Browsing by Department "Neuroscience"

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3D motion : encoding and perception
(2018-05) Bonnen, Kathryn L.; Huk, Alexander C.; Cormack, Lawrence K.; Carvalho, Carlos; Fiete, Ila; Geisler, Wilson; Hayhoe, Mary
The visual system supports perception and inferences about events in a dynamic, three-dimensional (3D) world. While remarkable progress has been made in the study of visual information processing, the existing paradigms for examining visual perception and its relation to neural activity often fail to generalize to perception in the real world which has complex dynamics and 3D spatial structure. This thesis focuses on the case of 3D motion, developing dynamic tasks for studying visual perception and constructing a neural coding framework to relate neural activity to perception in a 3D environment. First, I introduce target-tracking as a psychophysical method and develop an analysis framework based on state space models and the Kalman filter. I demonstrate that target-tracking in conjunction with a Kalman filter analysis framework produce estimates of visual sensitivity that are comparable to those obtained with a traditional forced-choice task and a signal detection theory analysis. Next, I use the target-tracking paradigm in a series of experiments examining 3D motion perception, specifically comparing the perception of frontoparallel motion with the perception of motion-through-depth. I find that continuous tracking of motion-through-depth is selectively impaired due to the relatively small retinal projections resulting from motion-through-depth and the slower processing of binocular disparities. The thesis then turns the neural representation of 3D motion and how that underlies perception. First I introduce a theoretical framework that extends the standard neural coding approach, incorporating the environment-to-retina transformation. Neural coding typically treats the visuals stimulus as a direct proxy for the pattern of stimulation that falls on the retina. Incorporating the environment-to-retina transformation results in a neural representation fundamentally shaped by the projective geometry of the world onto the retina. This model explains substantial anomalies in existing neurophysiological recordings in primate visual cortical neurons during presentations of 3D motion and in psychophysical studies of human perception. In a series of psychophysical experiments, I systematically examine the predictions of the model for human perception by observing how perceptual performance changes as a function of viewing distance and eccentricity. Performance in these experiments suggests a reliance on a neural representation similar to the one described by the model. Taken together, the experimental and theoretical findings reported here advance the understanding of the neural representation and perception of the dynamic 3D world, and adds to the behavioral tools available to vision scientists.
Adaptability of delay eyelid conditioning requires forebrain input to the cerebellum
(2011-12) Houck, Brenda Diane; Mauk, Michael D.; Johnston, Daniel; Huk, Alexander C.; Jones, Theresa A.; Morikawa, Hitoshi
The cerebellum is a region of the brain responsible for an organism’s ability to perform precise, coordinated movements. An abundance of research has characterized the anatomy of the cerebellum, and provides the foundation of current theories regarding the circuitry that supports motor learning. Delay eyelid conditioning is a form of motor learning. It is the learned association of a neutral stimulus and the reflexive response of an eyelid closure resulting in a well-timed eyelid closure in anticipation of the reflexive response. Two aspects of this learning are: different-conditioned stimulus savings and savings of timing. Different-CS savings is a rapid re-learning to a new, different neutral stimulus that occurs more quickly than learning to the original stimulus. Savings of timing is a phenomenon in which the timing of a response is preserved from a prior training experience. This dissertation presents evidence that forebrain input to the cerebellum is required for these aspects of delay eyelid conditioning. We trained animals with electrical stimulation as our neutral stimulus and thereby engaged a specific input pathway to the cerebellum, limiting forebrain inputs. In Chapter 2 we implement this technique and eliminate different-CS savings. These data suggest that forebrain input mediates this phenomenon. We then proceeded to investigate if the prefrontal cortex (PFC) is the forebrain region involved in supporting this aspect of delay eyelid conditioning. We administered electrolytic lesions to the PFC of animals and found their ability to express different-CS savings was impaired. Evidence from these two chapters suggests the PFC provides input to the cerebellum necessary for different-CS savings. Finally, in Chapter 4 we examine savings of timing. We again limit forebrain input to the cerebellum and implement electrical stimulation as our neutral training stimulus. With stimulation as the neutral stimulus, animals do not exhibit savings of timing. The data suggest that a forebrain region is necessary to sustain this phenomenon as well. This dissertation provides two lines of evidence strongly supporting forebrain involvement in these modifications of delay eyelid conditioning - savings and savings of timing. These results convey the importance of accommodating forebrain-cerebellum interactions when developing theories of cerebellar function.
