Browsing by Subject "Department of Neuroscience"
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Item Chronic stress shifts the phase of adrenal clock gene rhythms(2012-04-18) Karsten, CarleyThe hypothalamic-pituitary-adrenal (HPA) axis is characterized by a robust circadian rhythm in adrenal secretion of glucocorticoids (GC), driven in part by adrenal clock genes. The GC rhythm serves to synchronize other peripheral clocks and to maintain homeostasis. Mechanisms for entrainment of the adrenal clock remain unclear. Since stress activates the HPA axis, it is possible that entrainment of the adrenal clock and, concomitantly, glucocorticoid rhythms would be susceptible to stress. The present experiment aimed to test the hypothesis that chronic stress can alter adrenal circadian rhythms. The model of chronic subordinate stress used, consisting of daily exposure to a dominant mouse, has shown a robust metabolic phenotype in previous studies. Per2::Luc mice were used to assess rhythmic expression of the clock gene Per2. Per2::Luc mice express a luciferase reporter gene driven by the Per2 promoter, so that light output measured in tissue explants reflects PER2 expression.Item Differential morphine withdrawal profiles in high- and low-saccharin preferring rats(2012-01-26) Hupalo, Sofiya; Radke, Anna; Gewirtz, JonathanItem Dopamine in the Nucleus Accumbens Shell Mediates Acute Opiate Withdrawal(2012-04-18) Hupalo, SofiyaThe onset of withdrawal after cessation of drug use is one of the defining characteristics of opiate addiction. Addiction is in part driven by negative reinforcement in an attempt to alleviate negative emotional states during withdrawal. Evidence suggests that opiate withdrawal is characterized by diminished neurotransmission in the mesolimbic dopamine system. However, it is not known where dopamine’s actions may play a role during withdrawal. We hypothesized that acute withdrawal occurs when dopamine levels diminish after the initial morphine-induced surge. We microinfused a non-specific dopamine receptor agonist into three structures downstream of the ventral tegmental area, where morphine exerts its primary effects. Using the withdrawal-potentiated startle (WPS) paradigm to measure anxiety-like symptoms of withdrawal, we found that apomorphine, a dopamine receptor agonist, attenuates withdrawal symptoms when administered into the nucleus accumbens (NAc) shell. Our results demonstrate the involvement of dopamine receptor activity in morphine withdrawal, and suggest that withdrawal is brought on by declining levels of dopamine in the NAc. This finding is one of the first to show that dopamine modulates the rewarding as well as aversive properties of morphine, implicating a possible mechanism for the transition from early opiate use to dependence.Item Dopamine, but not noradrenaline, contributes to opiate withdrawal-induced anxiety in the VTA(2010-12-21) Hupalo, Sofiya•Research in the Gewirtz laboratory has shown that one of the brain structures involved in mediating withdrawal from opiate drugs such as morphine is the ventral tegmental area(VTA). Morphine causes the VTA to release dopamine and excite downstream targets,which maybe related to the onset of withdrawal. •In addition,increased levels of noradrenaline are also present during opiate withdrawal.3,4 •We aim to test whether both the dopaminergic and adrenergic systems engage to produce WPS when morphine is supplied to the VTA. Thus,we administer propranolol, an adrenergic receptor antagonist,to determine whether noradrenaline is recruited by the VTA during withdrawal. Apomorphine ,a dopamine agonist, is given to determine the actions of dopamine during withdrawalItem Effect of Variation in Speed on Target Interception(2009-04-08) Rao, HrishikeshIn day to day life, we make use of hand eye coordination to perform everyday tasks such as reaching out our hand to grab a glass of water or moving a finger over a keyboard to push a button. But we rarely think about the complex processes that occur inside our brains in the very short time span between when we think about moving our hand to actually making contact with the target. With this experiment, we wish to extend our knowledge of how sensory information is utilized to predict the motion of objects targeted by the hand and the extent of hand and eye coordination during this task. We also wish to examine how the speed and acceleration of a moving target affects the decision making process prior to the onset of motion of the subject's hand. To create variation in the speed and acceleration, the motion of the target was governed by one of three speed laws for each trial. With the first law, the target's motion was constructed from a sum of