicates that hyperthermia, septicaemia, central nervous system impairment and cardiovascular failure play important roles in the pathology of heat stroke. The current models of heat stroke advocate that heat stroke is triggered by hyperthermia but is driven by endotoxaemia. Endotoxaemia triggers the systemic inflammatory response, which can lead to systemic coagulation and haemorrhage, necrosis, cell death and multi-organ failure. However, the current heat stroke models cannot fully explain the discrepancies in high core temperature (Tc) as a trigger of heat stroke within and between individuals. Research on the concept of critical Tc: as a limitation to endurance exercise implies that a high Tc may function as a signal to trigger the protective mechanisms against heat stroke. Athletes undergoing a period of intense training are subjected to a variety of immune and gastrointestinal (GI) disturbances. The immune disturbances include the suppression of immune cells and their functions, suppression of cell-mediated immunity, translocation of lipopolysaccharide (LPS), suppression of anti-LPS antibodies, increased macrophage activity due to muscle tissue damage, and increased concentration of circulating inflammatory and pyrogenic cytokines. Common symptoms of exercise-induced GI disturbances include diarrhoea, vomiting, gastrointestinal bleeding, and cramps, which may increase gut-related LPS translocation. This article discusses the current evidence that supports the argument that these exercise-induced immune and GI disturbances may contribute to the development of endotoxaemia and heat stroke. When endotoxaemia can be tolerated or prevented, continuing exercise and heat exposure will elevate Tc to a higher level (> 42 degrees C), where heat stroke may occur through the direct thermal effects of heat on organ tissues and cells. We also discuss the evidence suggesting that heat stroke may occur through endotoxaemia (heat sepsis), the primary pathway of heat stroke, or hyperthermia, the secondary pathway of heat stroke. The existence of these two pathways of heat stroke and the contribution of exercise-induced immune and GI disturbances in the primary pathway of heat stroke are illustrated in the dual pathway model of heat stroke. This model of heat stroke suggests that prolonged intense exercise suppresses anti-LPS mechanisms, and promotes inflammatory and pyrogenic activities in the pathway of heat stroke.

Thalamic paraventricular nucleus lesions facilitate central amygdala neuronal responses to acute psychological stress

The thalamic paraventricular nucleus (PVT) is activated by stress and projects to forebrain structures directly implicated in processing stress-related information. Accordingly, it seems likely the PVT plays an important role in modulating stress responses. We examined effects of excitotoxic PVT lesions on forebrain Fos expression patterns normally elicited by an acute psychological stressor. PVT lesions significantly increased stress-induced Fos in a key stress-processing region, the central amygdala.