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PubMed2000

Features of structural brain abnormality detected in first-episode psychosis.

OBJECTIVE: Structural magnetic resonance imaging (MRI) studies that focus on first-episode psychosis avoid some common confounds, such as chronicity of illness, treatment effects, and long-term substance abuse. However, such studies may select subjects with poor short-term treatment response or outcome. In this study, the authors focus on structural brain abnormalities in never or minimally treated patients who underwent MRI scanning early in their first episode of psychosis. METHOD: The authors examined 37 patients (13 medication naive, 24 previously treated) who were experiencing their first episode of psychosis; the mean duration of symptoms was short (31 weeks). These patients were comparable in age, gender, handedness, ethnicity, and parental socioeconomic status to a group of 25 healthy comparison subjects. A three-dimensional, inversion recovery prepared, fast spoiled gradient/recall in the steady state scan of the whole brain that used 1.5-mm contiguous sections was performed to acquire a T(1)-weighted data set. Human ratings of volumetric measurement of brain structures were performed with stereological techniques on three-dimensional reconstructed MRIs. RESULTS: The patient group had significant deficits in cortical gray matter, temporal lobe gray matter, and whole brain volume as well as significant enlargement of the lateral and third ventricles. Structural deviations were found in both treatment-naive and minimally treated subjects. No relationships were found between any brain matter volumes and positive or negative symptoms. CONCLUSIONS: Structural brain abnormalities were distributed throughout the cortex with particular decrement evident in gray matter. This feature is consistent with altered cell structure and disturbed neuronal connectivity, which accounts for the functional abnormality of psychosis.

Adult↗

PubMed1999

Spatial working memory in asymptomatic HIV-infected subjects.

Many clinical and research findings converge to indicate that frontal lobe, basal ganglia, and related neuronal connections are primarily involved in human immunodeficiency virus (HIV) infection; frontal lobe, mainly the prefrontal cortex, has a specialized role in working memory processes. This study focused on neuropsychological evaluation of the spatial component of working memory in a sample of 34 asymptomatic HIV-infected subjects as compared with 34 age- and sex-matched seronegative control subjects. A computer-administered test assessing spatial working memory was used for the neuropsychological evaluation. The findings did not show any spatial working memory impairment during the asymptomatic phase of HIV infection.

Adult↗

PubMed1996

Functional anatomy of human hippocampal formation and related structures.

Data on the internal organization, and neuronal connections of the human hippocampal formation and related structures of the limbic system are briefly reviewed. In the healthy brain, somatosensory, visual, and auditory input proceeds through neocortical core and belt fields to a variety of association areas, and from here the data is transported via long corticocortical pathways to the extended prefrontal association cortex. Tracts generated from this highest organization level of the brain guide the data via the frontal belt (premotor cortex) to the frontal core (primary motor area). The striatal and cerebellar loops provide the major routes for this data transfer. The main components of the limbic system (the hippocampal formation, the entorhinal region, and the amygdala) maintain a strategic position between the sensory and the motor association areas. Part of the stream of data from the sensory association areas to the prefrontal cortex branches off and eventually converges on the entorhinal region and the amygdala, These connections establish the afferent leg of the limbic loop. In addition, the limbic centers receive substantial input from nuclei processing viscerosensory information. The entorhinal region, the hippocampal formation, and the amygdala are densely interconnected. Important among these connections is the perforant path, which originates in the entorhinal cortex and projects to the hippocampal formation (fascia dentata, Ammon's horn, and subiculum). The subiculum projects to the amygdala, entorhinal region, mamillary nuclei, and anterior and midline thalamic nuclei. The hippocampal formation, the entorhinal region, and the amygdala generate the efferent leg of the limbic loop, which is directed toward the prefrontal cortex. Additional projections reach the key nuclei that control endocrine and autonomic functions. Furthermore, the amygdala exerts influence on all nonthalamic nuclei projecting in a nonspecific manner to the cerebral cortex (ie, the cholinergic magnocellular forebrain nuclei, the histaminergic tuberomamillary nucleus, the dopaminergic nuclei of the ventral tegmentum, the serotonergic anterior raphe nuclei, and the noradrenergic locus ceruleus). The limbic loop centers thus are in the unique strategic position to perform integration of exteroceptive sensory data of various sources with interoceptive stimuli from autonomic centers. Their efferent projections exert influence on both the prefrontal association cortex and the key centers controlling endocrine and autonomic functions.

