Development Of Neuronal Networks Research Articles

Primordial respiratory-like rhythm generation in the vertebrate embryo

Respiration is a rhythmic motor behavior that appears in the fetus and acquires a vital importance at birth. It is generated centrally, within neuronal networks of the hindbrain. This region of the brain is of particular interest since it is the best understood with respect to the cellular and molecular mechanisms that underlie its development. Examination of hindbrain activities in the chick embryo has revealed that the central rhythm generator is active before fetal maturation and conforms to the rhombomeric organization of the embryonic hindbrain. Inactivation of genes required for the normal formation of rhombomeres in mice leads to perturbations of the reticular formation that affect respiration after birth and compromise the probability of survival. From studies of hindbrain development we might gain an understanding of how genes govern the early embryonic development of neuronal networks and how this might specify patterns of motor activities operating throughout life.

Regulation of gonadotropin-releasing hormone neurons by basic fibroblast growth factor

The development of a functional network of gonadotropin-releasing hormone (GnRH) neurons in the central nervous system requires a series of complex regulatory mechanisms, presumably mediated in part by neurotrophic factors. The difficulty in studying factors regulating the development of GnRH neurons stems from their paucity and scattered distribution in the brain; as a result, little was known about the role of neurotrophic factors in the development of the mature GnRH neuronal network. Recent utilization of immortalized GnRH neuronal cell lines (GT1) has enabled us to identify and study specific neurotrophic factors and their functions in vitro. The potent neurotrophic effect of basic fibroblast growth factor (bFGF) and the presence of a high abundance of receptors for bFGF in GT1 cells have led to the hypothesis that bFGF may be an important regulator of GnRH neuron expansion, survival, migration, and connectivity.

Neuronal cells cultured on modified microelectronic device surfaces

The recording of the electrical activity of a large number of neurons in tissue culture over a period of weeks or even months should be very helpful in the understanding of the development and function of biological neuronal networks. Ideally, a method for the detection of the changes in interacellular voltage in such a system should have both high spatial and temporal resolution. One approach could be to record with a fixed electrode array built into the floor of the tissue culture chamber. We have chosen to detect the electrical signal of the neuron by direct coupling with a field effect transistor. Such a coupling is the first step toward multisite recording in neuronal nets and the development of a neuronal network. On a microelectronic device surface it is necessary, to control adhesion and outgrowth of neurons on a microscopic scale. To achieve biocompatibility the chemical composition of the surfaces of such devices has to be modified. Our approach to control the chemical architecture at the interface is to attach ultrathin polymer films to the device surface by using a novel ‘‘grafting from’’ procedure. It can be shown that the chemical composition of the interface can be tuned in such a way that Purkinje neurons show good adhesion to such a surface and survive and grow on it for weeks.

Localization of the Synapsin II (SYN2) Gene to Human Chromosome 3 and Mouse Chromosome 6

The synapsins are a family of neuronal phosphoproteins evolutionarily conserved in invertebrate and vertebrate organisms. Their best-characterised function is to modulate neurotransmitter release at the pre-synaptic terminal, by reversibly tethering synaptic vesicles (SVs) to the actin cytoskeleton. However, many recent data have suggested novel functions for synapsins in other aspects of the pre-synaptic physiology, such as SV docking, fusion and recycling. Synapsin activity is tightly regulated by several protein kinases and phosphatases, which modulate the association of synapsins to SVs as well as their interaction with actin filaments and other synaptic proteins. In this context, synapsins act as a link between extracellular stimuli and the intracellular signalling events activated upon neuronal stimulation. Genetic manipulation of synapsins in various in vivo models has revealed that, although not essential for the basic development and functioning of neuronal networks, these proteins are extremely important in the fine-tuning of neuronal plasticity, as shown by the epileptic phenotype and behavioural abnormalities characterising mouse lines lacking one or more synapsin isoforms.In this review, we summarise the current knowledge about how the various members of the synapsin family are involved in the modulation of the pre-synaptic physiology. We give a comprehensive description of the molecular basis of synapsin function, as well as an overview of the more recent evidence linking mutations in the synapsin proteins to the onset of severe central nervous system diseases such as epilepsy and schizophrenia.

