Blockade of N-methyl-D-aspartate receptor activation suppresses learning-induced synaptic elimination.
Auditory filial imprinting in the domestic chicken is accompanied by a dramatic loss of spine synapses in two higher associative forebrain areas, the mediorostral neostriatum/hyperstriatum ventrale (MNH) and the dorsocaudal neostriatum (Ndc). The cellular mechanisms that underlie this learning-induced synaptic reorganization are unclear. We found that local pharmacological blockade of N-methyl-D-aspartate (NMDA) receptors in the MNH, a manipulation that has been shown previously to impair auditory imprinting, suppresses the learning-induced spine reduction in this region. Chicks treated with the NMDA receptor antagonist 2-amino-5-phosphonovaleric acid (APV) during the behavioral training for imprinting (postnatal day 0-2) displayed similar spine frequencies at postnatal day 7 as naive control animals, which, in both groups, were significantly higher than in imprinted animals. Because the average dendritic length did not differ between the experimental groups, the reduced spine frequency can be interpreted as a reduction of the total number of spine synapses per neuron. In the Ndc, which is reciprocally connected with the MNH and not directly influenced by the injected drug, learning-induced spine elimination was partly suppressed. Spine frequencies of the APV-treated, behaviorally trained but nonimprinted animals were higher than in the imprinted animals but lower than in the naive animals. These results provide evidence that NMDA receptor activation is required for the learning-induced selective reduction of spine synapses, which may serve as a mechanism of information storage specific for juvenile emotional learning events. (+info
Level of chronic life stress predicts clinical outcome in irritable bowel syndrome.
BACKGROUND: Life stress contributes to symptom onset and exacerbation in the majority of patients with irritable bowel syndrome (IBS) and functional dyspepsia (FD); research evidence is conflicting, however, as to the strength of these effects. AIMS: To test prospectively the relation of chronic life stress threat to subsequent symptom intensity over time. PATIENTS: One hundred and seventeen consecutive outpatients satisfying the modified Rome criteria for IBS (66% with one or more concurrent FD syndromes) participated. METHODS: The life stress and symptom intensity measures were determined from interview data collected independently at entry, and at six and 16 months; these measures assessed the potency of chronic life stress threat during the prior six months or more, and the severity and frequency of IBS and FD symptoms during the following two weeks. RESULTS: Chronic life stress threat was a powerful predictor of subsequent symptom intensity, explaining 97% of the variance on this measure over 16 months. No patient exposed to even one chronic highly threatening stressor improved clinically (by 50%) over the 16 months; all patients who improved did so in the absence of such a stressor. CONCLUSION: The level of chronic life stress threat predicts the clinical outcome in most patients with IBS/FD. (+info
Receptor binding, behavioral, and electrophysiological profiles of nonpeptide corticotropin-releasing factor subtype 1 receptor antagonists CRA1000 and CRA1001.
