The hippocampus is a brain structure involved in memory as well as anxiety and depression-related behavior. One unique property of the hippocampus is that adult neurogenesis occurs in this region. Rodent studies in which adult hippocampal neurogenesis is ablated have shown a role for this process in the cognitive domain, specifically in pattern separation tasks, as well as in mediating the behavioral effects of antidepressants. These studies have furnished the intriguing hypothesis that increasing adult hippocampal neurogenesis may improve these functions and therefore serve as a target for novel treatments for cognitive impairments as well as depression and anxiety disorders. Here, we use both genetic and pharmacological models to increase adult neurogenesis in mice. Under baseline conditions, we find that increasing adult hippocampal neurogenesis is sufficient to improve performance in a fear-based pattern separation task, but has no effect on exploratory, anxiety or depression-related behavior. In mice exposed to voluntary exercise, increasing adult hippocampal neurogenesis increases exploration, without affecting anxiety or depression-related behavior. Finally, in mice treated with chronic corticosterone, a model of anxiety and depression, increasing adult hippocampal neurogenesis is sufficient to prevent the behavioral effect of CORT on anxiety and depression-related behavior. Here, we therefore describe dissociations between the effects of increasing adult hippocampal neurogenesis under baseline, voluntary exercise and chronic stress conditions. Together, our results suggest that increasing adult hippocampal neurogenesis has therapeutic potential for both cognitive, and anxiety and depression-related disorders.

The astounding capacity for learning ranks among the nervous system’s most impressive features. This thesis comprises studies employing varied approaches to improve understanding, at the level of neural circuits, of the brain’s capacity for learning. The first part of the thesis contains investigations of hippocampal circuitry – both theoretical work and experimental work in the mouse Mus musculus – as a model system for declarative memory. To begin, Chapter 2 presents a theory of hippocampal memory storage and retrieval that reflects nonlinear dendritic processing within hippocampal pyramidal neurons. As a prelude to the experimental work that comprises the remainder of this part, Chapter 3 describes an open source software platform that we have developed for analysis of data acquired with in vivo Ca2+ imaging, the main experimental technique used throughout the remainder of this part of the thesis. As a first application of this technique, Chapter 4 characterizes the content of signaling at synapses between GABAergic neurons of the medial septum and interneurons in stratum oriens of hippocampal area CA1. Chapter 5 then combines these techniques with optogenetic, pharmacogenetic, and pharmacological manipulations to uncover inhibitory circuit mechanisms underlying fear learning. The second part of this thesis focuses on the cerebellum-like electrosensory lobe in the weakly electric mormyrid fish Gnathonemus petersii, as a model system for non-declarative memory. In Chapter 6, we study how short-duration EOD motor commands are recoded into a complex temporal basis in the granule cell layer, which can be used to cancel Purkinje-like cell firing to the longer duration and temporally varying EOD-driven sensory responses. In Chapter 7, we consider not only the temporal aspects of the granule cell code, but also the encoding of body position provided from proprioceptive and efference copy sources. Together these studies clarify how the cerebellum-like circuitry of the electrosensory lobe combines information of different forms and then uses this combined information to predict the complex dependence of sensory responses on body position and timing relative to electric organ discharge.

The capacity for memory is one of the most profound features of the mammalian brain, and the proper encoding and retrieval of information are the processes that form the basis of learning. The goal of this thesis is to further our understanding of the network-level mechanisms supporting learning and memory in the mammalian brain. The hippocampus has been long recognized to play a central role in learning and memory. Although being one of the most extensively studied structures in the brain, the precise circuit mechanisms underlying its function remain elusive. Principal cells in the hippocampus form complex representations of an animal's environment, but in stark contrast to the interneuron population -- and despite the apparent need for functional segregation -- these cells are largely considered a homogeneous population of coding units. Much work, however, has indicated that principal cells throughout the hippocampus, from the input node of the dentate gyrus to the output node of area CA1, differ developmentally, genetically, anatomically, and functionally. By employing in vivo two-photon calcium imaging in awake, behaving mice, we attempted to characterize the role of dened subpopulations of neurons in memory-related behaviors. In the first part of this thesis, we focus on the dentate gyrus input node of the hippocampus. Chapter 2 compares the functional properties of adult-born and mature granule cells. Chapter 3 expands on this work by comparing granule cells with mossy cells, another glutamatergic but relatively understudied cell type. The second part of this thesis focuses on the hippocampal output node, area CA1. In chapter 4, we characterize an inhibitory microcircuit that differentially targets the sublayers of area CA1. And in chapter 5, we directly compare the contributions of these sublayers to episodic and semantic memory.

