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Biomedical subjects

M C Austin

Publications and source records attributed to M C Austin.

At least 19 recordsLinked to original sources
PubMed2003

Increased corticotropin-releasing hormone immunoreactivity in monoamine-containing pontine nuclei of depressed suicide men.

A number of clinical investigations and postmortem brain studies have provided evidence that excessive corticotropin-releasing hormone (CRH) secretion and neurotransmission is involved in the pathophysiology of depressive illness, and several studies have suggested that the hyperactivity in CRH neurotransmission extends beyond the hypothalamus involving several extra-hypothalamic brain regions. The present study was designed to test the hypothesis that CRH levels are increased in specific brainstem regions of suicide victims with a diagnosis of major depression. Frozen tissue sections of the pons containing the locus coeruleus and caudal raphe nuclei from 11 matched pairs of depressed suicide and control male subjects were processed for radioimmunocytochemistry using a primary antiserum to CRH and a ([125])I-IgG secondary antibody. The optical density corresponding to the level of CRH-immunoreactivity (IR) was quantified in specific pontine regions from the film autoradiographic images. The level of CRH-IR was increased by 30% in the locus coeruleus, 39% in the median raphe and 45% in the caudal dorsal raphe in the depressed suicide subjects compared to controls. No difference in CRH-IR was found in the dorsal tegmentum or medial parabrachial nucleus between the subject groups. These findings reveal that CRH-IR levels are specifically increased in norepinephrine- and serotonin-containing pontine nuclei of depressed suicide men, and thus they are consistent with the hypothesis that CRH neurotransmission is elevated in extra-hypothalamic brain regions of depressed subjects.

Adult↗
PubMed2002

Localized decrease in serotonin transporter-immunoreactive axons in the prefrontal cortex of depressed subjects committing suicide.

A variety of postmortem brain studies and clinical investigations have provided evidence that reduced serotonin neurotransmission is associated with suicidal behavior and depression, and several serotonergic parameters have been found to be altered in the prefrontal cortex of suicide victims. However, the integrity of the serotonin innervation of the prefrontal cortex in mood disorders has not been directly investigated. The present study used immunocytochemical methods and an antibody against the serotonin transporter to examine the relative density of serotonin axons in the dorsolateral prefrontal cortex of suicide victims with a diagnosis of major depression. The mean total length of serotonin transporter-immunoreactive axons per unit area was unchanged in layers 2 and 4 of area 46 in the depressed suicide subjects compared to controls, but was significantly (P < 0.01) decreased by 24% in layer 6 in the depressed suicide group. The total length of serotonin transporter-positive axons in layer 6 was reduced in eight of the 12 depressed suicide subjects compared to their matched control subjects. These findings reveal that depressed subjects who have committed suicide exhibit a lamina-specific reduction in a marker of serotonin axons in the dorsolateral prefrontal cortex that may reflect an alteration in cortical serotonin neurotransmission.

Adult↗
PubMed2000

Normal cellular levels of synaptophysin mRNA expression in the prefrontal cortex of subjects with schizophrenia.

BACKGROUND: Previous studies have reported that the 38-kd synaptic vesicle-associated protein, synaptophysin, is decreased in the prefrontal cortex of subjects with schizophrenia. METHODS: To determine whether the decreased protein levels reflect diminished expression of the synaptophysin gene by prefrontal cortex neurons, we used in situ hybridization histochemistry to determine the cellular levels of synaptophysin messenger RNA in prefrontal cortex area 9 from 10 matched pairs of schizophrenic and normal control subjects. RESULTS: Neither the density of neurons with detectable levels of synaptophysin messenger RNA nor the mean level of synaptophysin messenger RNA expression per neuron differed between schizophrenic and control subjects in any cortical layer. CONCLUSIONS: These findings indicate that the expression of synaptophysin messenger RNA is not altered in this brain region in schizophrenia. Consequently, reduced levels of synaptophysin protein in the prefrontal cortex of subjects with schizophrenia are more likely to reflect either posttranscriptional abnormalities of synaptophysin in prefrontal cortex neurons or a diminished number of axonal projections to the prefrontal cortex from other brain regions.

