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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
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
Assessing the involvement of altered neurotensin signaling in anorexia nervosa
Creator
Schroeder, Laura Elizabeth
Date
2018
Collection
Electronic Theses & Dissertations
Description
ABSTRACTAssessing the Involvement of Altered Neurotensin Signaling inAnorexia NervosaByLaura Elizabeth SchroederAnorexia Nervosa (AN), characterized by a persistent and detrimental drive tolose weight via restriction of food intake and excessive exercise, is the psychiatricdisorder with the highest mortality rate. Very few options exist when consideringpharmacotherapies used to treat AN patients, and no drugs have been demonstrated tosignificantly improve weight gain. This highlights the need...
Show moreABSTRACTAssessing the Involvement of Altered Neurotensin Signaling inAnorexia NervosaByLaura Elizabeth SchroederAnorexia Nervosa (AN), characterized by a persistent and detrimental drive tolose weight via restriction of food intake and excessive exercise, is the psychiatricdisorder with the highest mortality rate. Very few options exist when consideringpharmacotherapies used to treat AN patients, and no drugs have been demonstrated tosignificantly improve weight gain. This highlights the need to not only find better drugbasedtherapies for AN but to also find druggable targets for this disorder. While AN isthought to be highly heritable, with heritability estimates ranging between 50-80%, it hasbeen challenging to identify significant genetic contributors. Thus, determining thegenetic risk factors of AN will first be required for development of better therapeutics.In an effort to better understand the genetic basis of AN, recent work has beenperformed to uncover rare genetic variants that confer high risk of disease development.Loss-of-function variants in Neurotensin (Nts) and Nts Receptor 1 (NtsR1) wereidentified in individuals with eating disorders. Nts is a neuropeptide known to regulateingestive and locomotor behavior. Nts modulates these behaviors centrally, and asubset of dopamine (DA) neurons with the ventral tegmental area (VTA) that coexpressNtsR1 are known to contribute to DA-mediated weight loss behaviors. Ablation of allNtsR1 VTA neurons was shown to promote excessive locomotor activity without asufficient increase in feeding, leading to low body weight. Finally, increased fiberdensities have been found within the lateral hypothalamic area (LHA) of individuals withAN, and the LHA is a region with a significant population of Nts neurons known tomodulate both feeding and activity. We therefore hypothesized that Nts populations infeeding centers, such as the LHA, receive altered input from structures associated withAN and that alterations and/or disruption of Nts signaling promotes AN-like behaviors.This hypothesis was explored via three different approaches. First, the locationand density of Nts populations within the brains of NtsCre; Floxed GFP mice weremapped, and this revealed the presence of Nts in regions implicated in regulation offeeding and AN. The next approach involved determining if disrupted Nts signalingincreases risk for development of AN-like behaviors. This was accomplished bycharacterizing NtsR1-deficient mice both at baseline and after exposure to anadolescent-stress model of AN. This study revealed that deficiency of NtsR1 is agenetic risk factor that, when interacting with risks of being female and exposure toadolescent stress, promotes aberrant feeding, excessive locomotor behaviors, andcompulsive anxiety behaviors analogous to those observed in AN. Finally, a rabiesvirus-based method was used to identify direct inputs to LHA Nts neurons, and thishighlighted the existence of afferents, and thus top-down control, from structuresimplicated in AN. In addition, densities of these inputs were determined in mousemodels of AN, and this demonstrated that afferent inputs to LHA Nts neurons areincreased from sites associated with AN.Altogether, the data presented in this thesis highlight the possible genetic andneurocircuitry alterations to the Nts-NtsR1 system that may promote and/or be the resultof development of AN. These data also indicate the need for future studies to betterunderstand the mechanism by which such alterations in Nts signaling promote thisdisease.
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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
The role of lateral hypothalamic neurotensin neurons in adaptive energy balance
Creator
Brown, Juliette Anne
Date
2017
Collection
Electronic Theses & Dissertations
Description
The lateral hypothalamic area (LHA), receives cues of energy and fluid status from the body and coordinates appropriate feeding, drinking and activity (e.g. adaptive responses) to ensure survival. The LHA contains many distinct populations of neurons, however, and it remains unclear how each of these contribute to energy balance. Here we sought to understand how LHA neurons expressing the neuropeptide neurotensin (LHA Nts neurons) coordinate distinct behaviors necessary for adaptive response...
Show moreThe lateral hypothalamic area (LHA), receives cues of energy and fluid status from the body and coordinates appropriate feeding, drinking and activity (e.g. adaptive responses) to ensure survival. The LHA contains many distinct populations of neurons, however, and it remains unclear how each of these contribute to energy balance. Here we sought to understand how LHA neurons expressing the neuropeptide neurotensin (LHA Nts neurons) coordinate distinct behaviors necessary for adaptive response and control of body weight. While activation of most LHA Neurons increases both feeding and drinking, activation of LHA Nts neurons specifically promotes drinking but reduces feeding. LHA Nts neurons may exert these divergent actions via distinct circuits, as they have been shown to modulate dopamine (DA) signaling and local orexin (OX) neurons. Consistent with this, we have distinguished two projection-specific and molecularly distinct subsets of LHA Nts neurons. One subset co-expresses Nts and the long form of the leptin receptor (LepRb), is activated by leptin and projects to the ventral tegmental area (VTA) and substantia nigra compacta (SNc); we refer to these as NtsLepRb neurons. A separate subset of LHA Nts neurons lacks LepRb, is activated by dehydration and does not project to the VTA or SNc; we refer to these as Nts Dehy neurons. Intriguingly, however, we found all LHA Nts neurons are similar in that they express the inhibitory neurotransmitter, GABA. We next investigated the role of the NtsLepRb subpopulation for adaptive response by studying mice lacking leptin signaling via Nts LepRb neurons. Loss of leptin regulation only via NtsLepRb neurons induced obesity, blunted adaptive response to leptin and to ghrelin (a hormonal activator of OX neurons) and dysregulated DA signaling. Finally, we defined the necessity of LHA Nts neurons for energy balance by genetically ablating or chemogenetically inhibiting them in adult mice. Prolonged loss of LHA Nts neurons decreased drinking, locomotor activity and deranged OX expression in target neurons that led to increased adiposity. By contrast, LHA Nts inhibition preserved OX expression but still blunted locomotor activity. Together these data suggest that LHA Nts neurons modulate physical activity that is not dependent on OX, but that the LHA Nts→OX circuit is necessary for regulation of drinking and adiposity. Collectively, our data show that LHA Nts neurons are necessary for regulation of adaptive energy balance, and that distinct subpopulations of LHA Nts neurons may control ingestive and locomotor behavior via OX-dependent and independent pathways. This work suggests that there may be unique LHA Nts circuits to regulate drinking, motivated feeding ingestive disorders such as obesity, anorexia nervosa, psychogenic polydipsia and dehydration.
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