Adaptation in a deep network
(2011-05) Ruiz, Vito Manuel; Pillow, Jonathan W.; Miikkulainen, Risto; Fiete, Ila; Geisler, Wilson; Seidemann, Eyal
Though adaptational effects are found throughout the visual system, the underlying mechanisms and benefits of this phenomenon are not yet known. In this work, the visual system is modeled as a Deep Belief Network, with a novel “post-training” paradigm (i.e. training the network further on certain stimuli) used to simulate adaptation in vivo. An optional sparse variant of the DBN is used to help bring about meaningful and biologically relevant receptive fields, and to examine the effects of sparsification on adaptation in their own right. While results are inconclusive, there is some evidence of an attractive bias effect in the adapting network, whereby the network’s representations are drawn closer to the adapting stimulus. As a similar attractive bias is documented in human perception as a result of adaptation, there is thus evidence that the statistical properties underlying the adapting DBN also have a role in the adapting visual system, including efficient coding and optimal information transfer given limited resources. These results are irrespective of sparsification. As adaptation has never been tested directly in a neural network, to the author’s knowledge, this work sets a precedent for future experiments.
Adaptive responses to cellular stress in neurons of the hippocampus
(2013-08) Clemens, Ann M.; Johnston, Daniel, 1947-; Harris, Kristen M.
Disruptions of endoplasmic reticulum (ER) Ca²⁺ homeostasis are heavily linked to neuronal pathology. Depletion of ER Ca²⁺ stores can result in cellular dysfunction and potentially cell death, although adaptive processes exist to aid in survival. This dissertation examines the age and region-dependence of one postulated adaptive response to ER store depletion, store depletion (SD) HCN channel plasticity, in neurons of the dorsal (DHC) and ventral (VHC) hippocampus from adolescent and adult rats. Using whole-cell patch clamp recordings from the soma and dendrites of CA1 pyramidal neurons, the change in h-sensitive measurements in response to store depletion, induced by treatment with cyclopiazonic acid (CPA), a sarco/endoplasmic reticulum Ca²⁺-ATPase blocker were observed. While DHC and VHC neurons in adolescent animals responded to store depletion with a peri-somatic expression of SD h plasticity, it was found that adult animals express SD h plasticity with a dendritic and somato-dendritic locus of plasticity in DHC and VHC neurons, respectively. Furthermore, SD h plasticity in adults was dependent on membrane voltage and on the activation of L-type voltage gated Ca²⁺ channels. These results suggest that cellular responses to the impairment of ER function, or ER stress, are dependent upon brain region and age, and that the differential expression of SD h plasticity could provide a neural basis for region and age-dependent disease vulnerabilities.
Advances in a C. elegans model of Alzheimer's disease for drug screening against neurodegeneration
(2015-04) Zuniga, Gabrielle; Pierce-Shimomura, Jon
Alzheimer’s disease (AD) is the sixth leading cause of death in the United States, yet no treatment effectively prevents, halts or reverses the disease. Progress in developing treatments is hampered by the extensive time required for traditional mouse models of AD to age before displaying histological hallmarks of AD. We set out to test whether a novel transgenic model of AD using the nematode Caenorhabditis elegans may be used to more rapidly determine efficacy of candidate treatments through high throughput screening of behaviors. Our lab previously showed that antagonists for the conserved Sigma-2 receptor (Sig2R) are protective against age- dependent degeneration of cholinergic neurons caused by the human plaque protein, amyloid precursor protein (APP), in this model. To investigate how inhibition of Sig2R protects neurons, we tested whether knockdown of Sig2R via RNA interference prevented decline of two behaviors that depend on these cholinergic neurons. We found that RNAi treatment normalized one of the two behaviors in this AD model suggesting that the antagonists act against the Sig2R in vivo for neuroprotection. The success of this study suggests that this behavioral readout might be used to screen for additional pharmaceutical and genetic modifiers of Sig2R on neurodegeneration. In addition to developing this high throughput behavioral screening, we also built transgene components to generate an improved second generation C. elegans model of AD that conveniently tags the APP protein with mCherry for in vivo fluorescent visualization. Our results set the stage for further drug discovery using our C. elegans models of AD.
Alcohol Disinhibition of Behaviors in C. elegans
(PLOS One, 2014-03-28) Topper, Stephen M.; Aguilar, Sara C.; Topper, Viktoria Y.; Elbel, Erin; Pierce-Shimomura, Jonathan T.
