No full-text available
To read the full-text of this research,
you can request a copy directly from the author.
Abstract
This book stemmed from an IBRO symposium that took place in Leipzig, from 12 to 14 August 1987. Local organizers were D. Biesold and V. Bigl from the Department of Neurochemistry at the Paul Flechsig Institute for Brain Research. Some of the contributors to this book were members of the International Program Committee: L. L. Butcher, M.-M. Mesulam, G. Pepeu, and M. Steriade. Leipzig was chosen as the site of a meeting devoted to brain cholinergic systems because some historical steps in this domain are related to the German city. Indeed, after the initial description of the substantia innominata (die ungennante Marksubstanz) by J. C. Reil (1809), T. Meynert, one of the founders of scientifically oriented psychiatry, designated this structure as Ganglion der Hirnschenkelschlinge in a volume published in Leipzig (1872). The name of Meynert was linked to the nucleus basalis by A. Koelliker in a Handbook, also published in Leipzig (1896).
Since edited volumes rarely allow the expression of coherence between the numerous authors, we decided to ask for chapters from only a limited number of participants and we invited other colleagues, who could not attend the symposium, to submit their contribution. Our goal was to present current data and concepts about the morphology, physiology, and pathology of brainstem and basal forebrain cholinergic systems controlling the excitability of the thalamus and cerebral cortex. It is a pleasure to extend our thanks to all colleagues, whose names and affiliations are listed, for taking time from busy lives to survey their fields of interest. We also express our appreciation to Oxford University Press for an agreeable collaboration and support in the preparation of this book.
Over the past several decades, acetylcholine (ACh) has been recognized as an important factor in neocortical function. The neocortical source of ACh arises from the basal forebrain, where specific nuclear groups supply the entire cortical mantle with this ubiquitous neurotransmitter (Mesulam et al., 1983; Rye et al., 1984; Wainer and Mesulam, 1990). Although numerous actions have been identified with ACh, in the cerebral cortex it appears to primarily enhance neural activity (for review see McCormick, 1992). ACh acts on both muscarinic and nicotinic receptors; however, the excitatory effect of ACh in the cerebral cortex is predominantly muscarinic and mediated by mechanisms that block K+ conductance (Krnjevic and Phillis, 1963; Krnjevic et al., 1971; Halliwell and Adams, 1982; Brown, 1983; McCormick and Prince, 1985). In the neocortex, ACh appears to work through several mechanisms; one of these blocks a voltage-dependent K+ current, which leads to a long-lasting increase in neural excitability (Brown and Adams, 1980; Madison and Nicoll, 1984; McCormick and Prince, 1987). It also impedes a Ca2+-activated potassium current, which is not substantially dependent on voltage (McCormick and Williamson, 1989). Additional contributions of a Na+-activated K+ current block and a slow afterdepolarization of unknown origin have also been implicated as potential mechanisms of ACh action in neocortex (McCormick and Prince, 1986; Schwindt et al., 1989).
We examined acetylcholine (ACh) release in the frontal cortex and in the vibrissae representation in the somatosensory cortex in rats during the acquisition of a tactile discrimination or during nondiscrimination control procedures. Microdialysis samples were collected for 1 h in the home cage and then for the duration of 30 discrimination or control trials, across 5 consecutive days. Both groups showed significant testing-induced increases in ACh release in both cortical sites. However, rats in the discrimination training group showed even greater testing-induced increases in ACh release in the somatosensory cortex and had a proportionately greater increase in somatosensory cortex than in frontal cortex, relative to controls. The results suggest that, in addition to the widespread enhancement of ACh release associated with appetitive conditioning procedures in general, tactile discrimination training causes a regionally specific enhancement in ACh release in the somatosensory cortex that is related to discrimination performance.
