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AKT Signaling within the Ventral Tegmental Area Regulates Cellular and Behavioral Responses to Stressful Stimuli

      Background

      The neurobiological mechanisms by which only a minority of stress-exposed individuals develop psychiatric diseases remain largely unknown. Recent evidence suggests that dopaminergic neurons of the ventral tegmental area (VTA) play a key role in the manifestation of stress vulnerability.

      Methods

      Using a social defeat paradigm, we segregated susceptible mice (socially avoidant) from unsusceptible mice (socially interactive) and examined VTA punches for changes in neurotrophic signaling. Employing a series of viral vectors, we sought to causally implicate these neurotrophic changes in the development of avoidance behavior.

      Results

      Susceptibility to social defeat was associated with a significant reduction in levels of active/phosphorylated AKT (thymoma viral proto-oncogene) within the VTA, whereas chronic antidepressant treatment (in mice and humans) increased active AKT levels. This defeat-induced reduction in AKT activation in susceptible mice was both necessary and sufficient to recapitulate depressive behaviors associated with susceptibility. Pharmacologic reductions in AKT activity also significantly raised the firing frequency of VTA dopamine neurons, an important electrophysiologic hallmark of the susceptible phenotype.

      Conclusions

      These studies highlight a crucial role for decreases in VTA AKT signaling as a key mediator of the maladaptive cellular and behavioral response to chronic stress.

