Mossy Cells Control Adult Neural Stem Cell Quiescence and Maintenance through a Dynamic Balance between Direct and Indirect Pathways

Yeh, Chia-Yu; Asrican, Brent; Moss, Jonathan; Quintanilla, Luis; He, Ting; Mao, Xiao‐Ming; Cassé, Frédéric; Gebara, Elias; Bao, Hechen; Lü, Wei; Toni, Nicolas; Song, Juan

doi:10.1016/j.neuron.2018.07.010

Cited by 93 publications

(109 citation statements)

References 42 publications

(58 reference statements)

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“…Viral expression in Drd2-Cre +/mice was characterized by large hilar mCherry + cells proximal to the injection site and a dense band of mCherry + labeling in the inner molecular layer (IML) throughout the septotemporal axis of the DG, consistent with the location of MCs and their major axon projection ( Figure 1C-D; Scharfman, 2016). The pattern of viral expression has been validated in previous work by our laboratory (Botterill et al, 2019;Bernstein et al, 2020) and confirmed by others (Danielson et al, 2017;Bui et al, 2018;Yeh et al, 2018;Azevedo et al, 2019;Oh et al, 2019).…”

Section: Viral Expressionsupporting

confidence: 80%

“…Importantly, electrophysiological studies from our lab (Botterill et al, 2019) and others (Yeh et al, 2018;Oh et al, 2019) have confirmed the excitatory and inhibitory effects of DREADDs in MCs. Control mice consisted of Drd2-Cre -/and Cre +/mice injected with a viral control fluorophore (mCherry).…”

Section: Experimental Design and Controlssupporting

confidence: 57%

“…Regarding GC c-Fos, the results can be explained by the two circuits that MCs use to influence GCs: the direct MC-GC pathway which excites GCs and the indirect MCGABAergic neuronGC pathway which inhibits GCs ( Figure 1E). The indirect pathway appears to dominate under standard conditions (Jinde et al, 2012;Hsu et al, 2016;Bui et al, 2018;Yeh et al, 2018). After eDREADD activation by CNO, there would be greater activation of both the direct and indirect pathways which appeared to cause no net change in GC c-Fos ( Figure 11A).…”

Section: Gcl C-fosmentioning

confidence: 99%

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Bidirectional regulation of cognitive and anxiety-like behaviors by dentate gyrus mossy cells in male and female mice

Botterill

Vinod

Gerencer

et al. 2020

Preprint

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ABSTRACTThe dentate gyrus (DG) of the hippocampus is important for cognitive and affective behaviors. However, the circuits underlying these behaviors are unclear. DG mossy cells (MCs) have been a focus of attention because of their excitatory synapses on the primary DG cell type, granule cells (GCs). However, MCs also activate DG GABAergic neurons which inhibit GCs. We took advantage of specific methods and a gain- and loss-of function strategy with Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) to study MCs in diverse behaviors. Using this approach, manipulations of MCs could bidirectionally regulate behavior. The results suggest that inhibiting MCs can reduce anxiety-like behavior and improve cognitive performance. However, not all cognitive or anxiety-related behaviors were influenced, suggesting specific roles of MCs in some but not all types of cognition and anxiety. Notably, several behaviors showed sex-specific effects, with females often showing more pronounced effects than the males. We also used the immediate early gene c-Fos to address whether DREADDs bidirectionally regulated MC or GC activity. We confirmed excitatory DREADDs increased MC c-Fos. However, there was no change in GC c-Fos, consistent with MC activation leading to GABAergic inhibition of GCs. In contrast, inhibitory DREADDs led to a large increase in GC c-Fos, consistent with a reduction in MC excitation of GABAergic neurons, and reduced inhibition of GCs. Taken together, these results suggest that MCs regulate anxiety and cognition in specific ways. We also raise the possibility that cognitive performance may be improved by reducing anxiety.SIGNIFICANCE STATEMENTThe dentate gyrus (DG) has many important cognitive roles as well as being associated with affective behavior. This study addressed how a glutamatergic DG cell type called mossy cells (MCs) contributes to diverse behaviors, which is timely because it is known that MCs regulate the activity of the primary DG cell type, granule cells (GCs), but how MC activity influences behavior is unclear. We show, surprisingly, that activating MCs can lead to adverse behavioral outcomes, and inhibiting MCs have an opposite effect. Importantly, the results appeared to be task-dependent and showed that testing both sexes was important. Additional experiments indicated what MC and GC circuitry was involved. Taken together, the results suggest how MCs influence behaviors that involve the DG.

