The accessory olfactory bulb (AOB) processes pheromonal signals which in turn drive social behaviors. Here we identify a tract of aromatase-expressing (arom+) fibers in the dorsal lateral olfactory tract (dLOT) which terminate in the granule cell layer (GCL) of the AOB. We utilized a retrograde tracer in aromatase reporter animals to delineate the source of these fibers. We show that these input fibers emerge almost exclusively from a contiguous population of arom+ neurons that spans the bed nucleus of the accessory olfactory tract (BAOT) and posterioventral subnucleus of the medial amygdala (MeApv). This population of neurons expresses the estrogen receptor alpha and contains more aromatase neurons in male mice than female mice. Thus, this population of feedback neurons can detect neuroendocrine changes and modulate the output of AOB projection neurons in a way that is sexually dimorphic and could influence every downstream target of the AOB.

Biological brains are composed of neurons, interconnected by synapses to create large complex networks. Learning and memory occur, in large part, due to synaptic plasticity -- modifications in the efficacy of information transmission through these synaptic connections. Artificial neural networks model these with neural "units" which communicate through synaptic weights. Models of learning and memory propose synaptic plasticity rules that describe and predict the weight modifications. An equally important but under-evaluated question is the selection of \textit{which} synapses should be updated in response to a memory event. In this work, we attempt to separate the questions of synaptic plasticity from that of memory addressing. Chapter 1 provides an overview of the problem of memory addressing and a summary of the solutions that have been considered in computational neuroscience and artificial intelligence, as well as those that may exist in biology. Chapter 2 presents in detail a solution to memory addressing and synaptic plasticity in the context of familiarity detection, suggesting strong feedforward weights and anti-Hebbian plasticity as the respective mechanisms. Chapter 3 proposes a model of recall, with storage performed by addressing through local third factors and neo-Hebbian plasticity, and retrieval by content-based addressing. In Chapter 4, we consider the problem of concurrent memory consolidation and memorization. Both storage and retrieval are performed by content-based addressing, but the plasticity rule itself is implemented by gradient descent, modulated according to whether an item should be stored in a distributed manner or memorized verbatim. However, the classical method for computing gradients in recurrent neural networks, backpropagation through time, is generally considered unbiological. In Chapter 5 we suggest a more realistic implementation through an approximation of recurrent backpropagation. Taken together, these results propose a number of potential mechanisms for memory storage and retrieval, each of which separates the mechanism of synaptic updating -- plasticity -- from that of synapse selection -- addressing. Explicit studies of memory addressing may find applications not only in artificial intelligence but also in biology. In artificial networks, for example, selectively updating memories in large language models can help improve user privacy and security. In biological ones, understanding memory addressing can help with health outcomes and treating memory-based illnesses such as Alzheimers or PTSD.

No description available.

No description available.

<p>Measurement of human tactile spatial acuity – the ability to perceive the</p> <p>fine spatial structure of surfaces contacting our fingertips – provides a valuable</p> <p>tool for probing both the peripheral and central nervous system. However,</p> <p>measures of tactile spatial acuity have long been plagued by a prodigious amount</p> <p>of variability present between individuals in their sense of touch. Previously</p> <p>proposed sources of variability include sex, and age; here we propose a novel</p> <p>source of variability – fingertip size. Building upon anatomical research, we</p> <p>hypothesize that mechanoreceptors are more sparsely distributed in larger fingers.</p> <p>In this thesis, I provide empirical and theoretical support for the hypothesis</p> <p>that fingertip growth from childhood into adulthood sets up an apparent sex</p> <p>difference in human tactile spatial acuity during young adulthood (Chapter 2), and</p> <p>also predicts changes in acuity more strongly than does age over development</p> <p>(Chapter 3). To further understand how fingertip size could limit an individual's</p> <p>tactile spatial acuity, we develop an ideal observer model using</p> <p>neurophysiological data collected by other labs (Chapter 4).</p> <p>In summary, this research provides support for a novel source of variability</p> <p>in the sense of touch: one that parsimoniously explains an apparent sex difference,</p> <p>and helps clarify the source of changes in tactile spatial acuity occurring with age</p> <p>during childhood.</p> / Doctor of Philosophy (PhD)

