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D M Armstrong

Publications and source records attributed to D M Armstrong.

At least 19 recordsLinked to original sources
PubMed1992

Ultrastructural examination of enkephalin and substance P input to cholinergic neurons within the rat neostriatum.

Enkephalin and substance P-containing inputs to cholinergic perikarya were examined in the rat neostriatum using an ultrastructural immunocytochemical double-labeling protocol. Sections of rat neostriatum were double-labeled for either choline acetyltransferase (ChAT) and substance P or ChAT and enkephalin using silver intensified colloidal gold and peroxidase as labels. Regions containing both ChAT-positive neurons and peroxidase reaction product were identified in the light microscope prior to sectioning for electron microscopy. Substance P-containing terminals which contained round synaptic vesicles and made symmetrical synaptic contacts were commonly observed in the neostriatum. Substance P synapses onto ChAT-positive perikarya and dendrites were frequently observed: up to 5 synaptic contacts were observed onto a ChAT-positive dendrite. Enkephalin labeling was also seen in a population of axon terminals containing round synaptic vesicles and exhibiting symmetrical synaptic specializations. In contrast to substance P-containing terminals, relatively few synaptic contacts were observed onto ChAT-positive labeled perikarya and dendrites although enkephalin-labeled terminals were seen in frequent contact with perikarya and dendrites of unlabeled spiny neurons. Since enkephalin and substance P are contained within different populations of striatal spiny neurons, the results of the present study suggest that these two types of neurons differ in their intrinsic striatal connections.

Acetylcholine↗
PubMed1992

A continuing signal maintains NGF receptor expression in hypoglossal motor neurons after crush injury.

Inhibition of axonal transport by vincristine applied to hypoglossal nerves 7 days after crush injury turns off the usual injured-induced expression of low affinity nerve growth factor receptor (p75NGFr). Vincristine applied proximal but not distal to the crush prevents p75NGFr induction. These results indicate that a continuing signal is axonally transported from the crush site that induces and maintains p75NGFr expression by injured motor neurons.

Animals↗
PubMed1992

Distribution of neurotensin immunoreactivity within the human amygdaloid complex: a comparison with acetylcholinesterase- and Nissl-stained tissue sections.

In a previous study, we reported marked depletion of neurotensin-immunoreactivity (NT-IR) within selected regions of the amygdala of patients with Alzheimer's disease. The significance of these observations was partly obscured largely because we lacked a thorough understanding of the innervation pattern of neurotensin in the normal human amygdala. Accordingly, in the present study, we used a polyclonal antibody against neurotensin to characterize the distribution and morphology of neurotensin-immunoreactive neuronal elements within the human amygdaloid complex. NT-IR occurred in a topographic manner that respected the cytoarchitectural boundaries of the amygdaloid subregions as defined by Nissl staining and acetylcholinesterase histochemistry. Most NT-IR in the amygdala was contained within beaded fibers and dot-like puncta. Within the subnuclei of the amygdala, immunoreactive neuritic elements were most dense within the central nucleus followed by the medial nucleus and intercalated nuclei. The anterior amygdaloid area, basal complex, paralaminar nucleus, cortical nucleus, cortical-amygdaloid transition area, and amygdalohippocampal area contained moderate densities of immunoreactivity. The accessory basal and lateral nuclei exhibited scant NT-IR. Immunoreactive neurons were found only within the anterior amygdaloid area and the central, medial, intercalated, and lateral capsular nuclei. The distribution of NT-immunoreactive processes and cell bodies within selected regions of the amygdala provides an anatomical substrate that may explain, in part, the neuromodulatory actions of neurotensin upon autonomic, endocrine, and memory systems.

Acetylcholinesterase↗
PubMed1992

Induction of nerve growth factor receptor (p75NGFr) mRNA within hypoglossal motoneurons following axonal injury.

