Thesis (M.D)--University of Hong Kong, 1999. / Includes bibliographical references (leaves 80-124).

Thesis (Ph. D.)--West Virginia University, 2009. / Title from document title page. Document formatted into pages; contains ix, 192 p. : ill. (some col.). Vita. Includes abstract. Includes bibliographical references (p. 171-190).

Memory serves an integral function in every aspect of human life. Losing that function can be adevastating consequence of disease, dementia, and trauma. In order to develop treatments or prophylactics for memory disorders we must identify the neural basis of memory. Animal research has made prominent strides studying the neural correlates of memory by examining the more easily observable and manipulable neural correlates of spatial context, since the brain regions necessary for declarative memory intersect profoundly with those needed for spatial navigation. My research has two main goals. My first two studies, in Chapters 2 and 3, translate animal research relating the neural correlates of space to memory processes, and go beyond animal work to explore how internal features of experience such as goal states influence these conjunctive representations of space and memory. In Chapter 4, I expand my scope to examine how another internal feature, emotional context, affects the same brain regions on a network level to influence memory representations in the human brain. To perform these studies I recorded directly from the human brain in epilepsy patients performing a variety of memory tasks. First, I measured single-neuron activity as subjects navigated a virtual environment, encountering various objects at unique locations. As subjects moved through the environments, they were instructed to recall the locations of specific objects they encountered—I identified neurons in the human entorhinal cortex, called “memory-trace cells”, which selectively activated near the object-location that people were instructed to retrieve from memory. This is the first evidence that neurons in the brain can be tuned to the spatial context of an event for memory, and demonstrated a direct link between memory retrieval and the spatial tuning properties of neurons. For my second study, I examined whether spatially-tuned neurons in the MTL discharge at intervals organized by theta (2–10 Hz) oscillations (which represent network level brain-activity). I identified a particular pattern that is prominent in rodents, called “phase precession”, during which spatially-tuned neurons spike slightly faster than the network oscillation, and which is theorized to hold great value throughout the brain for learning and memory. In addition to discovering this pattern for spatial sequences, I discovered that phase precession was also present during more abstract features of experience, like the specific goal a person was seeking. These findings suggest that principles of network-level brain activity for organizing spatial navigation may extend to humans, and to broader forms of cognition and memory. Finally, I examined the role of the amygdala in memory encoding during a verbal episodic memory task, finding that the emotional context of a word influenced the probability of its subsequent recall. By measuring the prevalence and coordination of brain oscillations in the amygdala-hippocampal circuit, I found that gamma oscillations (30–120 Hz) increased in both regions as a function of word arousal and encoding success, and connectivity within the amygdala-hippocampal circuit also showed significant theta-gamma coupling as a function of memory and high arousal. Furthermore, direct 50 Hz stimulation impaired memory for high arousal words. These findings suggest a causal relationship between gamma oscillations in the amygdala-hippocampal circuit for memory as a function of emotional context during encoding. My work generalizes important neuronal principles from animal studies to humans (such as spatially-tuned neurons and phase precession), but also extends those findings more deeply to memory, and to internal/subjective aspects of memory that are difficult to directly measure in animals. Overall this work represents an important step towards understanding how the human brain enables declarative memory.

One major challenge in developmental neuroscience research is the sheer number of choices researchers face when addressing even a single research question. Even once data collection is complete, the journey from raw data to interpretation of findings may depend on numerous decisions. To address this issue, this dissertation explores “multiverse” analysis techniques for following many analytical paths at once in the same dataset. In chapter 1, multiverses are used to examine which analyses of age-related change in amygdala-medial prefrontal cortex circuitry are robust versus sensitive to researcher decisions. Chapter 2 uses multiverse analysis to identify optimal solutions for mitigating breathing-induced artifacts in resting-state functional magnetic resonance imaging data. Chapter 3 uses a variety of model specifications to characterize simultaneous reward learning strategies in youth contingent on both visual task cues and spatial-motor information. Despite varied approaches and goals, each of the three studies highlight the benefits of conducting multiple parallel analyses for both addressing questions in developmental neuroscience and deepening understanding of the methods used to address them.

The motivation to eat is influenced by both internal physiological demands and by external stimuli with positive or negative associations. A conditioned stimulus (CS) associated with food can potentiate eating in sated subjects, whereas a CS associated with a negative affect can suppress eating in hungry subjects. Although the amygdala has been implicated in these behaviors, the neural mechanisms that underlie this type of non-homeostatic eating are poorly understood. To investigate the role of BLA neurons in CS+ potentiated eating and CS- lick suppression, we developed a behavioral paradigm in mice in which eating behavior could be assessed in conditions of low or high satiety and in relation to CS presentations while recording neural activity using freely-moving endoscopic calcium imaging. We found that satiety partially decreases responses to the CS+, and the neural representation of the CS+ becomes more similar to the CS-. Additionally, we tested the hypothesis that CS-evoked activity is casually involved in CS+ induced licking or CS- lick suppression by using optogenetics during this task. Silencing of BLA glutamatergic neurons labelled by NL189 prevents CS- lick suppression during low satiety and does not affect licking during the CS+. The combination of cellular imaging and optogenetics results indicates that BLA neuronal activity evoked by the CS- is critical for lick suppression, whereas CS+ activity might facilitate appetitive behavior, but this activity is not critical for cue-induced eating.

