scholarly journals Metabolic tuning of inhibition regulates hippocampal neurogenesis in the adult brain

2020 ◽  
Vol 117 (41) ◽  
pp. 25818-25829
Author(s):  
Xinxing Wang ◽  
Hanxiao Liu ◽  
Johannes Morstein ◽  
Alexander J. E. Novak ◽  
Dirk Trauner ◽  
...  
Keyword(s):  
Dentate Gyrus ◽  
Energy Homeostasis ◽  
Inhibitory Neuron ◽  
Hippocampal Neurogenesis ◽  
Adult Brain ◽  
Adult Hippocampal Neurogenesis ◽  
Neuron Activity ◽  
Adult Mice ◽  
Sphingosine 1 Phosphate ◽  
Underlying Mechanisms

Hippocampus-engaged behaviors stimulate neurogenesis in the adult dentate gyrus by largely unknown means. To explore the underlying mechanisms, we used tetrode recording to analyze neuronal activity in the dentate gyrus of freely moving adult mice during hippocampus-engaged contextual exploration. We found that exploration induced an overall sustained increase in inhibitory neuron activity that was concomitant with decreased excitatory neuron activity. A mathematical model based on energy homeostasis in the dentate gyrus showed that enhanced inhibition and decreased excitation resulted in a similar increase in neurogenesis to that observed experimentally. To mechanistically investigate this sustained inhibitory regulation, we performed metabolomic and lipidomic profiling of the hippocampus during exploration. We found sustainably increased signaling of sphingosine-1-phosphate, a bioactive metabolite, during exploration. Furthermore, we found that sphingosine-1-phosphate signaling through its receptor 2 increased interneuron activity and thus mediated exploration-induced neurogenesis. Taken together, our findings point to a behavior-metabolism circuit pathway through which experience regulates adult hippocampal neurogenesis.

scholarly journals GDF11 expressed in the adult brain negatively regulates hippocampal neurogenesis

2021 ◽  
Author(s):  
Brittany A Mayweather ◽  
Sean M Buchanan ◽  
Lee L Rubin
Keyword(s):  
Histological Analysis ◽  
Hippocampal Neurogenesis ◽  
Neural Progenitors ◽  
Adult Brain ◽  
Adult Hippocampal Neurogenesis ◽  
Negative Regulator ◽  
Target Cells ◽  
Adult Mice ◽  
Newborn Neurons

Abstract Growth differentiation factor 11 (GDF11) is a transforming factor-β superfamily member that functions as a negative regulator of neurogenesis during embryonic development. However, when recombinant GDF11 (rGDF11) is administered systemically in aged mice, it promotes neurogenesis, the opposite of its role during development. The goal of the present study was to reconcile this apparent discrepancy by performing the first detailed investigation into the expression of endogenous GDF11 in the adult brain and its effects on neurogenesis. Using quantitative histological analysis, we observed that Gdf11 is highly expressed in adult neurogenic niches and non-neurogenic regions within the hippocampus, choroid plexus, thalamus, habenula, and cerebellum. To investigate the role of endogenous GDF11 during adult hippocampal neurogenesis, we generated a tamoxifen inducible mouse that allowed us to reduce GDF11 levels. Depletion of Gdf11 during adulthood increased proliferation of neural progenitors and decreased the number of newborn neurons in the hippocampus, suggesting that endogenous GDF11 remains a negative regulator of hippocampal neurogenesis in adult mice. These findings further support the idea that circulating systemic GDF11 and endogenously expressed GDF11 in the adult brain have different target cells or mechanisms of action. Our data describe a role for GDF11-dependent signaling in adult neurogenesis that has implications for how GDF11 may be used to treat CNS disease.

scholarly journals GDF11 expressed in the adult brain negatively regulates hippocampal neurogenesis

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Brittany A. Mayweather ◽  
Sean M. Buchanan ◽  
Lee L. Rubin
Keyword(s):  
Histological Analysis ◽  
Hippocampal Neurogenesis ◽  
Neural Progenitors ◽  
Adult Brain ◽  
Adult Hippocampal Neurogenesis ◽  
Negative Regulator ◽  
Target Cells ◽  
Adult Mice ◽  
Newborn Neurons

