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S.28.03 Inflammation and adult hippocampal neurogenesis
S.28. Understanding the role of inflammation in the pathophysiology of depression Tryptophan is metabolized into kynurenine that enters the brain via the large amino acid transporter LAT1. In the brain kynurenine is further metabolized by kynurenine monooxygenase (KMO) into two neurotoxic metabolites, 3-hydroxy kynurenine and quinolinic acid, therefore disrupting the balance between neuroprotection mediated by another kynurenine metabolite, kynurenic acid, and neurotoxicity. Activated microglia also release glutamate in the extracellular milieu, which can synergize with quinolinic acid to induce excitotoxicity. Blockade of IDO by pharmacological or genetic means abrogates inflammation-induced depression without altering sickness behavior. Administration of ketamine, a NMDA receptor antagonist, has the same effect. In a model of spared nerve injury the depression-like behavior that develops concomitantly to chronic pain is abrogated by inhibition of IDO or KMO. These results open new ways of treating inflammationassociated depression by blocking the entry of kynurenine into the brain, reversing the alterations in the ratio of neurotoxic to neuroprotective kynurenine metabolites, or interfering with excess glutamatergic neurotransmission. S.28.03 Inflammation and adult hippocampal neurogenesis Y. Nolan1 ° 1 University College Cork Department of Anatomy & Neuroscience, Cork City, Ireland The hippocampus, which has a central role in learning, memory and emotion, is particularly vulnerable to inflammatory insult due to its high density of pro-inflammatory cytokine receptors. Chronic stress, which precipitates major depressive disorder, is also a well-known instigator of neuroinflammation. Dysregulation of adult hippocampal neurogenesis (the birth of new neurons) in response to stress and/or inflammation has been shown to contribute to emotional and cognitive impairment. Conversely, physical exercise is a positive modulator of adult hippocampal neurogenesis, emotion and cognition. This study examines the potential of physical exercise to counteract the anti-neurogenic effect of the pro-inflammatory cytokine, interleukin-1beta. The impact on hippocampal-dependent cognition was also assessed. Male C57BL/6 adolescent mice were singly or pair-housed with or without access to a running wheel for eight weeks. Four weeks after the initiation of the study, mice were bilaterally injected with a lentivirus overexpressing IL-1beta into the dorsal hippocampus. Performance in the open field, novel object recognition task and spontaneous alternation in the Y-maze task was assessed, and hippocampal tissue was analysed for neurogenesis (BrdU/NeuNpositive cells, DCX-positive cells). Results provide evidence that exercise has differential effects on IL-1beta-induced changes in hippocampal neurogenesis and behaviour depending on preexposure of mice to social isolation stress during adolescence. Disclosure statement: This material is based upon work supported by the Science Foundation Ireland under Grant No. SFI/IA/1537.
S151
S.28.04 A mouse model to study the inflammation hypothesis of depression: from psychopathology to target discovery C. Pryce1 °
1 University
of Z¨urich, Z¨urich, Switzerland
The complex aetio-pathophysiological pathway from stress to depression psychopathologies likely comprises several inter-related stages, including peripheral events that stimulate glial and neuronal changes in brain regions processing mood, reward and fatigue. Animal models are essential to elucidate this pathway and identify cellular and molecular therapeutic targets [1]. In mice, relative to handled controls, 15-day chronic social stress increased fear conditioning, helplessness and fatigue, and decreased motivation for reward [2]. The stress manipulation increased blood levels of proinflammatory cytokines [2] and kynurenines and spleen inflammatory monocytes and Th17 cells. In corticolimbic brain regions, kynurenines and microglial density were increased. Using region-specific transcriptomics, stressed mice exhibited decreased expression of genes for oligodendrocyte-myelin proteins (e.g. Mbp, Plp1, Cnp), dopamine receptors (Drd1a, Drd2), serotonin receptors (Htr1a, Htr2a), and GABA interneuron proteins (Pvalb, Gabrd) [2]. fMRI demonstrated that corticolimbic connectivity was increased in stressed mice. Pharmacological