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Title: Molecular mechanisms of seasonal responsiveness to testosterone in the green anole lizard
Creator: Kerver, Halie
Date: 2015
Collection: Electronic Theses & Dissertations
Description: "The goal of this research is to identify the molecular mechanisms that govern this seasonal responsiveness to T [testosterone] in male anoles. " -- Abstact.

Title: Exploring reward system responsivity in the nucleus accumbens across chronicity of binge eating in female rats
Creator: Hildebrandt, Britny
Date: 2017
Collection: Electronic Theses & Dissertations
Description: Objective: Binge eating is characterized by an overconsumption of palatable food, a natural reinforcer. Therefore, there is increased interest in the role of reward-based processes in binge eating. To date, results have been mixed across studies examining reward system responsivity and binge eating, showing both increased and decreased activation in the nucleus accumbens and other brain structures within reward pathways. One contributing factor to differences in results might be chronicity of...
Show moreObjective: Binge eating is characterized by an overconsumption of palatable food, a natural reinforcer. Therefore, there is increased interest in the role of reward-based processes in binge eating. To date, results have been mixed across studies examining reward system responsivity and binge eating, showing both increased and decreased activation in the nucleus accumbens and other brain structures within reward pathways. One contributing factor to differences in results might be chronicity of binge eating (i.e., early vs. chronic), where the reward system is initially hyper-responsive to binge eating, but over time, the system becomes hypo-responsive to binge eating. As a result, in later stages of binge eating, more frequent or more severe levels of binge eating might be needed to achieve the same level of responsivity. Despite chronicity of illness being a plausible mechanism to explain differences in reward-related responsivity, no studies have examined duration of binge eating as a potential factor contributing to differences in responsivity over time. The current study used an animal model of binge eating to directly examine differences in brain activation in response to palatable food in the nucleus accumbens across chronicity of binge eating. Methods: 120 Sprague-Dawley female rats were exposed to intermittent, palatable food feeding tests. Binge eating prone (BEP) and binge eating resistant (BER) rats were identified using established methods, and randomly assigned to the early stage (i.e., six feeding tests) or chronic stage (i.e., 24 feeding tests) group. Fos expression, a measure of neural activation, was quantified in the nucleus accumbens and compared across the BER and BEP groups. Results: While there were no changes in palatable food intake (i.e., behavioral responsivity) found over time in BEP rats, there were changes in neural responsivity over time in BEP rats. Specifically, BEP rats had higher levels of c-Fos expression in the nucleus accumbens core and shell at the early stage of binge eating, compared to BER rats, suggesting an initial hyper-responsivity to palatable food in BEP rats. At the chronic stage, BEP rats showed significantly lower levels of c-Fos in the nucleus accumbens core and shell, suggesting a downregulation in responsivity to palatable food over time. This change was specific to BEP rats, suggesting that the downregulation is in response to long-term, consistent, high-levels of palatable food intake found in BEP rats (rather than lower levels of consistent palatable food intake found in BER rats). Discussion: These data strongly suggest that duration of binge eating leads to differences in neural function of the reward system. Furthermore, findings point to duration of binge eating as a factor contributing to inconsistent findings in past studies examining reward system functioning and binge eating. Results from the current study strongly suggest a need to control of stage of binge eating in future studies by including duration of illness as a covariate or examining different stages of binge eating as independent groups. Work should also focus on other structures (e.g., prefrontal cortex) and mechanisms (e.g., incentive motivation) in the reward system in order to understand if similar or other processes exhibit the same downregulation over time.
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Title: Neurotensin engages mesolimbic dopamine circuits to regulate body weight
Creator: Woodworth, Hillary L.
Date: 2017
Collection: Electronic Theses & Dissertations
Description: Body weight is determined by feeding and volitional physical activity behaviors that are regulated, in part, by dopamine (DA) neurons of the ventral tegmental area (VTA). Here, we sought to understand how the neuropeptide, neurotensin (Nts) engages VTA DA neurons to modify body weight. The rationale for this work is that pharmacologic application of Nts into the VTA suppresses food intake and promotes locomotor activity, yet the endogenous circuits by which Nts acts on the VTA to modify these...
Show moreBody weight is determined by feeding and volitional physical activity behaviors that are regulated, in part, by dopamine (DA) neurons of the ventral tegmental area (VTA). Here, we sought to understand how the neuropeptide, neurotensin (Nts) engages VTA DA neurons to modify body weight. The rationale for this work is that pharmacologic application of Nts into the VTA suppresses food intake and promotes locomotor activity, yet the endogenous circuits by which Nts acts on the VTA to modify these behaviors and body weight remain unclear. First, we identified the endogenous sources of Nts input to the VTA; using retrograde tracing we found that the lateral hypothalamic area (LHA), a critical neural hub for coordinating energy balance, provides substantial Nts projections to the VTA. We next examined how Nts directly engages VTA DA neurons by identifying Nts receptor-expressing cells in the VTA. To do this, we generated mice expressing Cre-recombinase in Nts receptor 1 (NtsR1) or Nts receptor 2 (NtsR2) cells, which revealed that NtsR1 is expressed on many VTA DA neurons, whereas NtsR2 is predominantly restricted to glial cells. Furthermore, only the VTA NtsR1 neurons project to the nucleus accumbens (NA), where DA release is known to modify feeding and locomotor behavior. We therefore tested the physiologic necessity for Nts action via the VTA by genetically ablating VTA NtsR1 neurons. Mice lacking VTA NtsR1-DA neurons were hyperactive, failed to gain weight, and could not appropriately coordinate feeding behavior with peripheral energy cues, demonstrating that VTA NtsR1 neurons are essential for energy balance. Finally, we tested the hypothesis that endogenous Nts input from the LHA to the mesolimbic DA system would be sufficient to regulate body weight. Indeed, chemogenetic activation of LHA Nts neurons increased physical activity, restrained food intake, and promoted weight loss in lean mice. Interestingly, the anorectic effects of LHA Nts activation were mediated via NtsR1 and DA signaling, while the physical activity was NtsR1-independent. Furthermore, in hungry mice (a state in which increased appetitive drive can promote overeating and weight gain), activation of LHA Nts neurons suppressed intake of chow and palatable sucrose rewards. Collectively, this work defines an endogenous LHA Nts circuit that engages the mesolimbic DA system via NtsR1 to suppress food intake in both energy replete and energy depleted states. Enhancing action via this circuit may thus be useful to support dual weight loss behaviors in an obesogenic environment.