The hypoglossal nerve is a useful model system for analysis of gene expression in injured motoneurons. In particular, we sought to determine whether the increased appearance of the low affinity nerve growth factor receptor (p75NGFr) observed immunocytochemically following nerve injury can be directly correlated to increased levels of the p75NGFr mRNA. The present study also examined the relative effects of nerve crush versus nerve transection on the expression of p75NGFr mRNA. In sham-operated or intact animals, p75NGFr mRNA is detected rarely and then only at levels slightly higher than background. Following unilateral transection or crush of the rat hypoglossal nerve, the levels of p75NGFr mRNA increase in a time dependent fashion that parallels the appearance of the protein as reported previously. Moreover, this increase in p75NGFr mRNA following transection is dependent on a signal from the injured site, since blockage of axonal transport with vincristine also blocks the increased p75NGFr mRNA levels. When comparing the effect of nerve crush to nerve transection, we observed that the intensity of the response was greater in the crush paradigm versus that observed following transection. The duration of the response following nerve crush was shorter than that observed following transection of the nerve. The increase in p75NGFr mRNA after crush was most robust 4 days postlesion and appeared more robust primarily due to a 90-150% increased number of motoneurons expressing p75NGFr mRNA when compared to nerve transection. These data suggest that nerve crush is more effective than nerve transection in eliciting increased p75NGFr mRNA levels.

Animals↗
PubMed1991

Separate signals mediate hypoglossal motor neuron response to axonal injury.

Nerve transection causes decreased choline acetyltransferase (ChAT) expression and appearance of nerve growth factor receptor (NGFr) in hypoglossal motor neurons. Topical application of vincristine to the hypoglossal nerve blocks axonal transport of WGA for more than one week and causes loss of ChAT but no appearance of NGFr. These results indicate that loss of ChAT is related to interruption of axonal transport, but another signal induces de novo expression of NGFr.

Animals↗
PubMed1991

Expression of choline acetyltransferase and nerve growth factor receptor within hypoglossal motoneurons following nerve injury.

In the present study we employed light microscopic immunocytochemical techniques in order to investigate the temporal response of choline acetyltransferase (ChAT) and nerve growth factor receptor (NGFr) within hypoglossal motoneurons following unilateral transection or crushing of the XII nerve or after intraneural injections of ricin into the nerve. In control rats (i.e., sham operated) virtually all the motoneurons of the XII nucleus displayed intense immunolabeling for ChAT and were devoid of NGFr immunoreactivity. As early as 3 days post-operative the intensity and the number of ChAT-labeled neurons were reduced on the axotomized side compared to the non-lesioned side. This decrease was maximal approximately two weeks post-operative when virtually no ChAT-labeled cells were present on the lesioned side. In contrast, no loss of hypoglossal neurons was found using Nissl stains. This absence of ChAT immunolabeling persisted for several days, yet by 30 days many of the motoneurons had begun to re-express the enzyme. In contrast to the decrease in ChAT immunoreactivity, transection of the XII nerve also resulted in the expression of NGFr immunoreactivity within the lesioned motoneurons. This response was detected as early as one day post-operatively and continued throughout all time points thus far examined including times after many of the motoneurons had begun to re-express ChAT. Crushing of the XII nerve effected the expression of ChAT and NGFr in a manner comparable to, yet less intense than, that observed following transection. Ricin injected directly into the XII nerve resulted in the loss of hypoglossal motoneurons as demonstrated both in immunohistochemical and Nissl-stained tissue preparations. The cell loss was readily apparent 3 days post-operatively, and ChAT immunoreactivity permanently disappeared. NGFr immunolabeling was seen only in scattered surviving neurons but not in ricin poisoned cells. The possible mechanisms underlying the differential expression of ChAT and NGFr are discussed.

Animals↗
PubMed1991

Striatal glutamic acid decarboxylase immunoreactivity is increased after dopaminergic deafferentation: densitometric analysis.

