Unpredictability is one of the major drivers of associative learning. While unpredictability in the timing of events can enhance fear memory strength, the neural substrates that are involved in generating and processing these errors remain largely unknown. We first showed that unpredictability, generated by the varied timing of the aversive event following the predictive cue, greatly enhanced fear memory strength (Chapter 3). The unpredictability-processing neural network in basal and lateral amygdala (BLA) was then studied using time-lapse microendoscopy to monitor neuronal calcium response across fear conditioning and recall (Chapter 4). We identified four distinct functional classes of neurons based on the neuronal activity patterns during fear conditioning and long-term recall. “Memory Winner” neurons outcompeted the “Memory Loser” neurons to encode the fear memories; nonetheless, both classes of neurons exhibited learning-related plasticity during the fear conditioning. In contrast, Fear Expression neurons did not display learning-related plasticity during fear conditioning but did respond to the tone presentation during auditory fear recall. The introduction of temporal unpredictability during the fear conditioning increased the percentage of both the Memory Winner neurons and Fear Expression neurons, and decreased the percentage of Memory Loser neurons. Furthermore (Chapter 5), pharmacological inhibition of dorsal hippocampus and optogenetic silencing of CA1 revealed the essential involvement of dorsal hippocampus in the processing of negative prediction errors, which is generated by unpredictability in their timing. Collectively, our data suggest that the processing of temporal unpredictability of aversive events requires the dorsal hippocampal activation to process the negative prediction errors; and the rearrangement of the BLA neural representation of fear learning and memory. Taken together, these processes underlie the mechanism of the unpredictability-enhanced fear memory strength.

Understanding how molecular and cellular events integrate into a physiological behavior is a major question in neuroscience. Breathing can be easily studied using rhythmically active in vitro models that provide experimental access to perform cellular- and synapse-level experiments. While it is widely accepted that breathing depends on a specific region of the brainstem dubbed the preBotzinger complex (preBotC), the mechanisms responsible for rhythm generation remain unclear. In Chapter 1, we examine the pacemaker hypothesis, which posits that pacemaker properties and/or the persistent sodium current (/NaP) are obligatory for rhythm generation. We found that neither pacemaker properties nor /NaP are essential for respiratory rhythm generation in preBotC neurons. Next, we began testing the validity of the group pacemaker hypothesis, which posits that the respiratory rhythm is an emergent network property that depends on recurrent excitation coupled to intrinsic membrane properties in all preBotC neurons. During the inspiration in vitro, all preBotC neurons exhibit 300-500 ms bursts of electrical activity characterized by action potentials superimposed on a 10-30 mV envelope of depolarization, dubbed the inspiratory drive potential. Chapters 2 and 3 examine how synaptic and intrinsic membrane properties integrate to form inspiratory drive potentials. In Chapter 2, we found that the calcium-activated non-specific cationic current (/CAN) is responsible for ∼70% of the inspiratory drive potential. /CAN activation depends on Ca2+ influx from inositol 1,4,5-trisphosphate (IP3Rs)-mediated intracellular Ca2+ release coupled to group I metabotropic glutamate receptors (mGluRs), voltage-gated Ca2+ channels (VGCCs) and possibly to a smaller extent NMDA receptors. Chapter 3 examines how AMPARs trigger inspiratory burst potential generation. We found that AMPAR-mediated depolarizations open VGCCs, which activate /CAN directly. Moreover, Ca2+ influx from VGCC was required to trigger IP3R-mediated intracellular Ca2+ release. In Chapter 4, we interpret respiratory frequency modulation within the context of the group pacemaker hypothesis. We show that blocking low-frequency AMPAR-mediated excitatory postsynaptic potentials (EPSPs) causes rhythm cessation, which suggests that low-frequency EPSPs are important for kindling the initial phase of recurrent excitation. Through a meta-analysis of previously published work, we argue that frequency modulation depends on the temporal summation of EPSPs and is largely independent of changes in interburst spiking. In conclusion, our findings suggest that respiratory rhythm generation and frequency modulation depends on the coupling of synaptic and intrinsic membrane properties, which is most consistent with the group pacemaker hypothesis.

Many nutritionally beneficial plants contain bitter compounds that may cause people to exclude them from their diets. The perception of these compounds has been hypothesized to be modulated by the interaction of salivary proteins, but the effect of these proteins on the response of the taste nerves has yet to be studied. Our study is the first to demonstrate an effect of salivary proteins in diminishing the response of the chorda tympani nerve to quinine. In a follow-up experiment, we demonstrate that these salivary proteins are able to precipitate quinine out of solution, which may interfere with its ability to stimulate the taste receptors. These data suggest a role of salivary proteins in modulating bitter taste perception. / A Thesis submitted to the Department of Psychology in partial fulfillment of the requirements for the degree of Master of Science. / Summer Semester 2015. / May 21, 2015. / bitter, electrophysiology, quinine, saliva, tannin, taste / Includes bibliographical references. / Robert Contreras, Professor Co-Directing Thesis; Zuoxin Wang, Professor Co-Directing Thesis; Ann-Marie Torregrossa, Committee Member; Colleen Kelley, Committee Member.