Adult↗
PubMed2000

Analysis of tyrosine hydroxylase gene transcription using an intron specific probe.

The nuclear run-on assay is the most commonly used technique to determine transcription rates of specific genes such as tyrosine hydroxylase. Its application to studies in the nervous system is problematic, however, as a result of limitations in sensitivity and the loss of anatomical integrity. We observed that the relative levels of tyrosine hydroxylase intron 2-containing RNA using a ribonuclease protection assay in the adrenal medulla changed in response to pharmacological treatments consistently with changes shown by the nuclear run-on assay. Our results indicate that measures of tyrosine hydroxylase primary transcript levels offer an alternative to the nuclear run-on assay and validate the application of intron-specific in situ hybridization as a means of assessing the relative transcriptional activity of the tyrosine hydroxylase gene. Similar quantitative results were obtained using intron-specific in situ hybridization with oligonucleotide probes specific for rat tyrosine hydroxylase intron 2. Furthermore, we observed that intron-specific in situ hybridization could be used to measure tyrosine hydroxylase transcription rates in the locus coeruleus, providing resolution at the level of single neurons. Thus, measuring the levels of tyrosine hydroxylase intron 2 provides a sensitive measure of tyrosine hydroxylase transcription rate that can be applied to the study of brain catecholaminergic neurons.

Adrenal Medulla↗
PubMed2000

Decreased glutamic acid decarboxylase67 messenger RNA expression in a subset of prefrontal cortical gamma-aminobutyric acid neurons in subjects with schizophrenia.

BACKGROUND: Markers of gamma-aminobutyric acid (GABA) neurotransmission seem to be altered in the prefrontal cortex (PFC) of subjects with schizophrenia. We sought to determine whether the expression of the messenger RNA (mRNA) for the synthesizing enzyme of GABA, glutamic acid decarboxylase67 (GAD67), is decreased in the PFC of subjects with schizophrenia, whether this change is present in all or only some GABA neurons, and whether long-term treatment with haloperidol decanoate contributes to altered GAD67 mRNA expression. METHODS: Tissue sections from 10 pairs of subjects with schizophrenia and control subjects and 4 pairs of haloperidol-treated and control monkeys were processed for in situ hybridization histochemical analysis with sulfur-35-labeled oligonucleotide probes for GAD67 mRNA and exposed to nuclear emulsion. Within each layer of PFC area 9, neurons expressing a detectable level of GAD67 mRNA were quantified for cell density and the relative level of mRNA expression per cell (grain density per neuron). RESULTS: In subjects with schizophrenia, the density of labeled neurons was significantly (P<.05) decreased by 25% to 35% in cortical layers 3 to 5. In contrast, the mean grain density per labeled neuron did not differ across subject groups. Similar analyses in monkeys revealed no effect of long-term haloperidol treatment on either the density of the labeled neurons or the grain density per labeled neuron. CONCLUSIONS: These findings indicate that in subjects with schizophrenia, GAD67 mRNA expression is relatively unaltered in most PFC GABA neurons but is reduced below a detectable level in a subset of GABA neurons. Altered GABA neurotransmission in this subset may contribute to PFC dysfunction in subjects with schizophrenia.

Adult↗
PubMed2000

Increased transcription of the tyrosine hydroxylase gene in individual locus coeruleus neurons following footshock stress.

