Hymie Anisman

DO EARLY-LIFE EVENTS PERMANENTLY ALTER BEHAVIORAL AND HORMONAL RESPONSES TO STRESSORS ?

Early‐life stimulation (e.g. brief handling) attenuates the behavioral and neuroendocrine responses to stressors encountered in adulthood, particularly with respect to activation of hypothalamic‐pituitary‐adrenal (HPA) activity. In contrast, if neonates were subjected to a more severe stressor, such as protracted separation from the dam or exposure to an endotoxin, then the adult response to a stressor was exaggerated. These early‐life experiences program HPA functioning, including negative feedback derived from stimulation of hippocampal glucocorticoid receptors, and corticotropin‐releasing hormone (CRH) and arginine vasopressin (AVP) coexpression in PVN neurons, to modify the response to subsequent stressor experiences. The persistent variations of HPA activity observed in handled/stimulated animals may stem from alterations in dam–pup interactions (e.g. increased arched‐back feeding, licking, grooming). In addition genetic makeup is critical in determining stress reactivity. For instance, BALB/cByJ mice are more reactive to stressors than C57BL/6ByJ mice, exhibiting greater HPA hormonal alterations and behavioral disturbances. BALB/cByJ also fail to acquire a spatial learning response in a Morris water‐maze paradigm, which has been shown to be correlated with hippocampal cell loss associated with aging. Early‐life handling of BALB/cByJ mice prevented these performance deficits and attenuated the hypersecretion of ACTH and corticosterone elicited by stressors. The stressor reactivity may have been related to maternal and genetic factors. When BALB/cByJ mice were raised by a C57BL/6ByJ dam, the excessive stress‐elicited HPA activity was reduced, as were the behavioral impairments. However, cross‐fostering the more resilient C57BL/6ByJ mice to a BALB/cByJ dam failed to elicit the behavioral disturbances. It is suggested that genetic factors may influence dam–pup interactive styles and may thus proactively influence the response to subsequent stressors among vulnerable animals. In contrast, in relatively hardy animals the early‐life manipulations may have less obvious effects.

Depression: The predisposing influence of stress

Aversive experiences have been thought to provoke or exacerbate clinical depression. The present review provides a brief survey of the stress-depression literature and suggests that the effects of stressful experiences on affective state may be related to depletion of several neurotransmitters, including norepinephrine, dopamine, and serotonin. A major element in determining the neurochemical changes is the organisms ability to cope with the aversive stimuli through behavioral means. Aversive experiences give rise to behavioral attempts to cope with the stressor, coupled with increased utilization and synthesis of brain amines to contend with environmental demands. When behavioral coping is possible, neurochemical systems are not overly taxed, and behavioral pathology will not ensue. However, when there can be no behavioral control over the stressful stimuli, or when the aversive experience is perceived as uncontrollable, increased emphasis is placed on coping through endogenous neurochemical mechanisms. Amine utilization increases appreciably and may exceed synthesis, resulting in a net reduction of amine stores, which in turn promotes or exacerbates affective disorder. The processes governing the depletions may be subject to sensitization or conditioning, such that exposure to traumatic experiences may have long-term repercussions when the organism subsequently encounters related stressful stimuli. With continued uncontrollable stimulation, adaptation occurs in the form of increased activity of synthetic enzymes, and levels of amines approach basal values. It is suggested that either the initial amine depletion provoked by aversive experiences or a dysfunction of the adaptive processes, resulting in persistent amine depletion, contributes to behavioral depression. Aside from the contribution of behavioral coping, several organismic, experiential, and environmental variables will influence the effects of aversive experiences on neurochemical activity, and may thus influence vulnerability to depression.

Stress, depression, and anhedonia: caveats concerning animal models.

Numerous animal models of depression have been advanced, each having multiple attributes and some limitations. This review provides caveats concerning etiologically valid animal models of depression, focusing on characteristics of the depressive subtype being examined (e.g. typical vs atypical major depression, dysthymia, melancholia), and factors that contribute to the interindividual behavioral variability frequently evident in stressor-related behavioral paradigms. These include the stressor type (processive vs systemic stressors), and characteristics of the stressor (controllability, predictability, ambiguity, chronicity, intermittence), as well as organismic variables (genetic, age, sex), experiential variables (stressor history, early life events) and psychosocial and personality factors that moderate stressor reactivity. Finally, a model of depression is reviewed that evaluates the effects of stressors on hedonic processes, reflected by responding for rewarding brain stimulation. Anhedonia is a fundamental feature of depression, and assessment of stressor-related reductions in the rewarding value of brain stimulation, especially when coupled with other potential symptoms of depression, provides considerable face, construct and predictive validity. Stressful events markedly impact rewarding brain stimulation, and this effect varies across strains of mice differentially reactive to stressors, is modifiable by antidepressant treatments, and allows for analyses of the contribution of different brain regions to anhedonic processes. The paradigm is sensitive to several factors known to acts as moderators of stress responses, but analyses remain to be conducted with regard to several such variables.