      Key Words

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      References

        • Kendler K.S.
        • Karkowski L.M.
        • Prescott C.A.
        Causal relationship between stressful life events and the onset of major depression.
        Am J Psychiatry. 1999; 156: 837-841
        • Charney D.S.
        • Manji H.K.
        Life stress, genes, and depression: Multiple pathways lead to increased risk and new opportunities for intervention.
        Sci STKE. 2004; (March 16:re5)
        • Kessler R.C.
        • Sonnega A.
        • Bromet E.
        • Hughes M.
        • Nelson C.B.
        Posttraumatic stress disorder in the National Comorbidity Survey.
        Arch Gen Psychiatry. 1995; 52: 1048-1060
        • Charney D.S.
        Psychobiological mechanisms of resilience and vulnerability: Implications for successful adaptation to extreme stress.
        Am J Psychiatry. 2004; 161: 195-216
        • Yehuda R.
        • Ledoux J.
        Response variation following trauma: A translational neuroscience approach to understanding PTSD.
        Neuron. 2007; 56: 19-32
        • Yehuda R.
        • Flory J.D.
        Differentiating biological correlates of risk, PTSD, and resilience following trauma exposure.
        J Traum Stress. 2007; 20: 435-447
        • Hyman S.E.
        • Malenka R.C.
        • Nestler E.J.
        Neural mechanisms of addiction: The role of reward-related learning and memory.
        Annu Rev Neurosci. 2006; 29: 565-598
        • Kelley A.E.
        • Berridge K.C.
        The neuroscience of natural rewards: Relevance to addictive drugs.
        J Neurosci. 2002; 22: 3306-3311
        • Wise R.A.
        Dopamine, learning and motivation.
        Nature Rev. 2004; 5: 483-494
        • Dunlop B.W.
        • Nemeroff C.B.
        The role of dopamine in the pathophysiology of depression.
        Arch Gen Psychiatry. 2007; 64: 327-337
        • Nestler E.J.
        • Carlezon Jr, W.A.
        The mesolimbic dopamine reward circuit in depression.
        Biol Psychiatry. 2006; 59: 1151-1159
        • Brady K.T.
        • Sinha R.
        Co-occurring mental and substance use disorders: The neurobiological effects of chronic stress.
        Am J Psychiatry. 2005; 162: 1483-1493
        • Rush A.J.
        The varied clinical presentations of major depressive disorder.
        J Clin Psychiatry. 2007; 68: 4-10
        • Berton O.
        • McClung C.A.
        • Dileone R.J.
        • Krishnan V.
        • Renthal W.
        • Russo S.J.
        • et al.
        Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress.
        Science. 2006; 311: 864-868
        • Krishnan V.
        • Han M.H.
        • Graham D.L.
        • Berton O.
        • Renthal W.
        • Russo S.J.
        • et al.
        Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions.
        Cell. 2007; 131: 391-404
        • Bolanos C.A.
        • Nestler E.J.
        Neurotrophic mechanisms in drug addiction.
        Neuromolecular Med. 2004; 5: 69-83
        • Bolanos C.A.
        • Perrotti L.I.
        • Edwards S.
        • Eisch A.J.
        • Barrot M.
        • Olson V.G.
        • et al.
        Phospholipase Cgamma in distinct regions of the ventral tegmental area differentially modulates mood-related behaviors.
        J Neurosci. 2003; 23: 7569-7576
        • Eisch A.J.
        • Bolanos C.A.
        • de Wit J.
        • Simonak R.D.
        • Pudiak C.M.
        • Barrot M.
        • et al.
        Brain-derived neurotrophic factor in the ventral midbrain-nucleus accumbens pathway: A role in depression.
        Biol Psychiatry. 2003; 54: 994-1005
        • Horger B.A.
        • Iyasere C.A.
        • Berhow M.T.
        • Messer C.J.
        • Nestler E.J.
        • Taylor J.R.
        Enhancement of locomotor activity and conditioned reward to cocaine by brain-derived neurotrophic factor.
        J Neurosci. 1999; 19: 4110-4122
        • Russo S.J.
        • Bolanos C.A.
        • Theobald D.E.
        • Decarolis N.A.
        • Renthal W.
        • Kumar A.
        • et al.
        IRS2-Akt pathway in midbrain dopamine neurons regulates behavioral and cellular responses to opiates.
        Nature Neurosci. 2007; 10: 93-99
        • Grimm J.W.
        • Lu L.
        • Hayashi T.
        • Hope B.T.
        • Su T.P.
        • Shaham Y.
        Time-dependent increases in brain-derived neurotrophic factor protein levels within the mesolimbic dopamine system after withdrawal from cocaine: Implications for incubation of cocaine craving.
        J Neurosci. 2003; 23: 742-747
        • Pierce R.C.
        • Bari A.A.
        The role of neurotrophic factors in psychostimulant-induced behavioral and neuronal plasticity.
        Rev Neurosci. 2001; 12: 95-110
        • Franke T.F.
        • Yang S.I.
        • Chan T.O.
        • Datta K.
        • Kazlauskas A.
        • Morrison D.K.
        • et al.
        The protein kinase encoded by the Akt proto-oncogene is a target of the PDGF-activated phosphatidylinositol 3-kinase.
        Cell. 1995; 81: 727-736
        • Papapetropoulos A.
        • Fulton D.
        • Mahboubi K.
        • Kalb R.G.
        • O'Connor D.S.
        • Li F.
        • et al.
        Angiopoietin-1 inhibits endothelial cell apoptosis via the Akt/survivin pathway.
        J Biol Chem. 2000; 275: 9102-9105
        • Neve R.L.
        • Howe J.R.
        • Hong S.
        • Kalb R.G.
        Introduction of the glutamate receptor subunit 1 into motor neurons in vitro and in vivo using a recombinant herpes simplex virus.
        Neuroscience. 1997; 79: 435-447
        • Barrot M.
        • Olivier J.D.
        • Perrotti L.I.
        • DiLeone R.J.
        • Berton O.
        • Eisch A.J.
        • et al.
        CREB activity in the nucleus accumbens shell controls gating of behavioral responses to emotional stimuli.