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Title: Bk channel, 5-HT and sex in gastrointestinal motility in health and obesity
Creator: France, Marion
Date: 2015
Collection: Electronic Theses & Dissertations
Description: Highly regulated motor reflexes observed in gastrointestinal (GI) motility promote nutrient digestion and absorption as well as excretion of indigestible material. Motor reflexes are fundamentally regulated by the enteric nervous system (ENS), and can be modulated by 1) smooth muscle tone changes by the activation of large conductance Ca2+-activated K+ (BK) channels and by 2) intrinsic neuron activation by 5-hydroxytryptamine (5-HT, serotonin). Impairments in the modulation of motor reflexes...
Show moreHighly regulated motor reflexes observed in gastrointestinal (GI) motility promote nutrient digestion and absorption as well as excretion of indigestible material. Motor reflexes are fundamentally regulated by the enteric nervous system (ENS), and can be modulated by 1) smooth muscle tone changes by the activation of large conductance Ca2+-activated K+ (BK) channels and by 2) intrinsic neuron activation by 5-hydroxytryptamine (5-HT, serotonin). Impairments in the modulation of motor reflexes cause GI motility disorders. Although GI motility disorders are typically not life threatening, the quality of life of affected individuals can be poor. GI motility disorders are common in obesity that affects millions of people in the United States. GI motility dysfunction in obesity may be caused by perturbations in intestinal 5-HT dynamics. 5-HT located in enterochromaffin (EC) cells of the GI mucosa influences GI motility by coordinating the nerve circuits in the ENS. I investigated 1) the role BK channels in normal GI transit in mice and 2) 5-HT signaling in controlling GI transit in male and female mice fed a high fat diet (HFD) to produce diet-induced obesity (DIO). I used complimentary in vivo and in vitro methods to identify sex differences in small intestinal transit and 5-HT dynamics in obese mice. Overall, I found 1) BK channels are necessary for normal propulsive colonic transit and 2) sex and obesity-related alterations in small intestinal transit and 5-HT signaling. These sex differences in DIO must be considered when designing therapeutic approaches targeting intestinal 5-HT to treat impaired motility in obesity.
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Title: Sex differences in the mouse ventromedial nucleus of the hypothalamus
Creator: Brummet, Jennifer Lynn
Date: 2017
Collection: Electronic Theses & Dissertations
Description: The following dissertation examines the ventromedial nucleus of the hypothalamus (VMH), a brain region that is sexually dimorphic in rodents. The experiments in this dissertation were centered around the question of whether the VMH is sexually dimorphic in mice, and also explored the questions of what the role of circulating testosterone (T) and the androgen receptor (AR) are in this sex difference. The following chapters examine the role of circulating T and the AR in regulating the regional...
Show moreThe following dissertation examines the ventromedial nucleus of the hypothalamus (VMH), a brain region that is sexually dimorphic in rodents. The experiments in this dissertation were centered around the question of whether the VMH is sexually dimorphic in mice, and also explored the questions of what the role of circulating testosterone (T) and the androgen receptor (AR) are in this sex difference. The following chapters examine the role of circulating T and the AR in regulating the regional volume, neuron number, neuronal soma size, astrocyte number, and astrocyte complexity in the mouse VMH. The first experiment examines the question of whether sex differences exist in the mouse VMH by looking at unaltered adult male and female mice. The results showed that the VMH is larger in males than females, and that the difference is accounted for by differences in the VL and DM subregions. This experiment also examined sex differences in astrocyte number and complexity in the VMH. The results showed that males have more astrocytes than females in the VMH, and have more complex astrocytes in the VL subregion. Next, we ask if there is a role of circulating T or a functional AR in the VMH sex difference; the next study examines the role of circulating adult T and AR in VMH structure in males, females, and males without a functional AR (iTfm animals). The results showed that VMH volume, specifically of the dorsomedial (DM) and ventrolateral (VL) subregions, was greater in animals with circulating adult T regardless of genotype, including iTfm males, suggesting that T is acting through an AR-independent mechanism. Additionally, neuron number was greater in males and iTfm males as compared to females, suggesting that the sex difference in neuron number is independent of adult circulating T and AR. T treatment did lead to increased neuronal soma size in the VMH, and this response may be dependent on AR, as VMH somata were not significantly different between iTfms with or without adult T treatment. The last experiment examines the question of whether there is a role of AR or circulating T in the astrocyte sex difference using males, females, and iTfm males with and without T treatment to look at astrocyte number and complexity in the VMH. The results show that males and iTfms did not significantly differ in the number of VMH astrocytes, and both had more astrocytes than females. In the VL subregion of the VMH, adult T treatment resulted in more complex astrocytes regardless of genotype or AR status, while no differences were seen in the DM subregion. Together, these experiments show that the VMH is sexually differentiated in mice, with most of the differences being observed in the VL and DM subregions. Additionally, many of these sex differences are due to circulating T acting through an AR-independent mechanism.
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Title: Associations between ovarian hormones and emotional eating across the menstrual cycle : do ovulatory shifts in hormones matter?
Creator: Fowler, Natasha
Date: 2018
Collection: Electronic Theses & Dissertations
Description: "Prior research suggests a substantial role for ovarian hormones in increased risk for binge eating and emotional eating during the mid-luteal phase of the menstrual cycle. However, past studies have not examined how and if pronounced hormonal changes that precede the mid-luteal phase (i.e., the dramatic decrease in estradiol and increase in progesterone during/after ovulation) also contribute to mid-luteal increases in binge-related symptoms. Past theories and studies of phenotypes strongly...
Show more"Prior research suggests a substantial role for ovarian hormones in increased risk for binge eating and emotional eating during the mid-luteal phase of the menstrual cycle. However, past studies have not examined how and if pronounced hormonal changes that precede the mid-luteal phase (i.e., the dramatic decrease in estradiol and increase in progesterone during/after ovulation) also contribute to mid-luteal increases in binge-related symptoms. Past theories and studies of phenotypes strongly related to binge eating (e.g., depression) suggest that these pronounced hormonal changes may also play a role. This study examined this hypothesis in 390 female twins (aged 15-25 years) from the Michigan State University Twin Registry. Daily ratings of emotional eating (assessed with the Dutch Eating Behavior Questionnaire) and daily saliva samples of hormones were measured over 45 consecutive days. Results revealed no significant associations between pronounced changes in estradiol or progesterone across ovulation and emotional eating scores in the mid-luteal phase, even after controlling for BMI and negative affect and examining participants with clinical binge eating episodes. Taken together, data suggest that pronounced hormonal change across ovulation may play less of a role in emotional eating than changes in estradiol and progesterone that occur during the mid-luteal phase."--Page ii.