sines in the x and y directions; with the second law, the target's instantaneous velocity was inversely proportional to the curvature of the path at that point; and lastly, as per the third law, the target moved at a constant speed. Based on these three laws, the corresponding targets traveled quite differently around curves and straight paths due to the dissimilar acceleration or even the lack of tangential acceleration. Defining how subjects incorporate information about changes in direction, speed and acceleration provides insight into how the brain processes sensory information.Item Examining the Effects of Serotonin on Medium Spiny Neurons (MSNs)(2021) Belhe, Aishwarya; Tam, Daniel; Lanier, LoreneSerotonin is known to be the key hormone in stabilizing our mood and feelings of well-being. The relation of alterations in the levels of serotonin in the central nervous system and depression has been well-established. The most common antidepressants prescribed to alleviate the symptoms of depression are selective serotonin reuptake inhibitors (SSRIs). These are known to target serotonin and increase its levels in the brain. Due to this property, the consumption of antidepressants by pregnant women has been subject to scrutiny, as the effects of these drugs on the developing embryo have not been studied extensively. These include the effects of serotonin on the development of medium spiny neurons (MSNs), the major type of neuron that constitute the striatum that are known to have distinct morphological traits of cell body size, dendritic arborization pattern and high density of dendritic spines. Although many studies have focused on the role of serotonin in regulating function of the mature striatum, no studies (that we can find) have specifically examined the role of serotonin on MSN development. Based on its role in regulating striatal activity and effects on dendritic growth in other types of neurons, we hypothesize that serotonin will also regulate MSN dendritic arborization. However, mature MSNs express at least 7 different types of serotonin receptors. The effect of serotonin on MSN development will likely depend on which receptors are most highly expressed or active during development. It is therefore impossible to predict whether serotonin will enhance or reduce MSN dendritic arborization.Item Hand Muscle Activity for Digital Coarticulation in Pianists(2012-04-18) Faber, NathanielThis study exploited the variability across a group of normal, healthy pianists to provide a comprehensive description of the patterns of muscle activity used for various sequences of keypresses. The goal was to determine which features did and did not change across the various skill levels.Item Homelessness and End of Life Care: Analysis of the Living Wills of Homeless Individuals(2010-04-21) Grengs, LeahIn the Twin Cities metro area over 4,000 youth and adults are in temporary housing programs and over 600 are unsheltered. Homeless individuals experience a greater risk of death and more barriers to healthcare than any other disadvantaged population. As a result of barriers to regular healthcare, homeless individuals are hospitalized and admitted to the emergency room at four times the rate of the general population. Few other studies have looked at the content of advance directives and no other study has looked at what the homeless write in their advance directives. A qualitative study of 73 advance directives of homeless individuals from Minneapolis showed evidence against many misconceptions people may have regarding the homeless: The majority of people named a family member as their healthcare agent and discussed family throughout their living will. Many of the homeless individuals discussed specific healthcare goals and were eager to improve or maintain their health. Many of the people wrote about specific accomplishments when asked what they were most proud of and wanted to be remembered for their personal traits, such as being good, kind or helpful.Item Investigation of the Novel Peptide TUF1 in Context Conditioning(2011-08-11) Reise, Kathryn• TUF1 is a newly discovered peptide expressed in the hippocampus, amygdala, hypothalamus, and endocrine tissues (Figure 1B). These regions are crucial for the integration of external stimuli and play an important role in necessary responses for survival, such as fear acquisition to environments. •This study will measure the role of TUF1 in context and will measure whether TUF1 expression is altered after contextual conditioning. •Figure 1A shows the predicted structure of TUF1. Illustrated is the signal peptide (SP) and transmembrane region (TM). •TUF has a p75 receptor-binding domain, a domain commonly found in neurotrophins such