Thesis: Ph. D., Massachusetts Institute of Technology, Department of Brain and Cognitive Sciences, 2014. / Cataloged from PDF version of thesis. / Includes bibliographical references. / A fundamental goal in neuroscience is to understand mechanisms underlying the ability to create memories from sensory experience. While large structures such as the hippocampus are known to be critical for certain types of learning, memories are ultimately thought to be represented in sparsely distributed neuronal ensembles within these larger structures. Currently, there are few tools that allow for the identification and manipulation of these ensembles, which has limited our understanding of the molecular and cellular processes underlying learning and memory. We have previously reported that the activity-regulated transcription factor Npas4 is selectively induced in a sparse population of CA3 following contextual fear conditioning. Global knockout or selective deletion of Npas4 in CA3 both resulted in impaired contextual memory, and restoration of Npas4 in CA3 was sufficient to reverse the deficit in global knockout mice. Taking advantage of the critical role of Npas4 in contextual memory formation, we developed a set of novel molecular tools to gain access to cell populations activated by experience. Using this system, we identified and manipulated the properties of neurons activated by behavioral experience in a variety of neural circuits in mice, rats, and Drosophila. We believe that the tools developed in this thesis can provide a major advancement in the field, and will allow researchers to target any neural circuit activated by experience in a variety of species. / by Kartik Ramamoorthi. / Ph. D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Brain and Cognitive Sciences, 2005. / Includes bibliographical references (leaves 93-97). / A fundamental consideration in understanding neuronal networks is determining what sets the unitary functional strength of a synaptic connection between two cells, and what meta-processes such mechanisms answer to. This question can be asked either mechanistically, by characterizing the molecular processes that regulate the synapse's transmission, or ontologically, by considering the impact of this transmission from the standpoint of neighboring synapses, the post synaptic cell itself, or the network of neurons in which it is situated. The work presented here practices both approaches, by identifying a new molecular mechanism to which the quantal size of excitatory synapses can be attributed, and then beginning to explore how quantal size might be influenced by network activity and architecture. Chapter 1 identifies a new molecular control point for specifying the quantal size of excitatory transmission in the mammalian brain, and provides the first known demonstration that such specification can be provided by a presynaptic process. It then details how this mechanism is regulated by network activity. / (cont.) Chapter 2 makes use of a new methodology for designing the physical structure of cultured networks in order to begin to perturb network parameters and explore the role of quantal size in a network context. Applying this methodology I demonstrate that the quantal size of excitatory synapses is scaled by neurons inversely with their number of synaptic connections, and identify a set of mechanisms by which network firing is maintained at a constant level when the number of active synaptic partners is scaled. Chapter 3 demonstrates progress towards a methodology capable of producing and detecting changes in the unitary strength of multiple synapses with respect to one another within a dendritic tree. Future efforts can hopefully make use of similar principles to directly visualize how heterosynaptic processes establish and maintain a contrast in the strengths of unitary synapses to enable representation by synaptically-based memory traces. / by Nathan R. Wilson. / Ph.D.

Excessive tissue-damaging inflammation can exacerbate acute brain injury, and non-resolving inflammation is implicated in chronic neurodegeneration. Understanding the mechanisms that resolve deleterious inflammation in the brain is imperative to develop new therapeutic strategies. However current knowledge is limited, partly due to a lack of tractable models. Studies in extra-cerebral tissues have shown that myeloid cells are central to the inflammatory response. The aim of this thesis was to develop a model of self-limiting acute brain inflammation that is optimised to address mechanisms controlling resolution. The model was used to define the temporal profile of myeloid cell accumulation in the brain and establish the precise identities, origin and functional contribution of cell subsets in the resolution of the inflammatory response in the brain. Cerebral inflammation was induced by stereotaxic injection of inflammatory stimuli (LPS, HMGB1, MSU); LPS produced a robust inflammatory response and neutrophil influx and loss defined clear phases of initiation and resolution. Cellular changes (e.g. glial activation, endothelial activation and leukocyte influx) in response to LPS were characteristic of acute inflammation. Bone marrow chimaeric (Csf1r-EGFPC57Bl/6J) and monocyte reporter (Ccr2+/RFP) mice were used to distinguish between infiltrating macrophages and resident microglia. Analysis over 28 d showed the temporal profile of myeloid cells during brain inflammation, and monocyte accumulation contributed to expansion of the total mononuclear phagocyte population. Ccr2RFP/RFP knock-in mice showed that monocyte recruitment and resolution were independent of CCR2, and selective depletion of Ly6Clo monocytes with an anti- CSF1R antibody did not affect macrophage recruitment. Monocyte depletion using clodronate failed to deplete the Ly6Cint population and monocytes were still recruited into the brain. Together these results suggest multiple monocyte subsets could be involved in the inflammatory response in the brain. These data show that myeloid cell subsets of distinct origins accumulate in the inflamed brain. This work establishes a model system to identify endogenous mechanisms of resolution in cerebral inflammation and provides a platform to test CNS-targeted pro-resolution agents.

