Altered prefrontal functions are found in a number of neuropsychiatric disorders, such as schizophrenia, bipolar disorders, ADHD and autism. Thus, understanding how the prefrontal cortex interacts with other neural structures to modulate behavioral and cognitive functions will be invaluable for better characterizing the neural underpinning of human psychiatric disorders. To this end, the present proposal assesses will investigate the dynamic control of dorsolateral prefrontal cortex (dlPFC) by the hippocampus during working memory performance. This innovative and exploratory study combines pharmacological inactivation techniques with behavioral testing, functional neuro and PET imaging and neuroanatomical tracers to directly assess whether hippocampal modulation of dorsolateral PFC function occurs via the meso-limbic dopamine system (a circuit including the nucleus accumbens, ventral pallidum and ventral tegmental area (VTA)). Such a circuit has been demonstrated in rodents, however, this will be the first direct demonstration that this circuit exists and functions similarly in models with a highly developed dlPFC. In the first set of experiments, we will explore the effects of anterior or posterior inactivation of the hippocampus on performance of a working memory task known to depend upon the integrity of the dlPFC, the self-ordered task. Having demonstrated that hippocampal inactivation affects performance on this task, we will then use 18F-FDG PET imaging to assess that hippocampal inactivation directly impacted dlPFC activation during working memory. The results of these experiments will directly demonstrate the changes in prefrontal activity associated with hippocampal activity. The second group of experiments will directly assess the role of the meso-limbic dopamine system is the circuit by which hippocampus modulates dlPFC activity. Specifically, they will test the hypothesis that the ventral pallidum functions to tonically VTA neurons until inhibited by hippocampal evoked release from the nucleus accumbens. In these experiments, tonic inhibition from the nucleus accumbens to the pallidum will be lowered using the GABA-A antagonist bicuculline, resulting in activation of the pallidum. This increased activation will inhibit VTA activity, thereby reducing dopamine release into the dlPFC and resulting in reduced dlPFC metabolism and impairinged working memory. To confirm this circuit, the final study will use anterograde tracers into the anterior hippocampus and retrograde tracers into the ventral pallidum to demonstrate that the tracers co-localize in the nucleus accumbens. The data will provide a better characterization of the basic neural circuitry that can be profoundly altered in many psychiatric disorders and will help design better treatment and prevention of these debilitating human disorders. Relevance: Working memory disruptions are characteristic symptoms of a number of psychiatric and neurological illnesses including but not limited to: Schizophrenia, Bipolar Disorder (BPD), Alzheimer's Disease (AD) and Parkinson's Disease (PD). Identifying neurobiological circuits normally interacting with the dorsolateral prefrontal cortex is key in the search for ways of treatment or prevention of these disorders. Experimental models that possess a well-developed prefrontal cortex, may offer a way to study how this cortical region acts in conjunction with other brain areas to maintain normal working memory processes. This innovative proposal will use a combination of reversible inactivation, functional neuroimaging, cognitive testing and neuroanatomical procedures to manipulate and confirm the existence of a meso-limbic circuit connecting the hippocampus to the prefrontal cortex at the service of executive functions. The development of this multifaceted project will provide the starting point for many future studies aimed at the search for the causes (neurotransmitter imbalance, maternal alcoholism, drug abuse, or excitotoxic agents) of the hippocampal-prefrontal system in the neuropathology of schizophrenia, bipolar disorders and other psychiatric disorders associated with dlPFC dysfunction, as well as a search for possible therapeutic treatment.