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Scholarly Works (5 results)

  • Thesis
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UC Davis Electronic Theses and Dissertations (2021)

Adequate zinc intake during prenatal and postnatal period is important for brain development. During development, severe zinc deficiency can cause teratogenic effects including neuronal tube defects and multiple organ malformations. Marginal zinc deficiency during pregnancy and in the early postnatal period can have irreversible adverse effects on offspring neurodevelopment which can persist into adulthood. This can result in behavioral abnormalities including cognitive function, mood disorders, and motor dysfunctions. This thesis focused on investigating the effects of a decreased availability of zinc, primarily due to low zinc intake or secondarily to di-2-ethylhexyl phthalate (DEHP)-induced alterations in zinc homeostasis, during early development in rats on the genesis of the neuronal and/or oligodendroglial lineages. Cell signaling pathways that are involved in these processes were investigated. The impact of maternal marginal zinc deficiency on neurogenesis was evaluated in chapter one of the thesis. The progression of neurogenesis was evaluated at different developmental stages: embryonic day (E) 14, E19, postnatal day (P) 2, and P56. Results showed that the expression of protein markers neural stem cells (NSCs) (SOX2, PAX6), neuronal differentiation (TBR1, TBR2), mature neurons (NeuN), neuronal subtype glutamatergic neuron (VGLUT1) were significantly decreased due to maternal marginal zinc intake, whereas GABAergic neurons (GAD65) were not affected. This was associated with the downregulation of ERK1/2 signaling pathway, which participates in the regulation of NSCs self-renewal, proliferation, and differentiation. In chapter two we investigated the effects of maternal exposure to the environmental toxicant DEHP on neurogenesis. DEHP altered zinc homeostasis, decreasing zinc availability to the fetus in the developing E19 brain. Results indicated that DEHP had similar adverse effects on neurogenesis as the nutritional marginal zinc deficiency, causing decreased NSCs proliferation and differentiation into neurons and particularly affecting the glutamatergic neuron subtype but not markers of GABAergic neurons. In vivo and vitro mechanistic studies showed that the ERK1/2 signaling pathway was inhibited (decreased phosphorylation) in part through the activation of protein phosphatase 2A. Finally, chapter three investigated the effects of maternal marginal zinc deficiency on oligodendrogenesis and myelination and the consequences on behaviors in the offspring rat. The progression of oligodendrogenesis was evaluated at different developmental stages: P2, P5, P10, P20 and P60. Results showed that the expression of markers for oligodendrocytes progenitor cells (OPCs) (NG2, PDGFRα), OPCs differentiation (CNPase), mature oligodendrocytes (MBP, MAG, MOG, PLP) and transcription factors (Olig2, SOX10) were significantly decreased in the marginal zinc deficient offspring rat brain at certain stages of oligodendroglial development. Behavioral assessment results showed that early stages maternal marginal zinc nutrition had long-term impact on neuromuscular functions, locomotor activity and anxiety in the offspring rat. In summary, results from this thesis stress the need of an adequate zinc availability during early development to prevent alterations in neurogenesis and oligodendrogenesis and the long-lasting consequences on brain structure and function.

    Cover page: Effects of Developmental Zinc Deficiency on Neurogenesis and Oligodendrogenesis in the Offspring Rat Brain
    • Article
    • Peer Reviewed
    UC Davis Previously Published Works (2023)

    Background

    Oligodendrocytes are responsible for myelin production in the central nervous system (CNS). Hypomyelination may slow saltatory nerve signal conduction and affect motor performance and behavior in adults. Gestational marginal zinc deficiency in rats significantly decreases proliferation of neural stem cells (NSCs) in the offspring brain.

    Objectives

    Given that NSCs are precursors of oligodendrocytes, this study investigated if marginal zinc deficiency during early development in rats affects oligodendrogenesis in the offspring's CNS.

    Methods

    Rat dams were fed an adequate (25 μg zinc/g diet) (C) or a marginal zinc diet (MZD) (10 μg zinc/g diet), from gestation day zero until postnatal day (P) 20, and subsequently all offspring was fed the control diet until P60. Oligodendrogenesis was evaluated in the offspring at P2, P5, P10, P20, and P60, by measuring parameters of oligodendrocyte progenitor cells (OPCs) proliferation, differentiation, maturation, and of myelination.

    Results

    The expression of 1) proteins that regulate OPC proliferation (Shh, Sox10, Olig2); 2) OPC markers (NG2, PDGFRα); 3) myelin proteins (MBP, MAG, MOG, PLP) were lower in the brain cortex from MZD than C offspring at various stages in development. The amount of myelin after zinc replenishment continued to be low in the MZD young adult at P60. Accordingly, parameters of motor performance and behavior [grip strength, rotarod, elevated T-maze (ETM), and open-field tests] were impaired in the MZD offspring at P60.

