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.

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

2008 ◽  
Vol 105 (5) ◽  
pp. 1585-1594 ◽  
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.

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.

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.

In vivo and in vitro effects of vortioxetine on molecules associated with neuroplasticity

2016 ◽  
Vol 31 (3) ◽  
pp. 365-376 ◽  
Author(s):  
Pirathiv Kugathasan ◽  
Jessica Waller ◽  
Ligia Westrich ◽  
Aicha Abdourahman ◽  
Joseph A Tamm ◽  
...  
Keyword(s):  
Protein Level ◽  
Hippocampal Neurons ◽  
Transcript Level ◽  
Middle Aged ◽  
Α Subunit ◽  
Aged Mice ◽  
Positive Effects ◽  
Brain Functions

Neuroplasticity is fundamental for brain functions, abnormal changes of which are associated with mood disorders and cognitive impairment. Neuroplasticity can be affected by neuroactive medications and by aging. Vortioxetine, a multimodal antidepressant, has shown positive effects on cognitive functions in both pre-clinical and clinical studies. In rodent studies, vortioxetine increases glutamate neurotransmission, promotes dendritic branching and spine maturation, and elevates hippocampal expression of the activity-regulated cytoskeleton-associated protein (Arc/Arg3.1) at the transcript level. The present study aims to assess the effects of vortioxetine on several neuroplasticity-related molecules in different experimental systems. Chronic (1 month) vortioxetine increased Arc/Arg3.1 protein levels in the cortical synaptosomes of young and middle-aged mice. In young mice, this was accompanied by an increase in actin-depolymerizing factor (ADF)/cofilin serine 3 phosphorylation without altering the total ADF/cofilin protein level, and an increase in the GluA1 subunit of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor phosphorylation at serine 845 (S845) without altering serine 831 (S831) GluA1 phosphorylation nor the total GluA1 protein level. Similar effects were detected in cultured rat hippocampal neurons: Acute vortioxetine increased S845 GluA1 phosphorylation without changing S831 GluA1 phosphorylation or the total GluA1 protein level. These changes were accompanied by an increase in α subunit of Ca2+/calmodulin-dependent kinase (CaMKIIα) phosphorylation (at threonine 286) without changing the total CaMKIIα protein level in cultured neurons. In addition, chronic (1 month) vortioxetine, but not fluoxetine, restored the age-associated reduction in Arc/Arg3.1 and c-Fos transcripts in the frontal cortex of middle-aged mice. Taken together, these results demonstrated that vortioxetine modulates molecular targets that are related to neuroplasticity.

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 Immune responses of meningococcal B outer membrane vesicles in middle-aged mice

2020 ◽  
Vol 78 (5) ◽  
Author(s):  
Gabriela Trzewikoswki de Lima ◽  
Thais Sousa Rodrigues ◽  
Amanda Izeli Portilho ◽  
Victor Araujo Correa ◽  
Emanuelle Baldo Gaspar ◽  
...  
Keyword(s):  
Immune Response ◽  
Outer Membrane ◽  
Membrane Vesicles ◽  
The Elderly ◽  
Outer Membrane Vesicles ◽  
Control Group ◽  
Middle Aged ◽  
Aged Mice ◽  
Robust Immune Response

ABSTRACT The elderly are more likely to die when infected with Neisseria meningitidis. Aging is associated with immune system dysfunctions that impair responses to vaccines and infections. Therefore, immunization of middle-aged individuals could be beneficial. This study aims to evaluate the immunogenicity of N. meningitidis B outer membrane vesicles (OMVs) complexed to two different adjuvants. Middle-aged BALB/c and A/Sn mice were immunized and subsequent immune response was assessed by ELISA, immunoblotting and ELISpot. IgG levels were similar between the animals immunized with OMVs complexed to adjuvants. A total of 235 days after the last immunization only A/Sn mice presented higher IgG levels than those observed in the baseline, especially the group immunized with OMVs and aluminum hydroxide. The predominant IgG subclasses were IgG2a and IgG2b. Immunization with the three-dose regimen generated IgG antibodies that recognized a variety of antigens present in the homologous and heterologous meningococcal OMVs evaluated. There was an increase in the frequency of antigen-specific IFN-γ secreting splenocytes, after in vitro stimulation, in mice immunized with OMVs and adjuvants compared to the control group, almost 1 year after the last immunization. Both adjuvants showed similar performance. Immunization of middle-aged mice has generated a robust immune response and it appears to be advantageous.

scholarly journals LncRNA UCA1 alleviates aberrant hippocampal neurogenesis through regulating miR-375/SFRP1-mediated WNT/β-catenin pathway in kainic acid-induced epilepsy

2021 ◽  
Author(s):  
Limei Diao ◽  
Haichun Yu ◽  
Huaqiong Li ◽  
Yueqiang Hu ◽  
Mingfen Li ◽  
...  
Keyword(s):  
Kainic Acid ◽  
Hippocampal Neurons ◽  
Pearson Correlation ◽  
Hippocampal Neurogenesis ◽  
Neural Progenitors ◽  
Luciferase Assay ◽  
Control Group ◽  
Non Coding Rna

Temporal lobe epilepsy (TLE) is a chronic disease of the nervous system, associated with increased proliferation in the hippocampus. Urothcarcinoma associated 1 (UCA1) is a long long non-coding RNA that was shown to regulate proliferation and differentiation of neural progenitors in vitro. We hypothesised that TLE-associated abnormal proliferation is a consequence of the downregulation of UCA1. This hypothesis was tested in mice with kainic acid (KA)-induced seizures, and then the potential mechanism was explored in vitro and in vivo. Result showed that the expression of UCA1 and Secreted Frizzled Related Protein 1 (SFRP1) were significantly reduced in hippocampal tissues of epileptic mice, while miR-375 was increased compared with the control group. Pearson correlation analysis showed that UCA1 was positively correlated with SFRP1, while miR-375 was negatively correlated with UCA1 and SFRP1. Besides, UCA1 was overexpressed in mice and the overexpression of UCA1 significantly reversed the abnormal proliferation of hippocampal neurons in epilepsy mice. In vitro Luciferase assay showed that UCA1 and Sfrp1 are both the targets of miR-375, and UCA1 promotes the expression of Sfrp1 by competitively adsorbing miR-375, thereby inhibiting the activation of the WNT/β-catenin pathway. The inactivation of the WNT/β-catenin pathway prevented the abnormal proliferation of neural progenitors in the epileptic hippocampus. In conclusion, our findings provide a theoretical basis for the clinical application of UCA1.

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