Zul Merali

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.

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.

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.

Neurotransmitter, peptide and cytokine processes in relation to depressive disorder : Comorbidity between depression and neurodegenerative disorders

Given the array of biological changes induced by stressors, it is not surprising that these experiences may provoke a variety of illnesses. Among others things, stressors promote functional changes of neuropeptide and classical neurotransmitter systems. The peptidergic changes, for instance, include alterations of corticotropin releasing hormone, arginine vasopressin, and bombesin-like peptides at specific brain sites. Similarly some of the neurotransmitter systems influenced by stressors include GABAergic and monoamine functioning. Variations of these processes may limit neurogenesis (and dysregulation of growth factors such as BDNF) and influence cellular viability (through NFkappaB and MAP kinase pathways). As well, stressors activate the inflammatory immune system, notably the release of signaling molecules (cytokines), which may provoke many of the same neuropeptide (and other neurotransmitter) changes. By virtue of their actions on neuronal functioning, inflammatory processes may influence stress-related illness, such as depression, and may be a common denominator for the comorbidity that exists between depression and neurological conditions, including Parkinsons and Alzheimers diseases, as well as cardiovascular-related pathology. The present report provides an overview of biological endophenotypes associated with stressors that are thought to be related to major depressive disorder and related comorbid conditions. The view is taken that synergy between stressors and inflammatory factors may promote pathological outcomes through their actions on neuropeptides and several neurotransmitters. As well, stressful events may result in the sensitization of neurochemical and cytokine processes, so that later re-exposure to these stimuli may promote rapid and exaggerated responses that favor illness recurrence.

Cytokines as a Precipitant of Depressive Illness: Animal and Human Studies

Cytokines whose primary function is that of acting as signaling molecules of the immune system, have been implicated in the provocation or exacerbation of mood disorders such as depression. This position has been supported by several lines of evidence; (1) proinflammatory cytokines (interleukin-1beta, interleukin-6, tumor necrosis factor-alpha) and bacterial endotoxins elicit sickness behaviors (e.g., fatigue, soporific effects) and symptoms of anxiety/depression that may be attenuated by chronic antidepressant treatment. Interleukin-2 (IL-2) induces less profound sickness, but elicits anhedonia, a key symptom of depression; (2) neuroendocrine and central neurotransmitter changes, reminiscent of those implicated in depression, may be elicited by some of these cytokines, and these effects are exacerbated by stressors; (3) severe depressive illness is accompanied by elevations of cytokine production or levels, although these effects are not necessarily attenuated with antidepressant medication; and (4) immunotherapy, using IL-2 or IFN-alpha, promote depressive symptoms that are attenuated by antidepressant treatment. It is proposed that chronic cytokine elevations engender neuroendocrine and brain neurotransmitter changes that are interpreted by the brain as being stressors, and contribute to the development of depression. Further, the effects of the cytokine treatments may act synergistically with stressors, and cytokines may provoke a sensitization effect so that the effects of later stressor experiences are exacerbated.

Cytokines, Stress, and Depressive Illness

It has been suggested that immune activation, and particularly increased activity of several cytokines, notably interleukin-1, interleukin-2, interleukin-6, tumor necrosis factor-alpha as well as their soluble receptors is characteristic of depression. Normalization of cytokine activity does not necessarily occur following successful antidepressant, suggesting that cytokines may be trait markers of depression, or simply represent bystander effects of the illness. The relationship between cytokines and depression is complicated as a variety factors could directly or indirectly influence cytokine activity. While cytokine elevations are most pronounced in severe (melancholic) depression, their activity may also be related to chronicity of illness, neurovegetative features of depression (altered sleep patterns, food intake, weight changes, fatigue or general activity), or the high stress perception characteristic of depression. Although, studies assessing cytokines in depressive populations are basically correlational in nature, patients receiving cytokine immunotherapy frequently show depressive symptoms, which may be attenuated by antidepressant medication, supporting a causal role for cytokines in depressive disorders. The processes underlying such outcomes remain to be established, but the affective changes may stem from the neuroendocrine and central neurochemical changes elicited by cytokines, as these are reminiscent of those associated thought to subserve depression.

Therapeutic and protective effect of environmental enrichment against psychogenic and neurogenic stress.