Several lines of evidence suggest that dopamine exerts a chronic inhibitory action on GABAergic cells in the striatum, and striatal glutamic acid decarboxylase (GAD) mRNA levels are increased after ipsilateral dopaminergic denervation. In the present study we have used GAD immunocytochemistry to assess whether dopaminergic denervation results in an increase in GAD protein synthesis. In three 6-hydroxydopamine-lesioned animals, there was a perceptible increase in the density of GAD-immunoreactive (ir)staining on the side ipsilateral to the lesion. Computer-assisted densitometric analysis showed a significant increase in GAD-ir staining in the ipsilateral striatum compared to the contralateral (control) side. These data suggest that removal of striatal dopaminergic innervation results in an increase in the amount of immunoreactive GAD, the rate limiting enzyme in the synthesis of GABA.

Afferent Pathways↗
PubMed1991

Mapping the development of the rat brain by GAP-43 immunocytochemistry.

Growth-associated protein-43 (GAP-43) is a phosphoprotein of the nerve terminal membrane which has been linked to the development and restructuring of axonal connections. Using a monospecific antibody prepared in sheep against purified GAP-43, we examined the temporal and spatial changes in the distribution of this protein from embryonic stage day 13 (E13) to adulthood. At stages in which neurons are still dividing and migrating, levels of GAP-43 are extremely low, as is seen in the cortical plate throughout the embryonic period. With the onset of process outgrowth, intense GAP-43 immunoreactivity appears along the length of axons: by E13, such staining is already strong in the brainstem, where it continues up through the first postnatal week and then disappears. In the neocortex, intense fiber staining first appears several days later but ends at the same time as in the brainstem. At the end of the period of intense axonal staining there is a brief interval in which high levels of GAP-43 immunostaining are seen in the neuropil. In regions of the brain in which specific developmental events have been characterized anatomically and physiologically, the period of dense neuropil staining coincides with the formation of axonal end-arbors, the beginning of synaptogenesis, and the time at which synaptic organization can be modified by the impingent pattern of activity (i.e. the critical period). Over the next few days, staining in neuropil declines sharply in most regions except for certain structures in the rostral neuraxis which may be sites of ongoing synaptic remodeling.

Animals↗
PubMed1991

Glutamate receptor subtypes mediate excitatory synaptic currents of dopamine neurons in midbrain slices.

Although dopamine (DA)-containing neurons participate in a number of important cerebral functions, the physiology of their synaptic connections is poorly understood. By using whole-cell patch-clamp recording in thin slices of rat mesencephalon, we have investigated the biophysical properties of synaptic events and the nature of neurotransmitter(s) and receptors involved in the synaptic input to DA neurons in substantia nigra. The histological and electrophysiological characteristics of these cells were consistent with those described by recent in vivo and in vitro studies, thus allowing their unequivocal identification. Under appropriate experimental conditions, intranigral stimulation produced excitatory synaptic inputs in DA neurons. By voltage-clamp analysis, most of these excitatory postsynaptic currents (EPSCs) had a rise time of about 1.0 msec and a decay phase that could be fit by the sum of two exponential curves so that a fast and a slow component could be distinguished. The slow component was enhanced by glycine, by removing Mg2+ from the bath medium, or by membrane depolarization. Moreover, the slow component was consistently decreased by selective antagonists of NMDA receptors, whereas an antagonist for the non-NMDA receptors abolished the fast component slightly affecting the slow component and reduced peak EPSC amplitude. The results indicate that both NMDA-sensitive and non-NMDA-sensitive glutamate receptors contribute to EPSCs of DA neurons. Therefore, it is suggested that these receptors may play a critical role in the physiology (control of excitability, pacemaker firing, and dendritic DA release) as well as pathology (neuronal death in Parkinson's disease, psychosis, and mechanism of action of drugs of abuse, such as ethanol) related to DA neurons.

2-Amino-5-phosphonovalerate↗
PubMed1990

Reduction of neurotensin immunoreactivity in the amygdala in Alzheimer's disease.

The density of neurotensin immunoreactivity (NT-IR) was dramatically decreased in 6 of 12 amygdaloid nuclear subregions in patients with Alzheimer's disease (AD) compared to age-matched normals. Diminution of NT-IR was most pronounced in amygdaloid regions containing the greatest number of senile plaques. This contrasts to our previous findings of little, if any, loss of substance P or somatostatin immunoreactivity within these same regions. The present findings corroborate biochemical reports of a decrease in NT-IR in the AD amygdala and suggest that this peptide may be selectively affected relative to other neuropeptides.