No description available.

Thesis presented for the degree of Doctor of Medicine at the University of the Witwatersrand, Johannesburg. / WHSLYP2017

Thesis: Ph. D. in Neuroscience, Massachusetts Institute of Technology, Department of Brain and Cognitive Sciences, 2018. / Cataloged from PDF version of thesis. Page 176 blank. / Includes bibliographical references (pages 159-175). / Despite abundant evidence that dopamine modulates medial prefrontal cortex (mPFC) activity to mediate diverse behavioral functions, the precise circuit computations remain elusive. One potentially unifying theoretical model by which dopamine can modulate functions from working memory to schizophrenia is that dopamine serves to increase the signal-to-noise ratio in mPFC neurons, where neuronal activity conveying sensory information (signal) are amplified relative to spontaneous firing (noise). To connect theory to biology, we lack direct evidence for dopaminergic modulation of signal-to-noise in neuronal firing patterns in vivo and a mechanistic explanation of how such computations would be transmitted downstream to instruct specific behavioral functions. Here, we demonstrate that dopamine increases signal-to-noise ratio in mPFC neurons projecting to the dorsal periaqueductal gray (dPAG) during the processing of an aversive stimulus. First, using electrochemical approaches, we reveal the precise time course of tail pinch-evoked dopamine release in the mPFC. Second, we show that dopamine signaling in the mPFC biases behavioral responses to punishment-predictive stimuli, rather than reward-predictive cues. Third, in contrast to the well-characterized mPFC-NAc projection, we show that activation of mPFC-dPAG neurons is sufficient to drive place avoidance and defensive behaviors. Fourth, to determine the natural dynamics of individual mPFC neurons, we performed single-cell projection-defined microendoscopic calcium imaging to reveal a robust preferential excitation of mPFC-dPAG, but not mPFC-NAc, neurons to aversive stimuli. Finally, photostimulation of VTA dopamine terminals in the mPFC revealed an increase in signal-to-noise ratio in mPFC-dPAG neuronal activity during the processing of aversive, but not rewarding stimuli. Together, these data unveil the utility of dopamine in the mPFC to effectively filter sensory information in a valence-specific manner. / by Caitlin Miya Vander Weele. / Ph. D. in Neuroscience

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Brain and Cognitive Sciences, 1997. / Includes bibliographical references (p. 170-175). / by Raquel Olguin Jaakkola. / Ph.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Brain and Cognitive Sciences, 2004. / Includes bibliographical references. / How does the visual system achieve stable estimates of surface properties - such as reflectance and 3D shape - across changes in the illumination? Under arbitrary patterns of illumination this problem is ill-posed. However, in the real world, illumination is not arbitrary. Here I argue that the visual system exploits the statistical regularities of real-world illuminations to achieve stable estimates of shape and surface reflectance properties. Specifically, I suggest that the visual system derives measurements from specular reflections that are (i) diagnostic of surface properties and (ii) relatively well-conserved across real-world scenes. One consequence of the theory is that the visual system does not have to estimate and explicitly 'discount' illumination to recover shape and surface reflectance. In support of this idea, subjects are shown to be good at estimating surface reflectance and 3D shape without any context to specify the surrounding scene, as long as the illumination is realistic. However, when the pattern of illumination is unrealistic, shape and surface reflectance estimation degrade in predictable ways. Systematic manipulation of illumination statistics reveals some properties of illumination that are important for surface reflectance estimation. To understand 3D shape constancy, I discuss the way that 3D surface curvature distorts the reflected world. For the special case of mirrored surfaces, I show how populations of oriented linear filters can 'read' the pattern of distortions to recover 3D surface curvatures. Finally I show that this principle applies to cases other than perfect mirrors, and can predict both successes and failures of human shape constancy as the illumination changes. / by Roland W. Fleming. / Ph.D.