Cytokine-specific central monoamine alterations induced by interleukin-1, -2 and -6

Cytokine-specific alterations of monoamine activity were evident in the hypothalamus, hippocampus and prefrontal cortex 2 h following peripheral administration of recombinant interleukin (IL)-1 beta, IL-2 and IL-6 (200 ng, i.p.) in male, BALB/c mice. IL-1 induced the broadest range of neurochemical changes, affecting central norepinephrine (NE), serotonin (5-HT) and dopamine (DA) activity. In particular, IL-1 enhanced NE turnover in the hypothalamus and hippocampus, 5-HT turnover in the hippocampus and prefrontal cortex (owing to increased utilization and reduced content of the transmitters in these brain regions), and enhanced DA utilization in the prefrontal cortex. IL-6 increased 5-HT and DA activity in the hippocampus and prefrontal cortex in a manner similar to IL-1, but failed to affect central NE activity. Moreover, IL-2 increased hypothalamic NE turnover (reflecting a profound increase in NE utilization) and enhanced DA turnover in the prefrontal cortex, but did not influence central 5-HT activity. Hence, these cytokines differentially altered neurochemical activity in brain regions that mediate neuroimmune interactions and that are influenced by physical and psychological stressors. In addition to the neurochemical changes, plasma corticosterone concentrations were profoundly enhanced in IL-1-treated animals, but not significantly altered by IL-2 or IL-6 treatment. The IL-1-induced corticosterone elevations did not significantly correlate with alterations of hypothalamic NE activity.

Dysregulation in the Suicide Brain: mRNA Expression of Corticotropin-Releasing Hormone Receptors and GABAA Receptor Subunits in Frontal Cortical Brain Region

Corticotropin-releasing hormone (CRH) and GABA have been implicated in depression, and there is reason to believe that GABA may influence CRH functioning. The levels of CRH, and mRNA for CRH-binding protein, CRH1, and CRH2 receptors, as well as various GABAA receptor subunits (α1, α2, α3, α4, α5, δ, and γ2), were determined in several frontal cortical brain regions of depressed suicide victims and nondepressed individuals who had not died by suicide. Relative to the comparison group, CRH levels were elevated in frontopolar and dorsomedial prefrontal cortex, but not in the ventrolateral prefrontal cortex of suicide victims. Conversely, using quantitative PCR analyses, it was observed that, in frontopolar cortex, mRNA for CRH1, but not CRH2, receptors were reduced in suicide brains, possibly secondary to the high levels of CRH activity. In addition, mRNA of the α1, α3, α4, and δ receptor subunits was reduced in the frontopolar region of suicide victims. Interestingly, a partial analysis of the GABAA receptor functional genome revealed high cross-correlations between subunit expression in cortical regions of nondepressed individuals, suggesting a high degree of coordinated gene regulation. However, in suicide brains, this regulation was perturbed, independent of overall subunit abundance. These findings raise the possibility that the CRH and GABAA receptor subunit changes, or the disturbed coordination between these GABAA receptor subunits, contribute to depression and/or suicidality or are secondary to the illness/distress associated with it.

Religiosity as Identity: Toward an Understanding of Religion From a Social Identity Perspective

As a social identity anchored in a system of guiding beliefs and symbols, religion ought to serve a uniquely powerful function in shaping psychological and social processes. Religious identification offers a distinctive “sacred” worldview and “eternal” group membership, unmatched by identification with other social groups. Thus, religiosity might be explained, at least partially, by the marked cognitive and emotional value that religious group membership provides. The uniqueness of a positive social group, grounded in a belief system that offers epistemological and ontological certainty, lends religious identity a twofold advantage for the promotion of well-being. However, that uniqueness may have equally negative impacts when religious identity itself is threatened through intergroup conflict. Such consequences are illustrated by an examination of identities ranging from religious fundamentalism to atheism. Consideration of religion’s dual function as a social identity and a belief system may facilitate greater understanding of the variability in its importance across individuals and groups.

Effect of inescapable shock on subsequent escape performance: catecholaminergic and cholinergic mediation of response initiation and maintenance.

