The medial temporal lobe supports the encoding of new facts and experiences, and organizes them so that we can infer relationships and make unique associations during new encounters. Evidence from studies on humans and animals suggest that the hippocampus is specifically required for our ability to form these internal representations of the world. The mechanism by which the hippocampus performs this function remains unclear, but electrophysiological recordings in the hippocampus support a general model. One component of this model suggests that the cortex represents places, times, and events separately, and then the hippocampus generates conjunctive representations that connect the three. According to this hypothesis, the hippocampus binds places and events to an existing relational structure. This dissertation explores how item and place associations develop within cortex, and then examines the relational structure that organizes these events within the hippocampus. The first study suggests that contrary to previous models, events and places are bound together outside of the hippocampus in the entorhinal cortex and perirhinal cortex. The second study shows that this relational scaffold may be embodied by a continually changing code that permits both the association and separation of information across the continuum of time. The final study suggests that the hippocampus and entorhinal cortex contain qualitatively different time codes that may act in a complementary fashion to bind events and places and relate them across time. Overall, these studies support a theory wherein time is encoded in a range of brain regions that also contain conjunctive item and position information. In these regions, conjunctive representations of items, places, and times are organized not only by their perceptual similarity but also their temporal proximity.

Memory is the basis of all complex social relationships. In the brain, the hippocampus is a structure that is critical for remembering interactions with, and information about, other individuals; in other words, it is critical for social recognition memory. Social memory consists of two related processes: the general sense of whether and to what extent one has previously encountered another individual (familiarity) and the specific recall of details or episodes that involve another individual (recollection). It remains controversial whether the hippocampus contributes to one or to both of these processes. Teasing out the role of the hippocampus in the different components of memory is challenging because it is not a homogenous structure but rather consists of many subpopulations of neurons that are specifically organized along its various axes. Broadly, the hippocampus is divided into the Cornu Ammonis subfields (CA1, CA2, and CA3), as well as the dentate gyrus. In addition to these subfields, the hippocampus demonstrates remarkable variation in neural and functional properties along the dorsoventral axis. The past decade has revealed that the dorsal CA2 (dCA2) subfield is particularly important for social recognition memory. Although dCA2 has been shown to respond to and represent social information, it remains unclear as to whether it contributes to both familiarity and recollection processing. In my thesis, I address the nature of CA2 social coding using large-scale optical imaging of calcium activity in hundreds to thousands of pyramidal neurons selectively targeted within dCA2. Through intensive decoding and cross-condition analysis, my studies reveal that dCA2 contributes to the classification of novel from familiar individuals in a way that is separate from their identity, thus demonstrating familiarity processing in this region. In addition, I show that dCA2 neural activity can discern the identities of individuals with the same degree or novelty or familiarity, necessary to support recollection. Extended familiarization decreases the extent that neural activity in dCA2 generalizes across changes in context, enhancing social-spatial discrimination at the expense of generalization. While the role of dCA2 in social memory is clear, next to nothing is known about the ventral portion of this structure (vCA2); indeed, its very existence is controversial. In my efforts to understand the role of CA2 in familiarity and recollection processing, I investigated the structure and function of CA2 in the ventral hippocampus, a region generally implicated in regulating emotion, stress, and affect. My results indicate that vCA2 is a well-defined region with characteristic morphological, electrophysiological, and molecular properties in common with dCA2. However, vCA2 also shows differences in expression of certain proteins characteristic of dCA2. Notably, and dissimilar to its dorsal counterpart, this region is defined by at least two distinct populations of neurons defined by differences in molecular expression. In contrast to the importance of dCA2 in social memory, inhibition of one of the vCA2 populations did not alter social recognition memory. Although the functional role of these populations remains elusive, I found that vCA2 activity, as measured by c-Fos activation, is significantly and selectively modulated following acute social defeat, thus providing a potential novel role for CA2 in responses to social stress.