Showing papers in "Progress in Brain Research in 1989"

Organization of posture controls: an analysis of sensory and mechanical constraints.

Abstract: We analyse two components of posture control in standing human subjects: (1) the mechanical properties which constrain the body's ability to execute stabilizing postural movements and (2) the mechanical and neural properties which constrain the ability of the vestibular system to sense changes in body orientation. Rules are then proposed to describe the central organization of posture controls within the sensory and mechanical constraints. The organizational rules and knowledge of constraints are combined to predict the effects of selective semicircular canal and utricular otolith lesions on postural stability and the patterns of body and head movements used to maintain balance. Our analysis leads to the prediction that semicircular canal and otolith deficits destabilize patients at different frequencies, and force them to use different patterns of body and head movements. These predictions are compared to posture controls observed in patients with different types of vestibular deficits. The additional steps required to prove or disprove the theory are discussed.

Roles of muscle activity and load on the relationship between muscle spindle length and whole muscle length in the freely walking cat.

Abstract: The objective of this research was to compare the length of muscle spindles to the length of the whole muscle, during normal movements. Pairs of piezoelectric crystals were implanted near the origin and insertion of muscle fibres in the medial gastrocnemius (MG) muscle of cats. The distance between crystals was measured with pulsed ultrasound, the origin-to-insertion length of the MG muscle was measured with a transducer made of saline-filled silicone tubing, MG force was measured with a tendon force transducer and EMG activity was selectively recorded in the vicinity of implanted crystals. These signals were simultaneously recorded during posture or locomotion on a motorized treadmill. Three periods were identified in the step cycle, during which the relation between muscle length and spindle length changed dramatically. In period I (roughly corresponding to the late F and E 1 phases of swing), the MG muscle and spindles followed similar length changes: both were stretched and then shortened by about 6 mm. In period II (corresponding to the stance phase, E 2 −E 3 ) the MG muscle yielded under the weight of the body and was stretched by 1–3 mm, whereas the MG spindles typically continued shortening. In period III , the MG muscle shortened rapidly by 6–8 mm after the foot left the ground and then stretched again by about the same amount, whereas the spindles could remain nearly isometric. We attribute these large discrepancies in muscle and spindle length to the architecture of the MG muscle and the compliance of long tendinous elements in series with the spindles. We conclude that the length changes imposed on muscle spindles during voluntary movements are not simply related to the parent muscle length changes and cannot be estimated without taking into account the muscle architecture, the location of the spindle within the muscle, the level of muscle activation and the external load.

Control of forelimb muscle activity by populations of corticomotoneuronal and rubromotoneuronal cells.

Abstract: We review and synthesize evidence on the activity of corticomotoneuronal (CM) and rubromotoneuronal (RM) cells and single motor units in forearm muscles in monkeys performing alternating wrist movements. The CM and RM cells were identified by post-spike facilitation of rectified forelimb EMG activity. RM cells facilitated more muscles per cell (mean: 3.0 of 6 synergist muscles) than CM cells (2.4/6). Both groups had "reciprocal" cells which also suppressed antagonists of their facilitated target muscles. Unlike CM cells, some RM cells cofacilitated flexor and extensor muscles (5.8 or 12 muscles). During performance of a standard ramp-and-hold force tracking task the firing patterns of CM and RM cells, as well as single motor units, fell into distinct response types. Each population had phasic-tonic and tonic cells. Unique to the CM population were cells whose discharge increased during the static hold period; unique to RM cells were bidirectionally responsive and unmodulated neurons. Many motor units showed decrementing discharge. To estimate the ensemble activities of these populations the response histograms of different cells were summed (with force ramps aligned) in proportion to the relative frequency of each cell type. The population response histogram of CM cells was phasic-tonic, consistent with the predominant response type. The population response of RM cells was also phasic-tonic, but showed a shallower phasic modulation relative to discharge that was sustained during both directions of movement. The population histogram of motor units of a muscle was proportional to the average of rectified multiunit EMG, and typically exhibited decrementing activity during the static hold. The effects of excitatory postsynaptic potentials (EPSPs) on firing probability of motoneurons previously documented in intracellular studies are combined with the mean firing rates in the population histograms and the known amplitudes of CM-EPSPs and RM-EPSPs to infer the relative contributions of the supraspinal cells to tonic discharge of active motoneurons. This analysis suggests that for intermediate levels of force, the CM cells would increment motoneuron discharge by about 9 impulses/second (i.p.s.) and RM cells by about 2.4 i.p.s. The analysis also reveals differences in the population activity of CM and RM cells compared to their target motoneurons, which may be due to other input cells and to recruitment properties of motoneurons.

Presynaptic modulation of transmitter release by nicotinic receptors.

