Brain circuits and behavior

By combining their expertise in the neural circuitry of males versus females and the impact of neural circuitry architecture on function, Dr. Meital Oren-Suissa and Prof. Elad Schneidman have shed light on how the shape of brain wiring affects male versus female behavior.

When it comes to microscopic worms (Caenorhabditis elegans) and threats, while the female brain says, “Flee danger!”, the male brain says, “Hold my mold.” That is, should there be a looming threat and an available escape route open, female worms immediately flee while the males stay put until the threat has grown in strength.

Dr. Oren-Suissa studies sex-related differences in the brain and the rest of the nervous system, mainly using C. elegans as a model. Prof. Schneidman studies the relationship between the architecture of neural networks and their function. The Oren- Suissa and Schneidman labs, both in the Department of Brain Sciences, teamed up to use this puzzling difference between the sexes to explore one of the greatest enigmas surrounding the brain: how the structure of neural circuits shapes behavior.

As detailed in an article in Current Biology, the Oren-Suissa lab initially found that worms exposed to harmful chemical substances sense the danger using receptors like those that convey the sensation of pain in humans, and the response of these receptors to the dangerous cue is similar in worms of both sexes. The researchers also found that, while the neural circuit that picks up the danger signal consists of the same neurons in females and males, the wiring of these neurons—that is, how they are connected—differs in several ways between the sexes. The big unknown was which of these differences matter in terms of behavior.

That’s where the Schneidman lab came in, simulating the dangersensing circuits of females and males using mathematical models. One model predicted that the differences in the wiring of the circuits in the two sexes would be sufficient to generate the different behaviors. The labs then used the model to predict how changing the wiring might change the circuits’ function: Altering a single connection, or synapse, between two neurons. These two neurons were connected to one another in the female, but not the male, worms.

In a feat of molecular engineering, the Oren-Suissa group inserted the missing connection into the danger-sensing circuit of male worms. As the model had predicted, the males equipped with the synthetic synapse started fleeing from the danger, just like the females.

Why are normal male worms so prone to risk-taking? The researchers believe this may be due to the evolutionary force that Charles Darwin termed “sexual selection”: comparatively “brave” male worms are better at attracting mates than male worms that respond to danger or pain. Females, by contrast, practice pain avoidance.

This explanation was borne out by experiments. Whereas regular males rushed directly to the females—danger be damned—the engineered males with a synthetic synapse were much more hesitant, taking 10 times longer to reach potential mates.

The human brain, with its trillions of synapses, is vastly more complex than the nervous system of C. elegans—flipping a single synapse won’t lead to any such dramatic behavioral changes. But the findings shed new light on how the layout of neural circuits in the brain translates into behavioral tendencies and traits. These findings may prove relevant to building artificial systems that mimic the entire human brain or its parts. The study also suggests a new direction for investigating why the two sexes in higher species, including humans, perceive pain differently.

Meital Oren-Suissa is supported by:
- Azrieli Foundation
- Sagol Weizmann-MIT Bridge Program
- Dr. Barry Sherman Institute for Medicinal Chemistry
- Jenna and Julia Birnbach Family Career Development Chair

Elad Schneidman is supported by:
- Nella and Leon Benoziyo Center for Neurosciences
- Carl and Micaela Einhorn-Dominic Brain Research Institute
- Murray H. & Meyer Grodetsky Center for Research of Higher Brain Functions
- David Lopatie Center for Theoretical and Computational Neuroscience
- Joseph and Bessie Feinberg Professorial Chair