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Direct projections from the central amygdaloid nucleus to the globus pallidus and substantia nigra in the cat.

Employing both anterograde and retrograde axonal tracing, we investigated direct projections from the central amygdaloid nucleus to the basal ganglia in the cat. The anterograde axonal tracing of Phaseolus vulgaris-leucoagglutinin revealed that projection fibers from the central amygdaloid nucleus to the basal ganglia ended in the globus pallidus (the feline homolog to the external segment of the globus pallidus of primates) and substantia nigra. The amygdalopallidal fibers terminated chiefly in the medial most part of the globus pallidus at its caudal level. The amygdalonigral fibers terminated densely in the substantia nigra pars lateralis, and moderately in the dorsolateral part of the substantia nigra pars reticulata; none of them were found to end in the substantia nigra pars compacta. Both of the amygdalopallidal and amygdalonigral projections were ipsilateral. These neuronal connections were confirmed by retrograde axonal tracing of cholera toxin B subunit in the second set of the experiments: The cells of origin of the amygdalopallidal and amygdalonigral projections were located predominantly in the lateral part of the central amygdaloid nucleus, and additionally in the intercalated cell islands of the amygdala. Most of them were of small bipolar or multipolar type. The cells projecting to the globus pallidus were preferentially distributed at the rostral levels of the central nucleus and intercalated cell islands of the amygdaloid complex, while those projecting to the substantia nigra were mainly located at the caudal levels of these amygdaloid subdivisions. In the third set of the experiments, sequential double-antigen immunofluorescence histochemistry for transported cholera toxin B subunit and horseradish peroxidase showed that some single neurons in the lateral part of the central amygdaloid nucleus, particularly at its middle level, issued axon collaterals to both the globus pallidus and substantia nigra pars lateralis. The results of the present study indicate that the central amygdaloid nucleus sends projection fibers to the globus pallidus and substantia nigra possibly to exert a limbic influence upon forebrain motor mechanisms.

Amygdala↗

The stress-reaction process and the adaptive modification and reorganization of neuronal networks.

On the basis of a comprehensive definition of the stress-reaction process (SRP), the neurobiological and psychological consequences of this process, which are elicited by either controllable or uncontrollable stress, are described. We conclude that controllable stress triggers the stabilization and facilitation of neuronal networks involved in the generation of appropriate patterns of appraisal and coping, whereas uncontrollable stress favors the extinction of inappropriate patterns and the reorganization of neuronal connections underlying certain inappropriate behaviors. Both controllable and uncontrollable stress-reaction processes are therefore inherent challenges to the development and essential prerequisites of the adaptation of an individual's behavior to the demands of the ever-changing external world. The overabundance, as well as the lack, of either kind of SRP may lead to different psychodevelopmental failures and psychiatric disturbances.

Adaptation, Physiological↗

Acute and long-term proteome changes induced by oxidative stress in the developing brain.

The developing mammalian brain experiences a period of rapid growth during which various otherwise innocuous environmental factors cause widespread apoptotic neuronal death. To gain insight into developmental events influenced by a premature exposure to high oxygen levels and identify proteins engaged in neurodegenerative and reparative processes, we analyzed mouse brain proteome changes at P7, P14 and P35 caused by an exposure to hyperoxia at P6. Changes detected in the brain proteome suggested that hyperoxia leads to oxidative stress and apoptotic neuronal death. These changes were consistent with results of histological and biochemical evaluation of the brains, which revealed widespread apoptotic neuronal death and increased levels of protein carbonyls. Furthermore, we detected changes in proteins involved in synaptic function, cell proliferation and formation of neuronal connections, suggesting interference of oxidative stress with these developmental events. These effects are age-dependent, as they did not occur in mice subjected to hyperoxia in adolescence.

Animals↗

Regional distribution of tau, beta-amyloid and beta-amyloid precursor protein in the Alzheimer's brain: a quantitative immunolabelling study.

