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PubMed2005

The spanish connection: transcription and mRNA processing get even closer.

The synthesis of mRNA by RNA polymerase II appears coupled to numerous RNA-processing events, based on physical or functional connections revealed by biochemical or genetic tests. New findings were presented at a recent meeting in Spain that begin to illuminate the mechanisms underlying the connections between mRNA processing and specific steps in transcription (initiation, elongation, and termination) as well as recombination.

Eukaryotic Cells↗

PubMed2006

Small-world connectivity, motif composition, and complexity of fractal neuronal connections.

Connection patterns of the cerebral cortex consist of pathways linking neuronal populations across multiple levels of scale, from whole brain regions to local minicolumns. This nested interconnectivity suggests the hypothesis that cortical connections are arranged in fractal or self-similar patterns. We describe a simple procedure to generate fractal connection patterns that aim at capturing the potential self-similarity and hierarchical ordering of neuronal connections. We examine these connection patterns by calculating a broad range of structural measures, including small-world attributes and motif composition, as well as some global measures of functional connectivity, including complexity. As we vary fractal patterns by changing a critical control parameter, we find strongly correlated changes in several structural and functional measures, suggesting that they emerge together and are mutually linked. Measures obtained from some modeled fractal patterns closely resemble those of real neuroanatomical data sets, supporting the original hypothesis.

Animals↗

PubMed2006

Brain mechanisms of expectation associated with insula and amygdala response to aversive taste: implications for placebo.

The experience of aversion is shaped by multiple physiological and psychological factors including one's expectations. Recent work has shown that expectancy manipulation can alter perceptions of aversive events and concomitant brain activation. Accruing evidence indicates a primary role of altered expectancies in the placebo effect. Here, we probed the mechanism by which expectation attenuates sensory taste transmission by examining how brain areas activated by misleading information during an expectancy period modulate insula and amygdala activation to a highly aversive bitter taste. In a rapid event-related fMRI design, we showed that activations in the rostral anterior cingulate cortex (rACC), orbitofrontal cortex (OFC), and dorsolateral prefrontal cortex to a misleading cue that the taste would be mildly aversive predicted decreases in insula and amygdala activation to the highly aversive taste. OFC and rACC activation to the misleading cue were also associated with less aversive ratings of that taste. Additional analyses revealed consistent results demonstrating functional connectivity among the OFC, rACC, and insula. Altering expectancies of upcoming aversive events are shown here to depend on robust functional associations among brain regions implicated in prior work on the placebo effect.

Adolescent↗

PubMed2001

Sensorimotor control of knee stability. A review.

Traditionally, the concept of joint stability considered the displacement (or subluxation) of two bones relative to each other as the measurement index, and attributed the preservation of such stability in its physiologic range to the various ligaments associated with the joint. Although the ligaments are indeed the major restraints of any joint, the significant contribution of the musculature toward joint stability had been grossly overlooked or neglected until the last 15 years. The value and importance of muscular activity in that role becomes immediately apparent if one performs even a superficial functional comparison of muscles and ligaments. Ligaments are passive viscoelastic structures, whereas muscles are dynamic viscoelastic organs. The viscoelastic effects of the ligaments are activated and applied strictly upon the geometric and kinematic configuration of the joint traversing through its range of motion according to fixed force-displacement relationships. The musculature, however, can apply passive viscoelastic effects to the joint when not active (passive tone) and variable dynamic viscoelastic effects when contracting under voluntary or reflexive control, and at any desirable point in the range of motion and in response to joint speed, external load, gravity, pain, and so forth, while executing the functional objective of the movement set by the individual. Preservation of joint stability cannot be ascribed to the ligaments alone, but should be considered as a synergistic function in which bones, joint capsules, ligaments, muscles, tendons, and sensory receptors and their spinal and cortical neural projects and connections function in harmony. The objective of this report is to first review the anatomy and physiology of the various mechanoreceptors and their neural pathways about the joint, and describe some of the current concepts of the reflex arcs elicited by such receptors, with special emphasis on biomechanical outcomes relative to stability. The role of the musculature in maintaining stability while controlling joint motion is then reviewed, with data obtained from experiments performed on humans and animals. Finally, some clinical findings from patients with anterior cruciate ligament deficiency using a brace that simulates the ligament-muscle functions is described.