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Title: The role of affect in binge eating phenotypes : an examination of individual differences in emotion experience and interactions with ovarian hormones
Creator: Mikhail, Megan Elizabeth
Date: 2020
Collection: Electronic Theses & Dissertations
Description: Ovarian hormones significantly influence dysregulated eating in females. However, most women do not develop appreciable disordered eating, suggesting that ovarian hormones may not affect all women equally. In the first study of this thesis, I examined whether individual differences in trait negative affect (NA) moderate ovarian hormone-dysregulated eating associations in 446 women who provided saliva samples for hormone measurements and ratings of NA and emotional eating daily for 45...
Show moreOvarian hormones significantly influence dysregulated eating in females. However, most women do not develop appreciable disordered eating, suggesting that ovarian hormones may not affect all women equally. In the first study of this thesis, I examined whether individual differences in trait negative affect (NA) moderate ovarian hormone-dysregulated eating associations in 446 women who provided saliva samples for hormone measurements and ratings of NA and emotional eating daily for 45 consecutive days. Women were at greatest risk for emotional eating when they had high trait NA and experienced a hormonal milieu characterized by low estradiol or high progesterone. While effects were significant in all women, the combination of high trait NA and high progesterone was particularly risky for women with a history of clinically significant binge eating episodes. These findings provide initial evidence that affective and hormonal risk interact to promote dysregulated eating, and that effects may be amplified in women with clinically significant binge eating.Low emotion differentiation (the tendency to experience vague affective states rather than discrete emotions) is associated with psychopathology marked by emotion regulation deficits and impulsive/maladaptive behavior. However, research examining associations between emotion differentiation and dysregulated eating is still nascent. In the second study, I therefore examined associations between several measures of emotion differentiation and binge eating phenotypes across a spectrum of severity.
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Title: Role of hippocampal Delta-FosB in behavioral responses to chronic stress
Creator: Manning, Claire Elena
Date: 2019
Collection: Electronic Theses & Dissertations
Description: "Depression is a highly prevalent mood disorder which affects up to 20% of the population. While women are twice as likely as men to be diagnosed with a mood disorder, the neurophysiological contributions to this disparity are unclear. One brain region implicated in depression-like symptoms in both humans and rodents is the hippocampus (HPC). The HPC is uniquely susceptible to stress, has distinct patterns of information flow, and functional segregation of cognitive and affective memories...
Show more"Depression is a highly prevalent mood disorder which affects up to 20% of the population. While women are twice as likely as men to be diagnosed with a mood disorder, the neurophysiological contributions to this disparity are unclear. One brain region implicated in depression-like symptoms in both humans and rodents is the hippocampus (HPC). The HPC is uniquely susceptible to stress, has distinct patterns of information flow, and functional segregation of cognitive and affective memories across the dorsoventral axis; this suggests specific hippocampal subpopulations may be involved in different aspects of learning and memory. Previously, the transcription factor Delta-FosB was shown to regulate spatial learning and cell proliferation, and was found to be induced in dHPC after stress. Herein, I elucidate Delta-FosB's contributions in hippocampal subregions among specific behavioral domains: dentate gyrus (DG) influence on spatial learning, and vHPC influence on stress-behavior in both sexes. Specifically, I show that DG SGZ FosB gene products are necessary for normal neurogenesis and learning. As the vHPC is implicated in affective learning and memory through its connectivity to limbic regions, I examined the role of vHPC Delta-FosB in stress-induced behaviors. I describe divergent patterns of behavior in males, where Delta-FosB in vHPC-NAc is necessary and sufficient for resilience to stress but Delta-FosB in vHPC-BLA is necessary for the expression of fear and anxiety. These results demonstrate that individual genes can have disparate roles within a single brain region, based not only on heterogenous cell types but on the specific projections of the neurons in which they are expressed. I also show a basal sex difference in stress susceptibility which is mediated by the vHPC-NAc circuit and adult testosterone. These data show vHPC-NAc activity is causally linked to the sex difference in susceptibility to stress-induced anhedonia. This relationship is dependent upon long-term adaptation of vHPC-NAc projections and may reflect on the biological underpinning of female vulnerability to mood disorders related to stress."--Pages ii-iii.
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Title: The role of trpc2 in sex-specific brain circuits and behavior
Creator: Pfau, Daniel
Date: 2019
Collection: Electronic Theses & Dissertations
Description: The transient receptor potential cation channel 2 (TRPC2) is canonically known for carrying pheromonal information from the vomeronasal organ (VNO) to the brain in rodents. Mice with a disabled TRPC2 gene display drastic changes in sex-specific behaviors, including sexual and aggressive behavior. Specifically, male-male and maternal aggression is absent while both males and females show male-typical mounting behavior directed towards both sexes in a non-preferential manner. In short, sexual...
Show moreThe transient receptor potential cation channel 2 (TRPC2) is canonically known for carrying pheromonal information from the vomeronasal organ (VNO) to the brain in rodents. Mice with a disabled TRPC2 gene display drastic changes in sex-specific behaviors, including sexual and aggressive behavior. Specifically, male-male and maternal aggression is absent while both males and females show male-typical mounting behavior directed towards both sexes in a non-preferential manner. In short, sexual preference seems to be severely disrupted. Several groups have shown that the VNO of TRPC2 knockout (KO) mice show a markedly reduced activation of the VNO in response to pheromones, suggesting that pheromonal signaling via TRPP2 channels in the VNO shape these sex-specific behaviors. However, TRPC2 is also expressed in other tissues, including the reproductive organs, raising the possibility that disruption of TRPC2 function outside the VNO also contributes to changes in adult sex-specific behavior. My dissertation research aims to understand the underpinnings of this behavioral change, examining how the loss of TRPC2 function influences pre- and postnatal development, reproductive success and morphological sex differences in the brain. First, I found that mice lacking TRPC2 display defects in their development, with effects on pubertal timing and pup survival, along with effects on reproductive success. While maternal experience rescued pup survival in TRPC2 KO mice, it did not improve reproductive outcomes. Next, I examined two brain regions implicated in the control of mounting and aggression, the posterodorsal aspect of the medial amygdala and ventromedial hypothalamus. Ux phystilizing a Nissl stain and glial fibrillary acidic protein immunohistochemistry, I determined that TRPC2 KO mice show altered patterns of sex differences at the cellular level in both these regions, offering insight into the neural mechanisms underlying impaired sexual and aggressive behavior. Finally, I examined whether sexual experience can reverse deficits in behavior and rescue the brain's response to pheromones. I found that prolonged sexual experience did not reinstate normal sexual preference nor recover the brain response to pheromones. These experiments suggest TRPC2 function, driven by pheromones and possibly other incoming signals, participates in organizing sex-specific behavior and brain circuitry. TRPC2 function outside the VNO may also impact adult sex-specific behaviors.
