Thesis: Ph. D. in Neuroscience, Massachusetts Institute of Technology, Department of Brain and Cognitive Sciences, 2016. / Vita. Cataloged from PDF version of thesis. / Includes bibliographical references (pages 151-171). / Changes in the sensory experience of an animal shapes behavior through synaptic plasticity. Modification in the strength of synaptic drive can result from adjustments in the strength of existing synapses, creation of new synapses, or removal of existing ones and involves presynaptic, postsynaptic, and extra-synaptic mechanisms. Ocular dominance (OD) plasticity following brief periods of monocular deprivation (MD) is a classic example of experience-dependent change, which leads to a rapid weakening of cortical responsiveness to the deprived eye and a strengthening of responsiveness to the non-deprived eye. Though there is clear anatomical reorganization following long periods of lid suture, only recently has brief periods (3 days) of MD has been shown to drive structural plasticity of thalamic input to binocular visual cortex. The exact molecular and synaptic mechanisms responsible for rapid OD shifts remain unclear. In my thesis work, I address the requirement of proper microglial functioning via the fractalkine receptor (CX3CR1) in OD plasticity following 3 days of MD. I first identify increased lysosomal content in microglia within layer 4 (L4) of binocular visual cortex following MD, which suggests microglia participate in this structural rearrangement. As it is currently believed that a major axis of communication between neurons and microglia occurs via fractalkine and its specific receptor CX3CR1, I investigated OD plasticity within the CX3CR1 KO mouse. My experiments reveal increased lysosomal content, structural plasticity of thalamocortical synapses, and OD shifts measured with visually evoked potentials (VEPs) all occur normally in this mutant mouse as a result of 3 days of MD with only subtle differences when compared to WT mice. I conclude that, while microglia may have a role in the anatomical and functional experience-dependent cortical plasticity driven by brief lid suture, it does not require CX3CR1. / by Rachel W. Schecter. / Ph. D. in Neuroscience

Thesis (Ph.D.)--Massachusetts Institute of Technology, Dept. of Brain and Cognitive Sciences, 1999. / Includes bibliographical references. / I-han Chou. / Ph.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Brain and Cognitive Sciences, 2004. / Also issued in leaves. / Includes bibliographical references. / (cont.) increased activity whenever recollection was attempted, independent of the level of recollection success. The results are consistent with the hypothesis that increased left-lateralized retrieval activity in older adults supports recollection attempt. Age deficits in semantic memory are more subtle than in episodic memory. However, older adults are impaired when automatic, data-driven processes are not sufficient to support the retrieval of conceptual knowledge. The fMRI study described in Chapter 3 used semantic repetition priming to test two theories of the role LIPC plays in semantic retrieval. Young adults exhibited repetition-related BOLD response reductions in LIPC that were specific to the particular semantic task engaged, consistent with the hypothesis that LIPC supports controlled semantic retrieval. Older adults, in contrast, exhibited repetition-related signal reductions even when the semantic judgment made about a word differed across the two exposures, consistent with the hypothesis that older adults fail to gate irrelevant semantic information from working memory during initial presentation of the word. / Older adults are impaired in episodic and semantic retrieval but the extent of these deficits and their neural correlates is unknown. In episodic memory, older adults appear particularly impaired in retrieving bound information, such as conjunctions of items or of an item and its context. These retrieval deficits, however, may be merely the downstream effects of poor encoding. Chapter 1 presents a series of studies that test the theory that age-related recollection deficits are due to encoding failures. Results revealed that older adults were impaired in associative recognition when self-initiated processes were required at acquisition. Additional encoding support eliminated age differences, however, even when the retrieval task was made more difficult. The results support the hypothesis that recollection deficits are primarily due to poor encoding. Although older adults with encoding support can retrieve information as well as young adults, it is an open question whether brain activity supporting retrieval is identical in the two groups. In past studies, greater left prefrontal activity has been observed in older adults even when their performance does not differ from young adults. However, the circumstances under which this pattern arises and its functional significance are still unknown. Chapter 2 presents a functional magnetic resonance imaging (fMRI) study of associative recognition by young and older adults who performed equally well but who showed different patterns of recollection-related activity. Young adults exhibited greater activity in left inferior prefrontal cortex (LIPC) and inferior temporal/fusiform gyri for retrieval based on recollection relative to retrieval based on familiarity. In the same regions, older adults exhibit / by Gail O'Kane. / 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 109-130). / Despite being reflexive, primate view invariant object recognition is a complex computational task. These computations are thought to reside in the ventral visual stream, specifically culminating in inferior temporal (IT) cortex. Recent research in machine learning has made great progress in modeling primate ventral visual stream computations. While the end result of current machine learning approaches produces models that are highly predictive of the adult state of the ventral stream, the learning approaches themselves are not biologically plausible, requiring tens of thousands to millions of human-labeled training points. Understanding primate visual development is therefore not only interesting from the perspective of neuroscience, but also has practical value in building more robust learning algorithms capable of functioning in domains where large amounts of human-labeled training information may be difficult or impossible to create. Better learning algorithms may also produce agents capable of adapting and behaving in the world not unlike humans. This thesis first describes work on predicting visual responses across the human ventral stream using convolutional neural networks (CNNs). We then describe a set of natural image statistics automatically incorporated into high-performing CNNs from supervised training-it is possible primate development incorporates these or similar natural image statistics into its synaptic strengths. Finally, we describe the first-large scale characterization of IT in 19-32 week old macaques. While we find longer response latencies in these younger animals, we do not find any differences in representation between adults and juveniles suggesting that, at 19-32 weeks of age, IT already supports robust object recognition consistent with adults. Our data provide an upper limit on the amount of training data needed to reach adult-level performance-approximately 2,800 hours of waking visual experience. / by Darren Seibert. / Ph. D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Brain and Cognitive Sciences, 1997. / Includes bibliographical references (p. 135-146). / by Eleonora Fusco. / Ph.D.

