Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Brain and Cognitive Sciences, 1993. / Includes bibliographical references (p. 203-217). / by Anthony Passera. / Ph.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Brain and Cognitive Sciences, 2005. / Includes bibliographical references. / Flow does the brain meet shifting task demands? The experiments and formal theoretical framework presented in this dissertation characterize the cognitive and neural processes by which flexible performance is enabled during task switching. Chapter 1 reviews major findings and controversies in the task switching literature, highlighting (1) evidence that behavioral switch costs may derive from proactive interference due to the facilitated retrieval of irrelevant competitors from long-term memory and (2) the consistent finding of activation in ventrolateral prefrontal cortex (VLPFC) during task switching. These observations motivate the hypothesis that left VLPFC may resolve proactive interference arising from long-term memory during a task switch. Chapters 2 and 3 describe three fMRI experiments conducted in experimental contexts independent of task switching that directly link left mid-VLPFC (Brodmann's Area 45; inferior frontal gyrus pars triangularis) to a post-retrieval selection process that resolves proactive interference from irrelevant representations retrieved from long-term memory. Chapter 4 introduces a computational model that derives its task switch cost from interference due to performance-dependent changes in its associative structure, and that resolves this interference through a control process that biases retrieved conceptual representations. Critically, a conflict signal, derived from retrieved conceptual representations in the model, is shown to be characteristic of the pattern of response in left mid-VLPFC during an fMRI experiment that manipulates preparation and interference in task switching. Furthermore, this pattern dissociates left mid-VLPFC from other regions active during a task switch. / (cont.) These data strongly support the hypothesis that task switch costs derive from proactive interference due to facilitated retrieval of irrelevant representations and left mid-VLPFC serves to overcome this proactive interference. Chapter 5 provides further details of the model, demonstrates its power to explain a number of common task switching phenomena, and explores its relationship with three other prominent formal models of task switching. The experiments and associated theory presented in this thesis provide evidence that instances of flexible behavior, like task switching, may be understood as acts of memory, and are enabled by prefrontal cortex mechanisms that control memory to overcome interference. / by David Badre. / Ph.D.

Thesis (Ph. D. in Neuroscience)--Massachusetts Institute of Technology, Dept. of Brain and Cognitive Sciences, 2005. / Includes bibliographical references (p. 53-59). / The interactions between cortical and hippocampal circuits are critical for memory formation, yet their basic organization at the neuronal network level is not well understood. Here we investigate the timing relationships between neuronal activity in the medial prefrontal cortex of freely behaving rats and the hippocampal theta rhythm. We demonstrate that a significant portion of prefrontal neurons are phase-locked to the hippocampal theta rhythm and we compare the phase-locking properties of prefrontal and hippocampal cells. We also show that prefrontal neurons phase-lock best to theta oscillations delayed by approximately 50 ms and confirm this hippocampo-prefrontal directionality and timing at the level of correlations between single cells. Finally we demonstrate that phase-locking of prefrontal cells is predicted by the presence of significant correlations with hippocampal cells at positive delays up to 150 ms, suggesting that direct hippocampal input has an important contribution to the observed prefrontal phase-locking. The theta entrained activity across cortico-hippocampal circuits described here may be important for gating information flow and guiding the plastic changes that are believed to underlie the storage of information across these networks. / by Evgueniy V. Lubenov. / Ph.D.in Neuroscience

Thesis: Ph. D., Massachusetts Institute of Technology, Department of Brain and Cognitive Sciences, 2014. / Cataloged from PDF version of thesis. / Includes bibliographical references (pages 124-143). / The middle face patch is a region of cortex in the ventral visual pathway of the Inferior Temporal lobe in the macaque brain. This region has been identified by functional MRI to respond preferentially to images of faces over non-face images, similar to functionally defined face selective regions in the human brain. In this thesis we spatially map the category selective preference of 100's of multiunit sites in the cortical region localized to the fMRI face selective region with a novel X-ray imaging system. We observed evidence for an ~6mm region of cortex that was enriched with sites that demonstrate a category selective preference for images of faces. The number of face selective sites varied across the cortical region, and could peak as high as 96% near the center of the enriched zone to a baseline rate as low as 3% outside the face patch. Sites in the middle face patch displayed significant category selectivity for the conventional images of faces used in the experiment. Approximately 25% of the sites in the patch displayed high selectivity (d' > 2) for faces as compared to less than 1% of the sites sampled outside the patch. Given the limited image variability present in conventional image sets, we examined face detection performance in the middle face patch with a computationally non-trivial image set, that was nonetheless simple for human subjects. We found that under these conditions, sites in the middle face patch demonstrated a weak correlation to human face detection behavior. We conclude that the middle face patch is a region of cortex enriched with sites that participate in an intermediate level representation of faces. / by Paul Aparicio. / Ph. D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Brain and Cognitive Sciences, 1996. / Includes bibliographical references (leaves 162-198). / by Daniel Eric Emerling. / Ph.D.

