Our everyday lives involve numerous situations in which we base our choice of a particular action over possible others on our valuation of the corresponding outcomes. Such ability to dynamically estimate the value of actions and to reject suboptimal options in favor of more attractive ones is critical in complex and changing environments and is deficient in many neuropsychiatric disorders, particularly those involving dysregulation of dopamine signaling. My lab studies the circuitry that guides voluntary action selection based on the dynamic estimate of the rewarding consequences of different actions, as well as how this circuitry is perturbed in addiction and Parkinson's disease.
During my postdoctoral training, I began to assess the contribution of the reward system to the development and function of circuits underlying animal behavior by studying the rodent whisker system. Neonatal whisking in rodents has been found to be behaviorally important for the first rewarding experience in life, the mother-infant interactions. Remarkably, rodent primary somatosensory cortex shows exclusive transient up-regulation of the dopamine D3 receptor in layer 4 barrel cells over the second postnatal week, when the local circuitry matures. Using glutamate uncaging by laser-scanning photostimulation, I have found that blocking the D3 receptor by injecting animals subcutaneously daily with a specific antagonist over the second postnatal week leads to a dramatic uncoupling within the barrel cortex network that persists long after the end of the treatment. This change in a defined component of the whisker circuit correlates with a change in sensory perception in adulthood: animals treated with the antagonist as juveniles behave like sensory-deprived counterparts in the spontaneous gap-crossing assay. Thus the transient dopaminergic input is critical for the development of the fully functioning circuit and of proper sensory perception.
In general, however, relating the activity in specific neuronal circuits to physiological processes, behavioral responses, and disease states is a challenging task, especially in the highly complex mammalian brain. In classical studies, pharmacological or lesion approaches are used to inactivate neurons. These approaches have a variety of drawbacks. (1) Pharmacological agents often cannot select for particular cell types. (2) Controlling the spatial range of action of pharmacological agents requires local application and therefore surgery, but even with local application the spatial range of action of pharmacological reagents is often not well defined. (3) Pharmacological agents typically do not allow good temporal control. (4) Lesions produced electrolytically or by injection of cytotoxic compounds, such as kainite, are nonspecific, destroying all cell types in a region, and do not allow the manipulation of spatially extended subpopulations of neurons. (5) Except in some special cases, lesions are irreversible. The requirement for tools that allow rapidly inducible and reversible modulation of specific parts of neural circuits in vitro and in vivo has, thus, been widely recognized for some time. The past decade has seen an upsurge in the development and optimization of genetically encodable tools for perturbing neuronal activity, and several systems have been described. During my postdoctoral fellowship, I also developed a novel silencing system, which we refer to as MISTs (molecular systems for inactivation of synaptic transmission). MISTs, which interfere with synaptic transmission by chemical induction of dimerization of modified synaptic proteins, are effective at perturbing neural activity in vitro and in vivo. Initial in vivo applications of MISTs and other molecular tools have opened the exciting new field of highly specific perturbation of circuit function in behaving animals. We are planning to integrate precise circuit activity perturbation in defined brain regions.
In my lab, we are interested in analyzing the neural circuits underlying reward-dependent behaviors that rely on the function of the frontal cortex (FC). We are focusing on the neural circuits underlying action selection in the context of voluntary choice, and in particular on the role of the FC and its modulation by dopamine. We are also interested in how these circuits and the corresponding behaviors are deficient in disorders that manifest altered levels of dopamine, particularly addiction and Parkinson's disease. My lab combines specific perturbation of neural circuit function, using molecular tools; the identification of neural correlates of aspects of the behavioral tasks, using sophisticated electrophysiological and optical techniques with the analysis of functional connectivity in vitro, using robust techniques such as glutamate uncaging.
A grant from the National Institutes of Health and a grant from the Burroughs Wellcome Fund provided partial support for the work on MISTs and the role of dopamine in sensory cortex development.
As of May 22, 2009