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Thesis: Ph. D., Massachusetts Institute of Technology, Department of Biology, 2018., Cataloged from PDF version of thesis., Includes bibliographical references (pages 54-61)., Threatening and rewarding stimuli evoke a set of distinct stereotyped behaviors, which can be categorized as negative and positive valence-related behaviors, respectively. The stereotypic nature of negative and positive valence-related behaviors suggests that threatening and rewarding stimuli engage evolutionarily predetermined neural circuits in the brain. The amygdala is an important mammalian brain region that is activated by negative and positive stimuli and mediates negative and positive valence-related behaviors. The current prevailing circuit model of the amygdala mainly considers negative behaviors and only recently has cell-type specific models have been proposed. Hence, the substrates, genetically distinct neuronal populations, for negative and positive behaviors are not known. The work presented here describes a genetically-defined amygdala circuit model for negative and positive behaviors. Development of a genetic-based circuit model of the amygdala revealed anatomical and genetic circuit motifs that underlie that amygdala circuits that mediate valence-specific behaviors., NIH Pre-Doctoral Training Grant T32GM007287 RIKEN Brain Science Institute, by Joshua Kim., Ph. D.

Thesis: Ph. D., Massachusetts Institute of Technology, Department of Biology, 2018., Cataloged from PDF version of thesis., Includes bibliographical references (pages 54-61)., Threatening and rewarding stimuli evoke a set of distinct stereotyped behaviors, which can be categorized as negative and positive valence-related behaviors, respectively. The stereotypic nature of negative and positive valence-related behaviors suggests that threatening and rewarding stimuli engage evolutionarily predetermined neural circuits in the brain. The amygdala is an important mammalian brain region that is activated by negative and positive stimuli and mediates negative and positive valence-related behaviors. The current prevailing circuit model of the amygdala mainly considers negative behaviors and only recently has cell-type specific models have been proposed. Hence, the substrates, genetically distinct neuronal populations, for negative and positive behaviors are not known. The work presented here describes a genetically-defined amygdala circuit model for negative and positive behaviors. Development of a genetic-based circuit model of the amygdala revealed anatomical and genetic circuit motifs that underlie that amygdala circuits that mediate valence-specific behaviors., NIH Pre-Doctoral Training Grant T32GM007287 RIKEN Brain Science Institute, by Joshua Kim., Ph. D.

Thesis: Ph. D. in Neuroscience, Massachusetts Institute of Technology, Department of Brain and Cognitive Sciences, 2017., Cataloged from PDF version of thesis., Includes bibliographical references (pages 177-192)., Memory is a central function of the brain and is essential to everyday life. Memory disorders range from those of memory transience, such as Alzheimer's disease, to those of memory persistence, such as post-traumatic stress disorder. To treat memory disorders, a thorough understanding of memory formation and retrieval is critical. To date, most research has focused on memory formation, with the neurobiological basis of memory retrieval largely ignored due to experimental limitations. Here, I present our recent advances in the study of memory retrieval using technologies to engineer the representation of a specific memory, memory engram cells, in the brain. First, using animal models of retrograde amnesia, we demonstrated that direct activation of amnesic engram cells in the hippocampus resulted in robust memory retrieval, indicating the persistence of the original memory. Subsequent experiments identified retained engram cell-specific connectivity in amnesic mice although these engram cells lacked augmented synaptic strength and dendritic spine density. We proposed that a specific pattern of connectivity of engram cells may be the crucial substrate for memory information storage and that augmented synaptic strength and spine density critically contribute to the memory retrieval process. Second, we examined memory engrams in transgenic mouse models of early Alzheimer's disease, which required the development of a novel two-virus approach. We demonstrated that optical induction of long-term potentiation at input synapses on engram cells restored both spine density and long-term memory in early Alzheimer mice, providing causal evidence for the crucial role of augmented spine density in memory retrieval. Third, using activity-dependent labeling, we found that dorsal subiculum had enhanced neuronal activity during memory retrieval as compared memory encoding. Taking advantage of a novel transgenic mouse line that permitted specific genetic access to dorsal subiculum neur, by Dheeraj Roy., Ph. D. in Neuroscience

