Food aversion learning is thought to underlie restrictive eating behaviors seen in various eating disorders. Aversion learning paradigms such as taste neophobia and conditioned taste aversion serve to limit intake of food stimuli that may cause harm. Comparing neural structures involved in taste neophobia and conditioned taste aversion to structures involved in activity-based anorexia and anorexia nervosa may provide insight into structures that potentiate anorexic behaviors. Neural structures involved in taste neophobia include the basolateral amygdala and gustatory complex. Structures involved in conditioned taste aversion include the parabrachial nucleus, lateral hypothalamus, and amygdala. Additional structures such as the hippocampus, nucleus accumbens, and ventral tegmental area have been noted to be involved in reward processing in the activity based anorexia animal model. Structures involved in both gustatory aversion and reward and emotional processing have been cited to be involved in anorexia nervosa. Dysfunction of these structures may result from dysfunction of a single, central structure, the subcallosal cingulum.

Concussions in young athletes have become a critical public health concern36, with over 1 million pediatric sports-related concussions reported annually32. Despite the high prevalence of concussions, especially in contact sports, conclusive quantitative measurements of the damage associated with concussions is lacking. Most of these mild traumatic brain injuries (mTBIs) occur without macroscopic damage and have therefore been difficult to quantify with traditional imaging techniques such as conventional magnetic resonance imaging (MRI) and computed tomography (CT)22,32,46. Current concussion diagnosis criteria relies upon subjective reporting, which has shown to be inconsistent and underreported22,33. The absence of a sensitive, reliable, and conclusive diagnostic measure for concussions is dangerous, causing mild concussions to frequently go undiagnosed7,20,22. This is particularly unsafe for young athletes in contact-associated sports, who, due to age-related biomechanical differences, are at an increased risk of concussive events and lasting impairments16,29,33,36. Diffusion tensor imaging (DTI) has risen to the forefront of noninvasive concussion imaging research, as it is capable of indirectly measuring the integrity of the axons within the brain on a microstructural level15,20,22,38. Specifically, DTI measures the direction of water molecule diffusion and is able to detect even subtle changes in the brain tissue structure that may occur with axonal injury as a result of a concussion15,20,38. Previous studies have demonstrated the ability of DTI methods to measure significant differences in diffusivity between concussed individuals and uninjured controls6–8,17,20,26,29,30,32,34,39,44–46. Additionally, DTI is sensitive to normal neurodevelopmental changes that occur, making it especially applicable to the pediatric population20,46. It has shown to be capable of distinguishing between severities of concussions6,8,28 and predicting general functional outcomes8,22,26,33,46. While currently confined to use in research, DTI technology shows great promise in one day becoming a routine clinical imaging tool for use in concussion diagnosis2,22,23,38,45,46.

