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GUID: EA3A5ACDBC7D-A4EAE3E52 Abstract Psychosocial stress is a major risk factor for depression, stress leads to peripheral and central immune activation, immune activation is associated with blunted dopamine DA neural function, DA function single feeder mice reward interest, and reduced reward interest is a core symptom of depression.
These states might be inter-independent in a complex causal pathway.
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Whilst animal-model evidence exists for some specific steps in the pathway, there is currently no animal model in which it has been demonstrated that social stress leads to each of these immune, neural and behavioural states. Such a model would provide important existential evidence for the complex pathway and would enable the study of causality and mediating mechanisms at specific steps in the pathway.
Therefore, in the present mouse study we investigated for effects of day resident-intruder chronic social stress CSS on each of these states. Relative to controls, CSS mice exhibited higher spleen levels of granulocytes, inflammatory monocytes and T helper 17 cells; plasma levels of inducible nitric oxide synthase; and liver expression of genes encoding kynurenine pathway enzymes.
CSS led in the ventral tegmental area to higher levels of kynurenine and the microglia markers Iba1 and Cd11b and higher binding activity of DA D1 receptor; and in the nucleus accumbens NAcc to higher kynurenine, lower DA turnover and lower c-fos expression. Pharmacological challenge with DA reuptake inhibitor identified attenuation of DA stimulatory effects on locomotor activity and NAcc c-fos expression in CSS mice.
In behavioural tests of operant responding for sucrose reward validated as sensitive assays for NAcc DA function, CSS mice exhibited less reward-directed behaviour. Therefore, this mouse study demonstrates that a chronic social stressor leads to changes in each of the immune, neural and behavioural states proposed to mediate between stress and disruption of DA-dependent reward processing. The model can now be applied to investigate causality and, if demonstrated, underlying mechanisms in specific steps of this immune-neural-behavioural pathway, and thereby to identify potential therapeutic targets.
Keywords: Social stress, Immune activation, Mesolimbic dopamine system, Reward, Depression, Mouse model 1. Introduction Stress-related neuropsychiatric disorders often present with psychopathology of reward processing.
Depression is a prevalent example, with a core symptom being reduced interest in reward DSM-5,Pizzagalli, Within the research domain criteria RDoC framework, Positive valence systems is single feeder mice domain that includes dimensions of reward processing Cuthbert and Insel, Reward valuation including under effortful conditions Sherdell et al. Deficient reward processing co-occurs with reduced activation of the striatum, in particular the nucleus accumbens Pseudonym partnersuche Arrondo et al.
The NAcc receives dopamine DA inputs from cell bodies in the ventral tegmental area VTA and this is a major pathway in the mesolimbic DA neural circuit of reward processing Pizzagalli, Rodent studies have demonstrated the importance of the VTA-NAcc Single feeder mice pathway in regulating reward-directed behaviour, including approach motivation, reward valuation and reward expectancy Bergamini et al. Whilst it is often proposed that pathology in this pathway underlies impaired reward processing in depression Dunlop and Nemeroff,Pizzagalli,the responsible aetio-pathophysiological mechanisms are poorly understood.
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Stressful environmental life events are major aetiological factors in depression, with uncontrollable psychosocial stressors conferring particularly high risk to trigger and maintain episodes Kendler et al.
Animal models allow for the causal study of effects of environmental stressors on brain and behaviour.
In mice, the resident-intruder paradigm is used to induce social stress and has been applied in various forms, including repeated social defeat RSD Wohleb et al. In these paradigms, mice are exposed to chronic, uncontrollable social stress Azzinnari et al.
CSS involves placing the subject mouse with an aggressive resident mouse for a brief period of attack without injury followed by continuous distal exposure, and repeating this with a different resident across 15 days.
Behavioural effects of these stressors include increased anxiety RSD: Wohleb et al. There is human and animal evidence that stressors activate the immune-inflammatory system, single feeder mice noradrenaline released from the sympathetic branch of the autonomic nervous system binding to noradrenergic receptors on myeloid cells in the spleen and other immune tissues being a major brain-periphery mediator Bierhaus singles kreis kusel al.
In healthy humans, acute psychosocial stress increases blood levels of proinflammatory chemokines and cytokines Bierhaus et al.
One down-stream effect of higher proinflammatory cytokines is activation of the kynurenine pathway of tryptophan metabolism Campbell et al. Kynurenine metabolites include 3-hydroxykynurenine 3-HKa free radical generator that promotes oxidative stress Schwarcz et al. In mice, the stressors RSD, CSD and CSS induce higher blood levels of some proinflammatory cytokines e.