Biology subjects

Miller, D. R.

Publications and source records attributed to Miller, D. R..

25 records · Page 2Linked to original sources

bioRxiv2019

Mechanism of manganese dysregulation of dopamine neuronal activity

Manganese exposure produces Parkinsons-like neurological symptoms, suggesting a selective dysregulation of dopamine transmission. It is unknown, however, how manganese accumulates in dopaminergic brain regions or how it regulates the activity of dopamine neurons. Our in vivo studies suggest manganese accumulates in dopamine neurons of the ventral tegmental area and substantia nigra via nifedipine-sensitive Ca2+ channels. Manganese produces a Ca2+ channel-mediated current which increases neurotransmitter release and rhythmic firing activity of dopamine neurons. These increases are prevented by blockade of Ca2+ channels and depend on downstream recruitment of Ca2+-activated potassium channels to the plasma membrane. These findings demonstrate the mechanism of manganese-induced dysfunction of dopamine neurons, and reveal a potential therapeutic target to attenuate manganese-induced impairment of dopamine transmission.\n\nSignificance StatementManganese is a trace element critical to many physiological processes. Overexposure to manganese is an environmental risk factor for neurological disorders such as a Parkinsons disease-like syndrome known as manganism. We found manganese dose-dependently increased the excitability of dopamine neurons, decreased the amplitude of action potentials, and narrowed action potential width. Blockade of Ca2+ channels prevented these effects as well as manganese accumulation in the mouse midbrain in vivo. Our data provide a potential mechanism for manganese-regulation of dopaminergic neurons.

cell biology↗

bioRxiv2019

Antipsychotic behavioral phenotypes in the mouse Collaborative Cross recombinant inbred inter-crosses (RIX)

Schizophrenia is an idiopathic disorder that affects approximately 1% of the human population, and presents with persistent delusions, hallucinations, and disorganized behaviors. Antipsychotics are the standard pharmacological treatment for schizophrenia, but are frequently discontinued by patients due to inefficacy and/or side effects. Chronic treatment with the typical antipsychotic haloperidol causes tardive dyskinesia (TD), which manifests as involuntary and often irreversible orofacial movements in around 30% of patients. Mice treated with haloperidol develop many of the features of TD, including jaw tremors, tongue protrusions, and vacuous chewing movements (VCMs). In this study, we used genetically diverse Collaborative Cross (CC) recombinant inbred inter-cross (RIX) mice to elucidate the genetic basis of antipsychotic-induced adverse drug reactions (ADRs). We performed a battery of behavioral tests in 840 mice from 73 RIX lines (derived from 62 CC strains) treated with haloperidol or placebo in order to monitor the development of ADRs. We used linear mixed models to test for strain and treatment effects. We observed highly significant strain effects for almost all behavioral measurements investigated (p<0.001). Further, we observed strong strain-by-treatment interactions for most phenotypes, particularly for changes in distance traveled, vertical activity, and extrapyramidal symptoms (EPS). Estimates of overall heritability ranged from 0.21 (change in body weight) to 0.4 (VCMs and change in distance traveled) while the portion attributable to the interactions of treatment and strain ranged from 0.01 (for change in body weight) to 0.15 (for change in EPS). Interestingly, close to 30% of RIX mice exhibited VCMs, a sensitivity to haloperidol exposure, approximately similar to the rate of TD in humans chronically exposed to haloperidol. Understanding the genetic basis for the susceptibility to antipsychotic ADRs may be possible in mouse, and extrapolation to humans could lead to safer therapeutic approaches for schizophrenia.

systems biology↗

bioRxiv2019

Collaborative Cross Mouse Populations as a Resource for the Study of Epilepsy

Epilepsy is a neurological disorder with complex etiologies and genetic architecture. Animal models have a critical role in understanding the pathophysiology of epilepsy. Here we studied epilepsy utilizing a genetic reference population of Collaborative Cross (CC) mice with publicly available whole genome sequences. We measured multiple epilepsy traits in 35 CC strains, and we identified novel animal models that exhibit extreme outcomes in seizure susceptibility, seizure propagation, epileptogenesis, and sudden unexpected death in epilepsy. We performed QTL mapping in an F2 population and identified seven novel and one previously identified loci associated with seizure sensitivity. We combined whole genome sequence and hippocampal gene expression to pinpoint biologically plausible candidate genes and candidate variants associated with seizure sensitivity. These resources provide a powerful toolbox for studying complex features of seizures and for identifying genes associated with particular seizure outcomes, and hence will facilitate the development of new therapeutic targets for epilepsy.

neuroscience↗

bioRxiv2018

A diallel of the mouse Collaborative Cross founders reveals strong strain-specific maternal effects on litter size

Reproductive success in the eight founder strains of the Collaborative Cross (CC) was measured using a diallel-mating scheme. Over a 48-month period we generated 4,448 litters, and 24,782 weaned pups were used across 16 different published experiments. We identified factors that affect the average litter size in a cross by estimating the overall contribution of parent-of-origin, heterosis, inbred, and epistatic effects using a Bayesian zero-truncated overdispersed Poisson mixed model. The phenotypic variance of litter size has a substantial contribution (79%) from unexplained and environmental sources, but no detectable effect of seasonality. Most of the explained variance was due to additive effects (9.2%) and parental sex (maternal vs paternal strain; 5.8%), with epistasis accounting for 3.4%. Within the parental effects, the effect of the dams strain explained more than the sires strain (13.2% vs. 1.8%), and the dams strain effects account for 74.2% of total variation explained. Dams from strains C57BL/6J and NOD/ShiLtJ increased the expected litter size by a mean of 1.66 and 1.79 pups, whereas dams from strains WSB/EiJ, PWK/PhJ, and CAST/EiJ reduced expected litter size by a mean of 1.51, 0.81, and 0.90 pups. Finally, there was no strong evidence for strain-specific effects on sex ratio distortion. Overall, these results demonstrate that strains vary substantially in their reproductive ability depending on their genetic background and that litter size is largely determined by dam.strain rather than sire.strain effects, as expected. This analysis adds to our understanding of factors that influence litter size in mammals, and also helps to explain breeding successes and failures in the extinct lines and surviving CC strains.