Footshock-evoked change in transcriptional activity of tyrosine hydroxylase in neurons of the locus coeruleus was examined using an intron-specific in situ hybridization histochemical technique. A significant increase in the cellular concentration of tyrosine hydroxylase primary transcripts was found in locus coeruleus neurons 3h following 30 min of intermittent footshock. However, the footshock-induced increase in tyrosine hydroxylase transcription was not homogeneously expressed in locus coeruleus neurons. Similarly, administration of the alpha(2)-adrenergic receptor antagonist idazoxan produced a significant increase in the cellular concentration of tyrosine hydroxylase primary transcripts that was heterogeneously distributed among locus coeruleus neurons. Both footshock and idazoxan significantly increased the regional levels of tyrosine hydroxylase messenger RNA in the locus coeruleus. The time-course of changes in tyrosine hydroxylase transcription rate and messenger RNA levels in the locus coeruleus was examined after a 15 min exposure to footshock. A robust increase in tyrosine hydroxylase transcription rate was found at the end of 15 min of footshock, which remained elevated for 6h and was back to the control levels by 24h. In contrast, in response to a 15 min period of footshock tyrosine hydroxylase messenger RNA concentrations in the locus coeruleus did not increase until 6h and remained elevated at 24h. These findings demonstrate that transcription of the tyrosine hydroxylase gene in locus coeruleus neurons in response to footshock stress occurs rapidly, is sustained for many hours and is heterogeneously distributed. These data also suggest that the increase in tyrosine hydroxylase messenger RNA following footshock is mediated, at least in part, by an increase in tyrosine hydroxylase gene transcription.

Animals↗
PubMed1999

Regional distribution and cellular expression of tryptophan hydroxylase messenger RNA in postmortem human brainstem and pineal gland.

The characterization and cellular localization of tryptophan hydroxylase mRNA in the human brainstem and pineal gland were investigated by using northern blot analysis and in situ hybridization histochemistry. Northern analysis of human pineal gland revealed the presence of two mRNA species that were absent in RNA isolated from human raphe. In situ hybridization experiments revealed very dense hybridization signal corresponding to tryptophan hydroxylase mRNA in cells throughout the pineal gland. In contrast, tryptophan hydroxylase mRNA was heterogeneously distributed in neurons in the dorsal and median raphe nuclei. Within the dorsal raphe, the ventrolateral and interfascicular subnuclei contained the greatest number of tryptophan hydroxylase mRNA-positive neurons. Also, the cellular concentration of tryptophan hydroxylase mRNA varied widely within the dorsal and median raphe. Comparison of the cellular concentration of tryptophan hydroxylase mRNA between the pineal gland and the raphe nuclei revealed an 11- and 46-fold greater average grain density of tryptophan hydroxylase mRNA positive cells in the pineal gland compared with the dorsal and median raphe, respectively. These findings are the first to demonstrate the cellular localization of tryptophan hydroxylase mRNA in the human brain and pineal gland as well as heterogeneity in the cellular concentration within and between these tissues.

Autoradiography↗
PubMed1998

Oscillatory effects of repeated morphine on shock-induced hypoalgesia and beta-endorphin.

Recent research indicates that the sensitization that results from repeated drug or non-drug stress exposure may develop into a pattern of alternating increases and decreases (i.e., oscillation) in response to each subsequent stressor exposure. Oscillation, with or without prior sensitization, has been observed for a number of drug and non-drug stressors, and for various neurochemical and endocrine endpoints. The present studies investigated whether oscillation also occurs in the behavioral and endocrine effects of repeated morphine treatment and if a drug that normalizes the mood swings of bipolar disorder in humans will also attenuate drug oscillation in this animal model. In the first experiment, rats were given 1-5 pretreatments with morphine (15 mg/kg, i.p.), separated by 1-week intervals with the last injection occurring 1 hour prior to being tested for stressor-induced (i.e., 5 seconds, 2-mA electric footshock) hypoalgesia, as measured by latency to paw-lift or jump from a hot-plate. Plasma beta-endorphin also was measured. The second experiment replicated the behavioral findings of the first study and, in addition, assessed the effect of continuous lithium chloride, in the drinking water, on morphine-induced oscillation. Caffeine was used as a partial control for the lithium. The results were that one injection of morphine enhanced stress-induced hypoalgesia and subsequent morphine administrations resulted in oscillation. Beta-endorphin exhibited sensitization but not oscillation, suggesting that it did not mediate oscillation of the behavioral response. In addition, lithium, but not caffeine, eliminated oscillations of the behavioral response without affecting its initial enhancement.

