Biology subjects

Henderson, N. T.

Publications and source records attributed to Henderson, N. T..

3 recordsLinked to original sources

bioRxiv2023

EphrinB2 knockdown in spinal cord astrocytes preserves diaphragm innervation in a mutant SOD1 mouse model of ALS

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by motor neuron loss. Importantly, non-neuronal cell types such as astrocytes also play significant roles in disease pathogenesis. However, mechanisms of astrocyte contribution to ALS remain incompletely understood. Astrocyte involvement suggests that transcellular signaling may play a role in disease. We examined contribution of transmembrane signaling molecule ephrinB2 to ALS pathogenesis, in particular its role in driving motor neuron damage by spinal cord astrocytes. In symptomatic SOD1G93A mice (a well-established ALS model), ephrinB2 expression was dramatically increased in ventral horn astrocytes. Reducing ephrinB2 in the cervical spinal cord ventral horn via viral-mediated shRNA delivery reduced motor neuron loss and preserved respiratory function by maintaining phrenic motor neuron innervation of diaphragm. EphrinB2 expression was also elevated in human ALS spinal cord. These findings implicate ephrinB2 upregulation as both a transcellular signaling mechanism in mutant SOD1-associated ALS and a promising therapeutic target.

neuroscience↗

bioRxiv2021

Distributed processing for action control by prelimbic circuits targeting anterior-posterior dorsal striatal subregions.

Fronto-striatal circuits have been extensively implicated in the cognitive control of behavioral output for both social and appetitive rewards. The functional diversity of prefrontal cortical populations is strongly dependent on their synaptic targets, with control of motor output strongly mediated by connectivity to the dorsal striatum. Despite evidence for functional diversity along the anterior-posterior axis of the dorsomedial striatum (DMS), it is unclear how distinct fronto- striatal sub-circuits support neural computations essential for action selection. Here we identify prefrontal populations targeting distinct DMS subregions and characterize their functional roles. We first performed neural circuit tracing to reveal segregated prefrontal populations defined by anterior/posterior dorsomedial striatal target. We then probed the functional relevance of these parallel circuits via in vivo calcium imaging and temporally precise causal manipulations during a feedback-based 2-alternative choice task. Single-photon imaging revealed circuit-specific representations of task-relevant information with prelimbic neurons targeting anterior DMS (PL::A- DMS) uniquely encoded choices and responses to negative outcomes, while prelimbic neurons targeting posterior DMS (PL::P-DMS) encoded internal representations of value and positive outcomes contingent on prior choice. Consistent with this distributed coding, optogenetic inhibition of PL::A-DMS circuits strongly impacted choice monitoring and behavioral control in response to negative outcomes while perturbation of PL::P-DMS signals impaired task engagement and strategies following positive outcomes. Di-synaptic retrograde tracing uncovered differences in afferent connectivity that may underlie these pathways functional divergence. Together our data uncover novel PL populations engaged in distributed processing for action control. SUMMARYO_LIPrelimbic cortex engages A- and P-DMS via distinct circuits C_LIO_LIPL::A-DMS and PL::P-DMS pathways encode divergent aspects of a simple goal-directed task C_LIO_LIPL::A-DMS pathways shape responding to negative outcomes via multiple mechanisms C_LIO_LIPL::P-DMS pathways guide engagement and choices in response to positive outcomes C_LIO_LIAfferent connectomes of PL neurons defined by A-P DMS target are distinct C_LI

neuroscience↗

bioRxiv2018

How yeast cells find their mates

Accurate detection of extracellular chemical gradients is essential for many cellular behaviors. Gradient sensing is challenging for small cells, which experience little difference in ligand concentrations on the up-gradient and down-gradient sides of the cell. Nevertheless, the tiny cells of the yeast Saccharomyces cerevisiae reliably decode gradients of extracellular pheromones to find their mates. By imaging the behavior of polarity factors and pheromone receptors during mating encounters, we found that gradient decoding involves two steps. First, cells bias orientation of initial polarity up-gradient, even though they have unevenly distributed receptors. To achieve this, they measure the local fraction of occupied receptors, rather than absolute number. However, this process is error-prone, and subsequent exploratory behavior of the polarity factors corrects initial errors via communication between mating partners. The mobile polarity sites convert the difficult problem of spatial gradient decoding into the easier one of sensing temporal changes in local pheromone levels.

cell biology↗