Thesis (M.S.)--Massachusetts Institute of Technology, Dept. of Brain and Cognitive Sciences, 1996. / Includes bibliographical references (p. 21-22). / by Stephen Lines. / M.S.

Thesis: Ph. D. in Neuroscience, Massachusetts Institute of Technology, Department of Brain and Cognitive Sciences, 2017. / This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections. / Cataloged from student-submitted PDF version of thesis. "June 2017." Page 206 blank. / Includes bibliographical references. / Perceptual decision-making is an important and experimentally tractable paradigm for uncovering general principles of neural information processing and cognitive function. While the process of mapping sensory stimuli onto motor actions may appear to be simple, its neural underpinnings are poorly understood. The goal of this thesis is to better understand the neural mechanisms underlying perceptual decision-making by exploring three major questions: How is decision-relevant information encoded across the cortex? What cortical areas are necessary for perceptual decision-making? And finally, what neural mechanisms underlie the mapping of sensory percepts to appropriate motor outputs? We investigated the roles of visual (V1), posterior parietal (PPC), and frontal motor (fMC) cortices of mice during a memory-guided visual decision task. Large-scale calcium imaging revealed that neurons in each area were heterogeneous and spanned all task epochs (stimulus, delay, response). However, information encoding was distinct across regions, with V1 encoding stimulus, fMC encoding choice, and PPC multiplexing the two variables. Optogenetic inhibition during behavior showed that all regions were necessary during the stimulus epoch, but only fMC was required during the delay and response epochs. Stimulus information was therefore rapidly transformed into behavioral choice, requiring V1, PPC, and fMC during the transformation period, but only fMC for maintaining the choice in memory prior to execution. We further investigated whether the role of PPC was specific to visual processing or to sensorimotor transformation. Using calcium imaging during both engaged behavior and passive viewing, we found that unlike V1 neurons, most PPC neurons responded exclusively during task performance, although a minority exhibited contrast-dependent visual responses. By re-training mice on a reversed task contingency, we discovered that neurons in PPC but not V1 reflected the new sensorimotor contingency. Population analyses additionally revealed that task-specific information was represented in a dynamic code in PPC but not in V1. The strong task dependence, heterogeneity, and dynamic coding of PPC activity point to a central role in sensorimotor transformation. By measuring and manipulating activity across multiple cortical regions, we have gained insight into how the cortex processes information during sensorimotor decisions, paving the way for future mechanistic studies using the mouse system. / by Gerald N. Pho. / Ph. D. in Neuroscience

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Brain and Cognitive Sciences, 2012. / Cataloged from PDF version of thesis. / Includes bibliographical references. / The over-arching hypothesis that drives my work is that neural dynamics, fluctuating on millisecond to second time scales, powerfully impact perception. In this thesis, I employ correlative electrophysiological recording methods and causal optogenetic control of neural circuits to systematically test the importance of dynamics in the expression of pre-stimulus oscillations on perception. Specifically, I test the prediction that alpha oscillations expressed in a given sensory representation within a neocortical map predict diminished sensory capability in that region of sensory space, while gamma oscillations predict enhanced capacity. My model system throughout is primary somatosensory neocortex and tactile perception: I combine studies from human and mouse to benefit from the relative merits of each preparation. Several prior studies support this more generally stated view of oscillatory dynamics -- alpha predicting diminished and gamma predicting enhanced perceptual capacity. However, there is significant disagreement on even this broad assumption. Leading researchers have argued that alpha in fact predicts enhanced detection of tactile stimuli (e.g., Nicolelis and Fanselow, 2002). Further, there remains significant discord over whether gamma oscillations predict enhanced ability and, even if they do so, whether their expression is a causal contributor to this increased capacity or whether gamma is an epiphenomenal by-product of other beneficial shifts in neural dynamics. My thesis directly addresses these basic questions as to the predictive value of these oscillations, and favors the view that alpha and gamma are in general predictive of perception as stated. Further, I provide unique causal data showing that, under the conditions of our experiments, entrainment of a realistic and local gamma oscillation in neocortex can enhance stimulus detection. I also address important questions as to the independence of different frequency bands expressed in pre-stimulus oscillatory dynamics. Specifically, in contrast to prior reports, I provide evidence in humans and mouse that alpha and beta are unique in their expression and do not occur as a single coincident "mu" rhythm. I also provide direct evidence against the simplistic view-which has also been recently postulated-that alpha and gamma rhythms are inherently opposed in their expression (e.g., that increase in one is necessarily coincident with decrease in the other). Perhaps most importantly, while my data support the general view that alpha and gamma have opposing impacts on perception, I also show that there are more complex interactions between alpha and gamma in predicting perceptual success, suggesting that a simplistic view of each frequency as a 'state' is inappropriate, and that these oscillations are independent in their expression and potentially in their allocation to optimize perception, e.g., with selective attention. Our MEG results support the hypothesis that the alpha band oscillation is negatively correlated with perception. Further, using LFP in the mouse we observe that this alpha oscillation is a disengaging rhythm in rodents as well, contrary to prior work in barrel cortex in rats. More, we show that increased gamma power is correlated with perception of a liminal tactile stimulus. Then using optogenetic control of the fast-spiking interneurons, we causally entrain a gamma oscillation to show enhancement of perception. / by Dominique L. Pritchett. / Ph.D.

