RESUMEN

Stress has been considered as a major risk factor for depressive disorders, triggering depression onset via inducing persistent dysfunctions in specialized brain regions and neural circuits. Among various regions across the brain, the lateral habenula (LHb) serves as a critical hub for processing aversive information during the dynamic process of stress accumulation, thus having been implicated in the pathogenesis of depression. LHb neurons integrate aversive valence conveyed by distinct upstream inputs, many of which selectively innervate the medial part (LHbM) or lateral part (LHbL) of LHb. LHb subregions also separately assign aversive valence via dissociable projections to the downstream targets in the midbrain which provides feedback loops. Despite these strides, the spatiotemporal dynamics of LHb-centric neural circuits remain elusive during the progression of depression-like state under stress. In this review, we attempt to describe a framework in which LHb orchestrates aversive valence via the input-output specific neuronal architecture. Notably, a physiological form of Hebbian plasticity in LHb under multiple stressors has been unveiled to incubate neuronal hyperactivity in an input-specific manner, which causally encodes chronic stress experience and drives depression onset. Collectively, the recent progress and future efforts in elucidating LHb circuits shed light on early interventions and circuit-specific antidepressant therapies.

RESUMEN

Complete animal welfare evaluation in intensive farming is challenging. With this study, we investigate new biomarkers for animal physical and mental health by comparing plasma expression of biochemical indicators in dairy cows reared in three different systems: (A) semi-intensive free-stall, (B) non-intensive tie-stall, and (C) intensive free-stall. Additionally, protein levels of mature brain-derived neurotrophic factor (mBDNF) and its precursor form (proBDNF) and indoleamine 2,3-dioxygenase (IDO1) specific activity were evaluated in brain samples collected from 12 cattle culled between 73 and 138 months of age. Alterations in plasma lipid composition and in the kynurenine pathway of tryptophan metabolism were observed in the tie-stall-reared animals. The total plasma BDNF concentration was higher in tie-stall group compared to the two free-housing groups. Brain analysis of the tie-stall animals revealed a different mBDNF/proBDNF ratio, with a higher level of proBDNF (p < 0.001). Our data are similar to previous studies on animal models of depression, which reported that inhibition of the conversion of proBDNF in its mature form and/or elevated peripheral kynurenine pathway activation may underlie cerebral biochemical changes and induce depressive-like state behavior in animals.

RESUMEN

Whole-transcriptome data were used to study the changes in expression of genes coding proteins involved in the calcium regulation processes in the hippocampus of male mice with symptoms of depression caused by chronic social defeat stress. Cacna1g, Cacnb3, Camk1g, Camk2d, Camk2n2, Caly, Caln1, S100a16, and Slc24a4 genes were upregulated in the hippocampus of depressed mice compared to a control, while Cacna2d1, Cacng5, Grin2a, and Calm2 were downregulated. The greatest number of significant correlations was observed between the expression level of Calm2, which showed the highest transcriptional activity, and other differentially expressed genes. Calcium signaling in the hippocampus was assumed to be disrupted in mice exposed to chronic social defeat stress. The involvement of Calm2, Camk1g, Camk2d, and Camk2n2 genes in the process is discussed.

Asunto(s)

RESUMEN

BACKGROUND: Exposure to early life adversities (ELA) can influence a plethora of biological mechanisms leading to stress-related disorders later in life through epigenetic mechanisms, such as microRNAs (miRs). MiR-34 is a critical modulator of stress response and stress-induced pathologies and a link between ELA and miR-34a has been reported. METHODS: Here using our well-established model of ELA (Repeated Cross Fostering) we investigate the behavioral long-term effects of ELA in male and female mice. We also assess basal and ELA-induced miR-34a expression in adult mice and investigate whether ELA affects the later miR-34a response to adult acute stress exposure across brain areas (medial preFrontal Cortex, Dorsal Raphe Nuclei) and peripheral organs (heart, plasma) in animals from both sexes. Finally, based on our previous data demonstrating the critical role of Dorsal Raphe Nuclei miR-34a expression in serotonin (5-HT) transmission, we also investigated prefrontal-accumbal 5-HT outflow induced by acute stress exposure in ELA and Control females by in vivo intracerebral microdialysis. RESULTS: ELA not just induces a depressive-like state as well as enduring changes in miR-34a expression, but also alters miR-34a expression in response to adult acute stress exclusively in females. Finally, altered DRN miR-34a expression is associated with prefrontal-accumbal 5-HT release under acute stress exposure in females. LIMITATIONS: Translational study on humans is necessary to verify the results obtained in our animal models of ELA-induced depression. CONCLUSIONS: This is the first evidence showing long-lasting sex related effects of ELA on brain and peripheral miR-34a expression levels in an animal model of depression-like phenotype.