Abstract: Publisher Summary Nicotine acts on many transmitter systems in different parts of the brain to promote transmitter release, and these modulatory actions may underlie some of the psychopharmacological and behavioral effects of nicotine. Nicotine provoked the release of [ 3 H]dopamine from synaptosomes isolated from rat striata and preincubated with radiolabelled transmitter. Nicotine-evoked release was concentration-dependent over the range 10 -8 to 10 -3 M, and the half maximal response was observed with 3.8 μM nicotine. The presynaptic nicotinic receptor on dopaminergic nerve terminals and [ 3 H]nicotine binding sites may be equivalent. There are moderate numbers of [ 3 H]nicotine binding sites in the rat striatum compared with low levels of α-[ 125 I]bungarotoxin binding sites. Nicotinic modulation of transmitter release from hippocampal synaptosomes is discussed. From the data available concerning the presynaptic modulation of transmitter release by nicotine and other agonists, a model is proposed to account this phenomenon.

Organization of central cholinergic systems.

Abstract: Publisher Summary This chapter provides an update and overview of the anatomy of central cholinergic systems, and discusses some areas about which controversy and uncertainty still exist. Cholinergic neurons in the basal forebrain are distributed across several classically defined nuclei, including the medial septa1 nucleus, the nucleus of the diagonal band of Broca (vertical and horizontal limbs), the magnocellular preoptic area, the substantia innominata, and the globus pallidus. Many laboratories have studied the anatomy of these magnocellular neurons and there appears to be widespread agreement about their distribution in the basal forebrain. On the basis of connectivity patterns, the cholinergic neurons in the basal forebrain can be subdivided into four groups. Chl and Ch2 represent cholinergic neurons within the medial septal nucleus and the vertical limb of the diagonal band and provide the major source of cholinergic afferents to the hippocampus. Ch3 is contained primarily within the lateral part of the horizontal limb of the diagonal band, including the magnocellular preoptic area, and is the major source of cholinergic activity in the olfactory bulb. Ch4 consists of cholinergic neurons that are defined by the fact that they project to the neocortical mantle.

Sympathoexcitatory neurons of the rostroventrolateral medulla and the origin of the sympathetic vasomotor tone.

Abstract: In summary, a substantial portion of the excitatory drive to vasomotor sympathetic preganglionic neurons originates from reticulospinal tonically active cells located in the RVLM. This interpretation does not exclude the possible contribution of other tonically active bulbospinal or propriospinal inputs in generating the vasomotor outflow but under usual anesthetic conditions it seems that these alternative inputs are simply insufficient to bring the vasomotor preganglionic neurons to their firing threshold. Such may not be the case after plastic rearrangements consecutive to complete spinalization or chronic lesions of large portions of the RVLM have occurred (Cochrane and Nathan, 1987; for review see Schramm, 1986). It is also clear at present that the RVLM is not merely a final common pathway consisting of premotoneurons passively driven by tonic synaptic inputs originating elsewhere. Indeed the existence of a population of reticulospinal neurons with intrinsic pacemaker activity indicates that the RVLM contains at least one major intrinsic source of tonic activity. These neurons may release a glutamate-like substance and are not phenotypically adrenergic. They have no documented projections outside the cord and could subserve a tone-generating function specific to the sympathetic outflow, e.g. providing a background excitatory input to a large number of preganglionic neurons with vasoconstrictor of cardioaccelerator function. Strong anatomical evidence backed by weaker electrophysiological evidence also support the notion that C1 adrenergic neurons may have a vasomotor role and contribute an excitatory drive to preganglionic neurons. This could be mediated via alpha 1-adrenergic receptors or by receptors to substance P or neuropeptide Y. There is no evidence yet that C1 cells might have intrinsic pacemaker activity. The origin of the ongoing activity of many of these cells "in vivo" is therefore unclear and could depend on an excitatory drive from outside the RVLM. One might speculate that because these cells appear to have collateral interactions (PNMT-immunoreactive boutons synapse on C1 cells, Milner et al., 1987), they could play a role in synchronizing the sympathetic vasomotor outflow (an unexplained phenomenon observable even in the absence of baroreceptor input). Because of the large variety of peptides which they contain, another speculative view could be that they make rather specific connections with subsets of preganglionic neurons and therefore might be responsible for the differential control of regional blood flows by the rostral medulla (Dampney and McAllen, 1988). C1 cells are inhibited by low systemic doses of clonidine and therefore may be in part responsible for the hypotensive effect of this drug.(ABSTRACT TRUNCATED AT 400 WORDS)

Eye, head and skeletal muscle spindle feedback in the elaboration of body references.

Abstract: Evidence is presented to support the notion that the sensory feedback originating in muscles is of major importance in the central elaboration of motor representation. The muscle spindle messages during movement and postural performance may be processed in order to elaborate continuously updated static and dynamic body references. These may then form the basis for the interpretation of retinal information in terms of spatial coordinates. The main arguments supporting this view are as follows. Experimental manipulation of muscle spindle proprioceptive feedback by tendon vibration induced segmental or postural kinaesthetic illusory movements in the direction of stretch of the vibrated muscles. By modifying the spatial distribution (agonists and/or antagonists), the frequency and the duration of the vibratory stimuli it is possible to induce simple or complex kinaesthetic illusions the parameters of which may be predicted. Microneurographic recordings confirmed that vibration rather selectively excited spindle Ia afferents, eliciting 1:1 driving up to 80-100 Hz. Moreover painless vibration, applied at increasing frequency (from 10 to 80 Hz) to either the medial, lateral, superior or inferior rectus of a subject's eye, was found to induce directional perceptual and motor effects which were closely related to the postural context. Likewise, the subjects reported illusory directional shifts of a visually fixed target in darkness during extraocular muscle vibration. These data suggest that extraocular proprioception contributes to the coding of eye, head and body position in relation to postural and environmental conditions. As with eye muscle stimulation, directional visual and postural effects were induced by vibration of neck and/or ankle postural muscles. These effects were found to summate when vibrations were applied simultaneously to the eye, neck and ankle muscles. The likely involvement of extraocular proprioception in interrelating body space with extrapersonal space in oriented behaviour is discussed.

