scholarly journals Fluoxetine-induced dematuration of hippocampal neurons and adult cortical neurogenesis in the common marmoset

2019 ◽  
Author(s):  
Koji Ohira ◽  
Hideo Hagihara ◽  
Miki Miwa ◽  
Katsuki Nakamura ◽  
Tsuyoshi Miyakawa
Keyword(s):  
Cerebral Cortex ◽  
Hippocampal Neurons ◽  
Common Marmoset ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis ◽  
Cortical Neurogenesis ◽  
Primate Brain ◽  
Cortical Interneurons ◽  
Fast Spiking ◽  
Induced Changes

AbstractThe selective serotonin reuptake inhibitor fluoxetine (FLX) is widely used to treat depression and anxiety disorders. Chronic FLX treatment reportedly induces cellular responses in the brain, including increased adult hippocampal and cortical neurogenesis and reversal of neuron maturation in the hippocampus, amygdala, and cortex. However, because most previous studies have used rodent models, it remains unclear whether these FLX-induced changes occur in the primate brain. To evaluate the effects of FLX in the primate brain, we used immunohistological methods to assess neurogenesis and the expression of neuronal maturity markers following chronic FLX treatment (3 mg/kg/day for 4 weeks) in adult marmosets (n = 3 per group). We found increased expression of doublecortin and calretinin, markers of immature neurons, in the hippocampal dentate gyrus of FLX-treated marmosets. Further, FLX treatment reduced parvalbumin expression and the number of neurons with perineuronal nets, which indicate mature fast-spiking interneurons, in the hippocampus, but not in the amygdala or cerebral cortex. We also found that FLX treatment increased the generation of cortical interneurons; however, significant up-regulation of adult hippocampal neurogenesis was not observed in FLX-treated marmosets. These results suggest that dematuration of hippocampal neurons and increased cortical neurogenesis may play roles in FLX-induced effects and/or side effects. Our results are consistent with those of previous studies showing hippocampal dematuration and increased cortical neurogenesis in FLX-treated rodents. In contrast, FLX did not affect hippocampal neurogenesis or dematuration of interneurons in the amygdala and cerebral cortex.

scholarly journals The intellectual disability PAK3 R67C mutation impacts cognitive functions and adult hippocampal neurogenesis

2020 ◽  
Vol 29 (12) ◽  
pp. 1950-1968
Author(s):  
Charlotte Castillon ◽  
Laurine Gonzalez ◽  
Florence Domenichini ◽  
Sandrine Guyon ◽  
Kevin Da Silva ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Mouse Model ◽  
Spatial Memory ◽  
Adult Neurogenesis ◽  
Hippocampal Neurons ◽  
Memory Task ◽  
Clinical Signs ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis ◽  
Adult Born Neurons

Abstract The link between mutations associated with intellectual disability (ID) and the mechanisms underlying cognitive dysfunctions remains largely unknown. Here, we focused on PAK3, a serine/threonine kinase whose gene mutations cause X-linked ID. We generated a new mutant mouse model bearing the missense R67C mutation of the Pak3 gene (Pak3-R67C), known to cause moderate to severe ID in humans without other clinical signs and investigated hippocampal-dependent memory and adult hippocampal neurogenesis. Adult male Pak3-R67C mice exhibited selective impairments in long-term spatial memory and pattern separation function, suggestive of altered hippocampal neurogenesis. A delayed non-matching to place paradigm testing memory flexibility and proactive interference, reported here as being adult neurogenesis-dependent, revealed a hypersensitivity to high interference in Pak3-R67C mice. Analyzing adult hippocampal neurogenesis in Pak3-R67C mice reveals no alteration in the first steps of adult neurogenesis, but an accelerated death of a population of adult-born neurons during the critical period of 18–28 days after their birth. We then investigated the recruitment of hippocampal adult-born neurons after spatial memory recall. Post-recall activation of mature dentate granule cells in Pak3-R67C mice was unaffected, but a complete failure of activation of young DCX + newborn neurons was found, suggesting they were not recruited during the memory task. Decreased expression of the KCC2b chloride cotransporter and altered dendritic development indicate that young adult-born neurons are not fully functional in Pak3-R67C mice. We suggest that these defects in the dynamics and learning-associated recruitment of newborn hippocampal neurons may contribute to the selective cognitive deficits observed in this mouse model of ID.

scholarly journals Fluoxetine-induced dematuration of hippocampal neurons and adult cortical neurogenesis in the common marmoset

