September 21, 2009 |
by Warren Grill, senior technical editor
September 21, 2009
The ability to regulate the activity of specific populations of neurons—either stimulating them or silencing them—is an essential element of modern neuroscience and a promising approach for treatment of neurological disorders. The selective activation or inactivation of neurons has been accomplished in a number of ways including chemical stimulation or inactivation, electrical stimulation, and through ablative lesions. More recently we have seen the introduction of powerful optogenetic techniques that use light coupled to exogenously expressed light-responsive ionic channels to control neuronal activity [NBR Jan07 p1, NBR Oct08 p1].
However, all of these approaches rely, to some degree, on distance between the neurons and the “source”—be it a fiber optic, metal electrode, or chemical delivery cannula—and selective control of the activity of spatially diffuse populations of neurons remains a challenge. In a recent paper in Nature Neuroscience, Koda and colleagues from the National Institute on Drug Abuse Intramural Research Program introduced a novel approach to silence only those neurons that were electrically active during a specific behavior. This approach, called Daun02-inactivation, serves as a more selective approach to determine the role of a particular population of neurons than the classical tools of chemical or electrical stimulation.
Koda’s team developed the Daun02-inactivation method to determine the role of neurons in the nucleus accumbens in learned associations between cocaine administration and the physical environment. They used transgenic mice in which the promoter for the c-fos gene regulated the expression of the lacZ gene. c-fos is an immediate early gene, which encodes the Fos nuclear regulatory protein, and is expressed selectively and transiently in electrically active neurons. lacZ is a bacterial gene that encodes the protein β-galactosidase. Thus, in these mice, neuronal activity led to co-expression of c-fos and lacZ, and subsequent synthesis of both Fos and β-galactosidase.
As well, the drug Daun2 was locally microinjected into the nucleus accumbens, and β-galactosidase converted Daun2 into daunorubicin, an antitumor compound that kills cells or renders them electrically silent. Since β-galactosidase was only present in those cells that were electrically active, only those neurons were silenced or killed by the daunorubicin. This enabled the researchers to conclude that a diffuse ensemble of neurons in the nucleus accumbens was responsible for the association between the physical environment and cocaine administration.
In addition to its role as a powerful tool to study the function and dysfunction of neural circuits as well as their role in behavior, the Daun02-inactivation method may provide a novel intervention to treat neurological disorders. Although clearly in its infancy, selective disruption of active neurons may prove useful in diseases where there is abnormal activity in populations of neurons.
For example, this approach may enable much more selective elimination of epileptic foci than possible through surgical resection or selective silencing of neurons in movement disorders, where there appears to be a strong correlation between bursting activity in neurons of the basal ganglia and thalamus and symptoms.
