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Title: Lateral hypothalamic neurotensin neurons orchestrate ingestive behaviors
Creator: Kurt, Gizem
Date: 2019
Collection: Electronic Theses & Dissertations
Description: "Food and water are necessary for survival but can only be obtained via ingestive behaviors (feeding, drinking and moving). Survival thus depends on the ability of the brain to coordinate the need for water and energy with appropriate behaviors to modify their intake as necessary for homeostasis. However, the balance of these behaviors also inherently determines body weight, and imbalances contribute to the development of weight disorders such as obesity and anorexia nervosa. The lateral...
Show more"Food and water are necessary for survival but can only be obtained via ingestive behaviors (feeding, drinking and moving). Survival thus depends on the ability of the brain to coordinate the need for water and energy with appropriate behaviors to modify their intake as necessary for homeostasis. However, the balance of these behaviors also inherently determines body weight, and imbalances contribute to the development of weight disorders such as obesity and anorexia nervosa. The lateral hypothalamic area (LHA) of the brain is anatomically positioned to coordinate the sensation of osmotic and energy status with goal-directed ingestive behaviors necessary to maintain homeostasis and body weight, and, hence, may hold insight into potential treatment for energy balance disorders. This work was done to evaluate how neurotensin expressing LHA neurons (LHA Nts neurons) coordinate ingestive behaviors. The central hypothesis of this thesis was that the LHA neurotensin (Nts) neurons direct drinking behavior in response to physiologic need (thirst) via neural outputs to the lateral preoptic area (LPO), but do not modify feeding via LPO. The rationale for this hypothesis was that the LHA neurons promotes drinking, but suppresses feeding. In order to understand the nature of the drinking regulation by LHA Nts neurons, we experimentally activated LHA Nts neurons and studied drinking behavior under well-hydrated and dehydrated conditions. We observed that activation of LHA Nts neurons promotes voracious drinking of water and water-based solutions and with the given choice, animals prefer water and palatable solutions, regardless of the caloric content, rather than bitter and dehydrating solutions. We also found that activation increases the motivation to drink in well hydrated and thirsty animals beyond their perceived thirst. In addition, we showed that LHA Nts neural activation is not necessary for homeostatic and need based consumption. Furthermore, we mapped the connectivity of the LHA Nts neurons within the brain and provided a list of osmo- and energy-sensory and regulatory areas which are directly connected to LHA Nts neurons. Finally, we identified LHA Nts→LPO circuit that drives the drinking effect of LHA Nts neurons, but is not the route they suppress feeding. Overall, this work suggests that control of drinking and feeding by LHA Nts circuits is divergent and modulation of specific LHA Nts circuits may be useful therapeutic targets to treat dysregulated water intake."--Pages ii-iii.
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Title: Circuit-Specific Inhibition of Dopaminergic Signaling Associated with Phantom Gustatory Sensations in Disrupted-in-Schizophrenia-1 Mice
Creator: Fry, Benjamin R.
Date: 2022
Collection: Electronic Theses & Dissertations
Description: Schizophrenia is a severe neuropsychiatric disorder characterized by a suite of symptoms occurring across cognitive (delayed processing, paraphasia, attentional deficits), negative (anhedonia, blunted affect, catatonia), and positive (hallucinations, delusions) domains. Antipsychotics are the most commonly prescribed medication to treat positive symptoms, however their use is complicated by substantial side-effects and inadequate efficacy. This reflects a lack of progress in understanding the...