        Proc Nat Acad Sci U S A. 2002; 99: 11435-11440
        • Cryan J.F.
        • Page M.E.
        • Lucki I.
        Differential behavioral effects of the antidepressants reboxetine, fluoxetine, and moclobemide in a modified forced swim test following chronic treatment.
        Psychopharmacology. 2005; 182: 335-344
        • Stan A.D.
        • Ghose S.
        • Gao X.M.
        • Roberts R.C.
        • Lewis-Amezcua K.
        • Hatanpaa K.J.
        • et al.
        Human postmortem tissue: what quality markers matter?.
        Brain Res. 2006; 1123: 1-11
        • Chen Z.Y.
        • Jing D.
        • Bath K.G.
        • Ieraci A.
        • Khan T.
        • Siao C.J.
        • et al.
        Genetic variant BDNF (Val66Met) polymorphism alters anxiety-related behavior.
        Science. 2006; 314: 140-143
        • Ungless M.A.
        • Magill P.J.
        • Bolam J.P.
        Uniform inhibition of dopamine neurons in the ventral tegmental area by aversive stimuli.
        Science. 2004; 303: 2040-2042
        • Werkman T.R.
        • Olijslagers J.E.
        • Perlstein B.
        • Jansen A.H.
        • McCreary A.C.
        • Kruse C.G.
        • et al.
        Quetiapine increases the firing rate of rat substantia nigra and ventral tegmental area dopamine neurons in vitro.
        EurJ Pharmacol. 2004; 506: 47-53
        • Saal D.
        • Dong Y.
        • Bonci A.
        • Malenka R.C.
        Drugs of abuse and stress trigger a common synaptic adaptation in dopamine neurons.
        Neuron. 2003; 37: 577-582
        • Ungless M.A.
        • Singh V.
        • Crowder T.L.
        • Yaka R.
        • Ron D.
        • Bonci A.
        Corticotropin-releasing factor requires CRF binding protein to potentiate NMDA receptors via CRF receptor 2 in dopamine neurons.
        Neuron. 2003; 39: 401-407
        • Manning B.D.
        • Cantley L.C.
        AKT/PKB signaling: Navigating downstream.
        Cell. 2007; 129: 1261-1274
        • Yamada M.
        • Ohnishi H.
        • Sano S.
        • Nakatani A.
        • Ikeuchi T.
        • Hatanaka H.
        Insulin receptor substrate (IRS)-1 and IRS-2 are tyrosine-phosphorylated and associated with phosphatidylinositol 3-kinase in response to brain-derived neurotrophic factor in cultured cerebral cortical neurons.
        J Biol Chemistry. 1997; 272: 30334-30339
        • Lucki I.
        • Dalvi A.
        • Mayorga A.J.
        Sensitivity to the effects of pharmacologically selective antidepressants in different strains of mice.
        Psychopharmacol. 2001; 155: 315-322
        • Cryan J.F.
        • Markou A.
        • Lucki I.
        Assessing antidepressant activity in rodents: Recent developments and future needs.
        Trend Pharmacol Sci. 2002; 23: 238-245
        • Berton O.
        • Nestler E.J.
        New approaches to antidepressant drug discovery: Beyond monoamines.
        Nature Rev. 2006; 7: 137-151
        • Papp M.
        • Moryl E.
        • Willner P.
        Pharmacological validation of the chronic mild stress model of depression.
        Eur J Pharmacol. 1996; 296: 129-136
        • Willner P.
        Chronic mild stress (CMS) revisited: Consistency and behavioural-neurobiological concordance in the effects of CMS.
        Neuropsychobiology. 2005; 52: 90-110
        • Kuzman J.A.
        • Gerdes A.M.
        • Kobayashi S.
        • Liang Q.
        Thyroid hormone activates Akt and prevents serum starvation-induced cell death in neonatal rat cardiomyocytes.
        Journal of molecular and cellular cardiology. 2005; 39: 841-844
        • Sanna P.P.
        • Cammalleri M.
        • Berton F.
        • Simpson C.
        • Lutjens R.
        • Bloom F.E.
        • et al.
        Phosphatidylinositol 3-kinase is required for the expression but not for the induction or the maintenance of long-term potentiation in the hippocampal CA1 region.
        J Neurosci. 2002; 22: 3359-3365
        • Wang Q.
        • Liu L.
        • Pei L.
        • Ju W.
        • Ahmadian G.
        • Lu J.
        • et al.
        Control of synaptic strength, a novel function of Akt.
        Neuron. 2003; 38: 915-928
        • Fava M.
        • Kendler K.S.
        Major depressive disorder.
        Neuron. 2000; 28: 335-341
        • Yehuda R.
        Post-traumatic stress disorder.
        New Engl J Med. 2002; 346: 108-114
        • Hsiung S.C.
        • Adlersberg M.
        • Arango V.
        • Mann J.J.
        • Tamir H.
        • Liu K.P.
        Attenuated 5-HT1A receptor signaling in brains of suicide victims: Involvement of adenylyl cyclase, phosphatidylinositol 3-kinase, Akt and mitogen-activated protein kinase.
        J Neurochem. 2003; 87: 182-194
        • Karege F.
        • Perroud N.
        • Burkhardt S.
        • Schwald M.
        • Ballmann E.
        • La Harpe R.
        • et al.
        Alteration in kinase activity but not in protein levels of protein kinase B and glycogen synthase kinase-3beta in ventral prefrontal cortex of depressed suicide victims.
        Biol Psychiatry. 2007; 61: 240-245
        • Rosmond R.
        Role of stress in the pathogenesis of the metabolic syndrome.
        Psychoneuroendocrinology. 2005; 30: 1-10
        • Figlewicz D.P.
        • Evans S.B.
        • Murphy J.
        • Hoen M.
        • Baskin D.G.
        Expression of receptors for insulin and leptin in the ventral tegmental area/substantia nigra (VTA/SN) of the rat.
        Brain Res. 2003; 964: 107-115
        • Paxinos G.
        • Franklin K.B.J.
        The Mouse Brain in Stereotaxic Coordinates.
        Academic Press, San Diego2001
        • Vlahos C.J.
        • Matter W.F.
        • Hui K.Y.
        • Brown R.F.
        A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002).
        J Biol Chem. 1994; 269: 5241-5248