Liraglutide, a Glucagon-Like Peptide 1 (GLP-1) receptor agonist, is used as a treatment for Type 2 Diabetes Mellitus (T2DM) and obesity because it improves glycemia and decreases food intake. Here, we tested whether chronic activation of the GLP-1 receptor system with liraglutide would induce decreases in intake accompanied by changes in proportional food or macronutrient intake similar to those seen following RYGB in rats when a variety of palatable food options are available. A "cafeteria diet" was used that included: chow, refried beans (low-fat/low-sugar), low-fat yogurt (low-fat/high-sugar), peanut butter (high-fat/low-sugar) and sugar-fat whip (high-fat/high-sugar). Liraglutide (1 mg/kg daily, sc, n=6) induced significant reductions in body weight and total caloric intake compared to saline–injected control rats (n=6). Although access to a cafeteria diet induced increases in caloric intake in both groups relative to chow alone, liraglutide still effectively decreased intake compared with saline-injected rats suggesting that chronic GLP-1 activation competes with the energy density and palatability of available food options in modulating ingestive behavior. Even with the substantial effects on overall intake, liraglutide did not change food choice or relative macronutrient intake when compared to pre-treatment baseline. When drug treatment was discontinued, the liraglutide group increased caloric intake and rapidly gained body weight to match that of the saline group. These results demonstrate that, while liraglutide effectively decreases caloric intake and body weight in rats, it does not cause adjustments in relative macronutrient consumption, suggesting that such changes seen after RYGB are unlikely due to activation of the GLP-1 receptor system alone. / A Thesis submitted to the Department of Psychology in partial fulfillment of the requirements for the degree of Master of Science. / Fall Semester 2016. / November 22, 2016. / Food Choice, GLP-1, Roux-en-Y Gastric Bypass, Taste Preference, Weight Loss / Includes bibliographical references. / Alan C. Spector, Professor Directing Thesis; Pamela Keel, Committee Member; Diana Williams, Committee Member.

As one of the leading causes of disease burden and disability in the world, Major Depressive Disorder (MDD) is a persistent and ever expanding financial and public health concern. MDD is quite prevalent in children and adolescents with life-long negative consequences. Although there are treatments available for MDD, they lack in effectiveness, and have a potential for enduing negative side effects. These conventional treatments are even less effective in pediatric MDD as more than 50% of these patients are deemed treatment-resistant. Ketamine (KET), a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, has recently shown great promise as a rapid-acting and long-lasting treatment for MDD, especially for treatment-resistant MDD. Unfortunately, the efficacy, functionality, and biochemical consequences of KET exposure during periods prior to adulthood are not known. Therefore, the following sets of experiments were designed to examine the antidepressant efficacy of KET during adolescence as well as the potential neurobiological mechanisms involved. To do this, behavioral reactivity to stress- and anxiety-eliciting situations and responsiveness to KET treatment were characterized in adolescent male rats and mice in chapters two and three. Data presented in these chapters demonstrated that KET is an effective antidepressant in adolescent rodents; however, the neurobiological underpinning(s) mediating these effects required examination. Recent evidence has shown that KET reverses the deficits associated with stress within major mesocorticolimbic regions such as the prefrontal cortex (PFC), Nucleus Accumbens (NAc), and hippocampus. However little is known about KET’s effect in the ventral tegmental area (VTA), which provides the majority of dopaminergic input to these regions. Therefore, the experiments conducted in chapter four were designed to examine the neurobiological underpinnings of KET’s antidepressant effects in adolescent male mice. More specifically, the biochemical and electrophysiological effects produced by KET treatment during adolescence were characterized within the VTA and its major projection regions, the NAc and PFC, respectively. Combined, the findings within this dissertation indicate that KET treatment produces antidepressant-like effects in adolescence, and that these effects are mediated, at least in part, by changes in intracellular signaling and neuronal activity within VTA dopamine neurons and its connection to the NAc. Lastly, in chapter five, the potential clinical implications as well as future directions of this work are discussed. / A Dissertation submitted to the Department of Psychology in partial fulfillment of the requirements for the degree of Doctor of Philosophy. / Summer Semester 2016. / July 7, 2016. / Adolescent, Akt, Ketamine, NAc, VTA / Includes bibliographical references. / Carlos A. Bolaños-Guzmán, Professor Directing Dissertation; Branko Stefanovic, University Representative; Frank Johnson, Committee Member; Sanjay Kumar, Committee Member; Walter Boot, Committee Member.