Show moreSchizophrenia is a severe neuropsychiatric disorder characterized by a suite of symptoms occurring across cognitive (delayed processing, paraphasia, attentional deficits), negative (anhedonia, blunted affect, catatonia), and positive (hallucinations, delusions) domains. Antipsychotics are the most commonly prescribed medication to treat positive symptoms, however their use is complicated by substantial side-effects and inadequate efficacy. This reflects a lack of progress in understanding the precise neurobiological mechanisms underlying these symptoms, due in part to a lack of appropriate preclinical animal models. Here, I used an animal model of genetic vulnerability for neuropsychiatric illness known as Disrupted-in-schizophrenia-1 (DISC-1) to examine impaired reality testing, which reflects an aberrant internal representation of an absent event. In mice, this can be observed by an associatively evoked perception of an absent sweet taste. This effect is dopaminergically-dependent and associated with elevated activity in the insular cortex (IC). By combining sophisticated Pavlovian behavioral procedures with chemogenetic inhibition of dopamine neurons projecting from the ventral tegmental area (VTA) to the IC, I show that inactivation of the VTA --> IC dopaminergic circuitry leads to impaired reality testing in wild-type mice, and that DISC-1 mice have significantly less dopamine neurons which send projections to the IC, specifically. These data yield new insights with regard to the neurobiology underlying reality testing and the functional anatomical outcomes following perturbations of the DISC-1 genetic locus. My studies also suggest potential targets for the development of novel pharmacological treatments in humans with schizophrenia.
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Title: Delineation of Delta FosB's in vivo redox sensitivity
Creator: Lynch, Haley Marie
Date: 2021
Collection: Electronic Theses & Dissertations
Description: Many neurodegenerative diseases, including Alzheimer’s disease (AD), are driven by altered reduction/oxidation (redox) balance in the brain. Moreover, cognitive decline in AD is caused by neuronal dysfunction that precedes cell death, and this dysfunction is in part produced by altered gene expression. However, the mechanisms by which redox state controls gene expression in neurons are not well understood. Delta FosB is a neuronally enriched transcription factor critical for orchestrating...
Show moreMany neurodegenerative diseases, including Alzheimer’s disease (AD), are driven by altered reduction/oxidation (redox) balance in the brain. Moreover, cognitive decline in AD is caused by neuronal dysfunction that precedes cell death, and this dysfunction is in part produced by altered gene expression. However, the mechanisms by which redox state controls gene expression in neurons are not well understood. Delta FosB is a neuronally enriched transcription factor critical for orchestrating gene expression underlying memory, mood, and motivated behaviors and is dysregulated in AD. Delta FosB regulates gene expression by dimerizing with JunD to form activator protein 1 (AP-1) which binds the promoter regions of target genes to control transcription. In controlled in vitro conditions, AP-1 complex formation and DNA binding are modulated by redox-sensitive disulfide bonds and related redox-sensitive conformational changes in Delta FosB. Here, we show that the redox-dependence of the structure-function relationship of Fos-family proteins found in vitro is also conserved in Delta FosB in cells and in the mouse brain. Under oxidizing conditions, Delta FosB cysteine residues can form disulfide bridges, including at C222 and C172, which can stabilize its interaction with a partner protein; however, these conditions reduce complex binding to AP-1 consensus sequence DNA, specifically when C172 is oxidized. We present evidence that this effect occurs in cells and in mouse brain, altering Delta FosB target gene expression during redox stress. This evidence supports Delta FosB as an important mediator of oxidative stress-driven changes in gene expression seen in neurological conditions and implicates Delta FosB as a possible therapeutic target for intervention in diseases of oxidative stress like AD.
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Title: Role of the androgen receptor in testosterone's effects on anxiety-related behavior and corticosterone response in mice
Creator: Chen, Chieh
Date: 2013
Collection: Electronic Theses & Dissertations
Description: Anxiety disorders affect more women than men. Because gonadal hormones like testosterone (T) play a key role in establishing many sex differences, T may underlie the sex differences in human anxiety. Indeed, androgens act as anxiolytics in humans and other species. In mice, this effect normally requires functional androgen receptors (AR) since T has no such anxiolytic effects in genetic males carrying a dysfunctional allele for AR. Cre-LoxP technology was used to recombine AR, producing a...