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Title: Determination of the role of ventral tegmental area SGK1 catalytic activity and phosphorylation in drug behavior
Creator: Doyle, Marie Althea
Date: 2020
Collection: Electronic Theses & Dissertations
Description: Substance use disorder is a chronic, relapsing disease that affects 20.3 million people in the United States. Despite its prevalence, treatments remain inadequate in part due to our limited understanding of the neuroadaptations induced by drug use. Drugs of abuse are known to regulate the activity of the mesolimbic dopamine (DA) system, a key circuit for drug action and reward. Specifically, drug-induced changes in ventral tegmental area (VTA) cellular activity and gene regulation have been...
Show moreSubstance use disorder is a chronic, relapsing disease that affects 20.3 million people in the United States. Despite its prevalence, treatments remain inadequate in part due to our limited understanding of the neuroadaptations induced by drug use. Drugs of abuse are known to regulate the activity of the mesolimbic dopamine (DA) system, a key circuit for drug action and reward. Specifically, drug-induced changes in ventral tegmental area (VTA) cellular activity and gene regulation have been linked to behavioral outputs associated with addiction. Previous work determined that serum- and glucocorticoid-inducible kinase 1 (SGK1) mRNA expression, catalytic activity, and phosphorylation were increased by chronic administration of cocaine or morphine; however, it was unknown if these changes contributed to drug reward behaviors. In this thesis, I utilized transgenic and viral-mediated SGK1 manipulations to determine the impact of altered SGK1 expression and function on cocaine and morphine related-behaviors, primarily assessed by cocaine conditioned place preference (CPP) and voluntary morphine intake using a two-bottle choice task. I first established that that while SGK1 is transcriptionally upregulated and biochemically modified by chronic-drug administration, SGK1 deletion in either the VTA or in DA neurons was not capable of altering drug reward behaviors. Though SGK1 gene deletion did not alter reward, I next showed that viral-mediated overexpression of SGK1 mutants in the VTA of adult mice produced behaviorally relevant effects on cocaine and morphine reward. Specifically, intra-VTA infusion of a catalytically inactive SGK1 mutant (K127Q) significantly decreased cocaine CPP and morphine preference, suggesting that decreased VTA SGK1 activity is sufficient to impair drug reward. To more fully understand the role of VTA SGK1 in behaviors relevant to addiction, I manipulated SGK1 expression in a cell type-specific manner to determine whether SGK1 activity in VTA DA or GABA neurons drove the observed behavioral effects. Utilizing novel Cre-dependent viral constructs, I found that reduced SGK1 activity in VTA DA neurons significantly decreases cocaine CPP, while this same manipulation in VTA GABA neurons had no effect. Interestingly, this manipulation did not alter morphine preference. Future studies seek to determine a potential mechanism for these behavioral effects using ex vivo slice electrophysiology, and parallel studies currently explore the potential effects of a similarly regulated SGK1 phosphorylation site (Ser78) in drug-related behaviors. Altogether, these studies will allow for the identification of the specific cells and circuits that are critical for SGK1-mediated effects on drug reward and intake, a necessary step in assessing the feasibility of SGK1 inhibition as a novel therapeutic avenue for addiction.
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Title: Motherhood, stress, and serotonin receptors : influence on postpartum social and affective behaviors in female laboratory rats
Creator: Vitale, Erika
Date: 2020
Collection: Electronic Theses & Dissertations
Description: Mammalian mothers show a unique suite of behavioral responses beginning around the time of parturition that are necessary for successful rearing of young. These include caring for offspring, high levels of aggression, and low anxiety. These behaviors emerge in response to the unique neurochemical milieu resulting from pregnancy and parturition. Studies in this dissertation test the hypothesis that changes in receptors for the neurotransmitter serotonin (5-HT) are part of this neurochemistry...
Show moreMammalian mothers show a unique suite of behavioral responses beginning around the time of parturition that are necessary for successful rearing of young. These include caring for offspring, high levels of aggression, and low anxiety. These behaviors emerge in response to the unique neurochemical milieu resulting from pregnancy and parturition. Studies in this dissertation test the hypothesis that changes in receptors for the neurotransmitter serotonin (5-HT) are part of this neurochemistry in female laboratory rats. Experiments in chapter one found that there are reproductive state-dependent changes in expression of central 5-HT receptors that may be responsible for peripartum behavioral responses. Specifically, females examined at parturition and early lactation showed less serotonin 2C receptor (5-HT2C) mRNA expression in the midbrain dorsal raphe (DR), more serotonin 2A receptor (5-HT2A) mRNA in the medial preoptic area (mPOA), and more serotonin 1A (5-HT1A) mRNA in the shell subregion of the nucleus accumbens (NAcSh) compared to nulliparous females. Receptor autoradiography confirmed that binding density of 5-HT2A was higher in the mPOA of recently parturient females and that binding density of 5-HT1A in the NAcSh was higher in lactating females at particular rostrocaudal levels. Such differences in 5-HT receptor expression were not found in maternally acting virgin females, suggesting that pregnancy and parturition are necessary for these changes in central 5-HT receptors to occur. Because pregnancy stress derails most behavioral adaptations of motherhood, follow up experiments then explored whether the normative changes in 5-HT receptor expression across reproduction were prevented by daily application of mild-to-moderate stress beginning one week after mating. Stressed females showed lower maternal care and higher depression-like behaviors, which were correlated with 5-HT receptor mRNA in the mPOA, NAcSh and DR. Autoradiographic binding density of mPOA 5-HT2A receptors was not affected by pregnancy stress, although the stress reduced 5-HT1A binding in the NAcSh. Because the NAcSh is involved in motivation and reward processing, the last experiment directly tested whether 5-HT1A receptors in the NAcSh contribute to maternal caregiving and emotional behaviors. Long-term knock down of 5-HT1A in the NAcSh was established using an adeno-associated virus promoting shRNA against 5-HT1A mRNA. The 5-HT1A shRNA vector or a scrambled control vector was infused into the NAcSh during early pregnancy and mothers' later postpartum social and affective behaviors (i.e. caregiving, maternal motivation, aggression, anxiety- and depression-like behaviors) were observed. 5-HT1A knock down resulted in higher frequencies of self-grooming and sleeping away from the nest, delayed retrieval of displaced pups back to the nest, and increased anxiety-like behavior. Overall, I found that female reproduction is associated with changes in serotonin receptor expression in numerous brain sites involved in postpartum behavior. Of particular interest, the normative change in 5-HT1A expression in the nucleus accumbens shell is altered in response to stress during pregnancy, and disrupting its expression reduces maternal motivation and increases postpartum anxiety-like behavior. Together, the results from this dissertation provide new insights into how the serotonergic system contributes to postpartum social and affective behaviors and offer a potential mechanism via the brain's reward system through which pharmacological treatments that affect the serotonin system (e.g., SSRIs) may work to alleviate postpartum affective disorders in women.
