Finding the motivation to carry out our tasks, even simple ones, can be difficult for everyone at one point or another. I could get up from the couch to refill my cup of tea, or I could continue sitting here writing this article. Now, that seems like a trivial situation. But a persistent inability to find the motivation for any task can be a sign of a larger problem: depression.

It has been estimated that around 20 percent of people suffer from major depression []. In addition to symptoms such as persistent negative feelings, fatigue, and difficulty concentrating, depression can be marked by a debilitating lack of motivation []. Unfortunately, very little is known about the biological causes of depression, much less how it affects motivation. In a paper recently published in Nature, however, Professor Karl Deisseroth and his team have begun unraveling the dynamics behind motivation—and the lack thereof experienced in people with depression.

Meet the model organism

Since human experimentation is not always feasible or ethical, the researchers turned to mice. Granted, since we cannot identify thoughts of death or suicide in animals, scientists can never tell if mice are truly depressed. However, under extreme stress and anxiety—similar conditions under which humans also develop depression—mice show depressive symptoms that are alleviated with antidepressant drugs. To some extent, then, these mice can experience a degree of depression sufficient to help scientists model and study the disorder. In this case, Deisseroth’s lab studied mice placed under stressful conditions using a test known as the forced swim test (FST). During FST, mice are placed in a tank of water from which there is no escape. During this time in the tank, the mice show two kinds of behavior: active escape behavior, characterized by swim kicks, or despair behavior, indicated by passive floating.

While the mice were undergoing the FST, researchers recorded neural activity from the pre-frontal cortex, specifically the medial pre-frontal cortex (mPFC). This front-most region of the brain broadly controls decision-making and has previously been implicated in depression. By comparing the behavior of the mice during the FST with the neural recordings, Deisseroth and his team found that some neurons in the mPFC became active only when the mice were immobile (“in despair” / unmotivated), while others only became active when the mice were swimming (“trying to escape” / motivated).

Controlling brain circuits with light

To pinpoint the precise neural circuits behind motivation, the scientists used a technique that enables them to control neural activity through light. This technique, known as optogenetics, utilizes a light-sensitive ion channel originally found in algae called channelrhodopsin. These molecular “pores” for ions (electrically charged atoms), located on the surface of cells, open when exposed to a precise wavelength of light, allowing positively charged ions to flow into the cell. Since neurons are activated by an influx of positive charge, introducing these channels into brain cells allow scientists to activate specific brain cells on command by directing a certain wavelength of light at the cells.

Left: Neurons from the medial pre-frontal cortex (PFC; labeled in blue) extend to their targets in the dorsal raphe nucleus (DRN; in green) and the lateral habenula (LH; in yellow). Right: Since only the blue mPFC neurons contain channelrhodopsin, when a fiber-optic channel implanted in the brain emits light onto the DRN, only neurons from the mPFC are activated.

Using optogenetics, the authors first tried to activate all neurons in the mPFC by directing light to that region of the brain. Since the mPFC is composed of a range of neurons with different activity profiles, it was unclear if there would be a net effect on mouse behavior during the stress test—in fact, there was no apparent change in the animal’s behavior in the FST. However, this result does not exclude the possibility that the mPFC plays a role in regulating motivation. Rather, it is possible that certain subsets of circuits from the mPFC regulate motivation.

Serotonin: a chemical motivator?

To test this idea, the authors next tried activating specific areas of the brain that receive input from the mPFC. One region scientists examined was the dorsal raphe nucleus (DRN), a center in the brain that produces serotonin, a chemical known as a neurotransmitter.

Individual neurons are activated by an influx of positive ions, but to transmit this activity to the next neuron in the circuit, the neuron converts this electrical signal into a chemical one. At the very end of a neuron, an influx of positive charges causes the release of neurotransmitters, chemicals that bind to receptors on the next neuron to trigger an influx of positive ions there. One of these neurotransmitters is serotonin. Disruptions in serotonin levels have been implicated in depression. You’ve probably heard of serotonin in the context of selective serotonin re-uptake inhibitors (SSRIs). This group of drugs is commonly prescribed to patients suffering from depression—SSRIs extend the amount of time serotonin is present between neurons, correcting for the shortage that is thought to partially cause depression.

Since the scientists have only put the gene of channelrhodopsins into mPFC neurons, by illuminating the DRN, only neurons that extend (or “project”) into the DRN from the mPFC should be activated. Surprisingly, stimulating the DRN led to a robust increase in the frequency of mice that remain motivated to swim during the FST. When the scientists stimulated the DRN again once the mice were in their home environment instead, no behavioral changes occurred. Together, these results show that stimulating mPFC neurons projecting to the DRN rapidly and specifically increased the animal’s motivation to struggle against a challenge. Using a similar experiment, the authors also discovered that activation of another part of the brain called the lateral habenula, a region above the brain stem, left mice less motivated. Interestingly, this region of the brain has been shown to be reduced in size in people with depression, and is a target in clinical trials for deep brain stimulation therapy in patients with severe and treatment-resistant depression.

What’s next?

While uncovering the pathways behind motivation is by itself interesting, this study contributes to our understanding of the type of changes that occur in the brain of someone with depression. Further research along these lines may reveal other neural markers of depression, perhaps one day leading to the development of better, targeted treatments to improve the lives of individuals with depression.

Andrea Yung is a graduate student in neuroscience at Harvard Medical School.

References

[] NMIH (2011). What causes depression? <http://www.nimh.nih.gov/health/publications/depression/what-causes-depression.shtml>

[] Deisseroth, Karl (2010). Optogenetics: Controlling the Brain with Light. Scientific American. <http://www.scientificamerican.com/article.cfm?id=optogenetics-controlling>

[] Warden, Melissa R. et al (2012). A prefrontal cortex-brainstem neuronal projection that controls response to behavioural challenge. Nature. <http://www.nature.com/nature/journal/vaop/ncurrent/full/nature11617.html>

Further Reading

Optogenetics Illuminates Pathways of Motivation Through Brain: http://www.sciencedaily.com/releases/2012/11/121118141528.htm

, National Institute of Mental Health

Ed Boyden: A Light Switch for Neurons (TED Talks) http://www.ted.com/talks/ed_boyden.html

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