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Evidence for Psychosocial Stress-induced Inflammation, Altered Dopamine Status and Impaired Reward-directed Behaviour in Mice


Bergamini, Giorgio. Evidence for Psychosocial Stress-induced Inflammation, Altered Dopamine Status and Impaired Reward-directed Behaviour in Mice. 2015, University of Zurich, Faculty of Science.

Abstract

Stressful life events have been recognized as key proximal risk factors for depression, and exposure to stress is associated with altered immune function. Moreover, depression correlates with higher levels of inflammatory markers, at least in a subpopulation of patients. There is evidence that decreased dopamine (DA) neurotransmission in the mesocorticolimbic pathways leads to impaired reward and aversion processing and could underlie major psychopathologies, including motivational impairments that are common in depression. The psycho-neuro-immune hypothesis for depression presented here postulates that the inhibitory effects of stress-induced inflammatory signalling on DA neurotransmission represent a link between exposure to stressful environments and the emergence of depression-relevant behavioural abnormalities. Previous experiments have demonstrated that exposure to a chronic uncontrollable stressor – namely chronic social defeat (CSD) – increases fear learning-memory, helplessness and fatigue, and increases plasma levels of the pro-inflammatory cytokine TNF, in C57BL/6 young-adult male mice.
In this thesis I provide evidence that exposure to CSD activates the innate and adaptive immune system, alters DA transmission, and disrupts reward and punishment processing. Specifically, CSD led to increased splenic granulocytes, inflammatory monocytes and T helper 17 (Th17) cells, increased plasma levels of iNOS, and increased mRNA levels of kynurenine pathway enzymes in the liver. Moreover, microglia activation was evident in the ventral tegmental area (VTA). From the VTA, DA neurons project to different brain areas, including the nucleus accumbens (NAcc). In the NAcc, CSD mice showed decreased dopamine turnover (DOPAC/DA). CSD mice exhibited an attenuated hyper-locomotion response to a potent, selective DA transporter inhibitor. Behaviourally, CSD led to decreased operant responding for reward on a fixed-ratio schedule of reinforcement, and to reduced operant responses to an ambiguous reward stimulus in the learned non-reward (LNR) test, a behavioural assay for flexibility in the face of changing response-reinforcement contingencies.
To directly investigate the contribution of the DA mesolimbic system to the reward- and punishment-directed behaviours that are disrupted by CSD, I investigated the effects of 6-hydroxydopamine-induced DA depletion specific to the nucleus accumbens (NAcc) on mouse behaviour in the following test battery: reward motivation in a progressive ratio schedule (PRS) operant test, approach-avoid responding in a learned non-reward (LNR) operant test, footshock escape behaviour in a learned helplessness (LH) operant test, footshock avoid-escape behaviour in a treadmill operant test, and freezing behaviour in a Pavlovian fear conditioning test. NAcc DA depletion led to reduced responding: (i) for gustatory reward under effortful conditions in the PRS test; (ii) to a stimulus recently associated with gustatory non-reward in the LNR test; (iii) to footshock recently experienced as uncontrollable in the LH test; and (iv) to footshock that could only be avoided-escaped by physical effort in the treadmill test. Monoamine depletion was specific to DA and whereas 6-OHDA infusion into NAcc also led to a moderate DA reduction in prefrontal cortex, direct and specific DA depletion in the latter region did not impact on behaviour in the test battery used. Taken together, these novel mouse findings add significantly to the evidence that NAcc DA is a major regulator of motivational processing of both reward and aversion. They indicate the need for translational study of the targeting of pathophysiological DA function for the treatment of motivational psychopathologies in various psychiatric disorders.
In terms of antidepressant treatment, evidence indicates that the recently developed antidepressant agomelatine (Valdoxan), a melatonin receptor 1/2 agonist and serotonin receptor 2C antagonist, exhibits increased therapeutic efficacy relative to placebo in moderate-severe depression. Moreover, agomelatine (AGO) exhibits greater efficacy in treating interest-pleasure deficits relative to venlafaxine. I investigated AGO effects on mouse CSD-induced disruption of reward-directed behaviour in a progressive ratio schedule (PRS) test, a probabilistic reversal learning (PRL) test, and in terms of home cage reward wanting and consumption. Oral administration of AGO led to moderate brain exposure to the compound at 1 h. In the PRS test, CSD decreased reward motivation and sub-chronic per os AGO led to a non-significant reversal of this effect. In the PRL test, CSD decreased reward-stay probability and the number of reversals achieved, and AGO reduced the latter effect. In the home cage, CSD mice exhibited decreased operant responding for saccharin reward and water; in terms of consumption, CSD mice exhibited decreased saccharin drinking during the active period whereas they increased water drinking during the inactive period. Sub-chronic per os AGO was without effect on each of these CSD changes in reward-directed and homeostatic behaviours. With respect to the AGO effects in the PRS and PRL tests, it is noteworthy that, via 5-HT2C antagonism, AGO increases DA release in prefrontal cortex.
By combining environmental, neurochemical and pharmacological manipulations and investigating their effects on immune, neurochemical, cellular, molecular and behavioural readouts, this thesis provides mouse model evidence for the importance of stress-immune system-dopamine interactions in the aetiopathophysiology of the disrupted motivational processing that is common in psychiatric and immune disorders.

