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.

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.

The purpose of this project was to compare the Attention to Memory (AtoM) and the Episodic Buffer (EB) Models. The AtoM model proposes that the ventral parietal cortex (VPC) and dorsal parietal cortex (DPC) are responsive to bottom-up and top- down attention to memory, respectively, (Cabeza, 2008; Cabeza et al., 2008; Ciaramelli et al., 2008). The EB model, on the other hand, proposes that the VPC is involved in the episodic buffer component of Baddeley's working memory model (Vilberg & Rugg, 2008). Using objective (source) and subjective (Remember/Know) retrieval tasks, specific patterns of PPC activity were posited based on the propositions of the AtoM model. These expectations included greater VPC activity for Remember and False Alarms compared to Correct Rejections and Subjective Know, greater DPC activity for Know and Objective Remember compared to Subjective Remember and correct rejections, and no difference in VPC activity for remembering both font and color compared to remembering only one contextual detail. During encoding participants saw words in one of two colors, red or yellow, and in one of two fonts, curvy or straight, and were required to indicate the color the word was presented in. Following each encoding scan participants performed either an Objective or Subjective retrieval task. During Objective retrieval task, participants performed a forced-choice source memory test choosing the word with the correct fontand color or the "new" option. During Subjective retrieval participants were presented with the word in a neutral font and white color and performed a Remember/Know test. On the Subjective retrieval task both VPC and DPC were active for recollection compared to familiar items and Correct Rejections. On the Objective retrieval task the DPC was active for all correct old responses. Neither the VPC nor the DPC were significantly active for False Alarms on both the Subjective and Objective tasks. Both VPC and DPC were more active for Subjective Remember compared to Objective Remember response. Neither PPC region was more active for remembering font and color compared to remembering only font or color. Memory load effects for retrieval of information from long-term memory were only seen in the hippocampus on the Subjective retrieval task. These patterns of activity support the role of the VPC in recollection, as seen on the Subjective task, and the role of the DPC in familiarity, as shown in both the Subjective and Objective tasks. The role of the VPC and DPC during recollection and familiarity processing supports both the AtoM and the EB model. The key predictor of the Episodic Buffer model, memory load effects, was not supported and provides the only evidence against one of the two proposed models. Future work should examine the role of the posterior parietal cortex in spontaneous episodic retrieval to assess the validity of the AtoM model. Advanced imaging analysis techniques should be used to determine functional connectivity between the PPC and frontal and temporal memory regions.

Effective decision making depends on using memories of past experiences to inform choices in the present. This dissertation examines several ways in which memory is used in decision making, and further aims to establish that one way we adapt to the statistics of our environment is by modifying how we use our memories to guide behavior. In chapters one and two, I focus on how incremental trial-and-error learning and episodic memories of individual events may each contribute to choice. In chapter one, I ask how the brain may arbitrate rationally between these two systems to achieve a balance that maximizes reward. By manipulating the volatility of the environment to affect uncertainty, I show that participants rely on each system in the circumstances to which it is best suited. In chapter two, I then ask how decisions based on these memory systems each depend on striatal dopamine. By studying patients with Parkinson’s disease both on and off their medication, I find that a lack of dopamine alters only incremental learning, and that dopamine replacement remediates this deficit with few effects on the use of episodic memory. Finally, in chapter three, I examine a more difficult class of decisions that require individual memories to be used for planning future action. Using neuroimaging to decode memory access, I find that that the statistical structure of relationships between memories determines when they are used to support planning. Combined, these three chapters suggest that we are capable of flexibly employing multiple forms of memory, with distinct neural mechanisms, to guide a variety of choices.

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.

Identification of the pathways that could be targeted to alleviate ageing-related cognitive decline is of prime importance. One of the most promising target mechanisms is connected to healthy dopaminergic ageing. Extant research suggest that women may exhibit less ageing-related dopamine (DA) decline compared to men, implicating that women may suffer less from dopamine-related cognitive decline. However, to date, shortage of empirical investigations limit firm conclusions of sex differences. In the present work it is hypothesized that: (i) women as compared to men exhibit less aging-related DA losses, and (ii) less aging-related decline of episodic memory (EM), and that (iii) sex differences in episodic memory might be mediated by differences in DA integrity. To that end, sex-related differences in D1-type dopamine receptor (D1DR) integrity and episodic memory were investigated in a healthy cohort of young to old participants (age 20 – 80, n = 180, 50% women) through whole-brain voxel-wise analysis and linear regression models. Firstly, the dorsal caudate was identified as the main region of the EM-D1DR interrelation. Secondly, a significant female advantage was found for EM and D1DR in ageing. Finally, no mediation effect by D1DR on the sex-EM interaction was found. These results indicate the presence of correlational relationships between sex, cognition and D1DR, in ageing. However, D1DR was not found to be the mediating factor in the observed correlations. Future research, preferably using longitudinal design, should further investigate the underpinnings of sex differences in D1DR and EM.

Yes / It has been suggested that the isolation rearing paradigm models certain aspects of schizophrenia symptomatology. This study aimed to investigate whether isolation rearing impairs rats’ performance in two models of cognition: the novel object recognition (NOR) and attentional set-shifting tasks, tests of episodic memory and executive function, respectively. Two cohorts of female Hooded-Lister rats were used in these experiments. Animals were housed in social isolation or in groups of five from weaning, post-natal day 28. The first cohort was tested in the NOR test with inter-trial intervals (ITIs) of 1 min up to 6 h. The second cohort was trained and tested in the attentional set-shifting task. In the NOR test, isolates were only able to discriminate between the novel and familiar objects up to 1-h ITI, whereas socially reared animals remembered the familiar object up to a 4-h ITI. In the attentional set-shifting task, isolates were significantly and selectively impaired in the extra-dimensional shift phase of the task (P < 0.01). Rats reared in isolation show impaired episodic memory in the NOR task and reduced ability to shift attention between stimulus dimensions in the attentional set-shifting task. Because schizophrenic patients show similar deficits in performance in these cognitive domains, these data further support isolation rearing as a putative preclinical model of the cognitive deficits associated with schizophrenia.

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Academic achievement involves complex processes that are not fully understood. That being said, the connection between working memory and academic achievement is well developed and emphasized in the literature. However considering the complex nature of academic achievement, other processes are likely involved. The current study examined the contributions of recollection, familiarity, working memory, and verbal IQ longitudinally in children at ages 6 and then 9. Recollection, but not familiarity, contributed to measures of both reading and math at age 6, but not 9. Path models suggested that the direct and indirect effects of working and episodic memory to academic achievement change from age 6 to 9. Furthermore, this study examined the contributions of the neural correlates of recollection and working memory to measures of academic achievement at ages 6 and 9. The neural correlates of working memory and recollection did not contribute to academic achievement, but additional research is needed to draw concrete conclusions. Overall, the results suggest that episodic memory should be considered in addition to working memory when examining academic achievement. / Ph. D.