Responses to auditory stimuli in macaque lateral intraparietal area

The lateral intraparietal area (LIP) of macaque posterior parietal cortex participates in the sensorimotor transformations underlying visually guided eye movements. Area LIP has long been considered unresponsive to auditory stimulation. However, recent studies have shown that neurons in LIP respond to auditory stimuli during an auditory-saccade task, suggesting possible involvement of this area in auditory-to-oculomotor as well as visual-to-oculomotor processing. This dissertation describes investigations which clarify the role of area LIP in auditory-to-oculomotor processing.

Extracellular recordings were obtained from a total of 332 LIP neurons in two macaque monkeys, while the animals performed fixation and saccade tasks involving auditory and visual stimuli. No auditory activity was observed in area LIP before animals were trained to make saccades to auditory stimuli, but responses to auditory stimuli did emerge after auditory-saccade training. Auditory responses in area LIP after auditory-saccade training were significantly stronger in the context of an auditory-saccade task than in the context of a fixation task. Compared to visual responses, auditory responses were also significantly more predictive of movement-related activity in the saccade task. Moreover, while visual responses often had a fast transient component, responses to auditory stimuli in area LIP tended to be gradual in onset and relatively prolonged in duration.

Overall, the analyses demonstrate that responses to auditory stimuli in area LIP are dependent on auditory-saccade training, modulated by behavioral context, and characterized by slow-onset, sustained response profiles. These findings suggest that responses to auditory stimuli are best interpreted as supramodal (cognitive or motor) responses, rather than as modality-specific sensory responses. Auditory responses in area LIP seem to reflect the significance of auditory stimuli as potential targets for eye movements, and may differ from most visual responses in the extent to which they arc abstracted from the sensory parameters of the stimulus.

Macaque lateral intraparietal area and oculomotor behaviors

Neurons in the primate lateral intraparietal area (area LIP) carry visual, saccade-related and eye position activities. The visual and saccade activities are anchored in a retinotopic framework and the overall response magnitude is modulated by eye position. It was proposed that the modulation by eye position might be the basis of a distributed coding of target locations in a head-centered space. Other recording studies demonstrated that area LIP is involved in oculomotor planning. These results overall suggest that area LIP transforms sensory information for motor functions. In this thesis I further explore the role of area LIP in processing saccadic eye movements by observing the effects of reversible inactivation of this area. Macaque monkeys were trained to do visually guided and memory saccades and a double saccade task to examine the use of eye position signal. Finally, by intermixing visual saccades with trials in which two targets were presented at opposite sides of the fixation point, I examined the behavior of visual extinction.

In chapter 2, I will show that lesion of area LIP results in increased latency of contralesional visual and memory saccades. Contralesional memory saccades are also hypometric and slower in velocity. Moreover, the impairment of memory saccades does not vary with the duration of the delay period. This suggests that the oculomotor deficits observed after inactivation of area LIP is not due to the disruption of spatial memory.

In chapter 3, I will show that lesion of area LIP does not severely affect the processing of spontaneous eye movement. However, the monkeys made fewer contralesional saccades and tended to confine their gaze to the ipsilesional field after inactivation of area LIP. On the other hand, lesion of area LIP results in extinction of the contralesional stimulus. When the initial fixation position was varied so that the retinal and spatial locations of the targets could be dissociated, it was found that the extinction behavior could best be described in a head-centered coordinate.

In chapter 4, I will show that inactivation of area LIP disrupts the use of eye position signal to compute the second movement correctly in the double saccade task. If the first saccade steps into the contralesional field, the error rate and latency of the second saccade are both increased. Furthermore, the direction of the first eye movement largely does not have any effect on the impairment of the second saccade. I will argue that this study provides important evidence that the extraretinal signal used for saccadic localization is eye position rather than a displacement vector.

In chapter 5, I will demonstrate that in parietal monkeys the eye drifts toward the lesion side at the end of the memory saccade in darkness. This result suggests that the eye position activity in the posterior parietal cortex is active in nature and subserves gaze holding.

Overall, these results further support the view that area LIP neurons encode spatial locations in a craniotopic framework and is involved in processing voluntary eye movements.

Cell fate specification during Caenorhabditis elegans male tail development

The cells of the specialized mating structures of the nematode Caenorhabditis elegans adult male tail develop from sex-specific divisions of postembryonic blast cells. One male-specific blast cell, B, is the precursor to all the cells of the copulatory spicules. Both cell interactions and autonomous fate specification mechanisms are utilized in the B lineage to specify fate.

