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Biomedical subjects

Bruce McEwen

Publications and source records attributed to Bruce McEwen.

13 recordsLinked to original sources
PubMed2006

Cognitive effects of intravenous hydrocortisone in subjects with PTSD and healthy control subjects.

On the basis of peripheral (nonbrain) neuroendocrine findings in subjects with posttraumatic stress disorder (PTSD), it has been hypothesized that these individuals also have a greater central (brain) sensitivity to glucocorticoids. In nonpsychiatric subjects, it has been found that working and declarative memory performance is selectively impaired by acute glucocorticoid administration. We hypothesized that subjects with PTSD, as compared to nonpsychiatric controls, would show greater impairments in verbal declarative memory and working memory, but not attention, following exogenous glucocorticoid administration. These data are part of a larger study using functional neuroimaging and peripheral HPA axis measures in these same subjects. Subjects underwent a 0.5-mg dexamethasone suppression test and measurement of basal cortisol, basal plasma lymphocyte glucocorticoid receptor number, and postdexamethasone cortisol on a separate day. Under double-blind randomized crossover conditions, 17-mg hydrocortisone or placebo was administered by intravenous (i.v.) bolus to 15 medication-free PTSD subjects (4 female) and 12 nonpsychiatric control subjects (4 female) matched by age, sex, and education level. Participants then underwent positron emission tomography (PET) scanning and 90 min after the initial drug/placebo administration, cognitive testing was then performed. By repeated measures ANCOVA (covaried for baseline performance on that neuropsychological test), neither attention tasks of digit span forward nor backward showed significant change. However, there were significant drug (F = 17.644, df = 1,25 P < 0.001), group (F = 4.383, df = 1,25 P = 0.048), and drug by group interactions (F = 4.756, df = 1,25 P = 0.040) for verbal declarative memory. By t-test, there was not a difference in baseline performance on this measure between subject groups. The subject group with PTSD experienced a greater decline in verbal declarative memory performance following hydrocortisone administration. For working memory, there were significant group (F = 6.048, df = 1,25 P = 0.022) and drug by group interactions (F = 6.048, df = 1,25 P = 0.022) for verbal declarative memory. By t-test, there was not a difference in baseline performance on this measure between subject groups. The hydrocortisone administration led to impairment in working memory in the group of subjects with PTSD, but not in the control subject group. Exploratory correlations between percent cortisol suppression following dexamethasone and baseline plasma lymphocyte glucocorticoid receptor number with declarative and working memory measures among subject groups separately and in a combined way revealed a negative correlation between lymphocyte glucocorticoid receptor density and working memory (r = -0.54, df = 25, P = 0.008). Brain sensitivity to glucocorticoids appears to be greater in subjects with PTSD. Heightened vulnerability of declarative memory in subjects with PTSD may indicate hippocampal involvement, whereas working memory vulnerability suggests additional brain regions (prefrontal, cingulate, temporal, and parietal cortices) and neurotransmitter systems (dopamine and serotonin) particularly sensitive to glucocorticoids in persons with PTSD.

Adult↗
PubMed2005

Tissue plasminogen activator and plasminogen mediate stress-induced decline of neuronal and cognitive functions in the mouse hippocampus.

Repeated stress can impair function in the hippocampus, a brain structure essential for learning and memory. Although behavioral evidence suggests that severe stress triggers cognitive impairment, as seen in major depression or posttraumatic stress disorder, little is known about the molecular mediators of these functional deficits in the hippocampus. We report here both pre- and postsynaptic effects of chronic stress, manifested as a reduction in the number of NMDA receptors, dendritic spines, and expression of growth-associated protein-43 in the cornu ammonis 1 region. Strikingly, the stress-induced decrease in NMDA receptors coincides spatially with sites of plasminogen activation, thereby predicting a role for tissue plasminogen activator (tPA) in this form of stress-induced plasticity. Consistent with this possibility, tPA-/- and plasminogen-/- mice are protected from stress-induced decrease in NMDA receptors and reduction in dendritic spines. At the behavioral level, these synaptic and molecular signatures of stress-induced plasticity are accompanied by impaired acquisition, but not retrieval, of hippocampal-dependent spatial learning, a deficit that is not exhibited by the tPA-/- and plasminogen-/- mice. These findings establish the tPA/plasmin system as an important mediator of the debilitating effects of prolonged stress on hippocampal function at multiple levels of neural organization.

