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PubMed2002

Constrained synaptic connectivity in functional mammalian neuronal networks grown on patterned surfaces.

The use of ordered neuronal networks in vitro is a promising approach to study the development and the activity of small neuronal assemblies. However, in previous attempts, sufficient growth control and physiological maturation of neurons could not be achieved. Here we describe an original protocol in which polylysine patterns confine the adhesion of cellular bodies to prescribed spots and the neuritic growth to thin lines. Hippocampal neurons in these networks are maintained healthy in serum free medium up to 5 weeks in vitro. Electrophysiology and immunochemistry show that neurons exhibit mature excitatory and inhibitory synapses and calcium imaging reveals spontaneous activity of neurons in isolated networks. We demonstrate that neurons in these geometrical networks form functional synapses preferentially to their first neighbors. We have, therefore, established a simple and robust protocol to constrain both the location of neuronal cell bodies and their pattern of connectivity. Moreover, the long term maintenance of the geometry and the physiology of the networks raises the possibility of new applications for systematic screening of pharmacological agents and for electronic to neuron devices.

Action Potentials↗

PubMed1992

Dependence of cortical plasticity on correlated activity of single neurons and on behavioral context.

It has not been possible to analyze the cellular mechanisms underlying learning in behaving mammals because of the difficulties in recording intracellularly from awake animals. Therefore, in the present study of neuronal plasticity in behaving monkeys, the net effect of a single neuron on another neuron (the "functional connection") was evaluated by cross-correlating the times of firing of the two neurons. When two neurons were induced to fire together within a short time window, the functional connection between them was potentiated, and when simultaneous firing was prevented, the connection was depressed. These modifications were strongly dependent on the behavioral context of the stimuli that induced them. The results indicate that changes in the temporal contingency between neurons are often necessary, but not sufficient, for cortical plasticity in the adult monkey: behavioral relevance is required.

Acoustic Stimulation↗

PubMedDate not supplied

Functional interneuronal connections in the motor cortex of alert and anesthetized cats.

Neuronal interconnections in the motor cortex of alert and anesthetized cats were investigated. It is shown that the number of connections between neurons did not decrease within microareas of the cortex during deepening of anesthesia, but their reorganization occurred in the form of leveling of the input and output properties of all cells of the microareas. The number of interneuronal connections of various microareas with deepening of anesthesia considerably decreased and those neurons which were relatively inert in the cortex of alert cats were considerably activated during restructuring of the functional interconnections between microareas. The results of the investigations permitted the assumption of differentiated participation of neurons of the cat motor cortex generating spikes of various amplitude in information processing at the level of microareas when alert and under anesthesia.

Anesthesia↗

PubMed1996

A complexity measure for selective matching of signals by the brain.

We have previously derived a theoretical measure of neural complexity (CN) in an attempt to characterize functional connectivity in the brain. CN measures the amount and heterogeneity of statistical correlations within a neural system in terms of the mutual information between subsets of its units. CN was initially used to characterize the functional connectivity of a neural system isolated from the environment. In the present paper, we introduce a related statistical measure, matching complexity (CM), which reflects the change in CN that occurs after a neural system receives signals from the environment. CM measures how well the ensemble of intrinsic correlations within a neural system fits the statistical structure of the sensory input. We show that CM is low when the intrinsic connectivity of a simulated cortical area is randomly organized. Conversely, CM is high when the intrinsic connectivity is modified so as to differentially amplify those intrinsic correlations that happen to be enhanced by sensory input. When the input is represented by an individual stimulus, a positive value of CM indicates that the limited mutual information between sensory sheets sampling the stimulus and the rest of the brain triggers a large increase in the mutual information between many functionally specialized subsets within the brain. In this way, a complex brain can deal with context and go "beyond the information given."

Animals↗

PubMed2004

An event-related fMRI study of artificial grammar learning in a balanced chunk strength design.