as brain-derived neurotrophic factor (BDNF). This indicates that TUF1 could have possible effects on neuronal plasticity.Item The Investigation of the Novel Peptide TUF1 in Fear Potentiated Startle(2011-03-16) Reise, KathrynThe goal of this study is to determine the role of TUF1 and to measure if the administration of this peptide into the ventricles alters fear responses by affecting the acquisition and/or expression of acoustic startle.Item Methylene Blue as a Facilitator to Reverse Effects of Developmental Iron Deficiency(2019) Horejsi, Ashley; Bastian, Thomas; Lanier, Lorene; Georgieff, MichaelItem Modeling Rapid Perceptual Decisions(2009-04-08) Krause, BryanPerceptual decisions are often modeled as a "race to threshold" where evidence is accumulated up to a set point where the decision occurs. The threshold model is normally applied to decisions made over a long period of time, such as identifying motion or an object in noise. It is unclear how such models apply to rapid perceptual decisions. Previous studies in the macaque monkey measured firing rates in area MT during a rapid coherent motion detection task. I modeled the decision process for this task as "leaky" integration of the MT firing up to a decision threshold. The best fit to animal data was achieved by integrating over 20 Poisson neurons with a time constant of 100 ms and using a variable threshold. The model can account for the performance (correct, miss, and false alarm rates) and reaction times of the animal. This indicates that a similar mechanism may underlie decisions made from weak stimuli presented over a long period of time and strong stimuli presented quickly.Item Mu-Opioid Receptor Deletion Contributions to Neuroeconomic Decision Making(2022) Bogenrief, Hailie M.; Kocharian, Adrina; Rothwell, Patrick E.Item NMDA Induced Rhythmic Motor Patterns in Wild Type Zebrafish Larvae(2009-04-08) Tran, Anh C.The zebrafish larvae is a good model system for investigating the neural circuitry underlying rhythmic patterns of behavior, such as swimming, using techniques like electrophysiology, genetics, and optical imaging. Studies have shown that rhythmic motor patterns are evoked by the application of the excitatory amino acid agonist N-methyl-D-aspartate (NMDA) to spinalized zebrafish larvae at 3 days post-fertilization. In the present study, we utilized an intact preparation to monitor the motor activity in peripheral nerves using extracellular recording techniques. The fictive motor patterns induced by the application of NMDA was examined in wild type zebrafish (4-6 days post-fertilization) paralyzed with alpha-bungarotoxin. To determine the optimal concentration of NMDA required to induce rhythmic swimming behavior, we established a dose-response-curve ranging from 25 uM to 100 uM. We found that NMDA concentrations around 80 uM was most effective at evoking rhythmic patterns of swimming behavior. In addition, bout frequency was also found to be dose-dependent while other basic properties of the motor pattern, such as bout duration, burst frequency, cycle period, burst duration, and duty cycle, were dose-dependent.Item A novel in vivo approach to study circadian rhythmicity of glucocorticoids using adeno-associated virus(2011-09-01) Karsten, Carley; Hupalo, Sofiya; Yoder, J. Marina; Engeland, William C.The hypothalamic-pituitary-adrenal (HPA) axis regulates glucocorticoid release in a circadian rhythm as well as in response to stress. The adrenal gland is made up of two distinct tissues: the cortex, which produces glucocorticoids, and the medulla. The cortex responds to hormonal cues while the medulla receives input from the splanchnic nerve. Interestingly, cutting the splanchnic nerve has been shown to affect cortical function, indicating a possible interaction between the two tissues. However, the precise mechanism of this interaction remains unknown. An experimental approach that genetically manipulates adrenal activity could potentially delineate the functional relationship between medulla and cortex. One option is to infect adrenal tissue with recombinant adeno-associated virus (AAV) capable of silencing a gene of interest in a specific tissue type. This is a novel approach in the adrenal gland, so we must first develop a protocol that will optimize methodological variables such as AAV serotype, surgical procedure, injection volume, and infection time-course. We tested various combinations of these variables and used GFP-tagged AAV to assess the degree of infection in rats. Thus far, we have determined that the serotype AAV8 yields the greatest degree of infection, and AAV2 and AAV5 seem to selectively infect the cortex. In addition, the concentration of virus injected is more important