Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Brain and Cognitive Sciences, 2005. / This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections. / Includes bibliographical references. / What is the nature of the neural processes that allow humans to remember past events? The theoretical framework adopted in this thesis builds upon cognitive models that suggest that episodic retrieval can be decomposed into two classes of computations: (1) recovery processes that serve to reactivate stored memories, making information from a past episode readily available, and (2) control processes that serve to guide the retrieval attempt and monitor/evaluate information arising from the recovery processes. A multimodal imaging approach that combined fMRI and MEG was adopted to gain insight into the spatial and temporal brain mechanisms supporting episodic retrieval. Chapter 1 reviews major findings and theories in the episodic retrieval literature grounding the open questions and controversies within the suggested framework. Chapter 2 describes an fMRI and MEG experiment that identified medial temporal cortical structures that signal item memory strength, thus supporting the perception of item familiarity. Chapter 3 describes an fMRI experiment that demonstrated that retrieval of contextual details involves reactivation of neural patterns engaged at encoding. / (cont.) Further, leveraging this pattern of reactivation, it was demonstrated that false recognition may be accompanied by recollection. The fMRI experiment reported in Chapter 3, when combined with an MEG experiment reported in Chapter 4, directly addressed questions regarding the control processes engaged during episodic retrieval. In particular, Chapter 3 showed that parietal and prefrontal cortices contribute to controlling the act of arriving at a retrieval decision. Chapter 4 then illuminates the temporal characteristics of parietal activation during episodic retrieval, providing novel evidence about the nature of parietal responses and thus constraints on theories of parietal involvement in episodic retrieval. The conducted research targeted distinct aspects of the multi-faceted act of remembering the past. The obtained data contribute to the building of an anatomical and temporal "blueprint" documenting the cascade of neural events that unfold during attempts to remember, as well as when such attempts are met with success or lead to memory errors. In the course of framing this research within the context of cognitive models of retrieval, the obtained neural data reflect back on and constrain these theories of remembering. / by Itamar Kahn. / Ph.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Brain and Cognitive Sciences, 2010. / Cataloged from PDF version of thesis. / Includes bibliographical references. / This thesis is a collection of manuscripts addressing connectivity of neural circuits in cultured hippocampal neurons. These studies begin with an investigation of dopaminergic modulation of excitatory synapses in small circuits of neurons grown on glial micro islands. We found that dopamine transiently depressed excitatory synaptic transmission. Scaling up to larger circuits of neurons proved more challenging, since finding connected pairs became combinatorially more improbable. The discovery and use of light-activatable ion channel channel rhodopsin-2 (ChR2) promised to revolutionize the way in which we could map connectivity in vitro. We successfully delivered the gene for ChR2 in hippocampal cultures using recombinant adeno-associated virus and characterized the spatial resolution, as well as the reliability of stimulating action potentials. However, there were limitations to this technique that would render circuit maps ambiguous and incomplete. More recently, the engineering of rabies virus (RV) as a neural circuit tracer has produced an exciting method whereby viral infection can be targeted to a population of neurons and spread of the virus restricted to monosynaptically connected neurons. We further investigated potential mechanisms for previous observations which claim that RV spread is restricted to synaptically connected neurons by manipulating neural activity and synaptic vesicle release. We found that RV spread increased for blockade of synaptic vesicle exocytosis and for blockade of neural activity. The underlying premise for pursuing these methods to elucidate connectivity is that the computational power of the brain comes from changeable, malleable connectivity and that to test network models of computation in a biological brain, we must map the connectivity between individual neurons. This thesis builds a framework for experiments designed to bridge the gap between computational learning theories and networks of live neurons. / by Jennifer Lynn Wang. / Ph.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Brain and Cognitive Sciences, 2013. / Cataloged from PDF version of thesis. / Includes bibliographical references (p. 127-137). / Studies in the past decade have established gene expression as an inherently variable process. Accompanying this exciting finding is a fundamental question: how do physiological events, such as cell fate specification, proceed so robustly in the face of gene expression variability? In this thesis, I took a fresh attack at this question by examining the control of variability in the context of the stereotyped development of the nematode C. elegans. Specifically, I focused on the regulation of a Hox gene by the Wnt signaling pathway in a single C. elegans neuroblast. Analogous to vertebrate neural crest cells, Hox gene expression determines the migratory direction and the subsequent fate choices of cells that descend from the original neuroblast. Intrigued by the earlier observation that perturbation to Wnt signaling disrupts the wild-type stereotypy in migratory decision, I speculated that variable gene expression may underlie the partial penetrance in the mutants and subsequently questioned what mechanism safeguards against variability in the wild type. Combining single-cell transcript counting with genetic manipulation, I quantified the variability in Hox gene expression in the Q neuroblasts in both the wild type and a series of Wnt signaling mutants. Interestingly, I observed increased expression variability in a number of mutants and an overall complex relationship between expression variability and mean expression level. Distinct features in the gene expression profile embarked me on a search for network interactions, leading to the discovery of multiple novel feedback loops within the Wnt pathway. Applying computational network inference, I revealed a network of interlocking positive and negative feedback loops, which I subsequently show to have a topological advantage in dampening stochastic noise in gene expression. / by Ni Ji. / Ph.