Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Brain and Cognitive Sciences, 2009. / 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. / Includes bibliographical references. / The elucidation of the biological bases of a complex trait like human language proceeds from identification of precise behavioral phenotypes to investigation of the underlying genes. The human behavioral parts of this dissertation focus on understanding the reasons for children's overuse of definite article 'the', to refer to one of several objects in a context set, as opposed to the unique established referent. Competing theories argue the deficit is either in children's semantic computational knowledge (of uniqueness/maximality), or in their pragmatic/social awareness/theory-of-mind development. Experiments in this dissertation focused on children's comprehension and interpretation of the indefinite and definite determiners, as well as 'that', anaphors 'another' and 'same', and free relative clauses. The results in this thesis suggest that in typically developing (TD) children the late acquisition of determiner 'the' is due to the late maturation of the semantic principle of maximality. Children with autism spectrum disorders (ASD) and with Williams syndrome (WS) either manifested an adult-like competence, an absence of manifestation of knowledge, or a pattern found in TD younger children (where 'that' is understood better than 'the' as referring to the salient unique referent) -- indicating delay of development of the language faculty, but no deviance. This suggests that the observed deficits in ASD and WS pattern with those in TD, and hence are also semantic in nature. The mouse neurogenetic part of this dissertation investigates whether the GTF2I family of genes, causal to WS behavioral phenotype, also contributes to WS cortical development. / (cont.) By overexpression of Gtf2i and Gtf2ird1 in the mouse neocortex via in utero electroporation, their effects on laminar patterning and cell morphogenesis during brain development are characterized. The present results suggest that these genes can synergistically contribute to the abnormal neocortical development in WS, and thereby could contribute to language deficits in WS. Beyond posing an explanatory challenge to linguistic theories, the research comparing typical and atypical development sheds light on the mechanisms of language development and impairment, and provides endophenotypic descriptions of ASD and WS, which are crucial for elucidating not only genetics of neurodevelopmental disorders, but also the genetic basis of the human language faculty. / by Nadezhda N. Modyanova. / Ph.D.

Thesis: Ph. D., Massachusetts Institute of Technology, Department of Brain and Cognitive Sciences, February 2017. / Cataloged from PDF version of thesis. "September 2016." / Includes bibliographical references. / Neocortex learns predictive models of sensory input, allowing mammals to anticipate future events. A fundamental component of this process is the comparison between expected and actual sensory input, and the layered architecture of neocortex is presumably central to this computation. In this thesis, I examine the role of laminar differences, and specifically the role of layer 6 (L6) in the encoding and perception of stimuli that deviate from previous patterns. In awake mice, layer 4 neurons encode current stimulus deviations with a predominantly monotonic, faithful encoding, while neurons in layer 2/3 encode history dependent change signals with heterogeneous receptive fields. Corticothalamic (CT) cells in Layer 6 respond sparsely, but faithfully encode stimulus identity. Weak optogenetic drive of L6 CT cells disrupted this encoding in layer 6 without affecting overall firing rates. This manipulation also caused layer 2/3 to represent only current stimuli. In a head-fixed stimulus detection task, small stimulus deviations typically make stimuli more detectable, and the L6 manipulation removed this effect, without affecting detection of non-changing stimuli. Analogously, in free sensory decision making behavior, the manipulation selectively impaired perception of deviant stimuli, without affecting basic performance. In contrast, stronger L6 drive reduced sensory gain and impaired tactile sensitivity. These results show an explicit laminar encoding of stimulus changes, and that L6 can play a role in the perception of sensory changes by modulating responses depending on previous, or expected input. This finding provides a new perspective on how the layered cortical architecture can implement computations on hierarchical models of the world. / by Jakob Voigts. / Ph. D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Brain and Cognitive Sciences, 1990. / Includes bibliographical references (p. 185-201). / by David J. Bennett. / Ph.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Brain and Cognitive Sciences, 2011. / Cataloged from PDF version of thesis. / Includes bibliographical references (p. 121-130). / The visual system is a dynamic entity whose response properties depend on context and experience. In this thesis, I examine how the brain changes as we learn to see - what changes occur during the onset of recognition, in the mature visual system on the one hand, and in a developmentally nascent one, on the other? Working with normal adults, I focus on the processes that underlie the interpretation of images as meaningful entities. This interpretation is greatly facilitated by prior information about a stimulus. What are the neural sites that exhibit experience dependent changes? Using multivariate decoding techniques, I find pervasive evidence of such changes throughout the