Central control of the circulation by the rostral ventrolateral reticular nucleus: anatomical substrates.

Abstract: Publisher Summary Neurons in the rostral ventrolateral reticular nucleus (RVL), perhaps the hypothetical tonic vasomotor center, generate basal levels of sympathetic tone and arterial blood pressure (AP) and integrate cardiopulmonary and cerebrovascular reflexes. The critical zone precisely coincides a chemosensory area of the rostra1 ventrolateral quadrant, where most reticulospinal neurons projecting to the intermediolateral (IML) cosynthesize the putative neurotransmitters, adrenaline, and neuropeptide Y. Receptors in the RVL are responsive to a broad spectrum of cardioactive pharmacologic agents and the RVL is a major site of action of the imidazole, clonidine—a clinically effective antihypertensive drug. Nonetheless, still elusive is the identity of the neurotransmitter in RVL-generating sympathetic tone and whether it is, in fact, the C1 neurons of RVL that contribute to exaggerated sympathetic tone and, in turn, the circulatory changes involved in the initiation, expression, or maintenance of neurogenic hypertension. The RVL is the site of action for a broad spectrum of pharmacologic agents involved in cardiopulmonary control and derives its afferents from a variety of monoaminergic and peptidergic cell groups.

Flexible fusimotor control of muscle spindle feedback during a variety of natural movements.

Abstract: A refined version of an experimental iterative simulation method is described, which was used to infer, from chronic spindle afferent recordings, type and time course of static and dynamic fusimotor activation during a variety of voluntary movements. When used to estimate overall fusimotor drive (without distinction between static and dynamic action) the method provides unique solutions. However, when generating independent γs and γd activation profiles, the solutions no longer are strictly unique. Yet the boundary conditions imposed by the type specific characteristics of γ−action nevertheless permit detection of powerful activation, especially of dynamic efferents. Extending the finding of selective dynamic fusimotor activation during unpredictably imposed and resisted stretches, evidence for powerful, often transient activation of dynamic efferents has now been obtained for three additional motor paradigms. First, initiation of walking was accompanied by mixed fusimotor action. Static drive was stepped up and then maintained, whereas dynamic drive declined after an initial abrupt peak. Second, corrective balancing on a narrow walk beam was characterized by largely maintained static background drive, whilst dynamic activation profiles often exhibited powerful surges or transients, when the animal crouched to regain balance. These preceded subsequent EMG bursts during the stretch phase of crouching by about 300 ms. Third, preparation for landing from rapid lowering featured prominent and possibly selective activation of dynamic fusimotor neurones, which peaked while the animal was in mid-air and declined upon landing, and which preceded the sharp onset of EMG after landing by several hundred milliseconds. In all cases the fusimotor activation profiles were unrelated to the parent muscle EMG and difficult to reconcile with the notion of α−γ linkage or coactivation. These findings then clearly support the concept of flexible central control, particularly of dynamic γ−motoneurones during certain motor tasks.

Disturbances of motor preparation in basal ganglia and cerebellar disorders.

Abstract: Movements of the arms (execution) in standing human subjects are preceded (preparation), accompanied, and followed (compensation) by muscular activity in postural trunk and leg muscles. Postural muscular activity compensates inertial forces acting on the body at the beginning and during arm movements and keeps the centre of gravity within the limits of stable upright standing. Standing normal subjects and patients performed bilateral arm elevations in response to an acoustic trigger. The beginning of EMG activity in the anterior deltoid muscle reflects the reaction time. Postural activity prior to the arm movement was observed in anterior tibialis, paraspinalis, and hamstring muscles. Compensatory muscular action occurred in the triceps surae. Motor preparation and compensation thus are an integral part of a motor programme. Muscles involved, latencies, and amount of EMG activity change with variations in the motor task (e.g. range of arm movement, changes in inertia of the arm, changes in initial body position). Reaction times and the pattern of preparatory and compensatory postural EMG activity were normal in most of the patients with Parkinson's disease. Reaction times were significantly increased in patients with cerebellar atrophy. The most prominent pathological feature in cerebellar patients was the inadequate temporal sequence of motor preparation and execution. Our results indicate that the basal ganglia play a minor role in motor preparation, whereas the cerebellum seems to coordinate the relative timing between motor preparation and execution.

Nicotine dependence and tolerance in man: pharmacokinetic and pharmacodynamic investigations.