Thesis: Ph. D. in Neuroscience, Massachusetts Institute of Technology, Department of Brain and Cognitive Sciences, 2016. / Cataloged from PDF version of thesis. / Includes bibliographical references (pages 247-264). / The polyglutamine diseases are the most common form of inherited neurodegenerative disorders. Each of the polyglutamine diseases stems from the same underlying cause: a CAG expansion mutation in the coding region of a gene. This gives rise to a protein with an expanded glutamine repeat stretch. Despite the fact that all polyglutamine diseases are caused by the same type of mutation, the CAG expansion in different genes gives rise to different diseases, with differentially vulnerable neuronal populations and distinct pathologies. One of the most well-known polyglutamine disorders is Huntington's disease (HD), which results from a CAG repeat expansion in the huntingtin (Htt) gene. HD is characterized by psychiatric symptoms, cognitive decline, and movement disturbances, especially chorea. Interestingly, some presumed HD patients exhibited HD-like symptoms and characteristic striatal degeneration, but did not harbor a mutation in Htt. This led to the discovery of the Huntington's disease-like (HDL) disorders. One such disorder is Huntington's disease-like 2 (HDL2). Recent studies identified a specific polyglutamine protein hypothesized to contribute to HDL2 pathology. Given the similarities between HD and HDL2 patients, I used Drosophila to model these two genetically distinct disorders to compare polyglutamine-induced toxicity. This work represents the first time HDL2 has been modeled in Drosophila, and the first characterization of HDL2 polyglutamine protein pathology. My investigation highlights many distinctions between expanded Htt and HDL2 polyglutamine proteins. Importantly, my research demonstrates that nuclear localization of the polyglutamine protein is critical to disease pathogenesis in HDL2, but not HD. I also present the results from an in vivo RNAi screen to search for novel suppressors of toxicity in our HD and HDL2 models. Analyzing top RNAi suppressors from both models indicates different pathogenic pathways are at play in these two polyglutamine diseases, but some mechanisms may be shared. We conclude that while HD and HDL2 have similar clinical profiles, distinct pathogenic mechanisms contribute to the two neurodegenerative disorders. / by Megan Krench. / Ph. D. in Neuroscience

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Brain and Cognitive Sciences, 1995. / Includes bibliographical references (p. 97-101). / by Fun, Wey. / Ph.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Brain and Cognitive Sciences, 2005. / Includes bibliographical references. / Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline and memory loss. Although much is known about how AD affects the brain, the cause of this disease remains elusive. Current AD treatments target symptoms of the disease but do not prevent or slow the underlying neurodegeneration. Therefore, research into the biochemical mechanisms of AD is necessary in order to develop a better understanding of how to treat it. Misprocessing of the amyloid precursor protein (APP) in the brains of AD patients leads to accumulation of the amyloidogenic peptide AD. A soluble APP fragment (APPS) is formed when APP is cleaved within the AP region, thereby preventing AP formation. Activation of 5-HT2A or 5-HT2c receptors has been shown to increase APPS secretion in vitro; therefore, we determined whether activation of these receptors might have a similar effect in vivo. We found that a 5-HT2A/2c agonist affected brain APP metabolism in guinea pigs by increasing CSF levels of APPS and, following chronic treatment, by decreasing levels of AP. Our data indicate that activation of brain 5-HT2c receptors may be useful for treating AD by reducing AP production. Traumatic brain injury is a risk factor for AD, although the reason is unknown. To explore this relationship, we examined the effect of the inflammatory mediator PGE2 on production of APP in cultured microglia. We found that PGE2 treatment stimulated APP overexpression and that this effect was likely mediated by the prostaglandin EP2 receptor and the cAMP signaling cascade. Therefore, EP2 receptor antagonists may constitute an additional target for prevention of AD following brain injury. / (cont.) The neuropathology associated with AD includes neuritic dystrophy and degeneration. Therefore, restoration of neuritic growth and repair of phospolipid membranes may be important for treating AD. We found that treatment of NGF- differentiated PC 12 cells with the phospholipid precursor uridine enhanced neurite outgrowth by both enhancing phosphatide biosynthesis and by stimulating a G-protein receptor-coupled signaling pathway. Subsequently, we found that the HMG-CoA reductase inhibitor pravastatin enhanced neurite outgrowth in rat hippocampal neurons, not by affecting cholesterol synthesis, but by inhibition of isoprenoid formation. Stimulation of neurite growth by either uridine or statins may reduce AD risk by averting neuritic dystrophy and degeneration. However, further studies must be conducted to determine whether they are able to affect neuritic processes in vivo. / by Amy Melissa Pooler. / Ph.D.