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Title: An examination of between- and within-subject effects of stress on emotional eating over 49 consecutive days in women
Creator: Fowler, Natasha
Date: 2021
Collection: Electronic Theses & Dissertations
Description: Objective: Stress is associated with emotional eating (EE) in women cross-sectionally (between-subject). However, few studies have examined stress longitudinally limiting our understanding of how within-subject variations in stress level influence risk for EE over time and whether stress is in fact a risk factor or consequence of EE (within-subject). This study used an intensive, longitudinal study design to examine between- and within-subject effects of major life stress, daily stress impact...
Show moreObjective: Stress is associated with emotional eating (EE) in women cross-sectionally (between-subject). However, few studies have examined stress longitudinally limiting our understanding of how within-subject variations in stress level influence risk for EE over time and whether stress is in fact a risk factor or consequence of EE (within-subject). This study used an intensive, longitudinal study design to examine between- and within-subject effects of major life stress, daily stress impact, and cortisol on EE in women. Methods: An archival sample of 477 women aged 15-30 years recruited from the Michigan State University Twin Registry provided daily ratings of EE and stress impact for 49 consecutive days, along with self-reports of major life stress in the last 12 months and hair cortisol concentration (HCC), a longitudinal measure of cortisol secretion. Mixed linear models examined main and interactive effects of each stress variable on EE. Results: Both between- and within-subject analyses showed that daily stress more strongly predicted EE than major life stress. Specifically, women engaged in higher levels of EE when they experienced higher levels of daily stress impact relative to other women (between-subject) and their own daily stress levels (within-subject). There was a tendency for lower HCC to predict increased levels of EE (between-subject). Discussion: Findings confirm longitudinal associations between daily stress impact and cortisol with EE in women. Results also highlight the importance of within-subject shifts in a woman’s stress level in her risk for EE and suggest that stress management techniques may a be useful tool for treatment.
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Title: Masking and its neural substrates in day- and night-active mammals
Creator: Langel, Jennifer Lou
Date: 2016
Collection: Electronic Theses & Dissertations
Description: Light can directly and acutely alter arousal states, a process known as “masking”. Masking effects of light are quite different in diurnal and nocturnal animals with light increasing arousal and activity in the former and suppressing in the latter. Few studies have examined chronotype differences in masking or the neural substrates contributing to this process. However, in nocturnal mice, masking responses are mediated through a subset of retinal ganglion cells that are intrinsically...
Show moreLight can directly and acutely alter arousal states, a process known as “masking”. Masking effects of light are quite different in diurnal and nocturnal animals with light increasing arousal and activity in the former and suppressing in the latter. Few studies have examined chronotype differences in masking or the neural substrates contributing to this process. However, in nocturnal mice, masking responses are mediated through a subset of retinal ganglion cells that are intrinsically photosensitive (termed ipRGCs) due to their expression of the melanopsin protein. The goal of the studies in this dissertation was to first characterize masking responses in day- and night-active animals and then to evaluate the possibility that differences in ipRGC projections or the circuitry within their targets might contribute to species differences in masking.First, I compared behavioral and brain responses to light across individuals within a species (the Nile grass rat, Arvicanthis niloticus). In this diurnal species some individuals become night-active when given access to a running wheel, while others do not. I found that masking responses to light and darkness in these animals were dependent upon the chronotype of the individual. Additionally, the responsiveness of neurons within two brain regions, the intergeniculate leaflet (IGL) and olivary pretectal area (OPT), was associated with the behavioral response of the animal to light.Next, I compared behavioral responses to light and darkness across species, the diurnal grass rat and the nocturnal Norway rat (Rattus norvegicus: Long Evans (LE) strain). Overall, light suppressed general activity in LE rats, while darkness increased it, a pattern very different from that seen previously in grass rats, in which light stimulates activity, but darkness has no effect (Shuboni et al., 2012). I also found that light induced sleep and resting behavior in LE rats and suppressed it in grass rats and that these effects lasted for at least a full hour.To determine whether differences in the projections of ipRGCs may account for species differences in masking, I characterized the melanopsin system of the grass rat and compared it to that previously described in nocturnal rodents. I found that the grass rat retina contained the same basic subtypes of melanopsin cells and that the majority of these cells (87.7%) contained the neuropeptide, pituitary adenylate cyclase-activating polypeptide (PACAP), while 97.4% of PACAP cells contained melanopsin. Since, within the retina, PACAP is found almost exclusively in ipRGCs, I then examined the distribution of PACAP-labeled fibers originating in the retina to characterize ipRGCs projections to the brain. I found that although these were similar to those of nocturnal species, some differences existed in their density in the dorsal and ventral lateral geniculate nucleus (dLGN and vLGN) and in the rostrocaudal extent of the OPT.Finally, to determine whether differences exist in some features of the internal circuitry of ipRGC target areas, I first examined whether there were differences in retinal input to light responsive neurons within ipRGC target areas in a diurnal and nocturnal brain. Within the IGL, the majority of light responsive neurons had close contacts with retinal fibers in both grass rats and LE rats. I then determined whether differences exist in excitatory (glutamate) and inhibitory (GABA) neuronal populations in multiple ipRGC target areas. In many areas the distributions of glutamate and GABA cells were similar in the two species, but there were differences in the vLGN (more glutamate in LE rats than grass rats) and in the lateral habenula (GABA present in grass rats but not LE rats). Overall, these studies provide insight into chronotype differences in behavioral responses to light, as well as the brain regions that may mediate those differences.
