Biology subjects

Miller, A. H.

Publications and source records attributed to Miller, A. H..

3 recordsLinked to original sources

bioRxiv2025

Inhibition of Cxcr4 chemokine receptor signaling improves habituation learning and increases cAMP-PKA signaling in a zebrafish model of Neurofibromatosis type 1

Neurofibromatosis type 1 (NF1) is a neurogenetic disorder caused by loss of function mutations in the gene neurofibromin 1 (NF1). NF1 encodes neurofibromin, a multifunctional tumor suppressing protein that regulates Ras, cAMP, and dopamine signaling. NF1 predisposes patients to a wide range of symptoms, including peripheral nerve tumors, brain tumors, and cognitive dysfunction. Despite considerable work using animal models to investigate the role of neurofibromin in behavior, translating research into treatment for NF1-associated cognitive dysfunction has not yet been successful. Here, we identify Cxcr4 chemokine receptor signaling as a regulator of habituation learning and modulator of cAMP-PKA signaling in nf1 mutant larval zebrafish. Combining a small-molecule drug screen and RNAseq analysis, we show that cxcr4b expression is increased in nf1 mutants and that pharmacological inhibition of Cxcr4 with AMD3100 (Plerixafor) improves habituation learning in nf1 mutants. We further demonstrate that Plerixafor treatment activates cAMP-PKA pathway signaling but has limited effects on Ras-Raf-MEK-ERK pathway signaling in the nf1 mutant brain. CXCR4 was previously identified as a potential therapeutic target for neurofibromin-deficient tumorigenesis. Our results provide evidence that Cxcr4 signaling also regulates neurofibromin-dependent cognitive function.

neuroscience↗

bioRxiv2021

cacna2d3, a voltage-gated calcium channel subunit, functions in vertebrate habituation learning and the startle sensitivity threshold

The ability to filter sensory information into relevant versus irrelevant stimuli is a fundamental, conserved property of the central nervous system and is accomplished in part through habituation learning. Synaptic plasticity that underlies habituation learning has been described at the cellular level, yet the genetic regulators of this plasticity remain poorly understood, as do circuits that mediate sensory filtering. A forward genetic screen for zebrafish genes that control habituation learning identified a mutant allele doryp177 that caused reduced habituation of the acoustic startle response. Whole-genome sequencing identified the calcium voltage-gated channel auxiliary subunit alpha-2/delta-3 (cacna2d3) as a candidate gene affected in doryp177 mutants. Behavioral characterization of larvae homozygous for two additional, independently derived mutant alleles of cacna2d3, together with failure of these alleles to complement doryp177, confirmed a critical role for cacna2d3 in habituation learning. Notably, detailed analyses of the acoustic response in mutant larvae also revealed increased startle sensitivity to acoustic stimuli, suggesting a broader role for cacna2d3 in controlling innate response thresholds to acoustic stimuli. Taken together, our data demonstrate a critical role for cacna2d3 in sensory filtering, a process that is disrupted in human CNS disorders, e.g. ADHD, schizophrenia, and autism.

neuroscience↗

bioRxiv2021

Molecular phylogeny of Puerto Rico Bank dwarf geckos (Squamata: Sphaerodactylidae: Sphaerodactylus)

AO_SCPLOWBSTRACTC_SCPLOWThe genus Sphaerodactylus is a very species-rich assemblage of sphaerodactylid lizards that has undergone a level of speciation in parallel to that of the well-known Anolis lizards. Nevertheless, molecular phylogenetic research on this group consists of a handful of smaller studies of regional focus (e.g., western Puerto Rico, the Lesser Antilles) or large-scale analyses based on relatively limited sequence data. Few medium-scale multi-locus studies exist-- for example, studies that encompass an entire radiation on an island group. Building upon previous work done in Puerto Rican Sphaerodactylus, we performed multi-locus sampling of Sphaerodactylus geckos from across the Puerto Rico Bank. We then used these data for phylogeny estimation with near-complete taxon sampling. We focused on sampling the widespread nominal species S. macrolepis and in so doing, we uncovered a highly divergent and morphologically distinct lineage of Sphaerodactylus macrolepis from Puerto Rico, Culebra, and Vieques islands, which we recognize as S. grandisquamis (Stejneger, 1904) on the basis of molecular and morphological characters. S. grandisquamis co-occurs with S. macrolepis only on Culebra Island but is highly genetically differentiated and morphologically distinct. Sphaerodactylus macrolepis is now restricted to the eastern Puerto Rico Bank, from Culebra east through the Virgin Islands and including the topotypic population on St. Croix. We include additional discussion of the evolutionary history and historical biogeography of the Sphaerodactylus of the Puerto Rican Bank in the context of these new discoveries.

evolutionary biology↗