Ghrelin stimulates corticotropin-releasing factor and vasopressin gene expression in rat hypothalamic 4B cells

Corticotropin-releasing factor (CRF) and arginine vasopressin (AVP) play a central role in regulating the stress response. In response to stress, CRF and AVP neurons in the hypothalamic paraventricular nucleus secrete the peptides to stimulate the release of adrenocorticotropic hormone from the anterior pituitary. Ghrelin, an endogenous ligand of the growth hormone-releasing peptide receptors (GHSR), has been shown to stimulate the release of CRF and AVP by rat hypothalamic explants. However, little is known about the ability of the ghrelin signaling pathways to activate the CRF and AVP genes in the hypothalamus. In the present study, we examined the direct effect of ghrelin on CRF and AVP gene expression in hypothalamic 4B cells, which show the characteristics of the hypothalamic parvocellular paraventricular nucleus neurons. Cells were transfected with CRF or AVP promoter to examine the activity of each promoter. Ghrelin stimulated the promoter activities and mRNA levels for both CRF and AVP. The involvement of a protein kinase pathway was examined using inhibitors. Protein kinase A and phospholipase C pathways were shown to be involved in ghrelin-induced increases in both CRF and AVP promoter activities. GHSR type 1a (GHSR1a) mRNA levels were also increased by ghrelin, and these ghrelin-induced levels were suppressed by a GHSR1a antagonist. Thus, ghrelin-dependent pathways are involved in the regulation of CRF and AVP gene expression in the hypothalamus: ghrelin, an orexigenic hormone, stimulates CRF, an anorexigenic/anxiogenic factor in the hypothalamus, resulting in hypothalamic-pituitary-adrenal axis activation to stimulate the release of glucocorticoids.     

The hippocampus and amygdala mediate the locomotor stimulating effects of corticotropin-releasing factor in mice

We have previously demonstrated that both stress manipulations and corticotropin-releasing factor (CRF) elevate locomotor activity in mice primarily in the center region of an open field. In the present study, other than confirming these findings, we have further examined the roles of the dentate gyrus of the hippocampus, the amygdala, and the caudate nucleus in mediating the locomotor-stimulating effect of CRF. Results indicate that among the areas examined, the hippocampus is the most important neural substrate of the action of CRF. The amygdala is also partly responsible for the behavioral effect produced by CRF. The caudate nucleus, however, although is important in the expression of gross motor activity, is not involved in the effect of CRF on locomotion in mice. The results are compared with those obtained in rats and are discussed in terms of the interactions between CRF and stress.     

Human placental corticotropin-releasing factor (CRF) in the adaptive response to pregnancy

Several findings suggest a role of placental hormones in the regulation of maternal and fetal physiology during pregnancy. The placenta and its accessory membranes, amnion and chorion, although of fetal origin, actually undertake the role of intermediary barriers and active messengers in the maternal-fetal dialogue. They synthesize, metabolize and serve as targets for numerous hormones and cytokines which control all aspects of pregnancy and parturition. Among these, corticotropin-releasing factor (CRF) has been one of the most investigated in the last decade. The secretion of placental CRF is autonomous, but increasing evidence indicates that maternal or fetal physiological and pathological conditions may influence such secretion. In the event of acute or chronic metabolic, physical or infection stress, the placenta takes part in a stress syndrome by releasing CRF, which may contribute to restore local blood flow, and to influence the timing of delivery. Placental CRF and cytokines produced in case of intrauterine infection may activate labour, thereby helping the fetus to escape from a hostile environment.On the background of maternal and/or fetal stress elicited by a number of pathological conditions, CRF appears to play a role in coordinating adaptive changes in uterine perfusion,maternal metabolism, fluid balance and possibly uterine contractility.     