Abstract: Publisher Summary This chapter discusses the nicotine dependence and tolerance in man. Pharmacokinetic and pharmacodynamic characteristics of a drug are important determinants of dependence liability, the temporal patterns of drug use, and the level of drug use. Ultimately, an understanding of pharmacokinetics and pharmacodynamics may be useful in developing effective treatment strategies. Several pharmacokinetic and pharmacodynamic characteristics appear to be necessary or optimal for a drug to produce dependence: the drug must be effectively absorbed into the blood stream, the drug must rapidly enter into the brain, and the drug must be psychoactive and that psycho activity related to levels of the drug in the brain. These characteristics allow for the drug abuser to manipulate the dose of his or her drug to optimize mood and psychological functioning and are most likely to result in the behavior described as criteria for drug dependence. This chapter examines the pharmacokinetic and pharmacodynamic characteristics of nicotine and how these characteristics might determine cigarette smoking behavior and tobacco addiction.

A glutamate mechanism in the intermediolateral nucleus mediates sympathoexcitatory responses to stimulation of the rostral ventrolateral medulla.

Abstract: Publisher Summary The rostral ventrolateral medulla (RVL) contains a population of reticulospinal, sympathoexcitatory neurons. The regulation of the discharge of RVL-spinal vasomotor neurons by afferent pathways to the RVL underlies many reflex adjustments of circulation in response to peripheral and central stimuli. While vasomotor neurons of the RVL are presumed to exert their sympathoexcitatory effects over pathways terminating in the intermediolateral nucleus (IML) of the thoracolumbar spinal cord, little is known of the role played by specific spinal transmitter systems in mediating the increases in sympathetic nerve activity evoked by RVL neuronal discharge. This chapter discusses the combination of electrophysiological, immunocytochemical, and receptor autoradiographic techniques to test the hypothesis that an excitatory amino acid is the fast transmitter implicated in RVL-evoked excitation of sympathetic preganglionic neurons (SPNs). Results suggest that RVL stimulation causes the release of glutamate from nerve terminals in the IML that interacts with glutamate receptors of the kainate subtype to excite SPNs, thereby, producing an increase in sympathetic nerve activity and arterial pressure.

Ensemble proprioceptive activity in the cat step cycle: towards a representative look-up chart.

Abstract: Analysis of the control of movement in tasks such as stepping is severely restricted by the lack of quantitative data on the ensemble activity of afferents in the numerous muscles involved. We have started to build up a quantitative “look-up-chart” of the ensemble afferent and efferent profiles in the cat step cycle. To this end, we have developed software which allows us to digitize afferent firing, muscle length and electromyogram (EMG) activity, and to align segments for averaging by choosing one or more reference points in the step cycle. The ensemble firing of triceps surae la afferents showed lower than expected mean and peak rates, whereas triceps group II and Ib afferents were more active than predicted. There were small but significant transients in Ia firing at foot-off and touch-down which could not be explained in terms of origin-to-insertion length alone. They were most likely caused by propagated mechanical transients or tendon compliance effects giving rise to small differences between the origin-to-insertion length and the intramuscular length “seen” by spindles. Net ensemble Ia rates, based on previous estimates of spindle populations, probably exceed 25 kilo-impulses/second (ki.p.s.) in some muscles. Inputs as large as this are likely to contribute significantly to reflex control.

Attempts to visualize nicotinic receptors in the brain of monkey and man by positron emission tomography.

Abstract: Publisher Summary This chapter investigates the nicotinic receptors in the brain of monkey and man by positron emission tomography. The topographic distribution and the biochemical characteristics of these receptors is investigated by autoradiography in animals. The cholinergic nicotinic receptors appear, perhaps to a greater extent than other receptors, to be characterized by heterogeneity, diversity and plasticity which may be brought about through different combinations of receptor subunits. By use of positron emission tomography (PET) it has now become possible to visualize receptor binding in the brain in vivo. By labeling specific ligands with positron emitting radionuclides such as 11C or 18F, images of different neuroreceptor populations can be obtained from living animals or human subjects. Thus the technique contains a great potential for further research in psychopharmacology and neuropathology. The first attempt to visualize central nicotine receptors in vivo by use of PET was done in monkeys. Nine female Rhesus monkeys (6 - 10 kg) were anesthetized with 100 mg of ketamine and 50- 100 mg of diazepam. The animal was positioned in the positron emission tomography, so that the lowest of four horizontal transsections included the cerebellum and the basal parts of the temporal lobes. The present results from PET studies on monkeys and men support the evidence from previous pharmacological and neurophysiological studies that specific nicotinic binding sites are present in the brain. The time course of blood levels of [11C] nicotine and its rapid uptake into the brain were similar in the monkeys and the human subjects.

Possible functions of transmitter-controlled plateau potentials in alpha motoneurones.

