Unraveling Complexity: MIT’s Insights into Individual Neurons and Behavior

Researchers at MIT have delved into the intricate workings of a solitary neuron within the C. elegans worm, shedding light on its pivotal role in governing a multitude of behaviors. This particular neuron employs a diverse array of neurotransmitters and possesses the remarkable ability to “borrow” serotonin, potentially offering valuable insights into psychiatric treatment strategies for more complex organisms.

The study’s findings in worms center around the HSN neuron, which orchestrates egg-laying and locomotion activities over several minutes by employing various chemicals and connections.

In a groundbreaking MIT study, a microscopic examination of a single cell within one of nature’s most rudimentary nervous systems unveils the astonishing capacity of individual neurons to employ multiple mechanisms in steering intricate behaviors.

Within the C. elegans worm, a creature boasting a mere 302 nerve cells, the HSN neuron plays a pivotal role. It releases an array of chemicals and establishes multiple connections along its length to not only oversee the immediate processes of egg-laying and locomotion but also to induce a period of deceleration lasting several minutes after egg deposition. To regulate this latter phase of behavior, the HSN neuron transfers the neurotransmitter serotonin to a neighboring neuron, which subsequently re-releases it, exerting influence on behavior minutes later.

“Our results elucidate how a single neuron can exert influence over a broad spectrum of behaviors across varying timeframes, demonstrating that neurons have the capacity to exchange serotonin amongst themselves to govern behavior,” report the researchers in Current Biology.

The senior author of the study is Steven Flavell, an associate professor at The Picower Institute for Learning and Memory and the Department of Brain and Cognitive Sciences. Serving as the study’s first author is postdoctoral researcher Yung-Chi Huang.

Within the C. elegans worm, the HSN neuron assumes a pivotal role in coordinating several interrelated behaviors. The accompanying image highlights the HSN neuron in green, showcasing its extension from the body to the head of the worm, as indicated in red.

Prior to this study, researchers had already mapped out HSN’s connections with other neurons, a feat achieved exclusively in C. elegans among all animals. Additionally, the HSN neuron had been associated with egg-laying. Observations made by Flavell’s lab revealed that when these worms lay eggs, they exhibit rapid locomotion akin to a farmer dispersing seeds across fertile soil. Furthermore, it was noted that when HSN was removed or ablated, worms failed to engage in a characteristic feeding behavior, which involves slowing down to consume patches of food.

However, the manner in which this single neuron could simultaneously trigger seemingly contradictory behaviors, such as egg laying, accelerating to achieve this, and subsequently slowing down, remained an enigma. Flavell and Huang’s team embarked on a comprehensive array of techniques and experiments to decipher the multifaceted role of HSN.

To establish the causal relationship between HSN and these behaviors, they manipulated the neuron’s activity through optogenetics—a technique involving the genetic modification of cells to respond to light pulses. In addition to confirming HSN’s pivotal role in egg-laying, these genetic manipulation experiments affirmed that HSN instigated the worm’s acceleration and subsequent deceleration following a period of movement and egg-laying. The researchers also monitored HSN’s electrical activity during these behaviors, tracking the flow of calcium ions within the cell as the animals moved freely, revealing distinct patterns of activity associated with egg-laying and locomotion.

Having firmly established that HSN was responsible for these three interconnected behaviors, the researchers then honed in on the mechanisms driving them.

HSN is known to release a wide array of neurotransmitter chemicals, including serotonin, acetylcholine, and various peptides. The release of serotonin and a neuropeptide called NLP-3 by HSN is acknowledged to drive egg-laying. To ascertain how the neuron triggers rapid locomotion, the team systematically disrupted each HSN neurotransmitter and subsequently stimulated HSN to observe whether the worms could still accelerate when one of these chemicals was absent. The experiments revealed that HSN induces increased locomotion through the release of two neuropeptides known as FLP-2 and FLP-28.

The depletion of serotonin within HSN, on the other hand, impeded the worm’s deceleration behavior. Further investigations unveiled the mechanism behind this phenomenon. Flavell’s team had previously explored the NSM neuron, which employs serotonin to inhibit motor circuits and slow down a worm when it is feeding. In this study, they demonstrated that NSM’s action relied on a supply of serotonin sourced from HSN. When HSN was unable to produce serotonin, NSM struggled to decelerate the worms effectively. The team additionally illustrated how NSM employs the serotonin transporter SERT (referred to as MOD-5 in C. elegans) to uptake HSN’s serotonin and subsequently release it. This revelation underscores the capacity of serotonergic neurons to pool and exchange serotonin amongst themselves, directly influencing the animal’s behavior.

Analyzing HSN’s anatomical structure, the researchers discerned that the control of locomotion and egg-laying occurred at different points along HSN’s axon. HSN’s cell body resides in the midbody of the animal, forming synapses with the egg-laying circuit in this region. Subsequently, its axon extends to the head, where it establishes synapses with other neurons. Severing HSN’s axon between the midbody and head did not disrupt egg-laying but did prevent the coordination of egg-laying and locomotion. This suggests that HSN’s projection to the head coordinates its action on the egg-laying circuit with its influence on the locomotion circuit.

In summary, this study illuminates how HSN employs multiple parallel neurotransmitter outputs in distinct ways to regulate the animal’s behavior.

Furthermore, the discovery that neurons can uptake and re-release serotonin produced by other neurons to govern behavior unveils a novel facet of serotonin signaling that could hold significant medical implications, according to Flavell. The molecule responsible for serotonin uptake, SERT/MOD-5, serves as the target for serotonin-specific reuptake inhibitors (SSRIs) like Prozac. This study raises the possibility that SSRIs may impact how neurons share serotonin amongst themselves, potentially influencing their mode of action in the treatment of a wide array of psychiatric disorders.

Reference: “A single neuron in C. elegans orchestrates multiple motor outputs through parallel modes of transmission” by Yung-Chi Huang, Jinyue Luo, Wenjia Huang, Casey M. Baker, Matthew A. Gomes, Bohan Meng, Alexandra B. Byrne and Steven W. Flavell, 27 September 2023, Current Biology.
DOI: 10.1016/j.cub.2023.08.088

Apart from Huang and Flavell, the paper’s additional authors include Jinyue Luo, Wenjia Huang, Casey Baker, Matthew Gomes, Bohan Meng, and Alexandra Byrne.

Funding for the study was provided by The National Institutes of Health, the National Science Foundation, the McKnight Foundation, The Alfred P. Sloan Foundation, The Picower Institute, and The JPB Foundation.

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• MIT News Article
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