Seminars in Neuroscience最新文献

Stimulation of adenylyl cyclase by 5-hydroxytryptamine increases the excitability of central neurones through several ionic mechanisms. Prominent among these is enhancement of the hyperpolarization-activated inward rectifier, I_lv and inhibition of a calcium-sensitive potassium current responsible for the slow afterhyperpolarization following action potential discharge. Increased excitability results from a small depolarization coupled with more subtle effects on the integrative properties of neurones. Interestingly, pharmacologically distinct 5-HT receptors mediate these responses. In addition, the mechanisms by which cAMP modulates the target ion channels may also be different.

Centrifugal serotonergic pathways running from the rostroventral medulla (RVM) to the dorsal horn of the spinal cord have long been considered an integral component of mechanisms of ‘descending inhibition’ limiting the access of nociceptive information to higher centres. However, the hypothesis of a generalized antinociceptive role of these serotonergic projections no longer seems tenable. Indeed, multiple serotonin (5-HT) receptor types in the dorsal horn appear to fulfil differential roles in the control of nociception, reflecting their contrasting patterns of coupling to intracellular transduction mechanisms. Further, the importance of actions of 5-HT outside the dorsal horn should not be neglected. These aspects have been synthesized into a global view of the role of 5-HT in the control of nociception.

The REM phase of sleep has long been of interest because of its association with dreaming and its presence in almost all mammals. We are now beginning to understand the mechanisms of its rhythmic generation, and review current hypotheses in this article. A group of cholinergic neurons at the junction of the pons and midbrain, in the laterodorsal and pedunculopontine tegmental nuclei, begins to discharge before the onset of this phase of sleep. Projections to key brain stem reticular formation regions lead, primarily through actions of non-M1 muscarinic receptors, to heightened excitability and discharge activity in these effector regions for the phenomena of REM sleep. Cholinergic projections to the thalamus promote EEG activation. These mesopontine cholinergic neurons are, in turn, modulated by inhibitory and REM-suppressive projections: norepinephrinergic locus coeruleus projections act as α₂and serotonergic dorsal raphe projections act as 5-HT_1Areceptors. These mesopontine cholinergic neurons are self-modulating through recurrent collaterals and projections between different subgroups that act as muscarinic and nicotinic receptors. In addition, metabolically generated adenosine acts to inhibit these cholinergic neurons. All of the preceding inhibitory effects are mediated by inwardly rectifying potassium currents. Implications of this neural network for a model of REM sleep cycle generation are discussed.

Considerable evidence links the activity of mesopontine cholinergic neurons to the induction and maintenance of arousal and REM sleep through their projections to the thalamus and medial pontine reticular formation. In addition to acetylcholine, these cells synthesize neuropeptides and express high levels of the enzyme nitric oxide synthase suggesting they transmit complex chemical signals to their targets. This article reviews the physiological properties of these cells and the patterns of modulation by some putative transmitters. We also present new data which suggests that nitric oxide synthesis may be stimulated at the soma during repetitive firing and that nitric oxide plays a role in regulating the strength of excitatory synaptic input to these cells.

The cerebral cortex of the human brain receives an intense cholinergic innervation from the nucleus basalis of Meynert. This nucleus is very highly developed and quite heterogeneous in composition. The cholinergic contingent of neurons associated with the nucleus basalis is designated the Ch4 cell group. The Ch4 cell group has topographically organized cortical projections which are directed to all parts of the cerebral cortex, but particularly to the limbic cortex and the amygdala. The organization of this projection suggests that it may play a critical role in enhancing the neural encoding of behaviorally relevant events by the appropriate cortical neurons. The cortical cholinergic projection from Ch4 is a principal component of the ascending reticular activating system.

Recent immunoelectron microscopic studies of the acetylcholine innervation in adult rat cerebral cortex, neostriatum and hippocampus reveal a frequency of synaptic relationships as low for these axon terminals (varicosities) as previously demonstrated for the noradrenaline innervation in cerebral cortex or hippocampus, and the serotonin innervation in neostriatum. The dopamine system is more synaptic, but shows regional variability in this regard (50–100% synaptic in cerebral cortex and 30–40% in neostriatum). The microenvironment of non-synaptic varicosities consistently lacks the enrichment in dendritic spines commonly observed around control populations of unlabeled terminals randomly selected from the same electron micrographs. It is hypothesized that in brain regions densely innervated by varicosities that are mostly non-junctional (e.g. acetylcholine and dopamine in neostriatum), a basal level of transmitter is permanently maintained around all cellular elements, contributing to the modulatory properties of the corresponding systems.

Following the original description of an ascending reticular activating system located in the brainstem core, the chemical codes of several cellular aggregates with widespread projections to the thalamus and cerebral cortex have been identified by combining axonally transported tracers with immunocytochemistry, the state-dependent activities of brainstem cholinergic neurons with antidromically identified thalamic projections have been investigated in behaving animals, and the actions of generalized modulatory systems on postsynaptic thalamic and cortical targets have been explored intracellularlyin vivoandin vitro. In this concluding article on brain neuromodulatory systems I place emphasis on(a)fast (20–40 Hz) spontaneous rhythms of electrical activity that are synchronous in intracortical as well as corticothalamic networks and represent a major component of activated electrical patterns during brain arousal; the subthreshold depolarizing oscillations may bias neurons to respond synchronously within this frequency range when relevant signals reach the forebrain;(b)the converging and/or competitive effects of various activating systems; and(c)the similarities between the actions of ascending/descending glutamatergic activating projections and those of other (cholinergic and monoaminergic) modulatory systems.

Nitric oxide (NO), a free radical gas, has been widely suggested as a messenger molecule in the nervous system, whose biophysical mechanisms and biochemical pathways of action are radically different from those of more traditional transmitter candidates. The intention of the present seminar is to evaluate recent evidence indicating a close anatomical and physiological relationship between NO and subsystems in the brain associated with the circadian rhythm and the sleep/waking cycle, and thus to prompt the discussion about the functional significance and the teleological advantage of a ‘nitrergic’ link between two different sorts of synaptic activity: that which is generated within cellular networks of biological oscillators and that which is a consequence of activity in systems assumed to control or reset pacemaker activity.

The reticular activating system is thought to be composed of one or more thalamo-cortical afferents whose activation results in desynchronization of the electroencephalogram. In recent years, a strong body of correlative evidence has accumulated suggesting that mesopontine cholinergic neurons are a key component of the reticular activating system. However, despite intense study, several critical predictions of the hypothesis remain unfulfilled, and it is still not possible to conclude that mesopontine cholinergic neuronal activity is either necessary or sufficient for generation of desynchrony. Specific criteria required to satisfy this hypothesis are put forth, and potential experimental approaches required are outlined. Such rigorous treatment of this issue will assist in maintaining the rapid pace of advance in this field.