IU Indianapolis ScholarWorks :: Browsing by Subject "Neurogenesis"

Browsing by Subject "Neurogenesis"

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Aberrant Adult Neurogenesis in the Subventricular Zone-Rostral Migratory Stream-Olfactory Bulb System Following Subchronic Manganese Exposure
(Oxford University Press, 2016-04) Fu, Sherleen; Jiang, Wendy; Gao, Xiang; Zeng, Andrew; Cholger, Daniel; Cannon, Jason; Chen, Jinhui; Zheng, Wei; Department of Neurological Surgery, School of Medicine
Adult neurogenesis occurs in brain subventricular zone (SVZ). Our recent data reveal an elevated proliferation of BrdU(+) cells in SVZ following subchronic manganese (Mn) exposure in rats. This study was designed to distinguish Mn effect on the critical stage of adult neurogenesis, ie, proliferation, migration, survival and differentiation from the SVZ via the rostral migratory stream to the olfactory bulb (OB). Adult rats received a single ip-dose of BrdU at the end of 4-week Mn exposure to label proliferating cells. Immunostaining and cell-counting showed a 48% increase of BrdU(+) cells in Mn-exposed SVZ than in controls (P< .05). These BrdU(+) cells were identified as a mixed population of mainly GFAP(+) type-B neural stem cells, Nestin(+) type-C transit progenitor cells, DCX(+) migratory neuroblasts and Iba1(+) microglial cells. Another group of adult rats received 3 daily ip-injections of BrdU followed by subchronic Mn exposure. By 4-week post BrdU labeling, most of the surviving BrdU(+) cells in the OB were differentiated into NeuN(+) matured neurons. However, survival rates of BrdU/NeuN/DAPI triple-labeled cells in OB were 33% and 64% in Mn-exposed and control animals, respectively (P< .01). Infusion of Cu directly into the lateral ventricle significantly decreased the cell proliferation in the SVZ. Taken together, these results suggest that Mn exposure initially enhances the cell proliferation in adult SVZ. In the OB, however, Mn exposure significantly reduces the surviving adult-born cells and markedly inhibits their differentiation into mature neurons, resulting in an overall decreased adult neurogenesis in the OB.
Collapsin Response Mediator Protein 1 (CRMP1) Is Required for High-Frequency Hearing
(Elsevier, 2022) Li, Jinan; Liu, Chang; Zhao, Bo; Otolaryngology -- Head and Neck Surgery, School of Medicine
Collapsin response mediator protein 1 (CRMP1), also known as dihydropyrimidinase-related protein 1, participates in cytoskeleton remodeling during axonal guidance and neuronal migration. In cochlear hair cells, the assembly and maintenance of the cytoskeleton is of great interest because it is crucial for the morphogenesis and maintenance of hair cells. Previous RNA sequencing analysis found that Crmp1 is highly expressed in cochlear hair cells. However, the expression profile and functions of CRMP1 in the inner ear remain unknown. In this study, the expression and localization of CRMP1 in hair cells was investigated using immunostaining, and was shown to be highly expressed in both outer and inner hair cells. Next, the stereocilia morphology of Crmp1-deficient mice was characterized. Abolishing CRMP1 did not affect the morphogenesis of hair cells. Interestingly, scanning electron microscopy detected hair cell loss at the basal cochlear region, an area responsible for high-frequency auditory perception, in Crmp1-deficient mice. Correspondingly, an auditory brainstem response test showed that mice lacking CRMP1 had progressive hearing loss at high frequencies. In summary, these data suggest that CRMP1 is required for high-frequency auditory perception.
DNA Methylation program in normal and alcohol-induced thinning cortex
(Elsevier, 2017-05) Öztürk, Nail Can; Resendiz, Marisol; Öztürk, Hakan; Zhou, Feng C.; Anatomy and Cell Biology, School of Medicine
While cerebral underdevelopment is a hallmark of fetal alcohol spectrum disorders (FASD), the mechanism(s) guiding the broad cortical neurodevelopmental deficits are not clear. DNA methylation is known to regulate early development and tissue specification through gene regulation. Here, we examined DNA methylation in the onset of alcohol-induced cortical thinning in a mouse model of FASD. C57BL/6 (B6) mice were administered a 4% alcohol (v/v) liquid diet from embryonic (E) days 7–16, and their embryos were harvested at E17, along with isocaloric liquid diet and lab chow controls. Cortical neuroanatomy, neural phenotypes, and epigenetic markers of methylation were assessed using immunohistochemistry, Western blot, and methyl-DNA assays. We report that cortical thickness, neuroepithelial proliferation, and neuronal migration and maturity were found to be deterred by alcohol at E17. Simultaneously, DNA methylation, including 5-methylcytosine (5mC) and 5-hydroxcylmethylcytosine (5hmC), which progresses as an intrinsic program guiding normal embryonic cortical development, was severely affected by in utero alcohol exposure. The intricate relationship between cortical thinning and this DNA methylation program disruption is detailed and illustrated. DNA methylation, dynamic across the multiple cortical layers during the late embryonic stage, is highly disrupted by fetal alcohol exposure; this disruption occurs in tandem with characteristic developmental abnormalities, ranging from structural to molecular. Finally, our findings point to a significant question for future exploration: whether epigenetics guides neurodevelopment or whether developmental conditions dictate epigenetic dynamics in the context of alcohol-induced cortical teratogenesis.