The basal forebrain and in particular its cholinergic projections to the cerebral cortex have long been implicated in the maintenance of cortical activation. This review summarizes evidence supporting a close link between basal forebrain neuronal activity and the cortical electroencephalogram (EEG). The anatomy of basal forebrain projections and effects of acetylcholine on cortical and thalamic neurons are discussed along with the modulatory inputs to basal forebrain neurons. As both cholinergic and GABAergic basal forebrain neurons project to the cortex, identification of the transmitter specificity of basal forebrain neurons is critical for correlating their activity with the activity of cortical neurons and the EEG. Characteristics of the different basal forebrain neurons from in vitro and in vivo studies are summarized which might make it possible to identify different neuronal types. Recent evidence suggests that basal forebrain neurons activate the cortex not only tonically, as previously shown, but also phasically. Data on basal forebrain neuronal activity are presented, clearly showing that there are strong tonic and phasic correlations between the firing of individual basal forebrain cells and the cortical activity. Close analysis of temporal correlation indicates that changes in basal forebrain neuronal activity precede those in the cortex. While correlational, these data, together with the anatomical and pharmacological findings, suggest that the basal forebrain has an important role in regulating both the tonic and the phasic functioning of the cortex.
Neuronal plasticity that involves large scale anatomical changes is restricted to the early period of development. Beyond this there is a “critical period” during which processes of formation of arborization patterns of afferent axons and of synaptic contacts form a basis for plasticity (for a review see Rauschecker, 1991). Although these findings set limits on the prospects for plasticity in the mature nervous system, a number of experimental paradigms have demonstrated considerable functional plasticity in the adult brain. These involve study of the topographic representations of the somatosensory and motor cortices (for reviews see Dykes, 1990; Kaas, 1991; Calford, 1995), the auditory cortex (Robertson and Irvine, 1989; Rajan et al., 1993) and primary visual cortex (Kaas et al., 1990; Gilbert and Wiesel, 1992) following a restricted nerve injury or a behavioural manipulation (Recanzone et al., 1992a,b, 1993). These topographic representations have been chosen as appropriate models because they serve as scales against which any induced changes can be measured. Work in this laboratory over the past nine years has given emphasis to the role of inhibition in the early events following the loss (or inactivation) of a subset of the inputs to a brain area. The initial event is a disinhibition which allows expression (unmasking) of otherwise ineffective inputs (Calford and Tweedale, 1988, 1991a,b).
The orderly representations of sensory surfaces in the brains of adult mammals have the capacity to reor ganize after injuries that deprive these representations of some of their normal sources of activation. Such reorganizations can be produced by injury that occurs peripherally, such as nerve damage or amputation, or after injury to the CNS, such as spinal cord damage or cortical lesion. These changes likely are mediated by a number of different mechanisms, and can be extensive and involve the growth of new connections. Finally, some types of reorganizations may help mediate the recovery of lost functions, whereas others may lead to sensory abnormalities and perceptual errors. NEUROSCIENTIST 3:123-130, 1997
Multiunit recordings along mediolateral rows in the primary somatosensory cortex of the animals described by C. Avendafio, D. Umbriaco, R. W. Dykes, and L. Descarries (1995, J. Comp. Neurol. 354:321–332) provided information about the functional status of the regions in and near the deafferented cortex. Responses changed along this axis from normally organized receptive fields in the hindlimb representation through a transition zone of unusually small receptive fields into the clearly deafferented forelimb representation, where receptive fields were uncommon and often had unusual characteristics.
The most abrupt change along this axis was the appearance of a repetitive, bursting discharge pattern in the multiunit activity near the border of the deprived cortex. The appearance of this pattern was used as a reference to describe differences between normal and deprived cortices. The nature of these differences evolved with time. Much of the deprived cortex lacked identifiable receptive fields for months after the nerve transections and, 1 year later, still only about half of the recording sites within the deprived region displayed organized receptive fields. Some sites within the deprived region lacking definable receptive fields could be excited at long latencies by somatic stimuli anywhere on the body. With time, regions of normal cortex near the border with the deprived zone became more involved in these processes. Spontaneous activity and thresholds also changed with time in both normal and deprived cortices.
These electrophysiological responses occurred during a time when choline acetyltransferase staining was reduced in and around the deprived cortex (Avendaño et al., 1995); the effects of nerve transections were most pronounced between the 8th and 13th weeks, as was the reduction in immunostaining; however, although immunostaining had returned to normal levels at 1 year, many parts of the deprived cortex remained without new afferent drive, some being unresponsive to any somatic stimuli. © 1995 Wiley‐Liss, Inc.
