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PubMed1999

Anatomical and functional demonstration of a multisynaptic suprachiasmatic nucleus adrenal (cortex) pathway.

In view of mounting evidence that the suprachiasmatic nucleus (SCN) is directly involved in the setting of sensitivity of the adrenal cortex to ACTH, the present study investigated possible anatomical and functional connections between SCN and adrenal. Transneuronal virus tracing from the adrenal revealed first order labelling in neurons in the intermedio-lateral column of the spinal cord that were shown to receive an input from oxytocin fibres and subsequently second-order labelling in neurons of the autonomic division of the paraventricular nucleus. The latter neurons were shown to receive an input from vasopressin or vasoactive intestinal peptide (VIP) containing SCN efferents. The true character of this SCN input to second-order neurons was also demonstrated by the fact that third-order labelling was present within the SCN, vasopressin or VIP neurons. The functional presence of the SCN-adrenal connection was demonstrated by a light-induced fast decrease in plasma corticosterone that could not be attributed to a decrease in ACTH. Using intact and SCN-lesioned animals, the immediate decrease in plasma corticosterone was only observed in intact animals and only at the beginning of the dark period. This fast decrease of corticosterone was accompanied by constant basal levels of blood adrenaline and noradrenaline, and is proposed to be due to a direct inhibition of the neuronal output to the adrenal cortex by light-mediated activation of SCN neurons. As a consequence, it is proposed that the SCN utilizes neuronal pathways to spread its time of the day message, not only to the pineal, but also to other organs, including the adrenal, utilizing the autonomic nervous system.

Adrenal Cortex↗
PubMed1999

An fMRI study of Stroop word-color interference: evidence for cingulate subregions subserving multiple distributed attentional systems.

BACKGROUND: The goal of this study was to model the functional connectivity of the neural systems that subserve attention and impulse control. Proper performance of the Stroop Word-Color Interference Task requires both attention and impulse control. METHODS: Word-color interference was studied in 34 normal adult subjects using functional magnetic resonance imaging. RESULTS: Interregional correlation analyses suggested that the anterior cingulate is coupled functionally with multiple regions throughout the cerebrum. A factor analysis of the significant regional activations further emphasized this functional coupling. The cingulate or related mesial frontal cortices loaded on each of the seven factors identified in the factor analysis. Other regions that loaded significantly on these factors have been described previously as belonging to anatomically connected circuits believed to subserve sensory tuning, receptive language, vigilance, working memory, response selection, motor planning, and motor response functions. These seven factors appeared to be oriented topographically within the anterior cingulate, with sensory, working memory, and vigilance functions positioned more rostrally, and response selection, motor planning, and motor response positioned progressively more caudally. CONCLUSIONS: These findings support a parallel distributed processing model for word-color interference in which portions of the anterior cingulate cortex modify the strengths of multiple neural pathways used to read and name colors. Allocation of attentional resources is thought to modify pathway strengths by reducing cross-talk between information processing modules that subserve the competing demands of reading and color naming. The functional topography of these neural systems observed within the cingulate argues for the presence of multiple attentional subsystems, each contributing to improved task performance. The topography also suggests a role for the cingulate in coordinating and integrating the activity of these multiple attentional subsystems.

Adolescent↗
PubMed2005

Multimodal imaging of brain reorganization in motor areas of the contralesional hemisphere of well recovered patients after capsular stroke.

