<p> Infusion of 17&beta;-estradiol into the arcuate nucleus of the hypothalamus (ARH) 47.5 hours after estrogen benzoate (EB) priming rapidly facilitates sexual receptivity (lordosis) via G protein-coupled estrogen receptor 1 (GPER) that deactivates &micro;-opioid receptors (MOP) in the medial pre-optic nucleus of the hypothalamus (MPN). Initial estradiol inhibits lordosis via activating an ARH neurocircuit that activates MPN MOP, and simultaneously upregulates orphanin FQ/ nociception (OFQ/N), its cognate receptor (ORL-1), and progesterone receptor (PR) in the ARH. Subsequent ORL-1 activation 48 hours post-EB deactivates MPN MOP to facilitate lordosis. Thus, I hypothesized that GPER directly regulates OFQ/N neurons and tested whether EB increased coexpression of GPER and OFQ/N in ARH neurons. EB significantly increased the number of GPER OFQ/N expressing neurons. Antiestrogens, tamoxifen (TAM) and ICI 182,780 (ICI), are treatments for some estrogen responsive tumors, but sometimes exacerbate tumor proliferation via GPER. I hypothesized that TAM and ICI activate ARH GPER and facilitate lordosis via deactivation of MPN MOP. In EB-primed rats, ARH infusion of either TAM or ICI facilitated lordosis and deactivated MPN MOP. GPER antagonist, G15, blocked these results. Thus, TAM and ICI rapidly activate ARH GPER neurons that express OFQ/N to facilitate sexual receptivity.</p>

No description available.

It is well established that estrogens suppress feeding primarily by reducing meal size, and that this is partly mediated by enhancement of the response to satiation signals. Glucagon-like peptide 1 (GLP-1) acts on receptor populations both peripherally and centrally to affect food intake. Most research on the feeding effects of GLP-1 has used exclusively male subjects, and little is known about the effects of GLP-1 in females. We hypothesized that modulation of the central GLP-1 system is one of the mechanisms underlying the effects of estrogens on ingestive behavior. More specifically, we hypothesized that estradiol, a common estrogen, enhances the anorexic response to central GLP-1. To investigate this possibility, bilaterally ovariectomized female rats were placed on a cyclic regimen of either 2 μg β-estradiol-3-benzoate or oil vehicle and implanted with unilateral cannulas targeting the lateral ventricle. We assessed the food intake effects of 0, 1, or 10 μg doses of GLP-1 in oil- or EB-treated rats administered 30 min prior to dark onset on the day following hormone treatment. GLP-1 treatment significantly suppressed food intake in EB-treated rats at both doses compared to vehicle, whereas only the 10 μg dose was effective in oil-treated rats. We then examined whether estrogen status alters the neuronal response to GLP-1 by measuring GLP-1-induced c-Fos expression in several feeding-relevant brain areas. While GLP-1 significantly increased c-Fos expression, there were no significant differences between hormone treatment groups in the brain areas examined. These experiments suggest that modulation of the central GLP-1 system may be one of the mechanisms by which estrogens suppress food intake and support the need for further examination of this effect. / A Thesis submitted to the Department of Psychology in partial fulfillment of the requirements for the degree of Master of Science. / Fall Semester 2015. / October 29, 2015. / c-Fos, estradiol, food intake, GLP-1, glucagon-like peptide 1, pharmacology / Includes bibliographical references. / Diana L. Williams, Professor Directing Thesis; Lisa A. Eckel, Committee Member; Pamela K. Keel, Committee Member.