To test the hypothesis that cortical reorganization depends on acetylcholine and one or more of the monoamines, the hindpaw cortex was mapped in eight different groups of mature rats: (1) untreated; (2) after sciatic nerve transection; (3) after intraperitoneal injections of reserpine, to reduce the level of cortical monoamines; (4) after ibotenic acid lesion of the nucleus basalis of Meynert (NBM), to destroy cholinergic cells projecting to the cortex; (5) after reserpine treatment and transection; (6) after ibotenic acid lesion and transection; (7) after reserpine treatment and ibotenic acid lesion; and (8) after reserpine treatment, ibotenic acid lesion, and transection. Four days after transection, the cortex had reorganized in the transected group. However, this process of reorganization was prevented in transected animals with NBM lesions. Treatment with reserpine alone did not inhibit the process of reorganization, nor did it enhance the effect of NBM lesion. Nonetheless, the animals treated with reserpine and transected had higher response thresholds in the reorganized cortex than did the animals that were treated but not transected. These data suggest that acetylcholine plays an important role in the early reorganization that follows deafferentation, and that one or more of the monoamines may have other influences on reorganization of the primary somatosensory cortex of adult rats.
The functional reorganization of cerebral cortex following peripheral deafferentation is associated with changes in a number of neurotransmitters and related molecules. Acetylcholine (ACh) enhances neuronal responsiveness and could play a role in activity-dependent cortical plasticity. In this study, choline acetyltransferase (ChAT) immunohistochemistry was used to investigate ACh innervation of the primary somatosensory cortex in cats sustaining complete unilateral forearm and paw denervations. Survival times of 2-52 weeks were examined. The deafferented contralateral cortex was defined electrophysiologically, and quantitative estimates of ChAT-immunoreactive fiber density were obtained from the forelimb and hindlimb sectors of area 3b in both hemispheres. In the 3b forelimb sector contralateral to the deafferentation, a decrease in density of ChAT-positive fibers relative to the ipsilateral hemisphere was apparent at 2 weeks and most pronounced at 13 weeks, involving all cortical layers except layer I. There was no such decrease in the hindlimb sector, but the loss of ChAT immunoreactivity extended to sectors representing proximal forelimb and trunk. Changes in ChAT immunoreactivity were no longer found after 1 year of survival. This long-lasting but reversible lowering of ChAT immunoreactivity could result from a loss of afferent activity in basalis neurons and/or trophic influences retrogradely exerted by cortex on these cells. Reduced ACh transmission might then contribute to the loss of gamma aminobutyric acid (GABA) inhibition in the deafferented cortex by decreasing the activation of inhibitory interneurons. The long-term recovery of a normal ChAT immunoreactivity in cortex could be a consequence of its functional reorganization.
Muscarinic-type acetylcholine (ACh) receptor are involved in a variety of cortical functions. ACh "activates" neocortex; simultaneously modifying spontaneous subthreshold activity, intrinsic neuronal oscillations and spike discharge modes, and responsiveness to fast (putative glutamatergic) synaptic inputs. However, beyond the general involvement of muscarinic receptors, a mechanistic understanding of integrated cholinergic actions, and interactions with non-cholinergic transmission, is lacking. We have addressed this problem using intracellular recordings from the in vitro auditory neocortex. First, we investigated cholinergic modification of responses to the excitatory amino acid glutamate. ACh, or the muscarinic agonist methacholine, produced a lasting enhancement of glutamate-mediated membrane depolarizations. Muscarinic receptors of the M1 and/or M3 subtype, rather than M2 or nicotinic receptors, mediated this enhancement. Subsequently, we investigated whether second messenger systems contribute to observed muscarinic actions. Activation of protein kinase C with phorbol 12,13-dibutyrate (4 beta-PDBu), enhanced neuronal responses to glutamate. The effect of 4 beta-PDBu was attenuated by the kinase antagonist H7. Finally, we attempted to identify postsynaptic actions of endogenous ACh. Tetanic stimulation of cholinergic afferents elicited voltage-dependent effects, including reduced spike frequency adaptation and reduced slow afterhyperpolarization (sAHP) elicited by transmembrane depolarizing stimuli. These effects were mimicked by methacholine, enhanced by eserine, and antagonized by muscarinic receptor antagonists. These data suggest that cholinergic modulation in neocortex likely involves the integrated actions of diverse mechanisms, primarily gated by muscarinic receptors, and at least partly involving second messenger systems.
