Biomedical subjects

W G Tatton

Publications and source records attributed to W G Tatton.

At least 19 recordsLinked to original sources

PubMed1992

Deprenyl reduces the death of motoneurons caused by axotomy.

Deprenyl, a monoamine oxidase B inhibitor, appears to slow the progression of neurological deficits in Parkinson's disease and cognitive decline in Alzheimer's disease. The mechanisms for the slowing of the diseases are unknown. Deprenyl can reduce the death of murine substantia nigra neurons when administered after the neurons are damaged in MPTP parkinsonism by increasing the neurons' survival after they are damaged, rather than by just protecting the neurons against damage by blocking the conversion of MPTP to its active form as was previously thought. The death of immature motoneurons after separation from their muscle targets by axotomy provides a model for assessing trophically dependent neuronal survival. To determine whether deprenyl can alter the survival of neurons other than those in the substantia nigra, we examined the survival of rat facial motoneurons after axotomy at 14 days of age. Using a combination of immunocytochemistry for choline acetyl transferase and Nissl staining, we found that deprenyl treatment (10 mg/kg every second day) increased by 2.2 times the number of motoneurons surviving 21 days after the axotomy. This finding showed that deprenyl treatment can rescue neurons other than those in the substantia nigra and can compensate in part for the loss of target-derived trophic support caused by axotomy.

Animals↗

PubMed1992

Interactions between MPTP-induced and age-related neuronal death in a murine model of Parkinson's disease.

Abiotrophy is hypothesized to explain the onset and time course of deficits in Parkinson's disease (PD) Abiotrophy includes: 1) exposure to agent(s) causing the death of dopaminergic nigrostriatal neurons (DNSns), 2) gradual death of DNSns with age, 3) summation of 1) and 2) until DNSn numbers fall below a threshold for detectable neurological deficits. Murine DNSn death following methyl-phenyl-tetrahydropyridine (MPTP) exposure occurs according to an exponential relationship while age-related death of DNSns occurs according to a second exponential relationship. Summing the two exponential losses overestimates experimental DNSn death showing a simple abiotrophic model is not sufficient. Aged murine DNSns greatly increase their dopamine synthesis and the density of their striatal axon terminals which may explain the above threshold. Murine DNSns die gradually after MPTP exposure and L-deprenyl treatment rescues MPTP-damaged DNSns by a previously undiscovered action, altering the abiotrophic interactions and possibly explaining the slowed progression of PD found with deprenyl treatment.

Aging↗

PubMed1991

Transmitter synthesis increases in substantia nigra neurons of the aged mouse.

Striatal dopamine concentrations are relatively well maintained with age despite extensive death of the nigrostriatal neurons whose terminals contain the dopamine. Counts of nigrostriatal dopaminergic neurons in C57BL mice identified using immunocytochemistry, Fluoro-Gold retrograde axonal transport and Nissl staining were combined with measures of striatal dopamine and DOPA after saline, pargyline or NSD-1015 treatment. On average, 68% of the dopaminergic nigrostriatal neurons died between ages 8 and 104 weeks and there was a 3-fold increase in dopamine synthesis per average neuron in the aged mice. Increased transmitter synthesis by surviving neurons may serve to compensate brain function in old age.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1991

Rescue of dying neurons: a new action for deprenyl in MPTP parkinsonism.

Deprenyl slows the progression of disabling symptoms in Parkinson's disease (PD) by an unknown mechanism. It can block the action of MPTP on substantia nigra compacta (SNc) neurons by inhibiting monoamine oxidase B necessary to mediate the conversion of MPTP to MPP+, its active metabolite, in astroglia. Mice were pretreated with saline or the PD-producing toxin, MPTP (30 mg/kg) daily for 5 days and then after a further 3 days (to allow for the metabolism and excretion of the MPTP) were treated with deprenyl (0.25 or 10 mg/kg) or saline 3 times weekly for 20 days. In three series of mice treated with MPTP alone or MPTP-saline, serial sections through the SNc showed that averages of 37-42% of tyrosine hydroxylase (TH) immunoreactive neurons were lost gradually over 20 days. Joint counts of the numbers of TH-immunoreactive and Nissl-stained SNc somata from immediately adjacent sections established that the reductions in the numbers of TH-immunoreactive somata at 20 days after MPTP treatment represented neuronal death. Deprenyl treatment reduced the loss of TH-immunoreactive SNc neurons to averages of 14-16% for the 10-mg/kg and 0.25-mg/kg doses, respectively, and joint Nissl/TH counts for adjacent sections showed that reduction in the loss of TH-immunoreactive soma represented the rescue of SNc neurons that would have died by 20 days. The gradual loss of SNc neurons over the 20 days following MPTP exposure may reflect the toxin's axotomy-like effects on SNc neurons or the prolonged action of sequestered MPP+.(ABSTRACT TRUNCATED AT 250 WORDS)