Alcohol has a wide variety of effects on physiology and behavior. One of the most well-recognized behavioral effects is disinhibition, where behaviors that are normally suppressed are displayed following intoxication. A large body of evidence has shown that alcohol-induced disinhibition in humans affects attention, verbal, sexual, and locomotor behaviors. Similar behavioral disinhibition is also seen in many animal models of ethanol response, from invertebrates to mammals and primates. Here we describe several examples of disinhibition in the nematode C. elegans. The nematode displays distinct behavioral states associated with locomotion (crawling on land and swimming in water) that are mediated by dopamine. On land, animals crawl and feed freely, but these behaviors are inhibited in water. We found that additional behaviors, including a variety of escape responses are also inhibited in water. Whereas alcohol non-specifically impaired locomotion, feeding, and escape responses in worms on land, alcohol specifically disinhibited these behaviors in worms immersed in water. Loss of dopamine signaling relieved disinhibition of feeding behavior, while loss of the D1-like dopamine receptor DOP-4 impaired the ethanol-induced disinhibition of crawling. The powerful genetics and simple nervous system of C. elegans may help uncover conserved molecular mechanisms that underlie alcohol-induced disinhibition of behaviors in higher animals.
Alcohol use disorders : transcriptomic and bioinformatic approaches
(2018-06-18) Ferguson, Laura Brockway; Harris, R. Adron; Messing, Robert O; Eberhart, Johann; Zakon, Harold; Iyer, Vishwanath R
Excessive alcohol consumption causes widespread, persistent changes throughout the brain and body. These molecular and cellular adaptations are thought to be the mechanisms by which neurons and glia adapt to chronic alcohol use. These adaptations can eventually lead to Alcohol Use Disorder (AUD) depending on genetic predisposition and environmental factors including stress, age of drinking onset, and access to alcohol. Gene expression is believed to be the means by which these adaptations occur. There are now multiple transcriptome studies of brain from animals with genetic differences in alcohol traits, and after alcohol exposure in rodents and humans. Such studies often use gene network approaches to identify collections of the many and varied molecular targets of alcohol, providing a framework to investigate the multifaceted nature of alcohol’s effects on the brain. I apply network-based approaches to propose novel treatments and offer mechanistic insight into AUD. In the first part of this dissertation, I determined the transcriptomic effects of pharmacological and genetic perturbations that affect alcohol consumption, hypothesizing that these effects on gene expression are important for modulating alcohol-related behaviors. I initially explored the actions of a class of transcriptional regulators, PPAR agonists, that decrease alcohol consumption. I defined their effects on brain and liver gene expression and identified a strong neuronal signature associated with dopamine, neuropeptide, and glutamatergic pathways. Next, I characterized brain gene expression patterns from 7 brain regions from a genetic mouse model of intense, binge-like drinking (HDID-1 mice). These studies highlighted the importance of the extended amygdala in regulating binge drinking and suggested possible convergence with gene network changes observed in postmortem brain from patients with AUD. I applied transcriptome-based computational approaches that integrated the gene networks affected in HDID-1 mice and by chemical compounds, and validated that the top 2 candidates decreased alcohol intake in vivo. This dissertation provides insight into potential molecular facilitators of AUD and represents the first evidence for transcriptome-based drug discovery to target an addiction-related trait. The tools and approaches outlined here offer strategies to study molecular mechanisms underlying complex diseases and renewed opportunities to discover new or repurpose existing compounds to expedite treatment options In the first part of this dissertation, I determined the transcriptomic effects of pharmacological and genetic perturbations that affect alcohol consumption, hypothesizing that these effects on gene expression are important for modulating alcohol-related behaviors. I initially explored the actions of a class of transcriptional regulators, PPAR agonists, that decrease alcohol consumption. I defined their effects on brain and liver gene expression and identified a strong neuronal signature associated with dopamine, neuropeptide, and glutamatergic pathways. Next, I characterized brain gene expression patterns from 7 brain regions from a genetic mouse model of intense, binge-like drinking (HDID-1 mice). These studies highlighted the importance of the extended amygdala in regulating binge drinking and suggested possible convergence with gene network changes observed in postmortem brain from patients with AUD. I applied transcriptome-based computational approaches that integrated the gene networks affected in HDID-1 mice and by chemical compounds, and validated that the top 2 candidates decreased alcohol intake in vivo. This dissertation provides insight into potential molecular facilitators of AUD and represents the first evidence for transcriptome-based drug discovery to target an addiction-related trait. The tools and approaches outlined here offer strategies to study molecular mechanisms underlying complex diseases and renewed opportunities to discover new or repurpose existing compounds to expedite treatment options
Alcohol-Induced Histone Acetylation Reveals a Gene Network Involved in Alcohol Tolerance
(PLOS Genetics, 2013-12-12) Ghezzi, Alfredo; Krishnan, Harish R.; Lew, Linda; Prado III, Francisco J.; Ong, Darryl S.; Atkinson, Nigel S.
