2021
DOI: 10.1126/science.abe1931
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Cholinergic neurons constitutively engage the ISR for dopamine modulation and skill learning in mice

Abstract: The integrated stress response (ISR) maintains proteostasis by modulating protein synthesis and is important in synaptic plasticity, learning, and memory. We developed a reporter, SPOTlight, for brainwide imaging of ISR state with cellular resolution. Unexpectedly, we found a class of neurons in mouse brain, striatal cholinergic interneurons (CINs), in which the ISR was activated at steady state. Genetic and pharmacological manipulations revealed that ISR signaling was necessary in CINs for normal type 2 dopam… Show more

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Cited by 41 publications
(36 citation statements)
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“…67 By modulating CIN-mediated signalling we could be interfering with their constitutive integrated stress response, a biochemical process that influences which proteins are synthesized in cholinergic striatal neurons. 68 In particular, this integrated stress response is required for normal D2R-modulation of CINs and changes in its functionality can affect the vigor of learned tasks. 68 To evaluate if ACh and/or Glu are driving the observed behavioral changes, we also investigated reward-evoked dopamine release and reward-based learning in mice where CINs are incapable of releasing both neurotransmitters effectively (DKO mice).…”
Section: Discussionmentioning
confidence: 99%
See 1 more Smart Citation
“…67 By modulating CIN-mediated signalling we could be interfering with their constitutive integrated stress response, a biochemical process that influences which proteins are synthesized in cholinergic striatal neurons. 68 In particular, this integrated stress response is required for normal D2R-modulation of CINs and changes in its functionality can affect the vigor of learned tasks. 68 To evaluate if ACh and/or Glu are driving the observed behavioral changes, we also investigated reward-evoked dopamine release and reward-based learning in mice where CINs are incapable of releasing both neurotransmitters effectively (DKO mice).…”
Section: Discussionmentioning
confidence: 99%
“…68 In particular, this integrated stress response is required for normal D2R-modulation of CINs and changes in its functionality can affect the vigor of learned tasks. 68 To evaluate if ACh and/or Glu are driving the observed behavioral changes, we also investigated reward-evoked dopamine release and reward-based learning in mice where CINs are incapable of releasing both neurotransmitters effectively (DKO mice). When examining dopamine signalling in the DKO mice, similar to VAChTcKO mice, DKO mice have a lower dopamine peak in the nucleus accumbens shell.…”
Section: Discussionmentioning
confidence: 99%
“…The membrane channels that are expressed in CINs (e.g., Nav, HCN, Kv4, etc.) are targets for neuromodulation under normal, healthy circumstances (Deng et al, 2007; Helseth et al, 2021; Maurice, 2004; Song and Surmeier, 1996). Therefore, it is likely that the dendritic excitability of CINs can be modulated under physiological conditions, as well, as a way to adjust the tuning of CINs to their afferent inputs.…”
Section: Discussionmentioning
confidence: 99%
“…Writing in Science , Helseth, Hernandez‐Martinez, and colleagues have now identified a surprising new role for constitutive ISR signaling in the normal physiology and function of striatal cholinergic interneurons (CINs) 3 . The team developed a genetically encoded biosensor, termed ′SPOTlight′, that could be used to identify cells with active ISR signaling.…”
mentioning
confidence: 99%
“…2 Writing in Science, Helseth, Hernandez-Martinez, and colleagues have now identified a surprising new role for constitutive ISR signaling in the normal physiology and function of striatal cholinergic interneurons (CINs). 3 The team developed a genetically encoded biosensor, termed 0 SPOTlight 0 , that could be used to identify cells with active ISR signaling. SPOTlight reports ISR signaling by means of two fluorophores that are expressed with mutual exclusivity depending upon the phosphorylation status of eukaryotic initiation factor 2 alpha (eIF2α).…”
mentioning
confidence: 99%