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Neural Circuits Underlying Reward-Dependent Behavior and Their Perturbation in Diseases of Compulsive Drive
Summary: Alla Karpova's goal is to understand the circuitry behind the ability of animals to adapt their behavior to constantly changing reward contingencies. She is also interested in how dysfunctions in this circuitry lead to diseases of perseveration, such as addiction and obsessive-compulsive disorder. Her lab will combine specific in vivo manipulations of neural circuits in the context of quantitative behavioral studies with in vitro and in vivo analyses of circuit function.
Most animal behavior is motivated by the desire to acquire rewards. At the beginning of the 20th century, classic studies by Pavlov demonstrated that animals learn to associate a stimulus with a reward, and that this association can be reversed if subsequent experience shows that it is no longer valid. Furthermore, Pavlov hypothesized that dysfunctions of brain areas underlying this associative learning may be involved in mental disease. Today, it is appreciated that the network of neurons that accomplishes Pavlovian learning is astonishingly complex, but it remains unclear how, or even if, impairments in Pavlovian learning lead to mental disorders. To dissect this neural network, scientists must manipulate specific circuit components precisely. In my lab, we will invent molecular tools to do this, and we will use these tools to study the reward network and its relationship to mental 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.
Although these results are the first evidence suggesting a specific role for the dopaminergic system in the development of sensory processing, the systemic perturbation used in this study suffers from a standard drawback of various "lesion" techniques—lack of specificity. Probably the best approach to study the contribution of a particular component of a neuronal network to its overall function would be to rapidly and reversibly inactivate synaptic transmission mediated by that component. During my postdoctoral training, I—among others—developed a set of novel silencing systems that makes it possible to achieve this. We refer to these systems as MISTs (molecular systems for the inactivation of synaptic transmission). MISTs interfere with synaptic transmission by chemical induction of dimerization of modified synaptic proteins, and they are effective at perturbing neural activity in vitro and in vivo.
I am interested in analyzing the neural circuits underlying reward-based behaviors dependent on the prefrontal cortex. In particular, I am interested in understanding how animals adapt to changes in stimulus-reward contingencies within the context of reversal training paradigms. I am also interested in how these circuits are perturbed in diseases of compulsive drive, such as obsessive-compulsive disorder and drug addiction. My lab will combine specific perturbations of various components of the underlying complex neural circuit within the context of behavioral assays with in vitro and in vivo assessment of the effect on the functional circuitry.
Overall, I am interested in understanding the following: What circuitry guides reward-dependent behaviors in the prefrontal cortex, and how is it perturbed in neurological disorders? The combination of physiology with behavioral and genetic approaches that use "MISTed" mice, as well as animal models of the relevant neurological disorders, should provide an opportunity to make progress toward this ambitious goal. One potential problem is that the MISTs we have developed are useful only for transient inactivation of fast synaptic transmission; they do not allow other targeted manipulations of neural circuitry that might be helpful for pursuing the functional importance of the prefrontal cortex. Therefore, we will continue to develop novel molecular tools to address systems neuroscience problems in parallel with pursuing the applications described above.
This work has been supported in part by grants from the National Institutes of Health, the Helen Hay Whitney Foundation, and the Burroughs Wellcome Fund.
Dr. Karpova will start her lab at Janelia Farm in 2007.
Last updated: September 6, 2006
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