Artificial grammar learning (Reber, 1967) is a form of implicit learning in which cognitive, rather than motor, implicit learning has been found. After viewing a series of letter strings formed according to a finite state rule system, people are able to classify new letter strings as to whether or not they are formed according to these grammatical rules despite little conscious insight into the rule structure. Previous research has shown that these classification judgments are based on knowledge of abstract rules as well as superficial similarity ("chunk strength") to training strings. Here we used event-related fMRI to identify neural regions involved in using both sources of information as test stimuli were designed to unconfound chunk strength from rule use. Using functional connectivity analyses, the extent to which the sources of information are complementary or competitive was also assessed. Activation in the right caudate was associated with rule adherence, whereas medial temporal lobe activations were associated with chunk strength. Additionally, functional connectivity analyses revealed caudate and medial temporal lobe activations to be strongly negatively correlated (r= -.88) with one another during the performance of this task.

Adult↗

PubMed1991

Effect of conduction block at axon bifurcations on synaptic transmission to different postsynaptic neurones in the leech.

1. The cutaneous receptive field of the medial pressure (mP) sensory neurone in the leech has been examined. The cell has one major receptive field and an anterior and a posterior minor receptive field, principally on lateral and dorsal skin. The two minor receptive fields are contiguous with the major receptive field and are innervated by fine anterior and posterior axons, but there is no overlap between major and minor receptive fields. 2. At low frequencies of stimulation of the minor receptive fields, conduction block takes place in the mP cell at the central branch point within the leech ganglion. 3. The mP cell synapses directly with many other cells in the leech ganglion, including the anterior pagoda (AP) cell, longitudinal (L) motoneurone and the annulus erector (AE) motoneurone, which were studied as a group of postsynaptic neurones. Conduction block in the mP cell affects its synaptic transmission to all three postsynaptic neurones, but the effect can be different in different postsynaptic neurones. Block at the central branch point for an impulse travelling along the anterior axon reduces transmission to the AE cell much more than to the AP or L cells, while block at the central branch for an impulse travelling along the posterior axon has the reverse effect. 4. The distribution of functional connections of the branches of the mP cell with each postsynaptic cell was studied. For this analysis, branches of the mP cell were selectively silenced either during conduction block or by laser microsurgery. Generally, nearly all of the functional connections with the L and AP cell are made by anterior branches of the mP cell while the connection with the AE cell was primarily made by posterior branches of the mP cell. 5. The possible sites of contact between the mP cell and postsynaptic cells were determined by injecting separate markers into the mP cell and a postsynaptic cell. In confirmation of physiology, the mP cell's posterior branches had few, if any, contacts with the AP cell, while anterior branches had few, if any, contacts upon the AE cell. 6. Conduction block can thus act as a switch in the central nervous system (CNS), altering the mP cell's pattern of synaptic transmission to different postsynaptic neurons depending upon the region of a single sensory neurone's receptive field that is stimulated. This effect, dependent upon inputs to a single neurone, may be expected to influence the performance of the system and its outputs.

Action Potentials↗

PubMed2002

Nigral and pallidal inputs to functionally segregated thalamostriatal neurons in the centromedian/parafascicular intralaminar nuclear complex in monkey.

In primates, thalamostriatal projections from the centromedian (CM) and parafascicular (Pf) nuclei are strong and organized according to a strict pattern of functional connectivity with various regions of the striatal complex. In turn, the CM/Pf complex receives a substantial innervation from the internal globus pallidus (GPi). In this study, we demonstrate that the substantia nigra pars reticulata (SNr) also provides a massive input to Pf in monkeys. These pallidothalamic and nigrothalamic projections provide routes whereby information can flow in functional loops between the basal ganglia and the intralaminar nuclear group. To understand better the anatomical organization and the degree of functional specificity of these loops, we combined retrograde and anterograde labeling methods from functionally defined regions of the striatum and GPi/SNr to determine the relationships between thalamostriatal neurons and basal ganglia afferents. Together with previous studies, our data suggest the existence of tightly connected functional circuits between the basal ganglia and the CM/Pf in primates: 1) A "sensorimotor" circuit links together the medial two-thirds of CM, the postcommissural putamen, and the ventrolateral part of the caudal GPi; 2) a "limbic" circuit involves the rostral one-third of Pf, the ventral striatum, and the rostromedial pole of GPi; and 3) an "associative"circuit exists between the caudal two-thirds of Pf, the caudate nucleus, and the SNr. An additional "associative" circuit that involves the caudate-receiving territory of GPi (dorsal one-third), the dorsolateral Pf (Pfdl), and the precommissural putamen was also disclosed. In conclusion, findings of this study provide additional evidence for the high degree of functional specificity of the thalamostriatal system through which CM/Pf may provide attention-specific sensory information important for conditional responses to the primate striatum.