Hippocampus↗

PubMed2005

Combining functional and diffusion tensor MRI.

Functional magnetic resonance imaging (fMRI) of the perceptual, motor, and cognitive capacities in humans is of increasing importance for basic and clinical neurosciences. The explanatory power of current fMRI techniques could be greatly expanded, however, if the pattern of the neuronal connections between the active cortical areas could likewise be visualized. In this study, we acquired blood-oxygenation level dependent (BOLD) fMRI signals during the stimulation of subjects with a set of localizer stimuli for cortical visual areas. Subsequently, diffusion tensor imaging (DTI) data from the same subjects were obtained, and the activation areas identified through fMRI were utilized as seeding points for 3D DTI fiber reconstruction algorithms. The methods developed in this study have the potential to lay a foundation for in vivo neuroanatomy and the ability for noninvasive longitudinal studies of brain development.

Algorithms↗

PubMed2001

The neurobiology and consequences of epilepsy in the developing brain.

Epilepsy is a disorder in which the balance between cerebral excitability and inhibition is tipped toward uncontrolled excitability. There is now clear evidence that there are distinct differences between the immature and mature brain in the pathophysiology and consequences of seizures. Both the enhanced excitability of the immature brain compared with the mature brain and the unique pathologic consequences of seizures are related to the sequential development and expression of essential signaling pathways. Although the immature brain is less vulnerable than the mature brain to seizure-induced cell death, seizures in the developing brain can result in irreversible alterations in neuronal connectivity. Developing novel strategies to treat and avert the consequences of seizures in children will require further understanding of the unique mechanisms of seizure initiation and propagation in the immature brain.

Brain↗

PubMed2000

Brain volume in children with neurofibromatosis type 1: relation to neuropsychological status.

OBJECTIVE: To determine characteristics of brain morphology in children and adolescents with neurofibromatosis type 1 and relate these characteristics to neuropsychological functioning. BACKGROUND: Neurofibromatosis type 1 is associated with numerous CNS abnormalities and cognitive impairment. Abnormal high signal intensity visible on brain MRI, brain tumors, and macrocephaly are common. Research into links between neuroanatomic and cognitive features has been inconclusive. METHODS: Fifty-two children and adolescents with neurofibromatosis type 1 were compared with 19 control subjects on several quantitative neuroanatomic and neuropsychological measures. RESULTS: Total brain volume, especially gray matter, was significantly greater for neurofibromatosis type 1 subjects than the control subjects. Group differences in the ratio of gray matter to white matter were more prominent in younger than in older subjects. Volume of gray matter in the subjects with neurofibromatosis type 1 was related to their degree of learning disability. Corpus callosum size was significantly larger for subjects in the neurofibromatosis type 1 group, and diminished performance on measures of academic achievement and visual-spatial and motor skills were associated with greater regional corpus callosum size. CONCLUSIONS: Neuroanatomic morphology and the developmental pattern of gray matter and white matter in subjects with neurofibromatosis type 1 differed from in control subjects. Some of these differences are related to the neuropsychological status of the neurofibromatosis type 1 group. We propose that delayed developmental apoptosis results in macrocephaly and a delay in the development of appropriate neuronal connections in children with neurofibromatosis type 1. We further propose that these morphologic delays are related to the cognitive profile of neurofibromatosis type 1.

Adolescent↗

PubMed2005

Developmentally programmed remodeling of the Drosophila olfactory circuit.

Neural circuits are often remodeled after initial connections are established. The mechanisms by which remodeling occurs, in particular whether and how synaptically connected neurons coordinate their reorganization, are poorly understood. In Drosophila, olfactory projection neurons (PNs) receive input by synapsing with olfactory receptor neurons in the antennal lobe and relay information to the mushroom body (MB) calyx and lateral horn. Here we show that embryonic-born PNs participate in both the larval and adult olfactory circuits. In the larva, these neurons generally innervate a single glomerulus in the antennal lobe and one or two glomerulus-like substructures in the MB calyx. They persist in the adult olfactory circuit and are prespecified by birth order to innervate a subset of glomeruli distinct from larval-born PNs. Developmental studies indicate that these neurons undergo stereotyped pruning of their dendrites and axon terminal branches locally during early metamorphosis. Electron microscopy analysis reveals that these PNs synapse with MB gamma neurons in the larval calyx and that these synaptic profiles are engulfed by glia during early metamorphosis. As with MB gamma neurons, PN pruning requires cell-autonomous reception of the nuclear hormone ecdysone. Thus, these synaptic partners are independently programmed to prune their dendrites and axons.

