Depression and sickness behavior are Janus-faced responses to shared inflammatory pathways

It is of considerable translational importance whether depression is a form or a consequence of sickness behavior. Sickness behavior is a behavioral complex induced by infections and immune trauma and mediated by pro-inflammatory cytokines. It is an adaptive response that enhances recovery by conserving energy to combat acute inflammation. There are considerable phenomenological similarities between sickness behavior and depression, for example, behavioral inhibition, anorexia and weight loss, and melancholic (anhedonia), physio-somatic (fatigue, hyperalgesia, malaise), anxiety and neurocognitive symptoms. In clinical depression, however, a transition occurs to sensitization of immuno-inflammatory pathways, progressive damage by oxidative and nitrosative stress to lipids, proteins, and DNA, and autoimmune responses directed against self-epitopes. The latter mechanisms are the substrate of a neuroprogressive process, whereby multiple depressive episodes cause neural tissue damage and consequent functional and cognitive sequelae. Thus, shared immuno-inflammatory pathways underpin the physiology of sickness behavior and the pathophysiology of clinical depression explaining their partially overlapping phenomenology. Inflammation may provoke a Janus-faced response with a good, acute side, generating protective inflammation through sickness behavior and a bad, chronic side, for example, clinical depression, a lifelong disorder with positive feedback loops between (neuro)inflammation and (neuro)degenerative processes following less well defined triggers

Environmental enrichment reduces signs of boredom in caged mink

Animals housed in impoverished cages are often labelled 'bored'. They have also been called 'apathetic' or 'depressed', particularly when profoundly inactive. However, these terms are rarely operationally defined and validated. As a negative state caused by under-stimulation, boredom should increase interest in stimuli of all kinds. Apathy (lack of interest), by contrast, should manifest as decreased interest in all stimuli, while anhedonia (loss of pleasure, a depressive symptom) should specifically decrease interest in normally rewarding stimuli. We tested the hypotheses that mink, a model carnivore, experience more boredom, depression-like apathy, or anhedonia in non-enriched (NE) cages than in complex, enriched (E) cages. We exposed 29 subjects (13 E, 16 NE) to ten stimuli categorized a priori as aversive (e.g. air puffs), rewarding (e.g. evoking chasing) or ambiguous/neutral (e.g. candles). Interest in stimuli was assessed via latencies to contact, contact durations, and durations oriented to stimuli. NE mink contacted all stimuli faster (P = 0.003) than E mink, and spent longer oriented to/in contact with them, albeit only significantly so for ambiguous ones (treatment*type P<0.013). With stimulus category removed from statistical models, interest in all stimuli was consistently higher among NE mink (P<0.0001 for all measures). NE mink also consumed more food rewards (P = 0.037). Finally, we investigated whether lying down while awake and stereotypic behaviour (both increased by NE housing) predicted these responses. Lying awake positively co-varied with certain measures of increased exploration. In contrast, stereotypic 'scrabbling' or locomotion (e.g. pacing) did not. Overall, NE mink showed no evidence of apathy or depression, but instead a heightened investigation of diverse stimuli consistent with boredom. This state was potentially indicated by spending much time lying still but awake (although this result requires replication). Boredom can thus be operationalized and assessed empirically in non-human animals. It can also be reduced by environmental enrichment

Interplay between pro-inflammatory cytokines and growth factors in depressive illnesses

The development of depressive disorders had long been attributed to monoamine variations, and pharmacological treatment strategies likewise focused on methods of altering monoamine availability. However, the limited success achieved by treatments that altered these processes spurred the search for alternative mechanisms and treatments. Here we provide a brief overview concerning a possible role for pro-inflammatory cytokines and growth factors in major depression, as well as the possibility of targeting these factors in treating this disorder. The data suggest that focusing on one or another cytokine or growth factor might be counterproductive, especially as these factors may act sequentially or in parallel in affecting depressive disorders. It is also suggested that cytokines and growth factors might be useful biomarkers for individualized treatments of depressive illnesses

Molecular pathway reconstruction and analysis of disturbed gene expression in depressed individuals who died by suicide

Molecular mechanisms behind the etiology and pathophysiology of major depressive disorder and suicide remain largely unknown. Recent molecular studies of expression of serotonin, GABA and CRH receptors in various brain regions have demonstrated that molecular factors may contribute to the development of depressive disorder and suicide behaviour. Here, we used microarray analysis to examine the expression of genes in brain tissue (frontopolar cortex) of individuals who had been diagnosed with major depressive disorder and died by suicide, and those who had died suddenly without a history of depression. We analyzed the list of differentially expressed genes using pathway analysis, which is an assumption-free approach to analyze microarray data. Our analysis revealed that the differentially expressed genes formed functional networks that were implicated in cell to cell signaling related to synapse maturation, neuronal growth and neuronal complexity. We further validated these data by randomly choosing (100 times) similarly sized gene lists and subjecting these lists to the same analyses. Random gene lists did not provide highly connected gene networks like those generated by the differentially expressed list derived from our samples. We also found through correlational analysis that the gene expression of control participants was more highly coordinated than in the MDD/suicide group. These data suggest that among depressed individuals who died by suicide, wide ranging perturbations of gene expression exist that are critical for normal synaptic connectively, morphology and cell to cell communication