Alzheimer’s disease is a progressive and irreversible neurodegenerative disorder characterized by the accumulation of neurotoxic Aβ peptides and subsequent onset of secondary neuropathological changes, including aggregation of hyperphosphorylated tau protein. Aβ peptides, produced through the successive actions of β- and γ-secretase in the amyloidogenic processing pathway of APP, aggregate into neurotoxic oligomeric Aβ and amyloid plaques. The reduction of Aβ peptide formation through the inhibition of β- and γ-secretase of the amyloidogenic pathway and the activation of α-secretase of the nonamyloidogenic pathway has been a primary focus of many recent therapeutic research studies. Alternative strategies include increasing Aβ peptide clearance from the cerebral cortex through both active and passive immunization. Although some of these potential treatment options for Alzheimer’s disease have shown promise, they carry a great deal of risk with a variety of unintended side effects. Moreover, there are currently no diseasemodifying drugs available to treat Alzheimer’s disease, as most therapeutics are targeted to treat symptoms of the disease rather than the disease itself. Recent studies suggest a link between APP dimerization and Aβ production. Compound Y, which inhibited APP dimerization, was discovered by Pauline So and her colleagues in the Abraham lab at Boston University and was shown to reduce Aβ production by lowering sAPPβ levels, suggesting that the inhibition of APP dimerization affects the β-secretase cleavage of APP. A kinase profiling assay revealed that compound Y10, an analog of compound Y, exhibited its action through the inhibition of receptor tyrosine kinase cKit. Interestingly, inhibition of cKit enhanced APP phosphorylation, suggesting that cKit indirectly affects APP. Known cKit interactors with potential to affect downstream APP phosphorylation were studied, leading to the discovery of Shp2, a tyrosine phosphatase directly linked to cKit signaling. After demonstrating that known Shp2 inhibitors increase APP phosphorylation and lower Aβ production, it was hypothesized that both cKit and Shp2 are involved in APP processing. The objective of the current study is to explore the potential for Shp2 as a novel therapeutic target in Alzheimer’s disease. Potential Shp2-inhibiting compounds, synthesized in collaboration with Dr. John Porco and his colleagues at the Center for Molecular Discovery at Boston University, were screened for their ability to inhibit Shp2 using 6,8-difluoro-4-methylumbelliferyl phosphate (DiFMUP) as a substrate. Five compounds were shown to significantly inhibit Shp2, and these compounds were subsequently tested in a dose-dependent manner to determine their potency. All five compounds compared favorably with the potency of a known Shp2 inhibitor. As a result, these five compounds have become lead candidates in the next stage of evaluation. With a growing aging population and an ever-increasing economic burden placed on global healthcare systems, there is a pressing need to develop a disease-modifying treatment for Alzheimer’s disease. This study contributes to the scientific knowledge behind Alzheimer’s disease and provides the necessary tools for the discovery of potential therapeutics. / 2018-06-16T00:00:00Z

Recently, we reported that bilateral gustatory cortex (GC) lesions significantly impair taste sensitivity to salts in rats. Here we sought to extend the range of tastants tested to include sucrose and quinine in rats with ibotenic acid-induced lesions in GC (GCX) and in sham-operated controls (SHAM). Presurgically, on a single occasion, immediately after drinking 0.1 M NaCl (15 min), rats received either a LiCl or saline injection (i.p.), but postsurgical tests indicated a weak conditioned taste aversion (CTA) even in the SHAM LiCl-injected rats. The rats were then trained and tested in a gustometer to discriminate a tastant from water in a two-response operant taste detection task. Psychometric functions were derived separately for each tastant (sucrose, KCl, and quinine, in series) by lowering the stimulus concentration across test sessions. A mapping system was used to determine, in a blinded fashion, acceptable placement, size and symmetry of the bilateral lesions (~91% damage to GC on average). For KCl, there was a significant difference between GCX (n=22) and SHAM (n=13) rats indicated by a rightward shift (ΔEC50=0.57 log10 units, p<0.001) in the psychometric function, replicating our prior work. There was a significant lesion-induced impairment (ΔEC50=0.41 log10 units; SHAM [n=12], GCX [n=19], p=0.006) in quinine sensitivity as well. After taste sensitivity testing, a postsurgical CTA to a glucose polymer mixture, Maltrin, was trained in two conditioning trials and was then tested in a brief-access and 46-hr two-bottle preference test. The GCX rats displayed compromised CTA expression in the brief-access taste test, which focuses on orosensory characteristics of the tastant, whereas there was no deficit in CTA expression between surgical groups in the 46-hr preference test, which can be influenced by postingestive and olfactory factors. CTA was used here as a functional measure of the lesions as there is evidence in the literature that GC damage can impair CTA expression. Although taste sensitivities to KCl and quinine were attenuated, impairment with one stimulus was not significantly correlated with that of the other. Interestingly, unlike what was observed for KCl and quinine, taste sensitivity to sucrose was comparable between GCX (n=25) and SHAM (n=13) rats. Apparently, the degree to which the GC is necessary for the maintenance of normal taste detectability depends on the chemical and/or perceptual features of the stimulus. / A Thesis submitted to the Department of Psychology in partial fulfillment of the requirements for the degree of Master of Science. / Spring Semester, 2015. / February 11, 2015. / Animal Psychophysics, Gustatory Cortex, Taste Sensitivity / Includes bibliographical references. / Alan Spector, Professor Directing Thesis; Frank Johnson, Committee Member; Rick Wagner, Committee Member.