Animals↗

PubMed1988

Tissue interactions and cell differentiation: neurone-sensory cell interaction during otic development.

Statoacoustic ganglion neurones (SAG) are produced by the same group of cells (otic placode) that produce all of the receptor cells that populate the sensory areas of the inner ear. The observation that ingrowth of SAG neurites to presumptive sensory areas of the inner ear preceded cytodifferentiation of those receptor cells suggested a causal relationship. Results from in vivo, in ovo and in vitro studies do not support a causal relationship. These studies support the hypothesis that the programme for labyrinthine sensory cell differentiation is intrinsic and does not require the extrinsic stimulus of neuronal interaction to trigger its expression. In contrast, developing statoacoustic ganglion neurones appear to require a trophic influence that is supplied by either their peripheral or central target tissues for their survival and maturation in vitro. A mechanism for the ingrowth of SAG dendrites to their appropriate target sites within the inner ear proposes that attractant fields produced by areas of differentiating sensory cells act to guide the nerve growth cones of ingrowing SAG neurites to the appropriate tissues. Preliminary results from a heterochronic series of SAG implants to common age otocysts suggest that these SAG neurones are capable of responding to the attractant fields which are produced by presumptive labyrinthine sensory epithelium over an extended period of otic development. Both in ovo and in vitro studies suggest that spatiotemporal patterns of extracellular matrix molecules may be important components of the attractant fields which are produced by the sensory areas of the developing inner ear and may ultimately result in the specificity of their neuronal connections.

Animals↗

PubMed2001

Retinal axon growth cones respond to EphB extracellular domains as inhibitory axon guidance cues.

Axon pathfinding relies on cellular signaling mediated by growth cone receptor proteins responding to ligands, or guidance cues, in the environment. Eph proteins are a family of receptor tyrosine kinases that govern axon pathway development, including retinal axon projections to CNS targets. Recent examination of EphB mutant mice, however, has shown that axon pathfinding within the retina to the optic disc is dependent on EphB receptors, but independent of their kinase activity. Here we show a function for EphB1, B2 and B3 receptor extracellular domains (ECDs) in inhibiting mouse retinal axons when presented either as substratum-bound proteins or as soluble proteins directly applied to growth cones via micropipettes. In substratum choice assays, retinal axons tended to avoid EphB-ECDs, while time-lapse microscopy showed that exposure to soluble EphB-ECD led to growth cone collapse or other inhibitory responses. These results demonstrate that, in addition to the conventional role of Eph proteins signaling as receptors, EphB receptor ECDs can also function in the opposite role as guidance cues to alter axon behavior. Furthermore, the data support a model in which dorsal retinal ganglion cell axons heading to the optic disc encounter a gradient of inhibitory EphB proteins which helps maintain tight axon fasciculation and prevents aberrant axon growth into ventral retina. In conclusion, development of neuronal connectivity may involve the combined activity of Eph proteins serving as guidance receptors and as axon guidance cues.

Animals↗

PubMed1991

The shaker and shaking-B genes specify elements in the processing of gustatory information in Drosophila melanogaster.

Mutations that affect the physiological properties of neurones or the development of neuronal circuits are likely to have profound effects on sensory and motor pathways. We have examined the effects of mutations in two loci--the Shaker complex and shaking-B-on the taste pathway of Drosophila melanogaster Meigen at the behavioural and electrophysiological levels. The Shaker locus encodes a variety of A-type potassium channels that are likely to be tissue- and stage-specific. Flies containing the different Shaker alleles examined exhibit a variety of defects in their gustatory responses to sucrose, NaCl and KCl. The firing patterns of the labellar chemosensory neurones in response to these stimuli are normal. This suggests that the channels encoded by the Shaker locus are probably not involved in taste transduction, but affect central gustatory circuits. The shaking-B locus affects neuronal connectivity, though its molecular nature is unknown. Mutants at this locus show increased thresholds for detection of sucrose and fructose and lack the attraction response to 0.1 mol l-1 sodium chloride that is exhibited by the wild-type fly.

Action Potentials↗

PubMed2003

[Analysis of central synaptic transmission with the slice-patch-clamp technique].