Show moreAnxiety disorders affect more women than men. Because gonadal hormones like testosterone (T) play a key role in establishing many sex differences, T may underlie the sex differences in human anxiety. Indeed, androgens act as anxiolytics in humans and other species. In mice, this effect normally requires functional androgen receptors (AR) since T has no such anxiolytic effects in genetic males carrying a dysfunctional allele for AR. Cre-LoxP technology was used to recombine AR, producing a dysfunctional allele that resulted in androgen insensitivity in XY mice, a phenotype referred to as induced testicular feminization mutation (iTfm). These iTfm males show more anxiety related behavior than their wild type (WT) brothers in several tests, including the novel object test and elevated plus maze. When the mice were tested during the animals' resting phase (lights on period), iTfms did not differ from WT males in the light/dark box (L/D) test, replicating earlier results in our lab. However, when tested in the active phase, iTfm males appeared more anxious in the light-dark box than their WT brothers, consonant with the differences between these mice in other tests of anxiety. WT males castrated as adults and treated with T have a reduced HPA response to mild stress, as measured by corticosterone release, than untreated WT castrates. In contrast, iTfm males given T displayed a greater and more prolonged HPA response than WT males, indicating that AR activation normally attenuates the HPA axis. To determine whether ARs affect anxiety-related behaviors and HPA response by acting within the central nervous system (CNS), mice carrying a transgene utilizing the nestin promoter to drive expression of Cre recombinase were crossed with mice carrying a floxed allele of AR. Offspring carrying both constructs were designated NesARKO. Contradicting expectations, the NesARKO mice displayed only a partial knockout (KO) of AR expression in the brain: while there was a full KO in the hippocampus, medial prefrontal cortex (mPFC), bed nucleus of the stria terminalis (BNST), and periaqueductal grey (PAG), AR immunoreactivity was still seen in many cells in the amygdala and hypothalamus. No differences in anxiety-related behaviors or HPA function were seen between NesARKOs and WT males, demonstrating that full KO of AR in the mPFC and hippocampus had no effect on these behaviors. Consequently, those regions cannot be sites at which AR acts to modulate these behaviors in WT males. A subsequent study monitoring neuronal activity as reflected in cFos expression indicated that WT males with T have more cells respond in the basolateral amygdala (blAMY) and fewer cells respond in the suprachiasmatic nucleus of the hypothalamus (SCN) than either iTfms with T, or WTs without T. In WT males treated with T, approximately 65% of cells in the blAMY and SCN are AR positive, therefore AR may act directly on these cells to affect their response to mild stress. Together, these results demonstrate that T requires functional AR to modulate anxiety-related behavior and HPA function in mice, but does not act in the mPFC, hippocampus, BNST, or PAG to do so. T also acts through AR to affect the response of cells in the blAMY and SCN following mild stress, so these brain regions remain potential sites of action for T's anxiolytic effects in mice.
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Title: Effects of early life stress and mast cells on brain function and behavior in the mouse and pig
Creator: Durga, Kaitlin
Date: 2020
Collection: Electronic Theses & Dissertations
Description: Depression is a leading cause of disability worldwide, yet available treatments are ineffective for nearly half of treated patients. Depression has been linked to early life adversity and is exacerbated by stress, so uncovering how stress affects mood-related brain regions is critical to improve our understanding of depression etiology and potentially improving treatment. Depression patients often display reduced hippocampal volume, and many animal models of depression display a reduction in...
Show moreDepression is a leading cause of disability worldwide, yet available treatments are ineffective for nearly half of treated patients. Depression has been linked to early life adversity and is exacerbated by stress, so uncovering how stress affects mood-related brain regions is critical to improve our understanding of depression etiology and potentially improving treatment. Depression patients often display reduced hippocampal volume, and many animal models of depression display a reduction in hippocampal neurogenesis that is reversed by chronic exposure to antidepressants. Using a pig and mouse model, we were able to examine the effects of early life adversity on adult neurogenesis, and mast cell FosB on behaviors respectively. Our examination of female, castrated male, and intact male pigs, who underwent either early weaning or late weaning allowed us to see not only the effects of early life adversity, but any possible sex-specific effects as well. We found that early weaned female pigs expressed a significantly reduced number of new neurons in their hippocampi compared to their late weaned counterparts. Using a transgenic mouse model which had FosB floxed out of all mast cells, we observed the behavioral outcomes in various assays, including social interaction, elevated plus maze, and sucrose preference. We found that male mice homozygous for the mutation had a significantly increased preference for sucrose compared to the wildtype mice.