AbstractGrowth differentiation factor 11 (GDF11) is a transforming factor-β superfamily member that functions as a negative regulator of neurogenesis during embryonic development. However, when recombinant GDF11 (rGDF11) is administered systemically in aged mice, it promotes neurogenesis, the opposite of its role during development. The goal of the present study was to reconcile this apparent discrepancy by performing the first detailed investigation into the expression of endogenous GDF11 in the adult brain and its effects on neurogenesis. Using quantitative histological analysis, we observed that Gdf11 is most highly expressed in adult neurogenic niches and non-neurogenic regions within the hippocampus, choroid plexus, thalamus, habenula, and cerebellum. To investigate the role of endogenous GDF11 during adult hippocampal neurogenesis, we generated a tamoxifen inducible mouse that allowed us to reduce GDF11 levels. Depletion of Gdf11 during adulthood increased proliferation of neural progenitors and decreased the number of newborn neurons in the hippocampus, suggesting that endogenous GDF11 remains a negative regulator of hippocampal neurogenesis in adult mice. These findings further support the idea that circulating systemic GDF11 and endogenously expressed GDF11 in the adult brain have different target cells or mechanisms of action. Our data describe a role for GDF11-dependent signaling in adult neurogenesis that has implications for how GDF11 may be used to treat CNS disease.

Effects and Potential Mechanisms of Alcohol Use Disorder on the Fate Determination of Newly Born Neurons in the Hippocampus

2020 ◽  
Vol 55 (6) ◽  
pp. 598-602
Author(s):  
Zahra Shabani ◽  
Mohsen Jafarzadeh Gharehziaaddin
Keyword(s):  
Hippocampal Neurogenesis ◽  
Adult Brain ◽  
Adult Hippocampal Neurogenesis ◽  
Mammalian Brain ◽  
Extrinsic Factors ◽  
Proliferation And Differentiation ◽  
Underlying Mechanisms

Abstract In the adult mammalian brain, new functional neurons are generated throughout life because of sustained proliferation and differentiation of neural stem cells (NSCs). The subventricular zone (SVZ), lining the lateral ventricle, and the subgranular zone (SGZ) in the dentate gyrus (DG) of the hippocampus are the two major neurogenic regions in the adult brain. This process is not fixed but is highly modulated by numerous intrinsic and extrinsic factors. Neurogenesis has become in the focus of interest for its involvement in repairing the damaged brain and this motivates researchers to detect controlling mechanisms of this process. Recent evidence suggests that alcohol usage can directly influence adult hippocampal neurogenesis, but its mechanisms remain a matter for debate. Thus, this review summarizes in vivo/in vitro studies on the role of alcohol in hippocampal neurogenesis during adulthood and clarifies its underlying mechanisms by highlighting neurotransmitters and their receptors.

Is adult hippocampal neurogenesis really relevant for the treatment of psychiatric disorders?

2020 ◽  
Vol 18 ◽  
Author(s):  
Marco Carli ◽  
Stefano Aringhieri ◽  
Shivakumar Kolachalam ◽  
Biancamaria Longoni ◽  
Giovanna Grenno ◽  
...  
Keyword(s):  
Psychiatric Disorders ◽  
Emotional Processing ◽  
Imaging Techniques ◽  
Hippocampal Neurogenesis ◽  
Adult Brain ◽  
Adult Hippocampal Neurogenesis ◽  
Mood Stabilizers ◽  
Post Traumatic Stress ◽  
Newborn Neurons ◽  
Hippocampal Circuitry

: Adult neurogenesis consists in the generation of newborn neurons from neural stem cells taking place in the adult brain. In mammals, this process is limited to very few areas of the brain, and one of these neurogenic niches is the subgranular layer of the dentate gyrus (DG) of the hippocampus. Adult newborn neurons are generated from quiescent neural progenitors (QNPs), which differentiate through different steps into mature granule cells (GCs), to be finally integrated into the existing hippocampal circuitry. In animal models, adult hippocampal neurogenesis (AHN) is relevant for pattern discrimination, cognitive flexibility, emotional processing and resilience to stressful situations. Imaging techniques allow to visualize newborn neurons within the hippocampus through all their stages of development and differentiation. In humans, the evidence of AHN is more challenging, and, based on recent findings, it persists through the adulthood, even if it declines with age. Whether this process has an important role in human brain function and how it integrates into the existing hippocampal circuitry is still a matter of exciting debate. Importantly, AHN deficiency has been proposed to be relevant in many psychiatric disorders, including mood disorders, anxiety, post-traumatic stress disorder and schizophrenia. This review aims to investigate how AHN is altered in different psychiatric conditions and how pharmacological treatments can rescue this process. In fact, many psychoactive drugs, such as antidepressants, mood stabilizers and atypical antipsychotics (AAPs), can boost AHN with different results. In addition, some non-pharmacological approaches are discussed as well.