Generating Inner Ear Organoids from Mouse Embryonic Stem Cells
(Springer, 2016) Longworth-Mills, Emma; Koehler, Karl R.; Hashino, Eri; Otolaryngology -- Head and Neck Surgery, School of Medicine
This protocol describes a three-dimensional culture method for generating inner ear sensory epithelia, which comprises sensory hair cells and a concurrently arising neuronal population. Mouse embryonic stem cells are initially plated in 96-well plates with differentiation media; following aggregation, Matrigel is added in order to promote epithelialization. A series of small molecule applications is then used over the first 14 days of culture to guide differentiation towards an otic lineage. After 16-20 days, vesicles containing inner ear sensory hair cells and supporting cells arise from the cultured aggregates. Aggregates may be analyzed using immunohistochemistry and electrophysiology techniques. This system serves as a simple and relatively inexpensive in vitro model of inner ear development.
Genome-wide studies reveal the essential and opposite roles of ARID1A in controlling human cardiogenesis and neurogenesis from pluripotent stem cells
(BMC, 2020-07-09) Liu, Juli; Liu, Sheng; Gao, Hongyu; Han, Lei; Chu, Xiaona; Sheng, Yi; Shou, Weinian; Wang, Yue; Liu, Yunlong; Wan, Jun; Yang, Lei; BioHealth Informatics, School of Informatics and Computing
Background Early human heart and brain development simultaneously occur during embryogenesis. Notably, in human newborns, congenital heart defects strongly associate with neurodevelopmental abnormalities, suggesting a common gene or complex underlying both cardiogenesis and neurogenesis. However, due to lack of in vivo studies, the molecular mechanisms that govern both early human heart and brain development remain elusive. Results Here, we report ARID1A, a DNA-binding subunit of the SWI/SNF epigenetic complex, controls both neurogenesis and cardiogenesis from human embryonic stem cells (hESCs) through distinct mechanisms. Knockout-of-ARID1A (ARID1A−/−) leads to spontaneous differentiation of neural cells together with globally enhanced expression of neurogenic genes in undifferentiated hESCs. Additionally, when compared with WT hESCs, cardiac differentiation from ARID1A −/− hESCs is prominently suppressed, whereas neural differentiation is significantly promoted. Whole genome-wide scRNA-seq, ATAC-seq, and ChIP-seq analyses reveal that ARID1A is required to open chromatin accessibility on promoters of essential cardiogenic genes, and temporally associated with key cardiogenic transcriptional factors T and MEF2C during early cardiac development. However, during early neural development, transcription of most essential neurogenic genes is dependent on ARID1A, which can interact with a known neural restrictive silencer factor REST/NRSF. Conclusions We uncover the opposite roles by ARID1A to govern both early cardiac and neural development from pluripotent stem cells. Global chromatin accessibility on cardiogenic genes is dependent on ARID1A, whereas transcriptional activity of neurogenic genes is under control by ARID1A, possibly through ARID1A-REST/NRSF interaction.
Hippocampal and Cortical Primary Cilia Are Required for Aversive Memory in Mice
(Public Library of Science, 2014-09-03) Berbari, Nicolas F.; Malarkey, Erik B.; Yazdi, S.M. Zaki R.; McNair, Andrew D.; Kippe, Jordyn M.; Croyle, Mandy J.; Kraft, Timothy W.; Yoder, Bradley K.; Biology, School of Science
It has been known for decades that neurons throughout the brain possess solitary, immotile, microtubule based appendages called primary cilia. Only recently have studies tried to address the functions of these cilia and our current understanding remains poor. To determine if neuronal cilia have a role in behavior we specifically disrupted ciliogenesis in the cortex and hippocampus of mice through conditional deletion of the Intraflagellar Transport 88 (Ift88) gene. The effects on learning and memory were analyzed using both Morris Water Maze and fear conditioning paradigms. In comparison to wild type controls, cilia mutants displayed deficits in aversive learning and memory and novel object recognition. Furthermore, hippocampal neurons from mutants displayed an altered paired-pulse response, suggesting that loss of IFT88 can alter synaptic properties. A variety of other behavioral tests showed no significant differences between conditional cilia mutants and controls. This type of conditional allele approach could be used to distinguish which behavioral features of ciliopathies arise due to defects in neural development and which result from altered cell physiology. Ultimately, this could lead to an improved understanding of the basis for the cognitive deficits associated with human cilia disorders such as Bardet-Biedl syndrome, and possibly more common ailments including depression and schizophrenia.