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Title: AGGRESSION AND THE GUT-BRAIN AXIS
Creator: Kwiatkowski, Christine Carole
Date: 2022
Collection: Electronic Theses & Dissertations
Description: Violence is a widespread public health and justice system problem with far-reaching consequences for victims, offenders, and their communities. Aggression, the cognitive and behavioral antecedent to violent action, is mainly understood in terms of the psychosocial risk factors that increase the likelihood of aggressive behavioral strategies. Neighborhood context is a principal risk factor for violent crime perpetration, but the mechanisms that mediate the effect of the environment on...
Show moreViolence is a widespread public health and justice system problem with far-reaching consequences for victims, offenders, and their communities. Aggression, the cognitive and behavioral antecedent to violent action, is mainly understood in terms of the psychosocial risk factors that increase the likelihood of aggressive behavioral strategies. Neighborhood context is a principal risk factor for violent crime perpetration, but the mechanisms that mediate the effect of the environment on individual-level aggression behavior are poorly understood, especially the biological factors that may contribute to our understanding of violent behavior. In order to gain a better understanding of mechanisms that precipitate violence in specific geographic contexts, this dissertation explores the relationship between aggression behavior and the gut microbiome, a spatially determined physiological system that affects human health and behavior. Preclinical experiments elucidate the role of the gut microbiome in territorial, reactive aggression behavior in mice. Results show significant differences in gut microbiome composition across the spectrum of murine aggression behavior. Moreover, manipulation of the gut microbiome via administration of short-term antibiotics and sodium butyrate, a short-chain fatty acid byproduct of microbial fermentation, increases aggression behavior. The overall goal of this research is to use basic science findings in mice to better understand how environmental exposures could influence human health and behavior, thus revealing how community health affects individuals and supplying a potential target for future intervention.
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Title: ROLE OF VENTRAL TEGMENTAL AREA NEUROTENSIN RECEPTOR-1 NEURONS IN ENERGY BALANCE
Creator: Perez-Bonilla, Patricia
Date: 2021
Collection: Electronic Theses & Dissertations
Description: Dopamine (DA) neurons in the ventral tegmental area (VTA) modulate physical activity and feeding behaviors that are disrupted in obesity. Although the heterogeneity of VTA DA neurons has hindered determination of which ones might be leveraged to support weight loss, we have characterized a subset of VTA DA neurons that express NtsR1 (VTA NtsR1 neurons) that are involved in the coordination of energy balance. We hypothesized that 1) increased activity VTA NtsR1 neurons might promote weight...
Show moreDopamine (DA) neurons in the ventral tegmental area (VTA) modulate physical activity and feeding behaviors that are disrupted in obesity. Although the heterogeneity of VTA DA neurons has hindered determination of which ones might be leveraged to support weight loss, we have characterized a subset of VTA DA neurons that express NtsR1 (VTA NtsR1 neurons) that are involved in the coordination of energy balance. We hypothesized that 1) increased activity VTA NtsR1 neurons might promote weight loss behaviors, and that 2) deleting NtsR1 specifically from VTA DA neurons would promote weight gain by increasing food intake and decreasing physical activity. We first used Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) to activate VTA NtsR1 neurons in normal weight and diet-induced obese mice.Acute activation of VTA NtsR1 neurons (24hr) significantly decreased body weight in normal weight and obese mice by reducing food intake and increasing physical activity. Moreover, daily activation of VTA NtsR1 neurons in obese mice sustained weight loss over 7 days. Activating VTA NtsR1 neurons also suppressed how much mice worked to obtain sucrose rewards, even when there was high motivation to consume. However, VTA NtsR1 neural activation was not reinforcing, nor did it invoke anxiety, vasodepressor responses or hypothermia. We then used newly generated NtsR1 flox/flox mice to study NtsR1 deletion in both development and adulthood. Curiously, developmental deletion of VTA NtsR1 (by crossing DAT Cre mice with NtsR1 flox/flox mice) had no impact on feeding or body weight. Adult deletion of the receptor (by injecting adeno associated Cre into VTA of adult NtsR1 flox/flox mice), however, resulted in lower body weight and DA-dependent food intake. Altogether, these data suggest that modulating NtsR1 expression in the adult VTA may be useful to safely promote weight loss, and that NtsR1 is worth further exploration for managing obesity.