Interactions of the nervous and immune systems in development, normal brain homeostasis, and disease 1

Neurotransmitters, neuropeptides, neurotrophins, and neuroendocrine hormones have traditionally been assigned functions in normal development and homeostasis of neuronal networks; cytokines and adhesion molecules have been assigned functions within the peripheral immune system. Molecular dissection of the presence and function of these receptors and ligands during development of the immune and nervous systems, in normal healthy adult central and peripheral nervous tissue, and in the pathological response of immune elements in the brain and neuroelements in the immune system has forced us to alter these long-held concepts. Examples of how glia and neurons function in relationship to these paracrine and autocrine stimuli in health and disease are provided in this short review.

Implications of activity dependent neurite outgrowth for neuronal morphology and network development

Empirical studies have demonstrated that electrical activity of the neuron can directly affect neurite outgrowth. In this paper, we study the possible implications of activity-dependent neurite outgrowth for neuronal morphology and network development, using a model in which initially disconnected cells organize themselves into a network under the influence of their intrinsic activity. A neuron is modelled as a neuritic field, the growth of which depends on its own level of activity, and neurons become connected when their fields overlap. In a purely excitatory network, we have previously demonstrated that activity-dependent outgrowth in combination with a neuronal response function with some form of firing threshold is sufficient to cause a transient overproduction (overshoot) in the number of connections or synapses. Here we show that overshoot still takes place in a network of excitatory and inhibitory cells, and can even be enhanced. With delayed development of inhibition the growth curve of the number of inhibitoryconnections no longer exhibits overshoot. An interesting emergent property of the model is that, solely as the result of simple outgrowth rules and cell interactions, the (dendritic) fields of the inhibitory cells tend to become smaller than those of the excitatory cells, even if both type of cells have the same outgrowth properties. Other consequences of the interactions among outgrowth, excitation and inhibition are that (i) the spatial distribution of inhibitory cells becomes important in determining the level of inhibition; (ii) pruning of connections can no longer take place if the network has grown without proper electrical activity for longer than a certain critical period; (iii) inhibitory cells, by inducing outgrowth, can help to connect different parts of a structure. Further, the model predicts that excitatory cell death will be accompanied by an increased neuritic field of surviving neurons (“compensatory sprouting”). The similarities of the model with findings in developing tissue cultures of dissociated cells are extensively discussed.

Regulation of neurotrophin receptor expression during embryonic and postnatal development

Members of the NGF family of proteins act as neurotrophic agents for defined populations of peripheral and central neurons during embryonic and postnatal development. We have studied the presence of receptors for brain-derived neurotrophic factor (BDNF) and neurotrophin-3 and -4/5 (NT-3, NT-4/5) by cross-linking radioiodinated neurotrophins to specific cell surface receptors. We have identified neurotrophin receptors representing full-length TrkB and TrkC and their truncated forms (lacking a functional cytoplasmic kinase domain) in neuronal as well as in non-neuronal tissues. During chicken embryonic and early postnatal brain development, expression of full-length TrkB and TrkC proteins preceded the onset of the truncated forms of these receptors. A similar pattern was also observed in mouse embryonic and early postnatal brain. The relative levels of neurotrophin receptors in the basal forebrain and in the hippocampus did not change significantly with age in mice. High levels of receptors for the three neurotrophins were detected in the nigrostriatal system. Full-length TrkB and TrkC receptors were found in chicken and rat embryonic ventral spinal cord, as well as on purified motoneurons. Again, truncated TrkB appeared significantly later than the full-length form on spinal motoneurons. In chicken embryonic retina and optic tectum we detected full-length TrkB and TrkC; however, the optic tectum also expressed large amounts of the truncated form of TrkB. TrkC but not TrkB was detected in chicken embryonic skeletal muscle, suggesting that NT-3 may have a novel function in this tissue. The presence of neurotrophin receptors in a wide variety of embryonic and postnatal tissues underlines the significant role of BDNF, NT-3, and NT-4/5 in embryonic and postnatal development. The regulation of the ratio of full-length versus truncated neurotrophin receptors may play an important role in the development, maturation, and maintenance of various neuronal networks.

