Search bioRxiv⌕ Search

Biology subjects

Hao, E.

Publications and source records attributed to Hao, E..

2 recordsLinked to original sources

Disinhibition of a recurrent attractor gates a persistent goal signal for navigation

Recurrent attractor networks are widely thought to form the basis of working memory1-3, but how stable attractor activity can be rapidly switched on and off is unclear4-7. Here we investigate how stability and rapid switching can be combined in a discrete recurrent circuit of the fly navigation center8. h{Delta}K and PFG neurons are recurrently connected in a ring structure. Using in vivo imaging, we find that these two populations exhibit shared persistent bump activity that turns on with odor and terminates at the end of a goal-directed upwind run. Using whole-cell recordings, we show that persistence in h{Delta}K depends on recurrent signalling, and that h{Delta}K receives slow recurrent excitation and fast inhibition from its synaptic partners. Computational modeling reveals that this combination of slow excitation with fast inhibition yields persistent attractor dynamics over a range of excitation and inhibition strengths. Next we examine the mechanisms that allow this activity bump to be rapidly turned on and off. We find that while both populations show positionally stable bump activity during goal-directed runs, during turns and rest the PFG bump tracks heading while h{Delta}K is supressed. We can reproduce these differential dynamics in our model by using inhibition to dynamically uncouple activity in h{Delta}K from PFG. When h{Delta}K is inhibited, PFG neurons follow their inputs from the compass system; when h{Delta}K is disinhibited, recurrent interactions lock this input into place, forming a heading memory. Consistent with this model, we find that inhibitory inputs onto h{Delta}K increase during turns and are suppressed during odor input and goal-directed upwind runs. Our work reveals how disinhibition can serve as a gate to rapidly write an ongoing measurement to a recurrent memory circuit.

neuroscience↗

TRB3 augments IL1β-TLR4 signaling by engaging Flightless-homolog 1.

Signaling via IL1{beta} and TLR4 receptors (IL1R-TLR4) plays a crucial role in cytokine and fatty acid-induced beta cell inflammation, in type 1 and type 2 diabetes respectively. IL1R-TLR4 share signaling mechanisms via a common, cytoplasmic, toll-like-receptor domain to activate proinflammatory JNK and IKK kinases. We have previously reported that in response to IL1{beta}, pancreatic islets isolated from TRB3 knockout (TRB3KO) mice show attenuated kinetics of activation for MAP3K MLK3, and JNK stress kinases. Here we report that similar to MLK3 and JNK, TRB3KO islets also show a decrease in amplitude and duration of IL1{beta}/LPS-stimulated TAK1 and IKK phosphorylation. Thus, loss of TRB3 attenuates both pathways critically required for a full-blown, cytokine-inducible, proapoptotic response in beta cells. TRB3KO islets display a sharp decrease in cytokine-induced beta cell death, accompanied by a decrease in select downstream NFkB targets, most notably, inducible Nitric Oxide Synthase (iNOS/NOS2), a well-characterized mediator of beta cell dysfunction and death. In order to better understand the molecular basis of TRB3-enhanced IL1R-TLR4 signaling, we interrogated the TRB3 interactome and identified Flightless-homolog 1 (Fli1), an immunomodulatory, actin-binding, leucine-rich-repeat protein, as a novel TRB3-interaction factor. TRB3 binds and disrupts Fli1-dependent sequestration of MyD88, thereby increasing availability of this proximal adaptor to participate in IL1R-TLR4 signaling. Fli1 forms a multiprotein complex that can disconnect IL1R-TLR4 from MyD88, resulting in a brake on assembly of downstream signaling complexes. By interacting with Fli1, TRB3 lifts the brake on IL1R-TLR4 signaling to augment the proinflammatory response in beta cells.

biochemistry↗