Biology subjects

McMillen, A.

Publications and source records attributed to McMillen, A..

2 recordsLinked to original sources

bioRxiv2025

Dopaminergic Modulation of Short-Term Associative Memory in Caenorhabditis elegans

Forgetting, the inability to retrieve previously encoded memories, is an active process involving neurotransmission, second messenger signalling, and cytoskeletal modifications. Forgetting is thought to be essential to remove irrelevant memories and to increase the capacity to encode new memories. Therefore, identifying key regulators of active forgetting is crucial to advance our understanding of neuroplasticity. In this study, we utilised the compact and tractable Caenorhabditis elegans model to investigate the role of the neurotransmitter dopamine in forgetting. We conducted butanone associative learning assays based on an established protocol and used mutant strains deficient in dopamine synthesis (tyrosine hydroxylase CAT-2 and dopamine transporter DAT-1) and signalling (G protein-coupled receptors DOP-1, DOP-2, and DOP-3) to assess the impact on learning and memory retention. Learning was measured immediately post-training, and memory retention was evaluated every 0.5 hours up to 2 hours. Our results show that animals lacking dopamine display a modest enhancement in learning relative to wild-type, with the learned association persisting for at least 2 hours after training. We also found that D2-like receptors DOP-2 and DOP-3 act together to modulate the forgetting process, with D1-like receptor DOP-1 functioning redundantly. Furthermore, re-expression of CAT-2 tyrosine hydroxylase in ADE and/or CEP neurons was unable to rescue the memory retention phenotype observed in cat-2 mutants, suggesting that dopamine release from all dopaminergic neurons is required to modulate forgetting. These findings highlight the critical role of dopamine in forgetting, consistent with findings in Drosophila, and suggest potential relevance for understanding memory retention during healthy ageing and in conditions with dopamine imbalances such as Parkinsons disease.

neuroscience↗

bioRxiv2024

Identifying regulators of associative learning using a protein-labelling approach in C. elegans

The ability to learn and form memories is critical for animals to make choices that promote their survival. The biological processes underlying learning and memory are mediated by a variety of genes in the nervous system, acting at specific times during memory encoding, consolidation, and retrieval. Many studies have utilised candidate gene approaches or random mutagenesis screens in model animals to explore the key molecular drivers for learning and memory. We propose a complementary approach to identify this network of learning regulators: the proximity-labelling tool TurboID, which promiscuously biotinylates neighbouring proteins, to snapshot the proteomic profile of neurons during learning. To do this, we expressed the TurboID enzyme in the entire nervous system of C. elegans and exposed animals to biotin only during the training step of an appetitive gustatory learning paradigm. Our approach revealed hundreds of proteins specific to trained worms, including components of molecular pathways previously implicated in memory in multiple species such as insulin signalling, G protein-coupled receptor signalling, and MAP kinase signalling. Most (87-95%) of the proteins identified are neuronal, with relatively high representation for neuron classes involved in locomotion and learning. We validated several novel regulators of learning, including cholinergic receptors (ACC-1, ACC-3, LGC-46) and putative arginine kinase F46H5.3. These previously uncharacterised learning regulators all showed a clear impact on appetitive gustatory learning, with F46H5.3 showing an additional effect on aversive gustatory memory. Overall, we show that proximity labelling can be used in the brain of a small animal as a feasible and effective method to advance our knowledge on the biology of learning.

neuroscience↗