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Brain and Cognitive Sciences, 2001. / Includes bibliographical references (p. 123-128). / Language comprehension requires syntactic, semantic and pragmatic processing. The work presented in this thesis clarifies the role that the resource demands of syntactic and referential processing play in sentence complexity. Results are interpreted within the framework of the Dependency Locality Theory (Gibson, 1998), which provides a hypothesis about how computational resources constrain the process of sentence comprehension. These new results support and further develop the DLT's discourse-based distance metric for computing locality. The experiments presented here were designed to investigate the referential processing load imposed by relating noun phrase (NP) anaphors to their antecedents and to discover the ramifications of increased referential processing load on behavioral measures of language comprehension. Four questionnaire experiments tested the intuitive complexity of doubly nested sentences containing NPs that were differently referentially accessible. These experiments demonstrated that sentences with structural dependencies crossing less accessible referents are judged more difficult than sentences with structural dependencies crossing more accessible referents. They also showed that referential accessibility manipulations had a negligible effect on intuitive complexity in positions that did not interrupt long distance structural dependencies. / (cont.) Five self-paced word-by-word reading experiments elucidated the time course of the complexity ramifications of increased referential processing. Each of these experiments showed that when less accessible referents interrupted long distance structural dependencies, reading times slowed more at the completion of the structural dependency than at the referent itself. From the results of these experiments it is argued that performing referential processing during an incomplete structural dependency makes accessing the representation of the beginning of the dependency more difficult at the dependency's completion. This finding is important to the development of the DLT, expanding it to take both referential and syntactic processing into account when predicting complexity effects. This work also provides new evidence about the relative processing loads incurred by multiple referential processes, new evidence concerning the mechanisms underlying referent accessibility and new evidence about the allocation of resources to different subprocesses of the human language comprehension system. / by Tessa Cartwright Warren. / Ph.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Brain and Cognitive Sciences, February 2013. / Cataloged from PDF version of thesis. "February 2013." / Includes bibliographical references (p. 95-113). / An area of left occipitotemporal cortex commonly referred to as the visual word form area (VWFA), has consistently been shown to activate during the processing of written language. However, the exact nature of the region's selectivity is still under debate. In this thesis, I explore the selectivity of the visual word form area at three different levels. First, I examine whether the VWFA differentiates between letter strings of different lexicality and pronounceability and argue that the VWFA's selectivity is greatly influenced by attention. Second, I explore the developmental course of mirror discrimination in the VWFA, and show that children do not display adult-like mirror discrimination of letters even into early adolescence. Finally, I look at the developmental course of VWFA selectivity for words compared to nonlinguistic visual stimuli. While children have adult-like activation patterns when words are compared to a low-level visual control, they show less specialization compared to adults when objects are used as a control. / by Li-Wei King. / Ph.D.

Thesis (S.M.)--Massachusetts Institute of Technology, Dept. of Brain and Cognitive Sciences, 2009. / Includes bibliographical references (leaves 32-41). / The trafficking of essential proteins into spines is an important aspect of synaptic plasticity. MyosinVa, an actin-based motor protein, has been implicated in the synaptic delivery of AMPARs during LTP [1]. However an earlier study showed that LTP and LTD were unaffected in the MyosinVa-null dilute-lethal mice [2]. To evaluate the role of MyosinVa in synaptic plasticity, we studied different forms of LTP and LTD in the CA1 region of the hippocanmpus from MyosinVa dominant negative mutant flailer mouse using field potential recordings. Flailer mice showed no impairment of LTP or NMDAR-dependent LTD, consistent with the findings of the study on dilute-lethal. In addition, MyosinVa has been implicated in the transport of an RNA-binding protein into the spines upon mGluR activation [3]. We explored protein synthesis and mGluR-dcpendent LTD in flailer. The preliminary data we obtained show a transient impairment in mGluR.-LTD, suggesting a role for MyosinVa in protein synthesis dependent plasticity. / by Cansu Tunca. / S.M.