Thesis: Ph. D. in Neuroscience, Massachusetts Institute of Technology, Department of Brain and Cognitive Sciences, 2017., Cataloged from PDF version of thesis., Includes bibliographical references., The amygdala is a structure well known for its role in fear and reward learning, but how these mechanisms are used for decision-making is not well understood. Decision-making involves the rapid updating of cue associations as well as the encoding of a value currency, both processes in which the amygdala has been implicated. In this thesis I develop a strategy to study value-guided decision making in rodents using an olfactory binary choice task. Using a logistic regression model, I show that the value of expected rewards is a strong influence on choice, and can bias perceptual decisions. In addition, I show that decisions are influenced by events in the near past, and a specific bias towards correct choices in the near past can be detected using this analysis. Using genetic targeting of a sub-population of amygdala neurons, I show that this population is required for the rapid learning of an olfactory decision making task. Using in-vivo calcium imaging of this population I show that these neurons are active during the inter-trial interval and modulated by choice history, suggesting a mechanism by which choice history can influence current decisions., by Kean Jaime-Bustamante., Ph. D. in Neuroscience

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. 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. 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. 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, 2015., Cataloged from PDF version of thesis., Includes bibliographical references (pages 212-230)., Memories thread and unify our overall sense of being. With the accumulation of our knowledge about how memories are formed, consolidated, retrieved, and updated, neuroscience has reached a point where brain cells active during these discrete mnemonic processes can be identified and manipulated at rapid timescales. Here, I begin with historical studies that lead to the modem memory engram theory. Then, I present our recent advances in memory research that combine transgenic and optogenetic approaches to reveal underlying neuronal substrates sufficient for activating mnemonic processes. Our studies' conclusions are threefold: (1) we provide proof of principle evidence demonstrating that learning-related neural changes can be isolated at the level of single cells, and that these cells can then be tagged for subsequent manipulation; (2) a defined subset of hippocampus cells are sufficient to elicit the neuronal and behavioral expression of memory recall, as well as sufficient to modify existing positive and negative memories; (3) and finally, artificially activated memories can be leveraged to acutely and chronically suppress psychiatric disease-related states. We propose that hippocampus cells that show activity-dependent changes during learning construct a cellular basis for contextual memory engrams and that directly activating these endogenous neuronal processes may be an effective means to correct maladaptive behaviors., by Steve Ramirez., Ph. D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, February 2012., Cataloged from PDF version of thesis., Includes bibliographical references (p. 192-226)., Autism is a diverse and complex family of disorders, and its prevalence is on the rise: 1 in 110 children have autism. There is no effective treatment for the symptoms which often include language and communication deficits, repetitive behavior, intellectual disability, epilepsy, attention deficits, and hyperactivity. The quest for a cure is challenging due to the heterogeneity of the disorder, but also because more than 90% of cases of autism are idiopathic, meaning the cause is unknown. Fortunately, one cause of autism has been discovered: silencing of a single gene causes an autism-like disorder called Fragile X Syndrome (FXS). The knowledge of the genetic basis of FXS allowed for the development of a mouse model of autism. The fmr1 knockout (KO) mouse displays phenotypes similar to symptoms in the human condition - including hyperactivity, repetitive behaviors, and seizures. Humans and mice share not only behavioral expression of the disease, but also analogous abnormalities in the density and morphology of dendritic spines - the sites of connections between neurons and critical substrates for learning. Abnormal dendritic spines is a common feature in FXS, idiopathic autism, and intellectual disability. Thus, this neuroanatomical abnormality may contribute to disease symptoms and severity. Here we take a hypothesis-driven, mechanism-based approach to the search for an effective therapy for FXS. We hypothesize that a treatment that rescues the dendritic spine defect may also ameliorate behavioral symptoms. Thus, we targeted a protein that regulates spines through modulation of actin cytoskeleton dynamics: p21-activated kinase (PAK). In a healthy brain, PAK and FMRP - the protein product of fmr1 - antagonize one another to regulate spine number and shape. Inhibition of PAK with a strategy utilizing mouse genetics reverses spine abnormalities as well as cognitive and behavioral symptoms in fmr1 KO mice, as we demonstrated in our previous publication. This discovery, by Bridget M. Dolan., 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., Dopamine (DA) containing neurons project throughout the brain. DA has been implicated in mediating brain disorders such as