The taste system enables the detection and discrimination of potential nutrient sources necessary for maintaining essential life processes. Nutrients bind with taste receptors in the oral cavity that convert the food-derived signal into neural activity interpretable by the brain. The four independent, canonical taste qualities are "sweet", "salty", "sour", and "bitter" with additional proposed basic tastes, such as "umami", "polysaccharide", and "fat" taste, garnering support in the literature. A given taste quality is elicited by nutrient compounds that share chemical properties. The proposed qualities of interest here were "umami" and "polysaccharide" taste. Prior in vitro and in vivo studies suggest that the taste receptor mechanisms responsible for mediating "sweet" taste, elicited by sugars and sweeteners, and "umami" taste, elicited by L-glutamate, in mammals are heterodimers of the Taste Receptor Type 1 (T1R) proteins—T1R2+T1R3 and T1R1+T1R3, respectively. However, whether the T1R1+T1R3 heterodimer is the sole mediator of "umami" taste is not without controversy; other mechanisms have been proposed. Further disputes relate to the classification of "umami" as an independent taste quality. Whereas a portion of the literature implicates "umami" as a unique taste sensation, evidence suggests it represents a mere combination of "salty" and "sweet" taste. The experiments here (Chapters 2-6) combined psychophysical methodology with genetic knockout models to address the following: 1) Are the individual T1R proteins—T1R1, T1R2, and T1R3—necessary for maintaining sensitivity to "umami" stimuli? 2) Given the proposed commonalities between "umami" and "sweet" taste, is the T1R2+T1R3 involved in transducing the L-glutamate signal? 3) How is sensitivity to other non-"umami"-tasting amino acid stimuli affected upon deletion of one or more T1R proteins? The taste detection of the prototypical "umami" stimulus, monosodium glutamate (MSG), in wild-type (WT) controls, and T1R1, T1R2, T1R3, and T1R2+T1R3 knockout (KO) mice was severely impaired if not eliminated when the taste signal from the sodium component was minimized by the epithelial sodium channel (ENaC) blocker amiloride. Only when inosine monophosphate (IMP), a known potentiator of the L-glutamate taste signal, was prepared with the MSG and amiloride mixture were WT and T1R2 KO mice able to detect the compound stimulus due, in part, to the taste of IMP. In contrast, mice lacking T1R1 or T1R3 were incapable of detecting IMP alone, but showed sensitivity to at least the higher concentrations of MSG (+amiloride) when IMP was present. Similarly, T1R2+T1R3 KO mice showed significant sensitivity loss to the purportedly "sweet-like" achiral amino acid glycine. However, the sensitivity of T1R1 KO mice to L-lysine was unimpaired. Collectively, these data demonstrate the necessity, but not exclusivity, of the T1R subunits in the taste transduction of some amino acids such as MSG (in the presence of IMP) and glycine. The partial competence observed in some of the mice lacking the T1R1 or T1R3 subunit suggests the presence and activity of another receptor independent of the T1R1+T1R3 heterodimer—perhaps a novel protein or T1R homodimer. Furthermore, unimpaired sensitivity to L-lysine in the T1R1 KO mice suggests that some L-amino acids can be detected through T1R1+T1R3-independent mechanisms without sensitivity loss. Polysaccharides, specifically maltodextrins, such as Maltrin and Polycose, are composed of glucose polymer mixtures of varying glucose chain lengths. Although glucose and other sugars activate the T1R2+T1R3 heterodimer, maltodextrins are suggested to potentially bind with a different receptor leading to the generation of a qualitative taste perception distinguishable from that of sweeteners. Recent evidence supporting this hypothesis derives from T1R2 or T1R3 KO mice. While these KO mice display relatively normal responses to maltodextrins the slight impairments in behavioral responsivity raise the possibility that T1R homodimers might contribute to polysaccharide taste transduction. Therefore, experiments incorporating psychophysical methodology and mice lacking both T1R subunits of the sweet taste receptor (Chapter 6) were conducted to address the following questions: 1) Is the T1R2+T1R3 heterodimer necessary for maltodextrin taste detection? 2) Do maltodextrins and sweeteners possess discriminable taste characteristics? Most T1R2+T1R3 KO mice displayed similar sensitivity to Polycose as WT mice. However, some were only sensitive to the higher Polycose concentrations, implicating potential allelic variation in the polysaccharide taste receptor. Concentrated polysaccharide and sweetener solutions are characteristically viscous, at least at the higher concentrations, and this oral somatosensory stimulus feature may serve as a cue in this taste detection task. Therefore, viscosity-matched Maltrin and sucrose concentrations were presented to KO and WT mice in a 2-tastant operant discrimination procedure. Both WT and KO mice competently discriminated Maltrin from sucrose. However, performance in WT mice was likely driven by the different taste percepts of the two stimuli, while KO mice likely relied on the taste cue from Maltrin as opposed to sucrose. To my knowledge, these results represent the first demonstration that maltodextrin is qualitatively distinguishable from sucrose in an explicit taste discrimination task, and, coupled with the detection data, implicate that distinct dedicated taste pathways from the periphery to central circuits are mediating polysaccharide and sugar taste. / A Dissertation submitted to the Department of Psychology in partial fulfillment of the Doctor of Philosophy. / Fall Semester 2015. / September 11, 2015. / knock-out, psychophysics, taste / Includes bibliographical references. / Alan C. Spector, Professor Directing Dissertation; Jasminka Ilich-Ernst, University Representative; Robert Contreras, Committee Member; Michael Meredith, Committee Member; Jeanette Taylor, Committee Member.