Animals↗

PubMed2005

Functional frontoparietal connectivity during encoding and retrieval processes follows HERA model. A high-resolution study.

Recent neuroimaging studies of long-term episodic memory have suggested that left prefrontal cortex predominates in encoding condition, whereas right prefrontal cortex predominates in retrieval condition (hemispheric encoding and retrieval asymmetry, HERA model). The present electroencephalographic (EEG) study investigated the functional coupling of fronto-parietal regions during long-term memorization of visuo-spatial contents (i.e. landscapes, interiors of apartments), to test the predictions of the HERA model. Global fronto-parietal coupling was estimated by spectral coherence, whereas the "direction" of the fronto-parietal information flow was estimated by directed transfer function (DTF). The EEG rhythms of interest were theta (4-7 Hz), alpha (8-13 Hz), beta (14-30 Hz), and gamma (30-45 Hz). Statistically significant coherence in line with the HERA model was obtained at the gamma band. Namely, the fronto-parietal gamma coherence prevailed in the left hemisphere during the encoding condition and in the right hemisphere during the retrieval condition. The DTF estimates of the gamma band showed a dominant parietal-to-frontal directional flow in the right hemisphere during the encoding condition and in the left hemisphere during the retrieval condition (i.e. hemisphere-condition combination not involved by the HERA model). In contrast, a balanced bidirectional flow of the fronto-parietal coupling was observed in the left hemisphere during the encoding condition and in the right hemisphere during the retrieval condition (i.e. hemisphere-condition combination involved by the HERA model). In conclusion, the present encoding-retrieval conditions induced maximal fronto-parietal gamma coupling with bidirectional information flow in the hemisphere-condition combination predicted by the HERA model.

Alpha Rhythm↗

PubMed2002

Regulation of angiogenesis and endothelial cell function by connective tissue growth factor (CTGF) and cysteine-rich 61 (CYR61).

Connective tissue growth factor (CTGF) and cysteine-rich 61 (CYR61) are prototypical members of the CCN family which also contains nephroblastoma overexpressed (NOV) and Wnt-induced secreted proteins-1, -2 and -3 (WISP-1, -2, -3). These proteins function as extracellular matrix (ECM)-associated signaling molecules that contain structural modules allowing them to bind directly with other moieties in the pericellular environment. Although multiple target cell types have been identified for CCN proteins, there is strong evidence supporting a role for CTGF and CYR61 in the regulation of endothelial cell function and angiogenesis. Both CTGF and CYR61 can promote endothelial cell growth, migration, adhesion and survival in vitro and at least some of these effects are mediated through cell surface integrins. Both proteins are transcriptionally activated in endothelial cells in response to basic fibroblast growth factor (bFGF) or vascular endothelial growth factor (VEGF), and endothelial cell proliferation and migration in vitro is reduced by antagonists of CTGF production or action. The expression pattern of CTGF and CYR61 in endothelial cells of vessels in situ supports a role for these molecules in normal endothelial homeostasis, as well as participating in the angiogenic process during embryonic development, placentation, tumor formation, fibrosis, and wound healing. CTGF or CYR61 knockout mice exhibit vascular defects during embryogenesis and fetal development. Both CTGF and CYR61 are intrinsically active in in vivo asssays for angiogenic activity. However, they can also regulate the production and/or activity of other angiogenic molecules (e.g. bFGF, VEGF) as well molecules that affect the integrity or stability of the ECM (e.g. collagen, matrix metalloproteases (MMPs), tissue inhibitors of MMPs (TIMPs)). Therefore, through their paracrine action as products of cells such as fibroblasts or smooth muscle cells or through their autocrine action as products of endothelial cells, CTGF and CYR61 participate in a variety of direct and indirect mechanisms by which angiogenesis is regulated at multiple control points.