Abstract: An increasing number of vertebrate central neurones has been shown to possess complex membrane properties. However, the functional significance of such properties is unclear. The aim of the present paper is to review some old and new findings in this field from this laboratory. First, a bistability in α motoneurones in reduced preparations is described. Thereafter we present some new data on a bistable behaviour in motor units in unrestrained intact animals during posture. Finally, the possible role of motoneuronal bistability in locomotion and in spasticity is discussed. Recently a bistable firing behaviour in motoneurones was described in the unanaesthetized decerebrate cat. This behaviour is generated by a plateau potential, which causes long-lasting excitability increase and can be initiated and terminated by short-lasting synaptic excitation and inhibition respectively, and is contingent upon activity in descending noradrenergic and serotonergic systems. In an in vitro preparation of the turtle spinal cord the plateau potential was shown to be serotonin dependent and generated by a voltage-dependent non-inactivating calcium conductance. In order to elucidate possible functional consequences of a bistable firing behaviour in the intact animal, the firing pattern of individual soleus motor units was studied by means of chronic EMG registration in awake unrestrained rats during quiet standing. Implanted electrodes allowed the delivery of excitatory and inhibitory stimulus trains to the motoneurones. It was found that short-lasting synaptic stimulation could induce maintained shifts between two stable levels of motoneurone firing frequencies, as in the decerebrate cat. Spontaneous shifts between the same two levels were also present. It seems most likely that plateau potentials are responsible for this bistable firing property in intact animals. The role of plateau potentials in locomotion is difficult to study. At present there are no clear indications of the utilization of plateau potentials in locomotion in intact animals. However, “clamped frequency” bursts which are observed in fictive locomotion in spinal cats might be explained by plateaus. The existence of plateau potentials in motoneurones may also be of importance in spasticity. Therefore, the development of spasticity in two spinalized cats was followed for 3 weeks. Acute experiments demonstrated plateau potentials in some motoneurones in this preparation.

Inhibitory vasomotor neurons in the caudal ventrolateral region of the medulla oblongata.

Abstract: Publisher Summary This chapter gives a brief history of the discovery of sympathoinhibitory vasomotor neurons in the caudal ventrolateral medulla and then addresses particular aspects of their function by reviewing published work and presenting new experimental evidence. The definition of inhibitory vasomotor neuronal groups within the medulla oblongata is a relatively recent achievement, facilitated by advances made in neuroanatomical methodology. A new generation of functional studies utilized focal intramedullary injections of pharmacological agents known to excite or inhibit nerve cell bodies, thereby reducing the problems of interpretation because of effects on the fibers of passage. The injection of L-glutamate into the caudal ventrolateral medulla in anaesthetized rabbits, rats, and cats caused a dramatic fall in arterial pressure, accompanied by the inhibition of peripheral sympathetic vasomotor tone. The possible physiological importance of this observation was emphasized by the ability of neuroinhibitory agents to increase arterial pressure when injected into the same region of the caudal ventrolateral medulla. In particular, muscimol, a long acting gamma aminobutyric acid (GABA) receptor-stimulating agent, caused a major increase in arterial pressure, sometimes associated with cardiac arrhythmias and pulmonary congestion. These observations suggested that the vasodepressor neurons are tonically active, at least in the anaesthetized animal.

Chapter 33 The cholinergic receptor system of the human brain: neurochemical and pharmacological aspects in aging and Alzheimer

Abstract: Publisher Summary The cholinergic system of the brain has been implicated in memory function. Evidence for this role is anatomical, physiological and pharmacological. In all diseases, pathological and biochemical lesions in the cholinergic neuron are localized mainly to the presynaptic region. Alterations include biochemical and morphological changes in the structures storing, synthesizing and releasing acetylcholine (ACh) and possibly also in cholinergic receptors regulating ACh release. In a comparison between cholinergic terminals in the central nervous system of normally aged and Alzheimer disease (AD) patients, it is apparent that muscarinic and nicotinic receptors are not equally affected. A survey including percent changes in nicotinic receptors in the frontal cortex of AD patients reveals a striking difference from aging normal controls. Both biopsy and autopsy studies show that in contrast with muscarinic receptors, the number of nicotinic receptors is strongly reduced in the frontal cortex of AD patients. This decrease correlates closely to pathological and clinical findings. Biochemical findings such as AChE and ChAt activity and nicotinic receptor binding also correlate with pathology and clinical findings. The results suggest that biochemical data obtained from a cortical biopsy may correlate more closely to the clinical picture than histological results based purely on counts of neuritic plaques and tangles.

The role of nicotinic receptors in the pathophysiology of Alzheimer's disease.

Abstract: Publisher Summary This chapter discusses the role of nicotinic receptors in the pathophysiology of Alzheimer's disease (AD). The nicotinic receptor binding sites in human brain have been identified and characterized by various radioligands such as the nicotinic antagonists [ 3 H]α-bungarotoxin ([ 3 H]Btx), [ 3 H]tubocurarine and the agonists [ 3 H]ACh, [ 3 H]nicotine and [ 3 H]methylcarbamylcholine. In rodent brain receptor binding experiments in tissue homogenates or thin tissue slices (autoradiography) have demonstrated a different localization of the antagonist [3H]Btx sites compared to the agonist sites labeled by [3H]ACh and [3H]nicotine. The difference in antagonist/agonist sites is evident at molecular level. Subtypes of nicotinic receptors are widely distributed in the human brain. Some of the nicotinic receptors are presynaptically located. In AD/SDAT brains there is a loss of high affinity to low affinity nicotinic receptors which partly might be due to an interconversion of high affinity to low affinity nicotinic sites with a simultaneous reduction in binding affinity for the low affinity sites. By lowering the affinity of the nicotinic sites, quick desensitization phenomena can be devoided and the nicotinic receptors might influence the release of acetylcholine. The finding that cholinesterase inhibitors such as THA restore the ACh release in AD/SDAT brain tissue via interaction with the nicotinic receptors open up new therapeutic strategies in the treatment of AD/SDAT and related disorders.

