Small-animal positron emission tomography (PET) is one of a few available techniques that allow insight into the living brain. However, applications to mental health questions remain a challenge;in large part due to the limitations the PET technique imposes on the study of behavior, a core method in the neurosciences that is used to infer the function of the brain. The goal of the present proposal is to develop a powerful new hybrid technique which can be termed behavioral neuroimaging - the simultaneous study of receptor mechanisms and behavior in rodents. A critical device that makes this possible is the Rat Conscious Animal PET (RatCAP), a novel miniature PET scanner which for the first time provides brain images while the rat is awake and active. In order to test our hypothesis that transient changes in DA neurotransmission are reflected in changes in the amount and type of behavioral expression which occur during the PET scan, we will employ the RatCAP together with a recently developed dopamine (DA) D2/3 receptor agonist radiotracer, 11C-(+)-PHNO (4-propyl-9- hydroxynaphthoxazine), and the Bolus + Infusion (B/I) technique. We chose to study female sexual behavior in part because it is ideal in the context of method development, involving a number of distinct behavioral expressions which can be readily quantified and correlated with the PET data. It is also an important area of research in its own right. Sexual satisfaction in women is associated with emotional well-being, relationship satisfaction and overall quality of life, and may contribute to improved physical health, but prevalence data suggest a surprisingly high rate of sexual dysfunction in the US. In order to test our hypothesis, we will first develop PET methods for 11C-(+)-PHNO imaging in awaken rats (Specific Aim 1). These will include methods for appropriate administration of the radiotracer and the processing and analysis of the PET data.
Specific Aim 2 is to demonstrate the correlation between PET and behavioral data from female rats engaged in sexual behavior. Elevations in brain DA in the striatum and extra-striatal brain regions, such as the hypothalamus, were found to coincide with an enhanced expression of proceptive behaviors in female rats, including solicitations, darts, and hops and paced mating behavior, which may indicate sexual desire and reward. We will measure these and other forms of sexual behavior with the expectation that transient changes in DA D2/3 receptor occupancy as assessed with 11C-(+)-PHNO will be related to changes in the amount and type of sexual behavior during the PET scan. In the long run, the direct correlation of the simultaneous datasets is expected to provide unprecedented insight into the neurochemical substrates of behavior. The methods developed here will pave the way for using the RatCAP in innumerable combinations of behavioral paradigm and neurochemical probe, potentially comprising a truly transformative multidimensional tool for the neurosciences.
Positron emission tomography (PET) is one of a few available techniques that allow insight into the living brain. By taking advantage of a unique new imaging device, this proposal aims to develop a new research paradigm, which for the first time combines PET with the simultaneous study of behavior, an indispensable method to infer the uses of different brain regions and their molecular constituents. The result is expected to provide unprecedented insight into the workings of the brain and guide research most effectively towards improved treatment of mental disorders, such as addiction, depression, and schizophrenia.
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