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Brain and Cognitive Sciences, 2008. / This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections. / Includes bibliographical references (p. 178-186). / The ability to switch between tasks reflects a fundamental part of our intelligence. A foundation of this ability lies in perceiving and processing information pertinent to the situation at hand. It is our capacity to attend to specific objects and, more importantly, our ability to switch our attention from object to object, that supports complex cognitive behavior. Therefore, by understanding the neural mechanisms involved in directing attention we hope to better understand cognition. Previous work investigating the ability to control attention has suggested that attention is influenced from two sources -- attention can either be driven from external sources in an bottom-up, exogenous manner or directed internally in an top-down, endogenous manner.This project will utilize two different forms of visual search in order to emphasize these two different types of attentional control. Both the prefrontal and parietal regions are implicated as the source of this control. In order to investigate their relative roles we recorded simultaneously from both parietal cortex (specifically, the lateral intraparietal cortex) and prefrontal cortex (specifically, the frontal eye fields and dorsolateral prefrontal cortex). We address four main questions. First, we contrast the respective roles of frontal and parietal cortex in the direction of attention when it is under either top-down or bottom-up control. We use the timing of attention signals between frontal and parietal cortex to establish that frontal cortex directs top-down attention back into parietal cortex, while bottom-up attention is reflected first in parietal cortex, flowing forward to frontal cortex. Secondly, we investigated the role of synchrony and the inter-areal relationships underlying top-down and bottom-up control of attention. Our results suggest synchrony between areas shifts as the task shifts, likely aiding in the selection of the network best suited to the current task. Third, we compare the neural mechanisms between internal and external control of attention. / (cont) Finally, we investigate the neural correlates of the putative parallel and serial mechanisms underlying visual search, finding support for the existence of a serial search and for the role of the frontal eye fields in the direction of spatial attention. / by Timothy J. Buschman. / Ph.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Brain and Cognitive Sciences, 2013. / Cataloged from PDF version of thesis. Vita. / Includes bibliographical references. / General anesthesia is a drug-induced, reversible behavioral state characterized by hypnosis (loss of consciousness), amnesia (loss of memory), analgesia (loss of pain perception), akinesia (loss of movement), and hemodynamic stability (stability and control of the cardiovascular, respiratory, and autonomic nervous systems). Each year, more than 25 million patients receive general anesthesia in the United States. Anesthesia-related morbidity is a significant medical problem, including nausea, vomiting, respiratory distress, post-operative cognitive dysfunction, and post-operative recall. To eliminate anesthesia-related morbidity, the brain systems involved in producing general anesthesia must be identified and characterized, and methods must be devised to monitor those brain systems and guide drug administration. A priority for anesthesia research is to identify the brain networks responsible for the characteristic electroencephalography (EEG) signals of anesthesia in relation to sensory, cognitive, memory, and pain systems. In this thesis, we recorded simultaneous intracranial and surface EEG, and single unit data in patients with intractable epilepsy who had been previously implanted with clinical and/or research electrodes. The aims of this research were to characterize the neural signals of anesthesia in a regionally and temporally precise way that is relevant to clinical anesthesia, and to identify dynamic neuronal networks that underlie these signals. We demonstrated region-specific, frequency-band-specific changes in neural recordings at loss of consciousness. We related these findings to theories of how anesthetic drugs may impart their behavioral effects. / by Veronica Sara Weiner. / Ph.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Brain and Cognitive Sciences, 1991. / Includes bibliographical references. / by Manuel Esguerra. / Ph.D.

Thesis: Ph. D., Massachusetts Institute of Technology, Department of Brain and Cognitive Sciences, February 2016. / Cataloged from PDF version of thesis. / Includes bibliographical references (pages 134-157). / Autism and autism spectrum disorders (ASDs) are clinically defined by the symptoms of social impairment and repetitive behavior, affecting 1 in 68 children in the United States. Because patients with ASDs typically display symptoms before the age of three, the ASDs are classically categorized as developmental disorders. One of the key questions in autism research is whether the pathology is reversible in adults. Many studies of simple sensory systems have reported that there is a distinct critical period for synaptic plasticity. This is most famously supported by the monocular deprivation studies in young kittens, which resulted in irreversible visual impairment in adulthood (Hubel and Wiesel, 1970). However, it is not clear whether this principle extends to more complicated multi-modal behavioral systems. Here we demonstrate that adult rescue can lead to improvements in selective phenotypes of ASD by generating and using a novel Shank3 conditional knock-in mouse model. Estimated to contribute to about 1% of all ASD cases, Shank3 is one of the most prominent genes associated with autism. It is a master postsynaptic scaffolding protein that mediates synaptic plasticity and remodeling by regulating many neurotransmitter receptors including NMDAR, AMPAR, and numerous actin-binding regulators. Disruptions of Shank3 in mouse models have robustly recapitulated the cardinal phenotypes of autism including anxiety, social interaction deficits, and compulsive/stereotyped behavior. By specifically expressing Shank3 in adult mice that were initially born as Shank3 knockouts, we show that deficits in the synaptic protein composition and striatal neurotransmission can be fully recovered. We developed a novel neuronal tracing technique to study the dendritic spine density, and found that the dendritic spine number is also significantly increased in the rescue condition after development. In addition, we show that while anxiety and motor coordination are not improved, social interaction and repetitive behavior can be significantly rescued. This suggests that plasticity for certain neural circuits persist into adulthood in the diseased brain, and that the underlying mechanisms for different autistic-like phenotypes have distinct properties. / by Yuan (Karen) Mei. / Ph. D.