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Title: UCH-L1 as a susceptibility factor for nigrostriatal and mesolimbic dopamine neurons after neurotoxicant exposure and aging
Creator: Winner, Brittany Michele
Date: 2017
Collection: Electronic Theses & Dissertations
Description: Parkinson disease (PD), the second most prevalent neurodegenerative disorder, is most commonly diagnosed in elderly individuals and is characterized by manifestation of motor deficits such as bradykinesia, postural instability, resting tremor, and shuffling gait. These motor symptoms of PD arise when dopamine (DA) neurons in the nigrostriatal DA (NSDA) pathway degenerate, causing loss of basal ganglia regulation of voluntary motor coordination. Other DA neuronal pathways in the central...
Show moreParkinson disease (PD), the second most prevalent neurodegenerative disorder, is most commonly diagnosed in elderly individuals and is characterized by manifestation of motor deficits such as bradykinesia, postural instability, resting tremor, and shuffling gait. These motor symptoms of PD arise when dopamine (DA) neurons in the nigrostriatal DA (NSDA) pathway degenerate, causing loss of basal ganglia regulation of voluntary motor coordination. Other DA neuronal pathways in the central nervous system are less affected by neuronal death, however: mesolimbic DA (MLDA) neurons are less vulnerable to loss in PD. Therefore, we seek to understand how MLDA neurons resist degeneration. Since Lewy bodies, which are proteinaceous deposits of misfolded and aggregated proteins, are the hallmark pathology of PD, we predict that major deficits in protein degradation are involved in development and progression of this disease. MPTP exposure in rodents recapitulates loss of DA and oxidative stress observed in patients with PD and can also be used to recapitulate the differential susceptibility of NSDA and MLDA neurons. A gene found mutated in a rare case of familial PD called ubiquitin carboxy-terminal hydrolase L1 (UCHL1) is involved in proteostasis functioning as a deubiquitinating enzyme to maintain pools of available monomeric ubiquitin. UCH-L1 protein is decreased in the SN of mice exposed to MPTP. The goal of this Dissertation research was to investigate the role of UCH-L1 in influencing susceptibility of NSDA and MLDA neurons to acute neurotoxic insult, and if aging plays a role in determining vulnerability of NSDA and MLDA neurons or expression and function of UCH-L1. The results reveal that UCH-L1 expression and function are maintained in non-susceptible MLDA neurons, which corresponds to the pattern of MLDA susceptibility to MPTP exposure. UCH-L1 expression is not affected by advanced age in NSDA or MLDA neurons, despite impairment of UPS function in cell body regions with advanced age. Additionally, aged mice are not more sensitive to MPTP exposure, but astrocytes in the axon terminal regions of MLDA neurons retain the protective ability to metabolize DA after MPTP administration, highlighting their protective role and potential contribution to differential susceptibility. These studies shed light on the potential contribution of the PD-linked neuronal deubiquitinating enzyme UCH-L1 to selective vulnerability in PD.