evidence for a cause-effect relationship between increased kynurenine-pathway activity and altered brain-behaviour function was provided by reversal of stress-induced increased conditioned fear by an indoleamine dioxygenase/kynurenine pathway inhibitor. Of particular interest is decreased expression of oligodendrocyte-myelin genes in amygdala and prefrontal cortex, given the evidence that these same genes are down-regulated in the same regions in depressed human brain [3]. Oligodendrocytes function to synthesise myelin on principal neurons in excitatory and inhibitory networks and to metabolically support neurons via energy metabolite provision. Oligodendrocyte inhibition via inflammatory excitotoxicity and oxidative stress could be a major pathophysiology of depression and a necessary target of novel antidepressant pharmacotherapy. References [1] Pryce, C.R., Seifritz, E., 2011. A translational research framework for enhanced validity of mouse models of psychopathological states in depression. Psychoneuroendocrinol 36, 308–329. [2] Azzinnari, D., Sigrist, H., Staehli, S., Palme, R., Hildebrandt, T., Leparc, G., Hengerer, B., Seifritz, E., Pryce, C.R., 2014. Mouse social stress induces increased fear conditioning, helplessness and fatigue to physical challenge together with markers of altered immune and dopamine function. Neuropharmacology 85, 328–341. [3] Sibille, E., Wang, Y., Joeyen-Waldorf, J., Gaiteri, C., Surget, A., Oh, S., Belzung, C., Tseng, G.C., Lewis, D.A., 2009. A molecular signature of depression in the amygdala. Am J Psychiatry 166, 1011–1024.
S151
S.28.04 A mouse model to study the inflammation hypothesis of depression: from psychopathology to target discovery C. Pryce1 °
1 University
of Z¨urich, Z¨urich, Switzerland
The complex aetio-pathophysiological pathway from stress to depression psychopathologies likely comprises several inter-related stages, including peripheral events that stimulate glial and neuronal changes in brain regions processing mood, reward and fatigue. Animal models are essential to elucidate this pathway and identify cellular and molecular therapeutic targets [1]. In mice, relative to handled controls, 15-day chronic social stress increased fear conditioning, helplessness and fatigue, and decreased motivation for reward [2]. The stress manipulation increased blood levels of proinflammatory cytokines [2] and kynurenines and spleen inflammatory monocytes and Th17 cells. In corticolimbic brain regions, kynurenines and microglial density were increased. Using region-specific transcriptomics, stressed mice exhibited decreased expression of genes for oligodendrocyte-myelin proteins (e.g. Mbp, Plp1, Cnp), dopamine receptors (Drd1a, Drd2), serotonin receptors (Htr1a, Htr2a), and GABA interneuron proteins (Pvalb, Gabrd) [2]. fMRI demonstrated that corticolimbic connectivity was increased in stressed mice. Pharmacological evidence for a cause-effect relationship between increased kynurenine-pathway activity and altered brain-behaviour function was provided by reversal of stress-induced increased conditioned fear by an indoleamine dioxygenase/kynurenine pathway inhibitor. Of particular interest is decreased expression of oligodendrocyte-myelin genes in amygdala and prefrontal cortex, given the evidence that these same genes are down-regulated in the same regions in depressed human brain [3]. Oligodendrocytes function to synthesise myelin on principal neurons in excitatory and inhibitory networks and to metabolically support neurons via energy metabolite provision. Oligodendrocyte inhibition via inflammatory excitotoxicity and oxidative stress could be a major pathophysiology of depression and a necessary target of novel antidepressant pharmacotherapy. References [1] Pryce, C.R., Seifritz, E., 2011. A translational research framework for enhanced validity of mouse models of psychopathological states in depression. Psychoneuroendocrinol 36, 308–329. [2] Azzinnari, D., Sigrist, H., Staehli, S., Palme, R., Hildebrandt, T., Leparc, G., Hengerer, B., Seifritz, E., Pryce, C.R., 2014. Mouse social stress induces increased fear conditioning, helplessness and fatigue to physical challenge together with markers of altered immune and dopamine function. Neuropharmacology 85, 328–341. [3] Sibille, E., Wang, Y., Joeyen-Waldorf, J., Gaiteri, C., Surget, A., Oh, S., Belzung, C., Tseng, G.C., Lewis, D.A., 2009. A molecular signature of depression in the amygdala. Am J Psychiatry 166, 1011–1024.