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed1991

First expression of protamine message in trout testis.

In situ hybridizations were performed using a biotinylated riboprobe complementary to protamine messenger RNA in order to directly examine the various cell types in the trout testis for the presence of protamine message. Computer-aided optical density measurements were used to provide estimates of transcript abundance for cells identified by their DAPI-labeled nuclei. Optically detectable protamine hybridization occurred only in spermatid cells. These findings are in accord with results obtained in other species which report protamine mRNA only in the post-meiotic spermatid cell; but they are in conflict with a previous study employing solution hybridization which noted that protamine message first appears in the spermatocytes of rainbow trout.

Animals↗

PubMed1990

Dose-dependent destruction of the coeruleus-cortical and nigral-striatal projections by MPTP.

In order to determine whether 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces neuronal death or the loss of tyrosine hydroxylase (TH) immunoreactivity, 4 catecholaminergic nuclei in the mouse: substantia nigra compacta (SNc), locus coeruleus (LC), ventral tegmental area (VTA) and the A13 nucleus in the hypothalamus were quantitatively examined. Serial sections were taken through the rostrocaudal extent of each nucleus: alternate sections were incubated with TH antiserum and reacted with an immunoperoxidase technique while the alternate set was Nissl stained. Counts and 3 dimensional reconstructions of TH reactive somata were made for each nucleus for saline-treated controls and mice treated with different doses of MPTP (37.5, 75, 150 and 300 mg/kg). TH-positive neurons were counted along with their counterparts on the Nissl-stained alternative sections to both identify the catecholaminergic neurons and to measure their destruction. Concentrations of striatal dopamine and cortical norepinephrine were measured for all dosages of MPTP in order to determine the relationship between dosage, target tissue neurotransmitter concentration and neuronal destruction. By 20 days after MPTP injection there was a dose-dependent random loss of TH-immunoreactive neurons that was almost identical in all 4 nuclei examined. Analysis of the Nissl versus TH cell counts revealed that MPTP resulted in neuronal destruction in the SNc and the LC rather than just a loss of TH immunoreactivity. There was no difference in sensitivity to MPTP between the SNc and the LC. Decreases in cortical norepinephrine concentrations were about one third of the decreases of LC neuronal counts for all MPTP doses; while decreases in striatal dopamine and SNc cell loss was similar to the LC for the two lower doses of MPTP but for the higher doses, the relationship approached or exceeded a one to one ratio. Hence estimates of neuronal death based upon target tissue transmitter concentrations could not be made using the same relationship for SNc and the LC catecholaminergic neurons and use of the same relationship for higher MPTP dosages results in an underestimate of LC neuronal destruction relative to that in the SNc.

Animals↗

PubMed1990

MPTP produces reversible disappearance of tyrosine hydroxylase-containing retinal amacrine cells.