Sustained or repeated exposure to sedating drugs, such as alcohol, triggers homeostatic adaptations in the brain that lead to the development of drug tolerance and dependence. These adaptations involve long-term changes in the transcription of drug-responsive genes as well as an epigenetic restructuring of chromosomal regions that is thought to signal and maintain the altered transcriptional state. Alcohol-induced epigenetic changes have been shown to be important in the long-term adaptation that leads to alcohol tolerance and dependence endophenotypes. A major constraint impeding progress is that alcohol produces a surfeit of changes in gene expression, most of which may not make any meaningful contribution to the ethanol response under study. Here we used a novel genomic epigenetic approach to find genes relevant for functional alcohol tolerance by exploiting the commonalities of two chemically distinct alcohols. In Drosophila melanogaster, ethanol and benzyl alcohol induce mutual cross-tolerance, indicating that they share a common mechanism for producing tolerance. We surveyed the genome-wide changes in histone acetylation that occur in response to these drugs. Each drug induces modifications in a large number of genes. The genes that respond similarly to either treatment, however, represent a subgroup enriched for genes important for the common tolerance response. Genes were functionally tested for behavioral tolerance to the sedative effects of ethanol and benzyl alcohol using mutant and inducible RNAi stocks. We identified a network of genes that are essential for the development of tolerance to sedation by alcohol.
All's fly in love and war
(2019-05) Park, Annie, Ph. D.; Atkinson, Nigel (Nigel S.); Wolf, Fred; Harris, Robert Adron; Phelps, Steve; Pierce, Jonathan
Alcoholism is a serious and widespread disorder that has a complex pathophysiology and can cause extreme changes in behavior. These changes in behavior arise from alcohol affecting the neurobiological systems in an organism. Flies share many similar alcohol related behavior with humans and they also share many of the same neurobiological systems. There are many advantages with using flies to understand alcohol related behaviors in humans (e.g. large genetic toolkit). However, flies have fewer behavioral models that assess for alcohol-related behaviors, which can limit the potential of using this model organism. Can we model more sophisticated alcohol-related behaviors in flies? In this dissertation, I provide evidence that flies share a number of alcohol-related behaviors with humans. In the first section, I develop an alcohol preference assay that demonstrates sexually dimorphic alcohol preference. In the second section, I characterize a novel low dose alcohol behavior in male flies that is male flies become more aggressive when treated with alcohol. In the third section, I focus on the female response to low dose alcohol, which is females become more receptive to courtship and less choosy about mates after an alcohol treatment. In the fourth section, I present data that demonstrates how a gene fruitless is alcohol responsive and could be contributing to some alcohol behavioral phenotypes. Taken together, this work expands the potential of flies to be used as a model organism for alcohol-related behaviors in humans.
Attenuating enduring alcohol cue reactivity via extinction during memory reconsolidation
(2018-08-15) Cofresi, Roberto Ulises; Gonzales, Rueben Anthony; Lee, Hongjoo; Monfils, Marie; Chaudhri, Nadia; Fromme, Kim
One of the ways the brain can adapt to repeated alcohol intoxication is to learn about predictive environmental cues such as the sight, smell, and taste of an alcoholic beverage. Over a person’s drinking history, these cues can become associated with alcohol’s post-ingestive pharmacology and acquire the ability to elicit affective, behavioral, and physiological reactions that anticipate alcohol availability, access, and/or intoxication. This reactivity to alcohol-associated cues may facilitate problematic alcohol use and promote the progressive loss of control over alcohol use that typifies alcohol use disorder (AUD). Reactivity to alcohol cues before treatment has been linked to the course and severity of AUD. People suffering from AUD may benefit from cue exposure therapy (CET), which involves systematic exposure to these cues without subsequent alcohol ingestion, viz., cue extinction. However, many people do not benefit from cue extinction, and even for those who do, the benefit is limited. Enduring reactivity to alcohol cues, even after CET, has been linked to risk for relapse to AUD. One of the reasons alcohol cue reactivity is believed to be resistant to treatment is that cue extinction does not undo or erase the original cue-alcohol associative memory. In fact, in most cases, cue extinction is believed to favor the formation of a new response-inhibiting memory that must compete for expression with the original response-exciting memory. However, it may be possible to update the existing alcohol-associated cue memory by conducting behavioral treatments such as CET during an inducible period of memory instability known as the memory reconsolidation window. I set out to test this idea. Using a novel preclinical rodent model of alcohol cue reactivity that I developed and characterized as part of my dissertation, I found that alcohol cue reactivity was resistant to standard extinction, but persistently attenuated after extinction during the memory reconsolidation window. I hope that these promising initial findings prompt more work into the development of memory reconsolidation-based behavior updating approaches to CET in order to improve AUD treatment outcomes
Automated design of planar mechanisms
(2014-05) Radhakrishnan, Pradeep, 1984-; Deshpande, Ashish D.; Campbell, Matthew I.