HIV Tat Impairs Neurogenesis through Functioning As a Notch Ligand and Activation of Notch Signaling Pathway
(Society for Neuroscience., 2016-11-02) Fan, Yan; Gao, Xiang; Chen, Jinhui; Liu, Ying; He, Johnny J.; Neurological Surgery, School of Medicine
Alterations in adult neurogenesis have been noted in the brain of HIV-infected individuals and are likely linked to HIV-associated neurocognitive deficits, including those in learning and memory. But the underlying molecular mechanisms are not fully understood. In the study, we took advantage of doxycycline-inducible and astrocyte-specific HIV-1 Tat transgenic mice (iTat) and determined the relationship between Tat expression and neurogenesis. Tat expression in astrocytes was associated with fewer neuron progenitor cells (NPCs), fewer immature neurons, and fewer mature neurons in the dentate gyrus of the hippocampus of the mouse brain. In vitro NPC-derived neurosphere assays showed that Tat-containing conditioned media from astrocytes or recombinant Tat protein inhibited NPC proliferation and migration and altered NPC differentiation, while immunodepletion of Tat from Tat-containing conditioned media or heat inactivation of recombinant Tat abrogated those effects. Notch signaling downstream gene Hes1 promoter-driven luciferase reporter gene assay and Western blotting showed that recombinant Tat or Tat-containing conditioned media activated Hes1 transcription and protein expression, which were abrogated by Tat heat inactivation, immunodepletion, and cysteine mutation at position 30. Last, Notch signaling inhibitor N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester (DAPT) significantly rescued Tat-impaired NPC differentiation in vitro and neurogenesis in vivo Together, these results show that Tat adversely affects NPCs and neurogenesis through Notch signaling and point to the potential of developing Notch signaling inhibitors as HIV/neuroAIDS therapeutics. SIGNIFICANCE STATEMENT: HIV infection of the CNS causes cognitive and memory deficits, which have become more prevalent in the era of combination antiretroviral therapy (cART). Neurogenesis is impaired in HIV-infected individuals. But the underlying molecular mechanisms remain largely unknown. In this study, we have discovered that HIV Tat impairs neurogenesis through the Notch signaling pathway. These findings are particularly important because Tat protein has recently been detected in the brain of HIV-infected individuals with HIV replication in the periphery being effectively controlled by cART. The current study not only further highlights the importance of HIV Tat protein in HIV/neuroAIDS, but also presents a new strategy to develop novel HIV/neuroAIDS therapeutics, particularly in the era of cART.
Identification of a postnatal period of interdependent neurogenesis and apoptosis in peripheral neurons
(The Company of Biologists, 2024) Kaminski, Catherine L.; Banik, Debarghya Dutta; Schmitd, Ligia B.; Pierchala, Brian A.; Anatomy, Cell Biology and Physiology, School of Medicine
During neurogenesis, excessive numbers of neurons are produced in most regions of the central and peripheral nervous systems. Nonessential neurons are eliminated by apoptosis, or programmed cell death. This has been most thoroughly characterized in the peripheral nervous system (PNS) where targets of innervation play a key role in this process. As maturing neurons project axons towards their targets of innervation, they become dependent upon these targets for survival. Survival factors, also called neurotrophic factors, are produced by targets, inhibit apoptosis cascades, and promote further growth and differentiation. Because neurotrophic factors are limited, as is target size, neurons that do not correctly and efficiently innervate targets undergo apoptosis ( Levi-Montalcini, 1987; Davies, 1996). Thus, excessive neurogenesis acts to ensure that sufficient numbers of neurons are produced during development. In the superior cervical ganglion (SCG), this process of neurogenesis and subsequent apoptosis is reported to be complete by postnatal day 3-4 (P3-P4) in mice. Surprisingly, we observed significant numbers of apoptotic neurons out to P14, and neurogenesis was still present at P14 as well. In both the SCG and geniculate ganglion (GG), postnatal neurogenesis was dependent on apoptosis because little or no postnatal neurogenesis was observed in Bax-/- mice, in which apoptosis is eliminated. These results indicate that both neurogenesis and apoptosis continue to occur well after birth in peripheral ganglia, and that neurogenesis depends on apoptosis, suggesting that neurogenesis continues postnatally to replace neurons that are eliminated during synaptic refinement.