Schizophrenia, Parkinson's disease, Huntington's disease and drug addiction. The role of DA in working memory and procedural learning is also well established. DA is a ubiquitous neurotransmitter that affects much of the brain, but very little is known how dopamine functions in hippocampal dependent learning. It was only until recently that dopamine-containing neurons were found to project to the hippocampus. Even less understood are the expression patterns of DA receptors within the hippocampus and this is underlined by the inability of distinguishing the dopamine 1 receptor family (D1 and 5 receptors (D1/D5Rs)). Given the interaction of the D1 family with similar G-protein coupled receptors it has been assumed that these two receptors function in an analogous fashion. Additionally, the specific expressional pattern of each receptor lacks clarity due to non-specific binding by molecular probes. Moreover, D1 and D5 pharmacological and global KO studies cannot and have not functionally delineated D1Rs from D5Rs and global KOs of the D1Rs or D5Rs are not specific to the hippocampus, thus compensatory mechanisms likely ameliorate most physiological and behavioral deficits. Still, the aforementioned studies do point to the D1 family in modulating hippocampal synaptic plasticity, learning and memory consolidation. In order to characterize D1Rs distinctly from D5Rs we have generated three strains of conditional mutant mice (D1 KO, D5 KO, D1/5 KO). I present data that shows distinct expression patterns within the hippocampus, the importance of D1 Rs and D5Rs in modulating hippocampal plasticity, and hippocampal dependent learning. These data highlight distinct functional roles of D1Rs and D5Rs in hippocampal function., by Joshua Sariñana Jr., 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., Dopamine (DA) containing neurons project throughout the brain. DA has been implicated in mediating brain disorders such as Schizophrenia, Parkinson's disease, Huntington's disease and drug addiction. The role of DA in working memory and procedural learning is also well established. DA is a ubiquitous neurotransmitter that affects much of the brain, but very little is known how dopamine functions in hippocampal dependent learning. It was only until recently that dopamine-containing neurons were found to project to the hippocampus. Even less understood are the expression patterns of DA receptors within the hippocampus and this is underlined by the inability of distinguishing the dopamine 1 receptor family (D1 and 5 receptors (D1/D5Rs)). Given the interaction of the D1 family with similar G-protein coupled receptors it has been assumed that these two receptors function in an analogous fashion. Additionally, the specific expressional pattern of each receptor lacks clarity due to non-specific binding by molecular probes. Moreover, D1 and D5 pharmacological and global KO studies cannot and have not functionally delineated D1Rs from D5Rs and global KOs of the D1Rs or D5Rs are not specific to the hippocampus, thus compensatory mechanisms likely ameliorate most physiological and behavioral deficits. Still, the aforementioned studies do point to the D1 family in modulating hippocampal synaptic plasticity, learning and memory consolidation. In order to characterize D1Rs distinctly from D5Rs we have generated three strains of conditional mutant mice (D1 KO, D5 KO, D1/5 KO). I present data that shows distinct expression patterns within the hippocampus, the importance of D1 Rs and D5Rs in modulating hippocampal plasticity, and hippocampal dependent learning. These data highlight distinct functional roles of D1Rs and D5Rs in hippocampal function., by Joshua Sariñana Jr., Ph.D.

Thesis (S.B.)--Massachusetts Institute of Technology, Dept. of Nuclear Science and Engineering, 2010., Cataloged from PDF version of thesis., Includes bibliographical references (p. 34-36)., Based on extracellular field recordings and stimulations at the Schaeffer collateral-CA1 synapse, the synaptic tagging and capture (STC) model has hypothesized that at synapses that express any form of LTP and LTD (long-term potentiation and depression, respectively) are tagged in a protein synthesis-independent manner, the induction of LLTP/ L-LTD leads to protein synthesis, and all tagged synapses can use the resulting plasticity-related products to express L-LTP/L-LTD. Several models have hypothesized that STC works through somatically synthesized plasticity-related protein products available to synapses throughout the neuron, suggesting that, at the single neuronal level, memory engrams are formed at synapses throughout the dendritic arbor. However, the Clustered Plasticity Hypothesis suggests that neurons store long-term memory engrams at synapses that tend to be spatially clustered within dendritic branches, as opposed to dispersed throughout the dendritic arbor. This hypothesis suggests that the dendritic branch, as opposed to the synapse, is the primary unit for long-term memory storage. Evidence for this hypothesis has come from studies of LTP, however, and there is no such data for LTD. This thesis establishes a single-synapse marker for LTD, namely spine length changes, that can be used to study the role of LTD and dendritic branch-specific plasticity., by Alexander J. Murphy., S.B.