In vitro study of newborn rat brain maturation: implication for sudden infant death syndrome

We have used slice preparation from newborn rats to study the development of the nucleus tractus solitarius neuronal network and brain intracellular phosphorus metabolites. As shown previously on adults, the newborn preparation retains local excitatory and inhibitory synaptic connections and enables study of intrinsic electrical properties in the nucleus tractus solitarius. Electrophysiological investigation of inhibitory synaptic transmission demonstrated a maturationnal step at days 4–6 after birth. Nuclear magnetic resonance spectroscopy of brain slices revealed a metabolic maturation between postnatal days 11 and 17. Results emphasize the differential maturation steps during the postnatal development of rat central nervous system. Possibly, Sudden Infant Death Syndrome may result from the abnormal timing in the occurrence of these steps.

Functional development of neuronal networks in the kitten visual cortex studied by cross-correlation analysis

Functional development of neuronal networks in the kitten visual cortex studied by cross-correlation analysis

The brain as a self-organizing system.

Clinical evidence and numerous results from animal experimentation indicate that cognitive functions have to be learned. Brain structures subserving these functions require sensory experience for their maturation. Genetic instructions are in principle not sufficient to specify neuronal connections with sufficient precision. Self-organization processes are implemented in addition which allow to optimize genetically determined blue prints of connectivity by making use of functional criteria. Thus, neuronal activity becomes an important shaping factor in the development of the structural and functional architecture of the forebrain. To the extent that this neuronal activity is modulated by sensory signals, environmental factors can influence the development of neuronal networks. Recent experiments indicate that these shaping processes are additionally controlled by modulatory systems. Both, the noradrenergic projection from the locus coeruleus and the cholinergic projection from the basal forebrain facilitate activity-dependent long-term changes of neuronal connections during development. The activity of these modulatory systems in turn depends on central states such as arousal, attention, and perhaps also motivation. It is inferred from this evidence that experience-dependent self-organization should not be considered as a passive imprinting process but rather as an active dialogue between the brain and its environment. The hypothesis is discussed that many developmental disturbances which are commonly attributed to deprivation are in fact due to defaults of the CNS which either lead to the formulation of wrong questions or to the reduction of exploratory drive.

Synaptogenesis in rat cerebral cortex cultures is affected during chronic blockade of spontaneous bioelectric activity by tetrodotoxin

Reaggregated occipital cortex cells of 19-day-old fetal rats were grown in a serum-free, chemically defined medium, and chronically exposed to impulse-blocking levels of tetrodotoxin (TTX) in order to study the role of bioelectric activity in synaptogenesis. As judged by phase-contrast microscopy, no differences were noticed in the development of neuronal networks in the TTX-treated vs control cultures. In addition, when TTX was withdrawn from experimental cultures at any stage of development, bioelectric activity qualitatively comparable to that of the control cultures appeared within 1 min. However, quantitative stereological EM analysis revealed a significant retardation in synapse formation and ultrastructural maturation of synaptic junctions during the first 3 weeks. Around 23 days in vitro, the central zone of the reaggregates in control cultures started to degenerate, but not earlier then day 27 in TTX-treated cultures. During this time, the control, but not the experimental cultures showed (in intact tissue regions mainly situated at the outside of the aggregates) a large and selective loss of spine synapses. It is concluded that functional blockade not only retards the early growth and maturation of synaptic networks but also prevents the later occurring selective loss of spine synapses.

Sequential output-input maturation of kitten motor cortex.

Average response histograms of the responses of single cortical neurons to imposed forelimb displacements in the kitten were utilized to quantify: (1) Background activity, (2) excitatory response latency, (3) percentage responding neurons, and (4) synaptic effectiveness. Motor cortical neuronal responses to the input did not attain adult values until 55--65 days of age, while adult-like responses were found in somatosensory cortical neurons as early as 9 days postnatally. Motor cortical output to alpha-motoneurons innervating triceps brachii, as tested by intracortical and subcortical microstimulation, first appeared over an interval ranging from 37--45 days postnatally. Thus, motor cortical responses to forelimb mechanoreceptors develop after completion of the output linkages from motor cortex to forelimb motoneurons and, though the motor cortex can output at 45 days, motor cortical functions requiring somatosensory feedback cannot be operative until about 60 days. This system provides a discrete and "late" maturing model in which to study the postnatal development of neuronal networks underlying normal and abnormal motor behavior.