The Role Of Pituitary Adenylate Cyclase Activating Polypeptide In The Dentate Gyrus In Regulating Behavior And Neurophysiology
Fear and anxiety disorders are potentially crippling conditions that often stem from past experience of trauma and chronic stress. One clear feature of these disorders is the failure to use proximate spatial and contextual information presented in the environment to regulate reflexive physiological threat responses. The central nervous system networks that govern spatial navigation and contextual learning and memory are a series of complex circuitries in which the hippocampus is integrally involved. Deficits in hippocampal function have been linked to severe anterograde and mild retrograde amnesia of semantic and episodic memory, and specific deficits in contextual processing. These deficits manifest as failure to distinguish between the details of contexts that help predict for danger or safety and can thus lead to the overexpression of threat responses that compose the behavioral symptoms of fear disorders. The dentate gyrus (DG) is a subdivision of the hippocampus that serves as the first filter of excitatory flow through the hippocampus. The DG is hypothesized to function in “pattern separation” or the dissociation of similar inputs into dissimilar outputs. Failure in this domain leads to generalization between contexts, a common feature of pathology.
Pituitary adenylate cyclase activating polypeptide (PACAP) and the PAC1 receptor are associated with multiple behavioral disorders such as post-traumatic stress disorder, schizophrenia, and bipolar disorder. Mutations in the PAC1 receptor gene are associated with hypervigilance, and modified amygdalar and hippocampal activity. These results are mirrored by rodent studies where central PACAP infusion causes anxiety-like behavior, pain hypersensitivity, anorexia, and reinstatement of drug-seeking. PAC1 receptor transcript is found in high abundance in granule cells of the dentate gyrus and potentiation of DG synapses is impaired in PAC1 knockout mice. PACAP is known to have effects of long-duration, such as those in injury repair, growth, and development, but it also can affect ion channel physiology to control neuronal excitability through several parallel intracellular signaling cascades including those dependent on adenylyl cyclase, phospholipase C, and extracellular signal regulated kinase. Accumulated evidence suggests that recruitment of extracellular signal regulated kinase can be through either adenylyl cyclase-, phospholipase C-, or a receptor endocytosis-dependent mechanism.
The experiments described in this dissertation address the role of PACAP in the DG in regulating expression of fear behavior, the effects of PACAP on the excitability of DG granule cells, and the signaling pathways and ion channels responsible for these effects. We found that PACAP infused into the DG amplifies expression of fear to a context but does not affect fear acquisition. Electrophysiology studies demonstrate that treating DG neurons with PACAP increases their excitability, and that parallel signaling mechanisms recruit extracellular signal regulated kinase to drive this excitability. Furthermore, these effects on excitability are attenuated by blocking a persistent inward sodium current. This work represents novel regulation of the DG and its impacts on behavior and identifies a current that likely participates in modulating granule cell excitability in multiple domains. In aggregate, this research traces the path from ligand, to receptor and intracellular signaling, to neurophysiology in order to propose a comprehensive description of behavioral regulation by these processes.