The ability to recognize dangerous situations and environments is crucial for survival, but overestimating risk can lead to pathological avoidance of normal activities, potentially leading to anxiety disorders. Many studies over the past several decades have begun to identify the brain regions underlying threat detection and anxiety behavior. In particular, the ventral hippocampus has emerged as a critical structure for emotional behaviors, including innate anxiety. Recent work from our lab and others has shown that ventral CA1 pyramidal neurons encode information about anxiety, and these CA1 neurons preferentially target downstream structures such as hypothalamus and medial prefrontal cortex. However, the neural representation of anxiogenic environments in the initial stage of the trisynaptic circuit— the dentate gyrus— is unknown. Here, I use Dock10-Cre and Drd2-Cre mouse lines to gain optical access to granule cells and mossy cells, respectively, in the ventral dentate gyrus. Calcium activity was recorded during free exploration of the elevated plus maze (EPM) and open field test (OFT). Single cell activity and population coding were analyzed for mossy cells, granule cells, and CA1 pyramidal neurons. I found that anxiety-related activity was present in granule cells and vCA1, however mossy cells encoded novelty and spatial position. Furthermore, chemogenetic inhibition of mossy cells did not disrupt behavior in the EPM or OFT, but did disrupt acquisition of a contextual fear memory. These findings support the notion that different features of an anxiogenic environment are encoded by different cell types, and that anxiety information is present at the earliest stage of the trisynaptic circuit.

Neural circuits within the hippocampus, a mammalian brain structure critical for both the encoding and consolidation of episodic memories, are composed of intimately connected excitatory pyramidal cells and inhibitory interneurons. While decades of research have focused on how the in vivo physiological properties of pyramidal cells may support these cognitive processes, and the anatomical and physiological properties of interneurons have been extensively studied in vitro, relatively little is known about how the in vivo activity patterns of interneurons support memory encoding and consolidation. Here, I have utilized Acousto-Optic Deflection (AOD)-based two-photon calcium imaging and post-hoc immunohistochemistry to perform large-scale recordings of molecularly-defined interneuron subtypes, within both CA1 and CA3, during various behavioral tasks and states. I conclude that the subtype-specific dynamics of inhibitory circuits within the hippocampus are critical in supporting its role in memory encoding and consolidation.

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.

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.

No description available.

The AMP-activated protein kinase (AMPK) is a master metabolic regulator and energy sensor that has been extensively studied in the context of cancer and metabolic disorders. However, its role in neuronal function and morphology remains largely unexplored. This dissertation aims to bridge this gap by investigating the roles of AMPK in maintaining axon homeostasis and regulating mitochondrial morphology in neurons. By identifying novel regulators of AMPK across different cellular compartments, this thesis sheds light on the multifaceted functions of AMPK in shaping neuronal and mitochondrial architecture. The dissertation is organized into five chapters. Chapter 1 provides a brief background on AMPK, its activation mechanisms, and the downstream pathways it regulates. Chapter 2 introduces with-no-lysine kinase (WNK), a novel axon morphogenic kinase with dual roles in terminal axon branch development and maintenance in mature axons. Chapter 3 investigates the role of AMPK in mediating the loss-of-WNK axonal phenotypes, revealing a critical link between AMPK and axonal integrity. Chapter 4 shifts focus to the mitochondrial, characterizing mitochondrial fission regulator 1-like (MTFR1L) as a novel AMPK-activated protein that regulates mitochondrial morphology. Finally, Chapter 5 explores the role of AMPK in mediating activity-dependent mitochondrial morphology in hippocampal CA1 neurons, highlighting the dynamic interplay between neuronal activity and mitochondrial dynamics. Collectively, these findings provide novel insights into the multifaceted roles of AMPK in neuronal development, degeneration, and organelle regulation, underscoring the importance of this master kinase in maintaining neuronal health and homeostasis.

The memory system is adaptive in so far as it is able to provide the most robust predictions of what will happen next in our environment. Three means through which it can do this are: arbitrating between temporally embedded recollections and generalized knowledge; rescuing remote memories that are learned to be behaviorally relevant; and updating existing memories if they provide invalid predictions of the outside world. Here, I cover three studies that probe these functions in behavior and in the brain. In Chapter 1, I show how a data-driven parcellation reveals non-linear gradients in measures of signal heterogeneity across the body of the hippocampus, suggesting novel areas of investigation into how the memory system flexibly constructs fine- and coarse-grained memories. In Chapter 2, I then explore how memories might be rescued by later aversive experiences, finding novel evidence that the online inferences participants make as to what current stimuli are relevant to their arousal subtly shapes what previous stimuli they retroactively maintain in memory. Finally, in Chapter 3, I show that signals from the ventral tegmental area modulate the effect of replaying memories on the eventual updating of those memories. Each of these provides novel pieces of evidence into the neural and behavioral markers of how memories are constructed, strengthened, or updated in the brain.

Sutherland, Sparks and Lehmann (2010) proposed a new theory of memory consolidation, termed Distributed Reinstatement Theory (DRT), where the hippocampus (HPC) is needed for initial encoding but some types of memories are established in non-HPC systems through post-learning HPC activity. An evaluation of the current methodology of temporary inactivation was conducted experimentally. By permanently implanting two bilateral guide cannulae in the HPC and infusing ropivacaine cellular activity could be reduced by 97%. Rats were trained in a context-fear paradigm. Six learning episodes distributed across three days made the memory resistant to HPC inactivation while three episodes did not. Blocking post-learning HPC activity following three of six training sessions failed to reduce the rat’s memory of the fearful context. These results fail to support DRT and indicate that one or more memory systems outside the HPC can acquire context memory without HPC post-event activity. / x, 85 leaves : ill. ; 29 cm

Forty-eight rat pups were handled and isolated from postnatal days 3 through 13 in order to determine whether this manipulation would alter the postnatal development of the hippocampus. Half of these animals were then reared in enriched environments from weaning until maturity to determine whether enrichment would ameliorate the expected deficits in learning ability. Beginning at 90 days of age, all animals were tested on a T-maze, rotating bar and both place and cued versions of a water maze task. The study failed to find gross deficits in learning as a result of the handling/isolation procedure, although emotional differences between groups was evident, as were sex differences. Apparently more questions have been raised than answered by this study, and possible directions for future research are discussed.