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Title: Exploring the role of negative urgency in the etiology of binge eating : genetic/environmental associations and interactions with ovarian hormones
Creator: Racine, Sarah Elizabeth
Date: 2013
Collection: Electronic Theses & Dissertations
Description: Impulsivity has emerged as a critical personality trait contributing to individual differences in the development of binge eating, and research suggests that negative urgency (i.e., the tendency to engage in rash action in response to negative affect) is a particularly important form of impulsivity for these behaviors. However, studies investigating the extent to which genetic and/or environmental influences underlie the effects of negative urgency on binge eating are lacking. Moreover, it...
Show moreImpulsivity has emerged as a critical personality trait contributing to individual differences in the development of binge eating, and research suggests that negative urgency (i.e., the tendency to engage in rash action in response to negative affect) is a particularly important form of impulsivity for these behaviors. However, studies investigating the extent to which genetic and/or environmental influences underlie the effects of negative urgency on binge eating are lacking. Moreover, it remains unclear whether associations between negative urgency and binge eating are simply due to the well-established role of negative affect in the development/maintenance of binge eating. Study 1 addressed these gaps by examining phenotypic and etiologic associations between trait levels of negative urgency, negative affect, and binge eating in a sample of 444 same-sex female twins from the Michigan State Twin Registry. Negative urgency was significantly associated with two well-validated measures of binge eating tendencies, even after controlling for the effects of negative affect. Genetic factors accounted for the majority (62-77%) of this phenotypic association, although a significant proportion of this genetic covariation was due to genetic influences in common with negative affect. Non-shared environmental factors accounted for a relatively smaller (23-38%) proportion of the association between negative urgency and binge eating, but these non-shared environmental effects were independent of negative affect. Findings suggest that emotion-based rash action, combined with high levels of negative affect, may increase risk for binge eating, and that this likely occurs through both genetic and environmental mechanisms.Full article available at: http://psycnet.apa.org/journals/abn/ Study 2 considered whether, in addition to having main effects, negative urgency might interact with other well-established risk factors for binge eating. Within-person changes in estradiol and progesterone predict changes in binge eating tendencies across the menstrual cycle. However, all women have menstrual-cycle fluctuations in hormones, but few experience binge eating. Personality traits, such as negative urgency, may be critical individual difference factors that influence who will engage in emotional eating in the presence of a vulnerable hormonal environment. Self-reports of emotional eating and saliva samples for hormone measurement were collected for 45 consecutive days in adolescent and young adult females (N=239). Negative urgency and negative emotionality were measured once and were examined as moderators of hormone-emotional eating associations. Consistent with prior research, within-person changes in the interaction between estradiol and progesterone predicted emotional eating symptom changes. However, negative urgency and negative emotionality did not interact with changes in estradiol, progesterone, or the estradiol-progesterone interaction to predict changes in emotional eating across the menstrual cycle. Future research should consider additional factors, other than the two personality traits examined, that may account for individual differences in within-person associations between hormones and emotional eating. Full article available at: http://www.sciencedirect.com/science/journal/14710153
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Title: Sexual dimorphisms and androgen influence in medial posterodorsal amygdala astrocytes
Creator: Johnson, Ryan T.
Date: 2011
Collection: Electronic Theses & Dissertations
Description: The amygdala is a highly interconnected brain region involved in fear, anxiety, social and reproductive behaviors. In humans and laboratory species the amygdala exhibits sexual dimorphisms in neuroanatomy and function both in juveniles and adults. In rodents, the medial posterodorsal amygdala (MePD) is particularly sexually dimorphic and gonadal hormone sensitive, and while neurons have been examined in this region, few reports have examined the potential influence of gonadal hormones on...
Show moreThe amygdala is a highly interconnected brain region involved in fear, anxiety, social and reproductive behaviors. In humans and laboratory species the amygdala exhibits sexual dimorphisms in neuroanatomy and function both in juveniles and adults. In rodents, the medial posterodorsal amygdala (MePD) is particularly sexually dimorphic and gonadal hormone sensitive, and while neurons have been examined in this region, few reports have examined the potential influence of gonadal hormones on other cellular components of the MePD. Astrocytes are a subtype of glia involved in synapse formation and known to be plastic and dynamic cells sensitive to gonadal hormone influence in several brain regions. My dissertation reveals sexual dimorphisms in the number of astrocytes in the juvenile rat MePD and that this sexual dimorphism remains present in adult animals. I also found sex differences in the arbor complexity of astrocytes in adults that are not present prior to puberty. Astrocytes also respond to changes in circulating hormone levels in adulthood. Furthermore, while the sex difference in astrocyte numbers in juvenile animals is androgen receptor-independent, the sex differences found in adult astrocyte numbers and arbor complexity are both androgen receptor-dependent. Finally, I provide evidence that astrocytes in the MePD contain androgen receptors, suggesting that androgens may act directly on these cells. The influence of gonadal hormones on astrocytes in the MePD is likely an important part of pubertal development and has implications for our understanding of the cellular organization of the amygdala and its function.
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Title: Androgen toxicity on neuromuscular physiology in a novel model of SBMA
Creator: Oki, Kentaro
Date: 2013
Collection: Electronic Theses & Dissertations
Description: Spinal bulbar muscular atrophy (SBMA) is a progressive motor disease that appears only in men around mid-life and results in limb weakness, dysphagia (swallowing difficulties), and dysarthria (speech difficulties). The disease is believed to be neurogenic, originating from motoneuron dysfunction and its slow progressive death. Thus, most of the studies characterizing the disease in mice have focused on motoneuron as the site of disease although there is some clinical evidence suggesting...