The challenges in automating the design of planar mechanisms are tremendous especially in areas related to computational representation, kinematic analysis and synthesis of planar mechanisms. The challenge in computational representation relates to the development of a comprehensive methodology to completely define and manipulate the topologies of planar mechanisms while in kinematic analysis, the challenge is primarily in the development of generalized analysis routines to analyze different mechanism topologies. Combining the aforementioned challenges along with appropriate optimization algorithms to synthesize planar mechanisms for different user-defined applications presents the final challenge in the automated design of planar mechanisms. The methods presented in the literature demonstrate synthesis of standard four-bar and six-bar mechanisms with revolute and prismatic joints. But a detailed review of these methods point to the fact that they are not scalable when the topologies and the parameters of n-bar mechanisms are required to be simultaneously synthesized. Through this research, a comprehensive and scalable methodology for synthesizing different mechanism topologies and their parameters simultaneously is presented that overcomes the limitations in different challenge areas in the following ways. In representation, a graph-grammar based scheme for planar mechanisms is developed to completely describe the topology of a mechanism. Grammar rules are developed in conjunction with this representation scheme to generate different mechanism topologies in a tree-search process. In analysis, a generic kinematic analysis routine is developed to automatically analyze one-degree of freedom mechanisms consisting of revolute and prismatic joints. Two implementations of kinematic analysis have been included. The first implementation involves the use of graphical methods for position and velocity analyses and the equation method for acceleration analysis for mechanisms with a four-bar loop. The second implementation involves the use of an optimization-based method that has been developed to handle position kinematics of indeterminate mechanisms while the velocity and acceleration analyses of such mechanisms are carried out by formulating appropriate linear equations. The representation and analysis schemes are integrated to parametrically synthesize different mechanism topologies using a hybrid implementation of Particle Swarm Optimization and Nelder-Mead simplex algorithm. The hybrid implementation is able to produce better results for the problems found in the literature using a four-bar mechanism with revolute joints as well as through other higher order mechanisms from the design space. The implementation has also been tested on three new challenge problems with satisfactory results subject to computational constraints. The difficulties in the search have been studied that indicates the reasons for the lack of solution repeatability. This dissertation concludes with a discussion of the results and future directions.
Bayesian approaches for modeling protein biophysics
(2014-08) Hines, Keegan; Aldrich, R. W. (Richard W.)
Proteins are the fundamental unit of computation and signal processing in biological systems. A quantitative understanding of protein biophysics is of paramount importance, since even slight malfunction of proteins can lead to diverse and severe disease states. However, developing accurate and useful mechanistic models of protein function can be strikingly elusive. I demonstrate that the adoption of Bayesian statistical methods can greatly aid in modeling protein systems. I first discuss the pitfall of parameter non-identifiability and how a Bayesian approach to modeling can yield reliable and meaningful models of molecular systems. I then delve into a particular case of non-identifiability within the context of an emerging experimental technique called single molecule photobleaching. I show that the interpretation of this data is non-trivial and provide a rigorous inference model for the analysis of this pervasive experimental tool. Finally, I introduce the use of nonparametric Bayesian inference for the analysis of single molecule time series. These methods aim to circumvent problems of model selection and parameter identifiability and are demonstrated with diverse applications in single molecule biophysics. The adoption of sophisticated inference methods will lead to a more detailed understanding of biophysical systems.