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Koji Ohira ◽  
Hideo Hagihara ◽  
Miki Miwa ◽  
Katsuki Nakamura ◽  
Tsuyoshi Miyakawa
Keyword(s):  
Hippocampal Neurons ◽  
Common Marmoset ◽  
Cortical Neurogenesis ◽  
The Common

scholarly journals De novo DNA methylation controls neuronal maturation during adult hippocampal neurogenesis

2020 ◽  
Author(s):  
Sara Zocher ◽  
Rupert W Overall ◽  
Gabriel Berdugo-Vega ◽  
Nicole Rund ◽  
Anne Karasinsky ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Cell Fate ◽  
Adult Neurogenesis ◽  
Hippocampal Neurons ◽  
De Novo ◽  
Functional Integration ◽  
Stem Cell Differentiation ◽  
Dna Methyltransferases ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis

SummaryDynamic DNA methylation controls gene-regulatory networks underlying cell fate specification. How DNA methylation patterns change during adult hippocampal neurogenesis and their relevance for adult neural stem cell differentiation and related brain function has, however, remained unknown. Here, we show that neurogenesis-associated de novo DNA methylation is critical for maturation and functional integration of adult-born hippocampal neurons. Cell stage-specific bisulfite sequencing revealed a pronounced gain of DNA methylation at neuronal enhancers, gene bodies and binding sites of pro-neuronal transcription factors during adult neurogenesis, which mostly correlated with transcriptional up-regulation of the associated loci. Inducible deletion of both de novo DNA methyltransferases Dnmt3a and Dnmt3b in adult neural stem cells specifically impaired dendritic outgrowth and synaptogenesis of new-born neurons, resulting in reduced hippocampal excitability and specific deficits in hippocampus-dependent learning and memory. Our results highlight that, during adult neurogenesis, remodeling of neuronal methylomes is fundamental for proper hippocampal function.

scholarly journals Effects of Combined Anti-Hypertensive and Statin Treatment on Memory, Fear Extinction, Adult Neurogenesis, and Angiogenesis in Adult and Middle-Aged Mice

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1778
Author(s):  
Seungwoo Yoo ◽  
Matthew Stremlau ◽  
Alejandro Pinto ◽  
Hyewon Woo ◽  
Olivia Curtis ◽  
...  
Keyword(s):  
Hippocampal Neurons ◽  
Enzyme Inhibitor ◽  
Memory Function ◽  
Hippocampal Neurogenesis ◽  
Contextual Fear Conditioning ◽  
Adult Hippocampal Neurogenesis ◽  
Control Group ◽  
Post Traumatic Stress ◽  
Middle Aged ◽  
Aged Mice

Hyperlipidemia and hypertension are modifiable risk factors for cognitive decline. About 25% of adults over age 65 use both antihypertensives (AHTs) and statins to treat these conditions. Recent research in humans suggests that their combined use may delay or prevent dementia onset. However, it is not clear whether and how combination treatment may benefit brain function. To begin to address this question, we examined effects of atorvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, and Captopril, an angiotensin-converting enzyme inhibitor (ACEI), administration on memory function, anxiety-like behavior, adult hippocampal neurogenesis and angiogenesis in adult and middle-aged male C57Bl/6J mice. In adult mice (3-months-old) combination (combo) treatment, as well as administration of each compound individually, for six weeks, accelerated memory extinction in contextual fear conditioning. However, pattern separation in the touchscreen-based location discrimination test, a behavior linked to adult hippocampal neurogenesis, was unchanged. In addition, dentate gyrus (DG) neurogenesis and vascularization were unaffected. In middle-aged mice (10-months-old) combo treatment had no effect on spatial memory in the Morris water maze, but did reduce anxiety in the open field test. A potential underlying mechanism may be the modest increase in new hippocampal neurons (~20%) in the combo as compared to the control group. DG vascularization was not altered. Overall, our findings suggest that statin and anti-hypertensive treatment may serve as a potential pharmacotherapeutic approach for anxiety, in particular for post-traumatic stress disorder (PTSD) patients who have impairments in extinction of aversive memories.

