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  • 1
    Publication Date: 2012-12-14
    Description: Major depression is characterized by diverse debilitating symptoms that include hopelessness and anhedonia. Dopamine neurons involved in reward and motivation are among many neural populations that have been hypothesized to be relevant, and certain antidepressant treatments, including medications and brain stimulation therapies, can influence the complex dopamine system. Until now it has not been possible to test this hypothesis directly, even in animal models, as existing therapeutic interventions are unable to specifically target dopamine neurons. Here we investigated directly the causal contributions of defined dopamine neurons to multidimensional depression-like phenotypes induced by chronic mild stress, by integrating behavioural, pharmacological, optogenetic and electrophysiological methods in freely moving rodents. We found that bidirectional control (inhibition or excitation) of specified midbrain dopamine neurons immediately and bidirectionally modulates (induces or relieves) multiple independent depression symptoms caused by chronic stress. By probing the circuit implementation of these effects, we observed that optogenetic recruitment of these dopamine neurons potently alters the neural encoding of depression-related behaviours in the downstream nucleus accumbens of freely moving rodents, suggesting that processes affecting depression symptoms may involve alterations in the neural encoding of action in limbic circuitry.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4160519/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4160519/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tye, Kay M -- Mirzabekov, Julie J -- Warden, Melissa R -- Ferenczi, Emily A -- Tsai, Hsing-Chen -- Finkelstein, Joel -- Kim, Sung-Yon -- Adhikari, Avishek -- Thompson, Kimberly R -- Andalman, Aaron S -- Gunaydin, Lisa A -- Witten, Ilana B -- Deisseroth, Karl -- DP2 DA035149/DA/NIDA NIH HHS/ -- F32 MH880102/MH/NIMH NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Jan 24;493(7433):537-41. doi: 10.1038/nature11740. Epub 2012 Dec 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Picower Institute for Learning and Memory, Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA. kaytye@mit.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23235822" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Depression/chemically induced/*physiopathology ; Dopamine/metabolism ; Dopaminergic Neurons/drug effects/*metabolism/radiation effects ; Female ; Male ; Mice ; Models, Neurological ; Nucleus Accumbens/metabolism ; Optogenetics ; Phenotype ; Rats ; Rats, Long-Evans ; Stress, Psychological/physiopathology ; Time Factors ; Ventral Tegmental Area/cytology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2018-09-13
    Description: Retinoic-acid-receptor-related orphan nuclear receptor t (RORt) controls the transcription of interleukin-17A (IL-17A), which plays critical roles in the pathogenesis of autoimmune diseases. Severity of several human autoimmune diseases is correlated with frequencies of germinal center kinase–like kinase (GLK) (also known as MAP4K3)–overexpressing T cells; however, the mechanism of GLK overexpression–induced autoimmunity remains unclear. We report the signal transduction converging on aryl hydrocarbon receptor (AhR)–RORt interaction to activate transcription of the IL-17A gene in T cells. T cell–specific GLK transgenic mice spontaneously developed autoimmune diseases with selective induction of IL-17A in T cells. In GLK transgenic T cells, protein kinase C (PKC) phosphorylated AhR at Ser 36 and induced AhR nuclear translocation. AhR also interacted with RORt and transported RORt into the nucleus. IKKβ (inhibitor of nuclear factor B kinase β)–mediated RORt Ser 489 phosphorylation induced the AhR-RORt interaction. T cell receptor (TCR) signaling also induced the novel RORt phosphorylation and subsequent AhR-RORt interaction. Collectively, TCR signaling or GLK overexpression induces IL-17A transcription through the IKKβ-mediated RORt phosphorylation and the AhR-RORt interaction in T cells. Our findings suggest that inhibitors of GLK or the AhR-RORt complex could be used as IL-17A–blocking agents for IL-17A–mediated autoimmune diseases.
