Not making this up: A team of researchers has used light to make a mouse’s brain run better and relieve the mouse’s mousy version of depression. (Paper — a pdf download — is here.) This is potentially pretty big. For one thing, it’s what science writer John Pavlus would call awesome. For another, it expands and elaborates on remarkable work by neurologist Helen Mayberg and colleagues tweaking human depression circuits with conventional deep brain stimulators. This optogenetic work suggests a less intrusive, even more exacting way to test, define, and tweak such circuits.
The researchers, led by Stanford University’s Karl Deisseroth and UT Southwestern psychiatrist Eric Nestler, used optogenetics — a technique that makes specific neurons sensitive to light and then lets you use light to activate or silence them — to increase activity in a key part of a mouse’s prefrontal cortex.
As the researchers put it,
we used viral vectors to overexpress channel rhodopsin 2 (a light-activated cation channel) in mouse mPFC to optogenetically drive “burst” patterns of cortical firing in vivo and examine the behavioral consequences….. In … mice that expressed a strong depressive-like phenotype [in reaction to chronic social defeat — that is, losing dominance struggles with other mice] …, optogenetic stimulation of mPFC exerted potent antidepressant-like effects, without affecting general locomotor activity, anxiety-like behaviors, or social memory. These results indicate that the activity of the mPFC is a key determinant of depression-like behavior, as well as antidepressant responses.
The Guardian has a good description of this technique, and YouTube has a vid of Deisseroth, its main developer, describing it. This fancy intervention managed to ramp up the activity of a key part of the mouse’s forebrain and relieve their depression: That is, after the treatment, the mice, which had been made depressed by repeated “social defeat” experiences, ran mazes better, ate more normally, and did better in social contacts with other mice. They also showed gene expression and other changes in their brains consistent with feeling and doing better.
This follows up on a line of work I’ve been tracking for years: Emory neurologist Helen Mayberg’s experimental manipulation of depression circuits in humans. As I’ve explained before, Mayberg, working on small groups of patients in pilot studies, has relieved otherwise uncurable depression in about 60 percent of patients by snaking wires into their brains and sending low-voltage current to a highly particular spot called Area 25. Area 25 seems to be a hyperactive area in depressed people — a sort of gate that left open. Lightly buzzing Area 25 appears to calm both it and nearby areas such as the amygdala associated with anxiety and fear. And calming it seems to ramp up activity in the forebrain. When it works, anxiety areas ramp down; thinking areas ramp up; patient feels better, starts living again.
Mayberg has suggested several times, including in a recent talk at the Society of Neuroscience annual meeting, that she thought it might be possible to use other means less intrusive than drills and wires — optogenetics in particular — to tweak the circuit she’s been buzzing with her stimulators. (Optogenetics as now done is still pretty intrusive, but seems to have more potential for lower-impact use down the line. It can also be targeted more specifically than DBS can.)
Nestler, Deisseroth and company have now essentially used optogenetics to replicate Mayberg’s work in mice, and it seems to have worked. Their target — a particular area in the mouse’s ventral-medial PFC — is a rough mouse equivalent of Area 25 in humans, which Mayberg targets in her DBS pilot studies.
The usual needs-more-work caveats apply here, of course. Dynamics that affect mouse depression sometimes carry to people and sometimes don’t. And a key question is which of the many areas downstream of the ventral-medial PFC this affects, and whether this more exacting method actually ends up hitting the same or different areas that the DBS technique hits. Hitting specific areas with accuracy exact might be good. On the other hand, as with antibiotics, sometimes a little slop is a good thing. No one knows. But if Deisseroth et alia or others take this line of work further, they may find out.
Any way you cut it, this is a damned intriguing and potentially very significant piece of work. I’ll be interested to see what happens if — it’s probably more a matter of when — they, or Mayberg, or someone else tries it in humans.
Karl Deisseroth’s Oct 2010 Scientific American article on optogenetics
Controlling the Brain with Light (video)
Deisseroth Lab, Stanford University
Light switches on the brain (recent article on Deisseroth’s work by Mo Costandi)
Eric J. Nestler – Wikipedia, the free encyclopedia
Helen Mayberg on Charlie Rose
A Depression Switch? – My New York Times Magazine feature on Mayberg’s work