Cadmium Exposure Impairs Adult Hippocampal Neurogenesis

2019 ◽  
Vol 171 (2) ◽  
pp. 501-514 ◽  
Author(s):  
Hao Wang ◽  
Glen M Abel ◽  
Daniel R Storm ◽  
Zhengui Xia
Keyword(s):  
Signaling Pathways ◽  
Learning And Memory ◽  
Hippocampal Neurons ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis ◽  
Mitogen Activated Protein Kinase ◽  
Dependent Learning ◽  
Cd Exposure

Abstract Cadmium (Cd) is an environmental pollutant of considerable interest throughout the world and potentially a neurotoxicant. Our recent data indicate that Cd exposure induces impairment of hippocampus-dependent learning and memory in mice. However, the underlying mechanisms for this defect are not known. The goal of this study was to determine if Cd inhibits adult neurogenesis and to identify underlying signaling pathways responsible for this impairment. Adult hippocampal neurogenesis is a process in which adult neural progenitor/stem cells (aNPCs) in the subgranular zone (SGZ) of the dentate gyrus (DG) generate functional new neurons in the hippocampus which contributes to hippocampus-dependent learning and memory. However, studies concerning the effects of neurotoxicants on adult hippocampal neurogenesis and the underlying signaling mechanisms are limited. Here, we report that Cd significantly induces apoptosis, inhibits proliferation, and impairs neuronal differentiation in primary cultured aNPCs derived from the SGZ. In addition, the c-Jun NH2-terminal kinase and p38 mitogen-activated protein kinase signaling pathways are activated by Cd and contribute to its toxicity. Furthermore, we exposed 8-week-old male C57BL/6 mice to Cd through drinking water for 13 weeks to assess the effects of Cd on adult hippocampal neurogenesis in vivo. Cd treatment reduced the number of 5-week-old adult-born cells in the DG and impaired the differentiation of adult-born hippocampal neurons. These results suggest that Cd exposure impairs adult hippocampal neurogenesis both in vitro and in vivo. This may contribute to Cd-mediated inhibition of hippocampus-dependent learning and memory.

scholarly journals Astrocytic ApoE underlies maturation of hippocampal neurons and cognitive recovery after traumatic brain injury in mice

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Tzong-Shiue Yu ◽  
Yacine Tensaouti ◽  
Elizabeth P. Stephanz ◽  
Sana Chintamen ◽  
Elizabeth E. Rafikian ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Hippocampal Neurons ◽  
Late Onset ◽  
Hippocampal Neurogenesis ◽  
Conditional Knockout ◽  
Adult Hippocampal Neurogenesis ◽  
Morris Water Maze Test ◽  
Reversal Training ◽  
Reversal Phase

AbstractPolymorphisms in the apolipoprotein E (ApoE) gene confer a major genetic risk for the development of late-onset Alzheimer’s disease (AD) and are predictive of outcome following traumatic brain injury (TBI). Alterations in adult hippocampal neurogenesis have long been associated with both the development of AD and recovery following TBI and ApoE is known to play a role in this process. In order to determine how ApoE might influence hippocampal injury-induced neurogenesis, we generated a conditional knockout system whereby functional ApoE from astrocytes was ablated prior to injury. While successfully ablating ApoE just prior to TBI in mice, we observed an attenuation in the development of the spines in the newborn neurons. Intriguingly, animals with a double-hit, i.e. injury and ApoE conditionally inactivated in astrocytes, demonstrated the most pronounced impairments in the hippocampal-dependent Morris water maze test, failing to exhibit spatial memory after both acquisition and reversal training trials. In comparison, conditional knockout mice without injury displayed impairments but only in the reversal phase of the test, suggesting accumulative effects of astrocytic ApoE deficiency and traumatic brain injury on AD-like phenotypes. Together, these findings demonstrate that astrocytic ApoE is required for functional injury-induced neurogenesis following traumatic brain injury.

scholarly journals Ly6Chi Monocytes Provide a Link between Antibiotic-Induced Changes in Gut Microbiota and Adult Hippocampal Neurogenesis

Cell Reports ◽  
2016 ◽  
Vol 15 (9) ◽  
pp. 1945-1956 ◽  
Author(s):  
Luisa Möhle ◽  
Daniele Mattei ◽  
Markus M. Heimesaat ◽  
Stefan Bereswill ◽  
André Fischer ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis ◽  
Induced Changes

scholarly journals Astrocyte-derived ApoE is Required for the Maturation of Injury-induced Hippocampal Neurons and Regulates Cognitive Recovery After Traumatic Brain Injury

2021 ◽  
Author(s):  
Tzong-Shiue Yu ◽  
Yacine Tensaouti ◽  
Elizabeth P. Stephanz ◽  
Elizabeth E. Rafikian ◽  
Mu Yang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Hippocampal Neurons ◽  
Hippocampal Neurogenesis ◽  
Conditional Knockout ◽  
Adult Hippocampal Neurogenesis ◽  
Morris Water Maze Test ◽  
Reversal Training