Thesis (S.B.)--Massachusetts Institute of Technology, Dept. of Nuclear Science and Engineering, 2010., Cataloged from PDF version of thesis., Includes bibliographical references (p. 34-36)., Based on extracellular field recordings and stimulations at the Schaeffer collateral-CA1 synapse, the synaptic tagging and capture (STC) model has hypothesized that at synapses that express any form of LTP and LTD (long-term potentiation and depression, respectively) are tagged in a protein synthesis-independent manner, the induction of LLTP/ L-LTD leads to protein synthesis, and all tagged synapses can use the resulting plasticity-related products to express L-LTP/L-LTD. Several models have hypothesized that STC works through somatically synthesized plasticity-related protein products available to synapses throughout the neuron, suggesting that, at the single neuronal level, memory engrams are formed at synapses throughout the dendritic arbor. However, the Clustered Plasticity Hypothesis suggests that neurons store long-term memory engrams at synapses that tend to be spatially clustered within dendritic branches, as opposed to dispersed throughout the dendritic arbor. This hypothesis suggests that the dendritic branch, as opposed to the synapse, is the primary unit for long-term memory storage. Evidence for this hypothesis has come from studies of LTP, however, and there is no such data for LTD. This thesis establishes a single-synapse marker for LTD, namely spine length changes, that can be used to study the role of LTD and dendritic branch-specific plasticity., by Alexander J. Murphy., S.B.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Brain and Cognitive Sciences, 2011., Cataloged from PDF version of thesis., Includes bibliographical references (p. 190-212)., Declarative memory requires the integration and association of multiple input streams within the medial temporal lobe. Understanding the role each neuronal circuit and projection plays in learning and memory is essential to understanding how declarative and episodic-like memories are formed. This work here addresses the role of the medial entorhinal cortex layer III (MEC-III) to CA1 projections in episodic-like memory formation and recall. This circuit is addressed with a triple transgenic mouse which allows for the expression of tetanus toxin, an enzyme that disrupts synaptic vesicle fusion, specifically in MEC-III neurons. Utilizing this triple transgenic mouse model, which allows for the specific and reversible ablation of synaptic transmission only in medial entorhinal cortex layer III excitatory neurons, the function of this pathway in various learning and memory tasks is tested. Synaptic output from the medial entorhinal cortex layer III neurons is necessary for acquisition, but not recall of tone and contextual fear memories in trace fear conditioning, and not in delay conditioning. This is the first demonstration that acquisition and recall of the same memory engram do not require the exact same anatomy. Additionally, this pathway is necessary for performance in a delayed nonmatch-to-place working memory task, in which the animal must utilize memory from the previous trial to successfully complete the following trial. Both the trace and working memory paradigm require the integration of information across a delay, which we propose is supported by known persistent activity in entorhinal neurons. CAl receives input from both entorhinal layer III and CA3. We show that synaptic transmission from CA3 is not required for tone fear memory in the trace paradigm and not required for working memory in the same delayed nonmatch-to-place paradigm, further isolating the necessity for MEC-III inputs in both of these behaviors. Functional MEC-III synaptic transmission is a, by Alexander Jay Rivest., Ph.D.

