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Sink or Swim?

Jim Kling

To pinpoint the neural pathway responsible for motivation in rats, researchers turn to optogenetics.

Is it worth the bother? It’s a question as old as life itself. Organisms must decide whether a given action is worth the energy expenditure. The neural mechanism that underlies the question may be compromised in people with depression, who can struggle mightily with motivation because they find it hard to envision a positive outcome.

ChR2-expressing medial prefrontal neurons innervate the dorsal raphe nucleus. Dorsal raphe serotonin neural cell bodies are in red, axons originating from the prefrontal cortex are in green. Activation of this neural projection causes rats to select an active behavioral pattern in challenging situations. Source: Melissa R. Warden and Karl Deisseroth, Stanford University

Researchers at Stanford University believe they have pinpointed the neurons that drive that all-important decision-making process. In rats forced to swim in an enclosed water-tank, activation of a specific group of neurons prompted them to swim rather than float. The work was published online November 18 in Nature (1).

To identify these neurons, the Stanford researchers from Karl Diessorth’s lab used optogenetics. The technique involves the introduction of light-activated channelrhodopsin proteins into a subset of neurons. As a result, researchers can stimulate these neurons to fire by shining a light on them.

In the experiment, the rats underwent two separate surgeries. In the first, researchers implanted a virus to deliver channelrhodopsin to the prefrontal cortex. There the protein spreads out along synapses, delivering the protein to other regions of the brain. In a separate procedure, the rats were fitted with an optical fiber to illuminate specific regions of the brain. “We were able to target very specific circuits,” said study author Melissa Warden, a postdoc at Stanford.

To automatically detect swimming kicks, the group attached a small magnet to the hind paw of the rats and surrounded the water tank with an induction coil. Kicks induced a detectable current in the coil, which could then be correlated with neuron activation.

Warden and colleagues first targeted the prefrontal cortex, the region of the brain located just behind the forehead that controls so-called executive functions such as making moral decisions or navigating conflicting thoughts. To their surprise, the researchers found that the neuron activation in this region had no discernible effect on the rats’ motivation.

Although the decision to act is probably born in the prefrontal cortex, the team reasoned that it must then quickly travel to the nerves that initiate motor function. Warden and colleagues believed that they could then influence the signal as it traveled through this region instead.

Previous research had suggested that the dorsal raphe nucleus in the brain stem—an important source of serotonin production—plays a role in depression. So, the team turned their attention to links between it and the prefrontal cortex. The researchers illuminated that region in distressed rats, causing the neurons in that path to fire. “We could see the animals switch from escape-motivated behavior to passive behavior,” said Warden. In contrast, stimulation of the region in relaxed rats had no effect.

The next step is to delve deeper into the dorsal raphe nucleus. The region contains serotonin-producing neurons and neurons that produce gamma-aminobutyric acid, which inhibits serotonin production. Many antidepressants boost serotonin production, leading to the theory that heightened serotonin production combats depression. But there are anatomical reasons that reduced serotonin levels might also be beneficial. “We need to test that assumption,” said Warden.