Analysis of Variance↗
PubMed2005

Orbitofrontal cortex activity related to emotional processing changes across the menstrual cycle.

The orbitofrontal cortex (OFC) has been implicated in the representation of emotional stimuli, assignment of emotional valence/salience to stimuli, stimulus-reinforcement association learning, motivation, and socio-emotional control. Using functional magnetic resonance imaging in female subjects without premenstrual mood symptoms, we found that OFC activity to emotional linguistic stimuli varies depending on the menstrual cycle phase. Specifically, anterior-medial OFC activity for negative vs. neutral stimuli was increased premenstrually and decreased postmenstrually. The inverse pattern was seen in the lateral OFC. These findings suggest that specific subregional OFC activity to emotional stimuli is modulated across the menstrual cycle. The data also demonstrate that menstrual cycle phase is an important consideration in further studies attempting to elucidate the neural substrates of affective representation.

Adult↗
PubMed2004

Chronic non-invasive glucocorticoid administration decreases polysialylated neural cell adhesion molecule expression in the adult rat dentate gyrus.

The expression of the polysialylated neural cell adhesion molecule (PSA-NCAM) is increased in the hippocampus after chronic restraint stress (CRS) and may play a permissive role in structural changes that include dendrite reorganization in dentate gyrus (DG) and CA3 pyramidal neurons and suppression of neurogenesis in DG. We report that chronic oral corticosterone (CORT) administration decreases the number of PSA-NCAM immunoreactive granule neurons in the adult rat dentate gyrus, and the available evidence suggests that this is an indirect effect of CORT, possibly involving excitatory amino acids, that may not be directly related to neurogenesis. Because CORT treatment reduces but does not eliminate PSA-NCAM expression, the present results do not exclude a permissive role for PSA-NCAM in CORT or CRS-induced structural plasticity in hippocampus.

Administration, Oral↗
PubMed2004

Chronic stress alters amphetamine effects on behavior and synaptophysin levels in female rats.

Previous studies show that stress cross-sensitizes with or alters amphetamine (AMPH) effects in male rats; however, few studies include females. We investigated combining daily restraint stress (21 days for 6 h/day) with chronic AMPH (10 injections every other day) on locomotor activity, exploratory activity in an open field and object recognition, a memory task, in female rats. A synaptic protein, synaptophysin, was also quantified by radioimmunocytochemistry (RICC) in brain to determine possible mechanisms for behavioral changes. Beginning at 5 days after cessation of treatments, AMPH increased locomotion, modified exploration, impaired object recognition, and increased serum corticosterone (CORT) levels. Stress did not alter these parameters but blocked AMPH effects on exploration and object recognition, potentiated AMPH-dependent locomotor effects, and did not alter increased CORT levels. AMPH treatment decreased synatophysin expression in the hippocampus. In the caudate nucleus, the AMPH group showed increased synaptophysin expression which was reversed by stress. These results in females corroborate previously shown cross-sensitizations between stress and AMPH for locomotion in males and demonstrate that chronic stress counteracts AMPH-dependent impairments in recognition memory. Stress may counteract AMPH effects on the memory task by blocking both the induction of AMPH anxiety-like effects and neuroplastic changes in the caudate nucleus of female rats.

Amphetamine↗
PubMed2003

Chronic lithium treatment inhibits pilocarpine-induced mossy fiber sprouting in rat hippocampus.

Lithium remains the gold standard in the treatment of bipolar disorder. Long-term treatment with lithium may lead to specific adaptational changes in gene expression that contribute to a neuroprotective effect. In this study, the pilocarpine model of spontaneous limbic epilepsy was used to induce mossy fiber sprouting (axonal growth of the dentate granule cells that synapse on the pyramidal cells of the CA3 region) to examine the prophylactic neuroprotective effects of lithium in vivo. There were four groups of animals: pilocarpine treated (Pil+/Li-); pilocarpine treated followed by lithium (Pil+/Li+); lithium alone (Pil-/Li+); control (Pil-/Li-). Timm staining was used to obtain density measurements in the stratum oriens and the inner molecular layer of the hippocampus. Mossy fiber density was higher in the pilocarpine-treated animals compared to controls. Chronic lithium following pilocarpine treatment attenuated the density of mossy fibers but lithium alone had no effect. No changes in hilar volume or neuronal number were detected using stereological procedures. The ability of lithium to attenuate activation-induced reorganization in the hippocampus provides evidence for its role as a neuroprotective agent in an in vivo model that may be relevant to its clinical effects in bipolar disorder.