Epigenetic regulation of gene expression involves a steady-state balance of acetylation carried about by histone acetyltransferases (HATs) and histone deacetylases (HDACs). HATs act as transcriptional co-activators and HDACs interact with large multi-protein complexes to promote transcriptional repression. HDACs have only recently been characterized in mammalian cells, and most work has focused on the function of HDACs in vitro using biochemical analysis, inhibitors, and cultured cell types. HDAC4, a class II HDAC, displays the ability to shuttle between the cytoplasm and the nucleus where it can regulate transcriptional programs. HDAC4 plays a key role in calcium-dependent transcriptional regulation of many non-neuronal cell processes including cardiac hypertrophy and bone formation. HDAC4 mRNA is also highly expressed in brain; however protein expression and its underlying biological role in brain is still unclear. HDAC4 localization in cultured neurons is dependent on neural activity and calcium-dependent signaling pathways. Mechanisms governing long-term changes in synaptic plasticity and learning and memory take place on dendritic spines, a site affected by many cognitive disorders. Dendritic spines act to compartmentalize calcium signaling and second messenger cascades leading to activation of enzymes and proteins associated with transcriptional regulation. Inhibition of HDACs has become a prevalent tool in exploring the role of HDACs in brain and has proven useful in many models of psychiatric and neurodegenerative disorders with more recent implication in the recovery or enhancement of synaptic plasticity and learning and memory. HDAC inhibition, however, is non-specific, and the localization of specific HDACs in brain and their role in these neuronal functions needs to be addressed. The similarity between HDAC4 regulation in non-neuronal cells and the processes initiated within a dendritic spine led to the hypothesis that HDAC4 may be present at the dendritic spine, where it can relay alterations of synaptic activity to the nucleus in order to regulate transcriptional programs affecting synaptic plasticity or other cell function. For this dissertation, I report findings which establish the regional and novel subcellular localization pattern of HDAC4 expression in brain, identify a mechanism specific to synaptic activity at the dendritic spine which results in HDAC4 trafficking, and attempt to establish a direct interaction of HDAC4 to a key member of the scaffolding network within a dendritic spine. In additional studies, I report the effects of HDAC inhibition on learning and memory and lesion size using a model of traumatic brain injury (TBI) as well as the effects of amyloid plaque level on the localization pattern of HDAC4 in the hippocampus. These studies failed to illicit a significant change in the conditions tested and are not discussed in the main text, however, useful information regarding the role of HDAC inhibition and HDAC4 was obtained. In brief, I report the localization of HDAC4 across brain regions germane to many pathological conditions such as Huntington's, Parkinson's, and Alzheimer's disease. HDAC4 was found to be present in dendritic spines, enriched at the level of the post-synaptic density (PSD), and partially colocalized with post-synaptic density protein 95 (PSD-95), a key scaffolding protein for the formation and maintenance of dendritic spines. Furthermore, using hippocampal slice cultures to more closely represent in vivo synaptic connections, exogenous overexpression of HDAC4 localized to the cytoplasm and in dendritic spines. Dendritic spines, synaptic activity, and the ability to form memories are tightly regulated through the activation of N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. Blockade of both NMDA and AMPA receptors together was necessary to induce the nuclear localization of HDAC4 in these cultures, a shift that was reversed upon removal of the antagonists or reduced by HDAC inhibition. Finally, HDAC4 was expressed along with PSD-95 in vitro as well as extracted from hippocampal tissue to explore whether HDAC4 was a direct member of the PSD-95 scaffolding network in vivo. HDAC4 failed to show a complex with PSD-95, however, indirect interactions may still exist which anchor HDAC4 to the PSD. Together, these results suggest HDAC4 can act as a synaptic monitor, translocating to the nucleus during synaptic blockade where it can alter transcriptional programs and gene expression. Isolating the biological role for individual HDAC isoforms remains a critical step in understanding the mechanisms behind therapeutic candidates such as HDAC inhibitors, which have been used clinically in non-neuronal disruption of cancerous cells, and show much promise in the alleviation of many symptoms resulting from various psychiatric and neurodegenerative disorders. / A Dissertation submitted to the Department of Biological Science in partial fulfillment of the requirements for the degree of Doctor of Philosophy. / Degree Awarded: Spring Semester, 2010. / Date of Defense: December 2, 2009. / Morris Water Maze, Traumatic Brain Injury, Alzheimer's, Postsynaptic Density, Brain, Hippocampus, HDAC, Dendritic Spines / Includes bibliographical references. / Charles C. Ouimet, Professor Directing Dissertation; Colleen Kelley, University Representative; Mohamed Kabbaj, Committee Member; Carlos Bolaños, Committee Member; Laura Keller, Committee Member.