Thesis (S.B.)--Massachusetts Institute of Technology, Dept. of Nuclear Science and Engineering, 2010., Cataloged from PDF version of thesis., Includes bibliographical references (p. 34-36)., Based on extracellular field recordings and stimulations at the Schaeffer collateral-CA1 synapse, the synaptic tagging and capture (STC) model has hypothesized that at synapses that express any form of LTP and LTD (long-term potentiation and depression, respectively) are tagged in a protein synthesis-independent manner, the induction of LLTP/ L-LTD leads to protein synthesis, and all tagged synapses can use the resulting plasticity-related products to express L-LTP/L-LTD. Several models have hypothesized that STC works through somatically synthesized plasticity-related protein products available to synapses throughout the neuron, suggesting that, at the single neuronal level, memory engrams are formed at synapses throughout the dendritic arbor. However, the Clustered Plasticity Hypothesis suggests that neurons store long-term memory engrams at synapses that tend to be spatially clustered within dendritic branches, as opposed to dispersed throughout the dendritic arbor. This hypothesis suggests that the dendritic branch, as opposed to the synapse, is the primary unit for long-term memory storage. Evidence for this hypothesis has come from studies of LTP, however, and there is no such data for LTD. This thesis establishes a single-synapse marker for LTD, namely spine length changes, that can be used to study the role of LTD and dendritic branch-specific plasticity., by Alexander J. Murphy., S.B.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Brain and Cognitive Sciences, 2011., Cataloged from PDF version of thesis. Vita., Includes bibliographical references., Midbrain dopamine has demonstrated roles in locomotion, motivation, associative learning, habit formation, action selection and cognition. The many functions of dopamine can be attributed to the multiple projection targets of midbrain dopaminergic nuclei and to the multiple characteristic modes of dopamine neuron firing, tonic and phasic. Phasic transients of midbrain dopamine neurons are widely reported to signal errors conveying discrepancies between predicted and actual reward. Knocking out NMDARs in dopamine neurons has been shown to attenuate dopaminergic phasic firing providing a potential model for delineating the functions of tonic and phasic dopamine. In order to study the role of dopamine neuron NMDARs in rewardcontingent learning, we developed an auditory-cued binary choice task using complex auditory stimuli that lend themselves to efficient learning as well as morphing. We report that mice lacking NMDARs in dopamine neurons have a deficit in learning an auditory two-alternative choice task, in the absence of changes in response vigor. Dopamine neurons respond phasically to rewards as well as reward predictive cues. Updating the reward predictive value of cues is fundamental to shaping adaptive patterns of behavior and decision-making. Given the hypothesized role of dopamine in the updating of reward predictive cues, we were interested to see if an influence of reward history would be evident in the choices made by mice lacking dopamine neuron NMDARs. In an auditory-cued binary choice task, we find an influence of the difficulty of prior successes on subsequent decisions when mice are challenged with varying degrees of discrimination difficulty. In mice lacking dopamine neuron NMDARs, we find a lack of influence of prior decision difficulty. Our results identify a modulation of choices by prior decision difficulty in mice, and demonstrate the dopamine-dependent nature of this modulation. These findings are consistent with a role for dopamine neuron phasi, by Emily Hueske., Ph.D.

Thesis (S.B.)--Massachusetts Institute of Technology, Dept. of Nuclear Science and Engineering, 2010., Cataloged from PDF version of thesis., Includes bibliographical references (p. 34-36)., Based on extracellular field recordings and stimulations at the Schaeffer collateral-CA1 synapse, the synaptic tagging and capture (STC) model has hypothesized that at synapses that express any form of LTP and LTD (long-term potentiation and depression, respectively) are tagged in a protein synthesis-independent manner, the induction of LLTP/ L-LTD leads to protein synthesis, and all tagged synapses can use the resulting plasticity-related products to express L-LTP/L-LTD. Several models have hypothesized that STC works through somatically synthesized plasticity-related protein products available to synapses throughout the neuron, suggesting that, at the single neuronal level, memory engrams are formed at synapses throughout the dendritic arbor. However, the Clustered Plasticity Hypothesis suggests that neurons store long-term memory engrams at synapses that tend to be spatially clustered within dendritic branches, as opposed to dispersed throughout the dendritic arbor. This hypothesis suggests that the dendritic branch, as opposed to the synapse, is the primary unit for long-term memory storage. Evidence for this hypothesis has come from studies of LTP, however, and there is no such data for LTD. This thesis establishes a single-synapse marker for LTD, namely spine length changes, that can be used to study the role of LTD and dendritic branch-specific plasticity., by Alexander J. Murphy., S.B.