Thesis: Ph. D., Massachusetts Institute of Technology, Department of Brain and Cognitive Sciences, 2016. / Cataloged from PDF version of thesis. / Includes bibliographical references (pages 101-111). / The striatum is the largest nucleus in the basal ganglia and the recipient of dense dopamine input. Multiple cortico-basal ganglia-thalamic loops are thought to function together during the learning and performance of reinforced behaviors, with the dorsolateral circuit being particularly critical for the learning of habitual chains of action sequences. However, how this circuit works to generate such behavior is poorly understood. To explore the nature of striatal neural representations during learned action sequences, I designed a task targeted at disambiguating movement-related responses from habit representations in striatum. In combination with this task, I employed electrophysiology and optogenetics techniques to characterize task-related neuronal activity in the corticostriatal circuit. I found that, unlike in motor cortex, neurons in striatum did not respond simply to particular individual actions, but responded preferentially at the initiation and termination of learned action sequences. These experiments provide a test for the existence of a generalized striatal signal marking the start and end of units of habitual behaviors which may be produced with the contribution of striatal interneurons, providing a mechanism by which striatum can control the encoding and performance of chunked action sequences. In a separate set of experiments, I explored the effect of dopamine depletion on local field potential oscillations in the same region of striatum. My goal was to investigate the interaction between abnormal oscillations caused by dopamine depletion in Parkinson's disease and the functional task-related oscillations that normally occur in healthy striatum. Against our expectations, I found that local unilateral dopamine depletion in dorsolateral striatum did not result in changes in pre-task baseline strength of oscillations, but rather in the overexpression of the normal task-related oscillations. These studies add support to theories of striatal function and dysfunction that emphasize selective network modulation by learned behaviors. / by Nuné Martiros. / Ph. D.

Thesis: Ph. D., Massachusetts Institute of Technology, Department of Brain and Cognitive Sciences, 2013. / Cataloged from PDF version of thesis. / Includes bibliographical references (pages 104-106). / The optical modulation of neurons with channelrhodopsins, a class of genetically encoded light-gated ion channels, has enabled the spatiotemporally precise interrogation of the roles individual cell types play in neural circuit dynamics. A topic of great interest to the neuroscience community is the independent optical excitation of two distinct neuron populations with different wavelengths, which would enable the interrogation of emergent phenomena such as circuit dynamics, plasticity, and neuromodulation. Previous implementations have focused on maximizing spectral separation by driving one channelrhodopsin in the violet (405 nm) and the other in the yellow (590 nm), yet it has not been possible to achieve independent violet excitation without eliciting spikes from both populations, due to the intrinsic UV-blue light sensitivity of the retinal chromophore. This thesis designs and implements an improved two-color excitation scheme where effective light sensitivity is utilized to achieve independent optical excitation in blue (470 nm) and red (625 nm) channels. Zero post-synaptic crosstalk is demonstrated in acute murine slice, using two novel channeirhodopsins identified from a systematic screen of 80 naturally occurring, previously uncharacterized opsins in primary neuron culture. Gene88 is the first known yellow-peaked channelrhodopsin, with a peak 45 nm more red-shifted than any previous channelrhodopsin, while Gene90 has the fastest channel turn on, turn off, and recovery kinetics of any known channelrhodopsin. These opsins' novel properties enable the first known demonstration of post-synaptic crosstalk-free two-color excitation with temporally precise modulation of spatially inseparable neuron populations. / by Nathan Cao Klapoetke. / Ph. D.

