Primate inhibitory neurons in hippocampal CA3-CA1 intrinsic circuits

Abstract The hippocampus is associated with adaptive learning and memory, processing multimodal signals within its intrinsic circuits, where inhibitory neurons have a fundamental role. Studies of inhibitory hippocampal neurons in rodents have produced massive data on their types, physiology, and connectivity, organized into large databases, but not yet achieved for primates. Given the primate expansion of the hippocampus in parallel with the cortex, a primate animal model is crucial. Concomitant elaboration of the hippocampal inhibitory system across primates, facilitates primate-specific circuit interactions, as seen in the cortex, thalamus, and amygdala. In concert with the hippocampal expansion in primates, extensive evidence implicates disruption of distinct inhibitory hippocampal neurons in psychiatric diseases in humans, including schizophrenia and post- traumatic stress disorder. The goal of the proposed research is to investigate in a primate animal model inhibitory neurons in the intrinsic circuits of CA3-CA1 fields of anterior hippocampus through: 1- Estimation of the neurochemical inhibitory neuron makeup using unbiased stereology and analyses; 2- Study of biophysical properties of single-neurons using in-vitro electrophysiology, their detailed morphology through staining, confocal imaging, and quantitative measures and analyses; 3- Study of innervation targets and interconnectivity of hippocampal inhibitory neuron types at high resolution through confocal imaging and electron microscopy; and 4- Computational modeling to simulate the role of inhibitory neuron types in the intrinsic hippocampal network and dysfunction in psychiatric diseases, based on data from Studies 1-3 and the published literature. The focus of study is on the anterior hippocampus, based on its strong connections with the amygdala, and projection to prefrontal cortex. These pathways are associated with emotion and cognition, in processes that are disrupted in psychiatric diseases. The proposed studies will probe quantitatively the hippocampal inhibitory system in a primate model system, with novel studies that estimate the extent of expansion, neuronal specialization, and connectivity on intrinsic function. Data will be collected quantitatively and organized in databases for efficient dissemination to the research community to allow comparison with existing data from rats and mice. The combined studies will help identify specialized primate loci prone to disruption in the hippocampal inhibitory system, rendering humans uniquely susceptible to complex cognitive-affective disorders, and thus are of high clinical relevance for developing effective therapies.