To determine whether 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) alters the tyrosine hydroxylase (TH) immunoreactivity of murine dopaminergic retinal amacrine cells, 8-10-week-old C57BL/6J mice were treated with i.p. with saline or cumulative doses of MPTP ranging from 10 to 300 mg/kg. Paraformaldehyde-fixed retinal whole mounts and cross sections were examined using immunochemistry with a tyrosine hydroxylase (TH) or a choline acetyltransferase (ChAT) polyclonal antibody and an avidin-biotin peroxidase reaction. Both TH+ amacrines and ChAT+ retinal neurons showed somal and process morphology and distributions that were commensurate with previous studies of the same or several related species. At 20 days following the MPTP treatment, there was a loss of TH+ amacrines according to a logarithmic relationship relative to MPTP dosage. The loss ranged from 18 to 87% for the dosage range without any decrease in the numbers of ChAT+ neurons. The TH+ amacrines were deleted randomly from the retinas without any peripheral-central predilection. By 273 days after MPTP treatment, the number of TH+ amacrines had returned to values found for age-matched controls demonstrating that the loss of TH immunoreactivity was reversible and occurred without destruction of TH+ amacrines. Computer densitometry revealed that the MPTP-treated TH+ amacrines were divided into two distinct populations: one with normal TH immunodensity levels and a second with TH immunodensity levels below our detection capability. Increasing the MPTP dosage increased the proportion of TH amacrines in the second population. The transient and completely reversible disappearance in the number of TH+ amacrines: (1) appears to form the basis for the decreased concentrations of dopamine and the loss of catecholamine fluorescent neurons previously described for MPTP-treated mouse retinae; (2) may underlie the defects in the electroretinograms of MPTP-treated monkeys, and (3) may result as a response to neurite damage similarly to the alterations in protein synthesis in other central neurons following axonal damage.

Animals↗

PubMed1990

Determination of extracellular/intracellular fluid ratios from magnetic resonance images: accuracy, feasibility, and implementation.

This study determines the accuracy and feasibility of using localized spin-lattice (T1) relaxation time measurements from magnetic resonance (MR) images to follow changes in extracellular/intracellular fluid ratios in defined subvolumes of living tissue. A red blood cell suspension was used as a test system and a simple two-compartment model incorporating fast exchange was found to suffice for the conversion of T1 values to volume ratios. The technique requires the addition of gadolinium-DTPA to the model system to selectively enhance relaxation in the extracellular fluid space. No detectable amount of gadolinium-DTPA was found to enter the intracellular fluid space, and all magnetization decay plots obtained from both intracellular constituents and complete RBC suspensions consisted of a single exponential. Both of these results are compatible with assumptions underlying our physical model. The NMR-determined fluid ratio values were compared to those measured via the microhematocrit technique. Partial saturation image-mode determinations are strongly correlated to microhematocrit data (R2 = 0.945) and indicate that localized cell volume changes may be followed with a sensitivity of +/- 2.2%. These values compare favorably with those produced when nonimaging inversion-recovery techniques are used to determine the MR hematocrit (R2 = 0.962, sensitivity = +/- 1.1%). This technique, with modification, should be applicable to the comparison of ratios of extracellular/intracellular fluid volumes in structurally complex tissues where small subvolumes of homogeneous cell structure could be examined.

Body Fluids↗

PubMed1990

Joint receptors modulate short and long latency muscle responses in the awake cat.

Nerve cuff electrodes were chronically implanted around multiple peripheral nerves in adult cats, including the medial and posterior articular nerves (MAN and PAN) to the knee while EMG electrodes were implanted into seven hindlimb muscles. Randomized load perturbations producing mid-range knee flexions at varying angular velocities were subsequently applied to awake cats. Recordings were initially obtained with knee joint innervation intact and then after local anaesthetic or saline control solution was injected into the knee. Averaged neurogram and EMG responses to the imposed movements were utilized to assess the contribution of joint mechanoreceptor activity to the evoked muscle responses. Additionally, spike-triggered averaging techniques and peri-stimulus time histograms of single joint afferent units isolated from the articular nerve cuffs were utilized to characterize unitary joint receptor responses. The averaged whole nerve response to knee joint perturbations on each of the cuffed articular nerves revealed phasic increases in activity relative to constant background levels. The earliest phasic responses on the articular nerves were initiated at latencies that were too short to be voluntary, occurring in the short latency (reflex) period. Detectable joint receptors were not recruited until after the earliest excitatory responses of agonist/antagonist muscle pairs acting across the knee had occurred, presumably resulting in mechanical loading of the knee joint capsule and subsequent activation of articular mechanoreceptors. Introduction of local anaesthetic into the knee was accompanied by marked diminution in joint afferent activity. Perturbation-evoked muscle responses were characterized by increased activity above background levels in all seven muscles studied, including antagonist muscle pairs. Local anaesthetic-mediated loss of knee joint mechanoreceptor input altered the latency, amplitude and duration of EMG responses in each muscle. The effect of joint anaesthesia in the short latency period was a generalized decrease in all muscle responses relative to normal and saline controls. The loss of afferent input after joint anaesthesia was also associated with altered muscle responses during the long latency period, when both reflex and voluntary mechanisms could potentially contribute to the generation of EMG activity. Interestingly, long latency activity after joint anaesthesia was characterized by "unbalancing" in the EMG responses of some antagonist muscle pairs. This alteration of normal antagonist pair co-contraction patterns served to increase the magnitude of the imposed perturbations, rather than to bring the movements under control. Analysis of single joint afferents isolated from whole joint nerve recordings demonstrated that some joint afferent units were tonically active at quiescent, mid-range knee positions. Additionally, isolated afferents demonstrated different time courses of response to imposed perturbations.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1989