Asunto(s)

RESUMEN

Withania somnifera (WS) extracts have been used in traditional medicine for millennia to promote healthy aging and wellbeing. WS is now also widely used in Western countries as a nutritional supplement to extend healthspan and increase resilience against age-related changes, including sleep deficits and depression. Although human trials have supported beneficial effects of WS, the study designs have varied widely. Plant material is intrinsically complex, and extracts vary widely with the origin of the plant material and the extraction method. Commercial supplements can contain various other ingredients, and the characteristics of the study population can also be varied. To perform maximally controlled experiments, we used plant extracts analyzed for their composition and stability. We then tested these extracts in an inbred Drosophila line to minimize effects of the genetic background in a controlled environment. We found that a water extract of WS (WSAq) was most potent in improving physical fitness, while an ethanol extract (WSE) improved sleep in aged flies. Both extracts provided resilience against stress-induced behavioral changes. WSE contained higher levels of withanolides, which have been proposed to be active ingredients, than WSAq. Therefore, withanolides may mediate the sleep improvement, whereas so-far-unknown ingredients enriched in WSAq likely mediate the effects on fitness and stress-related behavior.

Asunto(s)

RESUMEN

Chronic, uncontrollable stress can result in psychiatric syndromes, including anxiety and major depressive disorder, in humans and mammalian disease models.1,2 Similarly, several days of chronic stress can induce depression-associated behavioral alteration in Drosophila accompanied by changes in biogenic amine levels in the adult brain.3-6 In our chronic stress paradigm, flies are subjected to 3 days of repetitive phases of 300 Hz vibrations combined with overcrowding and food deprivation. This treatment reduces voluntary behavioral activity, including the motivation to climb wide gaps (risk taking) and to stop for sweets (anhedonia), suggesting a depression-like state (DLS). These behavioral changes correlate with decreased serotonin release to the mushroom body (MB), a major behavioral control center in the central brain of the fly.7,8 Stressed flies are relieved from the DLS by feeding the anti-depressant serotonin precursor 5-HTP or the selective serotonin reuptake inhibitor fluoxetine. Notably, feeding sucrose to stressed flies results in elevated serotonin levels in the brain and ameliorates the DLS.3 Here, we show that this sugar relief is mediated by the neurotransmitter octopamine signaled from ventral unpaired medial neurons located in the subesophageal ganglion. The octopamine signaling of sweet sensation is transmitted to the MB via the dopaminergic PAM neurons. In addition, neuronal-silencing experiments reveal that the serotonergic dorsal paired medial (DPM) neurons innervating the MB are essential for sugar relief. Conversely, thermogenetic or optogenetic activation of DPMs can replace sweet sensation, elucidating that serotonergic signaling from DPMs takes part in positively modulating DLS-related behavioral changes.

Asunto(s)

RESUMEN

The review presents experimental data considered from the point of view of dynamic changes in the brain neurochemistry, physiology, and behavior of animals during the development of mixed anxiety/depression-like disorder caused by chronic social stress from norm to severe psychopathology. Evidences are presented to support the hypothesis that chronic anxiety rather than social defeat stress is an etiological factor in depression. The consequences of chronic anxiety for human health and social life are discussed.

Asunto(s)

RESUMEN

Social subordination, which causes severe stress in animals, can affect animal's behaviors, homeostasis, and mental health. In rodents, experiences of repeated social defeats, but not a single defeat, induce a depression-like state. However, it is unclear whether such experiences similarly affect behaviors of other model animals than rodents. Here, we established a behavioral paradigm for repeated social defeats with zebrafish, an emerging model for behavioral neuroscience and pharmacological analysis. We put fish into repeated social subordination for 6 consecutive days. Using behaviors during fighting as indicators, we observed that experiencing repeated social defeats led to a reduction in fight frequency and duration. The continuously-defeated zebrafish failed to win even against the transgenic fish with an impaired winning-associated neural pathway. These results suggest that repeated social defeats led to demotivation to fight and to win against opponents. Moreover, they showed strong activity in the ventral habenula, an evolutionary homolog of the mammalian lateral habenula. However, unlike the mice model, the continuously-defeated zebrafish showed no change in anxiety level and sociability. Our established behavioral paradigm will be a new tool to investigate neural mechanisms underlying social defeats.

Asunto(s)

RESUMEN

Dogs exposed to aversive events can become inactive and unresponsive and are commonly referred to as being "depressed", but this association remains to be tested. We investigated whether shelter dogs spending greater time inactive "awake but motionless" (ABM) in their home-pen show anhedonia (the core reduction of pleasure reported in depression), as tested by reduced interest in, and consumption of, palatable food (KongTM test). We also explored whether dogs being qualitatively perceived by experts as disinterested in the food would spend greater time ABM (experts blind to actual inactivity levels). Following sample size estimations and qualitative behaviour analysis (n = 14 pilot dogs), forty-three dogs (6 shelters, 22F:21M) were included in the main study. Dogs relinquished by their owners spent more time ABM than strays or legal cases (F = 8.09, p = 0.032). One significant positive association was found between the KongTM measure for average length of KongTM bout and ABM, when length of stay in the shelter was accounted for as a confounder (F = 3.66, p = 0.035). Time spent ABM also correlated with scores for "depressed" and "bored" in the qualitative results, indirectly suggesting that experts associate greater waking inactivity with negative emotional states. The hypothesis that ABM reflects a depression-like syndrome is not supported; we discuss how results might tentatively support a "boredom-like" state and further research directions.