No description available.

Thesis (M.S.)--West Virginia University, 1999. / Title from document title page. Document formatted into pages; contains viii, 138 p. : ill. (some col.). Vita. Includes abstract. Includes bibliographical references (p. 105-134).

Experiencing early life adversity (ELA) increases the risk of anxiety disorders, such as generalized anxiety disorder and post-traumatic stress disorder, with disproportionally higher risk in women compared to men. Neurodevelopmental and behavioral outcomes following ELA are multifaceted and are influenced heavily by the type of adversity experienced and sex of the individual. A major contributor to emotional dysfunction and anxiety disorders resulting from ELA are changes in fear and threat circuitry. Children who experienced ELA have been reported to show an accelerated development of the amygdala, a region involved in processing threat, and greater cerebrospinal levels of corticotrophin releasing hormone (Crh), an orchestrator of neuroendocrine and behavioral responses to stress. Work in rodents have linked Crh signaling within the lateral central amygdala (CeAL) with processing and responding to threat, core features disrupted in anxiety-related disorders. Further, sex biases in risk and symptom presentation have been proposed to be related to sexual dimorphic signaling of Crh across the brain that differentially influence a variety of Crh-dependent behaviors. However, it remains unclear what properties of ELA portend differential neurobiological risk, what is the basis of sex-differences for negative outcomes, and how specific mechanistic changes give rise to certain endophenotypes. In this work, I use genetic, cellular, and behavioral approaches to explore the impact of ELA and sex on perinatal development in mice and the functional consequences of altered Crh neuron activity in the CeAL on threat responding in adulthood. In Chapter 1, I review how factors such as sex and type of ELA influence amygdala development and Crh. In Chapter 2, I assess the impact of two forms of ELA, maternal separation (MS) and limited bedding and nesting (LBN) on perinatal development and anxiety-like behavior. Both forms of ELA shifted the timing of somatic maturation and basal CORT levels and led to increased anxiety-like behaviors, but the degree of the impact depended on the sex and type of adversity experienced. In Chapter 3, I demonstrate that a distinguishing feature between types of ELA was the predictability of maternal care. The type of ELA also contributed to sex-differences in Crh related gene expression in the perinatal amygdala. Increased expression was primarily observed in males following MS and in females following LBN. In Chapter 4, I investigate the functional consequences of ELA in the form of LBN on the activity of CeALCrh+ neurons in vivo and their causal role in threat reactivity indexed by the startle response. LBN rearing led to sustained activity of CeALCrh+ in female mice but diminished in male mice. Persistent activity of this population was necessary for and predicted the magnitude of startle responding. In Chapter 5, I discuss important considerations when integrating new advancements in the study of ELA and the use of sex as a biological variable. Collectively, this work deepens our understanding of the neurobiological mechanisms impacted by sex and ELA and holds promise for future strategies that may consider the sex and specific experiences of the individual to target specific endophenotypes and address the underlying root causes of anxiety disorders.

Indiana University-Purdue University Indianapolis (IUPUI) / Anxiety disorders are estimated to impact 1 in 4 individuals within their lifetime. For some individuals, repeated episodes of the stress response leads to pathological anxiety and depression. The stress response is linked to increased levels of corticotropin-releasing factor (CRF) in the basolateral nucleus of the amygdala (BLA), a putative site for regulating anxiety and associative processes related to aversive emotional memories, and activation of CRF receptors in the BLA of rats produces anxiety-like behavior. Mimicking repeated episodes of the stress response, sub-anxiogenic doses of urocortin 1 (Ucn1), a CRF receptor agonist, are microinjected into the BLA of rats for five consecutive days, a procedure called priming. This results in 1) behavioral sensitization, such that a previously non-efficacious dose of Ucn1 will elicit anxiety-like response after the 3rd injection and 2) the development of a persistent anxiety-like phenotype that lasts at least five weeks after the last injection without any further treatment. Therefore, the purpose of this thesis was to identify mechanisms involved in the Ucn1-priming-induced anxiogenesis. The first a set of experiments revealed that the anxiety-like behavior was not due to aversive conditioning to the context or partner cues of the testing environment. Next, Ucn1-priming-induced gene expression changes in the BLA were identified: mRNA expression for Sst2, Sst4, Chrna4, Chrma4, and Gabrr1 was significantly reduced in Ucn1-primed compared to Vehicle-primed rats. Of these, Sst2 emerged as the primary receptor of interest. Subsequent studies found that antagonizing the Sstr2 resulted in anxiety-like behavior and activation of Sstr2 blocked acute Ucn1-induced anxiety-like responses. Furthermore, pretreatment with a Sstr2 agonist delayed the behavioral sensitization observed in Ucn1-induced priming but did not stop the development of persistent anxiety-like behavior or the Ucn1-priming-induced decrease in the Sstr2 mRNA. These results suggest that the decrease in Sstr2 mRNA is associated with the expression of persistent anxiety-like behavior but dissociated from the mechanisms causing the behavioral sensitization. Pharmacological studies confirmed that a reduced Sstr2 mediated effect in the BLA is likely to play a role in persistent anxiety and should be investigated further.