Mice with reduced DAT levels recreate seasonal-induced switching between states in bipolar disorder

Young, Jared W.; Cope, Zackary A.; Romoli, Benedetto; Schrurs, Esther; Joosen, Aniek; Enkhuizen, Jordy van; Sharp, Richard F.; Dulcis, Davide

doi:10.1038/s41386-018-0031-y

Cited by 77 publications

(65 citation statements)

References 61 publications

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“…While previous studies have found intriguing effects of photoperiod in the dopaminergic system due to photoperiod [29][30][31] , no study has investigated photoperiodic effects due to developmental photoperiod, across multiple stages of development, or in mice that are melatonin competent, such as the C3Hf +/+ strain. In the current study we observed reduced levels of DA and DOPAC for Short winter-like photoperiod mice at P35, thus based on this data and prior work, we hypothesized that the expression of a key dopamine gene, TH, would be decreased for animals raised under Short photoperiodic conditions as well.…”

Section: Discussionmentioning

confidence: 99%

Photoperiodic Effects on Monoamine Signaling & Gene Expression Throughout Development in the Serotonin & Dopamine Systems

Siemann

Williams

Malik

et al. 2020

Preprint

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Photoperiod or the duration of daylight has been implicated as a risk factor in the development of mood disorders. The dopamine and serotonin systems are impacted by photoperiod and are consistently associated with affective disorders. Hence, we evaluated, at multiple stages of postnatal development, the expression of key dopaminergic (TH) and serotonergic (Tph2, SERT, and Pet-1) genes, and midbrain monoamine content in mice raised under control Equinox (LD 12:12), Short winter-like (LD 8:16), or Long summerlike (LD 16:8) photoperiods. Focusing in early adulthood, we evaluated the midbrain levels of these serotonergic genes, and also assayed these gene levels in the dorsal raphe nucleus (DRN) with RNAScope. Mice that developed under Short photoperiods demonstrated elevated midbrain TH expression levels, specifically during perinatal development compared to mice raised under Long photoperiods, and significantly decreased serotonin and dopamine content throughout the course of development. In adulthood, Long photoperiod mice demonstrated decreased midbrain Tph2 and SERT expression levels and reduced Tph2 levels in the DRN compared Short photoperiod mice. Thus, evaluating gene x environment interactions in the dopaminergic and serotonergic systems during multiple stages of development may lead to novel insights into the underlying mechanisms in the development of affective disorders.

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Section: Discussionmentioning

confidence: 99%

Photoperiodic Effects on Monoamine Signaling & Gene Expression Throughout Development in the Serotonin & Dopamine Systems

Siemann

Williams

Malik

et al. 2020

Preprint

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“…Our finding is the first instance of a molecular and cellular marker based on neurotransmitter phenotype to be associated with vulnerability to stress. Neurotransmitter plasticity, also referred to as neurotransmitter switching (Dulcis & Spitzer, 2012), has been shown to occur in response to other forms of stress such as altered photoperiod exposure (Dulcis et al, 2013;Young et al, 2018) or exposure to psychostimulants such as nicotine (Romoli et al, 2019) and methamphetamine (Kesby et al, 2017) . Interestingly, the change in number of TPH2+ neurons occurred exclusively in the DRv, but not in the other subnuclei of the mid-rostrocaudal DR.…”

Section: Discussionmentioning

confidence: 99%

Serotonergic plasticity in the dorsal raphe nucleus characterizes susceptibility and resilience to anhedonia