Thesis (Ph.D.)--Massachusetts Institute of Technology, Dept. of Brain and Cognitive Sciences, 2003. / Includes bibliographical references (p. 100-104). / There is broad agreement that the hippocampus is crucially involved in the formation of richly-detailed, long term memories of events in humans. A key aspect of such memories is the temporal order and spatial context of the events experienced. Evidence from a wide variety of behavioral and electrophysiological experiments indicates that the rodent hippocampal spatial memory system is a model system for studying this type of memory in humans. Here, we develop a new combinatorial method for analyzing sequential firing patterns involving an arbitrary number of neurons based on relative time order. We then apply this method to decode memories of sequential spatial experience in the rat hippocampus during slow wave sleep. Specificaly, rats are trained to repeatedly run through a sequence of spatial receptive fields ("place fields") of hippocampal CA1 "place cells" in a fixed temporal order. The spiking activity of many such individual cells is recorded before (PRE), during (RUN), and after (POST) this experience. By treating each place field traversed as an individual event, the rat's experience in RUN can be represeted by the resulting sequence of place fields traversed, and therefore by the activity of the corresponding place cells. Then to characterize the extent to which the sequential nature of the RUN experience has been encoded into memory, we search for firing patterns related to the RUN sequence in POST. To do so, we develop a method that statistically quantifies the similarity between any desired "reference sequence" (here chosen to be the RUN sequence) and arbitrary temporal firing patterns. We find that the RUN sequence is repeatedly re-expressed during POST slow wave sleep in brief bursts involving four or more cells firing in order, but not so during PRE. / (cont.) This provides direct neural evidence of the rapid learning of extended spatial sequences experienced in RUN. The results may shed light on the encoding of memories of events in time ("episodic memories") in humans. Furthermore, the multiple spike train analysis method developed here is general and could be applied to many other neural systems in many different experimental conditions. / by Albert K. Lee. / Ph.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Brain and Cognitive Sciences, 2008. / Includes bibliographical references (p. 144-156). / The hippocampus is necessary for the formation and storage of episodic memory, however, the computations within and between hippocampal subregions (CA1, CA3, and dentate gyrus) that mediate these memory processing functions are not completely understood. We investigate by recording in the hippocampal subregions as rats execute an augmented linear track task. From these recordings, we construct ensemble rate representations using a point process adaptive filter to characterize single-unit activity from each subregion. We compared the dynamics of these rate representations by computing average max rate and average rate modulation during different experimental epochs and on different segments of the track. We found that the representations in CA3 were modulated most when compared to CAl and DG during the first 5 minutes of experience. With more experience, we found the average rate modulation decreased gradually across all areas and converged to values that were not statistically different. These results suggest a specialized role for CA3 during initial context acquisition, and suggest that rate modulation becomes coherent across HPC subregions after familiarization. Information transfer between the hippocampus and neocortex is important for the consolidation of spatial and episodic memory. This process of information transfer is referred to as memory consolidation and may be mediated by a phenomena called "replay." We know that the process of replay is associated with a rise in multi-unit activity and the presence of ripples (100-250 Hz oscillations lasting from 75ms to 100ms) in CAl. Because ripples result from the same circuits as replay activity, the features of the ripple may allow us to deduce the mechanisms for replay induction and the nature of information transmitted during replay events. / (cont.) Because ripples are relatively short events, analytical methods with limited temporal-spectral resolution are unable to fully characterize all the structure of ripples. In the thesis, we develop a framework for characterizing, classifying, and detecting ripples based on instantaneous frequency and instantaneous frequency modulation. The framework uses an autoregressive model for spectral-temporal analysis in combination with a Kalman filter for sample-to-sample estimates of frequency parameters. We show that the filter is flexible in the degree of smoothing as well as robust in the estimation of frequency. We demonstrate that under the proposed framework ripples can be classified based on high or low frequency, and positive or negative frequency modulation; can combine amplitude and frequency information for selective detection of ripple events; and can be used to determine the number of ripples participating in "long ripple" events. / by David P. Nguyen. / Ph.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Brain and Cognitive Sciences, 1995. / Includes bibliographical references (leaves 156-163). / by Fei Xu. / Ph.D.