visual system. Critically, cortical regions previously implicated in such learning are not the same loci as sites of increased information. Examining the temporal mechanisms of recognition, I identify the perceptual state transitions corresponding to the onset of meaning in an observed image. Furthermore, decoding techniques reveal the flow of information during this 'eureka moment.' I find feedback processing when a degraded image is first meaningfully interpreted, and then a rapid transition into feed-forward processing for more coherent images. Complementing the studies with mature subjects, my work with developmentally nascent observers explores the genesis of visual interpretation. What neural changes accompany the earliest stages of visual learning? I show that children treated for congenital blindness exhibit significant cortical re-organization after sight onset, in contrast to the classical notion of a critical period for visual plasticity. The specific kind of reorganization suggests that visual experience enhances information coding efficiency in visual cortex. Additionally, I present evidence of rapid development of functionally specialized cortical regions. Overall, the thesis presents two complementary perspectives on the genesis of visual meaning. The results help advance our understanding of how short-term experience, as well as developmental history, shapes our interpretation of the complex visual world. / by Scott Gorlin. / Ph.D.

Thesis (Ph. D. in Neuroscience)--Massachusetts Institute of Technology, Dept. of Brain and Cognitive Sciences, 2013. / 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. / Includes bibliographical references. / The hippocampus is required for the formation, but not storage, of long-term episodic memories. During memory formation, however, the hippocampus is not a lone actor; rather it works in concert with various structures across the brain. The mechanisms by which diverse populations of cells are coordinated for the formation of a single, coherent memory remain unknown. This thesis is an investigation of the temporal and hemispheric structure of replay events. The timing of replay is investigated at the levels of hippocampal sharp-wave ripples and multi-unit activity. We found that, during sleep, ripples generation is modulated by a 10-15Hz rhythm. We also observed this rhythm in the multi-unit firing rate of hippocampal neurons. Next we investigated and quantified the level of coordination between the hippocampal during replay events. Using bilateral hippocampal recordings from several rats during spatial navigation and subsequent sleep epochs, we directly compared the activity of these two spatially isolated networks at the level of the local field potential and the information encoded by the two neuronal populations. We found that the neural activity of the two hippocampi was highly correlated in some aspects but not others. As previously reported in the mouse, we found that, in the rat, sharp-wave ripples were simultaneously generated spontaneously in both hippocampi and that, although the intrinsic frequencies of ripple oscillations were correlated bilaterally, the phases of the individual ripple wavelets were not. Finally, we found that information encoded by both hippocampal ensembles is highly correlated during replay events. / by Stuart Pope Layton. / Ph.D.in Neuroscience

Thesis: Ph. D., Massachusetts Institute of Technology, Department of Brain and Cognitive Sciences, 2017. / Cataloged from PDF version of thesis. "September 2016." / Includes bibliographical references (pages 115-118). / For the recognition of general objects in natural scenes, the current top-performing computer vision models owe a debt to visual neuroscience. The hierarchical architecture of convolutional networks, and related models such as HMAX, mimics that of the ventral stream of visual cortex. In essence, they apply the model of Hubel and Wiesel recursively, alternating layers of 'simple' cells, which are tuned to certain local features, and 'complex' cells, which pool the outputs of simple cells within a local region. With recent advances in deep learning, for many tasks in vision and speech, emphasis has moved away from so-called 'hand-designed' models and toward big data and high throughput computing, with models learning from millions of labeled examples. Yet CNNs only learn their features - the weights of connections in the network. All other aspects of the network (size, connectivity, response functions, etc.) are unlearned architectural choices made by their designers. Vision has not yet been reduced to a pure learning problem - human insight into the nature of visual problems continues to be important. To design a good vision system, one still has to understand vision. And, as evidenced by performance for many complex visual tasks, natural vision systems still 'understand' vision better than we do; there is still much to be learned from them. Our work is based on the HMAX model, which places greater weight on biological realism. Our goals are threefold: to better understand the ventral stream algorithm, as well as the visual problem it solves, and to improve the performance of artificial vision systems. In this work we take two main approaches. i-theory is an ongoing effort to explain the good performance of hierarchical models in terms of a formal theory of invariance to transformations. We provide a reinterpretation of V1 simple and complex cells in the context of i-theory as computing a high-dimensional, locally translation-invariant signature for the contents of a V1 receptive field. We describe a simple algorithm for learning them which can extend without modification