Thesis: Ph. D., Massachusetts Institute of Technology, Department of Brain and Cognitive Sciences, February 2017. / Cataloged from PDF version of thesis. "January 2016." / Includes bibliographical references (pages 101-107). / Gamma oscillations (20-50 Hz), a common local field potential signature in many brain regions, are generated by a resonant circuit between fast-spiking (FS)-parvalbumin (PV)-interneurons and pyramidal cells. Changes in gamma oscillations have been observed in several neurological disorders. However, the relationship between gamma oscillations and cellular pathologies of these disorders is unclear. Here, we investigated this relationship using the 5XFAD mouse model of Alzheimer's disease (AD) and found reduced behaviorally driven gamma activity before the onset of plaque formation or evidence of cognitive decline. Because of the early onset of gamma deficits, we aimed to determine if exogenous gamma manipulations could influence disease pathology progression. We discovered that optogenetically driving FS-PV-interneurons at gamma frequency (40 Hz) reduced levels of amyloid-[beta] (A[beta])₁-₄₀ and A[beta] ₁-₄₂ isoforms in the hippocampus of 5XFAD mice. Neither driving FS-PV-interneurons at other frequencies, nor driving excitatory neurons, reduced A[beta] levels. Furthermore, driving FS-PV-interneurons at 40 Hz reduced enlarged endosomes and amyloid precursor protein (APP) cleavage intermediates in hippocampus. Gene expression profiling revealed an induction of microglia specific genes associated with morphological transformation of microglia and increased A[beta] phagocytosis by microglia. Inspired by these observations, we designed a non-invasive light-flickering paradigm that induced 40 Hz activity in visual cortex. The light-flickering paradigm profoundly reduced A[beta]₁-₄₀ and A[beta]₁-₄₂ levels in the visual cortex of pre-depositing mice and mitigated plaque load in aged, depositing mice. A GABAA antagonist completely blocked this effect; further evidence that GABAergic signaling is essential for this neuroprotective gamma activity. Finally, we showed that 40 Hz activity reduced tau phosphorylation in the TauP301S mouse model. Overall, our findings uncover a previously unappreciated function of the brain's gamma rhythms in neuroprotection by recruiting both neuronal and glial responses to mitigate AD-associated pathology. / by Hannah Frances Iaccarino. / Ph. D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Brain and Cognitive Sciences, 2011. / Cataloged from PDF version of thesis. Vita. / Includes bibliographical references (p. 171-185). / Ocular dominance (OD) plasticity is a classic example of bidirectional experience-dependent plasticity in the primary visual cortex. This form of plasticity is most robust during early postnatal development (termed the "critical period"), when monocular deprivation (MD) leads to a rapid weakening of responses evoked through the deprived eye followed by a delayed strengthening of non-deprived eye inputs. It has been proposed that these bidirectional changes occur as a three-stage process: first, degradation of patterned visual input weakens deprived-eye responses via homosynaptic long-term depression (LTD); this is accompanied by a shift in the plasticity modification threshold (0m) that determines the direction of synaptic plasticity, such that synaptic strengthening is favored over synaptic weakening; finally, weak open-eye responses are strengthened via the mechanisms of homosynaptic long-term potentiation (LTP). Despite the growing evidence supporting this model of experience-dependent synaptic modification, the exact molecular and synaptic mechanisms that are responsible for these processes remain controversial. In my thesis work, I address three questions. First, I attempt to parse the relative contribution of excitatory and inhibitory processes to expression of the OD shift in order to understand how deprived-eye depression is expressed in the cortex. To address this, I first induce a shift in OD with 3 days of MD and then use several pharmacological methods to shut off cortical inhibitory synaptic transmission. I demonstrate that rapid deprived-eye depression is strongly expressed at excitatory thalamocortical synapses without any influences of polysynaptic intracortical inhibition. In the second part of my work, I try to resolve the nature/identity of the molecular mechanism that underlies the regulation of [theta]m. Using a transgenic mouse model, I find that a reduction in the NR2A/B subunit ratio of the N-methyl-d-aspartate (NMDA) receptor during MD alters the qualities of OD plasticity by impairing weakening of deprived-eye inputs and enhancing strengthening of open-eye inputs. These findings suggest that NMDAR subunit composition may specify the value and the rate of adjustment of synaptic 0m, which in turn determines the bidirectional cortical response to MD. The final portion of my thesis addresses the factors that limit OD plasticity beyond the critical period. I test the hypothesis that the developmental increase in intracortical GABAergic inhibitory synaptic transmission is a fundamental restricting factor for adult cortical plasticity and demonstrate that parvalbumin-expressing fast-spiking basket cells are specifically implicated in the absence of juvenile-like deprived-eye depression in adult mice. / by Lena A. Khibnik. / Ph.D.

Thesis: Ph. D., Massachusetts Institute of Technology, Department of Brain and Cognitive Sciences, 2015. / Cataloged from PDF version of thesis. / Includes bibliographical references (pages 83-92). / Although impressionists assure us that the world is just dabs of light, we cannot help but see surfaces and contours, objects and events. How can a visual system learn to organize pixels into these higher-level structures? In this thesis I argue that perceptual organization reflects statistical regularities in the environment. When visual primitives occur together much more often than one would expect by chance, we may learn to associate those primitives and to form a perceptual group. The first half of the thesis deals with the identification of such groups at the pixel level. I show that low-level image statistics are surprisingly effective at higher-level segmentation. I present an algorithm that groups pixels by identifying meaningful co-occurrences in an image's color statistics. Consider a zebra. Black-next-to-white occurs suspiciously often, hinting that these colors have a common cause. I model these co-occurrences using pointwise mutual information (PMI). If the PMI between two colors is high, then the colors probably belong to the same object. Grouping pixels with high PMI reveals object segments. Separating pixels with low PMI marks perceived boundaries. If simple color co-occurrences can tell us about object segments, what might more complex statistics tell us? The second half of the thesis investigates high dimensional visual data, such as image patches and video frames. In high dimensions, it is intractable to directly model co-occurrences. Instead, I show that modeling PMI can be posed as a simpler binary classification problem in which the goal is to predict if two primitives occur in the same spatial or temporal context. This allows us to model PMI associations between complex inputs. I demonstrate the effectiveness of this approach on three domains: discovering objects by associating image patches, discovering movie scenes by associating frames, and discovering place categories by associating geotagged photos. Together, these results shed light on how a visual system can learn to organize raw sensory input into meaningful percepts. / by Phillip Isola. / Ph. D.

Thesis (S.M.)--Massachusetts Institute of Technology, Dept. of Brain and Cognitive Sciences, 2007. / Includes bibliographical references (leaves 43-46). / Three studies look at whether the assumption of causal determinism (the assumption that all else being equal, causes generate effects deterministically) affects children's imitation of modeled actions. We show that, even when the frequency of an effect is matched, both preschoolers and toddlers imitate actions more faithfully when modeled actions are deterministically rather than probabilistically effective. A third study suggests that preschoolers' imitation is affected, not just by whether the agent's goal is satisfied but also by whether the action is a reliable means to the goal. Children's tendency to generate variable responses to probabilistically effective modeled actions could support causal learning. / by Catherine Amanda Jane Hooppell. / S.M.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Brain and Cognitive Sciences, 1997. / Includes bibliographical references. / by Tommi S. Jaakkola. / Ph.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Brain and Cognitive Sciences, 1992. / Includes bibliographical references (leaves 115-118). / by Ormond L. Wilkie, Jr. / Ph.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Brain and Cognitive Sciences, 1996. / Includes bibliographical references (leaves 112-113). / by Adee Matan. / Ph.D.

Thesis (M.D.)—Boston University