Behavioral and neural mechanisms of learning in groups of a social cichlid fish
(2020-09-11) Rodriguez Santiago, Mariana; Hofmann, Hans (Hans A.); Colgin, Laura; Drew, Michael; Curley, James; Gore, Andrea
As animals navigate through their environment, they must integrate external stimuli with previous experience to guide behavioral decisions. In group living animals, these decisions are embedded in a social context that influences their interactions, access to resources, and ultimately, their behavior. To acquire and learn new information that is vital to their survival, individuals must successfully navigate social interactions that are often embedded in dominance hierarchies. Such hierarchies arise from dyadic relationships between dominant and subordinate individuals and confer fitness benefits to those of high rank. A great deal is known regarding the ultimate underpinnings of dominance, especially as it pertains to differences between dominant and subordinate individuals (reviewed in Chapter 1, along with a summary of the social learning field). However, we have much to learn regarding the neurobiological mechanisms through which individuals navigate these social hierarchies in order to learn and acquire new information that is critical for their survival, such as finding food. To begin to address this knowledge gap in understanding the neurobiology of learning in dynamic social groups, I conducted a series of experiments using the African cichlid fish, Astatotilapia burtoni. Males of this species form dominance hierarchies which are vital for gaining territories and access to reproductive opportunities. In chapter 2, I examined the unique social traits that differentiate dominant and subordinate males in social groups, and how these traits influence group learning and decision-making. In chapter 3, I examined the neural activity patterns that drive learning in a social and asocial context by quantifying immediate-early gene expression at different time points during the learning process. Finally, in chapter 4, I examined how these neural activity patterns in key brain regions, the putative homologues of the basolateral amygdala and hippocampus, vary with the extent of social stability during the learning process. Taken together, my research offers important new insights into the behavioral and neural mechanisms underlying social learning and suggests several directions for future study
Behavioral and physiological differences associated with acquisition and maintenance of a social status in male green anole lizards, Anolis carolinensis
(2009-05) Hattori, Tomoko, 1979-; Wilczyński, W.; Delville, Yvon
Social experience can modify the behavior of adult animals, and this type of behavioral plasticity associated with territorial aggression has been observed in several species including green anole lizards. Previously dominant animals were more aggressive to a novel stimulus in a new context than previously subordinate animals after 10 days of agonistic interaction. This behavioral shift could be beneficial to an animal by increasing survival and/or reproductive success to maximize its fitness. Behavioral modification through social experience can involve alteration in some physiological properties such as variations in hormone titer and hormone receptors. Steroid hormones such as testosterone (T) and corticosterone (Cort) and neurotrasmitters such as arginine vasotocin (AVT) are well known for their association with territorial aggression. Hormonal mechanisms underlying the control of this behavior are, however, context dependent, temporally dynamic, and evolutionarily very diverse. I performed experiments aimed at gaining insights into the proximate mechanisms underlying status-dependent behavioral differences in territorial aggression. First, steroid binding globulins of green anole lizards were analyzed and the presence of androgen-glucocorticoid binding globulins and sex-hormone binding globulins (SHBG) was established. Next, status differences in steroid hormone levels and the temporal pattern of hormone changes were assessed. We found that winners/dominants had elevated total T levels shortly after the onset of fighting and reduced SHBG after 10 days of agonistic interaction. These changes seemed to cause sustained increases in free T levels in winners/dominants throughout 10 days of agonistic interactions. Then, androgen receptor (AR) mRNA density levels were compared in dominant and subordinate animals. The result showed that the preoptic area (POA) and anterior hypothalamus AR mRNA density levels were higher in dominants than subordinates shortly after the agonistic interaction. Lastly, AVT immunoreactive cell counts were compared in dominant and subordinate animals. We found that subordinate animals had reduced AVT immunoreactive cell counts in the POA compared to that of dominants or control males. Findings from this dissertation suggest possible mechanisms that might be responsible for status dependent behavioral differences in territorial aggression: elevation in T and reduction in SHBG capacity, and sustained elevation of AVT immunoreactive cell counts in the POA.
Binocular integration using stereo motion cues to drive behavior in mice
(2019-05) Choi, Veronica; Priebe, Nicholas; Zemelman, Boris; Huk, Alexander C; Colgin, Laura L; Geisler III, Wilson S; Nauhaus, Ian
The visual system presents an opportunity to study how two signals converge to generate a novel representation of the world: depth. The slight difference in positions between the two eyes means that different images are encoded by the left and right eyes by generating disparity signals. Another way to generate depth signals is by presenting different motion signals to the two eyes. Even though the binocular visual system has been studied for a long time, the mechanisms behind binocular integration when objects move in depth are largely unknown. In this dissertation, I demonstrate a new model for studying motion-in-depth signals using mice. Mice are an attractive animal to study the binocular visual system not only because they share common visual pathway as primates and other mammals, but also because there are genetic tools that can be used to study the underlying circuitry for binocular integration during motion-in-depth cues. Thus far there have been very few studies regarding binocularity in mice. This dissertation will focus on the behavioral output during stereoscopic motion-in-depth signals in mice and investigate visual areas involved in these behaviors. In the first section, I investigate whether mice discriminate motion-in-depth signals like primates, using disparity and motion signals presented to each eye. I find that mice are able to discriminate towards and away stimuli and that the binocular neurons in the visual cortex were critical for the computation of this signal. In the second section we measured optokinetic eye movement generated by motion-in-depth stimulus. I found that vergence eye movement in mice is driven primarily by the motion signals presented in each eye. This phenomenon can be explained largely by the summation of monocular motor signals of the two eyes that happens subcortically. These two experiments both show clear behavioral output that can be only generated when presented with binocular motion-in-depth signals. I find both cortical and subcortical components of binocular integration that are responsible for the generation of these behavior outputs which demonstrates the complicated nature of binocular integration associated with motion-in-depth signals. My work in this dissertation provides the foundation for studying binocular integration in rodents
Bioinformatic approaches to screening the molecular framework underlying local dendritic mRNA translation
(2017-05) Namjoshi, Sanjeev Vinayak; Hofmann, Hans (Hans A.); Raab-Graham, Kimberly F.; Atkinson, Nigel S.; Marcotte, Edward M.; Sullivan, Christopher S.