Att kunna uppskatta antal är en grundläggande förmåga som återfinns hos många djur förutom männinskan. Trippelkodmodellen (TKM) för numerisk kognition säger att antal representeras på tre olika sätt, som (arabiska) siffror, som sifferord och som ickesymboliska magnituder, vilka associeras till separata, men delvis överlappande, neurala substrat. Denna studie undersökte för första gången alla tre koder samtidigt på barn. 10 barn mellan 10-12 år genomgick fMRT-skanning för att söka neurala korrelat till antalsuppfattning. Oberoende uppgift &gt; kontroll-kontraster bekräftade delvis TKM, såsom funktionellt olika neurala substrat, ett fronto-parietalt nätverk och att barn nyttjar det ventrala uppmärksamhetsnätet mer än vuxna på grund av mindre automatisering. Därtill fanns aktiveringar i visuella områden V2 och V3 liksom i primära somatosensoriska området vilket överensstämmer med föreslagna kompletteringar av TKM. Parametriska kontraster kunde i viss mån bekräfta distanseffekten som innebär större kognitiv belastning vid särskiljning av närliggande antal jämfört med att skilja på tydligt olika antal. / Being able to approximate numbers is a basic skill present in many animals, including man. The Triple Code Model (TCM) of numerical cognition suggests that numerosity is represented in three different codes, each subserved by functionally dissociated, but partly overlapping, neural substrates. The codes are (arabic) numbers, number words, and non-symbolic magnitude. This study examined all three codes in children for the first time. 10 healthy children, 10-12 years old, had an fMRI in order to detect neural correlates to numerosity processing. Independent task-control contrasts partly confirmed the TCM as functionally dissociated neural substrates, with a fronto-parietal network and the fact that children, having automatized functions less, more heavily depends on the ventral attention network. Furthermore, activations in the visual areas V2 and V3 as well as in primary somatosensory cortex is in accordance with recent suggestions of updates to the TCM. Parametric contrasts did, to some extent, confirm the distance effect, where it is more difficult to discriminate closely spaced numbers than numbers of more different magnitude.

BACKGROUND: Abnormalities in glutamate transmission have been implicated in schizophrenia (SZ). A genome-wide association study (GWAS) associated single nucleotide polymorphisms (SNPs) in glutamate-related genes with the disorder. To elucidate a pathologic role of these variants, this study aims to examine the effects of these SNPs on hippocampal volume. METHOD: Six SNPs from five glutamate-related genes identified by the Psychiatric Genetics Consortium were selected in 279 controls and 284 probands recruited from the B-SNIP study. Hippocampal subfield volumes were extracted from T1 weighted images via the MAGeT pipeline. A mixed model analysis was conducted using SPSS to evaluate a diagnosis by SNP effect on volumes, with site as a random factor, age, sex, and principal component analysis values as fixed factors. P values were adjusted for multiple corrections. RESULTS: rs10520163 (CLCN3), rs2973155 (GRIA1), and rs9922678 (GRIN2A) displayed a significant main effect (p< .01) on bilateral total hippocampal volume. Post hoc comparison revealed individuals homozygous for the risk allele (HZ-Risk) had significantly smaller volumes than those who were homozygous for the non-risk allele (HZ-NoRisk) (p<.01). For the same SNPs, a significant diagnosis-by-genotype interaction (p<.01) was found for bilateral total hippocampal volume. Significant main effects (p<.01) for the same SNPs were found in subfield volumes bilaterally for the CA1, subiculum, and stratum, with HZ-Risk having smaller volumes. CONCLUSION: Our findings suggest CLCN3, GRIA1, and GRIN2A appear to be associated with reductions in bilateral hippocampal total volume and subfield regions, indicating a potential mechanism by which these genes may confer risk for the disorder. / 2019-07-03T00:00:00Z

