Biology subjects

Dickman, D.

Publications and source records attributed to Dickman, D..

21 records · Page 2Linked to original sources

bioRxiv2018

Neuronal thresholds and correlations in the peripheral vestibular system during rotation discrimination

Neuronal and behavioral thresholds were measured simultaneously as trained male macaques performed a yaw rotation discrimination task in darkness. When corrected to account for variations in neuronal direction preferences, neurons in the vestibular nuclei and semicircular canal afferents had discrimination thresholds that were only two-fold smaller than behavioral thresholds. There was no significant trial-by-trial correlation between neuronal activity and perceptual decisions, despite the presence of significant pair-wise noise correlations. The lack of choice-related activity during rotation discrimination contrasts with the robust correlations observed previously between brainstem neurons and choices during translation perception. These results suggest task-dependent differences in subcortical processing of vestibular signals, as well as how signals related to perceptual decisions may propagate back to early stages of sensory processing.\n\nSIGNIFICANCE STATEMENTThis is the first ever simultaneous recordings of neural and behavioral thresholds during rotation discrimination. Its importance lies on the fact that the vestibular system provides an excellent model to probe origins of perception because directional selectivity signals are similar at many levels of processing, from afferents to cortex. The findings of similar neuronal and behavioral discrimination thresholds, significant inter-neuronal correlations, but lack of correlations between behavior and neuronal activity of both afferents and central brainstem neurons are intriguing and suggest task-dependent organization of early sensory areas.

neuroscience↗

bioRxiv2017

Ribosome profiling reveals post-translational signaling mechanisms drive the retrograde enhancement of presynaptic efficacy

Presynaptic efficacy can be modulated by retrograde control mechanisms, but the nature of these complex signaling systems remain obscure. We have developed and optimized a tissue specific ribosome profiling approach in Drosophila. We first demonstrate the ability of this technology to define genome-wide translational regulations. We then leverage this technology to test the relative contributions of transcriptional, translational, and post-translational mechanisms in the postsynaptic muscle that orchestrate the retrograde control of presynaptic function. Surprisingly, we find no changes in transcription or translation are necessary to enable retrograde homeostatic signaling. Rather, post-translational mechanisms appear to ultimately gate instructive retrograde communication. Finally, we find that a global increase in translation induces adaptive responses in both transcription and translation of protein chaperones and degradation factors to promote cellular proteostasis. Together, this demonstrates the power of ribosome profiling to define transcriptional, translational, and post-translational mechanisms driving retrograde signaling during adaptive plasticity.\n\nAUTHOR SUMMARYRecent advances in next-generation sequencing approaches have revolutionized our understanding of transcriptional expression in diverse systems. However, transcriptional expression alone does not necessarily report gene translation, the process of ultimate importance in understanding cellular function. To circumvent this limitation, biochemical tagging of ribosomes and isolation of ribosomally-associated mRNA has been developed. However, this approach, called TRAP, has been shown to lack quantitative resolution compared to a superior technology, ribosome profiling, which quantifies the number of ribosomes associated with each mRNA. Ribosome profiling typically requires large quantities of starting material, limiting progress in developing tissue-specific approaches. Here, we have developed the first tissue specific ribosome profiling system in Drosophila to reveal genome-wide changes in translation. We first demonstrate successful ribosome profiling from a specific tissue, muscle, with superior resolution compared to TRAP. We then use transcriptional and ribosome profiling to define transcriptional and translational adaptions necessary for synaptic signaling at the neuromuscular junction. Finally, we utilize ribosome profiling to demonstrate adaptive changes in cellular translation following cellular stress to muscle tissue. Together, this now enables the power of Drosophila genetics to be leveraged with translational profiling in specific tissues.

neuroscience↗

bioRxiv2017

Extended Synaptotagmin Is A Presynaptic ER Ca2+ Sensor That Promotes Neurotransmission And Synaptic Growth In Drosophila

The endoplasmic reticulum (ER) is an extensive presynaptic organelle, exerting important influences at synapses by responding to Ca2+ and modulating transmission, growth, lipid metabolism, and membrane trafficking. Despite intriguing evidence for these crucial functions, how presynaptic ER influences synaptic physiology remains enigmatic. To gain insight into this question, we have generated and characterized mutations in the single Extended Synaptotagmin (Esyt) ortholog in Drosophila. Esyts are evolutionarily conserved ER proteins with Ca2+ sensing domains that have recently been shown to orchestrate membrane tethering and lipid exchange between the ER and plasma membrane. We first demonstrate that Esyt localizes to an extensive ER structure that invades presynaptic terminals at the neuromuscular junction. Next, we show that synaptic growth, structure, function, and plasticity are surprisingly unperturbed at synapses lacking Esyt expression. However, presynaptic overexpression of Esyt leads to enhanced synaptic growth, neurotransmission, and sustainment of the vesicle pool during intense levels of activity, suggesting that elevated Esyt at the ER promotes constitutive membrane trafficking or lipid exchange with the plasma membrane. Finally, we find that Esyt mutants fail to maintain basal neurotransmission and short term plasticity at elevated extracellular Ca2+, consistent with Esyt functioning as an ER Ca2+ sensor that modulates synaptic activity. Thus, we identify Esyt as a presynaptic ER Ca2+ sensor that can promote neurotransmission and synaptic growth, revealing the first in vivo neuronal functions of this conserved gene family.

neuroscience↗