Postnatal redistribution of pericruciate motor cortical projections within the kitten spinal cord.

The anatomical distribution of pericruciate cortical axons in the spinal cord was examined using anterograde transport of WGA-HRP from multiple unilateral injections into defined regions of the pericruciate cortex (PC) in 20 time-mated kittens and 3 adult cats. The gray matter and descending white matter tract distributions of WGA-HRP-labelled densities were analyzed using computerized morphometry and 3-dimensional reconstruction. In kittens older than 16 days postnatal (dPN), PC axon densities were found in dorsolateral column tracts corresponding to those of the adult, indicating that the white matter projections from the PC were largely established by this age. However, in kittens less than 38-44 dPN (about 105-109 days gestation), the spinal gray matter PC axon densities were distributed widely (so as to involve dorsal, intermediate and ventral laminae, e.g., I to IX) and bilaterally at all levels of the spinal cord. This contrasted sharply with the adult spinal cord in which the majority of densities was localized to laminae IV-VII on the contralateral side. The proportion of PC densities counted in the ipsilateral grey matter of neonates was found to average 23% of the total gray matter projection, while in adults this value was 9%. In all animals, by about 44 dPN, the terminal fields became effectively restricted to the adult distribution, that is, focused predominantly in the medial portions of laminae IV-VII in the gray matter contralateral to the cortical injection site.

Animals↗

PubMed1988

Postnatal growth of medial gastrocnemius motoneurons in the kitten.

Cat muscle nerves and ventral roots for the hindlimbs show a unimodal distribution of axon diameter at birth, followed, at about 20 days postnatal (dPN), by a marked change to a bimodal distribution resembling that of the adult. However, volumes calculated for motoneuron somata retrogradely labeled with HRP have been reported to be divided into two size populations at birth in the kitten. In the literature it is suggested that a dissociation between axonal and somal growth appears at a very early age. This apparent dissociation, not present in adults, prompted us to examine the somal growth patterns of kitten lumbar motoneurons. In the present report we have examined somal size development in medial gastrocnemius (MG) motor nuclei in 18 cats aged 2 dPN to adulthood using retrogradely transported horseradish peroxidase to label the motoneurons. Measurements of minimum and maximum diameter somal size, volume calculations and a double circle technique relating the diameters of an estimated spherical volume contained within the soma to that of a second spherical volume enclosing the soma clearly distinguish two subpopulations in the adult, a small and a large population. In contrast, in the kitten we show there is a unimodal distribution of small motoneuron somata at birth which at 19-23 dPN differentiates into a bimodal population. This sudden differentiation of somal size coincides with that reported for MG motoneuron axonal calibre, ruling against a neonatal dissociation of somal and axonal size distributions, and appears to correspond to the time of onset of functional characteristics and the histochemical differentiation of fiber types in the MG muscle.

Aging↗

PubMed1988

The center-tapped slotted tube autotransformer resonator: a coil for use with a high-resolution small animal imaging system.

A radiofrequency (rf) coil design based on a slotted tube resonator which allows high-resolution imaging of the rodent brain with excellent anatomic definition on a standard G.E. CSI II 2.0-T MR imaging unit with no modification of existing apparatus is described. The coil is easily constructed and permits very rapid tuning to different loading conditions, allowing a high sample throughput.

