Overview of Completed Research Projects


Published

May 12, 2022

DOI


Microglia Dysfunction in a Mouse Model of Neurodevelopmental Disorders

Many genetic and environmental associations are risk factors for neuropsychiatric disorders. I use mouse models to investigate the basic neurobiology of some of these risk factors in disease pathophysiology. I evaluated an environmental risk factor (developmental inflammation) in disease pathophysiology using the maternal immune activation (MIA) mouse model . After prenatal inflammation, I found a baseline increase in stress hormones in the periphery and altered protein oxidative stress in the brain consistent with observations from clinical studies . Furthermore, I found a blunted microglia reactivity, particularly in the striatum, after MIA, along with electrophysiological abnormalities in striatal circuits . The MIA microglia showed epigenetic changes and impaired transcriptional regulation in response to prenatal immune stress as a mechanism for the blunted reactivity . Finally, I determined the dysfunctional microglia were causal to the proper development of the striatal circuits . In summary, I determined that prenatal immune stress acts as a tolerizing stimulus on microglia leading to a long-term functional impairment and contribution to development of impaired neural circuits in the basal ganglia.

Data Analysis for Hayes et al.2022

single cell RNA-seq of mouse microglia from the striatum after LPS treatment

Clinical Inflammation & Oxidative Stress

The role of inflammation and oxidative stress in psychiatric disorders remains controversial. Previous data is confounded by extended exposure to medication, duration of illness, and lack of a clear cellular mechanism. In several translational psychiatry studies, we obtained cerebrospinal fluid and peripheral blood from drug-naïve, recent-onset, and chronic psychosis patients. We found increased inflammatory markers and altered oxidative stress pathways in schizophrenia and psychosis patients at the early stages of disease without the influence of extended medication. We observed increased levels of antibodies for infectious agents in psychosis patients, and many of the inflammatory markers were correlated with the inflammatory markers . Furthermore, cognitive function was found to correlate with one of the infectious agents . These data suggest that exposure to infectious agents may contribute to altered immune function in patients with psychotic disorders and impair cognitive function. Together these translational psychiatry studies provide further evidence for a neuroimmunological mechanism in the pathology of psychiatric disorders.

Analytes measured in CSF from SZ and ARMS participants

Developmental Biology Projects

Through a number of projects we determined how diversification of cellular identity is specified from a defined progenitor domain through close temporal and spatial control of progenitor cells. Deciphering cell fate specification is important for cell-based therapeutics targeting cell replacement and discovering how cells become susceptible in disease. Using combinatorial genetic fate mapping approaches, these studies defined how progenitors become specified before differentiation based on the spatial and temporal expression of key developmental genes (Shh, Gli1, Nkx2.1, and Wnt1). Furthermore, we were the first to demonstrate that cessation of Shh signaling after the critical period is important for midbrain patterning. In sum, we found that spatial location within the progenitor domain, timing of gene expression, and duration of downstream signaling are all critical for proper differentiation and subtype specification. These findings can provide a guide map for generation of specific cell types in vitro for cell replacement in neurodegenerative diseases.

Hayes et al. 2011 Fate Mapping of Shh and Gli1 progenitors in the mouse ventral mesencephalon