<p>Allosteric modulators are a newly emerging concept in the field of drug discovery which have shown remarkable success in their ability to alter G-protein coupled receptor (GPCR) activity in a precise and subtle manner. A GPCR of particular interest for allosteric targeting is the dopamine D2 receptor. This receptor has repeatedly been implicated in the etiology of complex neurological and neuropsychiatric disorders including Parkinson’s disease and schizophrenia. Previous studies from our lab have effectively developed allosteric modulators targeting the D2 receptor based on the pharmacophore of the endogenous tripeptide L-prolyl-L-leucyl-glycinamide (PLG). PLG and its potent peptidomimetics, particularly 3(R)-[(2(S)-pyrrolidinylcarbonyl)amino]-2-oxo-1-pyrrolidineacetamide (PAOPA) (PCT/CA2011/000968), have shown robust preclinical efficacy in treating models of Parkinson’s disease, depression, tardive dyskinesia and schizophrenia. These ligands modulate agonist binding to the D2 receptor in a biphasic manner, although further information on their mechanisms of action are currently unknown. Therefore, the overarching objective of this thesis was to enhance our knowledge on the mechanisms of action of the promising D2 allosteric ligands PLG and PAOPA. Results of the studies presented here show PAOPA to cause significant upregulation of D2 regulatory proteins and downstream signaling kinases, as well as cause an increase in D2 internalization. Additionally, the PLG allosteric binding site was narrowed down to be localized between transmembrane domains 5 and 6 on the D2 receptor. The collection of work presented here enhance our understanding of the mechanisms of action of the potentially therapeutic D2 allosteric ligands PLG and PAOPA, progressing them closer to helping clinically affected populations. The findings of these studies prove globally significant as they highlight the diverse cellular pathways which could be affected by allosteric modulators, and bring to light the importance of studying these candidate ligands for eventual improvements in the treatment of human health.</p> / Doctor of Philosophy (Medical Science)

<p>Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by a polyglutamine expansion in the huntingtin protein. Recent research demonstrates that post-translational modifications of huntingtin could be an important determinant of mutant huntingtin’s toxicity in HD. In particular, phosphorylation at residues serine 13 and 16 within the first 17 amino acids of huntingtin (N17), have been shown to be critical modulators of mutant huntingtin’s toxicity and localization, and can be triggered by stress. This project aims to study how phosphorylation within N17 alters the interactome at this site and what physiological stress results in the nuclear localization of N17 and huntingtin. The initial search to identify potential interactors was conducted through an affinity chromatography assay using a wild type striatal cell line derived from knock in mouse model of HD. Fluorescent lifetime imaging microscopy (FLIM) to determine Fӧrester resonance energy transfer (FRET), co-immunoprecipitation and co-immunofluorescence assays were then used to validate real interactors of N17. Analysis from this project has validated two previously unidentified interactors of N17; SET, a small nucleo-oncoprotein, and vimentin, a type 3 intermediate filament. Both interactors have suggested two potentially novel roles for N17 within huntingtin, in cell cycle regulation and intermediate filament dynamics. Finally, smart screening techniques using stress-inducing compounds reveal that the sensitivity of N17 to stress and its subsequent nuclear localization can be attributed in part to activation of oxidative stress pathways. Data shown here can be expanded upon to elucidate how huntingtin function and response to cell stress are regulated and mediated via N17 and potentially how this mechanism is disrupted within HD.</p> / Master of Science (MSc)

Due to the blood-brain barrier, delivery of many drugs to the brain has required intracranial surgery which is prone to complication. Here we show that Dopamine Neuron Stimulating Peptide 11 (DNSP-11), following non-invasive intranasal administration, protects dopaminergic neurons from a lesion model of Parkinson’s disease in the rat. A significant and dose-dependent increase in an index of dopamine turnover (the ratio of DOPAC to dopamine) was observed in the striatum of normal young adult Fischer 344 rats by whole-tissue neurochemistry compared to vehicle administered controls. Among animals challenged with a moderate, unilateral 6-hydroxy-dopamine (6-OHDA) lesion of the substantia nigra, those treated repeatedly with intranasally administered DNSP-11 exhibited greater numbers of tyrosine hydroxylase (TH) positive dopaminergic neuronal cell bodies in the substantia nigra and greater TH+ fiber density in the striatum when compared to animals treated intranasally with vehicle only or a scrambled version of the DNSP-11 sequence. Lesioned animals that received intranasal DNSP-11 treatment did not exhibit abnormal, apomorphine-induced rotation behavior, contrasted with animals that received only vehicle or scrambled peptide that did exhibit significantly greater rotation behavior. In addition, the endogenous expression of DNSP-11 from the pro-region of GDNF was investigated by immunohistochemistry with a custom, polyclonal antibody. Signal from the DNSP-11 antibody was found to be differentially localized from the mature GDNF protein both spatially and temporally. While DNSP-11-like immunoreactivity extensively colocalizes with GDNF immunoreactivity at post-natal day 10, the day of maximal GDNF expression, DNSP-11-like signal was found to be present in the 3 month old rat brain with signal in the substantia nigra, ventral thalamic nucleus, dentate gyrus of the hippocampus, with the strongest signal observed in the locus ceruleus where GDNF is not expressed. Results from immunoprecipitation of brain homogenate were not consistent with the synthetic, amidated 11 amino-acid rat DNSP-11 sequence. However, binding patterns in the literature of NPY, the only homologous sequence present in the CNS, do not recapitulate the immunoreactive patterns observed for the DNSP-11 signal. This study provides evidence for a potential easy-to-administer intranasal therapeutic using the DNSP-11 peptide for protection from a 6-OHDA lesion rat model of Parkinson’s disease.