Amino Acid Sequence↗

PubMed2005

Hippocampal-orbitofrontal connectivity in human: an electrical stimulation study.

OBJECTIVE: The identification of the pathways involved in seizure propagation remains poorly understood in humans. For instance, the respective role of the orbitofrontal cortex (OFC) and of the commissural pathways in the interhemispheric propagation of mesial temporal lobe seizures (mTLS) is a matter of debate. In order to address this issue, we have directly tested the functional connectivity between the hippocampus and the OFC in 3 epileptic patients undergoing an intra-cranial stereotactic EEG investigation. METHODS: Bipolar electrical stimulations, consisting of two series of 25 pulses of 1 ms duration, 0.2 Hz frequency, and 3 mA intensity, were delivered in the hippocampus. Evoked potentials (EPs) were analysed for each series, separately. Grand average of reproducible EPs was then used to calculate latency of the first peak of each individual potential. RESULTS: Hippocampal stimulations evoked reproducible responses in the OFC in all 3 patients, with a mean latency of the first peak of 222 ms (range: 185-258 ms). CONCLUSIONS: Our data confirm a functional connectivity between the hippocampus and the OFC in human. SIGNIFICANCE: This connectivity supports the potential role of the OFC in the propagation of mTLS.

Adolescent↗

PubMed2004

Disturbed fluctuations of resting state EEG synchronization in Alzheimer's disease.

OBJECTIVE: We examined the hypothesis that cognitive dysfunction in Alzheimer's disease is associated with abnormal spontaneous fluctuations of EEG synchronization levels during an eyes-closed resting state. METHODS: EEGs were recorded during an eyes-closed resting state in Alzheimer patients (N=24; 9 males; mean age 76.3 years; SD 7.8; range 59-86) and non-demented subjects with subjective memory complaints (N=19; 9 males; mean age 76.1 years; SD 6.7; range: 67-89). The mean level of synchronization was determined in different frequency bands with the synchronization likelihood and fluctuations of the synchronization level were analysed with detrended fluctuation analysis (DFA). RESULTS: The mean level of EEG synchronization was lower in Alzheimer patients in the upper alpha (10-13Hz) and beta (13-30Hz) band. Spontaneous fluctuations of synchronization were diminished in Alzheimer patients in the lower alpha (8-10Hz) and beta bands. In patients as well as controls the synchronization fluctuations showed a scale-free pattern. CONCLUSIONS: Alzheimer's disease is characterized both by a lower mean level of functional connectivity as well as by diminished fluctuations in the level of synchronization. The dynamics of these fluctuations in patients and controls was scale-free which might point to self-organized criticality of neural networks in the brain. SIGNIFICANCE: Impaired functional connectivity can manifest itself not only in decreased levels of synchronization but also in disturbed fluctuations of synchronization levels.

Aged↗

PubMed1993

Electrophysiological responses in foetal spinal cord transplants evoked by regenerated dorsal root axons.

Cut dorsal root axons regenerate into intraspinal transplants of foetal spinal cord (FSC) and establish synaptic connections there. The aim of the present study was to determine whether transplant neurons are driven synaptically in response to electrical stimulation of regenerated dorsal root axons. Adult Sprague-Dawley rats received FSC transplants (E14) into dorsal quadrant cavities at the lumbar enlargement. The cut L4 or L5 dorsal root stump was placed at the bottom of the lesion cavity and secured between the transplant and host spinal cord. Four to ten weeks later the animals were prepared for electrical stimulation and recording. We stimulated regenerated dorsal roots and recorded extracellular single unit post-synaptic activities which were evoked close to the dorsal root-transplant interface. We used intracellular recording to observe several examples of monosynaptic EPSPs in transplant neurons evoked by dorsal root stimulation. These results indicate that the regenerated dorsal root axons establish functional connections with neurons within the transplants and suggest that FSC transplants can be used to reconstruct functional connections between neurons that have been interrupted by spinal cord injury.

Animals↗

PubMed2026

Shared genetic architecture between major depression and intrinsic brain functional connectome organization.

