Biology subjects

Doll, C. A.

Publications and source records attributed to Doll, C. A..

5 recordsLinked to original sources

bioRxiv2023

Synchronicity in zebrafish locomotive circuit development mediated by electrical pacemaker interneurons

The earliest motor output in vertebrate animals is generated by clusters of early-born motor neurons that occupy distinct regions of the spinal cord, innervating stereotyped muscle groups. Even the simplest movements require coordinated activity across these motor pools, yet motor neurons are not directly interconnected and instead project to the periphery. Instead, emerging motor circuits might be synchronized by pacemaker interneurons. We hypothesize that pacemaker interneurons are required for synchronization of motor neuron activity throughout the spinal cord, coupling motor pools through electrical gap junctions to ultimately drive coordinated motor behavior. With functional imaging in the embryonic zebrafish spinal cord, we show that ipsilateral caudal interneurons possess periodic activity profiles prior to widespread motor circuit activity that transition to synchronized Ca2+ events in motor neurons throughout the spinal cord. Importantly, we also show that blockade of electrical gap junctions and ablation of pioneer pacemakers leads to desynchronization in developing motor circuits. Further, we use a genetic model of hyperactivity to gain critical insight into the consequences of errors in motor circuit formation and function, finding that Fragile X syndrome (FXS) model mutant zebrafish are hyperexcitable from the earliest phases of spontaneous behavior, show reduced sensitivity to blockade of electrical gap junctions, and have increased expression of the gap junction protein Connexin 36. Taken together, our work highlights the importance of pacemakers in the development of motor circuits and suggests that the origins of hyperactivity in neurodevelopmental disorders may be established during the initiation of motor circuit formation.

neuroscience↗

bioRxiv2022

Fmrp regulates neuronal balance in embryonic motor circuit formation

Motor behavior requires the balanced production and integration of a variety of neural cell types. Motor neurons are positioned in discrete locations in the ventral spinal cord, targeting specific muscles to drive locomotive contractions. Specialized spinal interneurons modulate and synchronize motor neuron activity to achieve coordinated motor output. Changes in the ratios of spinal interneurons could drastically alter motor output by tipping the balance of inhibition and excitation onto target motor neurons. Importantly, individuals with Fragile X syndrome (FXS) and associated autism spectrum disorders often have significant motor challenges, including repetitive behaviors and epilepsy. FXS stems from the transcriptional silencing of the gene Fragile X Messenger Ribonucleoprotein 1 (FMR1), which encodes an RNA binding protein that is implicated in a multitude of crucial neurodevelopmental processes, including cell specification. We find that zebrafish fmr1 mutants generate surplus ventral lateral descending (VeLD) interneurons, an early-born cell derived from the pMN domain. These GABAergic interneurons are also associated with changes in synaptogenesis, as fmr1 mutants show increased early expression of the scaffold Gephyrin, but these postsynaptic sites fail to mature. Our work shows that Fmrp regulates the proportionate production of neurons that comprise early embryonic motor circuits. As VeLD interneurons are hypothesized to act as central pattern generators driving the earliest spontaneous movements, this imbalance could profoundly influence the formation and long-term function of motor circuits driving locomotion.