Maternal antibiotic administration during gestation can affect the memory and brain structure in mouse offspring
(Frontiers Media, 2023-05-10) Shepilov, Dmytro; Osadchenko, Iryna; Kovalenko, Tetiana; Yamada, Chiaki; Chereshynska, Anastasiia; Smozhanyk, Kateryna; Ostrovska, Galyna; Groppa, Stanislav; Movila, Alexandru; Skibo, Galyna; Biomedical Sciences and Comprehensive Care, School of Dentistry
Maternal antibiotics administration (MAA) is among the widely used therapeutic approaches in pregnancy. Although published evidence demonstrates that infants exposed to antibiotics immediately after birth have altered recognition memory responses at one month of age, very little is known about in utero effects of antibiotics on the neuronal function and behavior of children after birth. Therefore, this study aimed to evaluate the impact of MAA at different periods of pregnancy on memory decline and brain structural alterations in young mouse offspring after their first month of life. To study the effects of MAA on 4-week-old offspring, pregnant C57BL/6J mouse dams (2-3-month-old; n = 4/group) were exposed to a cocktail of amoxicillin (205 mg/kg/day) and azithromycin (51 mg/kg/day) in sterile drinking water (daily/1 week) during either the 2nd or 3rd week of pregnancy and stopped after delivery. A control group of pregnant dams was exposed to sterile drinking water alone during all three weeks of pregnancy. Then, the 4-week-old offspring mice were first evaluated for behavioral changes. Using the Morris water maze assay, we revealed that exposure of pregnant mice to antibiotics at the 2nd and 3rd weeks of pregnancy significantly altered spatial reference memory and learning skills in their offspring compared to those delivered from the control group of dams. In contrast, no significant difference in long-term associative memory was detected between offspring groups using the novel object recognition test. Then, we histologically evaluated brain samples from the same offspring individuals using conventional immunofluorescence and electron microscopy assays. To our knowledge, we observed a reduction in the density of the hippocampal CA1 pyramidal neurons and hypomyelination in the corpus callosum in groups of mice in utero exposed to antibiotics at the 2nd and 3rd weeks of gestation. In addition, offspring exposed to antibiotics at the 2nd or 3rd week of gestation demonstrated a decreased astrocyte cell surface area and astrocyte territories or depletion of neurogenesis in the dentate gyrus and hippocampal synaptic loss, respectively. Altogether, this study shows that MAA at different times of pregnancy can pathologically alter cognitive behavior and brain development in offspring at an early age after weaning.
Neural Repair by Enhancing Endogenous Hippocampal Neurogenesis Following Traumatic Brain Injury
(2019-10) Wang, Xiaoting; Xu, Xiao-Ming; Chen, Jinhui; Jones, Kathryn J.; Meyer, Jason; Pollok, Karen E.
Traumatic brain injury (TBI) is a critical public health issue in the United States, affecting about 2.8 million people annually. Extensive cell death and neural degeneration directly and diffusively caused by the initial mechanical insult results in a wide range of neurological complications post-trauma. Learning and memory dysfunction is one of the most common complains. Hippocampal neuronal loss, together with other mechanisms, largely contributes to learning and memory impairment as well as other cognitive dysfunctions post-trauma. To date, no FDA-approved drug is available to target cell death or improve learning and memory following TBI. It is of great interest to develop alternative approaches targeting neural repair instead. Neural stem/progenitor cells (NSCs) in the adult hippocampus undergo life-long neurogenesis supporting learning and memory functions, thus hold great promise for post-traumatic neuronal replacement. The previous studies demonstrated that TBI transiently increase NSC proliferation. However, it is debated on whether TBI affects neurogenesis. The mechanism of TBI-enhanced NSC proliferation remains elusive. In the current studies, I have investigated post-traumatic neurogenesis after different injury severities, evaluated integration of post-injury born neurons, illustrated a molecular mechanism mediating TBI-enhanced NSC proliferation, proposed a de novo state of NSCs, and tested effects of a pharmacological approach on spatial learning and memory function recovery. My results demonstrated that post-traumatic neurogenesis is affected by injury severities, partially explained the pre-existing inconsistency among works from different groups. Post-injury born neurons integrate in neural network and receive local and distal inputs. TBI promotes functional recruitment of post-injury born neurons into neural circuits. Mechanistically, mechanistic target of rapamycin (mTOR) pathway is required primarily for TBI-enhanced NSC proliferation; NSCs feature a de novo alert state, in which NSCs are reversibly released from quiescence and primed for proliferation. Furthermore, my data demonstrated a beneficial role of ketamine in improving post-traumatic spatial learning possibly by activating mTOR signal in NSCs and/or promoting neuronal activity of post-injury born neurons. Together, my data support the feasibility of neurogenesis mediated neuronal replacement, provide a target for enhancing post-traumatic NSC proliferation and subsequent neurogenesis, and prove a potential pharmacological approach benefiting post-traumatic functional recovery in learning and memory.

Browsing by Subject "Neurogenesis"

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