Regional variation in the distribution of SP and NFT within the brain is well documented. Consideration of such variation is potentially of help in formulating models of disease progression. Several models propose that pathological changes in Alzheimer's disease (AD) progress in a step-wise fashion along neuronally connected regions. In this study, we measured tau, Abeta and betaAPP load in different brain regions and examined our results against models of AD progression. Blocks of brain tissue from 45 AD and 15 control cases were immunolabelled for tau, Abeta and betaAPP. Immunolabelled areas were measured as a proportion of the area of the field. Tau load was almost twice as great in the entorhinal cortex than elsewhere in the brain and was least in the cingulate gyrus. In contrast, Abeta was greatest in the cingulate gyrus and least in the entorhinal cortex. BetaAPP rankings were similar to those of tau. Thus the site with the greatest Abeta load (cingulate cortex) had the least tau and the site with the greatest tau load (entorhinal cortex) had the least Abeta. The entorhinal and cingulate cortex are neuronally interconnected. Our results might be explained on the basis that a neurone with its cell body in the entorhinal cortex and axonal terminals in the cingulate cortex shows predominately tau pathology in relation to the cell body and predominately Abeta pathology in relation to its axonal terminals. We conclude that our observations are consistent with previously described models of AD progression. It is possible that tau-rich neurones are associated through their projections to Abeta rich sites. Further work of this kind analysing differential pathological profiles in interconnected brain regions may contribute to refining this model.

Aged↗

Hypothyroidism selectively reduces the rate and amount of transport for specific SCb proteins in the hyt/hyt mouse optic nerve.

Thyroid hormone significantly affects molecular and neuroanatomical properties of the developing nervous system. Altered connectivity in hypothyroidism may reflect reductions in process growth, alterations in process maintenance, or changes in synaptogenesis or synaptic maintenance. These events are dependent on microtubules, neurofilaments, microfilaments, and associated molecular components. Reductions in delivery of microtubules and neurofilaments to the distal axon by slow component a (SCa) of axonal transport may contribute to the neuroanatomical abnormalities of hypothyroidism (Stein et al., J Neurosci Res 28:121-133, 1991). However, hypothyroidism might also affect the axon and synaptic connections by altering slow component b (SCb), which includes actin microfilaments and proteins that contribute to synaptic function, i.e., clathrin, HSC70 (clathrin uncoating ATPase), spectrin, and calmodulin. To determine the effect of hypothyroidism on SCb proteins, slow axonal transport was analyzed in optic nerves of hyt/hyt hypothyroid mice, which have severe primary hypothyroidism, and euthyroid control mice. Clathrin, spectrin, HSC70, and actin showed significant reductions in transport velocity in hyt/hyt optic nerves relative to euthyroid nerves, but the transport rate for calmodulin was less affected. However, the amount of calmodulin was significantly elevated in hyt/hyt nerve over euthyroid nerves. Hypothyroidism selectively reduces transport of SCb proteins, which are thought to play significant roles in synaptic function and in the growth cone. The effects of hypothyroidism on microtubules and neurofilaments combined with actions on SCb suggest that changes in neuronal function associated with reduced thyroid hormone during development and maturity (i.e., alterations in neuronal connectivity, nerve conduction, and synaptic function) may be mediated in part by effects on slow axonal transport.

Actins↗

Regulation of thalamocortical patterning and synaptic maturation by NeuroD2.

During cortical development, both activity-dependent and genetically determined mechanisms are required to establish proper neuronal connectivity. While activity-dependent transcription may link the two processes, specific transcription factors that mediate such a process have not been identified. We identified the basic helix-loop-helix (bHLH) transcription factor Neurogenic Differentiation 2 (NeuroD2) in a screen for calcium-regulated transcription factors and report that it is required for the proper development of thalamocortical connections. In neuroD2 null mice, thalamocortical axon terminals fail to segregate in the somatosensory cortex, and the postsynaptic barrel organization is disrupted. Additionally, synaptic transmission is defective at thalamocortical synapses in neuroD2 null mice. Total excitatory synaptic currents are reduced in layer IV in the knockouts, and the relative contribution of AMPA and NMDA receptor-mediated currents to evoked responses is decreased. These observations indicate that NeuroD2 plays a critical role in regulating synaptic maturation and the patterning of thalamocortical connections.

2-Amino-5-phosphonovalerate↗

Axonal damage associated with enlargement of ventricles during hydrocephalus: a silver impregnation study.