Prakash

Stark

Keisler

et al. 2019

Preprint

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critical feedback on the research and Dr.Byung Kook Lim for his valuable feedback and the use of his slide-scanning microscope. ABSTRACTChronic stress induces anhedonia in susceptible, but not resilient individuals, a phenomenon observed in humans as well as animal models, but the molecular mechanisms underlying susceptibility and resilience are not well understood. We hypothesized that the serotonergic system, which is implicated in stress, reward and antidepressant therapy, may play a role. We found that plasticity of the serotonergic system contributes to the differential vulnerability to stress displayed by susceptible and resilient animals. Stress-induced anhedonia was assessed in SIGNIFICANCE STATEMENTDepression and other mental disorders can be induced by chronic or traumatic stressors.However, some individuals are resilient and do not develop depression in response to chronic stress. A complete picture of the molecular differences between susceptible and resilient individuals is necessary to understand how plasticity of limbic circuits is associated with the pathophysiology of stress-related disorders. Using a rodent model, our study identifies a novel molecular marker of susceptibility to stress-induced anhedonia, a core symptom of depression, and a means to modulate it. These findings will guide further investigation into cellular and circuit mechanisms of resilience, and the development of new treatments for depression.

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“…The anatomical and functional connectivity of SCN NMS+ neurons suggest that they may have a role in regulating PeVN DA neuron activity 49 . To test whether chronic activation of SCN NMS+ neurons is sufficient to induce the kind of activity-dependent DA plasticity previously observed in the PeVN in response to short photoperiod 37,38 NMS-Cre mice (P85) expressing either Gq-DREADDs or GFP control virus in the SCN received daily clozapine (0.01 mg/kg) or saline injections at ZT17 for 2 weeks while kept in neutral (12L:12D) photoperiod. The mice were then sacrificed (P100) for IHC analysis.…”

Section: Chronic Activation Of Distinct Subsets Of Scn Neurons Regulamentioning

confidence: 99%

Photoperiod-Induced Neurotransmitter Switching in the Circadian Pacemaker Regulates Hypothalamic Dopamine Expression

Porcu

Booreddy

Welsh

et al. 2020

Preprint

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Light, circadian clocks, and rhythmic behaviors interact closely to produce a temporal order that is essential for the survival of most living organisms. In mammals, the principal circadian pacemaker in the brain is the suprachiasmatic nucleus (SCN), which receives direct retinal input and synchronizes itself and other brain regions to the external light-dark cycle. Altered day length (photoperiod) and disrupted circadian rhythms are associated with impaired memory and mood in both humans and animal models. Prior work demonstrated that altering photoperiod can change neurotransmitter (NT) expression in the periventricular nucleus (PeVN) of the hypothalamus in adult rat brain. Here we show that neuromedin S-(NMS-) and vasoactive intestinal polypeptide-(VIP-) expressing neurons in the SCN also display photoperiod-induced neurotransmitter switching. Such photoperiod-dependent NT plasticity is retained in Bmal1-KO mice, indicating that NT plasticity in the SCN does not require a functional circadian clock. Utilizing a conditional viral DO-DIO vector as an historical marker of NT expression in the SCN, we further reveal that short-day photoperiod induces a cluster of non-NMS-expressing neurons to undergo NT switching and acquire the NMS phenotype. Selective chemogenetic activation of NMS neurons, but not VIP neurons, during the dark phase induces a significant delay in the timing of locomotor activity onset and is sufficient to increase the number of dopaminergic neurons in the PeVN. Our findings provide novel insights into molecular adaptations of the SCN neuronal network in response to altered photoperiod that affect neuronal circuit function in the hypothalamus and lead to changes in circadian behavior.

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Mice with reduced DAT levels recreate seasonal-induced switching between states in bipolar disorder

Cited by 77 publications

References 61 publications

Photoperiodic Effects on Monoamine Signaling & Gene Expression Throughout Development in the Serotonin & Dopamine Systems

Photoperiodic Effects on Monoamine Signaling & Gene Expression Throughout Development in the Serotonin & Dopamine Systems

Serotonergic plasticity in the dorsal raphe nucleus characterizes susceptibility and resilience to anhedonia

Photoperiod-Induced Neurotransmitter Switching in the Circadian Pacemaker Regulates Hypothalamic Dopamine Expression

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