Animals↗
PubMed2003

A mechanism converting psychosocial stress into mononuclear cell activation.

Little is known about the mechanisms converting psychosocial stress into cellular dysfunction. Various genes, up-regulated in atherosclerosis but also by psychosocial stress, are controlled by the transcription factor nuclear factor kappaB (NF-kappaB). Therefore, NF-kappaB is a good candidate to convert psychosocial stress into cellular activation. Volunteers were subjected to a brief laboratory stress test and NF-kappaB activity was determined in peripheral blood mononuclear cells (PBMC), as a window into the body and because PBMC play a role in diseases such as atherosclerosis. In 17 of 19 volunteers, NF-kappaB was rapidly induced during stress exposure, in parallel with elevated levels of catecholamines and cortisol, and returned to basal levels within 60 min. To model this response, mice transgenic for a strictly NF-kappaB-controlled beta-globin transgene were stressed by immobilization. Immobilization resulted in increased beta-globin expression, which could be reduced in the presence of the alpha1-adrenergic inhibitor prazosin. To define the role of adrenergic stimulation in the up-regulation of NF-kappaB, THP-1 cells were induced with physiological amounts of catecholamines for 10 min. Only noradrenaline resulted in a dose- and time-dependent induction of NF-kappaB and NF-kappaB-dependent gene expression, which depended on pertussis-toxin-sensitive G protein-mediated phosphophatidylinositol 3-kinase, Ras/Raf, and mitogen-activated protein kinase activation. Induction was reduced by alpha(1)- and beta-adrenergic inhibitors. Thus, noradrenaline-dependent adrenergic stimulation results in activation of NF-kappaB in vitro and in vivo. Activation of NF-kappaB represents a downstream effector for the neuroendocrine response to stressful psychosocial events and links changes in the activity of the neuroendocrine axis to the cellular response.

Adrenocorticotropic Hormone↗
PubMed2003

Tissue plasminogen activator in the amygdala is critical for stress-induced anxiety-like behavior.

Although neuronal stress circuits have been identified, little is known about the mechanisms that underlie the stress-induced neuronal plasticity leading to fear and anxiety. Here we found that the serine protease tissue-plasminogen activator (tPA) was upregulated in the central and medial amygdala by acute restraint stress, where it promoted stress-related neuronal remodeling and was subsequently inhibited by plasminogen activator inhibitor-1 (PAI-1). These events preceded stress-induced increases in anxiety-like behavior of mice. Mice in which the tPA gene has been disrupted did not show anxiety after up to three weeks of daily restraint and showed attenuated neuronal remodeling as well as a maladaptive hormonal response. These studies support the idea that tPA is critical for the development of anxiety-like behavior after stress.

Amygdala↗
PubMed2002

Depression and anxiety symptoms in relation to anthropometry and metabolism in men.

Depression is associated with an increased risk of developing cardiovascular disease and type 2 diabetes mellitus. Abdominal obesity is also a high risk factor for these diseases. Therefore, symptoms of depression and anxiety were examined in relation to abdominal obesity. A total of 59 middle-aged men volunteered for measurements with the Hamilton Depression Scale (HDS), the Montgomery-Asberg Depression Rating Scale (MADRS), the Beck Depression Inventory (BDI) and the Hamilton Anxiety Scale (HAS). These results were examined in relation to body mass index (BMI), waist/hip ratio (WHR) and sagittal abdominal diameter, a measurement of intra-abdominal fat mass, and metabolic variables. Men with WHR>1.0 (n=26) in comparison with men with normal WHR (<1.0, n=33) showed significantly higher sum scores in all the scales used. There were positive correlations between the sum scores of all the depression scales and the WHR or the sagittal abdominal diameter. BMI correlated comparatively weakly only with the HDS. The correlations with the WHR remained when the influence of BMI was eliminated, suggesting that obesity is less involved than centralization of body fat. Insulin and glucose were significantly related to the HDS. Morning cortisol levels were negatively related to the BDI and (borderline) to the MADRS, suggesting perturbations of the regulation of the hypothalamic-pituitary-adrenal axis. We conclude that men with abdominal obesity have symptoms of depression and anxiety.

Anthropometry↗
PubMed2002

PSA-NCAM expression in the piriform cortex of the adult rat. Modulation by NMDA receptor antagonist administration.