Thesis: Ph. D., Massachusetts Institute of Technology, Department of Brain and Cognitive Sciences, February 2017. / Cataloged from PDF version of thesis. "February 2017." / Includes bibliographical references (pages 134-138). / Class II CRISPR-Cas RNA programmable DNA endonucleases enable high efficiency genome editing across the biological diversity for research, industrial, and biomedical applications. Human genome editing with CRISPR-Cas just recently made its debut in human clinical trials and has immense therapeutic potential to fix disease-causing mutations at the level of DNA. Ensuring the integrity and safety of research, industrial, and biomedical applications of CRISPR-Cas necessitates efficient, versatile, and comprehensive methods to evaluate of the specificity of genome editing. Here, we optimize the efficiency and characterize the targeting specificity of SpCas9 to ensure robust cleavage activity while minimizing off-target activity in human cells. We characterize SpCas9 mismatch tolerance between the guide RNA and target, and provide data-driven design software to guide the selection of high fidelity Cas9 targets. We find that SpCas9 binding activity is not predictive of DNA cleavage, limiting the efficacy of Cas9 ChIP for unbiased evaluation of Cas9 off-target activity. Alternatively, we demonstrate that insert capture - insertion of short DNA fragments at double strand breaks (DSBs) by non-homologous end-joining (NHEJ) - provides unbiased genomewide identification of off-target cleavage by Cas9 as well as relative rates of indel, chromosomal rearrangement, and translocation accompanying NHEJ repair. However, insert capture is largely limited to use in model cell lines and is fundamentally limited in sensitivity due to labeling of low frequency errors in DSB repair. To directly label DSBs from cell culture or tissue samples, we adapted BLESS (direct in situ breaks labeling, enrichment on streptavidin and next-generation sequencing) and BLISS (Breaks Labeling In Situ and Sequencing) for unbiased genome-wide analysis of CRISPR-Cas specificity. Finally, we consider how human genetic variation will affect the targeting specificity of CRISPR-Cas endonucleases for therapeutic applications. Using the ExAC and 1000 Genomes datasets we find that human variation has important implications for Cas enzyme choice as well as target efficacy and safety. From this analysis, we provide a framework for the design of CRISPR-based therapeutics to maximize efficacy and safety across patient populations. / by David Scott. / Ph. D.

Thesis (S.M.)--Massachusetts Institute of Technology, Dept. of Brain and Cognitive Sciences, 1998. / Includes bibliographical references (p. 26-27). / by Kara L. Ko. / S.M.