Aged↗
PubMed1990

Basal forebrain cell loss following fimbria/fornix transection.

Following fimbria/fornix transection, cells in the medial septum appear to undergo retrograde degeneration as shown by Nissl and acetylcholine esterase (AChE) staining. Recent studies using immunocytochemical techniques have also demonstrated loss of choline acetyltransferase (ChAT) and nerve growth factor receptor (NGFr) labeling of neurons in this region. Whether the apparent loss of ChAT- and NGFr-positive neurons is the result of the actual death of these neurons, or is instead a loss of ChAT enzyme or NGFr expression below levels detectable by immunocytochemical methods, remains an unresolved issue. In order to address this question, rhodamine-labeled fluorescent latex microspheres were injected into the hippocampus where they retrogradely transported to the cell bodies of the medial septum. Five days later these animals received either unilateral or bilateral fimbria/fornix lesions and were allowed to survive an additional 4 weeks. Compared to unlesioned control animals, unilaterally lesioned animals showed a 91% loss of fluorescently labeled cells and bilaterally lesioned animals showed a 93% loss. The inability to detect the fluorescent microspheres in the medial septum suggests that the majority of medial septal cells die after fimbria/fornix transection. ChAT and NGFr immunohistochemical staining were also performed. Cells stained for ChAT were reduced in number by 92% in animals with unilateral lesions and by 75% in animals with bilateral lesions, while NGFr-stained cells were reduced in number by 75% in animals with unilateral lesions and by 68% in animals with bilateral lesions.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholinesterase↗
PubMed1990

Changes in the discharge patterns of motor cortical neurones associated with volitional changes in stepping in the cat.

Extracellular recordings have been obtained from motor cortical neurones of cats walking along a horizontal ladder. We present responses obtained when the animal produced defined volitional changes in limb trajectory, and during different conditions of locomotion. Our results show substantial changes in discharge pattern of some cells under these different conditions. Encounters with displaced rungs produce marked changes in discharge pattern including some which precede foot contact and others graded to the magnitude and direction of displacement.

Animals↗
PubMed1990

Topographical organisation within the cerebellar nucleocortical projection to the paravermal cortex of lobule Vb/c in the cat.

The projection from the intracerebellar nuclei to the paravermal (intermediate) cerebellar cortex of lobule Vb/c has been investigated in the cat using a combined electrophysiological and neuroanatomical technique. A small (10-30 nl) injection of WGA-HRP was made into one of the three paravermal zones (c1, c2 or c3) after the mediolateral boundaries of the zones had been delimited on the cerebellar surface by recording climbing fibre field potentials evoked in response to percutaneous stimulation of one or more paws. The distribution of retrogradely labelled cell bodies within the intracerebellar nuclei was compared with the distribution of terminal labelling arising from anterograde transport by cerebellar Purkinje cells. The three paravermal zones displayed marked heterogeneity in their receipt of a projection from the intracerebellar nuclei. The c1 and c3 zones received virtually no such input, although injections in either zone resulted in significant terminal labeling (which was largely restricted to nucleus interpositus anterior). By contrast, the intervening c2 zone received a much heavier nucleocortical input which arose almost exclusively from nucleus interpositus posterior (to which the zone also projected). A sparse contralateral nucleocortical input to the c2 zone was also demonstrated. This arose primarily from nucleus fastigius. It is concluded that the nucleocortical projection to the paravermal cortex of lobule Vb/c displays marked topographical specificity and some functional implications of this are discussed.

Animals↗
PubMed1990

NGF-dependent sprouting and regeneration in the hippocampus.