Show moreSpinal bulbar muscular atrophy (SBMA) is a progressive motor disease that appears only in men around mid-life and results in limb weakness, dysphagia (swallowing difficulties), and dysarthria (speech difficulties). The disease is believed to be neurogenic, originating from motoneuron dysfunction and its slow progressive death. Thus, most of the studies characterizing the disease in mice have focused on motoneuron as the site of disease although there is some clinical evidence suggesting skeletal muscle may be an important site of disease. SBMA is caused by a mutation that leads to an expansion of CAG repeats coding for glutamine in the androgen receptor (AR) gene, and the male-specific phenotype is believed to be androgen-dependent as females carrying the mutation have little to no symptoms. The male-specific disease phenotype has been replicated in mouse models expressing similar mutations and can be improved with castration, reinforcing that the disease is androgen-dependent. Furthermore, female mice in these models are asymptomatic and only exhibit disease symptoms with androgen treatment. Although a CAG expansion in the AR gene is thought to underlie the disease, a similar phenotype is observed in a transgenic (Tg) mouse line engineered to express a rat AR cDNA with a wild type (WT) number of glutamine residues (22) at very high levels exclusively in skeletal muscle fibers. Although alteration of gene and protein expression is exclusive to the skeletal muscles, mice from this myogenic (141) model exhibit a phenotype similar to the other CAG-expanded mouse models of SBMA. Tg 141 female mice that exhibit an androgen-dependent loss of motor function after 3-5 days of testosterone (T) treatment exhibit skeletal muscle dysfunction, recorded by electrically stimulating isolated preparations of the extensor digitorum longus (EDL) and the soleus (SOL), prototypical fast- and slow-twitch muscles, respectively. T treatment in female 141 Tg mice over 3-5 days was enough to induce a precipitous decrease in force production in both muscles and alterations to kinetics during contractions in the EDL. To confirm that skeletal muscles could be a primary site of disease during SBMA, male mice of the same 141 model, as well as two other SBMA mouse models were examined. The other models were one expressing the full-length human AR with 97 CAG repeats (97Q model) and another expressing 113 CAG repeats in the first exon of the AR gene. Muscle dysfunction in the other models would further support myogenic contributions as being critical to the SBMA motor phenotype. Motor dysfunction was recorded in all mouse models, and male mice from the 141 and 97Q models exhibited dysfunction in the EDL and SOL. All muscles exhibited some deficit during force production, and contraction kinetics were altered in the EDL of Tg 141 males. These results indicate that severe muscle dysfunction can underlie the phenotype during SBMA, and androgens can act on the skeletal muscles to induce motor weakness. Furthermore, skeletal muscles may be an important target for therapeutics that could ameliorate disease symptoms.
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Title: Rat strain differences in binge eating : implications for genetic differences
Creator: Hildebrandt, Britny
Date: 2013
Collection: Electronic Theses & Dissertations
Description: Binge eating is a significantly heritable phenotype, but efforts to identify specific risk genes have fallen short. Identification of animal strain differences in risk for binge eating could highlight genetic differences across animals that can be exploited in future animal and molecular genetic research. The current study aimed to explore strain differences in risk for binge eating in Sprague-Dawley versus Wistar female rats using the Binge Eating Resistant/Binge Eating Prone model. A sample...
Show moreBinge eating is a significantly heritable phenotype, but efforts to identify specific risk genes have fallen short. Identification of animal strain differences in risk for binge eating could highlight genetic differences across animals that can be exploited in future animal and molecular genetic research. The current study aimed to explore strain differences in risk for binge eating in Sprague-Dawley versus Wistar female rats using the Binge Eating Resistant/Binge Eating Prone model. A sample of male Sprague Dawley rats, a known low-risk group for binge eating, was included as a comparison group. A total of 83 rats (23 Wistar female, 30 Sprague-Dawley female, 30 Sprague-Dawley male) completed a protocol of intermittently administered, palatable food. Binge eating prone (BEP) and binge eating resistant (BER) rats were identified using a tertile approach. Sprague-Dawley female rats consumed the highest amount of palatable food and were more likely to be classified as BEP compared to Wistar female and Sprague-Dawley male rats. Wistar female rats were not significantly different from Sprague-Dawley male rats in their palatable food intake and tendency to be classified as BER rather than BEP. Sprague-Dawley female rats appear to be a particularly vulnerable strain for binge eating. Comparisons between this strain and others could help identify specific genetic/biological factors that differentiate this strain from lower risk strains. The opioid and dopaminergic systems, linked to binge eating in humans, are possible candidates to explore. Strain differences in these reward processes and their genetic/biological underpinnings could help increase understanding of individual differences in risk for binge eating in humans.
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Title: Noradrenergic modulation of the ventral bed nucleus of the stria terminalis : effects on maternal and anxiety-related behaviors
Creator: Smith, Carl David
Date: 2011
Collection: Electronic Theses & Dissertations
Description: Postpartum rats spontaneously display pup-directed behaviors and exhibit lower anxiety-related behaviors compared to nulliparous rats. The ventral bed nucleus of the stria terminalis (BSTv) is a neural site critical for dams' maternal behaviors and, in male rats, for regulating anxiety-related behaviors. Neurotransmitters modulating the BSTv in females have not been previously identified. The BSTv contains one of the highest concentrations of norepinephrine (NE) in the brain and, in male rats...
Show morePostpartum rats spontaneously display pup-directed behaviors and exhibit lower anxiety-related behaviors compared to nulliparous rats. The ventral bed nucleus of the stria terminalis (BSTv) is a neural site critical for dams' maternal behaviors and, in male rats, for regulating anxiety-related behaviors. Neurotransmitters modulating the BSTv in females have not been previously identified. The BSTv contains one of the highest concentrations of norepinephrine (NE) in the brain and, in male rats, the release of (NE) in the BSTv is known to increase anxiety. It is also known that NE depresses neural excitability when applied to the BSTv. Given that: 1) maternal behavior is dependent on a functional BSTv, 2) NE inhibits the BSTv, 3) NE increases anxiety in male rats, and 4) dams exhibit pup-directed care and low anxiety, I hypothesized that dams maintain naturally low levels of NE release in their BSTv that account for their maternal responsiveness and low anxiety-related behaviors. To test this hypothesis, I examined the effects of increasing NE release in the BSTv on maternal behaviors, the effects of increasing or decreasing NE release in the BSTv on anxiety-related behaviors, and the concentrations of endogenous monoamines in female rats. Yohimbine or idazoxan (alpha-2 autoreceptor antagonists that increase NE release) significantly disrupted retrieving behaviors in postpartum rats. Idazoxan, but not yohimbine, also reduced the time dams spent nursing pups. Yohimbine also decreased exploration of the open arms in an elevated plus maze (EPM) when administered systemically or within the BSTv. Idazoxan, surprisingly, did not mimic the anxiogenic effects of yohimbine. Additionally, clonidine (an alpha-2 autoreceptor agonist that decreases NE release) did not affect anxiety-related behaviors in an EPM when administered systemically or within the BSTv. Finally, the concentrations of NE, dopamine, and serotonin were measured in the BSTv, medial preoptic area (mPOA), and dorsal bed nucleus of the stria terminalis (BSTd). Numerous differences in monoamine levels were found. Some notable results include postpartum rats containing higher levels of NE and turnover of serotonin compared to postpartum rats that had their litter removed or diestrous virgins. Together, these results demonstrate that increasing NE release in the BSTv of postpartum rats disrupts maternal behavior and increases anxiety-related behaviors. Furthermore, differences in NE and serotonin may account for the behavioral differences between postpartum and virgin rats.