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Title: SEX DIFFERENCES IN HYPERTENSION AND THE ROLE OF ENDOTHELIAL TRPV4 CHANNELS IN CEREBROVASCULAR AND COGNITIVE FUNCTION
Creator: Chambers, Laura Christine
Date: 2022
Collection: Electronic Theses & Dissertations
Description: Vascular cognitive impairment and dementia (VCID) describes a spectrum of cognitive disorders that have a cerebrovascular origin. VCID can range from mild cognitive impairment to frank vascular dementia. The mechanisms behind VCID development are not fully understood and there are no effective treatments available. VCID arises from functional impairment in the small arteries and arterioles in the brain. Hypertension, which affects nearly half of all American adults, is the leading modifiable...
Show moreVascular cognitive impairment and dementia (VCID) describes a spectrum of cognitive disorders that have a cerebrovascular origin. VCID can range from mild cognitive impairment to frank vascular dementia. The mechanisms behind VCID development are not fully understood and there are no effective treatments available. VCID arises from functional impairment in the small arteries and arterioles in the brain. Hypertension, which affects nearly half of all American adults, is the leading modifiable risk factor for VCID. Hypertension impairs cerebrovascular function that can starve neurons of necessary nutrients, increasing risk of cognitive impairment. My studies focus on cerebral parenchymal arterioles (PAs), which direct blood flow from the pial circulation to the capillaries. Because they lack collateral connections, PAs are considered the weak link in the cerebral perfusion. The occlusion of a single PA creates a discrete column of ischemic tissue that can produce cognitive impairment. PAs are dependent on TRPV4 channels for endothelium-dependent dilation, and there is a strong link between TRPV4 and cognitive function. Previous studies in male rodents showed that hypertension impairs TRPV4-mediated dilation in PAs, and this was associated with memory impairments. When mineralocorticoid receptor (MR) antagonists are administered alongside developing hypertension, these impairments are prevented. However, it is thus far unknown whether MR antagonist treatment can reverse cerebrovascular and cognitive impairments after they have developed. My first aim tests the hypothesis that rats with established hypertension will have impaired TRPV4 function in PAs that is associated with cognitive impairment, and that treatment with the MR antagonist eplerenone can reverse this damage after its development. My second aim focuses on sex differences in hypertension, as this is a major gap in the literature. Thus far, all studies linking TRPV4 function to cognition have been conducted in male mice. Given that estrogen is vasoprotective in other vascular beds, I hypothesize that hypertensive female mice would be protected against impaired TRPV4 function in PAs, and from the associated cognitive deficits observed in male mice. Lastly, my third aim addresses the importance of TRPV4 channels specifically in the endothelium. There is a consistent link between TRPV4 impairment and cognitive dysfunction, but due to the channel’s ubiquitous expression, its role in endothelial cells is unknown. Here, I test the hypothesis that male and female mice with endothelial TRPV4 channel deletion will have cognitive impairment. My studies show that MR antagonism reverses cerebrovascular and cognitive damage in hypertension, and that female sex protects against the development of these impairments. Further, I show that endothelial TRPV4 channel deletion results in cognitive dysfunction and increased inflammation in both male and female mice. My studies show for the first time that young female mice have preserved TRPV4 channel function in PAs that is associated with preserved cognitive function. Further, my data suggest the MR is a promising therapeutic target in hypertensive patients because it not only protects against neurovascular damage but can reverse it after it has developed.
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Title: SEX AND PHENOTYPIC DIFFERENCES OF OBESITY-INDUCED GHSR VENTRAL HIPPOCAMPAL DISRUPTIONS IN THE CONTROL OF APPETITE
Creator: KONDILIS, ATHANASIOS
Date: 2022
Collection: Electronic Theses & Dissertations
Description: The gastric hunger signal, ghrelin, influences feeding behavior via activation of the growth hormone secretagogue receptor (GHSR). GHSR’s are abundantly expressed in cells in the ventral hippocampus (VHPC) where they function to regulate food intake. In this study, we used a GHSR-IRES-Cre mouse to examine whether feeding behaviors driven by GHSR cells in the VHPC are influenced by vulnerability to dietary obesity. Both males and females were exposed to 8 weeks of a high fat diet (HFD)—the top...