<p>Organisms scan their sensors around their environment to build an internal representation of that environment in a process known as active sensation. The integration of information across time and space is critical to providing context as to what is the organism is perceiving. However, the neural circuits that encode and underlie the integration of incoming sensory information have predominantly been studied in the context of passive sensation. Studying these circuits in the context of active sensation is imperative to generating a better understanding of how the brain naturally encodes sensation. This would have profound impacts on understanding the mechanisms of a number of neural disorders, including autism and attention-deficit/hyperactivity disorder, as well as how to improve the acuity of artificial sensation implanted into disabled individuals. To better understand how the mammalian brain encodes and integrates information during active sensation, my collaborators and I developed several novel paradigms to study surround integration in the mouse barrel cortex during active whisking. In Chapter 1 I establish why this is an important problem, and briefly summarize what is already known about sensory coding in the mouse whisker system. In Chapter 2 my collaborators and I probe how mice represent the location of an object within its whisking field, and how the integration of information across surround whiskers affects this representation. In doing so we discover a novel thalamocortical transformation where surround integration in the cortex suppresses activity in layer 4 of the cortex, ultimately generating a smooth map of scanned space in cortical layer 2/3. In Chapter 3 I utilize a novel tactile display to better understand the logic of multi-whisker integration in two cortical layers. In this unpublished work, I show that contrary to the previous literature in anesthetized mice, cortical neurons in awake, whisking mice powerfully summate specific whisker combinations supralinearly, generating a sparse code representing the entire combinatoric space of whisker touch. In Chapter 4, I conclude with some closing thoughts and propose some future lines of inquiry to further this research.

<p> Damage to respiratory neural circuitry and consequent loss of diaphragm function is a major cause of morbidity and mortality following cervical spinal cord injury (SCI). Upon SCI, inspiratory signals originating in the rostral ventral respiratory group (rVRG) of the medulla become disrupted from their phrenic motor neuron (PhMN) targets, resulting in diaphragm paralysis. Using the rat model of C2 hemisection SCI, we investigated two mechanisms of axonal plasticity to drive respiratory revovery: promoting regeneration of injured rVRG axons and enhancing contralateral rVRG sprouting. We aimed to stimulate rVRG axon regeneration via induction of the mammalian target of rapamycin (mTOR) pathway, a signaling system that regulates neuronal-intrinsic axon growth potential. Specifically, we targeted two key components of this pathway via: viral vector-mediated expression of a constitutively-active form of ras homolog enriched in brain (Rheb); and systemic treatment with a small-molecule peptide inhibitor of phosphatase and tensin homolog (PTEN). Expression of cRheb selectively in rVRG neurons promoted significant regeneration of ipsilateral rVRG axons. PTEN peptide administration enabled injured rVRG axons to regrow through the lesion and back to the PhMN pool within C3-C5 spinal cord (i.e. several segments from the injury). This robust rVRG axon regrowth coincided with significant restoration of diaphragm activity, as assessed by <i> in vivo</i> electromyography (EMG) recordings. Furthermore, surgical &ldquo;re-lesion&rdquo; through the lesion ablated the functional improvement induced by PTEN inhibition. We also labeled contralateral rVRG axons in a separate cohort; we observed no increases in contralateral rVRG axon input to the PhMN pool ipsilateral to the hemisection, suggesting that increased drive from spared contralateral rVRG is likely not responsible for recovery. To address contralateral sprouting driving diaphragm recovery, we administered a PTP&sigma; inhibitory peptide following C2 hemisection. We found no increase in ipsilateral regeneration following treatment; however, we found robust contralateral rVRG sprouting at all three regions of the spinal cord, C3, C4, and C5. Enhanced sprouting also coincided with diaphragm recovery, which was not ablated upon relesion suggesting that the diaphragm recovery was through contralateral axonal plasticity. Collectively these exciting results demonstrate that targeting both ipsilateral regeneration and contralateral sprouting promotes rVRG-PhMN circuit re-connectivity and recovery of diaphragm function following cervical SCI.</p><p>

<p> Progress in systems neuroscience requires effective tools and techniques for probing neural circuits, and for analyzing the resulting data in ways that drive theoretical insight. This thesis consists of three parts, aimed broadly toward furthering the measurement and analysis of neural circuits. In the first part, we present methods for two-photon imaging of brain regions situated in deep fissures, enabling the use of cellular resolution optical tools for probing areas such as the medial prefrontal cortex (mPFC) and medial entorhinal cortex (MEC). We demonstrate recordings of population activity in the mPFC and grid cells in the MEC in behaving mice. In the second part, we present an optical approach for measuring dopaminergic input to the mPFC with high spatiotemporal resolution, which has not been feasible using traditional methods. We demonstrate recordings of mPFC dopamine signals in behaving mice, and present preliminary evidence for fine-scale heterogeneity across individual dopaminergic axons. In the third part, we present a new unsupervised learning algorithm for inferring underlying, nonlinear structure in neuronal population activity. We use this algorithm to characterize the geometric properties of hippocampal activity and their relationship to behavior. And, we propose a conceptual model explaining how neural coding and trial-to-trial variability both arise from movement along a low dimensional, nonlinear activity manifold, driven by internal cognitive processes.</p><p>