Anterior Cruciate Ligament Injuries↗

PubMed2006

Identification and analysis of evolutionarily cohesive functional modules in protein networks.

The increasing number of sequenced genomes makes it possible to infer the evolutionary history of functional modules, i.e., groups of proteins that contribute jointly to the same cellular function in a given species. Here we identify and analyze those prokaryotic functional modules, whose composition remains largely unchanged during evolution, and study their properties. Such "cohesive" modules have a large number of internal functional connections, encode genes that tend to be in close proximity in prokaryotic genomes, and correspond to physical complexes or complex functional systems like the flagellar apparatus. Cohesive modules are enriched in processes such as energy and amino acid metabolism, cell motility, and intracellular trafficking, or secretion. By grouping genes into modules we achieve a more precise estimate of their age and find that the young modules are often horizontally transferred between species and are enriched in functions involved in interactions with the environment, implying that they play an important role in the adaptation of species to new environments.

Computational Biology↗

PubMed1991

Long-term optical recording of patterns of electrical activity in ensembles of cultured Aplysia neurons.

1. Left upper quadrant (LUQ) cells isolated from the abdominal ganglion of Aplysia were maintained in culture to study how the cellular and synaptic properties of individual neurons contribute to the generation of patterns of electrical activity by neuronal ensembles. 2. Conventional microelectrodes were used to examine the spiking characteristics of individually cultured LUQ cells in vitro and to characterize their synaptic interactions. 3. In vitro, in contrast to in situ, LUQ neurons innervate other LUQ neurons. Intracellular recordings from pairs of LUQ cells showed that the prevalent type of postsynaptic potential was purely inhibitory. The other type of response was a dual-action postsynaptic potential, with inhibition followed by a delayed, slow excitation. 4. We established a set of criteria for the use of multiple-site optical recording techniques, in combination with impermeant probes of membrane potential, to observe the patterns of electrical activity generated by ensembles of co-cultured LUQ cells. 5. The spiking activity of individual cells within the neuronal ensembles was detected by means of the change in optical absorption of cells that were vitally stained with the dye RH155. The change in absorption was typically delta A congruent to 4 X 10(-4) per spike. We achieved a signal-to-noise (peak-to-peak) ratio of approximately 10 for a 50 X 50-microns photodetector field and an incident intensity of approximately 10 mW/cm2, close to the theoretical limit. 6. These conditions permitted, for the first time, continuous optical recording from cultured neurons for periods of up to 3 h with no discernible photodynamic damage or photobleaching. This long-term optical recording permitted examination of the different patterns of electrical activity generated by individual neuronal ensembles under several different experimental conditions. 7. An elaborate tracery of regenerated neurites present in these cultures resulted in individual photodetectors recording simultaneously the activity of multiple neurons. We reconstructed the temporal firing patterns for individual neurons within ensembles even with all the neurons active simultaneously and determined the functional connections in the ensemble by analyzing the temporal relationships between firing patterns of individual neurons. Excitatory as well as inhibitory functional interactions could be observed within the neuronal ensemble, the latter after the tonic activity of the neurons was increased by reducing the extracellular [Mg2+]. 8. Examination of the optical data from ensembles constructed from identified cells having characteristic physiological responses allowed us to address the question of how cellular and synaptic properties affect the patterns of electrical activity generated by neuronal ensembles.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1998

Interhemispheric EEG coherence in never-medicated patients with paranoid schizophrenia: analysis at rest and during photic stimulation.