    Electronic ISSN: 2375-2548
    Topics: Natural Sciences in General
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  • 3
    Publication Date: 2012-12-14
    Description: Ventral tegmental area (VTA) dopamine neurons in the brain's reward circuit have a crucial role in mediating stress responses, including determining susceptibility versus resilience to social-stress-induced behavioural abnormalities. VTA dopamine neurons show two in vivo patterns of firing: low frequency tonic firing and high frequency phasic firing. Phasic firing of the neurons, which is well known to encode reward signals, is upregulated by repeated social-defeat stress, a highly validated mouse model of depression. Surprisingly, this pathophysiological effect is seen in susceptible mice only, with no apparent change in firing rate in resilient individuals. However, direct evidence--in real time--linking dopamine neuron phasic firing in promoting the susceptible (depression-like) phenotype is lacking. Here we took advantage of the temporal precision and cell-type and projection-pathway specificity of optogenetics to show that enhanced phasic firing of these neurons mediates susceptibility to social-defeat stress in freely behaving mice. We show that optogenetic induction of phasic, but not tonic, firing in VTA dopamine neurons of mice undergoing a subthreshold social-defeat paradigm rapidly induced a susceptible phenotype as measured by social avoidance and decreased sucrose preference. Optogenetic phasic stimulation of these neurons also quickly induced a susceptible phenotype in previously resilient mice that had been subjected to repeated social-defeat stress. Furthermore, we show differences in projection-pathway specificity in promoting stress susceptibility: phasic activation of VTA neurons projecting to the nucleus accumbens (NAc), but not to the medial prefrontal cortex (mPFC), induced susceptibility to social-defeat stress. Conversely, optogenetic inhibition of the VTA-NAc projection induced resilience, whereas inhibition of the VTA-mPFC projection promoted susceptibility. Overall, these studies reveal novel firing-pattern- and neural-circuit-specific mechanisms of depression.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3554860/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3554860/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chaudhury, Dipesh -- Walsh, Jessica J -- Friedman, Allyson K -- Juarez, Barbara -- Ku, Stacy M -- Koo, Ja Wook -- Ferguson, Deveroux -- Tsai, Hsing-Chen -- Pomeranz, Lisa -- Christoffel, Daniel J -- Nectow, Alexander R -- Ekstrand, Mats -- Domingos, Ana -- Mazei-Robison, Michelle S -- Mouzon, Ezekiell -- Lobo, Mary Kay -- Neve, Rachael L -- Friedman, Jeffrey M -- Russo, Scott J -- Deisseroth, Karl -- Nestler, Eric J -- Han, Ming-Hu -- F31 MH095425/MH/NIMH NIH HHS/ -- F32 MH096464/MH/NIMH NIH HHS/ -- K99 MH094405/MH/NIMH NIH HHS/ -- R01 MH092306/MH/NIMH NIH HHS/ -- R25 GM064118/GM/NIGMS NIH HHS/ -- T32 MH020016/MH/NIMH NIH HHS/ -- T32 MH087004/MH/NIMH NIH HHS/ -- T32 MH096678/MH/NIMH NIH HHS/ -- England -- Nature. 2013 Jan 24;493(7433):532-6. doi: 10.1038/nature11713. Epub 2012 Dec 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pharmacology and Systems Therapeutics, Friedman Brain Institute, Mount Sinai School of Medicine, New York, New York 10029, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23235832" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Depression/etiology/*physiopathology ; Dopaminergic Neurons/*metabolism ; Food Preferences ; Male ; Mesencephalon/*cytology ; Mice ; Neural Pathways ; Nucleus Accumbens/physiology ; Optogenetics ; Phenotype ; Prefrontal Cortex/physiology ; *Social Behavior ; Stress, Psychological/complications/*physiopathology ; Sucrose/administration & dosage ; Time Factors ; Ventral Tegmental Area/physiology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
    ISSN: 0167-2738
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Physics
    Type of Medium: Electronic Resource
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  • 5
    Electronic Resource
    Electronic Resource
    Amsterdam : Elsevier
    Tetrahedron Letters 6 (1965), S. 2211-2216 
    ISSN: 0040-4039
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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