Analysis of Variance↗
PubMed1998

The effects of lithium on a potential cycling model of bipolar disorder.

1. Although bipolar disorder constitutes a major public health problem, with a high risk of suicide and an economic cost exceeding that of unipolar depression, it has received comparatively little attention, particularly at the basic science level. Perhaps as a result of this neglect, there is currently no animal model able to simulate the cyclicity which is its defining characteristic. 2. Consequently, drug development in this area is meager and has proceeded serendipitously rather than empirically. 3. The authors have recently reported that repeated exposure to cocaine and other stressors can induce an oscillation or cycling in a host of neurochemical and physiological systems. 4. In order to test whether such cycling might be of potential relevance to bipolar disorder, the authors examined whether cocaine-induced cyclicity of amphetamine-evoked efflux of dopamine from slices of rat nucleus accumbens and striatum and/or cocaine induced oscillation of a behavior, stress-induced hypoalgesia, could be prevented by lithium, the agent of choice in treating this disease. 5. The authors report that prophylactic treatment with lithium, completely and specifically prevented oscillations in each instance. This may represent an important initial step toward the development of the first cycling model of bipolar disorder.

Amphetamine↗
PubMed1998

Oscillatory-sensitization model of repeated drug exposure: cocaine's effects on shock-induced hypoalgesia.

1. The authors have recently proposed that the sensitization produced by repeated exposure to drugs or stress may give way to an alternating pattern of increases and decreases in the response to each subsequent exposure (i.e., oscillate), as the limits of the physiological system are approached. 2. Evidence for oscillation has been obtained for 6 drug/non-drug stressors and 9 neurochemical or endocrine endpoints. This paper extends the model to a behavioral outcome. 3. In the first experiment, rats were given 0, 1, 2 or 3 pretreatments with cocaine hydrochloride (COC; 12 mg/kg i.p.), separated by 1-week intervals, and then were tested for footshock-induced hypoalgesia (5-sec, 2-mA), as measured by withdrawal latencies from a hot-plate. 4. The second experiment replicated the first and extended the pretreatment sequence to 5 COC injections. 5. In both experiments, shock significantly increased latencies over the no-shock controls. COC enhanced shock-induced hypoalgesia and this sensitization reached its maximum after 2 COC pretreatments. Thereafter, oscillation developed such that the sensitization was attenuated by 3 as compared to 2 COC injections, enhanced by 4 injections, and reattenuated after 5 COC pretreatments. 6. These data complement other findings by demonstrating that the oscillation model extends to a stress-induced behavioral outcome.

Animals↗
PubMed1997

Differential distribution of corticotropin-releasing hormone immunoreactive axons in monoaminergic nuclei of the human brainstem.

Corticotropin-releasing hormone (CRH) has been implicated in a variety of physiological and behavioral responses to stress, as well as in the pathophysiology of certain psychiatric disorders. Although studies in rodents support a neuromodulatory influence of CRH on monoamine neurotransmission in a number of brain regions, little information in available to support a similar role for CRH in the human brain. The present study used immunocytochemistry to characterize the anatomical organization of CRH-immunoreactive axons in the human brainstem. Substantial regional differences in the density and distribution of CRH-immunoreactive axons were found in the dopamine-, noradrenaline- and serotonin-containing cell body regions of the human brainstem. Dense networks of CRH-immunoreactive axons were found in the medial subnuclei of the ventral mesencephalon and in the dorsolateral region of the locus coeruleus. Moderate densities of CRH-positive fibers were located in the median and dorsal raphe, whereas lower numbers of CRH-labeled axons appeared in the substantia nigra pars compacta. In addition, differences in CRH innervation density were observed within each region. For example, the dorsal tier of the substantia nigra contained a greater density of CRH-labeled axons than the ventral tier. In all monoamine-containing nuclei, CRH-labeled axons exhibited numerous beaded varicosities and fine intervaricose segments. The differential distribution of CRH-containing axons across these human brainstem nuclei suggests that the influence of CRH on monoamine function may be neurotransmitter-specific.