We assessed functional relationships between hemispheres by calculating interhemispheric EEG coherence at rest and during photic stimulation in 18 never-medicated patients with paranoid schizophrenia and 30 control subjects. Although no significant group differences were found in the resting EEG, the schizophrenic patients had significantly higher coherence on EEGs recorded during photic stimulation, compared to the control subjects. In this study, we also examined the changes in interhemispheric coherence from rest to the stimulus condition (i.e., stimulation-related coherence reactivity); the patients were found to show significantly greater coherence reactivity to photic stimulation. These findings provide further evidence that schizophrenic patients have a higher degree of interhemispheric functional connectivity and thus have less lateralized cerebral organization than normal subjects. Our results also suggest that schizophrenic patients have excessive functional reorganization between hemispheres in association with photic stimulation.

Adolescent↗

PubMed2001

Connectivity from source to action.

Recent advances in electronic connectivity technology make conceivable almost instantaneous movement of data from the patient or laboratory to any other point in the healthcare system. The Internet, combined with new standards for wireless data transmission, has erased many of the previous physical barriers. Interface engines and formatting/content standards have facilitated the connection of multiple disparate systems in medicine. However, major logical barriers persist, and overcoming these barriers is key to achieving functional connectivity. These include fundamental issues of patient safety (such as reliably identifying the patient), capture of the most clinically meaningful data (patient history, physical examination findings, physician diagnostic impressions, and full range of orders), unambiguous identification of data elements, and synchronization of control files among multiple different systems within the healthcare enterprise. Fortunately, tools exist to address each of these areas. This report cites illustrative examples of such tools.

Chemistry, Clinical↗

PubMed2000

Excitatory connections between spinal motoneurons in the adult rat.

OBJECTIVES: Dendro-dendritic and dendro-somatic projections are common between spinal motoneurons. We attempted to clarify whether there are functional connections through these projections. METHODS: Motoneurons were antidromically stimulated by the muscle nerve and recorded intracellularly to examine the direct interaction between them after the related dorsal roots had been cut. RESULTS: Excitatory connections, demonstrated by depolarizing potentials in response to muscle nerve stimulation, were found between motoneurons innervating the same muscle or synergistic muscles, but never between motoneurons innervating antagonistic muscles. These potentials were finely graded in response to a series of increasing stimuli and resistant to high frequency (50Hz) stimulation. CONCLUSIONS: These results indicate that excitatory connections, with certain specificity of spatial and temporal distribution, occur in the spinal motoneurons. It is also suggested that electrical coupling should be involved in these connections and this mechanism should improve the excitability of the motoneurons in the same column.

Action Potentials↗

PubMed2006

Catechol O-methyltransferase val158met genotype and neural mechanisms related to affective arousal and regulation.

CONTEXT: Catechol O-methyltransferase (COMT), the major enzyme determining cortical dopamine flux, has a common functional polymorphism (val(158)met) that affects prefrontal function and working memory capacity and has also been associated with anxiety and emotional dysregulation. OBJECTIVES: To examine COMT val(158)met effects on corticolimbic circuitry reactivity and functional connectivity during processing of biologically salient stimuli, as well as the relationship to the temperamental trait of novelty seeking. DESIGN: Within-subject functional magnetic resonance imaging study. SETTING: National Institute of Mental Health, Genes, Cognition, and Psychosis Program, Bethesda, Md. Patients One hundred one healthy subjects of both sexes. RESULTS: We found that the met allele was associated with a dose-dependent increase in hippocampal formation and ventrolateral prefrontal cortex activation during viewing of faces displaying negative emotion. In met/met homozygotes, limbic and prefrontal regions showed increased functional coupling. Moreover, in these same subjects, the magnitude of amygdala-orbitofrontal coupling was inversely correlated with novelty seeking, an index of temperamental inflexibility. CONCLUSIONS: Our results indicate that heritable variation in dopamine neurotransmission associated with the met allele of the COMT polymorphism results in heightened reactivity and connectivity in corticolimbic circuits. This may reflect a genetic predisposition for inflexible processing of affective stimuli, a mechanism possibly accounting for aspects of arousal and behavioral control that contribute to emotional dysregulation previously reported in met/met individuals.