Learning and memory systems within the brain are believed to be the result of molecular events that occur at the synapse. These molecular events control synaptic efficacy – the modulation of the underlying molecular architecture of the synapse to influence the strength or weakness of connections between pre- and postsynaptic neurons. Deficits in any of these molecular processes results in neuronal dysfunction. The Mammalian/Mechanistic Target of Rapamycin Complex (mTORC1) is a protein complex within the brain composed of the serine/threonine kinase mTOR and other interacting proteins. Dysregulation of mTOR disrupts the many processes under its control such as local dendritic translation at the synapse. Since mTOR is at the core of many important signaling pathways, aberrant mTOR activity results in neuronal disease. The network of interactions between these molecular components is vast, forming an interconnected system that is dynamic and directed. In order to better understand the mechanistic nature of these interactions, the application of high-throughput technologies must be employed. Here we utilize multiple bioinformatics approaches combined with high-throughput technologies to clarify the role of mTOR in local dendritic translation. Using mass spectrometry, we provide the first evidence that mTOR bidirectionally controls the expression of over 700 proteins in the cortex, many of which are known to be associated with diseases in which mTOR is overactive (Chapter 2). Our investigations reveal a novel role PARK7 in tuberous sclerosis complex. Furthermore, we use and develop multiple bioinformatics tools to further delineate the nature of the RNA-binding properties of PARK7 and alternative avenues for drug discovery (Chapter 3). Finally, we provide evidence that the Fragile-X Mental Retardation protein sequesters a population of mRNAs involved in trans-synaptic signaling that mTOR translates to remodel the synapse, providing a mechanistic basis for the action of rapidly-acting antidepressants (Chapter 4). Collectively, our work stresses the importance of applying high-throughput technologies to answer long-standing questions in the field of local dendritic translation. Our findings provide new avenues of investigation and research to better understand neuronal disease and synaptic plasticity
Calcium-activated potassium conductance in presynaptic terminals at the crayfish neuromuscular junction
(Rockefeller University Press, 1991-12-01) Sivaramakrishnan, Shobhana; Bittner, George D.; Brodwick, Malcolm S.; Sivaramakrishnan, Shobhana; Bittner, George D.
Membrane potential changes that typically evoke transmitter release were studied by recording intracellularly from the excitor axon near presynaptic terminals of the crayfish opener neuromuscular junction. Depolarization of the presynaptic terminal with intracellular current pulses activated a conductance that caused a decrease in depolarization during the constant current pulse. This conductance was identified as a calcium-activated potassium conductance, g~c~), by its disappearance in a zero-calcium/EGTA medium and its block by cadmium, barium, tetraethylammonium ions, and charybdotoxin. In addition to gK~c,), a delayed rectifier potassium conductance (gK) is present in or near the presynaptic terminal. Both these potassium conductances are involved in the repolarization of the membrane during a presynaptic action potential.
Category learning systems
(2008-08) Zeithamova, Dagmar; Maddox, W. Todd
Category learning is an essential cognitive function. Empirical evidence and theoretical reasons suggest existence of multiple dissociable category learning systems. Here, a proposal is made that different category learning tasks are dominated by different category learning systems. A dual system theory of category learning COVIS proposes dissociation between an explicit, hypothesis-testing system, and an implicit, procedural learning system. Two studies testing this dissociation are presented, supporting the notion that hypothesis testing, utilizing working memory and explicit reasoning, mediates learning in rule-based tasks, while gradual and automatic S-R learning mediates information-integration tasks. Inconsistent findings in the literature regarding a prototype learning task suggest that two versions of this task, the A/nonA, single prototype task and the A/B, two prototype task, are mediated by distinct category learning mechanisms. A novel methodology for studying the A/nonA task and the A/B task is proposed and utilized in a functional magnetic resonance imaging study. The study reveals that the A/B task is mediated by declarative memory while the A/nonA task is mediated by perceptual learning. We conclude that at least four category learning systems exist, based on four memory systems of the brain: working memory, procedural memory, declarative memory and perceptual memory. The four category learning systems compete or cooperate during learning, each system dominating in a different category learning task. Category learning tasks provide a useful tool to understand learning and memory systems of the brain.