Rats display marked variability in their willingness to consume the artificial sweetener sucralose. Most rats are classified as sucralose avoiders (~75%; SA) while the remaining subset can be classified as sucralose preferrers (~25%; SP). Here, I have shown that these phenotypic differences in the consumption of sucralose are the result of highly consistent and robust behaviors and potentially represent a meaningful, physiological difference in sensory processing with functional consequences for diet choice and weight gain. Specifically, the emergence of a sucralose preference profile is stable across both sexes and at least two rat strains. Furthermore, utilizing an adaptation of the two-response taste discrimination psychophysical paradigm, I have demonstrated that the differences in the consumption of sucralose are sensory based. The taste quality of sucralose appears to be sufficient to split rats into their respective phenotypic groups. These sensory differences appear to generalize to other artificial sweeteners and stimuli with a putative, binary sweet-like and bitter-like taste profile as SA and SP differ in their intakes of concentrated saccharin solutions and quinine-adulterated sucrose in a manner consistent with their responses to sucralose. These sensory differences appear to be mediated by a disparity in the processing of 'sweet' tastes. Immunohistochemical analysis of patterns of neuronal activation demonstrate that SA may perceive a more salient 'bitter' percept from sucralose, most likely due to a reduced sensitivity to the 'sweet'-like qualities of sucralose. Conversely, SP perceive identical concentrations of sucralose as a mixture of 'sweet' and 'bitter' with the most salient quality being that of a sucrose-like 'sweet' taste; a sensory profile consistent with a number of other artificial sweeteners. These differences in sensory processing may be the result of a genetic mutation in one of the Tas1R genes that encode the two proteins that form the functional 'sweet-taste' receptor. Evidence for such a conclusion is provided by the observed differential intake of sucralose and at least one other artificial sweetener, as well as differences in the avidity for sucrose solutions as assessed through brief-access licking tests. The demonstrated variation in sensory processing may play a central role in SP, relative to SA, failing to regulate caloric intake, and their subsequent increased propensity for weight gain, when given access to a highly palatable diet. As the increased availability to highly palatable, energy-dense foods has been identified as a contributing factor to the current obesity epidemic, these data may provide a direct, testable model for examining the influence of a 'sweet-tooth' on diet choice and excessive weight gain. / A Dissertation submitted to the Department of Psychology in partial fulfillment of the requirements for the degree of Doctor of Philosophy. / Fall Semester, 2014. / September 12, 2014. / Bimodal, Ingestive Behavior, Psychophysics, Sucralose, Sweeteners, Taste / Includes bibliographical references. / Lisa Eckel, Professor Directing Dissertation; Joyce Carbonell, Committee Member; Thomas Houpt, Committee Member; Alan Spector, Committee Member.