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21664号 / 医博第4470号 / 新制||医||1035(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 髙橋 良輔, 教授 浅野 雅秀, 教授 影山 龍一郎 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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Adult hippocampal neurogenesis, the generation of new neurons in the adult hippocampus, represents the most drastic form of ongoing plasticity in the human brain. When these adult-born neurons are a few weeks old, they have developed enough connections with surrounding hippocampal neurons to evoke meaningful change in network dynamics, but still have different morphological and physiological properties compared to developmentally generated neurons that render them more plastic. As such, and due to their location in the hippocampus, many have theorized that these new neurons play an important role in certain forms of learning memory as well as emotion. This dissertation outlines the first attempt to answer the question “what are new neurons in the hippocampus good for?” using human participants. Aerobic exercise is a lifestyle factor well-established from the animal literature to upregulate neurogenesis, while chronic stress is a known downregulator of neurogenesis. The second chapter of this thesis describes a study in which aerobic capacity and depression inventory scores demonstrated a significant positive correlation and a significant negative correlation with putative neurogenesis-dependent memory, respectively, in separate cohorts of healthy young adults. The third chapter outlines a study that expands on the one presented in the second by elucidating another potential role for neurogenesis in human cognition – remote memory. Finally, Chapter 4 describes a study investigating the utility of neurotrophins measured from peripheral blood as biomarkers for neurogenic activity in humans by examining how changes in their expression following chronic exercise predict changes in putative neurogenesis-dependent memory performance. These studies are the first to explicitly test and provide supporting evidence for the theoretical roles of adult hippocampal neurogenesis in humans. Taken together, these studies provide a strong foundation for how investigators and clinicians can indirectly quantify and test the function of adult-born neurons in the human brain. / Dissertation / Doctor of Philosophy (PhD) / New neurons are generated in the adult hippocampus throughout life. The hippocampus is a structure in the medial temporal lobe important for learning and memory as well as emotion. It is currently unknown what the contributions of newborn neurons are to these processes. This dissertation outlines the first attempt to answer the question “what are new neurons in the hippocampus good for?” using human participants. Aerobic exercise is a lifestyle factor well-known from research in rodents to positively influence the rate of birth of newborn neurons in the hippocampus, while long-term stress reduces the rate of birth. The second chapter of this thesis describes a study in which aerobic fitness and depression inventory scores demonstrated a significant positive correlation and a significant negative correlation with a memory test susceptible to high interference, respectively, in different populations of healthy young adults. The third chapter outlines a study that expands on the one presented in the second chapter by elucidating another potential role for neurogenesis in human cognition – long-term memory. Finally, Chapter 4 describes a study investigating the how measuring various proteins found in circulating blood may help us to understand how exercise influence the rate of birth of new hippocampal neurons in humans. These studies are the first to test and provide supporting evidence for the potential roles of newborn hippocampal neurons in humans. Taken together, these studies provide a strong foundation for how investigators and clinicians can indirectly quantify and test the role of adult-born neurons in the human brain.

A longstanding goal in neuroscience is to provide a biological understanding of episodic memory, our conscious recollection of prior experience. While the hippocampus is thought to be a critical locus for episodic learning in the mammalian brain, the nature of its involvement is unsettled. This thesis details several investigations that attempt to probe the neural mechanisms that support the encoding and organization of new experiences into memory. Throughout the included works, we utilize in vivo two-photon fluorescence microscopy and calcium imaging to study the functional dynamics of hippocampal networks in mice during memory-guided behavior. To begin, Chapter 2 examines how neural coding in hippocampal area CA1 is modified during trace fear conditioning, a common model of episodic learning in rodents that requires linking events separated in time. We longitudinally tracked network activity throughout the entire learning process, analyzing how changes in hippocampal representations paralleled behavioral expression of conditioned fear. Our data indicated that, contrary to contemporary theories, the hippocampus does not generate sequences of persistent activity to learn the temporal association. Instead, neural firing rates were reorganized by learning to encode the relevant stimuli in a temporally variable manner, which could reflect a fundamentally different mode of information transmission and learning across longer time intervals. The remaining chapters concern place cells---neurons identified in the hippocampus that are active only in specific locations of an animals' environment. In Chapter 3, we use mouse virtual reality to explore how the hippocampus constructs representations of novel environments. Through multiple lines of analysis, we identify signatures of place cells that acquire spatial tuning through a particularly rapid form of synaptic plasticity. These motifs were enriched specifically during novel exploration, suggesting that the hippocampus can dynamical tune its learning rate to rapidly encode memories of new experiences. Finally, Chapter 4 expands a model of hippocampal computation that explains the emergence of place cells through a more general mechanism of efficient memory coding. In theory and experiment, we identified properties of place cells that systematically varied with the compressibility of sensory information in the environment. Our preliminary data suggests that hippocampal coding adapts to the statistics of experience to compress correlated patterns, a computation generically useful for memory and which naturally extends to representation of variables beyond physical space.