Metabolic Regulation of Hippocampal Neuronal Development and Its Inhibition After Irradiation

2021 ◽  
Vol 80 (5) ◽  
pp. 467-475
Author(s):  
Yu-Qing Li ◽  
C Shun Wong
Keyword(s):  
Cell Fate ◽  
Metabolic Regulation ◽  
Energy Homeostasis ◽  
Neuronal Development ◽  
Adenosine Monophosphate ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis ◽  
Wild Type ◽  
Newborn Neuron ◽  
Negative Effect

Abstract 5′-Adenosine monophosphate-activated protein kinase (AMPK), a key regulator of cellular energy homeostasis, plays a role in cell fate determination. Whether AMPK regulates hippocampal neuronal development remains unclear. Hippocampal neurogenesis is abrogated after DNA damage. Here, we asked whether AMPK regulates adult hippocampal neurogenesis and its inhibition following irradiation. Adult Cre-lox mice deficient in AMPK in brain, and wild-type mice were used in a birth-dating study using bromodeoxyuridine to evaluate hippocampal neurogenesis. There was no evidence of AMPK or phospho-AMPK immunoreactivity in hippocampus. Increase in p-AMPK but not AMPK expression was observed in granule neurons and subgranular neuroprogenitor cells (NPCs) in the dentate gyrus within 24 hours and persisted up to 9 weeks after irradiation. AMPK deficiency in Cre-lox mice did not alter neuroblast and newborn neuron numbers but resulted in decreased newborn and proliferating NPCs. Inhibition of neurogenesis was observed after irradiation regardless of genotypes. In Cre-lox mice, there was further loss of newborn early NPCs and neuroblasts but not newborn neurons after irradiation compared with wild-type mice. These results are consistent with differential negative effect of AMPK on hippocampal neuronal development and its inhibition after irradiation.

NFIX-Mediated Inhibition of Neuroblast Branching Regulates Migration Within the Adult Mouse Ventricular–Subventricular Zone

2018 ◽  
Vol 29 (8) ◽  
pp. 3590-3604 ◽  
Author(s):  
Oressia Zalucki ◽  
Lachlan Harris ◽  
Tracey J Harvey ◽  
Danyon Harkins ◽  
Jocelyn Widagdo ◽  
...  
Keyword(s):  
Dentate Gyrus ◽  
Subventricular Zone ◽  
Adult Mouse ◽  
Adult Brain ◽  
Granule Cell Layer ◽  
Transcriptional Level ◽  
Olfactory Responses ◽  
Brain Functions ◽  
Neuroblast Migration ◽  
Adult Mice

Abstract Understanding the migration of newborn neurons within the brain presents a major challenge in contemporary biology. Neuronal migration is widespread within the developing brain but is also important within the adult brain. For instance, stem cells within the ventricular–subventricular zone (V-SVZ) and the subgranular zone of dentate gyrus of the adult rodent brain produce neuroblasts that migrate to the olfactory bulb and granule cell layer of the dentate gyrus, respectively, where they regulate key brain functions including innate olfactory responses, learning, and memory. Critically, our understanding of the factors mediating neuroblast migration remains limited. The transcription factor nuclear factor I X (NFIX) has previously been implicated in embryonic cortical development. Here, we employed conditional ablation of Nfix from the adult mouse brain and demonstrated that the removal of this gene from either neural stem and progenitor cells, or neuroblasts, within the V-SVZ culminated in neuroblast migration defects. Mechanistically, we identified aberrant neuroblast branching, due in part to increased expression of the guanylyl cyclase natriuretic peptide receptor 2 (Npr2), as a factor contributing to abnormal migration in Nfix-deficient adult mice. Collectively, these data provide new insights into how neuroblast migration is regulated at a transcriptional level within the adult brain.

scholarly journals Suppressor of fused controls perinatal expansion and quiescence of future dentate adult neural stem cells

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Hirofumi Noguchi ◽  
Jesse Garcia Castillo ◽  
Kinichi Nakashima ◽  
Samuel J Pleasure
Keyword(s):  
Stem Cells ◽  
Sonic Hedgehog ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis ◽  
Quiescent State ◽  
Shh Signaling ◽  
Suppressor Of Fused ◽  
Adult Mice ◽  
Adult Nscs ◽  
Signaling Activity

Adult hippocampal neurogenesis requires the quiescent neural stem cell (NSC) pool to persist lifelong. However, establishment and maintenance of quiescent NSC pools during development is not understood. Here, we show that Suppressor of Fused (Sufu) controls establishment of the quiescent NSC pool during mouse dentate gyrus (DG) development by regulating Sonic Hedgehog (Shh) signaling activity. Deletion of Sufu in NSCs early in DG development decreases Shh signaling activity leading to reduced proliferation of NSCs, resulting in a small quiescent NSC pool in adult mice. We found that putative adult NSCs proliferate and increase their numbers in the first postnatal week and subsequently enter a quiescent state towards the end of the first postnatal week. In the absence of Sufu, postnatal expansion of NSCs is compromised, and NSCs prematurely become quiescent. Thus, Sufu is required for Shh signaling activity ensuring expansion and proper transition of NSC pools to quiescent states during DG development.

