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      VTA dopaminergic neurons regulate ethologically relevant sleep–wake behaviors

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          Abstract

          Dopaminergic ventral tegmental area (VTA) neurons are critically involved in a variety of behaviors that rely on heightened arousal, but whether they directly and causally control the generation and maintenance of wakefulness is unknown. We recorded calcium activity using fiber photometry in freely behaving mice and found arousal-state-dependent alterations in VTA dopaminergic neurons. We used chemogenetic and optogenetic manipulations together with polysomnographic recordings to demonstrate that VTA dopaminergic neurons are necessary for arousal and that their inhibition suppresses wakefulness, even in the face of ethologically relevant salient stimuli. Nevertheless, before inducing sleep, inhibition of VTA dopaminergic neurons promoted goal-directed and sleep-related nesting behavior. Optogenetic stimulation, in contrast, initiated and maintained wakefulness and suppressed sleep and sleep-related nesting behavior. We further found that different projections of VTA dopaminergic neurons differentially modulate arousal. Collectively, our findings uncover a fundamental role for VTA dopaminergic circuitry in the maintenance of the awake state and ethologically relevant sleep-related behaviors.

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          Most cited references33

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          Rapid regulation of depression-related behaviors by control of midbrain dopamine neurons

          Ventral tegmental area (VTA) dopamine (DA) neurons in the brain’s reward circuit play a crucial role in mediating stress responses 1–4 including determining susceptibility vs. resilience to social stress-induced behavioural abnormalities 5 . VTA DA neurons exhibit two in vivo patterns of firing: low frequency tonic firing and high frequency phasic firing 6–8 . Phasic firing of the neurons, which is well known to encode reward signals 6,7,9 , is upregulated by repeated social defeat stress, a highly validated mouse model of depression 5,8,10–13 . Surprisingly, this pathophysiological effect is seen in susceptible mice only, with no change in firing rate apparent in resilient individuals 5,8 . However, direct evidence linking—in real-time—DA 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 demonstrate 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 DA 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, while inhibition of the VTA-mPFC projection promoted susceptibility. Overall, these studies reveal novel firing pattern- and neural circuit-specific mechanisms of depression.
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            Dopamine neurons modulate neural encoding and expression of depression-related behaviour.

            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.
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              Optogenetic identification of a rapid-eye-movement (REM) sleep modulatory circuit in the hypothalamus

              Rapid-Eye Movement (REM) sleep correlates with neuronal activity in the brainstem, basal forebrain and lateral hypothalamus (LH). LH melanin-concentrating hormone (MCH)-expressing neurons are active during sleep, however, their action on REM sleep remains unclear. Using optogenetic tools in newly-generated Tg(Pmch-Cre) mice, we found that acute activation of MCH neurons (ChETA, SSFO) at the onset of REM sleep extended the duration of REM, but not non-REM sleep episode. In contrast, their acute silencing (eNpHR3.0, ArchT) reduced the frequency and amplitude of hippocampal theta rhythm, without affecting REM sleep duration. In vitro activation of MCH neuron terminals induced GABAA-mediated inhibitory post-synaptic currents (IPSCs) in wake-promoting histaminergic neurons of the tuberomammillary nucleus (TMN), while in vivo activation of MCH neuron terminals in TMN or medial septum also prolonged REM sleep episodes. Collectively, these results suggest that activation of MCH neurons maintains REM sleep, possibly through inhibition of arousal circuits in the mammalian brain.
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                Author and article information

                Journal
                Nature Neuroscience
                Nat Neurosci
                Springer Science and Business Media LLC
                1097-6256
                1546-1726
                October 2016
                September 5 2016
                October 2016
                : 19
                : 10
                : 1356-1366
                Article
                10.1038/nn.4377
                5519826
                27595385
                08cb6d17-5d75-48db-99bb-d4c1816060e0
                © 2016

                http://www.springer.com/tdm

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