Animals↗

PubMed1987

Long-latency reflex activity in squirrel monkeys with occlusion of the middle cerebral artery.

The primate middle cerebral artery (MCA) preparation has been studied as an animal model of human spasticity resulting from stroke. MCA occlusion in 3 squirrel monkeys was accomplished through a transorbital approach and animals were evaluated by 'clinical' examinations and studies of EMG responses to torque motor imposed joint displacement. Animals were transiently hemiparetic but not spastic postoperatively, although all were found to have a large infarct in MCA territory on post-mortem examination. The electromyographic (EMG) response of biceps in normal animals to torque motor imposed elbow extension consisted of both early (M1) and late (M2) components (Tatton et al. 1975). These components were unchanged following MCA occlusion. The EMG response to metacarpophalangeal joint extension in finger flexors or normal animals consisted solely of a long-latency (M2) component (Lenz et al. 1983a). Following MCA occlusion the M2 component in this muscle was decreased or absent, but a short-latency (M1) component appeared.

Animals↗

PubMed1985

Kinematic representation of imposed forearm movements by pericruciate neurons (areas 4 and 3a) in the awake cat.

In eight awake cats, elbow flexion movements were imposed by a computer-controlled torque motor using three different classes of angular displacement inputs: force step-load displacements; sinusoidal displacements; and constant-velocity ramp displacements. Microelectrode recordings were obtained from 309 pericruciate neurons in areas 4 and 3a. Average response histograms for single-unit activity coupled with computer simulation of the imposed movements have shown in a neuronal population (n = 81), selected for receptive fields that were directly related to elbow movements, that both the magnitude and temporal features of the responses can be characterized by the coefficients of a third-order differential equation describing the movement's angular kinematics (i.e., position, velocity, acceleration, and jerk). To compare the responses of different neurons the coefficients were normalized to the angular velocity coefficient, which was assigned a weighted value of 1.0. The neurons' average responses were "predictable" by the normalized coefficients regardless of the imposed movements' temporal characteristics. Two distinct and spatially separate pericruciate areas containing neurons that responded to the imposed forearm movements were located: 1) one within area 4 at the lateral extent of the cruciate sulcus, which contained neurons that responded with predominant jerk and acceleration coefficients, exhibited either cutaneous or deep receptive fields, and demonstrated low microstimulation current thresholds to activate forelimb muscles; 2) a second, more laterally located area near the 3a/4 border in the postsygmoid gyrus, which contained neurons that responded with predominant velocity coefficients, and comparatively small jerk acceleration, and position coefficients, exhibited either cutaneous or deep receptive fields, and demonstrated high microstimulation thresholds (greater than 20 microA). Due to the sensitivity of the higher derivatives to changes in motion, the relative magnitude and time course of the average firing probability of area 4 neurons with prominent acceleration and jerk coefficients were dominated by these kinematic features during the more rapidly imposed movements. The findings are in accord with a hypothesis proposing that motor cortical neurons in area 4 form a sufficient substrate for a "predictive" feedback organization, and may constitute an essential component of a system capable of regulating errors in angular joint movements despite the relatively long conduction delays and the slow time course of muscle tension production inherent to mammalian neuromuscular systems.

Animals↗

PubMed1984

Characteristic alterations in responses to imposed wrist displacements in parkinsonian rigidity and dystonia musculorum deformans.

The amplitude and temporal modulation of the segmented EMG activity in flexor carpi radialis, evoked by imposed angular wrist extension, was studied with respect to the level of pre-existing background activity in rigid parkinsonian (PK) and dystonia musculorum deformans (DMD) patients. The interdependence of the evoked M1 and M2-3 segments on pre-existing background EMG activity and initial velocity of imposed displacement was established previously for a normal population. Individual responses of 21 parkinsonian and 12 dystonic patients were compared to the established normal "response volume". The augmented magnitude of the M2-3 segment in rigid PK patients, which correlates to the measure of rigidity, could not be accounted for by the low level of pre-existing EMG activity. Therefore, increased descending facilitation does not impinge directly on alpha motoneurons. Paradoxical excitation in the shortened muscle and resetting of tonic tremor of the stretched muscle by the imposed wrist extension are two other demonstrated abnormalities which may also contribute to PK rigidity. In contrast, DMD patients demonstrated normal amplitude modulation of the M1 and M2-3 segments, but exhibited a disturbance of normal temporal mechanisms that result in constant duration of the M1 and M2-3 responses with imposed force step loads.

