Impaired water-maze performance and altered adult hippocampal neurogenesis in histamine H1-receptor knockout mice

Abstract Deficits in learning and memory are often associated with disruption of hippocampal neurogenesis, which is regulated by numerous processes, including precursor cell proliferation, survival, migration, and differentiation to mature neurons. Recent studies demonstrate that adult born neurons in the dentate gyrus (DG) in the hippocampus can functionally integrate into the existing neuronal circuitry and contribute to hippocampal-dependent learning and memory. Here, we demonstrate that relatively short-term deltamethrin exposure (3 mg/kg every 3 days for 1 month) inhibits adult hippocampal neurogenesis and causes deficits in learning and memory in mice. Hippocampal-dependent cognitive functions were evaluated using 2 independent hippocampal-dependent behavioral tests, the novel object recognition task and Morris water maze. We found that deltamethrin-treated mice exhibited profound deficits in novel object recognition and learning and memory in water maze. Deltamethrin exposure significantly decreased bromodeoxyuridine (BrdU)-positive cells (39%) and Ki67+ cells (47%) in the DG of the hippocampus, indicating decreased cellular proliferation. In addition, deltamethrin-treated mice exhibited a 44% decrease in nestin-expressing neural progenitor cells and a 38% reduction in the expression of doublecortin (DCX), an early neuronal differentiation marker. Furthermore, deltamethrin-exposed mice exhibited a 25% reduction in total number of granule cells in the DG. These findings indicate that relatively short-term exposure to deltamethrin causes significant deficits in hippocampal neurogenesis that is associated with impaired learning and memory.

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Not all water mazes are created equal: cyclin D2 knockout mice with constitutively suppressed adult hippocampal neurogenesis do show specific spatial learning deficits

Genes Brain & Behavior ◽

10.1111/gbb.12130 ◽

2014 ◽

Vol 13 (4) ◽

pp. 357-364 ◽

Cited By ~ 49

Author(s):

A. Garthe ◽

Z. Huang ◽

L. Kaczmarek ◽

R. K. Filipkowski ◽

G. Kempermann

Keyword(s):

Spatial Learning ◽

Knockout Mice ◽

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis ◽

Cyclin D2 ◽

Learning Deficits

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Enriched Environment Ameliorates Adult Hippocampal Neurogenesis Deficits in Tcf4 Haploinsufficient Mice

10.21203/rs.3.rs-44375/v1 ◽

2020 ◽

Author(s):

Katharina Braun ◽

Benjamin M. Häberle ◽

Marie-Theres Wittmann ◽

Dieter Chichung Lie

Keyword(s):

Transcription Factor ◽

Intellectual Disability ◽

Knockout Mice ◽

Negative Impact ◽

Brain Regions ◽

Nervous System Development ◽

Hippocampal Neurogenesis ◽

Enriched Environment ◽

Adult Hippocampal Neurogenesis ◽

Wide Range

Abstract Background: Transcription factor 4 (TCF4) has been linked to human neurodevelopmental disorders such as intellectual disability, Pitt-Hopkins Syndrome (PTHS), autism, and schizophrenia. Recent work demonstrated that TCF4 participates in the control of a wide range of neurodevelopmental processes in mammalian nervous system development including neural precursor proliferation, timing of differentiation, migration, dendritogenesis and synapse formation. TCF4 is highly expressed in the adult hippocampal dentate gyrus – one of the few brain regions where neural stem / progenitor cells generate new functional neurons throughout life.Results: We here investigated whether TCF4 haploinsufficiency, which in humans causes non-syndromic forms of intellectual disability and PTHS, affects adult hippocampal neurogenesis, a process that is essential for hippocampal plasticity in rodents and potentially in humans. Young adult Tcf4 heterozygote knockout mice showed a major reduction in the level of adult hippocampal neurogenesis, which was at least in part caused by lower stem/progenitor cell numbers and impaired maturation and survival of adult-generated neurons. Interestingly, housing in an enriched environment was sufficient to enhance maturation and survival of new neurons and to substantially augment neurogenesis levels in Tcf4 heterozygote knockout mice.Conclusion: Haploinsufficiency for the transcription factor TCF4 has been linked to non-syndromic intellectual disability and PTHS. The present findings raise the possibility that TCF4 haploinsufficiency may have a continuous negative impact on hippocampal function by impeding hippocampal neurogenesis and suggest that behavioural stimulation may be harnessed to ameliorate a subset of TCF4 haploinsufficiency associated neural deficits during adulthood.