During development the anterior daughter of B, B.a, generates four distinct pairs of cells. Cell ablation experiments indicate that the cells of each pair respond to positional cues provided by other male-specific blast cells. F and U promote anterior fates, Y.p promotes some posterior fates, and the B.a progeny promote posterior fates. The cells within each pair may also interact.

The lin-3/let-23 signalling pathway, identified for its function in C. elegans hermaphrodite vulval induction, mediates the signal from F and U. Reduction-of-function mutations in lin-3 (EGF-like signal), let-23 (receptor), sem-5 (adaptor), let-60 (ras), or lin-45 (raf) disrupt the fates of the anterior cells, and mimic F and U ablation. In addition, ectopically expressed lin-3 disrupts the fates of the posterior cells, and can promote anterior fates even in the absence of F and U.

A genetic screen of over 9000 mutagenized gametes recovered 22 mutations in 20 loci that disrupt fate specification in male tail lineages. Seven of these mutations may represent new genes that play a role in male tail development.

The first division of the B cell is asymmetric. The gene vab-3 is required for specification of B.a fates, and it may represent a factor whose activity is localized to the B.a cell via the gene lin-17. lin-17 acts both at the first division of the B cell and at specific other cell divisions in the lineage.

Molecular genetics of the Drosophila eyes absent gene

The Drosophila compound eye has provided a genetic approach to understanding the specification of cell fates during differentiation. The eye is made up of some 750 repeated units or ommatidia, arranged in a lattice. The cellular composition of each ommatidium is identical. The arrangement of the lattice and the specification of cell fates in each ommatidium are thought to occur in development through cellular interactions with the local environment. Many mutations have been studied that disrupt the proper patterning and cell fating in the eye. The eyes absent (eya) mutation, the subject of this thesis, was chosen because of its eyeless phenotype. In eya mutants, eye progenitor cells undergo programmed cell death before the onset of patterning has occurred. The molecular genetic analysis of the gene is presented.

The eye arises from the larval eye-antennal imaginal disc. During the third larval instar, a wave of differentiation progresses across the disc, marked by a furrow. Anterior to the furrow, proliferating cells are found in apparent disarray. Posterior to the furrow, clusters of differentiating cells can be discerned, that correspond to the ommatidia of the adult eye. Analysis of an allelic series of eya mutants in comparison to wild type revealed the presence of a selection point: a wave of programmed cell death that normally precedes the furrow. In eya mutants, an excessive number of eye progenitor cells die at this selection point, suggesting the eya gene influences the distribution of cells between fates of death and differentiation.

In addition to its role in the eye, the eya gene has an embryonic function. The eye function is autonomous to the eye progenitor cells. Molecular maps of the eye and embryonic phenotypes are different. Therefore, the function of eya in the eye can be treated independently of the embryonic function. Cloning of the gene reveals two cDNA's that are identical except for the use of an alternatively-spliced 5' exon. The predicted protein products differ only at the N-termini. Sequence analysis shows these two proteins to be the first of their kind to be isolated. Trangenic studies using the two cDNA's show that either gene product is able to rescue the eye phenotype of eya mutants.

The eya gene exhibits interallelic complementation. This interaction is an example of an "allelic position effect": an interaction that depends on the relative position in the genome of the two alleles, which is thought to be mediated by chromosomal pairing. The interaction at eya is essentially identical to a phenomenon known as transvection, which is an allelic position effect that is sensitive to certain kinds of chromosomal rearrangements. A current model for the mechanism of transvection is the trans action of gene regulatory regions. The eya locus is particularly well suited for the study of transvection because the mutant phenotypes can be quantified by scoring the size of the eye.

The molecular genetic analysis of eya provides a system for uncovering mechanisms underlying differentiation, developmentally regulated programmed cell death, and gene regulation.

Wnt and FGF signaling in C. elegans vulval cell lineage polarity

The interpretation of extracellular cues leading to the polarization of intracellular components and asymmetric cell divisions is a fundamental part of metazoan organogenesis. The C. elegans vulva, with its invariant cell lineage and interaction of multiple cell signaling pathways, provides an excellent model for the study of cell polarity within an organized epithelial tissue. Herein I discuss the interaction of Wnt and FGF signaling in controlling vulval cell lineage polarity with emphasis on the posterior-most cell that forms the vulva, P7.p.