Administration of NMDA receptor antagonists upregulates the expression of the polysialylated form of the neural cell adhesion molecule (PSA-NCAM) in the adult hippocampus. Since the piriform cortex is also populated by PSA-NCAM immunoreactive neurons during adulthood, we sought to characterize them in detail and to test whether NMDA receptor antagonists also modulate PSA-NCAM in this cortical region. PSA-NCAM immunoreactivity is located mainly in layer II, where many neurogliaform and some pyramidal-semilunar transitional neurons are labeled. Many large neurons in layer III and endopiriform nucleus also express PSA-NCAM. Interestingly, some small labeled cells resembling migratory neuroblasts appear in these layers and in the ventral end of the corpus callosum subjacent to the piriform cortex. These putative migratory cells and some neurogliaform neurons in layer II do not express NeuN, a marker of differentiated neurons. Many of these PSA-NCAM immunoreactive cells also express doublecortin, a molecule involved in neuronal migration. The number of PSA-NCAM immunoreactive neurogliaform neurons increases significantly 7 days after the administration of an NMDA receptor antagonist. Moreover, 21 days after the treatment we observe a significant increase in the number of doublecortin expressing cells in the deep layers of the piriform cortex. These results expand the current knowledge of the neuronal populations expressing PSA-NCAM in the piriform cortex, suggesting that some of these cells could be involved in structural plastic events such as axonal outgrowth, synaptogenesis or even neuronal migration. Similar to the hippocampus, NMDA receptors appear to play a critical role in these processes in the adult piriform cortex.

Animals↗
PubMed2002

Allostasis, homeostats, and the nature of stress.

This essay continues discussion of a new formulation of homeostasis that uses the concepts of allostasis and homeostats. The new formulation moves beyond Cannon's concept of "homeostasis," which posits an ideal set of conditions for maintenance of the internal environment. The notion of allostasis recognizes that there is no single ideal set of steady-state conditions in life, and different stressors elicit different patterns of activation of the sympathetic nervous and adrenomedullary hormonal systems. Allostasis reflects active, adaptive processes that maintain apparent steady states, via multiple, interacting effectors regulated by homeostatic comparators--"homeostats." "Allostatic load" refers to the consequences of sustained or repeated activation of mediators of allostasis. From the analogy of a home temperature control system, the temperature can be maintained at any of a variety of levels (allostatic states) by multiple means (effectors), regulated by the thermostat (homeostat). Allostatic load and risks of system breakdown increase when, for example, the front door is left open in the winter. Applying these notions can aid in understanding how acute and chronic stress can exert adverse health consequences via allostatic load.

Homeostasis↗
PubMed2002

Estrogen actions throughout the brain.

Besides affecting the hypothalamus and other brain areas related to reproduction, ovarian steroids have widespread effects throughout the brain, on serotonin pathways, catecholaminergic neurons, and the basal forebrain cholinergic system as well as the hippocampal formation, a brain region involved in spatial and declarative memory. Thus, ovarian steroids have measurable effects on affective state as well as cognition, with implications for dementia. Two actions are discussed in this review; both appear to involve a combination of genomic and nongenomic actions of ovarian hormones. First, regulation of the serotonergic system appears to be linked to the presence of estrogen- and progestin-sensitive neurons in the midbrain raphe as well as possibly nongenomic actions in brain areas to which serotonin neurons project their axons. Second, ovarian hormones regulate synapse turnover in the CA1 region of the hippocampus during the 4- to 5-day estrous cycle of the female rat. Formation of new excitatory synapses is induced by estradiol and involves N-methyl-D-aspartate (NMDA) receptors, whereas downregulation of these synapses involves intracellular progestin receptors. A new, rapid method of radioimmunocytochemistry has made possible the demonstration of synapse formation by labeling and quantifying the specific synaptic and dendritic molecules involved. Although NMDA receptor activation is required for synapse formation, inhibitory interneurons may play a pivotal role as they express nuclear estrogen receptor-alpha (ERa). It is also likely that estrogens may locally regulate events at the sites of synaptic contact in the excitatory pyramidal neurons where the synapses form. Indeed, recent ultrastructural data reveal extranuclear ERalpha immunoreactivity within select dendritic spines on hippocampal principal cells, axons, axon terminals, and glial processes. In particular, the presence of ER in dendrites is consistent with a model for synapse formation in which filopodia from dendrites grow out to find new synaptic contacts and estrogens regulate local, post-transcriptional events via second messenger systems.

Animals↗