BACKGROUND: Major depression (MD) is increasingly understood as a disorder characterized by widespread abnormalities in intrinsic brain functional network organization. Although both MD and brain functional connectome architecture are highly heritable, the genetic architecture underlying their relationship remains poorly characterized. METHODS: We integrated genome-wide association studies of MD with 191 ICA-based resting-state functional connectome traits to investigate their shared genetic architecture. These traits captured intrinsic connectome organization across amplitude, functional connectivity, and global connectivity domains. Cross-trait genetic analyses were used to assess pleiotropic overlap between traits. Locus-level and gene-based analyses integrating multi-omics evidence were performed to characterize the biological relevance of shared genetic signals. RESULTS: We identified significant genetic overlap between MD and 148 of 191 brain functional connectome traits. Cross-trait analyses revealed widespread shared genetic signals organized into 627 genomic loci across amplitude, functional connectivity, and global connectivity measures. Among these, 193 loci showed evidence consistent with shared causal variants based on colocalization analyses. Gene-level integration mapped these loci to 1459 protein-coding genes (390 unique genes). Multi-layer prioritization identified 17 high-confidence genes supported by convergent genomic, transcriptomic, and proteomic evidence, with enrichment in neurodevelopmental and lipid-related metabolism pathways. CONCLUSIONS: This study provides a multi-scale characterization of the shared genetic architecture between MD and intrinsic brain functional connectome organization, revealing that shared genetic signals between MD and brain functional systems are distributed across multiple functional levels and converge at the molecular level.

Connectome↗

PubMed1985

The corticomotoneuronal component of the pyramidal tract: corticomotoneuronal connections and functions in primates.

Corticomotoneuronal fibers make up a functional component of the pyramidal tract-corticospinal system which is characteristic of primates. The corticomotoneuronal fibers include large, rapidly conducting axons. They arise from somatotopically arranged areas of precentral cortex and the largest concentration of pyramidal cells of origin in the deep part of lamina V is in area 4. Their influence is exerted contralaterally on the spinal cord, where monosynaptic excitation of spinal motoneurons occurs. Motoneurons innervating distally acting muscles are preferentially excited and marked convergence of corticomotoneuronal influences occurs on these. The excitatory post-synaptic potentials in these motoneurons are characterized by the property of temporal facilitation. Intraspinal divergence of the terminal arborizations of individual corticomotoneuronal fibers could permit the engagement of large populations of motoneurons and also the activation of excitatory and inhibitory interneurons and propriospinal neurons for that region of the spinal cord. Corticomotoneuronal synapses may be located more distally on the dendrites of motoneurons than are the monosynaptic connections from group Ia afferents. The corticomotoneuronal excitation has been demonstrated to be effective in natural functional states when the conscious animal is performing learned movement tasks. Abolition of corticomotoneuronal influences causes a permanent deficit in the fractionation of use of distal muscles and an inability to carry out independent movements of the fingers.

Animals↗

PubMed1983

[Locally adjusted linear regression and its possibilities for application].

A new numerical method is presented for a model free representation of the mean course in a series of measured data of an unknown functional connection. The usefulness of the method is demonstrated by some examples of different time series (chemical reaction kinetics, growth, damped oscillations of a physiological system, pharmacokinetics). The advantages of the new method compared with nonlinear regression or segmented linear regression are noted. For any argument within the interval of measurements, the local adjusted linear regression value may be calculated. In this way one get a continuous curve with a continuous 1st derivative, too. This local adjustment will be obtained by using a weight function which is from Gaussianlike type in our procedure. The calculated continuous approximation curve represents the mean course in the measured values and may serve for a further quantitative evaluation of the measured functional connection, for interpolative and smoothing purposes, or even for model construction and model proving procedures. The nonparametric estimation of a continuous (1 dimensional) distribution density function from realizations of a continuous random variable is another field of application of this method.

Animals↗

PubMed2000

Neuronal connections in the medial geniculate body of the guinea-pig.