The mirror symmetry of the C. elegans vulva is achieved by the opposite division orientation of the vulval precursor cells (VPCs) flanking the axis of symmetry. Opposing Wnt signals control the division patterns of the VPCs by controlling the localization of SYS-1/ β-catenin toward the direction of the Wnt gradient. Multiple Wnt signals, expressed at the axis of symmetry, promote the wild-type, anterior-facing, P7.p orientation, whereas Wnts EGL-20 and CWN-1 from the tail and posterior body wall muscle, respectively, promote the daughter cells of P7.p to face the posterior. EGL-20 acts through a member of the LDL receptor superfamily, LRP-2, along with Ror/CAM-1 and Van Gogh/VANG-1. All three transmembrane proteins control orientation through the localization of the SYS-1.

The Fibroblast Growth Factor (FGF) pathway acts in concert with LIN-17/Frizzled to regulate the localization of SYS-1. The source of the FGF ligand is the 1° VPC, P6.p, which controls the polarity of the neighboring 2° VPC, P7.p, by signaling through the sex myoblasts (SMs), activating the FGF pathway. The Wnt, cwn-1, is expressed in the posterior body wall muscle of the worm as well as the SMs, making it the only Wnt expressed on the posterior and anterior sides of P7.p at the time of the polarity decision. Both sources of cwn-1 act instructively to influence P7.p polarity in the direction of the Wnt gradient. The FGF pathway leads to the regulation of cwn-1 transcripts in the SMs. These results illustrate the first evidence of the interaction between FGF and Wnt in C. elegans development and vulval cell lineage polarity as well as highlight the promiscuous nature of Wnt signaling within C. elegans.

Molecular neurogenetics of eye development in Drosophila

The compound eye of Drosophila melanogaster begins to differentiate during the late third larval instar in the eye-antennal imaginal disc. A wave of morphogenesis crosses the disc from posterior to anterior, leaving behind precisely patterned clusters of photoreceptor cells and accessory cells that will constitute the adult ommatidia of the retina. By the analysis of genetically mosaic eyes, it appears that any cell in the eye disc can adopt the characteristics of any one of the different cell types found in the mature eye, including photoreceptor cells and non-neuronal accessory cells such as cone cells. Therefore, cells within the prospective retinal epithelium assume different fates presumably via information present in the environment. The sevenless^+ (sev^+) gene appears to play a role in the expression of one of the possible fates, since the mutant phenotype is the lack of one of the pattern elements, namely, photoreceptor cell R7. The sev^+ gene product had been shown to be required during development of the eye, and had also been shown in genetic mosaics to be autonomous to presumptive R7. As a means of better understanding the pathway instructing the differentiation R7, the gene and its protein product were characterized.

The sev+ gene was cloned by P-element transposon tagging, and was found to encode an 8.2 kb transcript expressed in developing eye discs and adult heads. By raising monoclonal antibodies (MAbs) against a sev^+- β-galactosidase fusion protein, the expression of the protein in the eye disc was localized by immuno-electronmicroscopy. The protein localizes to the apical cell membranes and microvilli of cells in the eye disc epithelium. It appears during development at a time coincident with the initial formation of clusters, and in all the developing photoreceptors and accessory cone cells at a time prior to the overt differentiation of R7. This result is consistent with the pluripotency of cells in the eye disc. Its localization in the membranes suggests that it may receive information directing the development of R7. Its localization in the apical membranes and microvilli is away from the bulk of the cell contacts, which have been cited as a likely regions for information presentation and processing. Biochemical characterization of the sev^+ protein will be necessary to describe further its role in development.

Other mutations in Drosophila have eye phenotypes. These were analyzed to find which ones affected the initial patterning of cells in the eye disc, in order to identify other genes, like sev, whose gene products may be involved in generating the pattern. The adult eye phenotypes ranged from severe reduction of the eye, to variable numbers of photoreceptor cells per ommatidium, to sub de defects in the organization of the supporting cells. Developing eye discs from the different strains were screened using a panel of MAbs, which highlight various developmental stages. Two identified matrix elements in and anterior to the furrow, while others identified the developing ommatidia themselves, like the anti-sev MAb. Mutation phenotypes were shown to appear at many stages of development. Some mutations seem to affect the precursor cells, others, the setting up of the pattern, and still others, the maintenance of the pattern. Thus, additional genes have now been identified that may function to support the development of a complex pattern.