scholarly journals Circulating unacylated-ghrelin impairs hippocampal neurogenesis and memory in mice and is altered in human Parkinson's disease dementia

2018 ◽  
Author(s):  
Amanda K E Hornsby ◽  
Vanessa V Santos ◽  
Fionnuala Johnston ◽  
Luke D Roberts ◽  
Romana Stark ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Brain Plasticity ◽  
Hippocampal Neurogenesis ◽  
Adult Brain ◽  
Adult Hippocampal Neurogenesis ◽  
Unexpected Finding ◽  
Unacylated Ghrelin ◽  
Memory Impairments ◽  
Acyl Ghrelin

Blood-borne factors regulate adult hippocampal neurogenesis (AHN) and cognition in mammals, albeit via mechanisms that are poorly understood. We report that elevating circulating unacylated-ghrelin (UAG), using both pharmacological and genetic methods, reduced hippocampal neurogenesis and plasticity in mice. Spatial memory impairments observed in GOAT-/- mice that lack acyl-ghrelin (AG) but have high levels of UAG, were rescued by treatment with AG. This unexpected finding suggests that the post-translational acylation of ghrelin is an important modulator of neurogenesis and memory in adult mammals. To determine whether this paradigm is relevant to humans we analysed circulating AG:UAG levels in Parkinson's disease (PD) patients diagnosed with dementia (PDD), cognitively intact PD patients and healthy controls. Uniquely, the ratio of plasma AG:UAG was reduced in the PDD cohort and correlated with cognitive performance. Our results identify UAG as a novel regulator of neurogenesis and cognition, and AG:UAG as a circulating diagnostic biomarker of dementia. The findings extend our understanding of adult brain plasticity regulation by circulating factors and suggest that manipulating the post-translational acylation of plasma ghrelin may offer therapeutic opportunities to ameliorate cognitive decline.

scholarly journals Reactive, Adult Neurogenesis From Increased Neural Progenitor Cell Proliferation Following Alcohol Dependence in Female Rats

2021 ◽  
Vol 15 ◽  
Author(s):  
Natalie N. Nawarawong ◽  
K. Ryan Thompson ◽  
Steven P. Guerin ◽  
Chinchusha Anasooya Shaji ◽  
Hui Peng ◽  
...  
Keyword(s):  
Alcohol Dependence ◽  
Dentate Gyrus ◽  
Adult Neurogenesis ◽  
Progenitor Cell ◽  
Neural Progenitor Cell ◽  
Neural Progenitor ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis ◽  
Female Rats ◽  
Immature Neurons

Hippocampal neurodegeneration is a consequence of excessive alcohol drinking in alcohol use disorders (AUDs), however, recent studies suggest that females may be more susceptible to alcohol-induced brain damage. Adult hippocampal neurogenesis is now well accepted to contribute to hippocampal integrity and is known to be affected by alcohol in humans as well as in animal models of AUDs. In male rats, a reactive increase in adult hippocampal neurogenesis has been observed during abstinence from alcohol dependence, a phenomenon that may underlie recovery of hippocampal structure and function. It is unknown whether reactive neurogenesis occurs in females. Therefore, adult female rats were exposed to a 4-day binge model of alcohol dependence followed by 7 or 14 days of abstinence. Immunohistochemistry (IHC) was used to assess neural progenitor cell (NPC) proliferation (BrdU and Ki67), the percentage of increased NPC activation (Sox2+/Ki67+), the number of immature neurons (NeuroD1), and ectopic dentate gyrus granule cells (Prox1). On day seven of abstinence, ethanol-treated females showed a significant increase in BrdU+ and Ki67+ cells in the subgranular zone of the dentate gyrus (SGZ), as well as greater activation of NPCs (Sox2+/Ki67+) into active cycling. At day 14 of abstinence, there was a significant increase in the number of immature neurons (NeuroD1+) though no evidence of ectopic neurogenesis according to either NeuroD1 or Prox1 immunoreactivity. Altogether, these data suggest that alcohol dependence produces similar reactive increases in NPC proliferation and adult neurogenesis. Thus, reactive, adult neurogenesis may be a means of recovery for the hippocampus after alcohol dependence in females.

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