Cellular interactions during neural repair
(2022-05) Williamson, Michael Ryan; Drew, Michael R., Ph. D.; Jones, Theresa A.; Dunn, Andrew; Noble, Linda; Monfils, Marie
Injury to the central nervous system induces a limited neural repair response that is causally linked to recovery of function. The goal of this dissertation is to better understand neural repair responses, including how different cell types respond to injury and how cellular interactions shape repair. I investigate repair processes in a mouse model of cortical stroke by applying behavioral, imaging, and genetic techniques. In Chapter 2, I characterize the spatiotemporal dynamics of vascular plasticity following stroke, and its association with restoration of blood flow and behavioral function. I find that stroke instigates a short time window during which vascular plasticity unfolds. This window of vascular plasticity is underpinned by transient activation of pro-angiogenic gene expression programs. The formation of new vessels is associated with the restoration of blood flow to peri-infarct regions, which is in turn associated with behavioral improvement. In Chapter 3, I examine reactive astrocyte responses after stroke and their interaction with vascular plasticity. I find that stroke triggers gene expression and functional changes in reactive astrocytes that enable them to support vascular remodeling and repair. Astrocytes orchestrate multiple aspects of vascular repair, including reorganization of extracellular matrix and pericyte attachment to vessels. Ablating reactive astrocytes results in reduced angiogenesis, prolonged blood flow deficits, increased vascular permeability, and worse functional recovery. In Chapter 4 I investigate the subventricular zone (SVZ) cytogenic response to stroke. I find that cells arising from the SVZ after stroke are predominantly undifferentiated precursors and astrocytes. Arrest of cytogenesis by ablation of neural stem cells or aging reduces behavioral recovery. SVZ cytogenesis provides trophic support via vascular endothelial growth factor (VEGF) that drives effective synaptic and vascular plasticity to improve recovery. Replacement of VEGF in peri-infarct cortex of mice lacking cytogenesis is sufficient to increase dendritic spine and vascular density and enhance recovery. Together, these studies refine our understanding of how different cell types response to injury and how cellular interactions coordinate neural repair.
A century of questions: Retrospective study of the controversy and efficacy of Alzheimer's disease models
(2015-05) Zuniga, Gabrielle; Pierce-Shimomura, Jon
Alzheimer’s disease (AD) has been a devastating challenge to the research, medical, and public community for more than a century. In 1906, Alois Alzheimer characterized it as a neurodegenerative disease associated with progressive cognitive and memory impairment. Today, the only way to conclusively diagnosis AD is by autopsy that shows hallmark accumulation of proteins throughout the brain as 1) senile plaques from extracellular accumulation of amyloid-β peptide (Aβ) and 2) neurofibrillary tangles from aberrant posttranscriptional modification of the microtubule-associated protein tau. The ability of an extra copy of APP carried on chromosome 21 to cause early onset AD in individuals with Down syndrome who are trisomic for chromosome 21 led to the amyloid cascade hypothesis. This hypothesis states that abnormal processing of the amyloid precursor protein (APP) to Aβ is both necessary and sufficient for the neurotoxic cascade that leads to neuron death and brain atrophy in the hippocampus, temporal lobe and regions of the neocortex.1 Only after the amyloid cascade hypothesis was proposed in the early 1990’s had research made significant headway on deciphering the molecular mechanism of disease. Many pre-clinical studies with drugs targeting APP or Aβ have shown efficacy in vivo and in vitro, but have failed in later clinical trials. Now, many will argue that the hypothesis “is intellectually flawed“ and is impeding progress. The question to be considered is whether the pharmacological industry has wasted time and money on a faulty hypothesis or whether they have been misled by model systems that fail to appropriately mimic the disease at a level necessary for translational results. It can be argued that the greatest source of debate that seems to prevent the field from moving forward remains with the experimental method: How do we generate a model system that appropriately recapitulates a disease which we do not fully understand? In this paper, I will address the controversy and debate surrounding the century-old study of AD by reviewing the leading hypothesis of disease, the relevancy and efficacy of current and past model systems, and the advantages and disadvantages of in vitro vs. in vivo analysis for clinical outcomes. By doing so, I will provide a retrospective timeline of AD research efforts and a concluding argument for the diversification of models that could allow investigators a) to collaborate on a national and international scale, b) reach a consensus as to whether neurodegeneration and neuron death are a necessary endpoint of disease c) identify new therapeutic targets and biomarkers shared among multiple model systems d) establish a standard neuropatholgical examination criteria and genotype-to-phenotype analysis for human and animal models, e) address AD-specific pathologies, nondegenerative pathologies and other proteinopathies, of this multifactorial disease in vivo.