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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: 2012-11-20
    Description: The prefrontal cortex (PFC) is thought to participate in high-level control of the generation of behaviours (including the decision to execute actions); indeed, imaging and lesion studies in human beings have revealed that PFC dysfunction can lead to either impulsive states with increased tendency to initiate action, or to amotivational states characterized by symptoms such as reduced activity, hopelessness and depressed mood. Considering the opposite valence of these two phenotypes as well as the broad complexity of other tasks attributed to PFC, we sought to elucidate the PFC circuitry that favours effortful behavioural responses to challenging situations. Here we develop and use a quantitative method for the continuous assessment and control of active response to a behavioural challenge, synchronized with single-unit electrophysiology and optogenetics in freely moving rats. In recording from the medial PFC (mPFC), we observed that many neurons were not simply movement-related in their spike-firing patterns but instead were selectively modulated from moment to moment, according to the animal's decision to act in a challenging situation. Surprisingly, we next found that direct activation of principal neurons in the mPFC had no detectable causal effect on this behaviour. We tested whether this behaviour could be causally mediated by only a subclass of mPFC cells defined by specific downstream wiring. Indeed, by leveraging optogenetic projection-targeting to control cells with specific efferent wiring patterns, we found that selective activation of those mPFC cells projecting to the brainstem dorsal raphe nucleus (DRN), a serotonergic nucleus implicated in major depressive disorder, induced a profound, rapid and reversible effect on selection of the active behavioural state. These results may be of importance in understanding the neural circuitry underlying normal and pathological patterns of action selection and motivation in behaviour.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Warden, Melissa R -- Selimbeyoglu, Aslihan -- Mirzabekov, Julie J -- Lo, Maisie -- Thompson, Kimberly R -- Kim, Sung-Yon -- Adhikari, Avishek -- Tye, Kay M -- Frank, Loren M -- Deisseroth, Karl -- 1F32MH088010-01/MH/NIMH NIH HHS/ -- F32 MH088010/MH/NIMH NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Dec 20;492(7429):428-32. doi: 10.1038/nature11617.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Bioengineering, Stanford University, Stanford, California 94305, USA. mwarden@stanford.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23160494" target="_blank"〉PubMed〈/a〉
    Keywords: Action Potentials ; Animals ; Axons/physiology ; Behavior, Animal/*physiology ; Depression/psychology ; Electrophysiology ; Locomotion/physiology ; Male ; Motivation/*physiology ; Neurons/*physiology ; Optogenetics ; Prefrontal Cortex/*physiology ; Raphe Nuclei/*physiology ; Rats ; Rats, Long-Evans ; Swimming/*physiology ; Synapses/physiology ; Time Factors
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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