Clinical recovery after stroke can be significant and has been attributed to plastic reorganization and recruitment of novel areas previously not engaged in a given task. As equivocal results have been reported in studies using single imaging or electrophysiological methods, here we applied an integrative multimodal approach to a group of well-recovered chronic stroke patients (n = 11; aged 50-81 years) with left capsular lesions. Focal activation during recovered hand movements was assessed with EEG spectral analysis and H2(15)O-PET with EMG monitoring, cortico-cortical connectivity with EEG coherence analysis (cortico-cortical coherence) and corticospinal connectivity with transcranial magnetic stimulation (TMS). As seen from comparisons with age-matched controls, our patients showed enhanced recruitment of the lateral premotor cortex of the lesioned hemisphere [Brodmann area (BA) 6], lateral premotor and to a lesser extent primary sensorimotor and parietal cortex of the contralesional hemisphere (CON-H; BA 4 and superior parietal lobule) and left cerebellum (patients versus controls, Z > 3.09). EEG coherence analysis showed that after stroke cortico-cortical connections were reduced in the stroke hemisphere but relatively increased in the CON-H (ANOVA, contrast analysis, P < 0.05), suggesting a shift of functional connectivity towards the CON-H. Nevertheless, fast conducting corticospinal transmission originated exclusively from the lesioned hemisphere. No direct ipsilateral motor evoked potentials (MEPs) could be elicited with TMS over the contralesional primary motor cortex (iM1) in stroke patients. We conclude that (i) effective recovery is based on enhanced utilization of ipsi- and contralesional resources, (ii) basic corticospinal commands arise from the lesioned hemisphere without recruitment of ('latent') uncrossed corticospinal tract fibres and (iii) increased contralesional activity probably facilitates control of recovered motor function by operating at a higher-order processing level, similar to but not identical with the extended network concerned with complex movements in healthy subjects.

Aged↗
PubMed2005

Inferring causality in brain images: a perturbation approach.

When engaged by a stimulus, different nodes of a neural circuit respond in a coordinated fashion. We often ask whether there is a cause and effect in such interregional interactions. This paper proposes that we can infer causality in functional connectivity by employing a 'perturb and measure' approach. In the human brain, this has been achieved by combining transcranial magnetic stimulation (TMS) with positron emission tomography (PET), functional magnetic resonance imaging or electroencephalography. Here, I will illustrate this approach by reviewing some of our TMS/PET work, and will conclude by discussing a few methodological and theoretical challenges facing those studying neural connectivity using a perturbation.

Brain Mapping↗
PubMed1986

Regeneration of normal afferent input does not eliminate aberrant synaptic connections of an identified auditory interneuron in the cricket, Teleogryllus oceanicus.

In the cricket, Teleogryllus oceanicus, the dendritic arborizations of an identified auditory interneuron (Int-1) are normally restricted to the ipsilateral auditory neuropile; unilateral deafferentation causes the medial portion of the dendritic field to sprout across the midline and make functional connections with the contralateral auditory neuropile (Hoy et al., '78: Soc. Neurosci. Abstr. 4:115, '85: Proc. Natl. Acad. Sci. USA 82:7772-7786; Hoy and Moiseff, '79: Soc. Neurosci. Abstr. 5:163). We have found that regeneration of the auditory afferents also results in an aberrant pattern of innervation of Int-1. Crickets were unilaterally deafferented during postembryonic development by crushing or cutting the auditory nerve. Regeneration of afferent-to-Int-1 connections was tested behaviorally. Of 86 nerve-crushed crickets tested as adults in the behavioral assay, 66% showed functional regeneration of the afferents. Similar results were obtained from the nerve-cut group. However, morphological investigations demonstrated that most of the regenerates still retained the aberrant contralateral dendritic projection. Electrophysiological recordings from these Int-1s showed that not only are some of them driven by their regenerated auditory afferents (the normal pathway) but that they retain their excitability via their contralateral dendrites (the aberrant pathway). This demonstrates that reinnervation of Int-1 by its normal afferent pool neither causes retraction nor prevents the formation of connections made with foreign, contralateral afferents. When the contralateral afferent pool was removed after Int-1 had sprouted, the sprouts remained present, but preliminary results suggest that if the contralateral afferents are removed before Int-1 is deafferented, sprouts are not formed. The results are discussed in relation to the roles of competition and conservation of membrane area in controlling synapse formation.

Animals↗
PubMed2005

Predictive models of molecular machines involved in Caenorhabditis elegans early embryogenesis.

Although numerous fundamental aspects of development have been uncovered through the study of individual genes and proteins, system-level models are still missing for most developmental processes. The first two cell divisions of Caenorhabditis elegans embryogenesis constitute an ideal test bed for a system-level approach. Early embryogenesis, including processes such as cell division and establishment of cellular polarity, is readily amenable to large-scale functional analysis. A first step toward a system-level understanding is to provide 'first-draft' models both of the molecular assemblies involved and of the functional connections between them. Here we show that such models can be derived from an integrated gene/protein network generated from three different types of functional relationship: protein interaction, expression profiling similarity and phenotypic profiling similarity, as estimated from detailed early embryonic RNA interference phenotypes systematically recorded for hundreds of early embryogenesis genes. The topology of the integrated network suggests that C. elegans early embryogenesis is achieved through coordination of a limited set of molecular machines. We assessed the overall predictive value of such molecular machine models by dynamic localization of ten previously uncharacterized proteins within the living embryo.