More than ten years have passed since the slice-patch-clamp technique was established as a powerful method for the analysis of central synaptic transmission. Although this technique was restricted only to young animal preparations, we can now apply it to several synapses in slices obtained from adult animals, owing to recent advances in optics or slicers. In addition, advanced techniques have been recently available such as paired whole-cell recording from two or more synaptically connected neurons, recording from dendrites or some presynaptic terminals. Further developments are expected in both of the two directions: more microscopic analysis such as investigating glutamatergic sensitivities of single dendritic spines in combination with two-photon photolysis of a caged-glutamate compound and analysis in a more physiological function-oriented manner such as investigation of pain perception mechanisms using in vivo patch-clamp technique.

Animals↗

PubMed1996

Results of lead research: prenatal exposure and neurological consequences.

The history of advances in the understanding of the toxic effects of lead over the past 20 years is an outstanding example of how knowledge learned from research can impact public health. Measures that have had the greatest impact on reducing exposure to lead are reduction of lead from gasoline, elimination of lead solder from canned food, removal of lead from paint, and abatement of housing containing lead-based paint. Nevertheless, continuing factors that enhance risk to lead exposure, particularly during fetal life, are low socioeconomic status, old housing with lead-containing paint, and less than ideal nutrition, particularly low dietary intake of calcium, iron, and zinc. Prenatal exposure may result from endogenous sources such as lead in the maternal skeletal system or maternal exposures from diet and the environment. Experimental studies have shown that the developing nervous system is particularly sensitive to the toxic effects of lead and that a large number of the effects in the nervous system are due to interference of lead with biochemical functions dependent on calcium ions and impairment of neuronal connections dependent on dendritic pruning. There is need for more study to determine whether these effects are a continuum of prenatal lead exposure or whether prenatal exposure to lead produces unique effects.

Animals↗

PubMed2001

Activity-dependent factors affecting poststroke functional outcomes.

Over the last several years, there has been increasing recognition of the potential for central nervous system (CNS) recovery after brain damage. One commonality across the recovery and brain plasticity literature is that practice induces plastic, dynamic changes in the CNS. However, more than simply repetition, it is the manipulation of specific practice variables that appears to drive these dynamic processes in the CNS. The experimental manipulations used in the studies on neuroplasticity largely derive from the concept that in the undamaged or healthy brain neuronal connections and cortical maps are continuously remodeled by experience and by the performance of specific, intensive, and complex movements used to solve motor problems and attain goals. Intervention designed to promote recovery rather than compensation after stroke would then manipulate these same practice variables that have consistently promoted behavioral recovery and neuroplasticity in laboratory settings. Three current intervention strategies that incorporate these practice variables are reviewed. Preliminary results provide evidence that manipulation of task intensity and specificity and the sensorimotor experience of the task training are the necessary ingredients for maximizing the tremendous potential for recovery in patients with stroke.

Journal Article↗

PubMed2006

The PTEN phosphatase is essential for long-term depression of hippocampal synapses.

Activity-induced long-term potentiation (LTP) and long-term depression (LTD) of synaptic transmission are two types of enduring changes in neuronal connections that are believed to underlie learning and memory functions. Here we show that CA1 synapses in hippocampal slices from PTEN-deficient mice exhibit LTP, but are resistant to LTD. PTEN reduces phosphatidylinositol-3-kinase (PI3-K) activity, and pharmacological inhibition of PI3-K restores LTD in PTEN-deficient mice, suggesting that inhibition of PI3-K by PTEN is necessary for LTD induction. These findings demonstrate a pivotal role for PTEN in LTD, and suggest that alterations in PTEN could have an impact on learning and memory processes.

Animals↗

PubMedDate not supplied

Role of the nucleus accumbens and the striatum in the production of turning behaviour in intact rats.

Recent knowledge of the mechanisms underlying turning or circling behaviour in intact rats is reviewed. Most interest has been directed towards the striatum because of the classical hypothesis that turning behaviour results from lateral differences in the activity of the bilateral nigrostriatal pathway. However, the assumption that asymmetrical activation of the striatum is a necessary condition for dopamine-dependent turning behaviour has been questioned by several studies showing that unilateral injection of amphetamine or dopamine receptor agonists into the nucleus accumbens, a target of the mesolimbic dopaminergic system, also produces reliable circling away from the side of injection. Apart from discussing differences in stepping patterns of turning and discussing the role of the dopamine D1/D2 receptor interaction, the present survey focuses attention upon the two-component hypothesis, especially in relation to our recent studies in which activities of dopamine D1 and D2 receptors in the striatum and the nucleus accumbens have been manipulated separately in intact rats. It is hypothesized that turning behaviour is produced by asymmetry within nucleus accumbens circuits which involve neuronal connections from the nucleus accumbens to the A9 cell area, which in turn projects to the ventrolateral striatum that determines the direction of turning.

