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Open Access Publications from the University of California

Scholarly Works (4 results)

  • Thesis
  • Peer Reviewed
UC Riverside Electronic Theses and Dissertations (2024)

The developmental environment, including the microbiome, can strongly influence offspring phenotypes. Investigating how microbes interact with developing offspring is the first step in understanding how the prenatal microbiome impacts physiological, immunological, and behavioral phenotypes in adults. In eutherian mammals, the current general consensus is that the placenta does not have a stable microbial community, and that the first microbial inoculation of embryos occurs during birth as offspring move through the vaginal tract. The main critique of early studies of the prenatal microbiome was centered around the high likelihood of contamination in the low-biomass samples. My dissertation addresses if and how species identity and embryonic genotype affect the prenatal microbes in two different mouse systems: first, with a hybrid cross between the house mouse (Mus musculus domesticus) and its sympatric congener, the Algerian mouse (Mus spretus), and second within M. m. domesticus, using two wild-derived strains that have maintained population-specific microbiomes after multiple generations of lab-rearing. Finally, in my last chapter, I utilized multiple methods to determine if live microbes are present in the gut of developing embryos. I found that there was no difference between embryonic guts or placental microbial communities based on embryonic genotype after contaminant removal. However, I observed an effect of embryonic genotype on beta diversity in embryonic guts and placenta in chapter two. Surprisingly, I also found an effect of embryonic genotype on the microbial community composition of maternal guts. Additionally, chapter two investigated which maternal source was the most likely contributor to the embryonic gut microbial community, including the oral cavity, blood, gut, and vaginal tract. Similar to previous reports, my data support the idea that microbes pass through the maternal gut to the circulatory system and, ultimately, from maternal blood flow via the placenta to the embryonic gut. In chapter three, I did not find any evidence of live microbes when attempting to quantify short chain fatty acids (SCFAs), the main products of anaerobic microbes in the adult gut. Despite a lack of evidence of SCFAs in the embryonic gut, prenatal exposure to microbial DNA may still affect embryonic development.

