Learning from Fruit Flies: How Memory Steers Action

By Sneha Makhijani

Image by Howard Vindin. [CC-BY-SA 4.0]

The fruit fly has created quite a buzz in the world of neuroscience and learning. Similar to the way humans are now conditioned to hear a notification and pick up their phone, animals show different behavioral responses to the same sensory input, depending on past experiences and current contexts. Learning is a permanent change in behavior that results from experience. One of the earliest learning techniques is classical conditioning, a learning process in which a neutral, unconditioned stimulus is paired with a conditioned response to naturally evoke a response. While the initial experiments were first done on dogs, the field of neuroscience is slowly understanding how synaptic plasticity, a change that occurs at the junctions of different neurons, and memory is steering this learning response. UNC-Chapel Hill’s Dr. Toshihide Hige is one of the scientists doing pioneering research on the neurophysiology and learning behavior in the fruit fly – Drosophila melanogaster. The brain enables flexibility to change its structure through mechanisms at the levels of synaptic plasticity, neural circuit, and behavior, where the neural circuit is a population of neurons that carry out a specific function. Dr. Hige first got involved in synaptic physiology during his PhD research. Using electrophysiology in mammalian systems, he studied the neural circuit basis of behavior in animals. As Dr. Hige progressed in his research, he started to use Drosophila melanogaster as a model organism. Although Dr. Toshihide Hige, PhD fruit flies have about 100,000 neurons, which is 1000 times fewer than that of mice, some of the important circuit motifs remain conserved across all animals, both in sensory circuits and higher-order brain areas. Circuit motifs are connectivity patterns between specific cell types across different species and brain areas. Simpler model organisms, such as Drosophila melanogaster, have small brains but exhibit a wide range of sophisticated, adaptive behaviors. Fruit flies make for an easier reading of the neural circuit and they offer a larger selection of which circuit brain area to use, with fewer pathways of each of the brain circuits. Genetic tools can label specific neuron types in every area of the brain, and such tools can also manipulate neuronal activity and address its molecular basis. Furthermore, the whole-brain connectome data is readily available and allows for an easier link between synaptic plasticity and behavior by understanding Drosophila neural circuits. Whole-brain connectome data is essentially a comprehensive map of the various neural connections in the brain that act as a wiring diagram of an organism’s nervous system. There is a pair of structures in the brain of insects called Corpora Pedunculate, or mushroom bodies. The structures are

known to play important roles in olfactory learning – that is, learning due to the sense of smell – and memory. The neurons that form the mushroom bodies are called Kenyon cells. In the Drosophila melanogaster there are about 2,000 Kenyon cells in each of the brain hemispheres. The mushrooms bodies are what store different memories, which can be repetitive, aversive, short, or long. The different regions of the mushroom body, which are nicely segregated, deal with specific types of memory, and, when running an experiment, the memory type and its storage can be chosen. The Kenyon cells in the mushroom bodies integrate information from the separate regions and are responsible for synthesizing different memories and relating them to decision making. One of the strengths of using Drosophila is the ease of studying the genetics and neuronal circuit. Accordingly, the synaptic plasticity can be separated into the different regions of the brain. Ultimately, the mushroom bodies have a cascade of events that pave the way for a motor response. The mechanism is useful because it allows researchers to artificially induce memory or plasticity and observe how it affects downstream neurons. Associative learning techniques such as that of classical conditioning use a molecule called dopamine as the main neurotransmitter in the brain circuit. For instance, synaptic depression, which is a decrease in the postsynaptic responses after repeated stimulation of a synapse, can be induced by dopamine activation in flies. Dopamine neurons in the brain project to different neuron bodies which are present in sensory pathways. Dr. Hige’s lab studies the olfactory pathways, some of which act

Figure 2. Long-term depression in the mushroom body downstream to the mushroom bodies. Based on how quickly the effects are seen in the downstream neurons of the circuit and when the synaptic transmission is induced, the transmission can affect downstream neurons’ behavior. The Hige lab is studying this mechanism to identify the co-transmitter which works with dopamine to induce depression in these neuronal bodies. One technique to study the synaptic depression in flies is by using Positron Emission Tomography (PET) scans. In this experiment, the flies are dissected alive after which an electrode is inserted in them. An odor is then applied to test the olfactory response in the neuron, based on the behavioral response. Upon dopamine stimulation, a decrease in the synaptic impulse can be observed. Using the olfactory sensory system, olfactory learning takes place. First, a particular odor is used to establish the behavior – the neutral stimulus. Then, the fly is given an immediate aversive response, such as a shock, which is the unconditioned stimulus. The unconditioned response will be the fly trying to avoid the shock. After a few trials of conditioning, the odor eventually becomes the conditioned stimulus so that whenever the fly detects the odor, it automatically anticipates and tries to avoid the shock. Thus, the smell of the odor becomes associated with the aversive shock and the fly learns to avoid both the shock and the odor. The behavior of the fly constitutes olfactory learning. Classical conditioning could also be done with a positive reinforcement and an odor. A positive reinforcement would be if ior is ob -

Figure 3. A tethered fly walking on a treadmill ball

something like a treat is given to the fly when a particular behavserved with a specific odor. In order to test if the flies have learned the classical conditioning behavior aversive to the shock, they are put on a treadmill ball and their reaction to the odor is observed. The response is recorded via electrodes as the flies are tethered to the treadmill balls when they move towards or away from the smell. Through this research, Dr. Hige hopes to visualize the neuronal changes that underlie learning by tracking the neural circuit of Drosophila melanogaster from the sensory input to the motor output. By studying this behavioral output, a precise circuit of the learning process that takes place in a fly’s brain can be obtained while integrating the sensory input to the behavioral output. Although humans have far more complex neural and behavioral circuits than flies’, this can be extrapolated to further research of the neuronal circuits in humans. Dr. Hige’s research can not only help us better understand how flies are engaged in learning behaviors, but also how it can be translated to neuronal activity and learning in humans.

References

1. Interview with Dr. Toshihide Hige, Ph.D. 09/20/20. 2. Hige, T., Aso, Y., Rubin, G.M., and Turner, G.C. Plasticitydriven individualization of olfactory coding in mushroom body output neurons. Nature. 2015, 526, 258-262. 3. Hige, T. What can tiny mushrooms in fruit flies tell us about learning and memory? Neurosci. Res.2017, 129, 8-16. 4. Takemura, S-Y., Aso, Y., Hige, T., et al. A connectome of a learning and memory center in the adult Drosophila brain.

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