Efficient methods for empirical tests of behavioral economics theories in laboratory and field experiments

In the quest for a descriptive theory of decision-making, the rational actor model in economics imposes rather unrealistic expectations and abilities on human decision makers. The further we move from idealized scenarios, such as perfectly competitive markets, and ambitiously extend the reach of the theory to describe everyday decision making situations, the less sense these assumptions make. Behavioural economics has instead proposed models based on assumptions that are more psychologically realistic, with the aim of gaining more precision and descriptive power. Increased psychological realism, however, comes at the cost of a greater number of parameters and model complexity. Now there are a plethora of models, based on different assumptions, applicable in differing contextual settings, and selecting the right model to use tends to be an ad-hoc process. In this thesis, we develop optimal experimental design methods and evaluate different behavioral theories against evidence from lab and field experiments.

We look at evidence from controlled laboratory experiments. Subjects are presented with choices between monetary gambles or lotteries. Different decision-making theories evaluate the choices differently and would make distinct predictions about the subjects' choices. Theories whose predictions are inconsistent with the actual choices can be systematically eliminated. Behavioural theories can have multiple parameters requiring complex experimental designs with a very large number of possible choice tests. This imposes computational and economic constraints on using classical experimental design methods. We develop a methodology of adaptive tests: Bayesian Rapid Optimal Adaptive Designs (BROAD) that sequentially chooses the "most informative" test at each stage, and based on the response updates its posterior beliefs over the theories, which informs the next most informative test to run. BROAD utilizes the Equivalent Class Edge Cutting (EC²) criteria to select tests. We prove that the EC² criteria is adaptively submodular, which allows us to prove theoretical guarantees against the Bayes-optimal testing sequence even in the presence of noisy responses. In simulated ground-truth experiments, we find that the EC² criteria recovers the true hypotheses with significantly fewer tests than more widely used criteria such as Information Gain and Generalized Binary Search. We show, theoretically as well as experimentally, that surprisingly these popular criteria can perform poorly in the presence of noise, or subject errors. Furthermore, we use the adaptive submodular property of EC² to implement an accelerated greedy version of BROAD which leads to orders of magnitude speedup over other methods.

We use BROAD to perform two experiments. First, we compare the main classes of theories for decision-making under risk, namely: expected value, prospect theory, constant relative risk aversion (CRRA) and moments models. Subjects are given an initial endowment, and sequentially presented choices between two lotteries, with the possibility of losses. The lotteries are selected using BROAD, and 57 subjects from Caltech and UCLA are incentivized by randomly realizing one of the lotteries chosen. Aggregate posterior probabilities over the theories show limited evidence in favour of CRRA and moments' models. Classifying the subjects into types showed that most subjects are described by prospect theory, followed by expected value. Adaptive experimental design raises the possibility that subjects could engage in strategic manipulation, i.e. subjects could mask their true preferences and choose differently in order to obtain more favourable tests in later rounds thereby increasing their payoffs. We pay close attention to this problem; strategic manipulation is ruled out since it is infeasible in practice, and also since we do not find any signatures of it in our data.

In the second experiment, we compare the main theories of time preference: exponential discounting, hyperbolic discounting, "present bias" models: quasi-hyperbolic (α, β) discounting and fixed cost discounting, and generalized-hyperbolic discounting. 40 subjects from UCLA were given choices between 2 options: a smaller but more immediate payoff versus a larger but later payoff. We found very limited evidence for present bias models and hyperbolic discounting, and most subjects were classified as generalized hyperbolic discounting types, followed by exponential discounting.

In these models the passage of time is linear. We instead consider a psychological model where the perception of time is subjective. We prove that when the biological (subjective) time is positively dependent, it gives rise to hyperbolic discounting and temporal choice inconsistency.

We also test the predictions of behavioral theories in the "wild". We pay attention to prospect theory, which emerged as the dominant theory in our lab experiments of risky choice. Loss aversion and reference dependence predicts that consumers will behave in a uniquely distinct way than the standard rational model predicts. Specifically, loss aversion predicts that when an item is being offered at a discount, the demand for it will be greater than that explained by its price elasticity. Even more importantly, when the item is no longer discounted, demand for its close substitute would increase excessively. We tested this prediction using a discrete choice model with loss-averse utility function on data from a large eCommerce retailer. Not only did we identify loss aversion, but we also found that the effect decreased with consumers' experience. We outline the policy implications that consumer loss aversion entails, and strategies for competitive pricing.