Thesis: S.M. in Neuroscience, Massachusetts Institute of Technology, Department of Brain and Cognitive Sciences, 2016. / Cataloged from PDF version of thesis. / Includes bibliographical references (pages 55-58). / Combined measurement of diverse molecular and anatomical traits that span multiple levels remains a major challenge in biology. Here, we introduce a simple method that enables proteomic imaging for scalable, integrated, high-dimensional phenotyping of both animal tissues and human clinical samples. This method, termed SWITCH, uniformly secures tissue architecture, native biomolecules, and antigenicity across an entire system by synchronizing the tissue preservation reaction. The heat- and chemical-resistant nature of the resulting framework permits multiple rounds (>20) of relabeling. We have performed 22 rounds of labeling of a single tissue with precise co-registration of multiple datasets. Furthermore, SWITCH synchronizes labeling reactions to improve probe penetration depth and uniformity of staining. With SWITCH, we performed combinatorial protein expression profiling of the human cortex and also interrogated the geometric structure of the fiber pathways in mouse brains. Such integrated high-dimensional information may accelerate our understanding of biological systems at multiple levels. / by Evan Murray. / S.M. in Neuroscience

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. / "June 2008." / Includes bibliographical references. / Perturbations of sensory experience in young animals are known to cause lasting changes in adult brain function. For example, monocular visual deprivation by lid closure (MC) leads to a loss of cortical responsiveness of the deprived eye and a concomitant visual impairment. This ocular dominance (OD) plasticity is a well-studied model of experience-dependent cortical plasticity. While much is known about the anatomical, physiological and biochemical changes that occur in primary visual cortex following OD plasticity, the input patterns that lead to these changes have not been characterized. Visual input travels from the retina through the dorsal lateral geniculate nucleus (dLGN) of the thalamus and then into visual cortex. Several models of the thalamic activity patterns which drive OD plasticity have been proposed, but the assumptions about the pattern and amount of input activity from thalamus to cortex during deprivation have not been experimentally validated. Therefore, we performed extracellular recordings from the dLGN of animals during periods of visual manipulation. Contrary to previous hypotheses, the present findings demonstrate that MC does not alter the overall firing rate of neural activity in the dLGN. Instead, MC alters the pattern of neural spike trains such that there is a decrease in simultaneous firing of neighboring neurons. Moreover, the elimination of visual input from the retina, a form of deprivation which does not lead to deprived-eye depression, leads to a dramatic increase in thalamic bursting. Additionally, there are subtle qualitative differences between dLGN activity in juveniles and adults during MC, and this may contribute to differences in OD plasticity with age. / by Monica L. Linden. / Ph.D.

Thesis: Ph. D., Massachusetts Institute of Technology, Department of Brain and Cognitive Sciences, 2018. / Cataloged from PDF version of thesis. / Includes bibliographical references (pages 161-173). / Primates are able to rapidly, accurately and effortlessly perform the computationally difficult visual task of invariant object recognition - the ability to discriminate between different objects in the face of high variation in object viewing parameters and background conditions. This ability is thought to rely on the ventral visual stream, a hierarchy of visual cortical areas culminating in inferior temporal (IT) cortex. In particular, decades of research strongly suggests that the population of neurons in IT supports invariant object recognition behavior. However, direct causal evidence for this decoding hypothesis has been equivocal to date, especially beyond the specific case of face-selective sub-regions of IT. This research aims to directly test the general causal role of IT in invariant object recognition. To do so, we first characterized human and macaque monkey behavior over a large behavioral domain consisting of binary discriminations between images of basic-level objects, establishing behavioral metrics and benchmarks for computational models of this behavior. This work suggests that, in the domain of basic-level core object recognition, humans and monkeys are remarkably similar in their behavioral responses, while leading models of the visual system significantly diverge from primate behavior. We then reversibly inactivated individual, millimeter-scale regions of IT via injection of muscimol while monkeys performed several interleaved binary object discrimination tasks. We found that inactivating different millimeter-scale regions of primate IT resulted in different patterns of object recognition deficits, each predicted by the local region's neuronal selectivity. Our results provide causal evidence that IT directly underlies primate object recognition behavior in a topographically organized manner. Taken together, these results establish quantitative experimental constraints for computational models of the ventral visual stream and object recognition behavior. / by Rishi Rajalingham. / Ph. D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Brain and Cognitive Sciences, 1992. / Includes bibliographical references. / by Eliot Robert Charles. / Ph.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Brain and Cognitive Sciences, 1991. / Includes bibliographical references (leaves 302-329). / by Fu-Chin Liu. / Ph.D.