Motor and cognitive deficits are commonly associated with hydrocephalus. Although the mechanisms responsible for these impairments have not been confirmed, neuronal cell death and axon degeneration may play an important role, and have long lasting consequences on neuronal connectivity. The goal of this study was to determine if neural degeneration occurred during hydrocephalus in structures anatomically related to cognitive motor functioning, namely, the sensorimotor cortex, neostriatum, hippocampus and corpus callosum. Neural damage, as visualized by silver staining, was examined in adult rats 2-10 weeks after obstructive hydrocephalus was induced by kaolin injection into the cisterna magna. In mild or moderate hydrocephalus, mostly occurring 2-6 weeks after kaolin injections, silver-labeled axons were scattered in the white matter of the sensorimotor cortex, corpus callosum, neostriatum, and hippocampus. In severe hydrocephalus, 10 weeks after kaolin injections, axon degeneration was more extensive in these areas, as well as in layers IV through VI of the sensorimotor cortex. Axons in the subiculum and the fimbria were heavily labeled, suggesting damage to hippocampal afferent and efferent fibers. In contrast, neuron cell death was rarely observed at any stage of hydrocephalus. The major pathological change of brain regions involved in motor and learning functions during hydrocephalus is axon degeneration, and this degeneration is correlated with an enlargement of the cerebral ventricles.

Animals↗

Stabilization of tetramethylbenzidine (TMB) reaction product at the electron microscopic level by ammonium molybdate.

The ability to use the tetramethylbenzidine (TMB) method for studying neuronal connections at the electron microscopic level is often difficult because the conditions of osmification and dehydration used in processing the tissue may result in significant loss and/or decreased electron density of the reaction product. In the present study, we report that stabilization of TMB reaction product with 5% ammonium molybdate (AM) prior to osmificating the tissue results in the formation of TMB-AM crystals that are many times more electron dense and resistant to ethanol extraction than non-stabilized TMB crystals. The nature of the chemical interaction that underlies the stabilization of TMB by AM is uncertain, but it may involve the formation of an insoluble salt between molybdic ions and the TMB polymer. The use of this simple procedure increases the sensitivity of the TMB procedure at the electron microscopic level and may be used to label neuronal pathways in the peripheral and central nervous systems with equal success.

Animals↗

Two-photon imaging of synaptic plasticity and pathology in the living mouse brain.

Two-photon microscopy (TPM) has become an increasingly important tool for imaging the structure and function of brain cells in living animals. TPM imaging studies of neuronal structures over intervals ranging from seconds to years have begun to provide important insights into the structural plasticity of synapses and the modulating effects of experience in the intact brain. TPM has also started to reveal how neuronal connections are altered in animal models of neurodegeneration, acute brain injury, and cerebrovascular disease. Here, we review some of these studies with special emphasis on the degree of structural dynamism of postsynaptic dendritic spines in the adult mouse brain as well as synaptic pathology in mouse models of Alzheimer's disease and cerebral ischemia. We also discuss technical considerations that are critical for the acquisition and interpretation of data from TPM in vivo.

Absorptiometry, Photon↗

Altered cyclic AMP levels in specific cardiovascular brain centers of spontaneously hypertensive rats (SHR).

The possible participation of cAMP in central regulation of arterial blood pressure was investigated in spontaneously hypertensive rats (SHR). Cyclic AMP concentrations of 36 microdissected individual brain areas-including primary and higher cardiovascular centers-were measured in adult SHR and compared with those of normotensive control rats of the same strain and age. In the adult SHR, elevated cAMP concentrations were found in brain areas which are in close connection with the central regulation of blood pressure: nucleus tractus solitarii, A1- and A2- catecholaminergic cell groups in the medulla oblongata, locus coeruleus, central grey matter (subnucleus medialis), and certain cortical areas (especially cingulate cortex and hippocampus). On the other hand, hypothalamic cell groups which have been also suggested to control blood pressure, such as paraventricular, anterior, ventromedial, dorsomedial and posterior hypothalamic nuclei, show lower concentrations of cAMP in the SHR than in normotensive controls. Cyclic AMP levels in 19 other brain areas of SHR which seem to be not involved in mechanisms of central blood pressure regulation practically do not differ from the values of normotensive rats. The results suggest that cAMP-dependent processes are involved in the regulatory mechanisms of central blood pressure control. The brain areas which show alterations of cAMP-levels are also distinguished by close neuronal connections to the baroreceptor reflex arc. It is supposed that these areas represent modulatory higher centers capable to affect baroreceptor reflex function.