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Section: Viral Expressionsupporting

confidence: 80%

Section: Experimental Design and Controlssupporting

confidence: 57%

Section: Gcl C-fosmentioning

confidence: 99%

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Bidirectional regulation of cognitive and anxiety-like behaviors by dentate gyrus mossy cells in male and female mice

Botterill

Vinod

Gerencer

et al. 2020

Preprint

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“…In contrast to most regions in the adult brain, the dentate gyrus of the hippocampus is endowed with radial glia-like neural stem cells and progenitor cells (NSPCs) that give rise to new neurons throughout one's life (Ming and Song, 2011). The generation and maturation of new neurons are shaped by sensory inputs and experiences via the activity of local interneurons (Song et al, 2012;Yeh et al, 2018). This process ultimately promotes new neuron integration into the preexisting network (Bergami et al, 2015;Temprana et al, 2015;Alvarez et al, 2016) and has important implications for cognition (Toda and Gage, 2018).…”

Section: Mitochondrial Dynamics In Adult Neurogenesismentioning

confidence: 99%

Pleiotropic Mitochondria: The Influence of Mitochondria on Neuronal Development and Disease

et al. 2019

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Mitochondria play many important biological roles, including ATP production, lipid biogenesis, ROS regulation, and calcium clearance. In neurons, the mitochondrion is an essential organelle for metabolism and calcium homeostasis. Moreover, mitochondria are extremely dynamic and able to divide, fuse, and move along microtubule tracks to ensure their distribution to the neuronal periphery. Mitochondrial dysfunction and altered mitochondrial dynamics are observed in a wide range of conditions, from impaired neuronal development to various neurodegenerative diseases. Novel imaging techniques and genetic tools provide unprecedented access to the physiological roles of mitochondria by visualizing mitochondrial trafficking, morphological dynamics, ATP generation, and ultrastructure. Recent studies using these new techniques have unveiled the influence of mitochondria on axon branching, synaptic function, calcium regulation with the ER, glial cell function, neurogenesis, and neuronal repair. This review provides an overview of the crucial roles played by mitochondria in the CNS in physiological and pathophysiological conditions.

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“…Indeed, granule neurons release secreted frizzled-related protein 3 (sFRP3) to maintain NSC quiescence in the SGZ [132]. The differential activation of MCs regulates the balance of quiescence and reactivation of NSCs within the SGZ, in which the direct MC-NSC glutamatergic pathway favors reactivation and indirect MC-interneuron-NSC gamma aminobutyric acid (GABA)ergic pathway favors quiescence [133][134][135]. In the V-SVZ, a new population of choline acetyltransferase (ChAT) + neurons release acetylcholine to stimulate NSC proliferation [136].…”

Section: The Role Of Neurons In Nsc Reactivationmentioning

confidence: 99%

Waking up quiescent neural stem cells: Molecular mechanisms and implications in neurodevelopmental disorders

2020

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Neural stem cells (NSCs) are crucial for development, regeneration, and repair of the nervous system. Most NSCs in mammalian adult brains are quiescent, but in response to extrinsic stimuli, they can exit from quiescence and become reactivated to give rise to new neurons. The delicate balance between NSC quiescence and activation is important for adult neurogenesis and NSC maintenance. However, how NSCs transit between quiescence and activation remains largely elusive. Here, we discuss our current understanding of the molecular mechanisms underlying the reactivation of quiescent NSCs. We review recent advances on signaling pathways originated from the NSC niche and their crosstalk in regulating NSC reactivation. We also highlight new intrinsic paradigms that control NSC reactivation in Drosophila and mammalian systems. We also discuss emerging evidence on modeling human neurodevelopmental disorders using NSCs.

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Mossy Cells Control Adult Neural Stem Cell Quiescence and Maintenance through a Dynamic Balance between Direct and Indirect Pathways

Cited by 93 publications

References 42 publications

Bidirectional regulation of cognitive and anxiety-like behaviors by dentate gyrus mossy cells in male and female mice

Bidirectional regulation of cognitive and anxiety-like behaviors by dentate gyrus mossy cells in male and female mice

Pleiotropic Mitochondria: The Influence of Mitochondria on Neuronal Development and Disease

Waking up quiescent neural stem cells: Molecular mechanisms and implications in neurodevelopmental disorders

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