Adult↗
PubMed1997

Sensitivity and specificity of 99mTc-HMPAO SPECT cerebral perfusion measurements during the first 48 hours for the localization of cerebral infarction.

BACKGROUND AND PURPOSE: There is no routinely used method for imaging the location of the extent and severity of cerebral tissue perfusion changes during the first hours of ischemic stroke, the period during which therapeutic intervention is most likely to be successful. Cerebral perfusion measurements with single-photon emission CT (SPECT) may potentially provide this information rapidly and noninvasively. In this study, the sensitivity and specificity of 99mTc-hexamethylpropyleneamine oxime (HMPAO) SPECT cerebral perfusion measurements during the first 48 hours of cerebral ischemia for the localization of cerebral infarction were determined. METHODS: One hundred and four patients with acute ischemic stroke underwent 99mTc-HMPAO SPECT and CT scanning during the first 48 hours. In each patient, the location of the SPECT perfusion abnormality was compared with the location of infarction on a second brain CT acquired at a mean of 8 days after stroke. RESULTS: During the first 48 hours of ischemic stroke, the sensitivity of 99mTc-HMPAO SPECT in locating the site of infarction was 79% (110/139), and the specificity was 95% (362/381). SPECT was more sensitive in the localization of the vascular territory of cortical infarction (sensitivity, 93%) than pure subcortical infarcts (sensitivity, 47%). During the first 48 hours, SPECT was significantly more sensitive than brain CT (sensitivity of brain CT during the first 48 hours, 35%; P < .001, Mann-Whitney U test). CONCLUSIONS: HMPAO SPECT measurement provides a widely available and practical technique of locating cerebral ischemia acutely and demonstrates high sensitivity and specificity within the first 48 hours for the localization of the vascular territory of cerebral infarction. It is most sensitive for cortical ischemia but is limited by its resolution in the subcortex, particularly of white matter perfusion changes.

Aged↗
PubMed1996

Changes in cerebral tissue perfusion during the first 48 hours of ischaemic stroke: relation to clinical outcome.

BACKGROUND: One major therapeutic strategy to minimise the extent of infarction after ischaemic stroke is to improve early reperfusion using thrombolytic agents. However, reperfusion may be hazardous and the period during which reperfusion may have a beneficial effect on tissue and clinical outcome is not known. METHODS: Fifty three patients were studied with serial cerebral perfusion (99mTcHMPAO SPECT) during the first 48 hours of ischaemic stroke to determine if changes in tissue perfusion during this time were prognostically significant. Single and multiple linear regression non-parametric analyses were used to include other factors during the same period which may influence outcome. RESULTS: In univariate analysis age, neurological score at admission, SPECT perfusion defect size in the first 24 hours, and percentage change in cerebral tissue perfusion at 24-48 hours (all P < 0.01) correlated significantly with the Barthel score at three months. In multiple linear regression analysis only age (P < 0.01) and percentage change in cerebral tissue perfusion at 24-48 hours (P < 0.01) provided independent prognostic information at three months. CONCLUSIONS: Changes in cerebral tissue perfusion during the first 48 hours of ischaemic stroke are significant outcome predictors and therapeutic effort aimed at increasing perfusion during this period seem to be justified.

Aged↗
PubMed1995

Localization of corticotropin-releasing hormone in the human locus coeruleus and pedunculopontine tegmental nucleus: an immunocytochemical and in situ hybridization study.