Animals↗

Formation and maturation of the vestibular ganglion.

The morphologic development of the vestibular ganglia with their peripheral neuronal connections was followed from terminal mitosis until the adult stage (CBA/CBA mouse). Schwann cells enclose vestibular ganglion cells and their peripheral nerve fibres already on the 15th-16th gestational days. The morphological basis for at least some physiological activity is present already before birth. As compared with the spiral ganglion, the vestibular ganglion and its peripheral pathways become mature as much as 5-7 days earlier. An adult morphology is reached during the first postnatal week.

Animals↗

Manipulation of gene expression in the mammalian nervous system: application in the study of neurite outgrowth and neuroregeneration-related proteins.

A fundamental issue in neurobiology entails the study of the formation of neuronal connections and their potential to regenerate following injury. In recent years, an expanding number of gene families has been identified involved in different aspects of neurite outgrowth and regeneration. These include neurotrophic factors, cell-adhesion molecules, growth-associated proteins, cytoskeletal proteins and chemorepulsive proteins. Genetic manipulation technology (transgenic mice, knockout mice, viral vectors and antisense oligonucleotides) has been instrumental in defining the function of these neurite outgrowth-related proteins. The aim of this paper is to provide an overview of the above-mentioned four approaches to manipulate gene expression in vivo and to discuss the progress that has been made using this technology in helping to understand the molecular mechanisms that regulate neurite outgrowth. We will show that work with transgenic mice and knockout mice has contributed significantly to the dissection of the function of several proteins with a key role in neurite outgrowth and neuronal survival. Recently developed viral vectors for gene transfer in postmitotic neurons have opened up new avenues to analyze the function of a protein following local expression in naive adult rodents. The initial results with viral vector-based gene transfer provide a conceptual framework for further studies on genetic therapy of neuroregeneration and neurodegenerative diseases.

Animals↗

Evidence for a role of GABA and Mas-allatotropin in photic entrainment of the circadian clock of the cockroach Leucophaea maderae.

Accumulating evidence suggests that the accessory medulla is the location of the circadian pacemaker in the fruit fly Drosophila melanogaster and the cockroach Leucophaea maderae. gamma-Aminobutyric acid (GABA) and Mas-allatotropin are two putative neurotransmitters, in the accessory medulla in the cockroach Leucophaea maderae. Neurons immunoreactive to the neuropeptide Mas-allatotropin are local neurons with arborizations in the noduli of the accessory medulla, while GABA-immunoreactive neurons connect the noduli of the accessory medulla to the medulla and to the lamina via processes in the distal tract. Injections of GABA and Mas-allatotropin into the vicinity of the accessory medulla resulted in stable phase-dependent resetting of the circadian locomotor activity of the cockroach. The resulting phase response curves closely matched light-dependent phase response curves, suggesting that both substances play a role in circuits relaying photic information from circadian photoreceptors to the central pacemaker.

Animals↗

Transcranial magnetic stimulation: the method and application.

Transcranial magnetic stimulation is a noninvasive method for stimulation of brain that is based on the ability of magnetic field to penetrate skull and brain meninges, subsequently inducing electric current in the brain tissues that produces neuronal depolarization and generation of action potentials. Moreover, transcranial magnetic stimulation has effects on neurochemical and synaptic processes in neurons. Due to its easy use and relatively fair side effects, nowadays, transcranial magnetic stimulation is widely used in neurosciences and medicine. The main areas of transcranial magnetic stimulation application are: 1) the investigation of cortical and spinal excitability, 2) the investigation of neuronal plasticity, 3) the investigation of neuronal connectivity, 4) functional mapping, and 5) the treatment of some neurological and psychiatric disorders. Transcranial magnetic stimulation alone or in combination with other noninvasive neuroimaging (PET--positron emission topography, MRI--magnetic resonance imaging) and neurofunctional (EEG--electroencephalography, ERP--event-related potentials, fMRI--functional magnetic resonance imaging) methods allows conducting research on brain functions. Thus, transcranial magnetic stimulation is suitable as a diagnostic tool in neurologic and neuropsychiatric brain research.

Action Potentials↗

The role of neurotrophins in neurotransmitter release.