Adult↗

PubMed2004

Amygdala enterostatin induces c-Fos expression in regions of hypothalamus that innervate the PVN.

Enterostatin selectively inhibits the intake of the dietary fat after both central and peripheral administration. Our previous studies have shown that a central site of action is the central nucleus of amygdala. Serotonergic agonists administered into the paraventricular nucleus (PVN) inhibit fat intake and serotonergic antagonists block the feeding suppression induced by amygdala enterostatin, suggesting that there are functional connections between the PVN and amygdala that affect the feeding response to enterostatin. Our purpose was to identify the anatomic and functional projections from the amygdala to the PVN and hypothalamic area that are responsive to enterostatin, by using a retrograde tracer fluorogold (FG) and c-Fos expression. Rats were injected with fluorogold unilaterally into the PVN and a chronic amygdala cannula was implanted ipsilaterally. After 10 days recovery, rats were injected with either enterostatin (0.1 nmol) or saline vehicle (0.1 microl) into the amygdala and sacrificed 2 h later by cardiac perfusion under anesthesia. The brains were subjected to dual immunohistochemistry to visualize both FG and c-Fos-positive cells. FG/c-Fos double-labeled cells were found in forebrain regions including the PVN, amygdala, lateral hypothalamus (LH), ventral medial hypothalamus (VMH) and arcuate nucleus (ARC). The data provides the first anatomical evidence that enterostatin activates amygdala neurons that have functional and anatomic projections directly to the PVN and also activates neurons in the arcuate, LH and VMH, which innervate the PVN.

Amygdala↗

PubMed2000

F1 and F0 connections in the bovine mitochondrial ATP synthase: the role of the of alpha subunit N-terminus, oligomycin-sensitivity conferring protein (OCSP) and subunit d.

We have studied the functional effect of limited proteolysis by trypsin of the constituent subunits in the native and reconstituted F1F0 complex and isolated F1 of the bovine heart mitochondrial ATP synthase (EC 3.6.1.34). Chemical cross-linking of oligomycin-sensitivity conferring protein (OSCP) with other subunits of the ATP synthase and the consequent functional effects were also investigated. The results obtained show that the alpha subunit N-terminus is essential for the correct, functional connection of F1 to F0. The alpha-subunit N-terminus contacts OSCP which, in turn, contacts the F0I-PVP(b) and the F0-d subunits. The N-terminus of subunit alpha, OSCP, a segment of subunit d and the C-terminal and central region of F0I-PVP(b) subunits are peripherally located with respect to subunits gamma and delta which are completely shielded in the F1F0 complex against trypsin digestion. This qualifies the N-terminus of subunit alpha, OSCP, subunit d and F0I-PVP(b) as components of the lateral element of the stalk. These subunits, rather than being confined at one side of the complex which would leave most of the central part of the gamma subunit uncovered, surround the gamma and the delta subunits located in the central stalk.

Adenosine Triphosphatases↗

PubMed2001

Direct neurotization of muscles by presynaptic motoneurons.

The spinal cord cannot heal after severance because the central nervous system is "non-permissive" to the advancement of axons that regrow from presynaptic motoneurons. With the aim of overcoming paraplegia, the author has carried out extensive experimental research since 1980, first in rats and subsequently in monkeys, severing the cord and connecting its cephalad stump with the muscular nerve branches by means of peripheral-nerve grafts, and using various surgical protocols. Functional connections were established, ascertained by physical, electrophysiologic, and histologic examinations. In this reported study, it is demonstrated that presynaptic motoneurons are also able to reconstruct the cytoskeleton of peripheral neurons, as well as motor end-plates. The possibility of elongation of the axons of presynaptic motoneurons into the peripheral nerve up to the muscle had not previously even been hypotheized. This possibility, which has now been validated, can open the door to new surgical techniques for spinal-cord lesions. In addition, the author presents preliminary results from a single human case, utilizing the surgical procedures of the preceding animal experiments.