Show moreThe gastric hunger signal, ghrelin, influences feeding behavior via activation of the growth hormone secretagogue receptor (GHSR). GHSR’s are abundantly expressed in cells in the ventral hippocampus (VHPC) where they function to regulate food intake. In this study, we used a GHSR-IRES-Cre mouse to examine whether feeding behaviors driven by GHSR cells in the VHPC are influenced by vulnerability to dietary obesity. Both males and females were exposed to 8 weeks of a high fat diet (HFD)—the top and bottom quartiles of weight gainers from each respective sex were designated as diet-induced obese (DIO) and diet resistant (DR), respectively. These mice received targeted injections of an excitatory (hM3Dq) or inhibitory DREADD (hM4Di) virus. This enabled chemogenetic control of GHSR-expressing cells in the VHPC as mice engaged in consumption of lab chow or HFD. Only DR female mice displayed the expected increase in food intake when tested with lab chow following DREADD stimulation, indicating that female mice that are resistant to dietary obesity maintain typical function for GHSR’s in VHPC. Surprisingly, in males, DREADD stimulation decreased meal intake, which for chow occurred in DIO mice, whereas for HFD testing this was observed in DR mice. On the other hand, DREADD inhibition attenuated chow intake only in female mice. In the final series of studies, I used licking microstructure to examine the pre-ingestive (e.g., orosensory, palatability) and post-ingestive (e.g., gastrointestinal negative feedback) variables that regulate GHSR-dependent food intake. Multiple findings were revealed, including that the increased consumption of food in female mice following GHSR stimulation reflects a reduction in gastrointestinal negative feedback. Overall, my findings stress the need to implement a rigorous examination of a host of variables with refined analyses of meal intake to determine a role for how feeding signals in the brain impact ingestive behavior.
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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: 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: 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 inflammation and the kynurenine pathway in mood disorders and pregnancy
Creator: Keaton, Sarah A.
Date: 2019
Collection: Electronic Theses & Dissertations
Description: "Inflammation and the kynurenine pathway are involved in multiple physiological and pathophysiological states, however their role in depression during and after pregnancy, suicidality, and pre-eclampsia remain to be understood. Here, we sought to understand how the kynurenine pathway and its metabolites as well as their interactions with inflammation may influence these conditions. First, we analyzed suicide warning in women with mood and anxiety disorders. We identified a distinct...
Show more"Inflammation and the kynurenine pathway are involved in multiple physiological and pathophysiological states, however their role in depression during and after pregnancy, suicidality, and pre-eclampsia remain to be understood. Here, we sought to understand how the kynurenine pathway and its metabolites as well as their interactions with inflammation may influence these conditions. First, we analyzed suicide warning in women with mood and anxiety disorders. We identified a distinct immunobiological profile linked to cross-diagnostic suicide risk in women with mood disorders, attending a psychiatric outpatient clinic. This consisted of a strong proinflammatory profile, containing white blood cell count and polymononuclear leukocyte cell count which may be associated with the underlying pathobiology of suicide warning.. Next, we analyzed inflammation and the kynurenine pathway in peripartum depression and postpartum depression and suicidality to understand how they could influence psychiatric health. We found plasma IL-6 predicted depression scores throughout the first, second, and third trimester. In the third trimester we found increased neurotoxic kynurenine metabolite quinolinic acid in the plasma of women with depression compared to health controls. Additionally, we found plasma IL-1beta and IL-6 correlated with placental tissue expression of indolamine 2,3-dioxygenase 1 (IDO) connecting the placenta with peripheral inflammation in the plasma. There was a different inflammatory profile in postpartum depression and suicidality, with increased IL-8 and decreased IL-2, indicating the mechanisms causing peripartum depression and postpartum depression may be different. Finally, we looked at placentas from women with pre-eclampsia compared to healthy controls and found they had dysregulated tryptophan metabolism. There was a decrease of IDO, a compensatory increase in expression of tryptophan-2,3-dioxygenase, and this was associated with a decrease of serum amyloid A. Collectively, this dissertation highlights the importance of inflammation and the kynurenine pathway in the pathophysiology of psychiatric disorders and pregnancy states in females. Further research of inflammation and the kynurenine pathway may lead to screening panels and treatments for suicide, peripartum depression, postpartum depression and suicidality, and pre-eclampsia."--Pages ii-iii.