The hippocampus has long been known to play a role in learning and memory as well as spatial navigation. However, studies over the past several decades have shown that the hippocampus is not just a cognitive structure, but is also involved in emotional behaviors, particularly through its ventral pole. Recent experiments, from our lab and others, have revealed that ventral CA1 neural activity is strongly modulated by anxiogenic environments. Furthermore, optogenetic manipulation of ventral CA1 cell bodies and projections modifies anxiety-like behavior in the open field and elevated plus maze. However, it is still unknown if ventral CA1 represents anxiogenic stimuli through a single cell or a population code. Additionally, whether ventral CA1 encodes the moment-to-moment behavioral state changes caused by anxiogenic stimuli is unresolved. I investigate these questions using in-vivo freely moving calcium imaging in combination with neural population decoding analysis and unsupervised behavioral segmentation. My results show that ventral CA1 encodes anxiogenic stimuli through a high dimensional, distributed population code that allows for the separation of aversive stimuli with different sensory properties. I also demonstrate that ventral CA1 represents behavioral states through a low dimensional, distributed population code that generalizes across distinct contexts. Thus, ventral CA1 possesses multiple population codes that represent different kinds of information.

Our laboratory has invented a series of oxime acetylcholinesterase (AChE) reactivators (US Patent 9,227,937) that enter the brain, reduce time to cessation of seizure-like activities, and prevent organophosphorus compound (OP) neuropathology, not seen with the current U.S. approved AChE reactivator, pralidoxime (2-PAM). Thus, 2-PAM fails to protect the brain against damage and long-term cognitive and behavioral deficits seen in humans after OP exposure. However, the mechanisms by which these novel oximes provide central neuroprotection through preservation of neuronal cell structures from damage in a rat model are not fully understood by AChE reactivation alone. This dissertation investigated neurotoxic mechanisms of NIMP as potential targets for additional direct and indirect neuroprotection by our lead in vivo AChE reactivator, Oxime 20. Male Sprague Dawley rats exposed to NIMP experienced neurotoxic effects in areas critical to OP-induced seizure generation (e.g., hippocampus and piriform cortex) such as the inhibition of multiple serine hydrolases (i.e., fatty acid amide hydrolase (FAAH), monoacylglycerol lipase (MAGL)), necrotic cell death evident by increased necrotic receptor-interacting serine/threonine-protein kinase 1 (RIPK1) levels and no apoptotic caspase-3 activity, and increased levels of neuroinflammation via elevated levels of pro-inflammatory oxylipins 4 days post lethal exposure. However, due to the lack of statistical significance, NIMP exposure did not definitively affect the subcellular location of either phosphorylated excitatory N-methyl-D-aspartate (NMDA) receptor or inhibitory γ-aminobutyric acid (GABA) receptor subunits. Results suggested that Oxime 20 therapy provided neuroprotection after NIMP exposure, such as limited reactivation of other serine hydrolase targets, significantly decreased RIPK1 levels (i.e., necrotic environment) in the hippocampus, and significantly decreased inflammatory oxylipins 4 days post-NIMP exposure. Thus, reducing OP-induced neuroinflammation might be the main contributor to the neuroprotection (i.e., neuronal cell structure preservation) previously observed in our laboratory.