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Neuronal misconnections and psychiatric disorder. Is there a link?

Brain damage can induce anomalous neuronal connections in experimental animals, which can sometimes result in maladaptive behaviour, particularly when damage occurs early in development. Anomalous patterns of neuronal connection can also arise from genetic disorders. In humans, neuronal misconnections could be involved in a variety of psychiatric disorders. For example, they may account for the link between hyperkinesis and childhood hemiplegia, and for the link between schizophrenia and 'alien tissue' lesions of the temporal lobes. Predictions from misconnection hypotheses can potentially be tested in neuropathological, neurophysiological, and clinical studies.

Brain↗

Excitatory connections between neurons of the central cervical nucleus and vestibular neurons in the cat.

The central cervical nucleus (CCN) of the cat receives input from upper cervical muscle afferents, particularly primary spindle afferents. Its axons cross in the spinal cord, and while in the contralateral restiform body give off collaterals to the vestibular nuclei. In order to study the connections between CCN axons and vestibular neurons, we stimulated the area of the CCN in decerebrate cats while recording intra- or extracellularly from neurons in the contralateral vestibular nuclei. CCN stimulation evoked excitatory postsynaptic potentials (EPSPs) or extracellularly recorded firing in the lateral, medial and descending vestibular nuclei. The latency of EPSPs (mean 1.6 ms) was on average 0.4 ms longer than the latency of antidromic spikes evoked in the CCN by stimulation of the contralateral vestibular nuclei (mean 1.2 ms), demonstrating that the excitation was typically monosynaptic. The results provide further evidence that the CCN is an important excitatory relay between upper cervical muscle afferents and neurons in the contralateral vestibular nuclei.

Animals↗

Functional connectivity in the human language system: a cortico-cortical evoked potential study.

A better understanding of the mechanisms involved in human higher cortical functions requires a detailed knowledge of neuronal connectivity between functional cortical regions. Currently no good method for tracking in vivo neuronal connectivity exists. We investigated the inter-areal connections in vivo in the human language system using a new method, which we termed 'cortico-cortical evoked potentials' (CCEPs). Eight patients with epilepsy (age 13-42 years) underwent invasive monitoring with subdural electrodes for epilepsy surgery. Six patients had language dominance on the side of grid implantation and two had bilateral language representation by the intracarotid amobarbital test. Conventional cortical electrical stimulation was performed to identify the anterior and posterior language areas. Single pulse electrical stimuli were delivered to the anterior language (eight patients), posterior language (four patients) or face motor (two patients) area, and CCEPs were obtained by averaging electrocorticograms (ECoGs) recorded from the perisylvian and extrasylvian basal temporal language areas time-locked to the stimulus. The subjects were not asked to perform any tasks during the study. Stimulation at the anterior language area elicited CCEPs in the lateral temporo-parietal area (seven of eight patients) in the middle and posterior part of the superior temporal gyrus, the adjacent part of the middle temporal gyrus and the supramarginal gyrus. CCEPs were recorded in 3-21 electrodes per patient. CCEPs occurred at or around the particular electrodes in the posterior language area which, when stimulated, produced speech arrest. Similar early and late CCEPs were obtained from the basal temporal area by stimulating the anterior language area (three of three patients). In contrast, stimulation of the adjacent face motor area did not elicit CCEPs in language areas but rather in the postcentral gyrus. Stimulation of the posterior language area produced CCEPs in the anterior language (three of four patients) as well as in the basal temporal area (one of two patients). These CCEPs were less well defined. These findings suggest that perisylvian and extrasylvian language areas participate in the language system as components of a network by means of feed-forward and feed-back projections. Different from the classical Wernicke-Geschwind model, the present study revealed a bidirectional connection between Broca's and Wernicke's areas probably through the arcuate fasciculus and/or the cortico-subcortico-cortical pathway. CCEPs were recorded from a larger area than the posterior language area identified by electrical stimulation. This suggests the existence of a rather broad neuronal network surrounding the previously recognized core region of this area.

Adolescent↗

Simulation of cross-correlograms resulting from synaptic connections between neurons.