Receptor binding, behavioral, and electrophysiological profiles of 2-[N-(2-methylthio-4-isopropylphenyl)-N-ethylamino]-4-[4-(3-flu orophe nyl)-1,2,3,6-tetrahydropyridin-1-yl)-6-methylpyrimidine (CRA1000) and 2-[N-(2-bromo-4-isopropylphenyl)-N-ethylamino]-4-[4-(3-fluoropheny l)- 1,2,3,6-tetrahydropyridin-1-yl)-6-methylpyrimidine (CRA1001), putative novel and selective antagonists for corticotropin-releasing factor1 (CRF1) receptor were examined. Both CRA1000 and CRA1001 inhibited 125I-ovine CRF binding to membranes of rat frontal cortex with IC50 values of 20.6 and 22.3 nM, respectively. Likewise, CRA1000 and CRA1001 inhibited 125I-ovine CRF binding to membranes of rat pituitary. In contrast, both CRA1000 and CRA1001 were without affinity for the CRF2beta receptor when examined using rat heart. In mice orally administered CRA1000 and CRA1001 reversed the swim stress-induced reduction of the time spent in the light area in the light/dark exploration task. In nonstress conditions, CRA1000 and CRA1001 were without effect on the time spent in the light area in the same task in mice. Orally administered CRA1000 and CRA1001 dose dependently reversed the effects of i.c.v. infusion of CRF on time spent in the open arms in the elevated plus-maze in rats. Lesioning of olfactory bulbs induced hyperemotionality, and this effect was inhibited by either acute or chronic oral administration of CRA1000 and CRA1001 in rats. The firing rate of locus coeruleus neurons was increased by i.c.v.-infused CRF. This excitation of locus coeruleus neurons was significantly blocked by pretreatment with i.v. administration of CRA1000 and CRA1001. CRA1000 and CRA1001 had no effects on the hexobarbital-induced anesthesia in mice, the rotarod test in mice, the spontaneous locomotor activity in mice, and a passive avoidance task in rats. These observations indicate that both CRA1000 and CRA1001 are selective and competitive CRF1 receptor antagonists with potent anxiolytic- and antidepressant-like properties in various experimental animal models, perhaps through inhibition of CRF1 receptors. CRA1000 and CRA1001 may prove effective for treating subjects with depression- and/or anxiety-related disorders without the side effects seen in the related currently prescribed medications. (+info
Development and application of an index of social function.
Brief indexes of social function were constructed in a project to develop a health index questionnaire designed to measure the social, emotional, and physical function of free-living populations. The social function items have been found to be generally applicable, capable of application by lay interviewers, and acceptable to interviewees. Initial evaluations to form composite scores for social function items have demonstrated their validity against concurrent assessments of a health professional. These social function indexes have been successfully applied in two randomized trials of innovative primary care services. The criteria for inclusion of items in the social function index questionnaire, the generation of the instrument, and the evaluation of questionnaire responses for their validity are summarized here. (+info
Emotional stress and characteristics of brain noradrenaline release in the rat.
We have investigated several characteristics of the rat brain noradrenaline (NA) release caused by various stressful situations. Stresses such as immobilization or electric foot shock, wherein the physical factors rather than emotional ones were greatly involved, caused more marked increases in NA release in the more extended brain regions, as compared to psychological stress and conditioned fear, which caused increases in NA release preferentially in the hypothalamus, amygdala and locus coeruleus (LC) region. When the electric shock stress and psychological stress for 1 hr daily were repeated for 5 consecutive days, increases in brain NA release induced by electric shock were rapidly reduced, but those caused by psychological stress were enhanced rather than reduced. Rats with no stressor controllability (uncontrollable) had more severe gastric lesions and more marked increases in NA release in such brain regions as the hypothalamus and amygdala after 21 hrs of training than controllable rats. Rats with no opportunity to predict electric shock exhibited more severe gastric lesions and more marked increases in hypothalamic NA release than the predictable rats. The rats not allowed to express their aggression had more severe gastric mucosal lesions and a more noticeable and persistent increases in extracellular NA content in the amygdala determined by intracerebral microdialysis than the rats allowed to express aggression by biting a wooden stick in front of them during stress exposure. In aged rats (12 months old), recovery from increases in NA release in the hypothalamus and amygdala and increases in plasma corticosterone were much later than in young (2-month-old) rats. When rats were exposed to a series of six 15-min stress interrupted by 18-min non-stress periods for 180 min, they had much greater increases in brain NA release than rats stressed continuously for 180 min. Based upon these findings, we suggest that such stresses might be harmful to our health as psychological, uncontrollable and unpredictable stresses, stress unable to express aggression, stress in elderly people, and stress with lack of suitable rest. (+info
T-lymphocyte activation increases hypothalamic and amygdaloid expression of CRH mRNA and emotional reactivity to novelty.