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Title: The medial prefrontal cortex contributes to binge eating proneness in female rats
Creator: Sinclair, Elaine
Date: 2017
Collection: Electronic Theses & Dissertations
Description: Eating disorders (EDs) are some of the most severe psychiatric conditions that primarily affect the female sex. Women are significantly more likely than men to suffer from EDs and the female bias in ED risk is one of the largest in all of psychiatry. The prevalence rates for EDs in women are on par with several other major psychiatric disorders, but the severity of medical complications and psychiatric co-morbidities inherent to EDs are far worse than most other psychiatric conditions. For...
Show moreEating disorders (EDs) are some of the most severe psychiatric conditions that primarily affect the female sex. Women are significantly more likely than men to suffer from EDs and the female bias in ED risk is one of the largest in all of psychiatry. The prevalence rates for EDs in women are on par with several other major psychiatric disorders, but the severity of medical complications and psychiatric co-morbidities inherent to EDs are far worse than most other psychiatric conditions. For this reason, uncovering the specific biological and neural mechanisms that contribute to ED risk, development, and exacerbation is crucial. To that end, functional MRI (fMRI) in women with EDs has become a common modality for investigating the neurobiological variables inherent to EDs, as fMRI techniques anatomically localize critical “hot spots” of apparently abnormal neural activity that may be associated with eating pathology. Indeed, several lines of working using fMRI in women with EDs have demonstrated aberrant activity within prefrontal cortex (PFC) circuitry specifically during tasks that engage behavioral control mechanisms, particularly in women with EDs associated with the core, maladaptive symptom of binge eating. These data provide compelling evidence that dysfunctional PFC-mediated regulation over food intake may underlie eating pathology, namely binge eating. To study the role of the PFC in the context of eating pathology, animal models are valuable tools as the rodent medial PFC (mPFC) has several executive functions that are analogous to the human PFC. In addition, the rodent mPFC exerts behavioral control over palatable food (PF) intake, at least in male rodents: the mPFC acts as a behavioral “brake” or limit over excessive PF intake. Thus, pathological eating behaviors, specifically binge eating, may be due in large part to deficient, mPFC-mediated behavioral control over PF intake. However, complete understanding of the underlying neural mechanisms by which the mPFC may contribute to binge eating is still lacking. Specifically, few studies, to date, have investigated whether the mPFC is implicated in binge eating using 1) a clinically-relevant rodent model of binge eating, or 2) female rodents. To that end, the goal of this dissertation was to identify the functional significance of the mPFC to PF intake and to binge eating using a well-validated animal model of binge eating proneness in female rodents. The experiments within this dissertation test the hypothesis that mPFC-mediated control over PF intake is weaker in female rats that are prone to binge eating. The first aim revealed different patterns of activation in the mPFC of binge eating prone (BEP) vs. binge eating resistant (BER) female rats, following exposure to PF. The second aim used double-label immunohistochemistry to identify that a vast majority of PF-activated neurons within the mPFC are excitatory, glutamatergic projection neurons, and that fewer excitatory neurons are engaged by PF in BEPs as compared to BERs. Using reversible, pharmacological inactivation of the mPFC, the third aim demonstrated that the mPFC of female rats indeed serves as a behavioral limit over excessive PF intake, but that the strength of the mPFC-mediated “brake” on PF intake is weaker in BEP rats as compared to BER rats. Thus, the experiments within this dissertation identify not only the cellular players within the mPFC that contribute to PF intake but also the functional significance of the mPFC to binge eating in the female sex.
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