This study examined the effects of a nerve transection on monoamine release from primary somatosensory cortex. The technique of microdialysis was employed to sample extracellular levels of norepinephrine (NE), 3,4-dihydroxyphenylacetic acid (DOPAC), 5-hydroxyindole-3-acetic acid (5-HIAA) and homovanillic acid (HVA) in the barrel field of freely moving rats following the surgical transection of the contralateral infraorbital nerve. Microdialysates obtained 3, 4, and 5 days after deafferentation were analyzed using high-performance liquid chromatography with electrochemical detection. We found a significant increase in the release of the dopamine metabolites, DOPAC and HVA from the deafferented cortex. Three days after deafferentation the release of DOPAC was three-fold higher in the deafferented than in the control animals, and remained about 100% higher in the next two days in this group of animals. The release of HVA showed a gradual increase following the deafferentation procedure, since a 92% larger value on day 3 increased to a 338% difference on day 5. On the other hand, the release rate of NE and the levels of the serotonin metabolite 5-HIAA were not significantly affected by the deafferentation procedure. These results are discussed in the context of the possible participation of dopamine in the reorganization of the deafferented somatosensory cortex.
Experiments involving single-unit recordings and microiontophoresis were carried out in the barrel cortex of awake, adult rats subjected to whisker pairing, an associative learning paradigm where deflections of the recorded neuron's principle vibrissa (S2) are repeatedly paired with those of a non-adjacent one (S1). Whisker pairing with a 300 ms interstimulus interval was applied to 61 cells. In 23 cases, there was no other manipulation whereas in the remaining 38, pairing occurred in the presence of one of three pharmacological agents previously shown to modulate learning, receptive field plasticity and long-term potentiation: N-methyl-D-aspartic acid (NMDA) (n=8), the NMDA receptor antagonist AP5 (n=17) or the nitric oxide synthase inhibitor L-nitro-arginine-N-methyl-ester (L-NAME) (n=13). Non-associative (unpaired) experiments (n=14) and delivery of pharmacological agents without pairing (n=14) served as controls. Changes in neuronal responsiveness to S1 following one of these procedures were calculated and adjusted relative to changes in the responses to S2. On average, whisker pairing alone yielded a 7% increase in the responses to S1. This enhancement differed significantly from the 17% decrease obtained in the non-associative control condition and could not be attributed to variations in the state of the animals because analysis of the cervical and facial muscle electromyograms revealed that periods of increased muscular activity, reflecting heightened arousal, were infrequent (less than 4% of a complete experiment on average) and occurred randomly. The enhancement of the responses to S1 was further increased when whisker pairing was performed in the presence of L-NAME (27%) or NMDA (35%) whereas AP5 reduced it to 1%. During the delivery period, NMDA enhanced both neuronal excitability and responsiveness to S1 whereas AP5 depressed them. However, the effects of both substances disappeared immediately after administration had ended. L-NAME did not affect the level of ongoing activity and responses to S1 significantly. From these data, we concluded that, since the changes in the responses to S1 lasted longer than the periods of both whisker pairing and drug delivery, they were not residual excitatory or inhibitory drug effects on neuronal excitability. Thus, our results indicate that, relative to the unpaired controls, whisker pairing led to a 24% increase in the responsiveness of barrel cortex neurons to peripheral stimulation and that these changes were modulated by the local application of pharmacological agents that act upon NMDA receptors and pathways involving nitric oxide. We can infer that somatosensory cerebral cortex is one site where plasticity emerges following whisker pairing.