Animals↗

PubMed2005

Mapping labels in the human developing visual system and the evolution of binocular vision.

Topographic representation of visual fields from the retina to the brain is a central feature of vision. The development of retinotopic maps has been studied extensively in model organisms and is thought to be controlled in part by molecular labels, including ephrin/Eph axon guidance molecules, displayed in complementary gradients across the retina and its targeting areas. The visual system in these organisms is primarily monocular, with each retina mapping topographically to its contralateral target. In contrast, mechanisms of retinal mapping in binocular species such as primates, characterized by the congruent, aligned mapping of both retinas onto the same brain target, remain completely unknown. Here, we show that the distribution of ephrin/Eph genes in the human developing visual system is fundamentally different from what is known in model organisms. In the human embryonic retina, EphA receptors are displayed along two gradients, sloping down from the center of the retina to its periphery. The EphB1 receptor, which controls the ipsilateral routing of retinal axons in the mouse, is expressed throughout the human temporal retina in coordination with the changes in EphA gene expression. In the dorsal lateral geniculate nucleus, ephrin-A/EphAs are displayed along complementary retinotopic gradients. Our data point to an evolutionary model in which the coordinated divergence of the distribution of the receptors controlling retinal guidance and retinal mapping enabled the emergence of a fully binocular system. They also indicate that ephrin/Eph signaling plays a potentially major role in the development of neuronal connectivity in humans.

Biological Evolution↗

PubMed2005

De novo GMP synthesis is required for axon guidance in Drosophila.

Guanine nucleotides are key players in mediating growth-cone signaling during neural development. The supply of cellular guanine nucleotides in animals can be achieved via the de novo synthesis and salvage pathways. The de novo synthesis of guanine nucleotides is required for lymphocyte proliferation in animals. Whether the de novo synthesis pathway is essential for any other cellular processes, however, remains unknown. In a search for genes required for the establishment of neuronal connectivity in the fly visual system, we identify the burgundy (bur) gene as an essential player in photoreceptor axon guidance. The bur gene encodes the only GMP synthetase in Drosophila that catalyzes the final reaction of de novo GMP synthesis. Loss of bur causes severe defects in axonal fasciculation, retinotopy, and growth-cone morphology, but does not affect photoreceptor differentiation or retinal patterning. Similar defects were observed when the raspberry (ras) gene, encoding for inosine monophosphate dehydrogenase catalyzing the IMP-to-XMP conversion in GMP de novo synthesis, was mutated. Our study thus provides the first in vivo evidence to support an essential and specific role for de novo synthesis of guanine nucleotides in axon guidance.

Amino Acid Sequence↗

PubMed2002

Axonal pathfinding mechanisms at the cortical midline and in the development of the corpus callosum.

The corpus callosum is a large fiber tract that connects neurons in the right and left cerebral hemispheres. Agenesis of the corpus callosum (ACC) is associated with a large number of human syndromes but little is known about why ACC occurs. In most cases of ACC, callosal axons are able to grow toward the midline but are unable to cross it, continuing to grow into large swirls of axons known as Probst bundles. This phenotype suggests that in some cases ACC may be due to defects in axonal guidance at the midline. General guidance mechanisms that influence the development of axons include chemoattraction and chemorepulsion, presented by either membrane-bound or diffusible molecules. These molecules are not only expressed by the final target but by intermediate targets along the pathway, and by pioneering axons that act as guides for later arriving axons. Midline glial populations are important intermediate targets for commissural axons in the spinal cord and brain, including the corpus callosum. The role of midline glial populations and pioneering axons in the formation of the corpus callosum are discussed. Finally the differential guidance of the ipsilaterally projecting perforating pathway and the contralaterally projecting corpus callosum is addressed. Development of the corpus callosum involves the coordination of a number of different guidance mechanisms and the probable involvement of a large number of molecules.

Agenesis of Corpus Callosum↗