Algorithms↗
PubMed1981

[Internal medicine and clinical physiopathology].

Internal medicine is understood as an applied part of medicine closely connected with the patient, the task of which is care of patients. Clinical pathophysiology is understood as theoretical and experimental field of medicine the task of which is the clarification of diseases by statement of functional connections. Among other things the two specialities used the clinico-diagnostical and clinico-physiological (experimental) functional diagnostics for the solution of their task. The results are usable for the medical care immediately for the individual patient (prophylaxis, therapy, metaphylaxis, rehabilitation) or they will be for the patient's benefit as medico-theoretical knowledge (etiopathogenesis, sanogenesis, prognostics). Problems of realisation are entered at the instance of the respiratory functional diagnostic in the preliminary, basis and complex region under the aspect of personal and localisation questions of functional diagnostics.

Diagnosis↗
PubMed2002

The connection between transcription and genomic instability.

Transcription is a central aspect of DNA metabolism that takes place on the same substrate as replication, repair and recombination. Not surprisingly, therefore, there is a physical and functional connection between these processes. In recent years, transcription has proven to be a relevant player in the maintenance of genome integrity and in the induction of genetic instability and diversity. The aim of this review is to provide an integrative view on how transcription can control different aspects of genomic integrity, by exploring different mechanisms that might be responsible for transcription-associated mutation (TAM) and transcription-associated recombination (TAR).

Animals↗
PubMed2001

Mechanisms of peritumoural brain dysfunction: metabolic and neuroreceptor findings in striatal C6 glioma.

The aetiology of the peritumoural brain dysfunction that is rectified by steroids is unknown. To determine potential aspects of its pathophysiological basis we performed metabolic, histochemical and neuroreceptor studies in rodents with striatal C6 glioma. This model is known to cause focal neurobehavioural and electrophysiological dysfunction. The fully quantitative [(14)C]-2-deoxyglucose autoradiographic technique of measuring local cerebral metabolism of glucose (LCMRglu) showed raised LCMRglu (22-29%) in the pallidum, substantia nigra and endopeduncular nucleus. Acetylcholinesterase (AChE) histochemistry and a range of ligand binding studies for dopamine type 1 and 2, and serotonergic 5-HT(2)receptors were negative in the tumour and normal in peritumoural brain. 5-HT uptake sites and strong peripheral benzodiazepine receptor expression were present in the tumour. There was extensive up-regulation of peripheral benzodiazepine receptor expression in the peritumoural brain. These studies show there is metabolic dysregulation in brain regions functionally connected to, but anatomically distant from the striatum. There is also a peritumoural region of up-regulated receptors that have many, predominantly inhibitory, functions. The relationship of these findings to peritumoural brain dysfunction is discussed.

Acetylcholinesterase↗
PubMed2004

Rotary F1-ATPase. Is the C-terminus of subunit gamma fixed or mobile?

F-ATP synthase synthesizes ATP at the expense of ion motive force by a rotary coupling mechanism. A central shaft, subunit gamma, functionally connects the ion-driven rotary motor, F(O), with the rotary chemical reactor, F(1). Using polarized spectrophotometry we have demonstrated previously the functional rotation of the C-terminal alpha-helical portion of gamma in the supposed 'hydrophobic bearing' formed by the (alpha beta)(3) hexagon. In apparent contradiction with these spectroscopic results, an engineered disulfide bridge between the alpha-helix of gamma and subunit alpha did not impair enzyme activity. Molecular dynamics simulations revealed the possibility of a 'functional unwinding' of the alpha-helix to form a swivel joint. Furthermore, they suggested a firm clamping of that part of gamma even without the engineered cross-link, i.e. in the wild-type enzyme. Here, we rechecked the rotational mobility of the C-terminal portion of gamma relative to (alpha beta)(3). Non-fluorescent, engineered F(1) (alpha P280C/gamma A285C) was oxidized to form a (nonfluorescent) alpha gamma heterodimer. In a second mutant, containing just the point mutation within alpha, all subunits were labelled with a fluorescent dye. Following disassembly and reassembly of the combined preparations and cystine reduction, the enzyme was exposed to ATP or 5'-adenylyl-imidodiphosphate (AMP-PNP). After reoxidation, we found fluorescent alpha gamma dimers in all cases in accordance with rotary motion of the entire gamma subunit under these conditions. Molecular dynamics simulations covering a time range of nanoseconds therefore do not necessarily account for motional freedom in microseconds. The rotation of gamma within hours is compatible with the spectroscopically detected blockade of rotation in the AMP-PNP-inhibited enzyme in the time-range of seconds.