Stimulation of T-cells with staphylococcal enterotoxin B (SEB) significantly elevates interleukin-2 (IL-2) and contemporaneous activation of the hypothalamic-pituitary-adrenal (HPA) axis and c-fos in the paraventricular nucleus (PVN) of BALB/cByJ mice. Such neural signaling may promote cognitive and emotional adaptation before or during infectious illness. Because corticotropin-releasing hormone (CRH) is an anxiogenic neuropeptide that may mediate the stressor-like effects of immunological stimuli, we measured neuronal CRH mRNA alterations in mice challenged with SEB. Increased CRH mRNA levels were observed in the PVN and central nucleus of the amygdala (ceA) 4-6 hr after SEB administration. This was associated with plasma ACTH increases, which could be abrogated by the systemic administration of anti-CRH antiserum. Additional experiments did not support a role for IL-2 or prostaglandin synthesis in activating the HPA axis. Behavioral experiments testing for conditioned taste aversion did not confirm that SEB challenge promotes malaise. However, consistent with the notion that central CRH alterations induced by SEB may affect emotionality (e.g., fear), SEB challenge augmented appetitive neophobia in a context-dependent manner, being marked in a novel and stressful environment. It is hypothesized that immunological stimuli generate a cascade of events that solicit integrative neural processes involved in emotional behavior. As such, these data support the contention that affective illness may be influenced by immunological processes and the production of cytokines and are consistent with other evidence demonstrating that autoimmune reactivity is associated with enhanced emotionality. (+info
Coping with infertility: distress and changes in sperm quality.
Infertility represents a serious stressor for some patients as well as a risk factor for a decrease in sperm quality. The purpose of the present study was to identify coping strategies that went along with both better emotional and physical adjustment to infertility. The sample consisted of 63 patients who contacted an andrological clinic more than one time. Prior to clinical examination, patients filled out a questionnaire referring to the way in which they coped with their wives' previous menstruation. Participants also completed a scale assessing perceived distress due to infertility. Change in sperm concentration since baseline semen analysis and the level of distress were used to evaluate patient's adjustment. The better-adjusted patients showed less prominent overall coping efforts, and a higher proportion of distancing coping strategies. An improvement in sperm quality also was associated with a low cognitive involvement in infertility. Situational uncontrollability of infertility could be a moderator of the effectiveness of coping employed by the better-adjusted patients. In addition, the coping behaviour related to better adjustment could be due to a dispositional stress resistance factor. For clinical implementation of the findings, the attitudes of a patient and the expectations of his wife have to be taken into consideration. (+info
Different contributions of the human amygdala and ventromedial prefrontal cortex to decision-making.
The somatic marker hypothesis proposes that decision-making is a process that depends on emotion. Studies have shown that damage of the ventromedial prefrontal (VMF) cortex precludes the ability to use somatic (emotional) signals that are necessary for guiding decisions in the advantageous direction. However, given the role of the amygdala in emotional processing, we asked whether amygdala damage also would interfere with decision-making. Furthermore, we asked whether there might be a difference between the roles that the amygdala and VMF cortex play in decision-making. To address these two questions, we studied a group of patients with bilateral amygdala, but not VMF, damage and a group of patients with bilateral VMF, but not amygdala, damage. We used the "gambling task" to measure decision-making performance and electrodermal activity (skin conductance responses, SCR) as an index of somatic state activation. All patients, those with amygdala damage as well as those with VMF damage, were (1) impaired on the gambling task and (2) unable to develop anticipatory SCRs while they pondered risky choices. However, VMF patients were able to generate SCRs when they received a reward or a punishment (play money), whereas amygdala patients failed to do so. In a Pavlovian conditioning experiment the VMF patients acquired a conditioned SCR to visual stimuli paired with an aversive loud sound, whereas amygdala patients failed to do so. The results suggest that amygdala damage is associated with impairment in decision-making and that the roles played by the amygdala and VMF in decision-making are different. (+info