Chemical signals are important for social communication in many rodent species. Detection and processing of these chemosignals is necessary for the production of reproductive and defensive behaviors that are important for species survival. The medial amygdala is the first site of convergence for input regarding these chemosignals, thus it is vital to investigate its role in chemosignal processing. Previous studies using immediate early gene (IEG) expression indicative of neuronal activation have demonstrated a categorical response in the medial amygdala subareas to different types of chemosignals. Both the anterior and posterior medial amygdala (MeA and MeP, respectively) show higher activation after exposure to conspecific odors, while only MeA has a higher response to heterospecific odors. These experiments also suggest that the primarily GABAergic, main intercalated nucleus (m-ICNc) may be involved in modulating the MeP response since there is a negative correlation in the IEG responses between these two areas after exposure to heterospecific odors. These data suggest that the medial amygdala and possibly the m-ICNc are involved in the processing of chemosignals, however little is known about the functional circuitry underlying chemosignal processing within and between these two areas. Using whole-cell patch clamp electrophysiology and immunohistochemical staining, the experiments included in this dissertation investigated the functional circuitry between the medial amygdala areas; the connections between the medial amygdala and m-ICNc; how this circuit may be modulated by input from other brain areas; and the potential involvement of phenotypically distinct subpopulations during chemosignal processing. Consistent with previous tract-tracing studies, I demonstrated functional excitatory and inhibitory connections between the anterior-dorsal (MeAd) and posterior dorsal (MePd) regions of the medial amygdala in electrophysiology experiments. These diverse connections may provide a means by which MeAd can directly affect MePd activity during chemosignal processing consistent with previously published IEG responses. Further electrophysiology experiments provide evidence for an indirect pathway allowing for even further modulation of MePd by MeAd. In these experiments, I found excitatory projections from MeAd to m-ICNc that were strong enough to drive action potential firing in my thin tissue slices. Projections from m-ICNc to MePd were also documented and stimulation of m-ICNc often resulted in hyperpolarization of MePd neurons. The m-ICNc-evoked hyperpolarization of MePd persisted during glutamate receptor blockade suggesting that there are direct inhibitory connections from m-ICNc to MePd. These data suggest that MeAd may also modulate MePd indirectly providing an even greater diversity of medial amygdala output in order to produce appropriate behavioral responses to various chemosignals. The neurotransmitter dopamine may also be involved in chemosignal processing. Dopamine decreased the excitability of m-ICNc neurons and decreased the m-ICNc-evoked hyperpolarization of MePd neurons, suggesting that this indirect pathway may also be modulated by other brain areas. I also found evidence of projections from infralimbic cortex and the localization of mu-opioid receptors to the m-ICNc. These two inputs may provide even further modulation of the circuitry and greater diversity in medial amygdala output depending on the brain state of the animal during chemosignal processing. Lastly, I investigated the potential role of phenotypically distinct subpopulations of presumably GABAergic medial amygdala neurons characterized by expression of calcium binding proteins in chemosignal processing. I found differential expression patterns of parvalbumin, calbindin and calretinin neurons throughout the medial amygdala areas. Parvalbumin was not expressed in the medial amygdala but was found in other amygdalar areas surrounding the medial amygala. Calbindin and calretinin neurons were found throughout the medial amygdala with different densities across subdivisions. Overall, very few calretinin or calbindin neurons were activated (as indicated by IEG expression) after exposure to the female conspecific odors. However, the overall pattern of activation of calbindin and calretinin-immunoreactive neurons was similar to the overall IEG expression, suggesting that these neuronal subpopulations may be involved in the inhibitory feedback networks within the medial amygdala. / A Dissertation submitted to the Department of Biological Science in partial fulfillment of the Doctor of Philosophy. / Spring Semester 2017. / January 30, 2017. / accessory olfactory system, chemosensory processing, electrophysiology, hamster, intercalated nucleus, medial amygdala / Includes bibliographical references. / Michael Meredith, Professor Directing Dissertation; Colleen Kelley, University Representative; Emily DuVal, Committee Member; Elaine Hull, Committee Member; Paul Trombley, Committee Member.