Fluoxetine inhibits corticotropin-releasing factor (CRF)-induced behavioural responses in rats

Corticotropin-releasing factor (CRF) is a potent neuromodulator of stress-related behaviour but the neural mechanisms underlying these effects are not clear. Studies were designed to test the hypothesis that CRF-induced behavioural arousal involves interactions with brainstem serotonergic systems. To examine interactions between CRF and serotonergic systems in the regulation of behaviour, CRF (1 microg, intracerebroventricular (i.c.v.)) or vehicle was infused in the presence or absence of the selective serotonin re-uptake inhibitor fluoxetine (0, 0.1, 1 or 10 mg/kg, intravenous (i.v.)). Fluoxetine was used at these doses because it is known to decrease serotonin cell firing rates while increasing extracellular serotonin concentrations in select forebrain regions. We then measured behavioural, neurochemical and endocrine responses. CRF increased locomotion and spontaneous non-ambulatory motor activity (SNAMA) in the home cages. Fluoxetine decreased tissue 5-hydroxyindoleacetic acid concentrations, a measure of serotonin metabolism, in specific limbic brain regions of CRF-treated rats (nucleus accumbens shell region, entorhinal cortex, central nucleus of the amygdala). Furthermore, fluoxetine inhibited CRF-induced SNAMA. CRF and fluoxetine independently increased plasma corticosterone concentrations, but the responses had distinct temporal profiles. Overall, these data are consistent with the hypothesis that CRF-induced facilitation of behavioural activity is dependent on brainstem serotonergic systems. Therefore, fluoxetine may attenuate or alleviate some behavioural responses to stress by interfering with CRF-induced responses.     

Self-fulfilling prophecies in the clinical context: Review and implications for clinical practice

The expectancies a therapist and client bring into the clinical relationship can act as self-fulfilling prophecies. This article reviews the literature bearing on three types of self-fulfilling prophecies in a clinical context. First, I look at how the initial expectancies held by a therapist may bias the diagnosis and treatment of the client. Second, I look at the client's own self-expectancies for improvement and how they can enhance or impede progress. Last, I look at how receiving mental health treatment may be regarded as a stigma by others, resulting in negative social interactions for the client. For each of these domains, practical examples and implications are discussed, and suggestions are offered to therapists for how they can avoid or minimize damaging effects of negative self-fulfilling prophecies.     

The role of neuropeptide Y in the amygdala on corticotropin-releasing factor receptor-mediated behavioral stress responses in the rat

Neuropeptide Y (NPY) is one of the most abundant peptides in the brain and has been shown to be a critical regulator of emotionality, most notably for its effect in decreasing anxiety-like behaviors. The stress response in both humans and animals has been shown to involve a cascade of biological events initiated by corticotropin releasing factor (CRF), another centrally acting peptide. Interestingly, NPY and CRF are present in similar brain regions mediating stress responses and may act in an opposing fashion. The basolateral nucleus of the amygdala (BLA) is a distinct division of the amygdala and contains CRF receptors and the highest concentration of NPY neurons. The current study investigates the behavioral effects in rodents when NPY is injected directly into the BLA prior to the pharmacological stressor, urocortin I (Ucn; a CRF receptor agonist) or the emotional stressor, restraint. The animals that underwent restraint were evaluated in the social interaction (SI) test, while those injected with Ucn into the BLA were assessed in the two floor choice test, a modified version of the conditioned-place avoidance paradigm. The results showed that injections of NPY into the BLA prior to Ucn significantly blocked the development of the avoidance behavior in the two floor choice test and the decrease in SI time that is usually seen following restraint stress. These results provide further support that an interaction between NPY and CRF within the BLA may be critical for maintaining a normal homeostatic emotional state.     

'Mid-Life crisis' and its implications in counselling

The term 'mid-life crisis' is increasingly used both in everyday speech and in the professional literature as an explanation of certain disturbing psychological symptoms and uncharacteristic behaviour in middle age. This paper outlines the symptoms and the causes presumed by a wide range o f literature (mainly American) to underlie them. It then examines empirical research for evidence of the existence and nature of the phenomenon labelled 'mid-life crisis' and, finding little, proposes alternative explanations for its symptoms and for the emergence and use of the concept in recent years. It concludes with an examination of implications for guidance and counselling.     