A cross-correlation simulation program is presented. It is intended for use as a rapid initial screening test, to discriminate between possible connection configurations that may underlie observed cross-correlations. It can also serve to introduce students to the event cross-correlation technique. The simulation employs a simple model of two neurons with noisy membranes that may excite or inhibit one another or receive a common input from a third neuron. The model differs from its predecessors in that the user specifies the neurons and their interconnections by the resulting membrane potential trajectories, rather than discharge statistics. Illustrations of some simple performance characteristics are given, as well as examples of cross-correlograms resulting from more complex interactions between neurons. The latter demonstrate the usefulness of the simulation in the interpretation of cross-correlograms obtained from experimental data. The simulation is a LabVIEW (National Instruments) program executable under the Windows operating system (Microsoft) and is available for downloading from website www.utoronto.ca/respgrp/sim.htm.

Action Potentials↗

[Science of learning and education: an approach with brain-function imaging].

From a biological viewpoint, learning and education are closely related to brain development because the brain is an adaptable information processor open to the environment. Stimuli from the environment cause new neuronal connections. Therefore, learning is the process in which the brain reacts to stimuli by making neuronal connections that act as an information processing circuit and provide information storage similar to a database. On the other hand, education is a process that should guide and inspire the construction of the basic architecture of brain information processing by preparing and controlling the input stimuli to the brain.

Brain↗

Diversity and cell type specificity of local excitatory connections to neurons in layer 3B of monkey primary visual cortex.

In the primary visual cortex of macaque monkeys, laminar and columnar axonal specificity are correlated with functional differences between locations. We describe evidence that embedded within this anatomical framework is finer specificity of functional connections. Photostimulation-based mapping of functional input to 31 layer 3B neurons revealed that input sources to individual cells were highly diverse. Although some input differences were correlated with neuronal anatomy, no 2 neurons received excitatory input from the same cortical layers. Thus, input diversity reveals far more cell types than does anatomical diversity. This implies relatively little functional redundancy; despite trends related to laminar or columnar position, pools of neurons contributing uniquely to visual processing are likely relatively small. These results also imply that similarities in the anatomy of circuits in different cortical areas or species may not indicate similar functional connectivity.

Animals↗

Oscillating neurons in the cochlear nucleus: I. Experimental basis of a simulation paradigm.

Anatomical and physiological auditory data and pitch measurements are presented including some additional analysis. The data provide the basis for a new computer model of sustained chopper neurons in the ventral cochlear nucleus. New and old evidence indicating a preference for multiples of 0.4 ms in oscillations of chopper neurons in the cochlear nucleus of different species such as man, cats, and Guinea fowls, is summarized. Our hypothesis is that the time constant of 0.4 ms is due to the minimum synaptic delay of chopper neuron connections. Anatomical findings show that chopper neurons are indeed connected and can excite each other; a model of a circular network of neurons that are connected via synapses with a delay of 0.4 ms is thus plausible. Results concerning frequency tuning and dynamical properties of periodicity encoding of chopper neurons are reviewed. It is concluded that chopper neurons receive input both from auditory nerve fibres and onset neurons.

Acoustic Stimulation↗

Evidence of functional connectivity between auditory cortical areas revealed by amplitude modulation sound processing.

The human auditory cortex includes several interconnected areas. A better understanding of the mechanisms involved in auditory cortical functions requires a detailed knowledge of neuronal connectivity between functional cortical regions. In human, it is difficult to track in vivo neuronal connectivity. We investigated the interarea connection in vivo in the auditory cortex using a method of directed coherence (DCOH) applied to depth auditory evoked potentials (AEPs). This paper presents simultaneous AEPs recordings from insular gyrus (IG), primary and secondary cortices (Heschl's gyrus and planum temporale), and associative areas (Brodmann area [BA] 22) with multilead intracerebral electrodes in response to sinusoidal modulated white noises in 4 epileptic patients who underwent invasive monitoring with depth electrodes for epilepsy surgery. DCOH allowed estimation of the causality between 2 signals recorded from different cortical sites. The results showed 1) a predominant auditory stream within the primary auditory cortex from the most medial region to the most lateral one whatever the modulation frequency, 2) unidirectional functional connection from the primary to secondary auditory cortex, 3) a major auditory propagation from the posterior areas to the anterior ones, particularly at 8, 16, and 32 Hz, and 4) a particular role of Heschl's sulcus dispatching information to the different auditory areas. These findings suggest that cortical processing of auditory information is performed in serial and parallel streams. Our data showed that the auditory propagation could not be associated to a unidirectional traveling wave but to a constant interaction between these areas that could reflect the large adaptive and plastic capacities of auditory cortex. The role of the IG is discussed.