Adenosine Triphosphate↗
PubMed2006

Kinetics of integrated electron transfer in the mitochondrial respiratory chain: random collisions vs. solid state electron channeling.

Recent evidence, mainly based on native electrophoresis, has suggested that the mitochondrial respiratory chain is organized in the form of supercomplexes, due to the aggregation of the main respiratory chain enzymatic complexes. This evidence strongly contrasts the previously accepted model, the Random Diffusion Model, largely based on kinetic studies, stating that the complexes are randomly distributed in the lipid bilayer of the inner membrane and functionally connected by lateral diffusion of small redox molecules, i.e., coenzyme Q and cytochrome c. This review critically examines the experimental evidence, both structural and functional, pertaining to the two models and attempts to provide an updated view of the organization of the respiratory chain and of its kinetic consequences. The conclusion that structural respiratory assemblies exist is overwhelming, whereas the expected functional consequence of substrate channeling between the assembled enzymes is controversial. Examination of the available evidence suggests that, although the supercomplexes are structurally stable, their kinetic competence in substrate channeling is more labile and may depend on the system under investigation and the assay conditions.

Animals↗
PubMed1994

Cross-correlation analysis of cuneothalamic interactions in the rat somatosensory system: influence of receptive field topography and comparisons with thalamocortical interactions.

1. We simultaneously recorded neuronal responses to cutaneous stimulation from matched somatotopic representations in the nucleus cuneatus and ventrobasal complex of intact, halothane-anesthetized rats. A total of 95 cuneate and 86 thalamic neurons representing hairy skin on the forelimb were activated by hair movements produced by air jets at multiple skin sites. Mean responsiveness was higher among neurons in nucleus cuneatus (34.4 spikes per stimulus) than in thalamus (23.7 spikes per stimulus), a result that was consistent with the greater proportion of "sustained" responses recorded in nucleus cuneatus (80%) than in the thalamus (62%). 2. Cross-correlation analysis of 166 pairs of cuneate and thalamic neurons showed that 56 neuron pairs displayed time-locked correlations in activity that were characterized primarily by excitatory interactions (44 pairs) or a combination of excitatory and inhibitory interactions (10 pairs). Unilateral interactions in the cuneothalamic direction (31 pairs) and reverse direction (11 pairs) were observed, as well as multiphasic interactions in both directions (14 pairs). Most excitatory interactions involved intervals of 1-7 ms between successive cuneate and thalamic discharges, whereas most inhibitory influences involved intervals > 7 ms. Connection strength, defined by the ratio of time-linked interactions to the number of cuneate discharges, varied widely among neuron pairs but was largest for interactions involving interspike intervals of < or = 15 ms. 3. The relationship between connection strength and receptive field topography was analyzed in 103 cuneate-thalamic neuron pairs. The region of skin shared by both neurons varied substantially among neuron pairs and the probability of detecting interactions increased proportionately with larger amounts of receptive field overlap. Neuron pairs with moderate (25-50%) amounts of receptive field overlap had connection strengths 3-4 times greater than neuron pairs with minimal (0-25%) overlap. Connection strength was essentially identical, however, for neuron pairs with moderate or large (> 50%) amounts of overlap. 4. Cuneate-thalamic neuron pairs displaying functional connections were usually tested at multiple peripheral sites, but only 37% (18 of 49) of these neuron pairs displayed interactions at more than one stimulation site. Stimulation at different sites altered the timing of interactions in seven neuron pairs, including three that showed timing shifts across time zero in the cross-correlation histogram. In neuron pairs displaying interactions at multiple sites, connection strengths for 67% of the cases were strongest when stimulation was delivered within the region of receptive field overlap.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1975

[Large cell neurosecretory nuclei of the anterior hypothalamus of mice following exposure to antibodies to nerve growth factor].

