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.