Post-lesion recovery of vestibular functions is a suitable model for studying adult central nervous system plasticity. The vestibular nuclei complex (VN) plays a major role in the recovery process and neurochemical reorganizations have been described at this brainstem level. The cholinergic system should be involved because administration of cholinergic agonists and antagonists modify the recovery time course. This study was aimed at analysing the postlesion changes in choline acetyltransferase immunoreactivity (ChAT-Ir) in the VN of cats killed 1 week, 3 weeks or 1 year following unilateral vestibular neurectomy. ChAT-positive neurons and varicosities were immunohistochemically labelled and quantified (cell count and surface measurement, respectively) by means of an image analysing system. The spatial distribution of ChAT-Ir within the VN of control cats showed darkly stained neurons and varicosities mainly located in the caudal parts of the medial (MVN) and inferior (IVN) VN, the nucleus prepositus hypoglossi (PH) and, to a lesser extent, in the medial part of the superior vestibular nucleus (SVN). Lesion-induced changes consisted in a significant increase in both the number of ChAT-positive neurons (IVN, SVN) and the surface of ChAT-positive varicosities (IVN, SVN, PH). They were observed bilaterally in the acute (1 year and 3 weeks) and compensated (1 year) cats for the SVN and PH, while they persisted only in the IVN on the lesioned side in the compensated cats. These findings demonstrate vestibular lesion-induced reorganization of the cholinergic system in the IVN, SVN and PH which could contribute to postural and oculomotor function recovery.
Studies of the effects of peripheral and central lesions, perceptual learning and neurochemical modification on the sensory representations in cortex have had a dramatic effect in alerting neuroscientists and therapists to the reorganizational capacity of the adult brain. An intriguing aspect of some of these investigations, such as partial peripheral denervation, is the short-term expression of these changes. Indeed, in visual cortex, auditory cortex and somatosensory cortex loss of input from a region of the peripheral receptor epithelium (retinal, basilar and cutaneous, respectively) induces rapid expression of ectopic, or expanded, receptive fields of affected neurons and reorganization of topographic maps to fill in the representation of the denervated area. The extent of these changes can, in some cases, match the maximal extents demonstrated with chronic manipulations. The rapidity, and reversibility, of the effects rules out many possible explanations which involve synaptic plasticity and points to a capacity for representational plasticity being inherent in the circuitry of a topographic pathway. Consequently, topographic representations must be considered as manifestations of physiological interaction rather than as anatomical constructs. Interference with this interaction can produce an unmasking of previously inhibited responsiveness. Consideration of the nature of masking inhibition which is consistent with the precision and order of a topographic representation and which has a capacity for rapid plasticity requires, in addition to stimulus-driven inhibition, a source of tonic input from the periphery. Such input, acting locally to provide tonic inhibition, has been directly demonstrated in the somatosensory system and is consistent with results obtained in auditory and visual systems.
Many studies have examined changes in the topographic representations of the special senses in cerebral cortex following partial peripheral deafferentations. This approach has demonstrated the short- medium- and long-term aspects of plasticity. However, the extensive capacity for immediate plasticity, while first demonstrated more than 15 years ago, still challenges explanation. What such studies indicate is that each locus in sensory cortex receives viable input from a far wider area of the sensory epithelium than is represented in the normal receptive field, with the implication that much of this input is normally inhibited. Consideration of the geometric and temporal aspects of receptive field plasticity suggests that this inhibition must be tonic and must derive its driving input from a tonically active periphery.
This chapter reviews the evidence from physiological and psychophysical studies for plasticity in spectral processing, the mechanisms underlying this plasticity, and its therapeutic applications. Before examining this evidence, the nature of the changes that constitute evidence of plasticity requires consideration. It must be acknowledged, however, that there remains a substantial division between the human psychophysical and animal electrophysiological evidence for such plasticity. The bulk of the human psychophysical evidence has been derived from studies of perceptual learning on basic frequency discrimination or more complex spectral processing tasks. In contrast, the overwhelming bulk of animal electrophysiological evidence has been derived from studies of behavioral conditioning or of injury-induced plasticity. A substantial body of evidence has demonstrated that the spectral processing ability of human and animal listeners and the response characteristics of neurons in circuits at higher brain levels that are involved in auditory spectral processing can be modified by experience. This plasticity can occur because of particular forms of training or perceptual experience, or because of damage to the cochlea that results in changes in input to the central nervous system and in partial hearing loss.
ResearchGate has not been able to resolve any references for this publication.