A TALE OF TWO NEUREXINS: NRX-1 AND NLR-1 FACILITATE FUNCTION OF MONOAMINE CIRCUITS AND FORAGING BEHAVIORS

Synaptic adhesion molecules (SAMs) have major roles in the structure and function of the neural circuits that control behavior. Alterations in neural circuits either from genetics or the environment can have major consequences on behavior and can be associated with conditions like autism spectrum and schizophrenia. Defining the mechanisms by which SAMs, such as neurexins and Casprs, alter neural circuits and behavior can thus improve our understanding of how mutations in these genes impact behavior. I use the model system C. elegans to define how the conserved neurexin and Caspr orthologues, nrx-1 and nlr-1 respectively, alter foraging behaviors and investigate how these genes alter the neural circuits underlying these foraging behaviors. I find that nrx-1 controls the behavioral response to food deprivation in an isoform-specific manner, with the short γ-isoform of nrx-1 controlling the initiation/early responses to food deprivation in part via octopamine signaling. Meanwhile the long α-isoform controls the maintenance response to food deprivation with an epistatic genetic interaction with nlg-1/neuroligin, a canonical binding partner of neurexins. I also find that nlr-1 controls responses to food and food deprivation by acting in different populations of neurons to promote or inhibit foraging activity, with nlr-1 acting in dopaminergic neurons to regulate dopamine signaling and the response to food deprivation. In addition to linking neurexins and Casprs to monoamine signaling, this work highlights several major understudied themes in investigations of these synaptic genes. My findings for nrx-1 shows that imbalance of isoform expression of a single gene can lead to alterations in behavior masked by whole gene manipulations. The work on nlr-1 shows imbalanced spatial expression of a gene can also lead to alterations in behavior masked by global gene manipulations, which can be particularly relevant for genes controlled by multiple transcription factors differentially expressed across neural populations. Thus, future investigations into synaptic adhesion molecules should consider how changes in spatial and isoform expression can interact to control neural circuits and behavior.

Author dc:creator

• Bastien, Brandon, Lee

Advisor dc:contributor.advisor

• Hart, Michael, P

• Neuroscience and Neurobiology

Language dc:language.iso

en

Repository record dc:identifier.uri

https://repository.upenn.edu/handle/20.500.14332/60041

OAI identifier oai:identifier

oai:repository.upenn.edu:20.500.14332/60041