AbstractPolymorphisms in the apolipoprotein E (ApoE) gene confer a major genetic risk for the development of late-onset Alzheimer’s disease (AD) and are predictive of outcome following traumatic brain injury (TBI). Alterations in adult hippocampal neurogenesis have long been associated with both the development of AD and recovery following TBI, and ApoE is known to play a role in this process. In order to determine how ApoE might influence hippocampal injury-induced neurogenesis, we developed a novel conditional system whereby functional ApoE from astrocytes was ablated just prior to injury. While successfully ablating 90% of astrocytic ApoE just prior to a closed cortical impact injury in mice, we observed an attenuation in the development of newly born neurons using a GFP-expressing retrovirus, but not in existing hippocampal neurons visualized with a Golgi stain. Intriguingly, animals with a “double-hit”, i.e. injury and ApoE conditionally inactivated in astrocytes, demonstrated the most pronounced impairments in the hippocampal-dependent Morris water maze test, failing to exhibit spatial memory after both acquisition and reversal training trials. In comparison, conditional knockout mice without injury displayed impairments but only in the reversal phase of the test, suggesting accumulative effects of astrocytic ApoE deficiency and traumatic brain injury on AD-like phenotypes. Together, these findings demonstrate that astrocytic ApoE is required for functional injury-induced neurogenesis following traumatic brain injury.Significance StatementApoE has long been implicated in the development of Alzheimer’s disease and recovery from traumatic brain injury via unknown mechanisms. Using a novel conditional ablation model of mouse ApoE and subsequent tracing of individual hippocampal neurons, we demonstrate its requirement in injury-induced neurogenesis for proper dendritic arborization and cognitive function in hippocampal-dependent learning and memory tasks.

scholarly journals Post Ischemia Intermittent Hypoxia Induces Hippocampal Neurogenesis and Synaptic Alterations and Alleviates Long-Term Memory Impairment

2013 ◽  
Vol 33 (5) ◽  
pp. 764-773 ◽  
Author(s):  
Yi-Wei Tsai ◽  
Yea-Ru Yang ◽  
Synthia H Sun ◽  
Keng-Chen Liang ◽  
Ray-Yau Wang
Keyword(s):  
Learning And Memory ◽  
Hippocampal Neurons ◽  
Memory Impairment ◽  
Intermittent Hypoxia ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis ◽  
Long Term Memory ◽  
Target Cells ◽  
Term Memory

Adult hippocampal neurogenesis is important for learning and memory, especially after a brain injury such as ischemia. Newborn hippocampal neurons contribute to memory performance by establishing functional synapses with target cells. This study demonstrated that the maturation of hippocampal neurons is enhanced by postischemia intermittent hypoxia (IH) intervention. The effects of IH intervention in cultured neurons were mediated by increased synaptogenesis, which was primarily regulated by brain-derived neurotrophic factor (BDNF)/PI3K/AKT. Hippocampal neo-neurons expressed BDNF and exhibited enhanced presynaptic function as indicated by increases in the pSynapsin expression, synaptophysin intensity, and postsynapse density following IH intervention after ischemia. Postischemia IH-induced hippocampal neo-neurons were affected by presynaptic activity, which reflected the dynamic plasticity of the glutamatergic receptors. These alterations were also associated with the alleviation of ischemia-induced long-term memory impairment. Our results suggest that postischemia IH intervention rescued ischemia-induced spatial learning and memory impairment by inducing hippocampal neurogenesis and functional synaptogenesis via BDNF expression.

scholarly journals Gut microbiota requires vagus nerve integrity to promote depression

2019 ◽  
Author(s):  
Eleni Siopi ◽  
Soham Saha ◽  
Carine Moigneu ◽  
Mathilde Bigot ◽  
Pierre-Marie Lledo
Keyword(s):  
Risk Factors ◽  
Gut Microbiota ◽  
Brain Plasticity ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis ◽  
Vagal Afferents ◽  
Microbiota Composition ◽  
Induced Changes ◽  
And Behavior ◽  
Gut Microbiota Composition

Chronic stress constitutes one of the strongest risk factors for depression and can disrupt various aspects of homeostasis, including gut microbiota composition. We found that stress-induced changes in gut microbiota promote depression and decrease adult hippocampal neurogenesis upon transfer to antibiotic-treated recipient mice. Subdiaphragmatic vagotomy abrogated the microbiota-induced effects on behavior and neurogenesis, suggesting that gut microbiota can influence brain plasticity and behavior through vagal afferents.

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