van der Kooy, D. | bioRxiv Science

bioRxiv2021

Arrestin-mediated Desensitization Enables Olfactory Discrimination in C. elegans

In the mammalian olfactory system, crosstalk among diverse olfactory signals is minimized through labelled line coding: individual neurons express one or few olfactory receptors among those encoded in the genome. Labelled line coding allows for separation of stimuli during mammalian olfactory signal transduction, however, in the nematode worm Caenorhabditis elegans, 1,300 olfactory receptors are primarily expressed in only 32 neurons, precluding this strategy. Here we report genetic, pharmacological and behavioural evidence that {beta}-arrestin-mediated desensitization of olfactory receptors, working downstream of the kinase GRK-1, enables discrimination between intra-neuronal olfactory stimuli, but that this discrimination relies on quantitative, rather than qualitative differences in signalling. Our findings suggest that C. elegans exploits {beta}-arrestin desensitization to maximize responsiveness to novel odors, allowing for behaviourally appropriate responses to olfactory stimuli despite the large number of olfactory receptors signalling in single cells. This represents a fundamentally different solution to the problem of olfactory discrimination than that which evolved in mammals, allowing for economical use of an extremely limited number of sensory neurons.

neuroscience↗

bioRxiv2020

Connexin-36-expressing Gap Junctions in VTA GABA Neurons Sustain Opiate Dependence

Drug dependence is characterized by a switch in motivation wherein a positively reinforcing substance becomes negatively reinforcing. Ventral tegmental area (VTA) GABA neurons form a point of divergence between two double dissociable pathways responsible for these respective motivational states. Here we show that this switch from drug-naive to opiate-dependent and withdrawn (ODW) motivation is contingent upon the gap junction-forming protein, connexin-36 (Cx36), in VTA GABA neurons. Intra-VTA infusions of the Cx36 blocker, mefloquine, in ODW rats resulted in a reversion to a drug-naive motivational state and a loss of opiate withdrawal aversions. Consistent with these data, conditional knockout mice lacking Cx36 in GABA neurons (GAD65-Cre;Cx36fl(CFP)/fl(CFP)) were perpetually drug-naive and never experienced opiate withdrawal aversions. Further, viral-mediated rescue of Cx36 in VTA GABA neurons was sufficient to restore their susceptibility to ODW motivation. Our findings reveal a functional role for VTA gap junctions that has eluded prevailing circuit models of addiction. SignificanceThe motivation to seek drugs can vary depending on prior exposure. For instance, recreational and habitual drug use can stem from a desire to experience the pleasurable or relieving properties of the substance, respectively. Here we identify a subpopulation of midbrain neurons that dictate opiate-seeking motivation via expression of the gap junction protein, connexin-36. We show that connexin-36 expression increases upon opiate dependence and withdrawal. We then demonstrate that this is not merely a correlation, as pharmacological or genetic manipulations that interfere with connexin-36 function prevent the development of opiate dependence in rats and mice. Our results identify gap junctions as a critical node in the pathogenesis of opiate addiction, and a potential new target for substance use disorder pharmacotherapies.

neuroscience↗