than the volume, and the injection method can have a large impact. Stress tests revealed that injection of AAV-GFP does not appear to alter adrenal function. AAVs thus appear to be promising tools in neuroendocrine studies, as they provide a means for genetically modifying the adrenal gland. Future experiments will use this new technique to analyze the functional relationship between adrenal cortex and medulla.Item Regulation of Cell Cycle Length in Progenitor Cells of the Developing Vertebrate Retina(2011-04-13) Ferguson, KatherineProgenitor cells exist in two distinct phases during development with different forms of division: preneurogenic and neurogenic. Preneurogenic progenitor cells produce two cells that divide again while neurogenic progenitor cells divide to produce one or both cells that withdraw from the mitotic cycle and differentiate. Preneurogenic and neurogenic cells are fundamentally different in that only preneurogenic progenitor cells express the Notch ligand, Delta 1, and only neurogenic progenitor cells express the bHLH transcription factor, E2A (Yang et. al., 2009). Additional differences in these cell types are not well understood. The vertebrate retina is an effective model system for studying these differences in progenitor cells because it is a part of the central nervous system that buds off from the brain during early development. As the retina develops, it matures from the center to the periphery with differentiated cells towards the center and progenitor cells replicating without differentiation in the periphery (Dutting et al., 1983). The neurogenic front marks the border between preneurogenic and neurogenic progenitor cells. Ganglion cells are the first postmitotic, differentiated cells to be generated at the neurogenic front, which is present for several days in chick embryo retina. It is well documented that as development progresses, cell cycle length increases (Takahashi et. al. 1995). It is unknown whether this is a gradual increase throughout development or if it is related to a change in cell type. In this study we explore the question, is the change in progenitor cell mode from preneurogenic to neurogenic accompanied by a change in cell cycle length? The retina will be used to answer this question because preneurogenic and neurogenic progenitor cells can be studied in the same animal during several days of early development. To determine if there is a difference in cell cycle length between these differentiated, neurogenic progenitor cells in the central retina and the undifferentiated, preneurogenic progenitor cells in the periphery during development, we used two BrdU injections. These thymidine analogs are incorporated into the cell’s DNA during S phase of the cell cycle and we detected them using immunohistochemistry. Immunohistochemistry with RA4 was also used to determine the location of the most peripheral ganglion cell, which marks the neurogenic front. The total number of cells and the number identified by each BrdU injection were counted in both preneurogenic and neurogenic retina. We used an equation considering the percentage of cells that incorporated only one of the thymidine analogs and the survival times after each injection to determine the total cell cycle length. Here we show that the cell cycle of neurogenic progenitor cells is longer than that of preneurogenic progenitor cells, indicating that this is a fundamental difference in the cell types and not due to a gradual increase in cell cycle length throughout development.Item Rhythmic clock gene expression in the spinal cord may underlie sympathetic nerve control of adrenal function(2012-04-18) Hupalo, SofiyaThe hypothalamic-pituitary-adrenal (HPA) axis is characterized by a circadian rhythm that entrains to the light-dark cycle via inputs from a central pacemaker in the suprachiasmatic nucleus (SCN). Similar molecular clock mechanisms have been identified in each component of the HPA axis including the adrenal cortex, which generates circadian rhythms in glucocorticoid secretion. However, the mechanisms by which the adrenal clock entrains to environmental signals have not been elucidated. Since corticosterone secretion in rodents is mediated in part by sympathetic nerve activity through the intermediolateral (IML) nucleus of the thoracic spinal cord, we tested the hypothesis that these neurons also possess an endogenous clock. Using immunohistochemistry, we detected expression of two clock gene proteins – Period 2 (PER2) and brain and muscle Arnt-like protein 1 (BMAL1) – in the dorsal horn, ventral horn, and intermediate gray within mouse thoracic and lumbar segments; double labeling for vesicular acetylcholine transporter showed cholinergic