While a variety of sprouting and regenerative responses have been investigated in the hippocampus, the cellular and molecular events responsible for these plastic responses have not been determined. One transmitter system, the cholinergic system, shows several distinct responses to damage in the septohippocampal circuit. Present evidence strongly supports a role for nerve growth factor (NGF) in these responses. NGF is not only important for the survival of the adult cholinergic neurons, but can also induce regrowth of the damaged fibers given an appropriate substratum for growth. These reparative effects of NGF can manifest themselves in functional recovery in the aged rat and the young rat with fimbria-fornix lesions. Finally, a role for glia cells is proposed to clarify how NGF availability may be regulated during the degenerative and regenerative events. While all plasticity events certainly cannot be explained by the coincidence of NGF and the cholinergic system, their interaction may provide a template for other transmitter/trophic factor interactions.

Animals↗
PubMed1990

Gene therapy in the CNS: intracerebral grafting of genetically modified cells.

Grafting cells to the CNS has been suggested and applied as a potential approach to CNS therapy through the selective replacement of cells lost as a result of disease or damage. Independently, studies aimed at direct genetic therapy in model systems have recently begun to suggest conceptually new approaches to the treatment of several kinds of human genetic disease, especially those caused by single gene enzyme deficiencies. We suggest that a combination of these two approaches, namely the graftment into the CNS of genetically modified cells, may provide a new approach toward the restoration of some functions in the damaged or diseased CNS. We present evidence for the feasibility of this approach, including a description of some current techniques for mammalian cell gene transfer and CNS grafting, and several possible approaches to clinical applications. Specifically, we report that fibroblasts, genetically modified to secrete NGF by infection with a retroviral vector and implanted into the brains of rats with a surgical lesion of the fimbria-fornix, prevented the degeneration of cholinergic neurons that would die without treatment.

Animals↗
PubMed1990

Locomotion-related variations in excitability of spino-olivocerebellar paths to cat cerebellar cortical c2 zone.

1. Cutaneous nerve stimulation was used to study the excitability of the spino-olivocerebellar pathways (SOCPs) to the c2 zone of the paravermal cerebellar cortex in the cat. Non-noxious single-shock stimulation of the right and left superficial radial (SR) nerves via implanted cuff electrodes was used to evoke field potentials in the cerebellar cortex via the SOCPs. 2. The evoked potentials were recorded extracellularly either in lobule V of the anterior lobe (three cats) or within the paramedian lobule of the posterior lobe (one cat) with glass-coated tungsten microelectrodes. Measurement of the amplitudes of the responses was used to monitor transmission in the SOCPs in cats at rest and during walking. 3. A total of eleven c2 recording sites were investigated in detail. At seven of these sites, responses were recorded both during locomotion and at rest. For all seven sites responses during locomotion were smaller, more variable in amplitude and less securely evoked (average reduction 59%). 4. At five out of the eleven recording sites (45%) the mean amplitude of responses elicited during different tenths of the step cycle fluctuated sufficiently that the largest response was more than twice the smallest. In the majority of these cases (4/5) the responses were largest in either mid-stance or late swing. These fluctuations in response size occurred without parallel fluctuation in the amplitude of the peripheral nerve volley. At the remaining sites fluctuation of the cerebellar field size was less and in some cases practically absent. 5. At six recording sites it was possible to record the climbing fibre potentials evoked by stimulation of both the ipsilateral and contralateral superficial radial nerves. In all six cases the fluctuations in size of the response during locomotion occurred in phase, despite the fact that the two limbs move out of phase. 6. The probability that an individual stimulus would evoke any cerebellar response also varied between the different tenths of the step cycle and such variations occurred in parallel with the fluctuations in response size. This shows that the SOCP regulatory mechanism(s) must, at least in part, operate at a precerebellar level.

Afferent Pathways↗
PubMed1989

Responses of motor cortical neurones in the cat to unexpected perturbations of locomotion.

Extracellular recordings have been obtained from individual motor cortical neurones of cats walking along a horizontal ladder. We present responses obtained when selected rungs dropped unexpectedly by a small amount beneath the animal's weight. Our results show that forelimb motor cortex is rapidly and in graded fashion informed of such events, which may produce appreciable changes in impulse activity in the corticospinal tract.

Animals↗