Subjective and behavioural effects of nicotine in humans: some sources of individual variation.

Abstract: Despite its addictiveness, the subjective effects of nicotine in "smoking doses" are of low intensity compared with those of other addictive drugs. Although mildly pleasurable to many regular users, it causes no striking euphoriant effects and its effects on mood, performance and the level of arousal are relatively small. This chapter does not attempt to list or review the numerous effects of nicotine, but focuses instead on some of the multiple sources of individual variation. The subjective and behavioral effects of nicotine in humans differ markedly, not only between individuals but also within individuals, according to the stage of their smoking career, their level of dependence and the time since their last few doses. Some of the influences and mechanisms discussed include innate and acquired factors, pharmacokinetic factors, acute and chronic tolerance, learning and conditioning. It is not clear to what extent the effects of nicotine are primary, or how much they reflect reversal or relief of acquired withdrawal effects. Only one study has found a "rebound" element in the effects of withdrawal and although chronic exposure to nicotine induces an increase in the number of nicotinic receptors, chronic tolerance to nicotine has not been demonstrated in humans. Acute tolerance (tachyphylaxis) develops rapidly to many of the effects of nicotine and is completely reversible after nicotine depletion. Other effects of nicotine are less sensitive to acute tolerance. It is suggested that it is the effects of nicotine at postsynaptic receptors that are most susceptible to acute tolerance and that those mediated by its action at presynaptic receptors are less sensitive to it. Due to accumulation of nicotine and other pharmacokinetic factors, for most of the day and much of the night, regular smokers have high levels of acute tolerance to nicotine. In other words, there is a chronic partial blockade of its agonist effects at postsynaptic receptors. This explains why nicotinic receptors are upregulated rather than downregulated and why heavy smokers experience no subjective effects from a cigarette smoked during the course of a normal smoking day. When the effects of acute tolerance are unmasked after abstinence for 24 h, it is the more addicted heavy smokers who experienced more severe withdrawal effects who also have stronger subjective and heart rate effects following the first post-abstinence cigarette. Their greater sensitivity to nicotine after abstinence may reflect their higher density of unoccupied nicotinic receptors. On the other hand, those who have higher innate sensitivity may be more likely to take up smoking and to become more dependent if they

Head kinematic during various motor tasks in humans.

Abstract: Head kinematic during various motor tasks was studied in ten subjects. The movement of the body was recorded with a video system (E.L.I.T.E.) which allows a computer reconstruction of three-dimensional motion of selected points on the body. Analysis is focused on head rotation in the horizontal and vertical planes. The results demonstrate that the amplitude and the maximum velocity do not exceed respectively 38 deg/s and 185 deg/s. However the head is intermittently stabilized and the angle of this stabilization is dependent upon the task and related to the direction of gaze. Darkness had no significant effect on head rotational velocity during walking but caused a decrease in velocity during running and hopping. The results suggest that head stabilization (1) is related to an ocular fixation point in the direction of gaze in space and (2) is probably regulated on the basis of a predictive mode of sensory motor control.

Control of neurosecretory vasopressin cells by noradrenergic projections of the caudal ventrolateral medulla.

Abstract: Publisher Summary Physiological stimuli capable of producing reflex alterations in arginine vasopressin (AVP) secretion, such as hemorrhage or pain, are well characterized Much less certain, however, are the identities of the pathways by which relevant sensory information entering the central nervous system at the level of the medulla oblongata or spinal cord reaches neurosecretory AVP cells of the hypothalamus Considerable attention has been devoted to the possible involvement of noradrenergic (NA) projections arising from the caudal ventrolateral medulla Anatomical studies suggest that visceral afferent information is relayed to the ventrolateral medulla (VLM) via both ventrolaterally directed projections from the nucleus of the tractus solitarius and ascending spinoreticular projections These inputs are thought to contribute to circulatory regulation both by altering the activity of VLM efferent projections controlling autonomic outflow to the heart and vascular beds and by altering the NA output of the caudal VLM to the supraoptic (SON) and paraventricular (PVN) nuclei, the areas in which neurosecretory AVP synthesizing perikarya are concentrated The activation of noradrenergic afferents arising from the A1 cell group of the caudal VLM excites neurosecretory AVP cells of both the supraoptic and paraventricular nuclei, thus, stimulating the release of this potent vasoconstrictor into the circulation

Mechanisms underlying the serotonergic modulation of the spinal circuitry for locomotion in lamprey.