Behavior and pro-inflammatory cytokine variations among submissive and dominant mice engaged in aggressive encounters: Moderation by corticosterone reactivity

Psychosocial stressors contribute to the pathophysiology of affective disorders and variations of cytokine functioning have been implicated in this process. The present investigation demonstrated, in mice, the impact of stressful aggressive encounters on activity levels, plasma corticosterone and cytokine concentrations, and on cytokine mRNA expression within the prefrontal cortex (PFC) and hippocampus. As glucocorticoids have been tied to cytokine variations, mice were subdivided into low or high corticosterone responders, defined in terms of circulating hormone levels 75 min post-confrontation. Interestingly, stressor-induced effects among low and high responders varied as a function of whether mice were submissive or dominant during the aggressive bout. Agonistic encounters elicited subsequent hyperactivity, particularly among low corticosterone responders and among dominant mice. Plasma levels of corticosterone and interleukin (IL)-6 concomitantly increased after aggressive encounters and varied with dominance status and with the low versus high corticosterone response. Among the low responders corticosterone and IL-6 increases were modest and only apparent among submissive mice, whereas among high responders these elevations were more pronounced and comparable in submissive and dominant mice. Aggressive episodes also increased IL-1β and IL-6 mRNA brain expression. The IL-1β rise was greater in the PFC and hippocampus of submissive mice that were low responders. Among high responders IL-1β and IL-6 increased in both groups, although in the PFC this effect was specific to dominant mice. The data are discussed in terms of their relevance to the impact of aggressive encounters on affective behaviors, and to the role that cytokines might play in this regard

Cognitive Bias in Ambiguity Judgements:Using Computational Models to Dissect the Effects of Mild Mood Manipulation in Humans

Positive and negative moods can be treated as prior expectations over future delivery of rewards and punishments. This provides an inferential foundation for the cognitive (judgement) bias task, now widely-used for assessing affective states in non-human animals. In the task, information about affect is extracted from the optimistic or pessimistic manner in which participants resolve ambiguities in sensory input. Here, we report a novel variant of the task aimed at dissecting the effects of affect manipulations on perceptual and value computations for decision-making under ambiguity in humans. Participants were instructed to judge which way a Gabor patch (250ms presentation) was leaning. If the stimulus leant one way (e.g. left), pressing the REWard key yielded a monetary WIN whilst pressing the SAFE key failed to acquire the WIN. If it leant the other way (e.g. right), pressing the SAFE key avoided a LOSS whilst pressing the REWard key incurred the LOSS. The size (0-100 UK pence) of the offered WIN and threatened LOSS, and the ambiguity of the stimulus (vertical being completely ambiguous) were varied on a trial-by-trial basis, allowing us to investigate how decisions were affected by differing combinations of these factors. Half the subjects performed the task in a 'Pleasantly' decorated room and were given a gift (bag of sweets) prior to starting, whilst the other half were in a bare 'Unpleasant' room and were not given anything. Although these treatments had little effect on self-reported mood, they did lead to differences in decision-making. All subjects were risk averse under ambiguity, consistent with the notion of loss aversion. Analysis using a Bayesian decision model indicated that Unpleasant Room subjects were ('pessimistically') biased towards choosing the SAFE key under ambiguity, but also weighed WINS more heavily than LOSSes compared to Pleasant Room subjects. These apparently contradictory findings may be explained by the influence of affect on different processes underlying decision-making, and the task presented here offers opportunities for further dissecting such processes

Cytokines as a stressor: Implications for depressive illness

Stressful events have been implicated in the provocation of depressive illness. Inasmuch as immunological challenge, and particularly cytokine administration, engender neuroendocrine and central neurochemical changes reminiscent of those provoked by psychogenic stressors, it was suggested that immune activation may also contribute to affective illness. The present report provides a brief overview of the neurochemical sequelae of acute and repeated interleukin-1β (IL-1β), tumour necrosis factor-α (TNF-α) and IL-2 treatment, describes some of the synergisms associated with these treatments, as well as their potential interactions with psychogenic stressors. In addition, a discussion is provided concerning the fact that cytokines, like stressors, may have time-dependent proactive effects, so that re-exposure to the treatments provoke greatly augmented neurochemical changes (sensitization). Given that the effects of cytokines are evident within hypothalamic, as well as extrahypothalamic sites, including various limbic regions, it is suggested that cytokines may impact on emotional changes, including depression