The spontaneous and evoked activities of individual pairs of single units were recorded simultaneously with the same microelectrode in the medial geniculate body (MGB) of ketamine-xylazine-anaesthetised guinea-pigs. Cross-correlograms (CCGs) of spike train pairs were computed and divided on the basis of correlation peak shape into four classes [a unilateral narrow (UN) peak, a centrally positioned wide (CW) peak, a complex peak and no significant peak] interpreted in terms of the functional connection between neighbouring neurones. The shift predictor procedure was applied with the aim of removing the effect of the stimulus on the final CCG shape. The occurrence of correlation peak types and the distribution of correlation coefficients were found to be similar for the spontaneous activity during silent periods following acoustical stimulation and for the long-lasting recording of spontaneous activity. CCGs in 38% of pairs computed during silent interstimulus intervals contained a UN peak, suggesting a monosynaptic excitatory connection. Almost 20% of all pairs expressed a CCG shape typical for a common input, i.e. a CW peak. In 5% of cases multiple, so-called complex peaks, were found. About 20% of the CCGs contained no significant correlation peak in the interstimulus period, which is typical for a very weak or absent functional connection between recorded neurones. No inhibitory interaction (groove in the CCGs) between recorded pairs was observed. The distribution of correlation peak shapes was similar when calculated during acoustical stimulation and during silent interstimulus intervals. CCGs computed during presentation of four acoustical stimuli (pure tone bursts, noise bursts, natural call whistle and artificially inverted whistle) showed most frequently a UN peak (28-37%) followed by CCGs with no significant peak (18-28%) and with a UN/CW peak (14-23%). On average, the occurrence of UN peaks tended to be less frequent during stimulus presentation than in silent conditions, but the difference was not statistically significant. The most frequent occurrence of clear UN peaks was found in the medial part of the MGB (from 52-64% of pairs depending on the type of acoustical stimulus), while the least was observed in the ventral part of the MGB (12-22%). In contrast, CW peaks were most frequently expressed in pairs located in the ventral part of the MGB (18-33%), while neuronal pairs in the medial part revealed a very low occurrence of CW peaks (0-7%). The occurrence of independently firing neurones was lowest in the medial part of the MGB (8-20% of pairs) in comparison with the ventral (31-39%) and dorsal (12-41%) parts. In 20% of pairs acoustical stimulation produced a change in the type of correlation peak present during spontaneous activity. Most frequently, a CW peak (shared input) changed to a flat CCG, which represents independently firing neurones. In some pairs higher connection strengths (as expressed by the value of the correlation coefficient) were found for silent interstimulus intervals than for acoustical stimulation. This suggests that in the MGB the stimulus may desynchronise the spontaneous activity of simultaneously firing units in neuronal pairs.

Acoustic Stimulation↗

PubMed1997

Expression of c-fos in bulbar nuclei involved in cardiovascular control following the electrical stimulation of sensorimotor cortex in the rat.

Previous studies have shown that electrical stimulation of the sensorimotor cortex (SMC) induces responses of the autonomic nervous system such as variations in heart rate and arterial pressure. Neuroanatomical studies have shown the existence of monosynaptic projections from the SMC to the nucleus tractus solitarius (NTS), the rostral ventrolateral medulla (RVLM) and the dorsal nucleus of the vagus nerve (DNV), which are bulbar nuclei involved in cardiovascular control. The aim of the present study was to establish whether there exists a functional connectivity between the SMC and these nuclei. Electrical stimulation applied to the SMC of 7 rats for 1 h induced the expression of c-fos-protein-like immunoreactivity in the nucleus of some neurons in NTS, RVLM and DNV. These data support the view that the SMC has functional connections with bulbar neurons involved in cardiovascular control.

Animals↗

PubMed1988

[Functional interneuronal connections in the motor cortex of waking and anesthetized cats].

Neuronal interconnections in the motor cortex of alert and anesthetized cats were studied using the techniques of multiunit activity recording and cross-correlative histograms. The number of neuronal interconnections did not decrease in cortical microareas during the deepening of anesthesia, but their reconstruction and levelling of inputs and outputs of all microareas' cells occurred. During the reconstruction of interrelationships among functional microareas an activation occurred in the neurons which had been rather inert in the cortex of alert cats. The data obtained suggest differential participation of the cat motor cortex' neurons in information processing at the level of microareas.

Action Potentials↗