Recognizing and understanding where and when events occurred is essential for normal learning and memory of life experiences. Disruptions in the normal processing of spatial and episodic memories can have devastating consequences; in particular, this is one component of the debilitating cognitive deficits of schizophrenia. We are just now beginning to understand the molecular changes in schizophrenia, but still very little is known about how neural circuit are disrupted that lead to behavioral and cognitive dysfunction. In my thesis I will attempt to address two primary questions; how does hippocampal circuitry support spatial-episodic memories, and what goes wrong when these circuits and memories are impaired? First, how precisely do hippocampal circuits support spatial and episodic learning? In 1885 Hermann Ebbinghaus published the first results of a quantitative study of the psychology of memory, showing the predictable forgetting of items over time. Since then, psychologists and cognitive scientists have investigated, described, and defined the precise nature of memory and the behaviors it drives. We eventually realized that memory is not a unitary function of the brain, but that it is dissociable at it’s broadest level into explicit, recollectable memories and the implicit memory of learned skills and abilities. We have now identified networks of brain regions that are essential for these functions. The first functional imaging of the human brain further advanced out understanding of the particular brain regions active during memory tasks and technological advances have allowed us to generate higher resolution functional maps of the brain. Moving to rodent models, we are now getting closer to the memory engram, the set of changes that occur in the brain that store an object, event, or association for future recall. In some particular instances, such as spatial and episodic memories, we already have a very good understanding. But, which particular cells store this information and how does that memory come to be? In my primary thesis project, I will show that the stabilization of firing patterns in principal cells in hippocampal area CA1 supports learning of a spatial reward task. More specifically, as task demands shift pyramidal cells in CA1 specifically encode the reward zone by firing when the mouse is at the correct location. Finally, by modeling the shift of pyramidal cell activity throughout learning, I show the way in which the population of cells shift their firing activity to encode the reward zone. Second, what goes wrong in the normal processing of information that leads to disrupted memory storage and recall? Deficits in spatial and episodic memory are two of the primary cognitive dysfunctions in schizophrenia. While, hallucinations and delusions are perhaps the most widely recognized, they are in part treatable with antipsychotics, while the cognitive and memory deficits are not as well understood, untreatable, and the greatest barrier to rehabilitation. Cognitive deficits observed in schizophrenia patients are, at their core, neuronal circuit disruptions, spanning multiple brain regions and cognitive domains. What can we learn about the circuits underlying these behavioral symptoms? What goes wrong in the brain that is driving these disruptions? I focused on one particular well-characterized brain region (the hippocampus) by recording the activity of hippocampal area CA1 principal cells in an etiologically-validated mouse model of schizophrenia while the mice are actively engaged in a spatial learning task. I identified specific features of the place cell population that are disrupted and predict behavioral deficits - the day-to-day firing stability of the neuronal population and the lack of over-representation of the reward zone. Overall, my work used head-fixed two-photon functional imaging of awake mice to chronically record the activity of distinct components of the hippocampal memory system: long-range inhibitory projections from the entorhinal cortex to hippocampal area CA1, adult-born granule cells in the dentate gyrus, and large heterogeneous populations of CA1 principal cells. I recorded activity during hippocampal-dependent learning and memory tasks in both schizophrenia-mutant and wildtype mice in order to directly probe hippocampal circuits involved in spatial learning. These experiments provided new evidence of the underlying cellular substrates of both healthy and diseased spatial memory processing.

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Thesis (Ph.D.), Memorial University of Newfoundland, 2000. / Bibliography: leaves 109-124.

Thesis (Ph. D.)--University of Hong Kong, 2010. / Includes bibliographical references (p. 256-292). Also available in print.

published_or_final_version / Medicine / Master / Doctor of Medicine

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