genetics↗

bioRxiv2018

Reciprocal F1 hybrids of two inbred mouse strains reveal parent-of-origin and perinatal diet effects on behavior and expression

Parent-of-origin effects (POEs) in mammals typically arise from maternal effects or from imprinting. Mutations in imprinted genes have been associated with psychiatric disorders, as well as with changes in a handful of animal behaviors. Nonetheless, POEs on complex traits such as behavior remain largely uncharacterized. Furthermore, although perinatal environmental exposures, such as nutrient deficiency, are known to modify both behavior and epigenetic effects generally, the architecture of environment-by-POE is almost completely unexplored. To study POE and environment-by-POE, we employ a relatively neglected but maximally powerful POE-detection system: a reciprocal F1 hybrid population. We exposed female NOD/ShiLtJxC57Bl/6J and C57Bl/6JxNOD/ShiLtJ mice, in utero, to one of four different diets, then after weaning recorded their whole-brain gene expression, as well as a set of behaviors that model psychiatric disease. Microarray expression data revealed an imprinting-enriched set of over a dozen genes subject to POE; the POE on the most significantly affected gene, Carmil1 (a.k.a. Lrrc16a), was validated using qPCR in the same and in a new set of mice. Several behaviors, especially locomotor behaviors, also showed POE. Interestingly, Bayesian mediation analysis suggests Carmil1 expression suppresses behavioral POE, and Airn suppresses POE on Carmil1 expression. A significant diet-by-POE was observed on one behavior, one imprinted gene, and over a dozen non-imprinted genes. Beyond our particular results, our study demonstrates a reciprocal F1 hybrid framework for studying POE and environment-by-POE on behavior.

genetics↗

bioRxiv2017

In vivo multiphoton fluorescence imaging with polymer dots

Deep in vivo imaging of vasculature requires small, bright, and photostable fluorophores suitable for multiphoton microscopy (MPM). Although semiconducting polymer dots (pdots) are an emerging class of highly fluorescent contrast agents with favorable advantages for the next generation of in vivo imaging, their use for deep multiphoton imaging has never before been demonstrated. Here we characterize the multiphoton properties of three pdot variants (CNPPV, PFBT, and PFPV) and demonstrate deep imaging of cortical microvasculature in C57 mice. Specifically, we measure the two-versus three-photon power dependence of these pdots and observe a clear three-photon excitation signature at wavelengths longer than 1300 nm, and a transition from two-photon to three-photon excitation within a 1060 - 1300 nm excitation range. Furthermore, we show that pdots enable in vivo two-photon imaging of cerebrovascular architecture in mice up to 850 m beneath the pial surface using 800 nm excitation. In contrast with traditional multiphoton probes, we also demonstrate that the broad multiphoton absorption spectrum of pdots permits imaging at longer wavelengths ({lambda}ex = 1,060 and 1225 nm). These wavelengths approach an ideal biological imaging wavelength near 1,300 nm and confer compatibility with a high-power ytterbium-fiber laser and a high pulse energy optical parametric amplifier, resulting in substantial improvements in signal-to-background ratio (>3.5-fold) and greater cortical imaging depths of 900 m and 1300 m. Ultimately, pdots are a versatile tool for MPM due to their extraordinary brightness and broad absorption, which will undoubtedly unlock the ability to interrogate deep structures in vivo.

bioengineering↗

bioRxiv2017

Diallel analysis reveals Mx1-dependent and Mx1-independent effects on response to influenza A virus in mice

1.Influenza A virus (IAV) is a respiratory pathogen that causes substantial morbidity and mortality during both seasonal and pandemic outbreaks. Infection outcomes in unexposed populations are affected by host genetics, but this host genetic architecture is not well understood. Here we obtain a broad view of how heritable factors affect a mouse model of response to IAV infection using an 8x8 diallel of the eight inbred founder strains of the Collaborative Cross (CC). Expanding on a prior statistical framework for modeling treatment response in diallels, we explore how a range of heritable effects modify acute host response to IAV through 4 days post-infection. Heritable effects in aggregate explained about 57% of the variance in IAV-induced weight loss. Much of this was attributable to a pattern of additive effects that became more prominent through day 4 post-infection and was consistent with previous reports of anti-influenza myxovirus resistance 1 (Mx1) polymorphisms segregating between these strains; the additive effects largely recapitulated haplotype effects observed at the Mx1 locus in a previous study of the incipient CC (pre-CC), and are also replicated here in a CC recombinant intercross (CC-RIX) population. Genetic dominance of protective Mx1 haplotypes was observed to differ by subspecies origin: relative to the domesticus null Mx1 allele, musculus acts dominantly whereas castaneus acts additively. After controlling for Mx1, heritable effects, though less distinct, accounted for about 34% of the phenotypic variance. Implications for future mapping studies are discussed.

genetics↗