Abstract: The central nervous system of the lamprey contains serotonergic (5-hydroxytryptamine, 5-HT) neurones both in the spinal cord and in the brainstem. Endogenously released 5-HT from these systems modulates the pattern of fictive locomotion induced in the in vitro preparation; the burst rate is lowered and burst discharges become longer and of higher intensity. Local application of 5-HT, mimicking activation of the 5-HT systems, has a specific effect on the late phase of the afterhyperpolarization (AHP) in motoneurones and interneurones. 5-HT markedly reduces the amplitude of the late AHP without affecting passive membrane properties or the shape or threshold of the action potential. This 5-HT effect appears to result from a direct action on the calcium-dependent potassium channels underlying the late phase of the AHP. A reduction of the amplitude of the AHP will result in altered spike discharge characteristics, with potentiation of the response (discharge rate) to a given excitatory input in all neurones influenced by 5-HT. It is suggested that the modulatory effect of 5-HT on fictive locomotion can be attributed to its action on the late AHP and thereby to the potentiation of excitability in excitatory and inhibitory interneurones in the generator circuitry. This has been further corroborated in computer simulation studies of a network model, where the action of 5-HT was simulated by decreasing AHP amplitude, resulting in a slowing of the rhythm analogous to the effect demonstrated experimentally.

The role of stretch and vestibulo-spinal reflexes in the generation of human equilibrating reactions.

Abstract: Equilibrating reactions in standing humans were examined for evidence that either vestibulo-spinal or proprioceptive long loop stretch reflexes from ankle muscles, or both, are responsible for the control and organization of rapid postural responses. Specifically, the hypothesis was tested that the same postural response could be evoked by rotation of the support surface that mimics the ankle rotation occurring during support surface translations. Rotation perturbations evoked postural responses in leg and trunk muscles that were different in strategy, synergy and coactivation from translation responses, even though the short-latency response in the stretched triceps surae muscles was equal in latency and size. Movement patterns consisted of a stiffening strategy and hardly any compensating ankle rotation for rotation stimuli, and a multi-link strategy with motion focused about the neck, hip and ankle joints for translation stimuli. Dorsiflexion rotations caused earlier and stronger responses in tibialis anterior and quadriceps muscles just post to the onset of paraspinal muscles, whereas rearward translation activated soleus and abdominals strongest, both just prior to hamstring muscles. Correlated activation strengths of agonist and antagonist activity was a common feature for both types of perturbation, albeit, only in the ankle muscles for rotations and only in the trunk muscles for translations. These data suggest that sensory inputs, other than those generated in the lower leg predominate, in the triggering and modulation of equilibrating reactions. Possible candidates are those of the vestibular system or proprioceptive inputs from the trunk.

Adrenergic neurons in the rostral ventrolateral medulla: Ultrastructure and synaptic relations with other transmitter-identified neurons

Abstract: The first part of this chapter demonstrates that the C1 adrenergic neurons have high mitochondrial content and a close proximity to capillaries and glia suggestive of a high metabolic activity and a possible chemosensory function. Adrenergic terminals arising primarily from these neurons (1) can influence sympathetic nerve discharge through direct contacts on sympathetic preganglionic neurons in the IML of the spinal cord; and (2) are one of the more prevalent synaptic inputs to the principally noradrenergic neurons in the locus coeruleus. In both the IML and locus coeruleus, adrenergic terminals may be either excitatory (asymmetric synapses) or inhibitory (symmetric synapses) depending on their distribution on the post-synaptic target. The second part of this chapter shows that C1 adrenergic neurons in the RVL are modulated by synaptic associations with a variety of transmitter systems (see schematic Fig. 8). Specifically, C1 adrenergic neurons receive (1) major inhibitory input (symmetric synapses) from GABA-ergic and opioid terminals as well as from unidentified (unlabelled) transmitter-containing terminals; (2) major excitatory input (asymmetric synapses) from terminals containing substance P as well as other unidentified terminals and (3) minor inputs from cholinergic, adrenergic and noradrenergic pathways. Moreover, cholinergic terminals in the RVL form symmetric synapses mainly on unidentified transmitter-containing neurons rather than the C1 neurons suggesting that the reported cardiovascular effects of cholinergic agents in the RVL are most likely mediated via inhibitory interneurons. Within the RVL, adrenergic and noradrenergic terminals innervate cholinergic and opioid neurons. Thus, these results not only provide direct evidence that a number of transmitters modulate the activity of C1 adrenergic neurons, but also suggest new directions for studies of functional interactions involving catecholaminergic regulation of other transmitter-containing neurons within the RVL.

Chapter 34 Significance of proprioceptive mechanisms in the regulation of stance

Abstract: Compensatory electromyographic (EMG) responses and several biomechanical parameters were studied following impulsive disturbance of the limbs during stance of human volunteers on a treadmill. Treadmill acceleration impulses were backwards or forwards directed, or their initial direction was reversed after 30 ms. Backwards directed impulses were followed by gastrocnemius, forwards directed ones by tibialis anterior EMG responses (latency 65 to 75 ms) whose durations depended on impulse duration. When the direction of the impulse was reversed, the respective antagonistic leg muscles were activated again with a delay of 68 to 75 ms after onset of stretch of these muscles. The behaviour of the EMG responses could best be correlated to the displacement at the ankle joint and may be described in terms of a stretch reflex response. The results indicate that these stretch reflex responses help control of the body' centre of gravity thereby preventing falling. Head movements induced by the impulses showed little correlation with the appearance of the EMG responses, suggesting that the vestibular system is unlikely to be directly involved in the generation of these responses. Vestibular signals may, however, significantly contribute to slow body sway stabilizaton.