Thesis: Ph. D., Massachusetts Institute of Technology, Department of Brain and Cognitive Sciences, 2014. / Cataloged from PDF version of thesis. Vita. / Includes bibliographical references (pages 160-185). / The synaptic proteins Fragile X mental retardation protein (FMRP) and metabotropic glutamate receptor 5 (mGluR5) act in functional opposition to regulate local translation of synaptic mRNAs. Fragile X is the most common form of inherited intellectual disability and autism, and is expressed by a loss of FMRP. Previous studies have implicated mGluR5 in the pathogenesis of the disease, but a crucial unanswered question is if pharmacological mGluR5 inhibition is able to reverse an already established FX phenotype. Here we use the novel, potent and selective mGluR5 inhibitor CTEP to address this issue. Chronic treatment beginning in young adulthood results in comprehensive phenotype correction, suggesting that FX is in part a disease of acutely altered synapses. These results hold promise for clinical trials currently underway using similar approaches. Identifying mouse phenotypes to model cognitive impairment is especially important in FX because intellectual disability is at the core of the disorder. Here, we describe instrumental extinction as an assay for testing cognitive function, and report that this process is altered in FX model mice. In parallel, we characterize the role of mGluR5 in regulating synaptic and experience-dependent plasticity in wild-type mouse visual cortex. We report that NMDA receptor-dependent long-term depression (LTD) is reduced specifically in layer IV of visual cortex in mGluR5 knockout mice, as well as in wild-type mice treated chronically with CTEP. However, LTD induction is normal in the presence of acute mGIuR5 antagonism in wild-type mice, suggesting an important difference between acute and chronic mGluR5 function. In vivo, monocular deprivation results in experience-driven weakening of synaptic strength, which occurs through similar mechanisms as LTD in vitro. We report that this ocular dominance plasticity is impaired following chronic mGluR5 inhibition. This study shows that specifically in layer IV, chronic but not acute downregulation of mGIuR5 signaling has important consequences for forms of NMDA receptor-dependent plasticity in vitro and in vivo. Taken together, this work addresses both the basic function of mGluR5 as a regulator of plasticity and its potential as a therapeutic target in Fragile X. / by Michael S. Sidorov. / Ph. D.

Thesis (Sc. 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 (leaves 87-97). / Sequential processing --- using multiple sensory stimuli to plan and control a set of ordered movements --- is a central aspect of human behavior. Because previous and future movements must be stored during the execution of any movement in a sequence, memory is an indispensable aspect of sequential behavior. To study how memory is used to link sensory inputs to sequential motor outputs, we have used the oculomotor system as a model. We trained monkeys to remember the location of two spatial cues over a brief delay, and then make two eye movements to the remembered locations in the order that they appeared. We explored the role of two different frontal eye movement areas, the frontal and supplementary eye fields (FEF and SEF) during this memory delay. While both the FEF and SEF have shown to be important for sequential behavior, their individual roles are unknown. Here, using physiology, we show that the FEF is important for storing the location of multiple cues and their order in memory. In the SEF, we show that memory period stimulation can affect the order of a sequence, changing the goal of the entire sequence but not the individual movement components. / (cont.) Thus, both areas appear to play complementary roles in sequential planning: the FEF stores target locations, while the SEF appears to control the order of a response sequence, coding entire sequences without affecting the locations of the intermediate targets. This work bears on several outstanding questions in the field. It clarifies the individual roles of the FEF and SEF during sequencing: the FEF may serve as a buffer for multiple memories while the SEF plays a role in organizing movement sequences. It relates several prior SEF results, suggesting that a primary role of SEF may be to specify movements by their goal. Finally, we suggest that this goal-centered scheme may be a fundamental way that many different types of movements are encoded. / by Hark H. Histed. / Sc.D.