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, 2007., Includes bibliographical references (leaves 82-92)., NMDA receptors play an essential role in many forms of experience-dependent plasticity in the visual system. NMDA receptors support the ocular dominance (OD) shift, development of receptive field properties in cortical neurons, and learning tasks associated with the visual cortex, as well as the cellular correlates of such plasticity measurements, ie long-term potentiation (LTP) and long-term depression (LTD). Complete removal of NMDA receptors abolishes plasticity, while selective removal of NMDA receptors from distinct circuits in the visual system can reveal a more specific requirement and identify circuits required for plasticity. Using this approach, I aimed to delineate the brain circuits involved in two forms of experience-dependent plasticity. First, I determined a layer-specific requirement for NMDA receptors in stimulus-specific response potentiation (SRP), which is a model for the plastic changes that may underlie perceptual learning. SRP acquisition requires NMDA receptors in the cortex, and it can be supported by expression of NMDA receptors in only deep layer 4 and layer 5. In contrast, this minimal expression of NMDA receptors did not support a paradigm for OD plasticity in adult mice. The contrasting requirements for NMDA receptors in these two forms of experience-dependent plasticity suggest that distinct forms of plasticity can be supported in separate cortical circuits., by Audrey Bing-Yu Chang., Ph.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, February 2005., Vita., Includes bibliographical references., Long-lasting changes must take place in the brain to store the skills and memories that have been learned by the organism throughout its history. Long-term memory (LTM), and its cellular correlate, the late-phase of long-term potentiation (L-LTP), require protein synthesis. It has generally been assumed that the regulation of transcription underlies L-LTM and LTM. Chapter 2 of this thesis demonstrates that transgenic mice with inhibited ERK MAP Kinase pathway activity in the cortex and CA1 region of the hippocampus show inhibited LTM and L-LTP. Moreover, the L-LTP phenotype resembles a deficit in translation and not transcription. Experiments using hippocampal cultured cells demonstrate that neuronal activity induces translation of a large number of mRNAs in an ERK MAP Kinase pathway-dependent manner via phosphorylation of the translation factors S6, elF4E and 4E-BP1. Increased phosphorylation of translation factors was observed along with increased translation after the induction of L-LTP; lastly, LTM formation occurred concomitantly with ERK MAP Kinase pathway-dependent phosphorylation of S6 and elF4E. Chapter 3 extends these findings to demonstrate that other stimuli that cause protein synthesis-dependent forms of plasticity also upregulate protein synthesis via the same mechanisms., (cont.) As some of these stimuli cause L-LTP and others cause L-LTD, it is proposed that induction of these forms of plasticity, though opposite in terms of synaptic-weight changes, produce the same proteins, and that activated synapses capture the appropriate proteins to express the appropriate form of synaptic plasticity. Cellularly, it is believed that these long-lasting changes involve structural plasticity in the neurons. However, as it has generally been difficult to show such a correlation between structural changes and behavioral changes after behavioral training, a correlation between structural changes and affective behaviors after chronic-stress treatment was sought. Chapter 4 shows that transgenic mice overexpressing BDNF only in forebrain pyramidal cells have reduced chronic stress-induced atrophy in the apical dendrites of CA3 pyramidal cells. This structural change is correlated with improved performance in the Porsolt forced-swim test. Increased spinogenesis was observed in the amygdala concomitantly with an increase in anxiety, thus demonstrating a strong correlation between structural change and behavior., by Arvind Govindarajan., Ph.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, 1994., On t.p., "[gamma]" appears as the lower case Greek letter., Includes bibliographical references., by Asa Abeliovich., Ph.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, February 2005., Vita., Includes bibliographical references., Long-lasting changes must take place in the brain to store the skills and memories that have been learned by the organism throughout its history. Long-term memory (LTM), and its cellular correlate, the late-phase of long-term potentiation (L-LTP), require protein synthesis. It has generally been assumed that the regulation of transcription underlies L-LTM and LTM. Chapter 2 of this thesis demonstrates that transgenic mice with inhibited ERK MAP Kinase pathway activity in the cortex and CA1 region of the hippocampus show inhibited LTM and L-LTP. Moreover, the L-LTP phenotype resembles a deficit in translation and not transcription. Experiments using hippocampal cultured cells demonstrate that neuronal activity induces translation of a large number of mRNAs in an ERK MAP Kinase pathway-dependent manner via phosphorylation of the translation factors S6, elF4E and 4E-BP1. Increased phosphorylation of translation factors was observed along with increased translation after the induction of L-LTP; lastly, LTM formation occurred concomitantly with ERK MAP Kinase pathway-dependent phosphorylation of S6 and elF4E. Chapter 3 extends these findings to demonstrate that other stimuli that cause protein synthesis-dependent forms of plasticity also upregulate protein synthesis via the same mechanisms., (cont.) As some of these stimuli cause L-LTP and others cause L-LTD, it is proposed that induction of these forms of plasticity, though opposite in terms of synaptic-weight changes, produce the same proteins, and that activated synapses capture the appropriate proteins to express the appropriate form of synaptic plasticity. Cellularly, it is believed that these long-lasting changes involve structural plasticity in the neurons. However, as it has generally been difficult to show such a correlation between structural changes and behavioral changes after behavioral training, a correlation between structural changes and affective behaviors after chronic-stress treatment was sought. Chapter 4 shows that transgenic mice overexpressing BDNF only in forebrain pyramidal cells have reduced chronic stress-induced atrophy in the apical dendrites of CA3 pyramidal cells. This structural change is correlated with improved performance in the Porsolt forced-swim test. Increased spinogenesis was observed in the amygdala concomitantly with an increase in anxiety, thus demonstrating a strong correlation between structural change and behavior., by Arvind Govindarajan., Ph.D.