    Conclusions

    Results support the concept that maternal and early postnatal exposure to MZD affects oligodendrogenesis causing long-lasting effects on myelination and on motor performance in the young adult offspring.
      Cover page: Marginal Zinc Deficiency during Gestation and Lactation in Rats Affects Oligodendrogenesis, Motor Performance, and Behavior in the OffspringCreative Commons 'BY-NC-ND' version 4.0 license
      • Article
      • Peer Reviewed
      UC Davis Previously Published Works (2019)
      During pregnancy, a decreased availability of zinc to the fetus can disrupt the development of the central nervous system leading to defects ranging from severe malformations to subtle neurological and cognitive effects. We previously found that marginal zinc deficiency down-regulates the extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway and affects neural progenitor cell (NPC) proliferation. This study investigated if marginal zinc deficiency during gestation in rats could disrupt fetal neurogenesis and affect the number and specification of neurons in the adult offspring brain cortex. Rats were fed a marginal zinc deficient or adequate diet throughout gestation and until postnatal day (P) 2, and subsequently the zinc adequate diet until P56. Neurogenesis was evaluated in the offspring at embryonic day (E)14, E19, P2, and P56 measuring parameters of NPC proliferation and differentiation by Western blot and/or immunofluorescence. At E14 and E19, major signals (i.e., ERK1/2, Sox2, and Pax6) that stimulate NPC proliferation and self-renewal were markedly downregulated in the marginal zinc deficient fetal brain. These alterations were associated to a lower number of Ki67 positive cells in the ventricular (VZs) and subventricular zones (SVZs). Following the progression of NPCs into intermediate progenitor cells (IPCs) and into neurons, Pax6, Tbr2 and Tbr1 were affected in the corresponding areas of the brain at E19 and P2. The above signaling alterations led to a lower density of neurons and a selective decrease of glutamatergic neurons in the young adult brain cortex exposed to maternal marginal zinc deficiency from E14 to P2. Current results supports the concept that marginal zinc deficiency during fetal development can disrupt neurogenesis and alter cortical structure potentially leading to irreversible neurobehavioral impairments later in life.
        Cover page: Early Developmental Marginal Zinc Deficiency Affects Neurogenesis Decreasing Neuronal Number and Altering Neuronal Specification in the Adult Rat Brain
        • Article
        • Peer Reviewed
        UC Davis Previously Published Works (2024)
        Acute intoxication with organophosphorus (OP) cholinesterase inhibitors can produce seizures that rapidly progress to life-threatening status epilepticus. Significant research effort has been focused on investigating the involvement of muscarinic acetylcholine receptors (mAChRs) in OP-induced seizure activity. In contrast, there has been far less attention on nicotinic AChRs (nAChRs) in this context. Here, we address this data gap using a combination of in vitro and in vivo models. Pharmacological antagonism and genetic deletion of α4, but not α7, nAChR subunits prevented or significantly attenuated OP-induced electrical spike activity in acute hippocampal slices and seizure activity in mice, indicating that α4 nAChR activation is necessary for neuronal hyperexcitability triggered by acute OP exposures. These findings not only suggest that therapeutic strategies for inhibiting the α4 nAChR subunit warrant further investigation as prophylactic and immediate treatments for acute OP-induced seizures, but also provide mechanistic insight into the role of the nicotinic cholinergic system in seizure generation.
          Creative Commons 'BY' version 4.0 license
          • Article
          UC Davis Previously Published Works (2024)
          Abstract: Acute intoxication with organophosphorus (OP) cholinesterase inhibitors can produce seizures that rapidly progress to life-threateningstatus epilepticus. Significant research effort has been invested investigating the involvement of muscarinic acetylcholine receptors (mAChRs) in OP-induced seizure activity. In contrast, there has been far less effort focused on nicotinic AChRs (nAChRs) in this context. Here, we address this data gap using a combination ofin vitroandin vivomodels. Pharmacological antagonism and genetic deletion of α4, but not α7, nAChR subunits prevented or significantly attenuated OP-induced electrical spike activity in acute hippocampal slices and seizure activity in mice, indicating that α4 nAChR activation is necessary for neuronal hyperexcitability triggered by acute OP exposures. These findings not only suggest that therapeutic strategies for inhibiting the α4 nAChR subunit warrant further investigation as prophylactic and acute treatments for acute OP-induced seizures, but also provide mechanistic insight into the role of the nicotinic cholinergic system in seizure generation.
            Cover page: The α4 nicotinic acetylcholine receptor is necessary for the initiation of organophosphate-induced neuronal hyperexcitabilityCreative Commons 'BY-ND' version 4.0 license
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