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Characterization of adult hippocampal neurogenesis and hippocampal function in p53 knockout mice

IBRO Reports ◽

10.1016/j.ibror.2019.07.1489 ◽

2019 ◽

Vol 6 ◽

pp. S473

Author(s):

Ye Won Lee ◽

Seonghee Jung ◽

Seongwon Choe ◽

Hyeonjeong Jeong ◽

Seong-Woon Yu

Keyword(s):

Knockout Mice ◽

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis ◽

Hippocampal Function

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Mouse genetic differences in voluntary wheel running, adult hippocampal neurogenesis and learning on the multi-strain-adapted plus water maze

Behavioural Brain Research ◽

10.1016/j.bbr.2014.11.030 ◽

2015 ◽

Vol 280 ◽

pp. 62-71 ◽

Cited By ~ 29

Author(s):

Jennifer R. Merritt ◽

Justin S. Rhodes

Keyword(s):

Water Maze ◽

Wheel Running ◽

Genetic Differences ◽

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis ◽

Voluntary Wheel Running ◽

Mouse Genetic ◽

Voluntary Wheel

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Focused ultrasound-induced blood-brain barrier opening improves adult hippocampal neurogenesis and cognitive function in a cholinergic degeneration dementia rat model

Alzheimer s Research & Therapy ◽

10.1186/s13195-019-0569-x ◽

2019 ◽

Vol 11 (1) ◽

Cited By ~ 6

Author(s):

Jaewoo Shin ◽

Chanho Kong ◽

Jihyeon Lee ◽

Bo Young Choi ◽

Jiyeon Sim ◽

...

Keyword(s):

Spatial Memory ◽

Water Maze ◽

Focused Ultrasound ◽

Amyloid Β ◽

Acetylcholinesterase Activity ◽

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis ◽

Cholinergic Degeneration ◽

Barrier Opening ◽

Blood Brain Barrier Opening

Abstract Background The persistence of adult hippocampal neurogenesis (AHN) is sharply decreased in Alzheimer’s disease (AD). The neuropathologies of AD include the presence of amyloid-β deposition in plaques, tau hyperphosphorylation in neurofibrillary tangles, and cholinergic system degeneration. The focused ultrasound (FUS)-mediated blood-brain barrier opening modulates tau hyperphosphorylation, the accumulation of amyloid-β proteins, and increases in AHN. However, it remains unclear whether FUS can modulate AHN in cholinergic-deficient conditions. In this study, we investigated the effect of FUS on AHN in a cholinergic degeneration rat model of dementia. Methods Adult male Sprague-Dawley rats (n = 48; 200–250 g) were divided into control (phosphate-buffered saline injection), 192 IgG-saporin (SAP), and SAP+FUS groups; in the two latter groups, SAP was injected bilaterally into the lateral ventricle. We applied FUS to the bilateral hippocampus with microbubbles. Immunohistochemistry, enzyme-linked immunosorbent assay, immunoblotting, 5-bromo-2′-deoxyuridine labeling, an acetylcholinesterase assay, and the Morris water maze test were performed to assess choline acetyltransferase, acetylcholinesterase activity, brain-derived neurotrophic factor expression, neural proliferation, and spatial memory, respectively. Statistical significance of differences in between groups was calculated using one-way and two-way analyses of variance followed by Tukey’s multiple comparison test to determine the individual and interactive effects of FUS on immunochemistry and behavioral analysis. P < 0.05 was considered significant. Results Cholinergic degeneration in rats significantly decreased the number of choline acetyltransferase neurons (P < 0.05) in the basal forebrain, as well as AHN and spatial memory function. Rats that underwent FUS-mediated brain-blood barrier opening exhibited significant increases in brain-derived neurotrophic factor (BDNF; P < 0.05), early growth response protein 1 (EGR1) (P < 0.01), AHN (P < 0.01), and acetylcholinesterase activity in the frontal cortex (P < 0.05) and hippocampus (P < 0.01) and crossing over (P < 0.01) the platform in the Morris water maze relative to the SAP group after sonication. Conclusions FUS treatment increased AHN and improved spatial memory. This improvement was mediated by increased hippocampal BDNF and EGR1. FUS treatment may also restore AHN and protect against neurodegeneration, providing a potentially powerful therapeutic strategy for AD.

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