Development of the central nervous system is guided by patterns of molecular expression and by cellular interactions. One important component of the cellular interactions that guide development of neural pathways relates to the electrical activity of neurons and the chemical signals released from active nerve fibers. A role of neural activity in guiding development is especially important in the development of sensory pathways. The elimination of afferent activity results in cell death and atrophy in a variety of sensory systems and many of these effects are most pronounced in developing systems. The purpose of this report is to further the understanding of the activity-dependent signals that are necessary for maintaining healthy neurons and to examine the sequence of events that lead towards death following the loss of afferent activity. The chick auditory brain stem has been a useful model system for examining the afferent-dependent signals that regulate postsynaptic neurons. Like other sensory systems, compromised afferent input results in rapid death and atrophy of postsynaptic neurons. To understand the afferent regulation of cell viability, one must examine: 1) the intercellular signals that serve as trophic factors, and 2) the intracellular chain of events that lead towards cell death. The studies in this dissertation explore aspects of both issues. First, anatomical techniques are used to evaluate the expression of a receptor called metabotropic glutamate receptor (mGluR) that is believed to play a role in maintaining the health of auditory neurons. Second, the possible contributions of an oxidative stress pathway in determining neuronal fate following deafferentation were also explored. Towards this end, levels of reactive oxygen species (ROS), lipid damage measured by 4-hydroxynonenal (4-HNE) formation, and a compensatory ROS response regulated by glutathione s transferase M1 (GSTM1) and the ROS-sensitive transcriptional factor, nuclear respiratory factor 1 (Nfr1) were examined. Unilateral cochlea removal surgery was performed on chicks ages P0-P1 and P7-P10. Opposite sides of the same tissue sections were compared for analysis. These studies confirmed that mGluRs are located in the auditory system and their expression appears to increase early following cochlea removal. Evidence was also provided to support a role for oxidative stress in determining neuronal survival following deafferentation. A dramatic increase in ROS was accompanied by lipid damage and a compensatory upregulation of both GSTM1 and Nrf1 following cochlea removal. Together, these data identify some anatomical features of mGluR localization and suggest an oxidative pathway that might be significant in determining whether a given neuron survives following deafferentation. / A Dissertation submitted to the Program in Neuroscience in partial fulfillment of the requirements for the degree of Doctor of Philosophy. / Summer Semester, 2005. / June 30, 2005. / Mitochondria, Reactive Oxygen Species, Avian, Auditory System, Cell Death, Deafferentation / Includes bibliographical references. / Richard L. Hyson, Professor Directing Dissertation; Timothy Logan, Outside Committee Member; Thomas Joiner, Committee Member; Debra Ann Fadool, Committee Member; Frank Johnson, Committee Member.

Migraines are one of the most disabling neurovascular disorders of which there is still no exact etiology. Most of the studies concerning the pathophysiology of migraines revolve around the notion that the key players are meningeal vascular mechanisms working in conjunction with local trigeminal afferents. Cortical spreading depression, the Trigeminovascular system, and the Blood-Brain-Barrier are other potential contributors but need further investigation. This literature thesis will explore the relationship between the vasculature and neurological mechanisms in the initiation of migraine episodes and provide a plausible mechanism that combines current evidence provided by the literature.

The goal of medical educators is to teach their students in a manner that is effective for long-term, accurate knowledge retention, but measurement of long-term retention is difficult. Recent work by our lab has explored the use of gaze tracking to document and measure learning in medical gross anatomy students. In this study we combine gaze tracking and EEG to examine knowledge retention by these students. Medical gross anatomy students (n=22) were asked to identify anatomical structures displayed on a computer screen immediately following the gross anatomy course and again six months after the course ended. In this experiment the participants were instructed to visually fixate on the named structure of interest, or to indicate uncertainty by fixating on the upper left corner of the screen. Immediately after the course ended the students correctly fixated on the structures 70% of the time, incorrectly fixated 26.5% of the time, and indicated uncertainty 3.5% of the time. Preliminary results indicate that six months after the end of the course the students' performance at this task had not diminished (67% correct, 26% incorrect, 7% uncertain). However, the speed with which the students made their final decision was significantly longer 6 months after the course ended. The average time to identify the structure by fixating for the final time on the region of interest was 2.22s immediately after the course and 3.0s at the 6 month follow up (p<0.001). These results indicate that 6 months after the end of the course the subjects have solid knowledge retention but require more time to think before answering correctly. Visuospatial ability did not significantly correlate with speed to identify the structure (r = -0.279; ns). Additionally, our results confirm that the students' correct behavioral responses of a task by visual fixation demonstrate signals associated with familiarity and recollection, 300-500 ms and 500-800ms post-stimulus onset respectively, on waveforms generated from EEG activity.