Epistemic supererogation and its implications

Supererogatory acts, those which are praiseworthy but not obligatory, have become a significant topic in contemporary moral philosophy, primarily because morally supererogatory acts have proven difficult to reconcile with other important aspects of normative ethics. However, despite the similarities between ethics and epistemology, epistemic supererogation has received very little attention. In this paper, I aim to further the discussion of supererogation by arguing for the existence of epistemically supererogatory acts and considering the potential implications of their existence. First, I offer a brief account of moral supererogation and how morally supererogatory acts generate a strong intuition that a similar phenomenon should exist in epistemology. Afterward, I argue for the existence of epistemically supererogatory acts by examining five cases where an epistemic activity appears to be epistemically supererogatory. Epistemic supererogation appears to provide the best explanation for our considered judgments about the individuals’ behavior in these different cases. Finally, I consider how epistemic supererogation might impact the contemporary study of epistemology, particularly with regard to how we appraise certain epistemic duties.     

Signal transduction mechanisms within the entorhinal cortex that support latent inhibition of cued fear conditioning

Latent inhibition is a phenomenon by which pre-exposure to a conditioned-stimulus (CS), prior to subsequent pairings of that same CS with an unconditioned-stimulus (US), results in decreased conditioned responding to the CS. Previous work in our laboratory has suggested that the entorhinal cortex is critically involved in the establishment of latent inhibition of cued fear conditioning. Furthermore, utilizing systemic pharmacology, we have demonstrated a role for of NMDA receptors, protein kinase A (PKA), and mitogen activated protein kinase (MAPK, also known as ERK) in latent inhibition of cued fear conditioning, but until now, where these cell signaling cascades are critically activated during latent inhibition of cued fear was unknown. Here, we use direct drug infusion to demonstrate that cell signaling via NMDA receptors, the cAMP/PKA pathway, and the MAPK pathway within the entorhinal cortex are critically involved in latent inhibition of cued fear conditioning. In the present study, CS pre-exposed mice received 20 CS pre-exposures 24h prior to two pairings of the same CS with a 0.53 mA foot shock US, while control animals receive no pre-exposure to the CS. The NMDA antagonist APV (0.25 or 2.5 microg/side), the cAMP inhibitor Rp-cAMP (1.8 or 18.0 microg/side), or the MAPK inhibitor U0126 (0.1 or 1.0 microg/side) were directly infused into the entorhinal cortex prior to pre-exposure. All three drugs produced dose-dependent disruptions in latent inhibition of cued fear conditioning. Importantly, none of the drugs had any effect on cued fear conditioning when administered on training day, suggesting that the effects of each of the drugs were specific to CS pre-exposure. These results are discussed in relation to the potential mechanisms of plasticity that support latent inhibition of cued fear conditioning.     

Body dysmorphic disorder: implications for its validity as a DSM-III-R clinical syndrome

A sample of 258 college students responded to three items in Likert-format designed by the authors to elicit information relating directly to the three criteria for body-dysmorphic disorder described in DSM-III-R (1987). 70% of the participants endorsed some agreement with an item regarding dissatisfaction with some aspect(s) of their bodies. 46% indicated some preoccupation with this aspect of their appearance, and 48% indicated some exaggeration of their perceived body image. Sex differences were significant on all three items. 28% of the sample endorsed all three of the items taken together. These results raise questions about the utility of a diagnosis which, as it is currently defined, could conceivably apply to a large percentage of the population and which disproportionately targets women.     

