The Nematode Corner: Delaying Forgetting – How Ice and Lithium Affect Memory in C. elegans

In a groundbreaking study, researchers have discovered a tunable and druggable mechanism to delay the forgetting of olfactory memories in Caenorhabditis elegans (C. elegans). This finding has significant implications for developing new therapeutic approaches to enhance memory retention, potentially benefiting those suffering from memory and psychiatric disorders. 

The preprint study (not yet peer-reviewed) titled “A Tunable and Druggable Mechanism to Delay Forgetting of Olfactory Memories in C. elegans” reveals that placing worms on ice or treating them with lithium salts can extend their memory retention by at least eight times. The mechanism involves two opposing brain states that regulate memory and forgetting, highlighting potential targets for drug development to enhance memory retention in other organisms.

Key highlights from the study:

Worms have associative learning memory: Worms that are attracted to a particular stimulus can be trained to dislike it by pairing it with a period of starvation, forming a negative association. The same is true for the opposite: a smell or other stimulus that worms dislike can be paired with a food source to form a positive association.

Worms have short memories: These associative learned responses are usually quickly forgotten in these simple organisms. Tracking the movement towards or away from a stimulus indicates the worms being attracted or repelled by a stimulus, respectively. In this study, a conditioned negative response (to an odour they usually like) is forgotten and they move towards it, instead of remembering to dislike it.

Can memory be enhanced in worms? When chilled on ice, the worms were able to retain this conditioned response memory for longer, shown by their negative association towards the smell. The same is true for when treated with lithium salts, even without cold-treatment.

Cold tolerance cancels chilled-enhanced memory: When the worms were acclimated to cold temperatures before the experiment, the delayed forgetting effect of the ice was cancelled.

How Was This Research Performed?

In this study, researchers used two methods to delay forgetting:

1. Cooling on Ice: Researchers placed the worms on ice, which slowed down their metabolic processes, potentially preserving memory-related molecular structures and functions. Specifically, the worms were trained to dislike a particular odour they usually like by pairing it with a period of starvation. After two hours, worms normally forget this negative association and are again attracted to the odour. However, when placed on ice, the worms retained their negative smell-associated memories for at least 16 hours. Once removed from ice, their memory ‘clock’ restarted, and after three hours, they forgot the negative association, reverting to their original attraction to the smell.

2. Lithium Salts: They also treated the worms with lithium salts, known to affect neurotransmitter systems involved in mood regulation and neural plasticity. The study found that both lithium-treated and chilled worms retained their memory. Even without chilling, lithium-treated worms retained their memory, whereas non-lithium-treated worms did not. The preserved memory was linked to reduced diacylglycerol levels, as lithium inhibits an enzyme that produces a precursor to diacylglycerol. Memory retention was associated with increased cell membrane rigidity, which occurs at low temperatures.

How Memory Works in C. elegans

C. elegans are nematodes extensively used in neurobiological research due to their simplicity and well-mapped neural circuitry. These worms exhibit olfactory memory, which allows them to remember and respond to specific scents. The balance between memory retention and forgetting is governed by intricate molecular pathways involving neurotransmitters and signalling proteins.

• Non-Associative Memory: Refers to the organism’s response to a single type of stimulus, such as habituation or sensitization. For example, a worm might decrease its response to a repeated gentle touch over time.
• Associative Memory: Involves learning to associate one stimulus with another, such as associating a particular odour with the presence of food. This type of memory is more complex and involves linking multiple sensory inputs.

Why Worms Are a Good Model to Study Memory?

C. elegans are ideal for memory studies for several reasons:

• Simplified Neural Network: With only 302 neurons, their nervous system is more straightforward, making it easier to study involved neural processes compared to more complex organisms with a larger nervous system.
• Genetic Tractability: Their fully sequenced and highly researched genome and ease of genetic manipulation allow for precise studies of gene function.
• Rapid Life Cycle: Their short lifespan and rapid generation time facilitate quick experimental turnaround.
• Conservation of Pathways: Many molecular pathways involved in their neural processes are conserved in higher organisms, including humans.

Applications in Human Health

Understanding these mechanisms in C. elegans can provide insights into similar processes in humans, paving the way for developing drugs that target these pathways to treat memory-related disorders such as Alzheimer’s disease.

Interested in Memory Research?

At Magnitude Biosciences, we use established assays to test different types of memory responses in C. elegans. For example:

• Non-Associative Learning: Measured through changes in movement after mechanical stimulation.
• Associative Learning: Assays involving odorants, chemicals, or temperature associated with food presence or absence to measure movement responses.
• T-Maze Validation Studies: Our T-Maze validation studies assess learning and memory, demonstrating how worms can acquire and retain information from navigational tasks, which can be used to evaluate the effectiveness of potential therapeutic compounds.

Training maze: Strongly biased navigational outcome with preference to the side of the maze with food (learning & acquires memory)

Testing maze: Acquired memory makes worm prefer the same side of the maze

By integrating our advanced C. elegans research capabilities with the latest scientific discoveries, Magnitude Biosciences is at the forefront of accelerating drug discovery and improving health outcomes. If you are interested in testing your compounds to assess their impact on memory, contact us today.