    Cover page: Exploring the Prenatal Microbiome in Mus
    • Article
    • Peer Reviewed
    UC Berkeley Previously Published Works (2018)
    α2δ-4 is an auxiliary subunit of voltage-gated Cav1.4 L-type channels that regulate the development and mature exocytotic function of the photoreceptor ribbon synapse. In humans, mutations in the CACNA2D4 gene encoding α2δ-4 cause heterogeneous forms of vision impairment in humans, the underlying pathogenic mechanisms of which remain unclear. To investigate the retinal function of α2δ-4, we used genome editing to generate an α2δ-4 knock-out (α2δ-4 KO) mouse. In male and female α2δ-4 KO mice, rod spherules lack ribbons and other synaptic hallmarks early in development. Although the molecular organization of cone synapses is less affected than rod synapses, horizontal and cone bipolar processes extend abnormally in the outer nuclear layer in α2δ-4 KO retina. In reconstructions of α2δ-4 KO cone pedicles by serial block face scanning electron microscopy, ribbons appear normal, except that less than one-third show the expected triadic organization of processes at ribbon sites. The severity of the synaptic defects in α2δ-4 KO mice correlates with a progressive loss of Cav1.4 channels, first in terminals of rods and later cones. Despite the absence of b-waves in electroretinograms, visually guided behavior is evident in α2δ-4 KO mice and better under photopic than scotopic conditions. We conclude that α2δ-4 plays an essential role in maintaining the structural and functional integrity of rod and cone synapses, the disruption of which may contribute to visual impairment in humans with CACNA2D4 mutations.SIGNIFICANCE STATEMENT In the retina, visual information is first communicated by the synapse formed between photoreceptors and second-order neurons. The mechanisms that regulate the structural integrity of this synapse are poorly understood. Here we demonstrate a role for α2δ-4, a subunit of voltage-gated Ca2+ channels, in organizing the structure and function of photoreceptor synapses. We find that presynaptic Ca2+ channels are progressively lost and that rod and cone synapses are disrupted in mice that lack α2δ-4. Our results suggest that alterations in presynaptic Ca2+ signaling and photoreceptor synapse structure may contribute to vision impairment in humans with mutations in the CACNA2D4 gene encoding α2δ-4.
      Cover page: α2δ-4 Is Required for the Molecular and Structural Organization of Rod and Cone Photoreceptor Synapses.
      • Article
      • Peer Reviewed
      UC Berkeley Previously Published Works (2018)
      α2δ-4 is an auxiliary subunit of voltage-gated Cav1.4 L-type channels that regulate the development and mature exocytotic function of the photoreceptor ribbon synapse. In humans, mutations in the CACNA2D4 gene encoding α2δ-4 cause heterogeneous forms of vision impairment in humans, the underlying pathogenic mechanisms of which remain unclear. To investigate the retinal function of α2δ-4, we used genome editing to generate an α2δ-4 knock-out (α2δ-4 KO) mouse. In male and female α2δ-4 KO mice, rod spherules lack ribbons and other synaptic hallmarks early in development. Although the molecular organization of cone synapses is less affected than rod synapses, horizontal and cone bipolar processes extend abnormally in the outer nuclear layer in α2δ-4 KO retina. In reconstructions of α2δ-4 KO cone pedicles by serial block face scanning electron microscopy, ribbons appear normal, except that less than one-third show the expected triadic organization of processes at ribbon sites. The severity of the synaptic defects in α2δ-4 KO mice correlates with a progressive loss of Cav1.4 channels, first in terminals of rods and later cones. Despite the absence of b-waves in electroretinograms, visually guided behavior is evident in α2δ-4 KO mice and better under photopic than scotopic conditions. We conclude that α2δ-4 plays an essential role in maintaining the structural and functional integrity of rod and cone synapses, the disruption of which may contribute to visual impairment in humans with CACNA2D4 mutations.SIGNIFICANCE STATEMENT In the retina, visual information is first communicated by the synapse formed between photoreceptors and second-order neurons. The mechanisms that regulate the structural integrity of this synapse are poorly understood. Here we demonstrate a role for α2δ-4, a subunit of voltage-gated Ca2+ channels, in organizing the structure and function of photoreceptor synapses. We find that presynaptic Ca2+ channels are progressively lost and that rod and cone synapses are disrupted in mice that lack α2δ-4. Our results suggest that alterations in presynaptic Ca2+ signaling and photoreceptor synapse structure may contribute to vision impairment in humans with mutations in the CACNA2D4 gene encoding α2δ-4.
        • Article
        • Peer Reviewed
        UCLA Previously Published Works (2018)
        Addressing behavioral health impacts of major disasters is a priority of increasing national attention, but there are limited examples of implementation strategies to guide new disaster responses. We provide a case study of an effort being applied in response to the 2016 Great Flood in Baton Rouge. Resilient Baton Rouge was designed to support recovery after major flooding by building local capacity to implement an expanded model of depression collaborative care for adults, coupled with identifying and responding to local priorities and assets for recovery. For a descriptive, initial evaluation, we coupled analysis of documents and process notes with descriptive surveys of participants in initial training and orientation, including preliminary comparisons among licensed and non-licensed participants to identify training priorities. We expanded local behavioral health service delivery capacity through subgrants to four agencies, provision of training tailored to licensed and non-licensed providers and development of advisory councils and partnerships with grassroots and government agencies. We also undertook initial efforts to enhance national collaboration around post-disaster resilience. Our partnered processes and lessons learned may be applicable to other communities that aim to promote resilience, as well as planning for and responding to post-disaster behavioral health needs.
          Cover page: Case Study of Resilient Baton Rouge: Applying Depression Collaborative Care and Community Planning to Disaster Recovery.
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