Thesis (Ph.D.)--Massachusetts Institute of Technology, Dept. of Biology, 1999., Vita., Includes bibliographical references (p. 158-179)., CDS+ T lymphocytes recognize short peptide fragments when bound to self-class I major histocompatibility proteins. On a mature lymphocyte, such recognition results in activation of the T cell. On an immature thymocyte, such recognition may result in either positive selection, allowing the cell to mature, or negative selection, eliminating that T cell clone from the host's repertoire. The parameters that determine thymocyte fate have remained unclear. An experimental study was carried out to determine these parameters. A variety of peptide ligands were tested for their influence on the positive and negative selection of T cell receptor-transgenic thymocytes. It was found that peptides with limited amino-acid sequence homology and vastly different affinity values for the T cell receptor could promote positive and negative selection of T cells in a dose dependent manner. It was found that the outcome of selection was also influenced by the type of antigen presenting cell present. The levels of surface expression of class I MHC proteins was significantly different on these cells types and correlated with their physiological roles in positive and negative selection. Mice that co-express a transgenic T cell receptor and a cognate-ligand developed an autoimmune disease, the pathology of which was reminiscent of psoriasis. The disease was strictly dependent on the presence of both the T cell receptor and antigen. Interestingly, only certain inbred strains of mice developed the disease. The phenotype of transgenic cells differed from affected to unaffected animals. Analysis of these mice could reveal novel genetic factors that influence T cell responses. Furthermore, these mice may also develop into a useful model for human autoimmune psoriasis or other disorders of the skin., by Joseph R.C. Delaney., Ph.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, 1998., Includes bibliographical references., by Kenneth D. Poss., Ph.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Brain and Cognitive Sciences, 2001., Vita., Includes bibliographical references (leaves 153-180)., Long term potentiation (LTP) of synaptic transmission at the CA3-CA1 hippocampal synapse is a model synaptic plasticity mechanism that may underlie hippocampal dependent learning and memory. Inhibition of post-synaptic calcium/calmodulin protein kinase II (CaMKII) has been shown to block LTP, and a global knockout of the highly expressed a isoform of CaMKII caused an impairment in LTP and hippocampus dependent learning. We examined the role of CaMKII in CA3-CA1 LTP by selectively deleting [alpha]-CaMKII in adult hippocampal CA1 or CA3 pyramidal cells using conditional gene targeting. With this approach, we could investigate the locus of change that underlies LTP expression, as both pre- (CA3) and post- (CA1) synaptic CaMKII dependent mechanisms have been implicated, and further examine how CaMKII dependent plasticity contributes to learning and memory in a background of normal brain development. CA3-CA1 LTP is reduced in CA1 [alpha]-CaMKII knockout mice, suggesting that post-synaptic CaMKII is required for normal LTP. These mice are strikingly reminiscent of the a-CaMKII global knockout mice, demonstrating comparable LTP impairments and abnormal behaviors. In contrast, CA3 [alpha]-CaMKII knockout mice have normal LTP at CA3-CA1 synapses, suggesting that CaMKII phosphorylation of pre-synaptic synapsin I is not required for LTP expression. Contextual and cued fear conditioning were also normal in CA3 mutants, demonstrating that one form of hippocampus dependent learning is intact., (cont.) While several pre-synaptic short term plasticity mechanisms were unaffected in CA3 [alpha]-CaMKII knockout mice, repetitive stimulation protocols using short trains of stimuli of increasing frequency revealed enhanced frequency facilitation in mutants compared with controls. This suggests that CaMKII may be acting pre-synaptically as a negative regulator of neurotransmitter release during certain repetitive stimulation conditions, and as a "frequency detector" of calcium spikes, reaching higher levels of activation with increasing frequency of stimulation. Modulation of facilitation could be important to prevent synaptic terminals from depleting their vesicle stores during episodes of repetitive firing, or to maintain synaptic activity in an optimal range for information coding., by Heather L. Hinds., Ph.D.