Acoustic Stimulation↗

Connectivity of neurons in identified auditory circuits studied with transport of dextran and microspheres plus intracellular injection of lucifer yellow.

The components of a neural circuit are usually distinguished in separate experiments to identify long connections, presynaptic, and postsynaptic components. We describe a procedure to visualize these components in the same experiment. Neurons in the inferior colliculus the axons of which project to the medial geniculate body were identified by retrograde transport of latex microspheres, while their innervation from the cochlear nucleus was simultaneously visualized by anterograde transport of dextrans. In aldehyde-fixed slices, the microsphere-labeled neurons near dextran-labeled axons were injected with biotinylated Lucifer Yellow. Subsequent avidin-biotin histochemistry allowed permanent visualization. The specific neurons involved in this circuit and the axonal contacts they received were easily visualized with the light microscope. This method allows the study of complex innervation patterns in the mammalian central nervous system.

Animals↗

Detection of ligands in regions anatomically connected to neurons expressing the Eph receptor Bsk: potential roles in neuron-target interaction.

Neuron-target interaction is a key feature in the establishment of neuronal networks. However, the underlying mechanism remains unclear. We have shown that at the time of target innervation, Bsk, an eph family receptor, is expressed at high levels in several brain regions including the hippocampus, olfactory bulb, and retina. To study whether the ligands are expressed in the target tissues, we investigated the expression of Bsk ligands using a ligand-affinity probe, Bsk-AP, which consisted of the extracellular domain of Bsk fused in frame with a human placental alkaline phosphatase. These analyses showed that the ligands were expressed at high levels in the developing septum, hypothalamus, olfactory neural epithelium, and tectum. In situ hybridization studies revealed that at least three different factors were responsible for the Bsk-AP binding. In the septum, Elf-1, Lerk3 (Eff-2), and AL-1/Lerk7 were transcribed. In the hypothalamus, AL-1/Lerk7 was the ligand detected by Bsk-AP. In the olfactory system, high levels of Lerk3 were detected in the sensory neurons. Both Elf-1 and AL-1/Lerk7 were present in the tectum. These ligand-positive areas are known to be anatomically connected to Bsk-expressing regions. These observations strongly suggest that Bsk and the ligands participate in neuron-target interactions in multiple systems and provide support for their involvement in topographic projection.

Alkaline Phosphatase↗

Deriving physical connectivity from neuronal morphology.

A model is presented that allows prediction of the probability for the formation of appositions between the axons and dendrites of any two neurons based only on their morphological statistics and relative separation. Statistics of axonal and dendritic morphologies of single neurons are obtained from 3D reconstructions of biocytin-filled cells, and a statistical representation of the same cell type is obtained by averaging across neurons according to the model. A simple mathematical formulation is applied to the axonal and dendritic statistical representations to yield the probability for close appositions. The model is validated by a mathematical proof and by comparison of predicted appositions made by layer 5 pyramidal neurons in the rat somatosensory cortex with real anatomical data. The model could be useful for studying microcircuit connectivity and for designing artificial neural networks.

Animals↗

Electrophysiological connections of neurons in ventral pallidal regions of the olfactory tubercle with the main olfactory bulb and piriform cortex.

Field potential and single unit recordings were used to assess the connections of the olfactory tubercle (OT) with the main olfactory bulb (MOB) and the piriform cortex (PC) in urethane-anesthetized rats. Current generators of depth profiles evoked in OT following MOB stimulation were localized 300 microns superficial to those elicited by PC shocks, suggesting that afferents from the MOB and PC end in different regions of the OT. Following MOB and PC stimulation antidromically invaded neurons were recorded in the ventral pallidal regions of the OT and in the vicinity of the islands of Calleja, respectively. These results demonstrate that the OT, which receives a monosynaptic input from the MOB, projects back to the bulb and that the PC seems to be also reciprocally linked with differentiated structures in the OT.

Animals↗

Specificity of synapse formation between Lymnaea heart motor neuron and muscle fiber is maintained in vitro in a soma-muscle configuration.