Animals↗

PubMed1997

Transcranial magnetic stimulation during positron emission tomography: a new method for studying connectivity of the human cerebral cortex.

We describe a new technique permitting the mapping of neural connections in the living human brain. The method combines two well established tools of brain research: transcranial magnetic stimulation (TMS) and positron emission tomography (PET). We use TMS to stimulate directly a selected cortical area while simultaneously measuring changes in brain activity, indexed by cerebral blood flow (CBF), with PET. The exact location of the stimulation site is achieved by means of frameless stereotaxy. In the first study using this technique, we found significant positive correlations between CBF and the number of TMS pulse trains at the stimulation site, namely the left frontal eye field (FEF) and, most importantly, in the visual cortex of the superior parietal and medial parieto-occipital regions. The pattern of these distal effects was consistent with the known anatomic connectivity of the monkey FEF. We suggest that the combined TMS/PET technique offers an objective tool for assessing the state of functional connectivity without requiring the subject to engage in any specific behavior.

Adult↗

PubMed1996

Avian olfactory receptors: differentiation of olfactory neurons under normal and experimental conditions.

The bird olfactory system has a simple structure and affords an attractive developmental model for the study of olfactory morphogenesis and differentiation. We have cloned and characterized several chick olfactory receptor (COR) genes belonging to the superfamily of seven-transmembrane domain proteins. In situ hybridization analysis of their spatiotemporal patterns of expression during development reveals several important characteristics. COR expression starts early in placodal cells (Embryonic Day 5, E5). Changes in their expression pattern then correlate with the onset of synaptogenesis (E8). The adult pattern, achieved before hatching, shows that cells expressing a particular COR are not regionalized within the epithelium. By double-label in situ hybridization, we clearly demonstrate that a single cell does not coexpress different COR genes (or subsets of CORs) at any stage of development. Following bulbar deafferentation, COR expression ceases more rapidly than expected from previous axotomy experiments. Concomitantly, a reactivation of the Cash-1 gene, which is involved in early neuronal specification, could be an early sign of olfactory neuronal regeneration. Modulation of COR and Cash-1 expression points to a simultaneous process of neuronal degeneration and regeneration in the olfactory epithelium after axotomy. COR expression is restricted to the olfactory epithelium except during early stages (before synaptogenesis). At that time, cells distributed along the olfactory nerve, from the placode to the anterior telencephalon, also express CORs. This cell population is different from the luteinizing hormone releasing hormone neurons migrating from the placode. Our results show that the olfactory neurons or neuroblasts choose to express one COR before establishing functional connections with the bulb. Later on, bulboepithelial connections seem important not only for olfactory neuron survival but also for stimulation of COR expression. In addition, beyond their implication in functional odor detection, CORs could be involved, at early stages, in processes of olfactory morphogenesis, including the establishment of a bulbar chemotopy.

Amino Acid Sequence↗

PubMed2000

The endoplasmic reticulum as one continuous Ca(2+) pool: visualization of rapid Ca(2+) movements and equilibration.

We investigated whether the endoplasmic reticulum (ER) is a functionally connected Ca(2+) store or is composed of separate subunits by monitoring movements of Ca(2+) and small fluorescent probes in the ER lumen of pancreatic acinar cells, using confocal microscopy, local bleaching and uncaging. We observed rapid movements and equilibration of Ca(2+) and the probes. The bulk of the ER at the base was not connected to the granules in the apical part, but diffusion into small apical ER extensions occurred. The connectivity of the ER Ca(2+) store was robust, since even supramaximal acetylcholine (ACh) stimulation for 30 min did not result in functional fragmentation. ACh could elicit a uniform decrease in the ER Ca(2+) concentration throughout the cell, but repetitive cytosolic Ca(2+) spikes, induced by a low ACh concentration, hardly reduced the ER Ca(2+) level. We conclude that the ER is a functionally continuous unit, which enables efficient Ca(2+) liberation. Ca(2+) released from the apical ER terminals is quickly replenished from the bulk of the rough ER at the base.