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Title: Prenatal testosterone exposure and developmental differences in risk for disordered eating
Creator: Culbert, Kristen Marie
Date: 2011
Collection: Electronic Theses & Dissertations
Description: Prenatal testosterone may masculinize (i.e., lower) risk for disordered eating and account for sex differences in prevalence, yet how these effects emerge and whether these effects remain static across development is unknown. Opposite-sex (OS) twins provide a natural design to investigate such effects, as OS female twins are thought to be exposed to elevated testosterone in utero from their male co-twin. Although OS female twins have shown masculinized disordered eating relative to other...
Show morePrenatal testosterone may masculinize (i.e., lower) risk for disordered eating and account for sex differences in prevalence, yet how these effects emerge and whether these effects remain static across development is unknown. Opposite-sex (OS) twins provide a natural design to investigate such effects, as OS female twins are thought to be exposed to elevated testosterone in utero from their male co-twin. Although OS female twins have shown masculinized disordered eating relative to other females, findings have been mixed. The current research used a series of studies to investigate whether there are developmental differences in the masculinizing/protective effects of prenatal testosterone exposure in risk for disordered eating. Study 1 examined whether age moderates the masculinizing effects of prenatal testosterone on disordered eating. OS female twins have shown masculinized disordered eating in early young adulthood, but these effects have not been robustly observed in other time periods, e.g., mid-to-late adolescence or mid-to-late young adulthood. Participants included 764 male and female twins (ages 15-30) and 74 non-twin females (ages 15-23) from the Michigan State University Twin Registry (MSUTR). Two well-validated measures (i.e., Minnesota Eating Behaviors Survey and the Eating Disorder Examination Questionnaire) were used to assess several disordered eating symptoms. Results indicated no evidence for masculinization of disordered eating in OS female twins during mid-to-late adolescence (ages 15-20). In contrast, OS female twins showed substantially masculinized levels of disordered eating across several scales in early young adulthood (ages 21-23). Masculinization of disordered eating in OS female twins also appeared to be present in mid-to-late young adulthood (ages 24-30), but effects were weaker and more variable across disordered eating scales. These findings suggest developmental windows of expression for the protective effects of prenatal testosterone on disordered eating, with effects strongest under "average" risk periods (i.e., young adulthood) and attenuated under higher risk periods (i.e., mid-to-late adolescence, the peak period for eating disorder onset). Study 2 was a translational extension of study 1 that aimed to determine if prenatal testosterone's masculinizing effects on disordered eating only become prominent during young adulthood (as observed in study 1), or whether, as predicted by animal data, masculinization effects emerge with puberty. In female animals, early testosterone exposure decreases sensitivity to ovarian hormones during and after puberty. Thus, one potential mechanism for prenatal testosterone's effects on disordered eating may be via decreased sensitivity to the activating effects of ovarian hormones on disordered eating risk. Study 2 examined whether puberty underlies the emergence of prenatal testosterone's masculinization of disordered eating, independent of the confounding effects of several other factors (e.g., adiposity, mood, autonomy, being reared with a brother). Participants included 394 male and female twins and 63 non-twin females (ages 10-15) from the MSUTR. Well-validated measures assessed disordered eating, pubertal status, mood symptoms, and autonomy difficulties. Body mass index was used as a marker of adiposity. Disordered eating did not differ amongst twin types in pre-early puberty, whereas OS female twins fell intermediate to males and SS female twins on levels of disordered eating during mid-late puberty. Masculinization effects in mid-late pubertal OS female twins were not accounted for by adiposity, mood symptoms, autonomy difficulties or being reared with a brother. Taken together, findings indicate that other key factors (e.g., sensitivity to circulating gonadal hormones) likely underlie prenatal testosterone's protective effects on disordered eating.
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Title: Pathology at the neuromuscular junction in mouse models of spinal bulbar muscular atrophy
Creator: Poort, Jessica Erin
Date: 2014
Collection: Electronic Theses & Dissertations
Description: Spinal bulbar muscular atrophy (SBMA) is a progressive, late onset neuromuscular disease that results in muscle weakness and atrophy, as well as motoneuron death in men. While pathology at the neuromuscular junction (NMJ) is noted in numerous neurodegenerative diseases, disease-related changes at the NMJ in SBMA have not been explored. Characterizing such changes is not only important for determining whether the NMJ has any role in the functional changes underlying motor dysfunction, but also...
Show moreSpinal bulbar muscular atrophy (SBMA) is a progressive, late onset neuromuscular disease that results in muscle weakness and atrophy, as well as motoneuron death in men. While pathology at the neuromuscular junction (NMJ) is noted in numerous neurodegenerative diseases, disease-related changes at the NMJ in SBMA have not been explored. Characterizing such changes is not only important for determining whether the NMJ has any role in the functional changes underlying motor dysfunction, but also in determining how such potential pathology at the NMJ develops as disease progresses. If for example, pathology emerges first at the NMJ followed by motoneuron death, then the NMJ offers future promise as a therapeutic target for preventing or reversing symptoms of SBMA before motoneurons are lost. We evaluated three different mouse models of SBMA, one overexpressing a wildtype androgen receptor (AR) exclusively in muscle fibers (so called "myogenic" model), a second which expressed the endogenous AR gene with the first exon of the human mutant AR gene "knocked in" (the so called "knock-in" model), and a final model that broadly expresses a full length human AR transgene harboring the SBMA mutation (the so called "97Q" model). Using both confocal microscopy and electron microscopy, I found that all three mouse models show a pathological fragmentation of the NMJ suggestive of functionally weakened synapses. Other changes at the neuromuscular synapse suggesting decreases in synaptic strength that were found in some but not all models include a decline in the number of docked vesicles ready for release in nerve terminals, a widening of synaptic clefts, simplified postsynaptic folds, and an abnormal accumulation of synaptic vesicle and neurofilament proteins. Retrograde axonal transport of endosomes was also characterized in the 97Q model using live imaging confocal microscopy. Despite previously published data, I found no evidence for a disease-related defect in retrograde transport in the 97Q model. The strikingly abnormal morphology of NMJs in all three models raises the possibility that synaptic function is impaired. Such synaptic dysfunction may contribute to or underlie the impairments in motor function associated with SBMA.
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