Neurophysiological and Optogenetic Tools

Our Program Project Grant faculty use state-of-the-art neurophysiological recording techniques—including recordings from identified neurons in vivo and in brain slices—to characterize the many types of changes that drugs of abuse induce in the electrical excitability of their target neurons. Such functional plasticity encompasses changes in the intrinsic excitability of whole neurons (sometimes referred to as homeostatic plasticity), as well as changes in the efficiency of individual synapses (referred to as synaptic plasticity, such as long-term depression and long-term potentiation). There is now considerable evidence—much from this Program Project Grant—that stimulant and opiate drugs of abuse induce both major forms of plasticity in neurons that comprise the brain's reward circuitry and that these plastic adaptations are important mediators of the behavioral abnormalities that define a state of addiction.

The figure shows that medium spiny neurons of the nucleus accumbens show greater intrinsic excitability upon activation of the transcription factor, CREB (caCREB), and less excitability upon blockade of CREB (dnCREB). Our Program Project Grant has, over the past decade, been instrumental in demonstrating that activation of CREB in this brain region, via increasing the excitability of these neurons, mediates tolerance and dependence to stimulant and opiate drugs of abuse.

Optogenetics describes the ability to regulate the activity of a protein with light. In its most commonly used version, mutant forms of non-mammalian ion channels or pumps that are activated by specific wavelengths of light are expressed in neurons and used to control the activity those cells in vivo. In this way, it is possible to directly demonstrate what role a particular change in neuronal activity plays in the addiction process. Program Project Grant faculty are leading the field in using optogenetic tools to decipher the neural circuitry of addiction.

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