The present study utilized immunocytochemistry and in situ hybridization histochemistry to examine the localization of corticotropin-releasing hormone immunoreactivity and messenger RNA in neurons of the human brainstem. A large population of corticotropin-releasing hormone-immunoreactive neurons appeared in the lateral region of the pontomesencephalic tegmentum. These corticotropin-releasing hormone-containing neurons are predominantly located in the compact subnucleus of the pedunculopontine tegmental nucleus. Proceeding caudally, corticotropin-releasing hormone-immunoreactive neurons in the pedunculopontine tegmental nucleus travel in a dorsomedial direction approaching the ventral border of the locus coeruleus in a dispersed fashion and cluster in a region ventromedial to the locus coeruleus which corresponds to the ventral aspect of the laterodorsal tegmental nucleus. Dense corticotropin-releasing hormone-immunoreactive fibers are present in the dorsal portion of the locus coeruleus and are most prominent in the middle to rostral levels of the nucleus. The cellular and regional localization of corticotropin-releasing hormone messenger RNA in the human brainstem is identical to the perikaryal distribution visualized by immunocytochemistry. Neurons in the laterodorsal tegmental nucleus and pedunculopontine tegmental nucleus express abundant levels of corticotropin-releasing hormone messenger RNA as revealed by dense silver grains overlying these neurons on the emulsion autoradiograms. Within the locus coeruleus, the cellular expression of corticotropin-releasing hormone-immunoreactive and corticotropin-releasing hormone messenger RNA is exclusively localized to non-pigmented neurons. The present study confirms a previous finding describing dense corticotropin-releasing hormone-immunoreactive fibers innervating the human locus coeruleus and extends these findings by identifying corticotropin-releasing hormone immunoreactive and corticotropin-releasing hormone messenger RNA-containing perikarya in the pedunculopontine tegmental nucleus, in the ventral portion of the laterodorsal tegmental nucleus and in the locus coeruleus proper. From morphological observations, the corticotropin-releasing hormone-containing neurons in human pontomesencephalic tegmentum form a continuous population of neurons that are positioned anatomically to exert a putative neuromodulatory influence on locus coeruleus neurons.

Adult↗
PubMed1995

SPECT in the localisation of extratemporal and temporal seizure foci.

The yield of ictal, postictal, and interictal SPECT was compared in the localisation of seizure foci in 177 patients with partial epilepsy. In 119 patients with known unilateral temporal lobe epilepsy ictal SPECT (97% correct localisation) was superior to postictal SPECT (71% correct), which was better than interictal studies (48% correct). Similarly, in cases of known or suspected extratemporal epilepsy the yield of ictal SPECT studies was high (92%). By contrast, the yield of postictal studies was much lower (46%) and usually only very early postictal studies were diagnostic. Interictal SPECT was of little value. The accuracy of ictal SPECT in localising temporal lobe seizures is now well established. Extratemporal seizures are often brief and difficult to localise. This report shows that ictal SPECT also has a high diagnostic yield in a wide range of extratemporal epilepsies. The brevity of many extratemporal seizures means that true ictal SPECT examinations can be difficult to achieve, but the high diagnostic yield justifies the special organisational effort needed to obtain such studies.

Epilepsies, Partial↗
PubMed1995

Early reperfusion in the 'spectacular shrinking deficit' demonstrated by single-photon emission computed tomography.

The "spectacular shrinking deficit" (SSD) refers to a syndrome of profound hemispheric ischemia that resolves rapidly over hours to days, leaving patients with minimal residual neurologic deficits. The SSD is postulated to result from rapid embolic lysis, fragmentation, and migration along the internal carotid/middle cerebral artery axis, leading to restored tissue perfusion before irreversible tissue damage has occurred. We performed serial single-photon emission computed tomographic (SPECT) cerebral perfusion measurements during the first 48 hours in 36 patients admitted with major hemispheric ischemia, to compare the cerebral perfusion changes between patients who developed SSD (n = 5) and those who did not (n = 31). The two groups were similar for severity of neurologic deficit, time of SPECT study, and size of perfusion defect on the SPECT images. Patients with SSD were younger (p = 0.02, Mann-Whitney U), demonstrated significantly greater tissue reperfusion during the first 48 hours (p < 0.01), and had smaller infarcts on CT (p = 0.02). This syndrome provides an opportunity to understand the mechanism by which early reperfusion may result in early tissue salvage and clinical recovery.

Aged↗