to the learning of higher-order representations for V2 and beyond. The algorithm yields model V1 cells having a good fit to data from several animal species. We also demonstrate that a precondition of i-theory, covariance, can hold in upper layers, even for transformations not anticipated in the training of lower layers. No current hierarchical object recognition model incorporates realistic retinal resolution. Incorporating this detail forces a reevaluation of the role of the ventral stream's feedforward core in the larger task of scene understanding as well as many details of the model itself, particularly with respect to scale. We investigate the optimal shape of the input window used to select a subset of the visual information available in a scene for processing in a single feedforward pass, defined as a region in (x, y, A), the handling of the A dimension within the hierarchy, and the problem of clutter. Our main experimental results are (1) spatial wavelengths too small for the retina to perceive across the entire object do not play a significant role in the no-clutter case, but confer robustness in the presence of clutter, and (2) preservation by the hierarchy of information about the relative scale (distance along A) of feature activations is more important than current models reflect. / by Jim Mutch. / Ph. D.

Thesis: Ph. D. in Neuroscience, Massachusetts Institute of Technology, Department of Brain and Cognitive Sciences, 2016. / Cataloged from PDF version of thesis. Page 114 blank. / Includes bibliographical references (pages 107-113). / While animals tend to prefer immediate rewards to delayed ones [1], delayed gratification is often advantageous [2]. Appropriate choice about future rewards is critical for survival. The dorsal raphe serotonergic neurons have been long implicated in the control of temporal discounting of reward [3] [4], but it is not clear whether their activities in fact direct the decision making process. In this thesis, I designed a cued intertemporal choice task for mice that allows the combination of highly specific genetic manipulations with sophisticated behavioral interrogations. The task utilizes odors to communicate upcoming reward contingencies to the mouse subjects. I found that optogenetically augmenting or silencing the activities of dorsal raphe serotonergic neurons precisely at decision epochs resulted in an increase or a reduction in the choice for the delayed and larger reward, respectively. These manipulations do not alter the subjects' choice in trials involving immediate rewards, suggesting that serotonin might only be important for conditions in which difficult trade-offs are required. I also demonstrated that the nucleus accumbens, a major component of the mesolimbic reward pathway, is a possible downstream target of the aforementioned serotonin action. Taken together, these results show that serotonergic neurons regulate inter-temporal choice behavior bidirectionally, possibly through actions in nucleus accumbens. / by Sangyu Xu. / Ph. D. in Neuroscience

Thesis: Ph. D., Massachusetts Institute of Technology, Department of Brain and Cognitive Sciences, 2017. / Cataloged from PDF version of thesis. / Includes bibliographical references (pages 158-173). / Neuropsychiatric Disorders are the leading category contributing to disability-adjusted life years (DALYs) in the U.S. according to the World Health Organization. These findings underline the vast burden caused by neuropsychiatric disorders on patients. However, effective treatments do not exist for many of the neuropsychiatric disorders mostly due to lack of understanding of disease pathology. Evidence from whole genome sequencing of psychiatric disorder patients increasingly suggest that Wnt signaling and cortical development - in addition to other perturbations - may underlie the pathophysiology of multiple disorders. Furthermore, besides autism spectrum disorder, contribution of neurodevelopmental dysregulations to disease etiology in late-onset disorder such as schizophrenia are becoming widely accepted. Therefore, a better understanding of cortical development and functions of Wnt signaling could prove critical in determining the cellular and molecular mechanisms underlying the causes of psychiatric disorders. The work presented in this thesis aims to understand the functions of multiple neuropsychiatric disorder risk genes in brain development, and the converging role of Wnt signaling in neurodevelopment. First, we determined ASD risk gene Chd8 to be a positive regulator neural progenitor proliferation in the developing mouse brain through its transcriptional regulation of cell cycle and Wnt signaling genes. Surprisingly, Chd8 exhibits a cell type-specific modulation of Wnt signaling. Furthermore, knockdown of Chd8 in the upper cortical layer neurons caused ASD-related behavioral abnormalities in adult mice, which could be rescued via induction of Wnt signaling. Secondly, we made the novel observation that bipolar disorder risk gene Ank3 (ankyrin-G) plays a crucial role in cortical neurogenesis through regulation of subcellular localization of [beta]-catenin, which is an essential component of Wnt signaling. Finally, the effects of brain-specific deletion of BcI9 on brain development and behavior were characterized using a heterozygous BcI9 deletion transgenic mouse line. Behavioral and brain development defects associated with BcI9 were shown to mimic some of the clinical symptoms observed in patients. Collectively, our results demonstrate a central role for Wnt signaling and cortical development in pathophysiology of neurodevelopmental and neuropsychiatric disorders. / by Omer Durak. / Ph. D.

