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Hyperactivity in brain’s “self-control” center may stifle the pleasure-seeking urge

no fun signDiagnosing depression in a rodent is no mean feat. If you ask a rat how it's feeling, it won't tell you. But with a little ingenuity you can test that rat's willingness to expend some energy in the quest for a pleasurable outcome.

And with the right technology, you can manipulate the rat's so-called reward circuitry - a network of brain areas collectively responsible for enjoyment - and see what happens. That provides strong clues about how the reward circuitry works in us people, because rats' reward circuitry looks and functions very much like ours.

Practiced wisely, the pursuit of happiness ennobled by Thomas Jefferson in the Declaration of Independence is a successful species-survival strategy. It gets us to do more of exactly the kinds of things that keep us alive and result in our having more offspring: food-seeking and ingestion, hunting and hoarding, selecting a mate and, last but not least, actually mating.

The reward circuitry includes nerve bundles that run from deep inside the brain to numerous spots including, for example, the nucleus accumbens (associated with pleasure) and the more recently evolved prefrontal cortex, an executive-control center that guides our planning and decision-making, focuses our attention and generally keeps us organized. It's also the case that nerve bundles convey signals in the opposite direction, from the prefrontal cortex to various components of the reward circuitry.

The medial prefrontal cortex, with its portfolio of high-level "executive function" activities, plays its own obvious role in survival. After all, what if all we did was seek momentary pleasures, ignoring our top-down control center's "hey, cool it!" or "skip dessert!" or "get back to work!" commands? (When the reward circuitry escapes from this kind of control, the result can be addictive behavior.)

But Stanford neuroscientist and Howard Hughes Medical Institute investigator Karl Deisseroth, MD, PhD, in a study conducted with help from numerous other Stanford researchers and recently published in Science, has shown in rats that hyperactivity in the medial prefrontal cortex reduces signaling between key components of the reward circuitry and impairs rats' reward-seeking behavior. In humans, this dulling of the drive to pursue pleasure, known as anhedonia, is seen in a number of psychiatric conditions including, notably, depression.

To prove that increased signaling in the medial prefrontal cortex actually causes rather than results from or merely accompanies the physiological and behavioral results mentioned just above (and to show how the cortex exerts this influence), Deisseroth and his colleagues combined two techniques, optogenetics and functional magnetic resonance imaging (fMRI for short).

Optogenetics, a technology pioneered by Deisseroth over the past decade, entails installing light-sensitive proteins on the surface of selected nerve cells so that these cells - and only these cells - can be directly excited or inhibited by specific frequencies of laser light delivered via an optical fiber surgically implanted into the brains of living, moving animals; fMRI simultaneously monitors nerve-activity levels in multiple brain regions. Combining the two allowed the scientists to excite or inhibit specific nerve cells at will in particular clusters of nerve cells and watch what the rest of the brain did.

When the scientists stimulated or inhibited midbrain reward circuits, they saw, respectively, increased or reduced reward-seeking behavior. When instead they optogenetically predisposed nerve cells in the medial prefrontal cortex to be more excitable, they observed that reward-circuit components were no longer able to communicate with each other, and that this in turn suppressed reward-seeking behavior.

The findings could lead to new ways of diagnosing, treating and preventing depression. Or, for that matter, maybe to a whole new philosophy of life.

Previously: A word with Karl Deisseroth, Stanford researchers tie unexpected brain structures to creativity - and to stifling it, Party animal: Scientists nail "social circuit" in rodent brain (and probably ours, too) and Revealed: The brain's molecular mechanism behind why we get the blues
Photo by Tiffa Day

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