Autocrine regulation of adult neurogenesis by the endocannabinoid 2-arachidonoylglycerol (2-AG)

AbstractThe endocannabinoid system (ECS) modulates adult hippocampal neurogenesis by promoting the proliferation and survival of progenitor cells. Specifically, deleting cannabinoid CB1 receptors on neuronal stem cells (NSCs) or the constitutive deletion of the endocannabinoid 2-arachidonoylglycerol (2-AG) producing enzyme diacylglycerol lipase alpha (DAGLa) disrupts adult hippocampal neurogenesis. However, it is not known which cells are the producers of 2-AG relevant to neurogenesis. In this paper, we investigated the cellular source of endocannabinoids in the subgranular zone (SGZ) of the hippocampus, an important neurogenic niche. For this purpose, we used two complementary Cre-deleter mouse strains to delete DAGLa either in neurons or astroglia and neuronal progenitor cells. Surprisingly, neurogenesis was not altered in mice with a specific deletion of Dagla in neurons (Syn-Dagla KO), although these cells are the main source for the endocannabinoids in the brain. In contrast, mice with a specific inducible deletion of Dagla in neuronal progenitor cells and astrocytes (GLAST-CreERT2-Dagla KO) showed a strongly impaired neurogenesis with significantly reduced proliferation and survival of newborn cells. These results identify Dagla in neuronal progenitor cells in the SGZ of dentate gyrus or in astrocytes, as the cellular source for 2-AG in adult hippocampal neurogenesis. In summary, 2-AG produced by progenitor cells or astrocytes in the SGZ regulates adult hippocampal neurogenesis. The implications of these findings and the depressive-like phenotype in Dagla-deficient genetic mouse models are discussed.

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Exercise enhances the proliferation of neural stem cells and neurite growth and survival of neuronal progenitor cells in dentate gyrus of middle-aged mice

Journal of Applied Physiology ◽

10.1152/japplphysiol.90775.2008 ◽

2008 ◽

Vol 105 (5) ◽

pp. 1585-1594 ◽

Cited By ~ 118

Author(s):

Chih-Wei Wu ◽

Ya-Ting Chang ◽

Lung Yu ◽

Hsiun-ing Chen ◽

Chauying J. Jen ◽

...

Keyword(s):

Progenitor Cells ◽

Middle Age ◽

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis ◽

Treadmill Running ◽

Middle Aged ◽

Aged Mice ◽

Neuronal Progenitor Cells ◽

Neuronal Progenitor ◽

Immature Neurons

Aging is an important determinant of adult hippocampal neurogenesis as the proliferation of neural stem/precursor cells (NSCs) declines dramatically before middle age. Contrary to this, physical exercise is known to promote adult hippocampal neurogenesis. The objective of this study is to investigate the effects of mandatory treadmill running (TR) on neurogenesis, including 1) NSCs proliferation, 2) neurite outgrowth of neuronal progenitor cells, and 3) the survival of newborn neurons in dentate area of middle-aged animals. Compared with 3-mo-old mice, numbers of mitotic cells and neuronal progenitor cells decreased dramatically by middle age and remained at low levels after middle age. Five weeks of TR not only increased NSC proliferation and the number of immature neurons but also promoted the maturation and survival of immature neurons in middle-aged mice. The neurogenic and neurotrophic effects of TR were not due to the reduction of the age-related elevation of serum corticosterone. Significantly, 5 wk of TR restored the age-dependent decline of brain-derived neurotrophic factor and its receptor, TrkB, which are known to promote neuronal differentiation and survival. Taken together, mandatory running exercise alters the brain chemistries of middle-aged animals toward an environment that is favorable to NSC proliferation, survival, and maturation.

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A role for Lin28a in aging-associated decline of adult hippocampal neurogenesis

10.1101/2022.01.03.474756 ◽

2022 ◽

Author(s):

Zhechun Hu ◽

Jiao Ma ◽

Huimin Yue ◽

Xiaofang Li ◽

Chao Wang ◽

...

Keyword(s):

Progenitor Cells ◽

Neural Progenitor Cells ◽

Rna Binding ◽

Functional Integration ◽

Neural Progenitor ◽

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis ◽

Pattern Separation ◽

Neurogenic Niche ◽

Newborn Neurons

Hippocampal neurogenesis declines with aging. Wnt ligands and antagonists within the hippocampal neurogenic niche regulate the proliferation of neural progenitor cells and the development of new neurons, and the changes of their levels in the niche mediate aging-associated decline of neurogenesis. We found that RNA-binding protein Lin28a remained existent in neural progenitor cells and granule neurons in the adult hippocampus, and decreased with aging. Loss of Lin28a inhibited the responsiveness of neural progenitor cells to niche Wnt agonist and reduced neurogenesis, thus impairing pattern separation. Overexpression of Lin28a increased the proliferation of neural progenitor cells, promoted the functional integration of newborn neurons, restored neurogenesis in Wnt-deficient dentate gyrus, and rescued the impaired pattern separation in aging mice. Our data suggest that Lin28a regulates adult hippocampal neurogenesis as an intracellular mechanism by responding to niche Wnt signals, and its decrease is involved in aging-associated decline of hippocampal neurogenesis as well as related cognitive functions.

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Regulation of adult neurogenesis by the endocannabinoid-producing enzyme diacylglycerol lipase alpha (DAGLa)

Scientific Reports ◽

10.1038/s41598-021-04600-1 ◽

2022 ◽

Vol 12 (1) ◽

Author(s):

Lena-Louise Schuele ◽

Britta Schuermann ◽

Andras Bilkei-Gorzo ◽

Sara Gorgzadeh ◽

Andreas Zimmer ◽

...

Keyword(s):

Adult Neurogenesis ◽

Cannabinoid Receptors ◽

Endocannabinoid System ◽

Cell Types ◽

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis ◽

Mouse Strains ◽

Specific Cell ◽

Experimental Conditions ◽

Diacylglycerol Lipase

AbstractThe endocannabinoid system modulates adult hippocampal neurogenesis by promoting the proliferation and survival of neural stem and progenitor cells (NSPCs). This is demonstrated by the disruption of adult neurogenesis under two experimental conditions: (1) NSPC-specific deletion of cannabinoid receptors and (2) constitutive deletion of the enzyme diacylglycerol lipase alpha (DAGLa) which produces the endocannabinoid 2-arachidonoylglycerol (2-AG). However, the specific cell types producing 2-AG relevant to neurogenesis remain unknown. Here we sought to identify the cellular source of endocannabinoids in the subgranular zone of the dentate gyrus (DG) in hippocampus, an important neurogenic niche. For this purpose, we used two complementary Cre-deleter mouse strains to delete Dagla either in neurons, or in astroglia and NSPCs. Surprisingly, neurogenesis was not altered in mice bearing a deletion of Dagla in neurons (Syn-Dagla KO), although neurons are the main source for the endocannabinoids in the brain. In contrast, a specific inducible deletion of Dagla in NPSCs and astrocytes (GLAST-CreERT2-Dagla KO) resulted in a strongly impaired neurogenesis with a 50% decrease in proliferation of newborn cells. These results identify Dagla in NSPCs in the DG or in astrocytes as a prominent regulator of adult hippocampal neurogenesis. We also show a reduction of Daglb expression in GLAST-CreERT2-Dagla KO mice, which may have contributed to the neurogenesis phenotype.

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