Genetic Disruption of Circadian Rhythms in the Suprachiasmatic Nucleus Causes Helplessness, Behavioral Despair, and Anxiety-like Behavior in Mice

Landgraf, Dominic; Long, Jaimie; Proulx, Christophe D.; Barandas, Rita; Malinow, Roberto; Welsh, David K.

doi:10.1016/j.biopsych.2016.03.1050

Cited by 179 publications

(139 citation statements)

References 38 publications

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“…Strong evidence is found in recent papers showing that SCN-specific Bmal1 knockdown mice exhibit depression-like behavior (Landgraf et al, 2016) and anhedonic-like behavior is observed in cryptochrome-deficient mice (Savalli et al, 2015). Further, studies have been published investigating the effect of stress on the expression of clock genes in rodents.…”

Section: Discussionmentioning

confidence: 88%

Altered Expression Pattern of Clock Genes in a Rat Model of Depression

Christiansen

Bouzinova

Fahrenkrug

et al. 2016

IJNPPY

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Background:Abnormalities in circadian rhythms may be causal factors in development of major depressive disorder. The biology underlying a causal relationship between circadian rhythm disturbances and depression is slowly being unraveled. Although there is no direct evidence of dysregulation of clock gene expression in depressive patients, many studies have reported single-nucleotide polymorphisms in clock genes in these patients.Methods:In the present study we investigated whether a depression-like state in rats is associated with alternations of the diurnal expression of clock genes. The validated chronic mild stress (CMS) animal model of depression was used to investigate rhythmic expression of three clock genes: period genes 1 and 2 (Per1 and Per2) and Bmal1. Brain and liver tissue was collected from 96 animals after 3.5 weeks of CMS (48 control and 48 depression-like rats) at a 4h sampling interval within 24h. We quantified expression of clock genes on brain sections in the prefrontal cortex, nucleus accumbens, pineal gland, suprachiasmatic nucleus, substantia nigra, amygdala, ventral tegmental area, subfields of the hippocampus, and the lateral habenula using in situ hybridization histochemistry. Expression of clock genes in the liver was monitored by real-time quantitative polymerase chain reaction (PCR).Results:We found that the effect of CMS on clock gene expression was selective and region specific. Per1 exhibits a robust diurnal rhythm in most regions of interest, whereas Bmal1 and in particular Per2 were susceptible to CMS.Conclusion:The present results suggest that altered expression of investigated clock genes is likely associated with the induction of a depression-like state in the CMS model.

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Section: Discussionmentioning

confidence: 88%

Altered Expression Pattern of Clock Genes in a Rat Model of Depression

Christiansen

Bouzinova

Fahrenkrug

et al. 2016

IJNPPY

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“…Shorter days during winter are associated with seasonal affective disorder and cognitive dysfunction in both humans and nocturnal animals, whereas bright light is an effective therapy for human patients with seasonal or non-seasonal depression 11,13,[79][80][81][82][83][84][85] . Our study showing lightdependent NT plasticity in the SCN-PeVN network is a new mechanism for seasonal adaptation that might prove useful for the development of novel targets and therapeutic approaches for treating seasonal depression and cognitive impairment induced by altered light-dark cycles.…”

Section: Discussionmentioning

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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“…A mutation of casein kinase 1 epsilon specifically in GABAergic neurones results in a lengthened period in constant darkness and reduced body weight at the age of 3‐5 months with no severe metabolic effects . Adeno associated virus‐delivered Bmal1 deletion in the SCN also lengthens the behavioural period, although mutant animals at the same time gain more weight and show altered stress responses . Sf1‐Cre driven clock disruption in the ventromedial hypothalamus was found to reduce body weight in mice, besides comparable food intake, as a result of an increased energy expenditure with a shortened activity period under constant conditions .…”

Section: The Scn Master Clock In Energy Homeostasismentioning

confidence: 97%

“…Bmal1 deletion in the SCN also lengthens the behavioural period, although mutant animals at the same time gain more weight and show altered stress responses 90. Sf1-Cre driven clock disruption in the ventromedial hypothalamus was found to reduce body weight in mice, besides comparable food intake, as a result of an increased energy expenditure with a shortened activity period under constant conditions 91.…”

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confidence: 99%

Interplay of central and peripheral circadian clocks in energy metabolism regulation

Kolbe

Brehm

Oster

2018

J Neuroendocrinology

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Metabolic health founds on a homeostatic balance that has to integrate the daily changes of rest/activity and feeding/fasting cycles. A network of endogenous 24‐hour circadian clocks helps to anticipate daily recurring events and adjust physiology and behavioural functions accordingly. Circadian clocks are self‐sustained cellular oscillators based on a set of clock genes/proteins organised in interlocked transcriptional‐translational feedback loops. The body's clocks need to be regularly reset and synchronised with each other to achieve coherent rhythmic output signals. This synchronisation is achieved by interplay of a master clock, which resides in the suprachiasmatic nucleus, and peripheral tissue clocks. This clock network is reset by time signals such as the light/dark cycle, food intake and activity. The balanced interplay of clocks is easily disturbed in modern society by shiftwork or high‐energy diets, which may further promote the development of metabolic disorders. In this review, we summarise the current model of central‐peripheral clock interaction in metabolic health. Different established mouse models for central or peripheral clock disruption and their metabolic phenotypes are compared and the possible relevance of clock network interaction for the development of therapeutic approaches in humans is discussed.

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Genetic Disruption of Circadian Rhythms in the Suprachiasmatic Nucleus Causes Helplessness, Behavioral Despair, and Anxiety-like Behavior in Mice

Cited by 179 publications

References 38 publications

Altered Expression Pattern of Clock Genes in a Rat Model of Depression

Altered Expression Pattern of Clock Genes in a Rat Model of Depression

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

Interplay of central and peripheral circadian clocks in energy metabolism regulation

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