Environmental enrichment (EE) has beneficial neurobiological, physiological and behavioral effects. The purpose of the present paper is to review the animal research literature pertaining to the impact of EE on altering physiological and behavioral anxiety outcomes. Evidence supports the view that EE attenuates responses to certain anxiety provoking situations, and that these effects persist over time. Specifically, EE attenuates behavioral anxiety-type responses and endocrine responses mediated via the hypothalamic-pituitary-adrenal (HPA) axis evoked by psychogenic and/or neurogenic stressors. EE is not only able to protect from excessive anxiety in response to a present stressor, but also attenuates the enduring or persistent effects engendered by past psychogenic stressor(s) such as prenatal stress or neonatal maternal separation. It is noteworthy that the protective effects of EE are particularly apparent in animals that are highly anxious or when the task is highly challenging for the subject. Various mechanisms of action of EE have been proposed, ranging from behavioral/cognitive to cellular/molecular processes. A pronounced variability in the enrichment protocols used by different investigators may account for some of the inconsistencies noted in the effect of EE on behavioral (e.g. anxiety) and endocrine (e.g. plasma corticosterone) responses. Although the occasional inconsistencies highlight the need for further research, a preponderance of the animal research data indicates that EE exerts therapeutic and protective (anxiolytic) effects against (a) impending threat, (b) enduring effects of past stressor(s) and (c) subsequent stressors.

Functional interactions between dopamine, serotonin and norepinephrine neurons: an in-vivo electrophysiological study in rats with monoaminergic lesions

Anatomical studies have established the existence of reciprocal relationships between the main population of monoamine, serotonin (5-HT), norepinephrine (NE) and dopamine (DA) neurons in the brain. The present study was thus conducted to examine the firing activity of 5-HT and NE neurons in DA-depleted rats, as well as the firing activity of DA neurons in 5-HT- or NE-depleted rats. The selective lesion of DA neurons elicited by 6-hydroxydopamine (6-OHDA) decreased the spontaneous firing activity of dorsal raphe (DR) nucleus 5-HT neurons by 60%, thus revealing the excitatory effect of the DA input on these 5-HT neurons. In contrast, the selective lesion of 5-HT neurons produced by 5,7-dihydroxytryptamine (5,7-DHT) enhanced by 36% the firing activity of VTA DA neurons, thereby indicating an inhibitory effect of the 5-HT input on these DA neurons. With regard to the reciprocal interaction between DA and NE neurons, it was observed that the selective loss of DA neurons achieved by the intra-ventral tegmental area (VTA) injection of 6-OHDA increased the firing activity of a subset of locus coeruleus (LC) NE neurons by 47%. The selective loss of NE neurons in response to the intra-LC injection of 6-OHDA enhanced the firing activity of VTA DA neurons by 70%, demonstrating a net inhibitory role of the NE input on VTA DA neurons. These findings have important consequences for antidepressant treatments aimed at enhancing simultaneously 5-HT, NE and DA transmission. Indeed, based on the understanding of such interactions, it may be possible to develop strategies to improve the effectiveness of antidepressant drugs by preventing counter-productive negative feedback actions.

Anhedonic and Anxiogenic Effects of Cytokine Exposure

Systemic interleukin IL-1 beta, TNF alpha, and IL-2 profoundly influenced central monoamine activity, as well as behavioral outputs. The effects of the various cytokines were clearly distinguishable from one another, although synergistic effects were detected between several of these cytokines and between the actions of cytokines and stressors. Acutely applied IL-2 appeared to affect reward processes, but did not affect anxiety. When chronically administered, this cytokine markedly influenced working memory in a spatial learning test. In contrast to IL-2, both IL-1 beta and TNF alpha appeared to provoke an anxiogenic action, and provoked clear signs of illness. While these cytokines induced anorexia, they did not appear to affect reward processes. IL-1 beta and TNF alpha were found to act synergistically, and the TNF alpha provoked a sensitization with respect to the action of subsequent TNF alpha treatment. The findings indicated that cytokine treatments profoundly influence extrahypothalamic neurochemical functioning and may thus impact on behavioral outputs. Analyses of the behavioral and neurochemical changes elicited by cytokines, and particularly TNF alpha, need to consider not only the immediate impact of such treatments, but also the proactive effects that may be engendered.