The basal ganglia are primitive brain structures important for learning, decision making, and locomotion. Though the striatum is central for basal ganglia functions, it remains largely unknown how different types of neurons in the striatum support diverse behaviors. We here deployed two-color, wide-field calcium imaging and examined the distinct contributions of MSNs and interneuron subtypes during voluntary movement. First, to promote the use of scientific complementary metal-oxide semiconductor (sCMOS) cameras in wide-field calcium imaging at high spatiotemporal resolution, we developed a Teensy 3.2 microcontroller-based interface capable of integrating novel behavioral paradigms with sCMOS cameras. We quantified the performance of the Teensy interface in a locomotion experiment and in a trace-conditioning experiment. We show that this Teensy interface provides flexibility in integrating sCMOS cameras into diverse experimental designs with high temporal precision. In parallel, we utilized two-color wide-field calcium imaging, labelling striatal neurons with the green calcium indicator GCaMP6f (fast), while additionally targeting two interneuron classes, parvalbumin-positive (PV) and cholinergic interneurons (CHIs) using red fluorophores in two transgenic mice. We found that PVs are highly correlated with motor output and precipitate a decrease in MSN-MSN (medium-spiny neuron) coactivity. In contrast, CHI activation elicits a decrease in locomotion and precipitates an increase in MSN coactivity. These results provide the first experimental evidence for the distinct contribution of striatal interneuron subtypes during locomotion. Finally, we performed a cluster analysis to examine the relationship of MSN networks with motor output upon pharmacological elevation of striatal cholinergic tone or dopaminergic tone. We found that striatal activity becomes uncoupled from motor output in both conditions, and individual MSN clusters become less correlated and less predictive of motor output. These results suggest that balanced levels of acetylcholine and dopamine in the striatum are important for striatal encoding of motor function. In this dissertation we extend our knowledge about how the striatum coordinates locomotion and improve upon existing neurotechnologies to study the striatum. Future studies might extend such findings to build a more intricate network model of the striatum to better understand its function in normal locomotion or in disease conditions.

Ketamine is an NMDA receptor antagonist with powerful anesthetic, antidepressant, and psychotomimetic effects. At all therapeutic doses, ketamine generates robust gamma oscillations between 30-80 Hz that are typical of active, structured cognition; yet, under ketamine, gamma oscillations persist into profound sedation and anesthetic unconsciousness. Here, I use experimental and computational approaches to characterize ketamine gamma oscillations, examine their mechanistic origins, and offer a potential explanation for their paradoxical ability to support unconsciousness. First, I analyze local field potentials and single unit activity from ketamine anesthesia in non-human primates to show that the neocortex under ketamine is hyperactive based on all common measures of neural activity. Furthermore, I demonstrate that spiking UP-states that underlie gamma bursts wax and wane in a synchronous fashion across the majority of the neocortex, entraining local field potentials in the intralaminar thalamus, a major subcortical regulator of arousal. While cortical gamma activity becomes hyper-coherent at the local level, globally synchronous beta oscillations from the awake state vanish entirely under ketamine. These phenomena may indicate an impaired local and long-range cortico-cortical communication, respectively, providing one explanation for loss of consciousness despite hyperexcitation. To examine the effect of ketamine on cortical circuits, I built a computational network model of pyramidal cells and fast-spiking interneurons connected via synapses that include an experimentally verified scheme of NMDA receptor kinetics. I show that increased trapping, a known molecular feature of ketamine binding to the NMDA receptor, inhibits both pyramidal cells and interneurons by proportionally decreasing the magnitude of their NMDAR currents during the receptor’s brief opening. Due to higher NMDAR conductance on the interneurons, this antagonism produces net disinhibition of pyramidal cells and initiates a gamma rhythm. Adding a homeostatic spike-rate adaptation variable to such a hyperactive network can produce fragmented spiking activity that resembles UP-DOWN states of ketamine anesthesia. Together, my findings (1) demonstrate that anesthesia is possible even with high and simultaneous spiking activity across most of the neocortex, and (2) provide the first model that accounts for both ketamine gamma oscillations at subanesthetic doses and their discontinuity during unconsciousness. / 2021-10-07T00:00:00Z