In future work, BROAD can be widely applicable for testing different behavioural models, e.g. in social preference and game theory, and in different contextual settings. Additional measurements beyond choice data, including biological measurements such as skin conductance, can be used to more rapidly eliminate hypothesis and speed up model comparison. Discrete choice models also provide a framework for testing behavioural models with field data, and encourage combined lab-field experiments.

Establishing the C. elegans uterine seam cell (utse) as a novel model for studying cell behavior

The molecular inputs necessary for cell behavior are vital to our understanding of development and disease. Proper cell behavior is necessary for processes ranging from creating one’s face (neural crest migration) to spreading cancer from one tissue to another (invasive metastatic cancers). Identifying the genes and tissues involved in cell behavior not only increases our understanding of biology but also has the potential to create targeted therapies in diseases hallmarked by aberrant cell behavior.

A well-characterized model system is key to determining the molecular and spatial inputs necessary for cell behavior. In this work I present the C. elegans uterine seam cell (utse) as an ideal model for studying cell outgrowth and shape change. The utse is an H-shaped cell within the hermaphrodite uterus that functions in attaching the uterus to the body wall. Over L4 larval stage, the utse grows bidirectionally along the anterior-posterior axis, changing from an ellipsoidal shape to an elongated H-shape. Spatially, the utse requires the presence of the uterine toroid cells, sex muscles, and the anchor cell nucleus in order to properly grow outward. Several gene families are involved in utse development, including Trio, Nav, Rab GTPases, Arp2/3, as well as 54 other genes found from a candidate RNAi screen. The utse can be used as a model system for studying metastatic cancer. Meprin proteases are involved in promoting invasiveness of metastatic cancers and the meprin-likw genes nas-21, nas-22, and toh-1 act similarly within the utse. Studying nas-21 activity has also led to the discovery of novel upstream inhibitors and activators as well as targets of nas-21, some of which have been characterized to affect meprin activity. This illustrates that the utse can be used as an in vivo model for learning more about meprins, as well as various other proteins involved in metastasis.

Essays in Behavioral Decision Theory

This thesis studies decision making under uncertainty and how economic agents respond to information. The classic model of subjective expected utility and Bayesian updating is often at odds with empirical and experimental results; people exhibit systematic biases in information processing and often exhibit aversion to ambiguity. The aim of this work is to develop simple models that capture observed biases and study their economic implications.

In the first chapter I present an axiomatic model of cognitive dissonance, in which an agent's response to information explicitly depends upon past actions. I introduce novel behavioral axioms and derive a representation in which beliefs are directionally updated. The agent twists the information and overweights states in which his past actions provide a higher payoff. I then characterize two special cases of the representation. In the first case, the agent distorts the likelihood ratio of two states by a function of the utility values of the previous action in those states. In the second case, the agent's posterior beliefs are a convex combination of the Bayesian belief and the one which maximizes the conditional value of the previous action. Within the second case a unique parameter captures the agent's sensitivity to dissonance, and I characterize a way to compare sensitivity to dissonance between individuals. Lastly, I develop several simple applications and show that cognitive dissonance contributes to the equity premium and price volatility, asymmetric reaction to news, and belief polarization.

The second chapter characterizes a decision maker with sticky beliefs. That is, a decision maker who does not update enough in response to information, where enough means as a Bayesian decision maker would. This chapter provides axiomatic foundations for sticky beliefs by weakening the standard axioms of dynamic consistency and consequentialism. I derive a representation in which updated beliefs are a convex combination of the prior and the Bayesian posterior. A unique parameter captures the weight on the prior and is interpreted as the agent's measure of belief stickiness or conservatism bias. This parameter is endogenously identified from preferences and is easily elicited from experimental data.

The third chapter deals with updating in the face of ambiguity, using the framework of Gilboa and Schmeidler. There is no consensus on the correct way way to update a set of priors. Current methods either do not allow a decision maker to make an inference about her priors or require an extreme level of inference. In this chapter I propose and axiomatize a general model of updating a set of priors. A decision maker who updates her beliefs in accordance with the model can be thought of as one that chooses a threshold that is used to determine whether a prior is plausible, given some observation. She retains the plausible priors and applies Bayes' rule. This model includes generalized Bayesian updating and maximum likelihood updating as special cases.