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Footnotes

    References

    Brown, Ashly, Jason T Machan, Lindsay Hayes, and Mark Zervas. 2011. “Molecular Organization and Timing of Wnt1 Expression Define Cohorts of Midbrain Dopamine Neuron Progenitors in Vivo.” J. Comp. Neurol. 519 (15): 2978–3000.
    Carloni, Elisa, Adriana Ramos, and LN Hayes. 2021. “Developmental Stressors Induce Innate Immune Memory in Microglia and Contribute to Disease Risk.” Int. J. Mol. Sci. 22 (23): 13035.
    Carney, Rosalind S E, Jean-Marie Mangin, Lindsay Hayes, Kevin Mansfield, Vitor H Sousa, Gord Fishell, Robert P Machold, Sohyun Ahn, Vittorio Gallo, and Joshua G Corbin. 2010. “Sonic Hedgehog Expressing and Responding Cells Generate Neuronal Diversity in the Medial Amygdala.” Neural Dev. 5 (1): 14.
    Coughlin, Lindsay N. Hayes, Teppei Tanaka, Meifang Xiao, Robert H Yolken, Paul Worley, F Markus Leweke, and Akira Sawa. 2017. “Reduced Superoxide Dismutase-1 (SOD1) in Cerebrospinal Fluid of Patients with Early Psychosis in Association with Clinical Features.” Schizophr. Res. 183 (May): 64–69.
    Coughlin, Y Wang, E B Ambinder, R E Ward, I Minn, M Vranesic, P K Kim, et al. 2016. “In Vivo Markers of Inflammatory Response in Recent-Onset Schizophrenia: A Combined Study Using [(11)C]DPA-713 PET and Analysis of CSF and Plasma.” Transl. Psychiatry 6 (4): e777.
    Fukudome, Daisuke, LN Hayes, Travis E Faust, Catherine A Foss, Mari A Kondo, Brian J Lee, Atsushi Saito, et al. 2018. “Translocator Protein (TSPO) and Stress Cascades in Mouse Models of Psychosis with Inflammatory Disturbances.” Schizophr. Res. 197 (July): 492–97.
    Hayes, Kyongman An, Elisa Carloni, Fangze Li, Elizabeth Vincent, Manish Paranjpe, Gül Dölen, et al. 2021. “Prenatal Immune Stress Induces a Prolonged Blunting of Microglia Activation That Impacts Striatal Connectivity.” bioRxiv.
    Hayes, Sherry Ralls, Hui Wang, and Sohyun Ahn. 2013. “Duration of Shh Signaling Contributes to mDA Neuron Diversity.” Dev. Biol. 374 (1): 115–26.
    Hayes, Emily G Severance, Jeffrey T Leek, Kristin L Gressitt, Cathrin Rohleder, Jennifer M Coughlin, F Markus Leweke, Robert H Yolken, and Akira Sawa. 2014. “Inflammatory Molecular Signature Associated with Infectious Agents in Psychosis.” Schizophr. Bull. 40 (5): 963–72.
    Hayes, Alexey Shevelkin, Mariela Zeledon, Gary Steel, Pei-Lung Chen, Cassandra Obie, Ann Pulver, et al. 2016. “Neuregulin 3 Knockout Mice Exhibit Behaviors Consistent with Psychotic Disorders.” Mol. Neuropsychiatry 2 (2): 79–87.
    Hayes, Zhiwei Zhang, Paul Albert, Mark Zervas, and Sohyun Ahn. 2011. “Timing of Sonic Hedgehog and Gli1 Expression Segregates Midbrain Dopamine Neurons.” J. Comp. Neurol. 519 (15): 3001–18.
    Mueller, Flavia S, Juliet Richetto, LN Hayes, Alice Zambon, Daniela D Pollak, Akira Sawa, Urs Meyer, and Ulrike Weber-Stadlbauer. 2019. “Influence of poly(I:C) Variability on Thermoregulation, Immune Responses and Pregnancy Outcomes in Mouse Models of Maternal Immune Activation.” Brain Behav. Immun. 80 (August): 406–18.
    Nucifora, L G, T Tanaka, L N Hayes, M Kim, B J Lee, T Matsuda, F C Nucifora Jr, et al. 2017. “Reduction of Plasma Glutathione in Psychosis Associated with Schizophrenia and Bipolar Disorder in Translational Psychiatry.” Transl. Psychiatry 7 (8): e1215–15.
    Tanaka, Teppei, Taro Matsuda, LN Hayes, Shuojia Yang, Katrina Rodriguez, Emily G Severance, Robert H Yolken, Akira Sawa, and William W Eaton. 2017. “Infection and Inflammation in Schizophrenia and Bipolar Disorder.” Neurosci. Res. 115 (February): 59–63.