neuroscience↗

bioRxiv2021

Fmrp regulates oligodendrocyte lineage cell specification and differentiation

Neurodevelopment requires the precise integration of a wide variety of neuronal and glial cell types. During early embryonic development, motor neurons and then oligodendrocyte precursor cells (OPCs) are specified from neural progenitors residing in the periventricular pMN progenitor domain of the spinal cord. Following gliogenesis, OPCs can differentiate as oligodendrocytes (OLs) - the myelinating glial cells of the central nervous system - or remain as OPCs. To generate unique cell types capable of highly divergent functions, these specification and differentiation events require specialized gene expression programs. RNA binding proteins (RBPs) regulate mRNA localization and translation in the developing nervous system and are linked to many neurodevelopmental disorders. One example is Fragile X syndrome (FXS), caused by the loss of the RBP fragile X mental retardation protein (FMRP). Importantly, infants with FXS have reduced white matter and we previously showed that zebrafish Fmrp is autonomously required in OLs to promote myelin sheath growth. We now find that Fmrp regulates cell specification in pMN progenitor cells and subsequently promotes differentiation of OPCs, such that fmr1 mutant zebrafish embryos generate excess OPCs and fewer differentiating OLs in the developing spinal cord. Although the early patterning of spinal progenitor domains appears largely normal in fmr1 mutants during early embryogenesis, Shh signaling is greatly diminished. Taken together, these results suggest cell stage-specific requirements for Fmrp in the specification and differentiation of oligodendrocyte lineage cells.

developmental biology↗

bioRxiv2020

Neonicotinoids Disrupt Circadian Rhythms and Sleep in Honey Bees

Honey bees are critical pollinators in ecosystems and agriculture, but their numbers have significantly declined. Declines in pollinator populations are thought to be due to multiple factors including habitat loss, climate change, increased vulnerability to disease and parasites, and pesticide use. Neonicotinoid pesticides are agonists of insect nicotinic cholinergic receptors, and sub-lethal exposures are linked to reduced honey bee hive survival. Honey bees are highly dependent on circadian clocks to regulate critical behaviors, such as foraging orientation and navigation, time-memory for food sources, sleep, and learning/ memory processes. Because circadian clock neurons in insects receive light input through cholinergic signaling we tested for effects of neonicotinoids on honey bee circadian rhythms and sleep. Neonicotinoid ingestion by feeding over several days results in neonicotinoid accumulation in the bee brain, disrupts circadian rhythmicity in many individual bees, shifts the timing of behavioral circadian rhythms in bees that remain rhythmic, and impairs sleep. Neonicotinoids and light input act synergistically to disrupt bee circadian behavior, and neonicotinoids directly stimulate wake-promoting clock neurons in the fruit fly brain. Neonicotinoids disrupt honey bee circadian rhythms and sleep, likely by aberrant stimulation of clock neurons, to potentially impair honey bee navigation, time-memory, and social communication.

animal behavior and cognition↗

bioRxiv2019

The RNA Binding Protein FMRP Promotes Myelin Sheath Growth

During development, oligodendrocytes in the central nervous system extend a multitude of processes that wrap axons with myelin. The highly polarized oligodendrocytes generate myelin sheaths on many different axons, which are far removed from the cell body. Neurons use RNA binding proteins to transport, stabilize, and locally translate mRNA in distal domains of neurons. Local synthesis of synaptic proteins during neurodevelopment facilitates the rapid structural and functional changes underlying neural plasticity and avoids extensive protein transport. We hypothesize that RNA binding proteins also regulate local mRNA regulation in oligodendrocytes to promote myelin sheath growth. Fragile X mental retardation protein (FMRP), an RNA binding protein that plays essential roles in the growth and maturation of neurons, is also expressed in oligodendrocytes. To determine whether oligodendrocytes require FMRP for myelin sheath development, we examined fmr1-/- mutant zebrafish and drove FMR1 expression specifically in oligodendrocytes. We found oligodendrocytes in fmr1-/-mutants developed myelin sheaths of diminished length, a phenotype that can be autonomously rescued in oligodendrocytes with FMR1 expression. Myelin basic protein (Mbp), an essential myelin protein, was reduced in myelin tracts of fmr1-/- mutants, but loss of FMRP function did not impact the localization of mbpa transcript in myelin. Finally, expression of FMR1-I304N, a missense allele that abrogates FMRP association with ribosomes, failed to rescue fmr1-/- mutant sheath growth and induced short myelin sheaths in oligodendrocytes of wild-type larvae. Taken together, these data suggest that FMRP promotes sheath growth through local regulation of translation.

neuroscience↗