Abstract

Stressful life events have been recognized as key proximal risk factors for depression, and exposure to stress is associated with altered immune function. Moreover, depression correlates with higher levels of inflammatory markers, at least in a subpopulation of patients. There is evidence that decreased dopamine (DA) neurotransmission in the mesocorticolimbic pathways leads to impaired reward and aversion processing and could underlie major psychopathologies, including motivational impairments that are common in depression. The psycho-neuro-immune hypothesis for depression presented here postulates that the inhibitory effects of stress-induced inflammatory signalling on DA neurotransmission represent a link between exposure to stressful environments and the emergence of depression-relevant behavioural abnormalities. Previous experiments have demonstrated that exposure to a chronic uncontrollable stressor – namely chronic social defeat (CSD) – increases fear learning-memory, helplessness and fatigue, and increases plasma levels of the pro-inflammatory cytokine TNF, in C57BL/6 young-adult male mice.
In this thesis I provide evidence that exposure to CSD activates the innate and adaptive immune system, alters DA transmission, and disrupts reward and punishment processing. Specifically, CSD led to increased splenic granulocytes, inflammatory monocytes and T helper 17 (Th17) cells, increased plasma levels of iNOS, and increased mRNA levels of kynurenine pathway enzymes in the liver. Moreover, microglia activation was evident in the ventral tegmental area (VTA). From the VTA, DA neurons project to different brain areas, including the nucleus accumbens (NAcc). In the NAcc, CSD mice showed decreased dopamine turnover (DOPAC/DA). CSD mice exhibited an attenuated hyper-locomotion response to a potent, selective DA transporter inhibitor. Behaviourally, CSD led to decreased operant responding for reward on a fixed-ratio schedule of reinforcement, and to reduced operant responses to an ambiguous reward stimulus in the learned non-reward (LNR) test, a behavioural assay for flexibility in the face of changing response-reinforcement contingencies.
To directly investigate the contribution of the DA mesolimbic system to the reward- and punishment-directed behaviours that are disrupted by CSD, I investigated the effects of 6-hydroxydopamine-induced DA depletion specific to the nucleus accumbens (NAcc) on mouse behaviour in the following test battery: reward motivation in a progressive ratio schedule (PRS) operant test, approach-avoid responding in a learned non-reward (LNR) operant test, footshock escape behaviour in a learned helplessness (LH) operant test, footshock avoid-escape behaviour in a treadmill operant test, and freezing behaviour in a Pavlovian fear conditioning test. NAcc DA depletion led to reduced responding: (i) for gustatory reward under effortful conditions in the PRS test; (ii) to a stimulus recently associated with gustatory non-reward in the LNR test; (iii) to footshock recently experienced as uncontrollable in the LH test; and (iv) to footshock that could only be avoided-escaped by physical effort in the treadmill test. Monoamine depletion was specific to DA and whereas 6-OHDA infusion into NAcc also led to a moderate DA reduction in prefrontal cortex, direct and specific DA depletion in the latter region did not impact on behaviour in the test battery used. Taken together, these novel mouse findings add significantly to the evidence that NAcc DA is a major regulator of motivational processing of both reward and aversion. They indicate the need for translational study of the targeting of pathophysiological DA function for the treatment of motivational psychopathologies in various psychiatric disorders.
In terms of antidepressant treatment, evidence indicates that the recently developed antidepressant agomelatine (Valdoxan), a melatonin receptor 1/2 agonist and serotonin receptor 2C antagonist, exhibits increased therapeutic efficacy relative to placebo in moderate-severe depression. Moreover, agomelatine (AGO) exhibits greater efficacy in treating interest-pleasure deficits relative to venlafaxine. I investigated AGO effects on mouse CSD-induced disruption of reward-directed behaviour in a progressive ratio schedule (PRS) test, a probabilistic reversal learning (PRL) test, and in terms of home cage reward wanting and consumption. Oral administration of AGO led to moderate brain exposure to the compound at 1 h. In the PRS test, CSD decreased reward motivation and sub-chronic per os AGO led to a non-significant reversal of this effect. In the PRL test, CSD decreased reward-stay probability and the number of reversals achieved, and AGO reduced the latter effect. In the home cage, CSD mice exhibited decreased operant responding for saccharin reward and water; in terms of consumption, CSD mice exhibited decreased saccharin drinking during the active period whereas they increased water drinking during the inactive period. Sub-chronic per os AGO was without effect on each of these CSD changes in reward-directed and homeostatic behaviours. With respect to the AGO effects in the PRS and PRL tests, it is noteworthy that, via 5-HT2C antagonism, AGO increases DA release in prefrontal cortex.
By combining environmental, neurochemical and pharmacological manipulations and investigating their effects on immune, neurochemical, cellular, molecular and behavioural readouts, this thesis provides mouse model evidence for the importance of stress-immune system-dopamine interactions in the aetiopathophysiology of the disrupted motivational processing that is common in psychiatric and immune disorders.

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Additional indexing

Item Type:Dissertation
Referees:Pryce Christopher, Sheridan John
Communities & Collections:04 Faculty of Medicine > Psychiatric University Hospital Zurich > Clinic for Psychiatry, Psychotherapy, and Psychosomatics
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:December 2015
Deposited On:20 Jan 2016 13:12
Last Modified:28 Jun 2016 11:55
Number of Pages:135
Funders:Swiss National Science Foundation

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