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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
- 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
- Traumatic stress responses in rats reveal fundamental sex differences that mirror PTSD in men and women
- Creator
- Pooley, Apryl E., 1986-
- Date
- 2017
- Collection
- Electronic Theses & Dissertations
- Description
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Post-traumatic stress disorder (PTSD) develops after exposure to trauma and is associated with dysfunction in the normal stress response. Women are twice as likely as men to develop PTSD and tend to experience different symptoms and comorbidities than men, but the neurobiological basis for these pervasive sex differences is poorly understood due to the overwhelming male bias in the preclinical research. My dissertation work tested the novel hypothesis that the neurobiological mechanisms...
Show morePost-traumatic stress disorder (PTSD) develops after exposure to trauma and is associated with dysfunction in the normal stress response. Women are twice as likely as men to develop PTSD and tend to experience different symptoms and comorbidities than men, but the neurobiological basis for these pervasive sex differences is poorly understood due to the overwhelming male bias in the preclinical research. My dissertation work tested the novel hypothesis that the neurobiological mechanisms underlying the traumatic stress response in male and female rats are fundamentally different and may be related to normal sex differences in circulating levels of adult gonadal hormones. These experiments are the first to compare adult male and female rats across two rodent models of PTSD, single prolonged stress and predator exposure. I report a highly sex-specific traumatic stress response that recapitulates fundamental differences of PTSD in men and women. Surprisingly, these sex differences were largely independent of adult circulating gonadal hormones, housing conditions, and types of stress. Two standard measures, the acoustic startle response and dexamethasone suppression test to measure the negative feedback control of the stress hormone response, suggest that female rats, unlike male rats, are resilient to the effects of traumatic stress. However, other measures like sucrose preference and social interaction make it clear that females are not resilient, but simply respond differently to trauma than males. Dramatic sex differences in how trauma affects cFos activation and glucocorticoid receptor expression in the brain lend further support to the idea that the trauma response of males and females is fundamentally different, and likely determined prior to adulthood. Factors that mediate differences in how individuals adjust after trauma are attractive targets for the prevention and treatment of PTSD, and identifying such factors of resilience depends on understanding the various ways the traumatic stress response manifests in different individuals. I propose that sex differences offer a promising inroad for addressing this issue.
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- Title
- The role of muscle-derived neurotrophic factors in spinal bulbar muscular atrophy
- Creator
- Halievski, Katherine
- Date
- 2016
- Collection
- Electronic Theses & Dissertations
- Description
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"Muscle-derived neurotrophic factors are critical to the survival and maintenance of a healthy neuromuscular system and their expression is often perturbed in neuromuscular disease, such as in spinal bulbar muscular atrophy (SBMA). SBMA is a disease that occurs only in men, is androgen-dependent, and is characterized by the progressive weakness and atrophy of muscles that are innervated by lower motoneurons of the brain stem and spinal cord. Moreover, a polyglutamine expansion mutation in the...
Show more"Muscle-derived neurotrophic factors are critical to the survival and maintenance of a healthy neuromuscular system and their expression is often perturbed in neuromuscular disease, such as in spinal bulbar muscular atrophy (SBMA). SBMA is a disease that occurs only in men, is androgen-dependent, and is characterized by the progressive weakness and atrophy of muscles that are innervated by lower motoneurons of the brain stem and spinal cord. Moreover, a polyglutamine expansion mutation in the androgen receptor (AR) gene is linked to SBMA. CHAPTER 1 provides a general introduction on SBMA pathophysiology, and describes the various implicated roles of neurotrophic factors in health and disease, with a particular emphasis on the role of brain-derived neurotrophic factor in the neuromuscular system. In this dissertation, I examine the status and potential contribution of muscle-derived brain-derived neurotrophic factor in SBMA pathogenesis using two mouse models of this disease. I conclude that supplementing diseased muscle with exogenous BDNF may offer therapeutic benefit for treating symptoms of SBMA. In CHAPTER 2, I describe my discovery that skeletal muscle from diseased SBMA mice were deficient in BDNF. I found this deficit in two different mouse models of SBMA (one that overexpresses wild-type AR in a muscle-specific manner as well as one that globally expresses a polyglutamine-expanded AR). I also found comparable deficits in BDNF in both fast and slow muscles. To explore whether the deficit in muscle BDNF is relevant to SBMA pathology, I asked whether it was androgen-dependent like the disease. Indeed, BDNF mRNA levels were reduced in the presence of androgens, correlating with motor dysfunction, and when androgens were removed, both BDNF expression and motor function were restored to normal. Moreover, I found that BDNF levels were reduced prior to the loss of motor function, thus indicating that impaired BDNF expression in skeletal muscles is an early and possibly precipitating event in the emergence of motor dysfunction in SBMA. In CHAPTER 3, I sought to examine whether relieving the deficit in muscle BDNF would ameliorate disease symptoms, given the strong correlation found in CHAPTER 2, as well as the substantial evidence linking BDNF to the maintenance of proper neuromuscular function. To do so, I used a transgenic Cre/loxP approach to specifically overexpress BDNF in muscle cells of diseased SBMA mice. I found that overexpression of muscle BDNF slowed disease progression after its onset, slowing the normal rate of decline in hang performance. Moreover, this improvement was associated with an improvement in the expression of genes relevant to muscle contraction in slow-twitch muscle, but not fast. CHAPTER 4 provides an overview of my findings and describes remaining questions and future work to be done. The approach to delineate which disease mechanisms are improved by muscle BDNF to slow disease progression will be discussed in CHAPTER 4. Candidate mechanisms include improved neuromuscular transmission and muscle contractile force tension in slow-twitch muscles."--Pages ii-iii.
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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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