<p>Upon an inflammation the immune system signals the brain by secreted cytokines to elicit central nervous responses such as fever, loss of appetite and secretion of stress hormones. Since the blood brain barrier, (BBB) protects the brain from unwanted material, molecules like cytokines are not allowed to cross the barrier and enter the brain. However, it is clear that they in some way can signal the brain upon an inflammation. Many suggestions concerning this signaling has been made, one being that cytokines bind to receptors on the endothelial cells of the blood vessels of the brain and trigger the production of prostaglandins that can cross the BBB. This conversion is catalyzed by the enzyme cyclooxygenase-2, (COX-2), which is induced by transcription factors like NF-κB in response to cytokines. One of the central nervous responses to inflammatory stimuli is activation of the HPA-axis whose main purpose is glucocorticoid production. Glucocorticoids inhibit the inflammatory response by suppressing gene transcription of pro-inflammatory genes including those producing prostaglandins through direct interference with transcription factors such as NF-κB or initiation of transcription of anti-inflammatory genes like IκB or IL-10. It has however not been clear if glucocorticoids can target the endothelial cells of the brain in order to provide negative feed-back on the immune-to-brain signaling, and in that way inhibit central nervous inflammatory symptoms. An anatomical prerequisite for such a mechanism would be that the induced prostaglandin production occurs in cells expressing GR. This has however never been demonstrated. Here I show that a majority of the brain endothelial cells expressing the prostaglandin synthesizing enzyme COX-2 in response to immune challenge also express the glucocorticoid receptor, (GR). This indicates that immune-to-brain signaling is a target for negative regulation of inflammatory signaling executed by glucocorticoids and identifies brain endothelial GR as a possible future drug target for treatment of central nervous responses to inflammation such as fever and pain.</p>

Upon an inflammation the immune system signals the brain by secreted cytokines to elicit central nervous responses such as fever, loss of appetite and secretion of stress hormones. Since the blood brain barrier, (BBB) protects the brain from unwanted material, molecules like cytokines are not allowed to cross the barrier and enter the brain. However, it is clear that they in some way can signal the brain upon an inflammation. Many suggestions concerning this signaling has been made, one being that cytokines bind to receptors on the endothelial cells of the blood vessels of the brain and trigger the production of prostaglandins that can cross the BBB. This conversion is catalyzed by the enzyme cyclooxygenase-2, (COX-2), which is induced by transcription factors like NF-κB in response to cytokines. One of the central nervous responses to inflammatory stimuli is activation of the HPA-axis whose main purpose is glucocorticoid production. Glucocorticoids inhibit the inflammatory response by suppressing gene transcription of pro-inflammatory genes including those producing prostaglandins through direct interference with transcription factors such as NF-κB or initiation of transcription of anti-inflammatory genes like IκB or IL-10. It has however not been clear if glucocorticoids can target the endothelial cells of the brain in order to provide negative feed-back on the immune-to-brain signaling, and in that way inhibit central nervous inflammatory symptoms. An anatomical prerequisite for such a mechanism would be that the induced prostaglandin production occurs in cells expressing GR. This has however never been demonstrated. Here I show that a majority of the brain endothelial cells expressing the prostaglandin synthesizing enzyme COX-2 in response to immune challenge also express the glucocorticoid receptor, (GR). This indicates that immune-to-brain signaling is a target for negative regulation of inflammatory signaling executed by glucocorticoids and identifies brain endothelial GR as a possible future drug target for treatment of central nervous responses to inflammation such as fever and pain.