Precise neuronal connectivity during development is subservient to all nervous system functions in adult animals. However, the cellular mechanisms that mastermind this neuronal connectivity remain largely unknown. This lack of fundamental knowledge regarding nervous system development is due in part to the immense complexity of mammalian brain, as cell-cell interactions between defined sets of pre- and postsynaptic partners are often difficult to investigate directly. In this study, we developed a novel model system which has allowed us to reconstruct synapses between identified motor neurons and their target heart muscle cell in a soma-muscle configuration. Utilizing this soma-myocardial cell synapse model, we demonstrate that synapses between somata and heart muscle cells can be reconstructed in cell culture. The soma-myocardial cell synapses required 12-24 h to develop and thus differed temporally from conventional neuromuscular synapses (seconds to a few minutes). We also demonstrate that the synapses are target cell-type-specific and are most likely independent of transmitter phenotypic characteristics of presynaptic neurons.

Animals↗

Self-wiring in neural nets of point-like cortical neurons fails to reproduce cytoarchitectural differences.

We propose a model for description of activity-dependent evolution and self-wiring between binary neurons. Specifically, this model can be used for investigation of growth of neuronal connectivity in the developing neocortex. By using computational simulations with appropriate training pattern sequences, we show that long-term memory can be encoded in neuronal connectivity and that the external stimulations form part of the functioning neocortical circuit. It is proposed that such binary neuron representations of point-like cortical neurons fail to reproduce cytoarchitectural differences of the neocortical organization, which has implications for inadequacies of compartmental models.

Action Potentials↗

Altered local cerebral glucose utilization by unilateral frontal cortical ablations in rats.

Alterations in local cerebral glucose utilization (LCGU) following ablations of the unilateral frontal cortex in rats were studied to elucidate the effect of the lesion on the functional activity in the related cerebral structures. Frontal cortical ablations (areas 2, 4, 6 and 10) were made by aspiration on the left side, and LCGU was evaluated at 7 days after the operation, using the [14C]deoxyglucose method. Significant decreases in LCGU in rats with unilateral frontal cortical ablations, were observed in the ipsilateral thalamic nuclei (ventroanterior-ventrolateral (VAL), ventrobasal (VB), reticular), red nucleus and pontine nucleus. The ipsilateral globus pallidus showed a significant LCGU increase. The contralateral cerebellar cortex showed a tendency toward a decrease in LCGU. The striatum, which receives direct projections from the frontal cortex, showed no LCGU change. These results indicated that ablations of unilateral frontal cortex in rats produced LCGU changes in the cerebral structures which have direct or indirect neuronal connections with the ablated area. These LCGU changes were, for the most part, brought about by alteration in the neuronal activity. Particularly, the LCGU increase in the globus pallidus which receives transsynaptic neuronal input from the frontal cortex, without changes in the striatum, which receives direct projection, was attributed to the functional alteration of the globus pallidus produced by the cortical ablation. Destructive lesion of a cerebral structure, therefore, does not necessarily cause functional depressions in the pertinent structures, but it may enhance the function of some structures, depending on the functional characteristics of each neuronal connection and functional organization of those structures.

Animals↗

"Specificity versus (quasi-) randomness" revisited.

Speculation on neuron connectivity in the cerebral cortex, made some ten years ago, were re-evaluated in the light of modern cross identification methods. The identification of individual neurons and their synapses, including physiological characterization, detailed light microscope analysis of the same neurons, and immunocytochemical analysis of these neurones on the light microscope level and of their synapses on the level of the electron microscope, indicate that the specificity of local neuronal connections was underestimated in the earlier studies. Although the new methods revealed a higher degree of specificity in the choice of their connections, there seems to remain ample room for epigenetic (or functionally induced) plasticity of re-arrangement in neuronal circuits during later - even in postnatal - stages of development.

Animals↗

The functional significance of neurotransmitter diversity.

A major continuing theoretical issue in neurobiology is the nature of the information encoded into chemical neurotransmitters. This problem has been intensified by major recent advances in cellular neurobiology in three specific areas of work: neuronal connectivity, synaptic mechanisms, and neuronal transmitters. Countless new interneuronal connections have been revealed through the use of sensitive new cellular tracing methods, revealing a far more detailed picture of the complexities and principles of brain organization. A whole range of ionic conductance mechanisms has been detailed by the application of new methods of electrophysiological analysis, particularly useful with the in vitro preparations. Many of these mechanisms were not previously recognized, and together they provide a much richer repertoire of receptor response mechanisms upon which neurotransmitters can operate. Last, the modern methods of chemical analysis have provided an ever-increasing list of new neurotransmitter molecules, which fall conveniently into three chemical categories: amino acids, monoamines, and neuropeptides. This review considers some possible underlying principles by which the rich signaling capacity of the central nervous system may be approached conceptually and experimentally.

Biomechanical Phenomena↗