neurons immunoreactive for clock gene proteins in the IML and ventral horn. To examine whether spinal cord neurons possess clock gene rhythms, we used the reporter mPer2::Luciferase knockin mouse to monitor real-time gene expression in vitro. We found that explants of thoracic spinal segments exhibit rhythms in mPER2 bioluminescence with a 22.0 ± 0.3 h period and a peak phase of 14.8 ± 0.1 h circadian time (CT), which precedes the peak of the adrenal rhythm (CT~16). Our results demonstrate that spinal cord neurons, including those in the IML, express clock gene proteins and that explants of thoracic segments exhibit an endogenous rhythm in PER2 expression. These findings suggest that circadian expression of clock genes in the IML drives sympathetic nerve activity to synchronize adrenal glucocorticoid release with daily changes in the external environment.Item Role of different subtypes of dopamine receptors in response to acute opiate withdrawal.(2011-01-06) Leslie, Jacob•Those experiencing withdrawal from drugs of abuse display negative emotional symptoms such as anxiety. Anxiety during withdrawal from an acute opiate exposure also causes potentiation of the acoustic startle reflex (“withdrawal-potentiated startle”).2,4,5 •Experiments in the Gewirtz lab with a general dopamine receptor agonist, apomorphine have suggested that anxiety during acute withdrawal from opioidsis mediated by levels of dopamine in the brain. •While we know dopamine is important in this phenomena we do not know which dopamine receptors play a role in producing anxiety symptoms. •There are five subtypes of dopamine subunits that are classified in two populations: D1-like and D2-like receptors. Both have been shown to play a role in producing withdrawal symptoms. 1,3 •Our goal is to discover which receptor family plays a role in producing withdrawal-potentiated startle. We will test this by administering either a D1-like agonist or D2-like agonist, or both in a cocktail with the expectation that withdrawal potentiated startle will be blocked in the groups that are important for producing anxiety.Item Role of Dopamine in Anxiety Production During Acute Opiate Withdrawal(2012-04-18) Leslie, JacobThe use of addictive substances is characterized by a positive emotional state followed by drug withdrawal and a negative affective state. These highs and lows are caused by neuroadaptational changes in multiple brain structures when exposed to drugs of abuse. However, the neural events responsible for triggering the negative affective component of withdrawal during the early stages of morphine and nicotine dependence has yet to be definitively determined. By measuring the acoustic startle reflex in rats, we show that decreased dopaminergic activity causes the characteristic anxiety observed during withdrawal from drugs of abuse. These results parallel the substantial research showing the importance of the mesolimbic dopamine system in regulating the effects of drugs of abuse.Item Sex Differences and Effects of Modafinil and Allopregnanolone on a Rat Model of Methamphetamine Relapse(2011-04-13) Rehbein, TylerModafinil (MOD) is an analeptic drug currently being examined as a treatment for stimulant dependence. This experiment examined MOD’s potential for use in treatment of methamphetamine (METH) addiction and further investigated the role of sex differences in drug-seeking behavior and treatment receptivity. The effects of allopregnanolone (ALLO), a progesterone metabolite that has been previously shown to reduce drug-seeking behavior in female rats, were also examined. Rats were trained to self-administer IV injections of METH during daily 5-hr sessions, and continued stable METH-seeking behavior over a 10 day maintenance period. Next, METH was replaced with saline, and drug-seeking behavior extinguished over an 18-day period. Following extinction, rats began a reinstatement procedure lasting 9 days in which an ALLO, MOD, or control pre-treatment injection was given 30 minutes prior to daily session, followed by a METH or saline priming injection that was given at the start of session. This reinstatement phase is considered an animal model of human relapse. Females showed greater responding on the previously METH-paired lever during reinstatement compared to males. MOD attenuated METH-seeking behavior equally in males and females, while MOD priming injections did not increase responding compared to saline control. ALLO attenuated METH-seeking behavior in females, but had no effect on males. These results illustrate the potential utility of MOD as a treatment for METH addiction and illustrate the role of gonadal hormones, such as ALLO, in the sex differences observed in drug-seeking behavior.