Thesis (Ph.D.)--Massachusetts Institute of Technology, Dept. of Brain and Cognitive Sciences, 2002. / Includes bibliographical references. / The thesis collects five essays on how neurons in four motor areas of the frontal lobe process the movement dynamics. In the experiments described, monkeys executed visually instructed reaching movements while holding the handle of a robotic arm. Motors attached to the robot allowed turning on and off perturbing forces that deviated the hand of the monkeys. After some exposure, the monkeys adapted to the perturbation. The experiments were designed to dissociate the activity related to the desired kinematics from that related to the dynamics. Furthermore, the experiments dissociated the activity related to motor performance (desired kinematics and dynamics) from that related to motor learning (learning a new dynamics). The thesis describes the following results. 1. During motor execution, the movement dynamics is processed across multiple areas. Specifically, dynamics-related activity is found in all areas projecting to the spinal cord under study, namely the primary motor cortex (M1), supplementary motor area (SMA), dorsal premotor (PMd), and ventral premotor area (PMv). 2. Dynamics-related activity is also present during motor planning in both PMd and SMA, but not in M1 and PMv. This suggests that the dynamics is processed "upstream" of M1. The activity of SMA reflects during motor planning a kinematics-to-dynamics transformation. Neuronal correlates of that transformation are observed both at the level of the population and for single cells. 3. Extensive neuronal plasticity is observed in these areas when monkeys learn a new dynamics. The activity of single neurons modifies as monkeys adapt to the force, and changes outlast the exposure to the perturbation. / (cont.) With respect to M1, comparison of the movement-related activity recorded prior to, during, and after exposure to the perturbing force reveals a double level of neuronal coding. As a population, neurons in M1 display changes that mirror the changes observed in the EMG of muscles. In a statistical sense, the population activity of M1 after re-adaptation is not distinguishable from that before exposure to the force. Thus, the population activity of M1 reflects motor performance. However, single neurons maintain -after re-adaptation -trace of the adaptation experience. Thus, the activity of M1 neurons also reflects motor learning. / by Camillo Padoa-Schioppa. / Ph.D.

Thesis: S.M., Massachusetts Institute of Technology, Department of Brain and Cognitive Sciences, 2015. / Cataloged from PDF version of thesis. / Includes bibliographical references (pages 25-26). / Organisms have a remarkable ability to respond to complex sensory inputs with intricate, tuned motor patterns. How does the brain organize and tune these motor responses, and are certain circuit architectures, or connectivity patterns, optimally suited for certain sensorimotor applications? This thesis presents progress towards this particular problem in three subprojects. The first section re-analyzes a large data set of single-unit recordings in zebra finch area HVC during singing. While HVC is known to be essential for proper expression of adult vocalization, its circuit architecture is contentious. Evidence is presented against the recently postulated gesture-trajectory extrema hypothesis for the organization of area HVC. Instead, the data suggest that the synaptic chain model of HVC organization is a better fit for the data, where chains of RA-projecting HVC neurons are synaptically connected to walk the bird through each time-step of the song. The second section examines how optimal sensorimotor estimation using a Bayesian inference framework could be implemented in a cerebellar circuit. Two novel behavioral paradigms are developed to assess how rats might tune their motor output to the statistics of the sensory inputs, and whether their behavior might be consistent with the use of a Bayesian inference paradigm. While neither behavior generated stable behavior, evidence indicates that rats may use a spinal circuit to rapidly and dynamically adjust motor output. The third section addresses the formation of habitual behaviors in a cortico-striatal network using rats. Stress and depression are known to significantly alter decision-making abilities, but the neural substrate of this is poorly understood. Towards this goal, rats are trained on a panel of decision-making tasks in a forced-choice T-maze, and it is shown that a chronic stress procedure produces a dramatic shift in behavior in a subset of these tasks but not the rest. This behavioral shift is reversed by optogenetic stimulation of prelimbic input to striatum, pinpointing a circuit element which may control stress-induced behavioral changes. Furthermore, a circuit hypothesis is presented to explain why sensitivity to changing reward values diminishes with overtraining. / by Michael Lynn. / S.M.