Thesis (S.M.)--Massachusetts Institute of Technology, Dept. of Brain and Cognitive Sciences, 2012. / Cataloged from PDF version of thesis. / Includes bibliographical references (p. 37-42). / Chronic stress has been linked to variation in gene regulation in the hippocampus (HIP) among other areas. These lead to cytoskeletal and volumetric rearrangements in various nuclei of the central nervous system and are thought to contribute to several stress-sensitive disorders. One such gene that has been shown to be downregulated in HIP in response to stress is somatotropin, colloquially known as growth hormone (GH). These experiments were conducted to develop a novel assay for examination of working memory in rats and explore the nature of stress-induced impairment of hippocampal function and determine whether infusion of a modified herpes simplex virus (HSV) carrying the recombinant rodent growth hormone (GH) would be sufficient to restore normal hippocampal function. After 21 days of chronic immobilization stress (CIS), animals received bilateral infusions into the dorsal HIP of 2[mu]l HSV carrying either GH with green florescent protein (GFP) or GFP only. On the second day following the infusion, the animals received trace conditioning, a HIP-dependent task, with five tone-shock pairings of a 16 second tone followed by a 30 second trace interval terminating with a 1 second 0.85 milliamp footshock. An inter-trial interval of 3 minutes was used to separate the tone-shock pairings. The following day the animals were tested for fear to the context and for fear to the tone in a novel context, measured by amount of time the animal spent freezing. Using this criterion, animals that had undergone stress that received the control vector were less likely to freeze when presented with the tone, indicating an impairment of hippocampal function. Viral-mediated overexpression of GH in the dorsal HIP was able to reverse the CIS-related impairment in hippocampal function. ELISA was used to verify the expression of GH from the infused vector. These experiments may yield future directions of investigation for stress-based disorders. / by Christopher M. Saenz. / S.M.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Brain and Cognitive Sciences, 2004. / Includes bibliographical references (leaves 99-112). / Synaptic plasticity is the rearrangement of neuronal connections that likely underlies learning and memory. It requires the expression of a set of genes essential for the synaptic changes that occur during plasticity, candidate plasticity gene 2 (cpg2) was isolated in a screen for genes that effect synaptic plasticity. In this thesis, I analyze the regulation and function of cpg2 in neurons. I find that cpg2 is a splice-variant of the syne-1 gene that is expressed only in brain regions capable of plasticity and encodes a protein specifically localized to a postsynaptic endocytic zone of excitatory synapses, often in the vicinity of clathrin-coated pits. I further show that, through its C-terminal coiled-coil motifs, CPG2 binds to the actin cytoskeleton and to endophilin B2, a member of a family of proteins involved in membrane trafficking. RNAi-mediated knock-down of CPG2 increased the number of postsynaptic clathrin-coated vesicles, some of which trafficked NMDA receptors, and disrupted the internalization of glutamate receptors. In addition, alterations in its protein levels affected dendritic spine size, supporting a role for CPG2 in regulating membrane trafficking. These data suggest that CPG2 organizes a network of proteins at the postsynaptic endocytic zone critical for glutamate receptor internalization. Due to its unique expression profile and subcellular localization, CPG2 may underlie a novel adaptation of the clathrin-mediated endocytosis pathway that enables the capacity for postsynaptic plasticity in excitatory synapses. / by Jeffrey Richard Cottrell. / Ph.D.