Adult↗

PubMed1981

Descending projections to the cervical spinal cord in the developing kitten.

The distribution of neurons filled by retrograde axonal transport of horseradish peroxidase from the cervical enlargement is described in kittens prior to and following the time of appearance of mature alpha-motoneuron responses to motor cortical stimulation (at 107-111 days gestational age; about 41 days postnatally). Cortex and brainstem reconstructions of the distributions of filled neurons demonstrate a well-defined, discrete projection from cortical area 4 to spinal cord segments C3 to C8, both in mature and immature (20 and 24 days postnatal) animals. In addition, appropriate rubrospinal, reticulospinal and vestibulospinal projections were present at all ages studied.

Animals↗

PubMed1979

Motor unit responses in muscles stretched by imposed displacements of the monkey wrist.

Imposed angular displacements of monkey's wrist produce three major peaks of activity (terms M1, M2, and M3 peaks) in the averaged gross EMG activity ot the stretched muscles. The displacements were imposed on monkey's wrist by computer controlled step loads (range 60--540 g). Gross EMG was recorded simultaneously with the activity of single motor units (SMUs) in the stretched muscles. SMUs were identified and separated using a computer "shape-fitting" program. Average response histograms (ARHs) were constructed for each SMU's responses to randomly presented repetitions of up to five different step loads. Eighty-three percent of the SMUs showed a single excitatory response peak that was limited to a time interval corresponding to that of only one of the gross EMG peaks. Despite marked differences in the time courses of the imposed displacements, the time courses of the SMU excitatory responses were maintained. By increasing the background load and hence the tonic firing of the individual SMUs, the histograms show that the long latency of the M2 peak is not due to an inhibitory-excitatory sequence. The SMUs responding at longer latencies (M2 and M3 SMUs) show firing characteristics in keeping with those reported for fast twitch motor units while those of M1 SMUs correlate with those found for slow twitch units. These results establish that the M1, M2, and M3 peaks do not merely represent synchronized oscillatory activity of the motoneurons but largely result from the reflex excitation of separately responding motoneuron "subpopulations", each of which contributes to the generation of only one of the gross EMG peaks.

Afferent Pathways↗

PubMed1979

Input-output properties of motor unit responses in muscles stretched by imposed displacements of the monkey wrist.

Reflex responses are "servo-like" where the output is graded with the input or are "triggered" where the output is independent of input once an input threshold is exceeded. Imposed displacements of monkey or human upper limb joints result in prolonged EMG output in the muscles stretched by the displacements. The longer-latency portions of the prolonged output have been variously reported to be servo-like or to be triggered in nature. In monkeys and humans, angular wrist displacements imposed by step loads result in three peaks (M1, M2 and M3) in the gross EMG recorded from the stretched muscles. Each gross EMG peak largely results from the firing of a separately-responding subpopulation of single motor units (SMUs). We studied the responses of SMUs to loads that were presented to the monkeys in a random order as to magnitude, duration and onset time. Average response histograms were constructed for the SMU responses for individual step load magnitudes. Averages were also constructed for the simultaneously-recorded gross EMG responses for each step load magnitude. The input parameters used were the initial velocity of displacement or the magnitude of step load, while the output was taken as the probability of firing/millisecond/presentation above baseline for the SMUs or the area under the response peaks above baseline for gross EMG. The results establish: 1) That it is not possible to unambiguously determine the input-output properties of the responses to imposed displacements utilizing the analysis of gress EMG activity due to the response characteristics of the various subpopulations of motor units contributing to the gross response. 2) That the SMU activity during all of the peak intervals is monotonically graded with increases in magnitude of the step load or the initial velocity of displacement. Hence, the long-latency portions of the EMG responses are servo-like in nature and are not preprogrammed or triggered responses. 3) That the gain (output/input) of the gross EMG responses almost entirely reflects the variation in the number of motoneurons recruited by changes in magnitude of the step loads rather than variation in the firing rates of motoneurons during the reflex responses.

Animals↗