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. / Includes bibliographical references (p. 97-103). / It is the goal of this thesis to examine the frontal cortex-basal ganglia system during arbitrary visuomotor association learning, the forming of arbitrary links between visual stimuli and motor responses (e.g. red means stop), a fundamental learning process that underlies much of our complex behavior such as written language. The experiments contained in this thesis investigate the involvement of four components of this system in the acquisition of these associations: dorsolateral prefrontal cortex (dlPFC), caudate nucleus (Cd), frontal eye field (FEF), and the internal segment of the globus pallidus (GPi). Extracellular electrophysiological recordings were performed in awake-behaving primates performing three different learning tasks. In the different behavioral paradigms used in these studies, learning with and without reversals is investigated and compared both directly within the same experiment and indirectly across experiments. The results of these studies suggest that a complex interplay between brain areas in the frontal cortex-basal ganglia system exists. The study of FEF during reversal learning revealed that FEF contains task-related information from the start of learning, suggesting that it may be passing information onto PFC and Cd to aid the learning process. In addition, GPi is shown to contain more specific information about the learned association during the reversal task, providing evidence for an increase in the complexity of information processing through the basal ganglia. / (cont.) The in-depth study of dlPFC and Cd suggests that the frontal cortex-basal ganglia system functions only when competition between learning contexts exist. When all competition is eliminated by removing reversal learning from the behavioral task, Cd does not show involvement in the learning process. But when competition exists, both Cd and PFC show learning-related changes in task-relevant information. As determined by coherence analysis of local field potentials, communication between dlPFC and Cd is greater during reversal learning, when competition is heightened. This communication also decreases as learning progresses suggesting a role in the transfer of information between areas in facilitating the learning process. Overall, these studies further the understanding of the role of the frontal cortex-basal ganglia system in arbitrary visuomotor learning and posit that the function of the system is dependent on the existence of competition between learned information. / by Michelle S. Machon. / Ph.D.

Thesis (S.M.)--Massachusetts Institute of Technology, Dept. of Brain and Cognitive Sciences, 2003. / Includes bibliographical references (v. 2, leaves 268-271). / (cont.) the functionality of the fMRI data analysis and visualization tools used at Massachusetts General Hospital. I analyze and interpret an 18-subject fMRI experiment I ran using the new task design and software tools. Finally, I present preliminary findings on linguistic questions as well as the nature of fMRI signal, using direct Electrophysiological data recorded from electrodes implanted in the brains of two Epilepsy patients. These patients had electrodes implanted through or near classical language areas of their brains, as a necessary clinical step in locating and surgically removing the seizure-causing tissue. The main findings of this thesis are: 1.) Morphology alone can activate Broca's area, 2.) Other areas are involved, including BA47, anterior insula, and SMA, 3.) Broca's area and BA47 respond to application of abstract grammatical features, even without phonological manipulations, 4.) Morphophonological manipulation additionally recruits insula and SMA, 5.) While simply accessing nouns versus verbs may involve separable brain regions, inflectional processing of the two categories may be done by the same process, 6.) Regularly and Irregularly inflected verbs show a double dissociation of activation in frontal and medial regions, 7.) Processing of English noun more than verb morphology may rely on some contribution from number processing brain systems ... / Inflectional morphology is the component of language concerned with changing a word's form to reflect context-specific meaning, such as the affixing of"-ed" for English verbs in the past tense, or adding "-s" in order to signal a noun's plural form. Although it is but one part of language, morphology may be useful as a model system for larger issues in language and cognition. Morphological processing touches on: the manipulation of memorized items (the vocabulary of words, and maybe word endings), the application and power of combinatorial rules (to generate correct forms, even of unknown words), and the binding of units of information into meaning. Morphology's relationship with other more traditional facets of language such as syntax (sentence structure) and semantics (meanings of individual words) is debated, as is the objective reality of grammatical categories (e.g. noun/verb) as well as combinatorial rules. Functional Magnetic Resonance Imaging (fMRI) is an exciting technique for peering into the brain and answering questions about its function. However, the technique has limited temporal and spatial resolution, and indexes the brain basis of cognition only indirectly, via blood response to cellular metabolism. In this thesis I propose a task for manipulating morphological production, embedded in a 2*2*3 design simultaneously varying grammatical class (nouns versus verbs), regularity of inflection (e.g. words like "walk" which take the stereotyped or regular ending "-ed", versus those like "bring" and "sing" which have idiosyncratic past tense forms), and three types of morphological task aimed to separate the assignment of grammatical features (e.g. present/past tense) from changes in word sound. I introduce and utilize software to extend / by Nedim T. Sahin. / S.M.