Reflections on the clinical implications of symbolism

We start by stressing the idea that the process itself of constructing the symbol in its different components and its vicissitudes is centrally important to contemporary psychoanalysis as symbols are essential for thinking and for storing emotional experiences in our memory and for conveying our affects to others and to ourselves. Our implicit idea is that internal attacks are not directed only at the internal objects, but also include attacks on the structure or forms of the mental representations before and while they become constituted in symbols. It is by this means that destructive impulses invade the processes of symbolic construction. Symbols can lose their plasticity and thus silence the emotions and therefore cut off the patient from their meanings. Our clinical material allows us to increase our understanding of how the formal qualities of symbols operate in mental life, and how they can interfere in the capacity to work through emotional experiences. Finally, our reflections based on the analysis of a patient with difficulty in relating with the meanings of the symbols he produced will highlight the importance of the analyst's reverie along the process of formulating an interpretation. This paper is also part of a development in the study of the process of reverie.     

Heuristics in learning classifiers: The acquisition of the classifier system and its implications for the nature of lexical acquisition

Classifiers are like nouns in that they classify entities in the world into lexical categories. However, the lexical nature of the classifier system is very different from that of nouns. We discuss how Japanese and Chinese children learn the meanings of classifiers. We focus on two specific questions: How classifier acquisition is different from noun acquisition; and what the prerequisites are for spontaneously extracting the meanings of classifiers. It is shown that children are very conservative in assigning meaning to classifiers. The pace of learning largely depends on semantic complexity, across languages and within each language. Furthermore, we suspect that learning the meanings of classifiers requires a certain cognitive ability – an ability to synthesize pieces of partial knowledge and form them into a cohesive whole. It may be only when children have developed such an ability that they are able to extract the complex semantic rules of classifiers on their own. We conclude that children take very different routes in learning nouns and classifiers: Unlike noun acquisition, classifier acquisition is guided by a slow, bottom-up process.     

Fractal dynamics of heart beat interval fluctuations in corticotropin-releasing factor receptor subtype 2 deficient mice

Non-linear fractal analysis of cardiac interbeat time series was performed in corticotropin-releasing factor receptor subtype 2 (CRFR2) deficient mice. Heart rate dynamics in mice constitutes a self-similar, scale-invariant, random fractal process with persistent intrinsic long-range correlations and inverse power-law properties. We hypothesized that the sustained tachycardic response elicited by intraperitoneal (ip) injection of human/rat CRF (h/rCRF) is mediated by CRFR2. In wildtype control animals, heart rate was increased to about maximum levels (~ 750 bpm) while in CRFR2-deficient animals baseline values were retained (~ 580 bpm). The tachycardic response elicited by ip-application is mediated by CRFR2 and is interpreted to result from sympathetic stimulation. However, the functional integrity of CRFR2 would not present a prerequisite to maintaining the responsiveness and resiliency of cardiac control to external environmental perturbations experimentally induced by extrinsic ip-application of h/rCRF or under physiological conditions that may be associated with an increased peripheral release of CRF. Under stressful physiological conditions achieved by novelty exposure, CRFR2 is not involved in the cardiodynamic regulation to external short-term stress. While the hypothesis of involvement of CRFR2 in cardiac regulation upon pharmacological stimulation cannot be rejected, the present findings suggest that the mechanism of action is by sympathetic stimulation, but would not unambiguously allow to draw any conclusions as to the physiological role of CRFR2 in the control of cardiac dynamics.     

Identity: recent findings and clinical implications

After a review of foundational contributions to the concept of identity, including Erikson's, the author discusses the research methods and findings of the Personality Disorders Institute of the Joan and Sanford I. Weill Medical College of Cornell University regarding the concepts of normal identity and identity diffusion, toward an elucidation of the psychopathology of personality disorders--their etiology, diagnosis, and treatment. The application of an object relations theory model to analyze the development of identity clarifies the relationship of individual identity with the social and cultural frame that influences identity formation and may amplify the effects of pathological identity development. Detailed excerpts are presented from a diagnostic structural interview at the Personality Disorders Institute.