The vestibulo-ocular reflex: an outdated concept?

Abstract: Traditionally, the vestibulo-ocular reflex (VOR) is described as a distinct, phylogenetically old oculomotor subsystem, which serves to stabilize gaze direction. It is supposed to act as a stereotyped reflex with definite input-output relations, which can be measured by rotating a subject passively in darkness, and which are kept at an ideal level by adaptive, parametric adjustments. This paper argues that such a view is not realistic: (1) the VOR in darkness does not have an ideal, or even well defined, gain; (2) a fixed, automatic VOR is not appropriate in most behavioural situations, and would need continuous conditioning by other subsystems. As there is no compelling phylogenetic, physiological or anatomical evidence for an independent VOR subsystem, a more fruitful hypothesis may be that vestibular signals are just one of many inputs to a spatial localization process, which computes the relative position (and motion) between the subject and a target of his choice. The VOR in darkness may represent no more than a default operation, based on incomplete information, of this larger, multiple input gaze control system. Likewise, adaptation phenomena of the VOR in darkness may be merely an epiphenomenon of adaptation of gaze control with vision active.

Chemical neuroanatomy of the parapyramidal region of the ventral medulla in the rat.

Abstract: Publisher Summary The parapyramidal region of the ventral medulla is a neurochemically complex group of cells that projects to cardiovascular-related central nervous system (CNS) nuclei and that affects sympathetic activity to the cardiovascular system Anatomical, neurochemical, and functional evidence showed that several regions of the ventral medulla are involved in cardiovascular control One of these regions, an area that is referred to as the parapyramidal region, consists of neurons located close to the ventral surface and lateral to the pyramidal tract The neurons of the parapyramidal region of the ventral medulla project to the intermediolateral cell column (IML) of the thoracic spinal cord and to the nucleus of the solitary tract (NTS) The activation of the parapyramidal region increases mean arterial blood pressure, an effect that is independent of the more laterally located C1 (rostra1ventrolateral medulla) region Classical studies by several investigators showed that the exposure of the ventral surface of the medulla to various excitatory and inhibitory drugs, alterations in pC0 2 and electrical stimulation or focal cooling results in marked changes in cardiovascular function

The selectivity of descending vasomotor control by subretrofacial neurons.

Abstract: Publisher Summary The notion that neurons in the rostral ventrolateral medulla play an important part in cardiovascular control is now widely accepted. This chapter focuses on a compact group of spinally projecting neurons termed as the “subretrofacial nucleus” (SRF) and argues that this set of neurons is responsible for mediating the region's vasopressor actions. It also presets evidence that SRF neurons selectively drive cardiovascular sympathetic nerves—that is, to heart, blood vessels and, adrenal medulla. The chapter presents data that support the view that within SRF there are neural subpopulations with even greater specificity of action and that these may be functionally dedicated to control vasomotor supply to single tissues. The SRF consists of a compact column of medium-small cells on either side of the medulla, ventral to and separated from the retrofacial nucleus. Electrophysiological recording experiments have provided data to support the idea that SRF neurons form a descending vasomotor pathway. In the cat, studies from two laboratories have localized bulbospinal neurons with cardiovascular properties in a compact group ventral to the retrofacial nucleus.

Nucleus tractus solitarius innervation of supraoptic nucleus: anatomical and electrophysiological studies in the rat suggest differential innervation of oxytocin and vasopressin neurons.

Abstract: Publisher Summary There is substantial anatomical documentation of projections to the hypothalamic paraventricular nucleus from the caudal ventrolateral and dorsomedial medulla. Moreover, electrophysiological data do indeed indicate that electrical stimulation in the caudal ventrolateral medulla (cVLM) and the caudal nucleus tractus solitarius (cNTS) is facilitatory to paraventricular vasopressin-secreting magnocellular neurosecretory neurons. Data from supraoptic nucleus, which is composed almost exclusively of magnocellular neurons projecting to the neurohypophysis, also support a selective excitatory input from A1 ventrolateral medulla cells to vasopressin-secreting neurons. In contrast, preliminary observations indicate that electrical stimulation in cNTS excites both vasopressin- and oxytocin-secreting supraoptic neurons. Inputs to the NTS arriving in glossopharyngeal and vagal afferents have at least two pathways whereby they can influence hypothalamic magnocellular neurosecretory neurons. Information destined to enhance the activity of vasopressinergic neurons—for example, through the unloading of peripheral baroreceptors consequent to hemorrhage or the loss of blood volume—seems to be preferentially channeled through the A1 neurons of the caudal ventrolateral medulla.

Protective effects of chronic nicotine treatment on lesioned nigrostriatal dopamine neurons in the male rat

Abstract: The present results demonstrate that chronic nicotine treatment can in part protect against mechanically-induced and neurotoxin-induced degeneration of nigrostriatal DA neurons. These results indicate that in sufficient doses chronic treatment with nicotine may be considered in the pharmacological treatment of Parkinson's disease. It remains to be demonstrated whether these protective actions can be extended to include also other injured neurons such as the cholinergic neurons, known to be severely affected in Alzheimer's disease.