Studies of morphology of the secretory hypothalamo-neurohypophyseal system under conditions of inhibition of the function of the peripheral region of the sympathetic nervous system were carried out. Desympathyzation was achieved by administration to newly born animals of antibodies to the factor of growth of nerves. In addition to the survey histological methods, morphometry, autoradiography and spectrophotometric investigations were also used. The aim of the work was to establish with the help of the methods referred to above the functional state of the hypothalamo-neurohypophyseal secretory system (HNSS) under deep immunological desympathyzation of the organism. The data obtained confirm the existence of a functional connection between the peripheral region of the sympathetic nervous system and HNSS. A hypofunctional state of the sympathetic department caused a rise in the functional activity to HNSS--in supraoptic and paraventricular nuclei of the hypothalamus there were observed enlarged neurones and their nuclei; this was accompanied by an intensification of the biosynthesis processes and secretion of neurosecretory material, neurohypophysis containing lesser amounts of neurosecret than in the norm. The rise of the functional activity of HNSS was accompanied by a higher specific hormonal effect upon the periphery (the effect of the hormone on "target"), which was confirmed by manifestations of working hypertrophy of the medullar of kidneys. The reaction of HNSS was apparently mediated through a complex of pathological changes in the organism and was directed at the maintenance of the optimal tonus of vessels and at preservation of homoestasis as a whole.

Animals↗
PubMed2003

Elimination and strengthening of glycinergic/GABAergic connections during tonotopic map formation.

Synapse elimination and strengthening are central mechanisms for the developmental organization of excitatory neuronal networks. Little is known, however, about whether these processes are also involved in establishing precise inhibitory circuits. We examined the development of functional connectivity before hearing onset in rats in the tonotopically organized, glycinergic pathway from the medial nucleus of the trapezoid body (MNTB) to the lateral superior olive (LSO), which is part of the mammalian sound localization system. We found that LSO neurons became functionally disconnected from approximately 75% of their initial inputs, resulting in a two-fold sharpening of functional topography. This was accompanied by a 12-fold increase in the synaptic conductance generated by maintained individual inputs. Functional elimination of MNTB-LSO synapses was restricted to the period when these glycinergic/GABAergic synapses are excitatory. These results provide new insights into the mechanisms by which precisely organized inhibitory circuits are established during development.

Aging↗
PubMed2001

Functional analyses of the leech swim oscillator.

The oscillations that underlie swimming movements in the leech arise from a series of identified concatenated circuits within the ventral nerve cord. In the intact nerve cord, ascending and descending intersegmental interactions via axons within the lateral connectives function both to generate robust oscillations throughout the cord and to establish an anterior-to-posterior phase delay among segmental oscillators. We addressed two questions about this system. First, do the intrasegmental swim circuits in each ganglion function as a single oscillator or do they comprise a pair of coupled oscillators? Second, what are the relative strengths of the ascending and descending intersegmental interactions between the segmental oscillators? Experiments were carried out on semi-intact leeches (Hirudo medicinalis) and on isolated leech nerve cords in which "Z-cut" ganglia were generated by cutting one lateral connective nerve anterior and the contralateral connective nerve posterior to the target ganglion. In these Z-cut ganglia, all rhythmic ascending intersegmental input is conveyed via one lateral connective while rhythmic descending input is conveyed via the contralateral connective. We found that rhythmic bursting recorded from the left and right sides of Z-cut ganglia had identical cycle periods with no phase difference, despite strong intersegmental inputs with differing periods from the two swimming ends of the preparations. We conclude that the swim circuits within individual leech ganglia act as single units. Moreover, we determined through correlation and Fourier spectral analyses, that the functional strengths of ascending and descending intersegmental inputs to Z-cut ganglia located in the middle of the nerve cord are approximately equal.

