Neural Mechanisms of Motivation and Reward

National Institute Of Mental Health

Investigators

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Abstract

We have been studying the neural underpinnings of reward value processing in the striatum. In doing so we discovered that inhibiting the neural activity of the ventral striatum in one side of the brain, a structure implicated in learning about reward values, altered motor impulsivity in our subjects. Impulsivity is the tendency towards rapid reactions to stimuli without consideration of the possible consequences. In our studies, impulsivity was modeled by the subjects inability to complete trials in a reward task that required a bar to be released after a variable wait period. When muscimol, a GABA-agonist that silences neurons, was injected into the striatum of the subjects, this suppression of the striatal region resulted in increased impulsivity (releasing the before the waiting period was finished we call these bar release errors). In a subsequent experiment, a viral construct expressing the gene to synthesize the DREADD (Designer Receptor Exclusively Activated by Designer Drug, an altered muscarinic receptor) was injected into the same region where the muscimol had been injected. After waiting 6 weeks for the gene to express, we were able to confirm expression of the hM4Di protein by imaging the gene in a PET (positron emission tomography) scan using a radioactive carbon (11C) label. In behavioral experiments, on separate days clozapine N-oxide and deschloroclozapine were injected systemically (intramuscularly) to activate the DREADD. Activation of the DREADD suppresses neuronal activity. Normally the monkeys seem to have little trouble waiting for the go signal. On the days when a DREADD activating drug were injected, impulsive behavior increased by a large amount the monkeys frequently released the bar before the go signal appeared. The subject continued to perform the task, eventually obtaining as much reward as on days without DREADD activation, indicating that the subject remained motivated to perform. Thus, both the pharmacological and DREADD methods of suppression of neural activity increased impulsivity, supporting the conclusion that this ventral caudate region of the striatum important for inhibition of motor impulses. Above we reported that virally introduced artificial genes, such as the DREADD, allows us to manipulate neural activity in targeted regions. We would like to develop this technology further. Small molecules, inhibitory RNAs (siRNAs) block translation of normal RNA protein synthesis. We have expressed a gene to make siRNA targeting the RNA that codes for synthesis of Choline Acetyltransferase (ChAT), an important enzyme needed to make the neurotransmitter acetylcholine. When we express the DREADD gene in the same construct, we find that when the DREADD level is high, the level of Choline Acetyltransferase (ChAT) is low. This shows that we can use the DREADD to monitor the ChAT activity in vivo through use of PET (positron emission tomography). We are now extending this technique to control the expression of siRNAs using the antibiotic Doxycycline (Dox). Dox gating of protein synthesis is a standard method in rodents not yet applied to primates. We have thus far shown that the Dox apparatus is expressed, and that we can turn the Dox apparatus on at the local injection site when Dox is given systemically. We are now testing whether we can detect control of the ChAT synthesis using the Dox apparatus.