Search bioRxiv⌕ Search

Biology subjects

van der Kooy, D.

Publications and source records attributed to van der Kooy, D..

3 recordsLinked to original sources

A Novel Memory Type in C. elegans Exhibits Post-Training Consolidation

Memories are often categorized into types, reflecting their behavioral, anatomical and molecular diversity: these classifications both aid understanding of the differences among varieties of memory and help delineate the unifying cross-species principles underlying them. In the nematode worm Caenorhabditis elegans, we find that an associative memory of the pairing of the normally attractive odorant benzaldehyde and starvation depends on de novo translation, is independent of CREB, and is produced by massed training: a pattern which does not correspond to any of the well-characterized molecular categories of invertebrate memory. Further, as has been shown for many memories in vertebrates, but not previously in nematodes, we find that formation of this memory continues after removal of the stimuli initially causing it, and that it is labile to disruption through protein synthesis inhibition following training, but that inhibition of proteasomal activity does not extend the duration of the memory. Previous findings have implicated insulin pathway signaling, which canonically regulates the transcription factor DAF- 16, as a key component of this benzaldehyde/starvation memory, however our results suggest that transcriptional inhibition has, at most, only moderate effects on memory formation. We find that insulin signaling instead acts to regulate phospholipase C, which in turn regulates memory through diacylglycerol signaling. These findings better characterize this model associative memory in relation to other invertebrate memory types and identify ways in which it both shares their traits and differs from them, as well as revealing a more complete picture of the molecular pathway underlying it.

neuroscience↗

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↗

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↗