Genetic animal models have become an increasingly useful tool in addressing pathophysiological changes in neuropsychiatric disorders at the molecular, synaptic and circuitry levels. Previous genetic and postmortem studies have identified several 14-3-3 isoforms as potential candidate risk genes for schizophrenia. 14-3-3 proteins are a family of homologous proteins involved in many biological processes including signaling, neurite outgrowth and ion channel regulation. In order to investigate the potential associate between 14-3-3 dysregulation and schizophrenia, our lab has created a novel mouse model that addresses the collective function of all 14-3-3 isoforms in the brain. These transgenic mice express a 14-3-3 peptide inhibitor (YFP-difopein) that antagonizes 14-3-3 binding to its endogenous partners and is thus considered a 14-3-3 functional knockout (FKO). We have shown that these 14-3-3 FKO mice exhibit a variety of behavioral and morphological deficits reminiscent of the core endophenotypes of established schizophrenia animal models. This dissertation aims to dissect the molecular pathways and region-specific circuit connections that may be responsible for induction of particular schizophrenic endophenotypes. In Chapter 2, we found that when 14-3-3 proteins are inhibited in the 14-3-3 FKO mice this causes dysregulation of NMDA receptors and actin-signaling at the synapse, possibly leading to deficits in synaptic activity and spine formation. In Chapter 3, we created adeno-associated viruses (AAVs) to determine the brain regions responsible for the circuit control of particular schizophrenic-associated behaviors. We determined that disruption of 14-3-3 function within the dorsal hippocampus alone or the hippocampus and prefrontal cortex together is sufficient to induce schizophrenia-associated behavioral endophenotypes. This effect is most likely due to disturbance in circuit connections within the prefrontal cortex and hippocampus, as restoring 14-3-3 function in both brain regions was necessary in order to attenuate psychomotor disturbances in the 14-3-3 FKO mice. Together, the work presented in this dissertation sheds some light on the role that 14-3-3 plays in the development of psychiatric disorders and provides a framework for future research of schizophrenic models. / A Dissertation submitted to the Department of Biomedical Sciences in partial fulfillment of the requirements for the degree of Doctor of Philosophy. / Spring Semester 2017. / April 3, 2017. / Includes bibliographical references. / Yi Zhou, Professor Directing Dissertation; P. Bryant Chase, University Representative; Mohamed Kabbaj, Committee Member; Yanchang Wang, Committee Member; Zuoxin Wang, Committee Member.

The primary visual cortex (V1) has been classically viewed as an immutable feature detector, with robust responses to low-level characteristics of objects in the visual field. Recent studies have shown the capacity of this cortical area to perform more complex computations. Nominally, the phenomenon of sequence learning relies on the ability of V1 to encode the serial order and temporal frequency of a spatiotemporal visual sequence. Investigating the mechanisms driving this phenomenon through the lens of predictive coding will further the understanding of how V1 operates locally to encode time and learns to predict the future based on minimal sensory information. Through in vivo multi-unit recordings from awake mice, this study sought to isolate neural evidence for predictive processing within the paradigm of sequence learning. Seventy unique units were isolated from forty-two mice subjected to experimentation. Preliminary analyses revealed a significant effect that agrees with the initial report on sequence learning but contradicts predictive processing theory. Further investigation is required to draw more robust conclusions about the predictive computations that occur during sequence learning. Increased sample size and refinement of data analysis will likely lead to interesting results

The thalamus is a subcortical structure that has been popularly coined as the “relay center” of the brain due to its central role in both first-order and executive function. Like a gate, the thalamus can redirect, initiate, sustain, and switch cortical activity. This is accomplished by the topographically organized pathways the thalamus and cortex reciprocally share. These pathways are categorized into two types of circuits; core and matrix. Core pertains to parvalbumin-positive thalamocortical projecting neurons, usually carrying sensory information. On the other hand, matrix pertains to the calbindin-positive network of widespread thalamocortical projecting neurons, typically related to association processes. The integration of both circuits allows for complex and dynamic interactions, including regulation of consciousness, alertness, perception, emotion, and action. The matrix-core theory was first proposed by Edward Jones (1998) and neuroscientists have since developed hypotheses as to how the distinct neurochemical/molecular systems may be linked to cognition. In this paper we discuss the proportions of parvalbumin- and calbindin-positive core and matrix pathways seen traveling through and innervating different regions of the thalamic reticular nucleus (TRN), an inhibitory nucleus directly superficial to the thalamus, that filters thalamocortical communications. Attention modulation, memory consolidation, and consciousness are a few cognitive functions regulated by the reticular nucleus, however, little is known about the extent in which it aids in these executive processes, the molecular mechanisms underlying them, or how its architecture may differentially affect sensory and association pathways. Even though it was thought that the TRN is organized homogeneously, recent findings suggest regional molecular specializations. Based on this, and the organization of the thalamus in distinct core and matrix circuits, we hypothesize that core and matrix thalamocortical projections will target the TRN in a topographical manner at different ratios, defining functionally, connectionally, and molecularly distinct and heterogeneous TRN sectors. For both primates and non-human primates, we predict there to be clear similarities in the reciprocal innervating patterns of the TRN as well as specific immunoreactive protein concentrations that rapidly or gradually change along its dorsal-ventral extent. / 2024-05-20T00:00:00Z

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