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PHOTOGRAPH BY SAM KAPLAN

Karl Deisseroth believes optogenetics is well suited to studying neuropsychiatric disorders, and many of his experiments in rodents aim to parse different neural circuits that account for varied aspects of depression and its diverse causes. Recently, he and his collaborators have concentrated on learning how neurons in one brain region may connect to others within the same region and also to other regions.

For example, Deisseroth and Kay Tye, a principal investigator in neuroscience at MIT, who was previously a post-doctoral researcher in Deisseroth’s lab, wanted to manipulate a “microcircuit” of connections within the amygdala, which numerous previous studies have implicated in stress and anxiety. They wanted to control signals running from the basal lateral amygdala (BLA) to the central amygdala (CeA), and see whether exciting BLA neurons increased anxious behaviors and whether inhibiting those neurons ameliorated the anxiety.

But directing light at the neural cell bodies in the BLA did not have the anticipated effect on anxious behavior—likely because the neurons project along pathways that can have opposing functions and counteract the anxiety circuit. Tye wanted to selectively activate or inhibit just the BLA cells that projected to the CeA, so she exploited the fact that when neurons express the gene for an opsin, the light-activated protein appears all over the neuron’s membrane, including on the axon fibers that connect to other neurons. The BLA axons reaching the CeA had the light-activated proteins, but none of the neurons residing in the CeA had them. As a result, shining the light on the CeA just controlled the BLA neurons projecting into the CeA; it didn’t affect the CeA neurons themselves or any BLA neurons projecting to other regions that counteract the anxiety circuit. And indeed, as reported in a March 2011 paper in Nature, this more targeted control allowed her to dial anxiety up and down in mice.

In a December 2012 Nature study, Tye and Deisseroth used a similar method to regulate two different manifestations of depression in rodents—lack of pleasure and lack of motivation—by controlling the circuit leading from the brain’s reward processing center (the ventral tegmental area) to its pleasure center (the nucleus accumbens). They illuminated projections from neurons producing dopamine, a neurotransmitter normally associated not with depression but with habits, addiction and movement disorders. Current antidepressants and deep brain stimulation treatments for major depression do not target the dopamine circuit. But the knowledge generated by such optogenetic studies could help tweak these therapies to be more effective.

Such studies show that antidepressant treatments could potentially focus on circuits linked to a particular psychological symptom, and they could help determine an appropriate 
treatment for an individual. “We won’t have one antidepressant drug that works for everybody,” says Tye, “but it might be possible to have treatments tailored to each individual patient.”

To extend this work further, optogenetic researchers hope to determine not just which brain regions the axon projections extend to but also the precise kinds of neurons the axons connect to. Such information could enable scientists to explore feedback loops within a circuit, including those implicated in epilepsy.

One type of epilepsy results from a traumatic head injury that causes a stroke in the cerebral cortex—the brain’s outer layer in which higher-order processing occurs. But intervening there with surgery—the typical approach to controlling seizures that drugs can’t prevent—risks worse damage.

Studies have suggested that the injured cortex communicates with the remote thalamus during epileptic seizures with back-and-forth signals that become self-perpetuating. By inducing this type of seizure in rats and then examining the brain tissue, Stanford neurologist John Huguenard surmised that although the seizure originates in the cortex, it’s the thalamus that becomes hyperexcited and propagates the seizure. In collaboration with Deisseroth’s lab, he used halorhodopsin, the light-activating protein that silences neurons, to dampen the thalamus’s excitability when a seizure began. Upon illumination, the seizures immediately stopped, the oscillations between the thalamus and the cortex returned to normal, and the rat again behaved normally.

The researchers also engineered a method for detecting and then silencing seizures as they occurred. They coupled the optical device that delivers the light with an electrode that could detect abnormal firing in the thalamus and trigger the light to pulse on. That illumination inhibited the neurons with the halorhodopsin, and it prevented the seizures. The study, published in the January 2013 issue of Nature Neuroscience, proved that the thalamus was necessary to maintain the seizure—the first evidence that it plays a part in epilepsy—and suggested that targeting the thalamus, rather than the cortex, could successfully treat this type of seizure.

“This is a great illustration of how a structure remote from primary brain damage but connected to it by long-range projections can be involved in abnormal brain network activity, and that it can be targeted therapeutically,” says Bruce Rosen, director of the Martinos Center for Biomedical Imaging at MGH, who was not involved in the study. “It shows us a new site for deep brain stimulation that we didn’t know before.”

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Scientist Walter Rudolf Hess conducted one of the first experiments to test whether neural activity in a defined part of a cat's brain causes specific actions.

What’s Next for Optogenetics?

Using flashes of light to control brain cells may be only the beginning for a remarkable research tool.

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1. “A History of Optogenetics: The Development of Tools for Controlling Brain Circuits with Light,” by Edward S. Boyden, F1000 Biology Reports, May 3, 2011. This account of the development of optogenetics, by one of its inventors, includes middle-of-the-night “aha!” moments, with credit given to other researchers and to serendipity.

2. “Dopamine Neurons Modulate Neural Encoding and Expression of Depression-Related Behaviour,” by Kay M. Tye et al., Nature, January 2013. This study provided new insights into the role of dopamine in symptoms of depression by probing for the underlying neural circuits. The researchers integrated optogenetics with electrophysiology and pharmacology and used specially designed devices to precisely track behavior.

3. “Optogenetics, Sex, and Violence in the Brain: Implications for Psychiatry” by David J. Anderson, Biological Psychiatry, June 15, 2012. This study found a surprising neural link between aggression and sex, raising provocative questions about whether faulty wiring could account for some sexual pathologies.

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