Neuronal activity regulates neurotransmitter switching in the adult brain following light-induced stress

Meng, Da; Li, Huiquan; Deisseroth, Karl; Leutgeb, Stefan; Spitzer, Nicholas C.

doi:10.1073/pnas.1801598115

Cited by 52 publications

(58 citation statements)

References 44 publications

(57 reference statements)

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“…In long photoperiods however, PDF from the lLNvs is necessary and sufficient for proper entrainment, whereas the sLNvs do not contribute to E peak timing (Schlichting et al, 2016). Our data therefore point to a profound circuit switch in response to photoperiod, analogous to the neurotransmitter switching that occurs in the mammalian paraventricular nucleus in response to long photoperiods (Meng et al, 2018).…”

Section: Discussionmentioning

confidence: 51%

Light-mediated circuit switching in the Drosophila neuronal clock network

Schlichting

Weidner

Díaz

et al. 2019

Preprint

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150 word limit) 12 The circadian clock is a timekeeper but also helps adapt physiology to the outside world. This 13 is because an essential feature of clocks is their ability to adjust (entrain) to the environment, 14 with light being the most important signal. Whereas Cryptochrome-mediated entrainment is 15 well understood in Drosophila, integration of light information via the visual system lacks a 16 neuronal or molecular mechanism. Here we show that a single photoreceptor sub-type is 17 essential for long day adaptation. These cells activate key circadian neurons, namely the 18 lLNvs, which release the neuropeptide PDF. Using a cell-specific CRISPR/Cas9 assay, we 19 show that PDF directly interacts with neurons important for evening (E) activity timing. 20Interestingly, this pathway is specific for light entrainment and appears to be dispensable in 21 constant darkness (DD). The results therefore indicate that external cues cause a 22 rearrangement of neuronal hierarchy, which is a novel form of plasticity. 23 65 receive light input and release PDF upon illumination, thereby adjusting their downstream 66 target neurons to the LD cycle (Yoshii et al., 2016). 67To investigate the impact of the visual input pathway at the behavioral and neuronal 68 level, we investigated fly behavior under long day conditions. Long days cause plastic 69 changes in fly behavior: In standard light-dark cycles of 12h light and 12h darkness (LD 70 12:12), flies show a bimodal activity pattern with a M anticipation peak around lights-on and 71 an E anticipation peak around lights-off; this results in a phase relationship of approximately 72 12h between the two peaks. Flies are able to adjust to longer photoperiods by delaying the E 73 5 peak, which reduces the potentially harmful impact of hot summer days (Rieger et al., 2003). 74Previous experiments implicated the visual system in long day adaptation: Flies lacking the 75 compound eyes fail to appropriately adjust their peak timings (Rieger et al., 2003). It is still 76 unknown however which receptors and which neuronal pathways are involved in this 77 adjustment. 78Here we show that R8 of the compound eyes is essential for long day adaptation. 79These photoreceptor cells connect to the PDF-containing lLNvs and trigger the release of 80 this neuropeptide. Using a cell-specific CRISPR/Cas9 strategy, we demonstrate that light-81 mediated PDF directly signals to the PDF receptor (PDFR) on E cells and hence delays E 82 activity. The data implicate a mammal-like structure of clock entrainment, with the visual 83 system activating PDF-expressing clock neurons. Our data further indicate a prominent shift 84 of PDF targets between LD and DD conditions as well as a more quantitative reorganization 85 of neuronal dominance within the clock network by changes in photoperiod. 86 87 6 Material and Methods 88Fly strains and rearing 89 The following fly lines were used in this study: CantonS, w 1118 , cli eya (Bonini et al., 1993), 90 ninaE 5 (BL 3545), rh3 1 rh4 1 (Vasiliauskas et al...

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Section: Discussionmentioning

confidence: 51%

Light-mediated circuit switching in the Drosophila neuronal clock network

Schlichting

Weidner

Díaz

et al. 2019

Preprint

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“…Our current work shows that receptor mechanisms and concentrationdependent control of spinal network output is also state-dependent. This is important because receptor expression, modulator concentration and network excitability are not fixed and fluctuate dynamically [59,60]. Therefore, these three factors need to be considered if we wish to understand how networks create diverse neuromodulator-dependent outputs ( Figure 8A).…”

Section: Dopaminementioning

confidence: 99%

A dynamic role for dopamine receptors in the control of mammalian spinal networks

Sharples

Burma

Borowska-Fielding

et al. 2019

Preprint

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Dopamine is well known to regulate movement through the differential control of direct and indirect pathways in the striatum that express D1 and D2 receptors respectively. The spinal cord also expresses all dopamine receptors however; how the specific receptors regulate spinal network output in mammals is poorly understood. We explore the receptor-specific mechanisms that underlie dopaminergic control of spinal network output of neonatal mice during changes in spinal network excitability. During spontaneous activity, which is a characteristic of developing spinal networks operating in a low excitability state, we found that dopamine is primarily inhibitory. We uncover an excitatory D1-mediated effect of dopamine on motoneurons and network output that also involves co-activation with D2 receptors. Critically, these excitatory actions require higher concentrations of dopamine; however, analysis of dopamine concentrations of neonates indicates that endogenous levels of spinal dopamine are low. Because endogenous levels of spinal dopamine are low, this excitatory dopaminergic pathway is likely physiologically-silent at this stage in development. In contrast, the inhibitory effect of dopamine, at low physiological concentrations is mediated by parallel activation of D2, D3, D4 and α2 receptors which is reproduced when endogenous dopamine levels are increased by blocking dopamine reuptake and metabolism. We provide evidence in support of dedicated spinal network components that are controlled by excitatory D1 and inhibitory D2 receptors that is reminiscent of the classic dopaminergic indirect and direct pathway within the striatum. These results indicate that network state is an important factor that dictates receptor-specific and therefore dose-dependent control of neuromodulators on spinal network output and advances our understanding of how neuromodulators regulate neural networks under dynamically changing excitability.Significance statement: Monoaminergic neuromodulation of neural networks is dependent not only on target receptors but also on network state. We studied the concentration-dependent control of spinal networks of the neonatal mouse, in vitro, during a low excitability state characterized by spontaneous network activity. Spontaneous activity is an essential element for the development of networks. Under these conditions, we defined converging receptor and cellular mechanisms that contribute to the diverse, concentration-dependent control of spinal motor networks by dopamine, in vitro. These experiments advance understanding of how monoamines modulate neuronal networks under dynamically changing excitability conditions and provide evidence of dedicated D1 and D2 regulated network components in the spinal cord that are consistent with those reported in the striatum.

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“…Neurotransmitter plasticity is activity-dependent (Borodinsky et al, 2004;Velazquez-Ulloa et al, 2011;Guemez-Gamboa et al, 2014;Meng et al, 2018). To investigate whether the recruitable reserve pool of TPH2-neurons in the DRv experiences any change in neuronal activity in response to social defeat, we assessed cFos expression by immunohistochemistry across stress conditions (Fig.…”

Section: Stressed Rats Display Lower Cfos Expression In Drv Neuronsmentioning

confidence: 99%

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

Prakash

Stark

Keisler

et al. 2019

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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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Neuronal activity regulates neurotransmitter switching in the adult brain following light-induced stress

Cited by 52 publications

References 44 publications

Light-mediated circuit switching in the Drosophila neuronal clock network

Light-mediated circuit switching in the Drosophila neuronal clock network

A dynamic role for dopamine receptors in the control of mammalian spinal networks

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

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