The neurotrophins (NTs) have recently been shown to elicit pronounced effects on quantal neurotransmitter release at both central and peripheral nervous system synapses. Due to their activity-dependent release, as well as the subcellular localization of both protein and receptor, NTs are ideally suited to modify the strength of neuronal connections by "fine-tuning" synaptic activity through direct actions at presynaptic terminals. Here, using BDNF as a prototypical example, the authors provide an update of recent evidence demonstrating that NTs enhance quantal neurotransmitter release at synapses through presynaptic mechanisms. The authors further propose that a potential target for NT actions at presynaptic terminals is the mechanism by which terminals retrieve synaptic vesicles after exocytosis. Depending on the temporal demands placed on synapses during high-frequency synaptic transmission, synapses may use two alternative modes of synaptic vesicle retrieval, the conventional slow endosomal recycling or a faster rapid retrieval at the active zone, referred to as "kiss-and-run." By modulating Ca2+ microdomains associated with voltage-gated Ca2+ channels at active zones, NTs may elicit a switch from the slow to the fast mode of endocytosis of vesicles at presynaptic terminals during high-frequency synaptic transmission, allowing more reliable information transfer and neuronal signaling in the central nervous system.

Animals↗

The microtubule-severing protein Spastin is essential for axon outgrowth in the zebrafish embryo.

Hereditary spastic paraplegia (HSP) is a collection of neurological disorders characterized by developmental failure or degeneration of motor axons in the corticospinal tract and progressive lower limb spasticity. SPG4 mutations are the most common cause of autosomal dominant HSP and Spastin (the SPG4 gene product) is a microtubule severing protein that shares homology with katanin, the microtubule severing activity of which promotes axon growth in cultured neurons. Given the sequence and functional similarity between spastin and katanin, we hypothesized that spastin promotes the dynamic disassembly and remodelling of microtubules required for robust, properly directed motor axon outgrowth. To investigate this hypothesis, we cloned the zebrafish spg4 orthologue and used morpholino antisense oligonucleotides directed against the translation start site and the intron 7-8 splice donor site to knock down spastin function in the developing zebrafish embryo. Reduced spg4 function caused dramatic defects in motor axon outgrowth without affecting the events driving the initial specification of motor neurones. Other neuronal subtypes also exhibited a requirement for spg4 function, since spg4 knock down caused both widespread defects in neuronal connectivity and extensive CNS-specific apoptosis. Our results reveal a critical requirement for spastin to promote axonal outgrowth during embryonic development, and they validate the zebrafish embryo as a novel model system to dissect the pathogenetic mechanisms underlying HSP. Taken together with other recent studies, our findings suggest that axon outgrowth defects may be a common feature of childhood SPG3A and SPG4 cases.

Adenosine Triphosphatases↗

Olivo-cerebellar cluster-based universal control system.

The olivo-cerebellar network plays a key role in the organization of vertebrate motor control. The oscillatory properties of inferior olive (IO) neurons have been shown to provide timing signals for motor coordination in which spatio-temporal coherent oscillatory neuronal clusters control movement dynamics. Based on the neuronal connectivity and electrophysiology of the olivo-cerebellar network we have developed a general-purpose control approach, which we refer to as a universal control system (UCS), capable of dealing with a large number of actuator parameters in real time. In this UCS, the imposed goal and the resultant feedback from the actuators specify system properties. The goal is realized through implementing an architecture that can regulate a large number of parameters simultaneously by providing stimuli-modulated spatio-temporal cluster dynamics.

Animals↗

Focal dystonia: advances in brain imaging and understanding of fine motor control in musicians.

This article reviews the neuroanatomic and neurophysiologic foundations of music performance and learning. Music performance is regarded as complex voluntary sensorimotor behavior that becomes automated during extensive practice with auditory feedback. It involves all motor, somatosensory, and auditory areas of the brain. Because of the life-long plasticity of neuronal connections, practicing a musical instrument results first in a temporary and later in a stable increase in the amount of nerve tissue devoted to various component tasks. Motor and somatosensory brain regions corresponding to specific subtasks of music performance are larger in musicians starting younger than age 10 years than in the general population. In rare cases, overuse of movement patterns may induce a degradation of motor memory that results in a loss of voluntary control of movements, called musician's cramp. Specific therapeutic options for this condition are reviewed.

Biomechanical Phenomena↗