Acetylcholine↗

PubMed2006

Increased olfactory sensitivity in euthymic patients with bipolar disorder with event-related episodes compared with patients with bipolar disorder without such episodes.

OBJECTIVE: Some patients with bipolar disorder experience mood episodes following emotional life events, whereas others do not. There is evidence that orbitofrontal hypoactivity may be related to this, because the orbitofrontal cortex is involved in the regulation of emotional and behavioural responses to external events. The close anatomical and functional connection between the orbitofrontal cortex and olfactory processing suggests that patients with bipolar disorder and heightened emotional reactivity may exhibit altered olfactory function compared with patients with bipolar disorder who do not exhibit this sensitivity. METHODS: In this pilot study, olfactory function was assessed in patients with bipolar disorder and a history of event-triggered episodes (n = 7) and in patients with bipolar disorder without such a history (n = 9) at the Department of Psychiatry and the Taste and Smell Clinic of the University of Dresden, Germany. Each patient's bipolar disorder was in remission at study entry, and they were on monotherapy with mood stabilizers. Assessment included olfactory event-related potentials (ERP) and psychophysical tests for odour threshold, odour identification and olfactory quality discrimination. RESULTS: Odour thresholds were lower in patients with bipolar disorder and event-triggered episodes compared with the other patient group. In addition, patients with event-triggered episodes exhibited shorter N1 peak latencies of the olfactory ERP. CONCLUSIONS: Our findings indicate disinhibition of orbitofrontal areas involved in the processing of emotional events in a subset of patients with bipolar illness.

Adult↗

PubMed1990

A relation between synaptic specificity and the acquisition of presynaptic properties.

1. The specificity of synaptogenesis of identified adult neurons of Helisoma was determined in cell culture. Cholinergic neuron B5 indiscriminately forms the presynaptic element of chemical connections with novel cholinoceptive target neurons and muscle. By contrast, cholinergic neuron B19 is selective and discriminates between novel and appropriate target cells. Neuron B19 forms chemical connections with appropriate muscle targets only. 2. The acquisition of presynaptic properties independent of target contact was studied for both identified neurons. Functional connections form between neuron B5 and novel targets within seconds of contact, indicating that this cell has synthesized the presynaptic apparatus before target contact. In contrast, neuron B19 showed no evidence of possessing the ability to release neurotransmitter. 3. To further study the development of presynaptic properties, a model system of giant synaptic terminals was developed. The soma of neuron B5, acutely isolated from the nervous system is non-secretory. In conditions that prevent the extension of neurites, somata gain the ability to release neurotransmitter. This experimentally tractable system was used to study the calcium currents of presynaptic neuron B5. Acutely-isolated non-secretory somata contain two types of calcium currents: low-voltage-activated (LVA) and high-voltage-activated (HVA). The types of calcium currents in the soma change when B5 gains its secretory capacity. Secretory somata contain HVA calcium current only. 4. Neuron B5 was also plated in conditions which permit the extension of neurites. LVA and HVA calcium currents were maintained in its soma (non-secretory) but HVA calcium current only was maintained in its growth cones (secretory). Thus, B5 differentially regulates the presence of specific calcium currents in its membrane in relation to local secretory capacity without target-derived cues. 5. These data suggest that neuron B5 has an intrinsic program which generates presynaptic calcium channels and secretory apparatus prior to target contact. This autonomy of initial presynaptic development may underlie the lack of target cell discrimination exhibited by B5 in synaptogenesis.

Acetylcholine↗