Following exposure to inescapable shock, subsequent escape performance is disrupted if the task is one in which animals receive forced exposure to shock for several seconds before escape is possible. The extent of the deficit is directly related to the severity of the initial stress and the duration of escape delay used during test. Treatment with a tyrosine hydroxylase inhibitor, α-methyl-p-tyrosine (α-MpT), a dopamine-β-hydroxylase inhibitor, FLA-63, or dopamine antagonists, haloperidol, and pimozide, mimicked the effects of inescapable shock in the different escape paradigms. The effects of haloperidol were antagonized by treatment with scopolamine. As observed in the case of inescapable shock, prior escape training abated the disruptive effects of the drug treatments. Finally, decreasing or blocking catecholamine activity or increasing cholinergic activity exacerbated the effect of a moderate amount of inescapable shock on subsequent escape performance. These treatments also induced reductions in shock-elicited activity. Conversely, treatment with a catecholamine stimulant, l-dopa, or a cholinergic blocker, scopolamine, anatagonized the reduction in shock-elicited activity and the escape deficits engendered by prior inescapable shock. It was hypothesized that both DA and NE, as well as ACh, are involved in the escape deficit observed after inescapable shock, and that these transmitters mediate the interference by their influence on response initiation and maintenance, rather than on associative or cognitive processes.

Cyclin-dependent kinase 5 is a mediator of dopaminergic neuron loss in a mouse model of Parkinson's disease.

Recent evidence indicates that cyclin-dependent kinases (CDKs, cdks) may be inappropriately activated in several neurodegenerative conditions. Here, we report that cdk5 expression and activity are elevated after administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a toxin that damages the nigrostriatal dopaminergic pathway. Supporting the pathogenic significance of the cdk5 alterations are the findings that the general cdk inhibitor, flavopiridol, or expression of dominant-negative cdk5, and to a lesser extent dominant-negative cdk2, attenuates the loss of dopaminergic neurons caused by MPTP. In addition, CDK inhibition strategies attenuate MPTP-induced hypolocomotion and markers of striatal function independent of striatal dopamine. We propose that cdk5 is a key regulator in the degeneration of dopaminergic neurons in Parkinsons disease.

Cytokines, stress and depressive illness: brain-immune interactions.

Cytokines, signaling molecules of the immune system, have been implicated as a contributing factor for mood disorders such as depression. Several lines of evidence supporting this contention are briefly reviewed and caveats are introduced. Essentially, a relationship between cytokines and depression is based on the findings that: 1) proinflammatory cytokines (interleukin‐1, interleukin‐6, tumor necrosis factor‐α) and bacterial endotoxins elicit sickness behaviors (e.g., fatigue, soporific effects) and symptoms of anxiety/depression that may be attenuated by chronic antidepressant treatment, 2) cytokines induce neuroendocrine and central neurotransmitter changes reminiscent of those implicated in depression, and these effects are exacerbated by stressors, 3) severe depressive illness is accompanied by signs of immune activation and by elevations of cytokine production or levels, and 4) immunotherapy, using interleukin‐2 or interferon‐α, promotes depressive symptoms that are attenuated by antidepressant treatment. It is argued that cytokine synthesis and release, elicited upon activation of the inflammatory response system, provoke neuroendocrine and brain neurotransmitter changes that are interpreted by the brain as being stressors, and contribute to the development of depression. Furthermore, such effects are subject to a sensitization effect so that a history of stressful experiences or cytokine activation augment the response to later challenges and hence the evolution of depression

The pathogenesis of clinical depression: Stressor- and cytokine-induced alterations of neuroplasticity

Stressful events promote neurochemical changes that may be involved in the provocation of depressive disorder. In addition to neuroendocrine substrates (e.g. corticotropin releasing hormone, and corticoids) and central neurotransmitters (serotonin and GABA), alterations of neuronal plasticity or even neuronal survival may play a role in depression. Indeed, depression and chronic stressor exposure typically reduce levels of growth factors, including brain-derived neurotrophic factor and anti-apoptotic factors (e.g. bcl-2), as well as impair processes of neuronal branching and neurogenesis. Although such effects may result from elevated corticoids, they may also stem from activation of the inflammatory immune system, particularly the immune signaling cytokines. In fact, several proinflammatory cytokines, such as interleukin-1, tumor necrosis factor-alpha and interferon-gamma, influence neuronal functioning through processes involving apoptosis, excitotoxicity, oxidative stress and metabolic derangement. Support for the involvement of cytokines in depression comes from studies showing their elevation in severe depressive illness and following stressor exposure, and that cytokine immunotherapy (e.g. interferon-alpha) elicited depressive symptoms that were amenable to antidepressant treatment. It is suggested that stressors and cytokines share a common ability to impair neuronal plasticity and at the same time altering neurotransmission, ultimately contributing to depression. Thus, depressive illness may be considered a disorder of neuroplasticity as well as one of neurochemical imbalances, and cytokines may act as mediators of both aspects of this illness.