Animals↗
PubMed2003

Altered effective connectivity during working memory performance in schizophrenia: a study with fMRI and structural equation modeling.

The present study aimed to explore altered effective connectivity in schizophrenic patients while performing a 2-back working memory task. Twelve right-handed, schizophrenic patients treated with typical or atypical antipsychotics and 6 healthy control subjects were studied with fMRI while performing a "2-back" working memory task. Effective connectivity within a cortical-subcortical-cerebellar network for mnemonic information processing was assessed and compared between both groups. The path model included cortico-cortical connections comprising the parietal association cortex, ventrolateral prefrontal cortex (VLPFC), and the dorsolateral prefrontal cortex (DLPFC) as well as a cortico-cerebellar feedback loop comprising prefrontal cortex, contralateral cerebellum, and thalamus. Group differences were analyzed with a stacked models approach. Relative to normal controls, both patient groups revealed a pattern of reduced connectivity within the prefrontal-cerebellar and the cerebellar-thalamic limbs but enhanced connectivity in the thalamo-cortical limb of the cortical-cerebellar circuit. Moreover, a direct comparison of both treatment groups revealed enhanced connectivity in the interhemispheric connections between the cortical association areas in patients treated with atypical antipsychotics. However, right prefrontal and left parieto-frontal path coefficients were lower in the patient group receiving atypical antispychotic drugs. The findings suggest that the relationship between pathology in cortical-subcortical cerebellar networks and associated functional connectivity is complex and may include aspects of increased and decreased levels of connectivity consistent with the notion of "cognitive dysmetria" in schizophrenia. The observed pronounced connectivity within thalamo-cortical projections could be attributed to a compensatory increase of thalamic input in the presence of disrupted effective connectivity within the preceding limb of the cortical-cerebellar circuitry. The study demonstrated the feasibility of structural equation modeling for the investigation of group and treatment-related differences in effective connectivity and provides a promising approach to further disentangle the relationship between altered functional capacity and associated fMRI signal changes.

Adult↗
PubMed2005

Functional interactions between oculomotor regions during prosaccades and antisaccades.

Human behavior reflects a continual negotiation of automatic and directed actions. The oculomotor network is a well-characterized neural system in which to study this balance of behavioral control. For instance, saccades made toward and away from a flashed visual stimulus (prosaccades and antisaccades, respectively) are known to engage different cognitive processes. Brain regions important for such controlled execution include the presupplementary motor area (pre-SMA), frontal eye fields (FEF), and intraparietal sulcus (IPS). Recent work has emphasized various elements of this network but has not explored the functional interactions among regions. We used event-related fMRI to image human brain activity during performance of an interleaved pro/antisaccade task. Since traditional univariate statistics cannot address issues of functional connectivity, a multivariate technique is necessary. Coherence between fMRI time series of the pre-SMA with the FEF and IPS was used to measure functional interactions. The FEF, but not IPS, showed significant differential coherence between pro- and antisaccade trials with pre-SMA. These results suggest that the pre-SMA coordinates with FEF to maintain a controlled, preparatory set for task-appropriate oculomotor execution.

Adult↗
PubMed2005

Melanopsin-dependent photoreception provides earliest light detection in the mammalian retina.

BACKGROUND: The visual system is now known to be composed of image-forming and non-image-forming pathways. Photoreception for the image-forming pathway begins at the rods and cones, whereas that for the non-image-forming pathway also involves intrinsically photosensitive retinal ganglion cells (ipRGCs), which express the photopigment melanopsin. In the mouse retina, the rod and cone photoreceptors become light responsive from postnatal day 10 (P10); however, the development of photosensitivity of the ipRGCs remains largely unexplored. RESULTS: Here, we provide direct physiological evidence that the ipRGCs are light responsive from birth (P0) and that this photosensitivity requires melanopsin expression. Interestingly, the number of ipRGCs at P0 is over five times that in the adult retina, reflecting an initial overproduction of melanopsin-expressing cells during development. Even at P0, the ipRGCs form functional connections with the suprachiasmatic nucleus, as assessed by light-induced Fos expression. CONCLUSIONS: The findings suggest that the non-image-forming pathway is functional long before the mainstream image-forming pathway during development.

Animals↗