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Karolina P Skibicka - One of the best experts on this subject based on the ideXlab platform.
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key role for hypothalamic interleukin 6 in food Motivated Behavior and body weight regulation
Psychoneuroendocrinology, 2021Co-Authors: Lorena Lopezferreras, Karolina P Skibicka, Francesco Longo, Jennifer E Richard, Kim Eerola, Olesya T Shevchouk, Madeleine TuzinovicAbstract:The pro-inflammatory role of interleukin-6 (IL-6) is well-characterized. Blockade of IL-6, by Tocilizumab, is used in patients with rheumatoid arthritis and those diagnosed with cytokine storm. However, brain-produced IL-6 has recently emerged as a critical mediator of gut/adipose communication with the brain. Central nervous system (CNS) IL-6 is engaged by peripheral and central signals regulating energy homeostasis. IL-6 is critical for mediating hypophagia and weight loss effects of a GLP-1 analog, exendin-4, a clinically utilized drug. However, neuroanatomical substrates and Behavioral mechanisms of brain IL-6 energy balance control remain poorly understood. We propose that the lateral hypothalamus (LH) is an IL-6-harboring brain region, key to food intake and food reward control. Microinjections of IL-6 into the LH reduced chow and palatable food intake in male rats. In contrast, female rats responded with reduced Motivated Behavior for sucrose, measured by the progressive ratio operant conditioning test, a Behavioral mechanism previously not linked to IL-6. To test whether IL-6, produced in the LH, is necessary for ingestive and Motivated Behaviors, and body weight homeostasis, virogenetic knockdown by infusion of AAV-siRNA-IL6 into the LH was utilized. Attenuation of LH IL-6 resulted in a potent increase in sucrose-Motivated Behavior, without any effect on ingestive Behavior or body weight in female rats. In contrast, the treatment did not affect any parameters measured (chow intake, sucrose-Motivated Behavior, locomotion, and body weight) in chow-fed males. However, when challenged with a high-fat/high-sugar diet, the male LH IL-6 knockdown rats displayed rapid weight gain and hyperphagia. Together, our data suggest that LH-produced IL-6 is necessary and sufficient for ingestive Behavior and weight homeostasis in male rats. In females, IL-6 in the LH plays a critical role in food-Motivated, but not ingestive Behavior control or weight regulation. Thus, collectively these data support the idea that brain-produced IL-6 engages the hypothalamus to control feeding Behavior.
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glp 1 modulates the supramammillary nucleus lateral hypothalamic neurocircuit to control ingestive and Motivated Behavior in a sex divergent manner
Molecular metabolism, 2019Co-Authors: Lorena Lopezferreras, Jennifer E Richard, Kim Eerola, Olesya T Shevchouk, Devesh Mishra, Fredrik H. Nilsson, Matthew R. Hayes, Karolina P SkibickaAbstract:Abstract Objective The supramammillary nucleus (SuM) is nestled between the lateral hypothalamus (LH) and the ventral tegmental area (VTA). This neuroanatomical position is consistent with a potential role of this nucleus to regulate ingestive and Motivated Behavior. Here neuroanatomical, molecular, and Behavior approaches are utilized to determine whether SuM contributes to ingestive and food-Motivated Behavior control. Methods Through the application of anterograde and retrograde neural tract tracing with novel designer viral vectors, the current findings show that SuM neurons densely innervate the LH in a sex dimorphic fashion. Glucagon-like peptide-1 (GLP-1) is a clinically targeted neuro-intestinal hormone with a well-established role in regulating energy balance and reward Behaviors. Here we determine that GLP-1 receptors (GLP-1R) are expressed throughout the SuM of both sexes, and also directly on SuM LH-projecting neurons and investigate the role of SuM GLP-1R in the regulation of ingestive and Motivated Behavior in male and female rats. Results SuM microinjections of the GLP-1 analogue, exendin-4, reduced ad libitum intake of chow, fat, or sugar solution in both male and female rats, while food-Motivated Behaviors, measured using the sucrose Motivated operant conditioning test, was only reduced in male rats. These data contrasted with the results obtained from a neighboring structure well known for its role in motivation and reward, the VTA, where females displayed a more potent response to GLP-1R activation by exendin-4. In order to determine the physiological role of SuM GLP-1R signaling regulation of energy balance, we utilized an adeno-associated viral vector to site-specifically deliver shRNA for the GLP-1R to the SuM. Surprisingly, and in contrast to previous results for the two SuM neighboring sites, LH and VTA, SuM GLP-1R knockdown increased food seeking and adiposity in obese male rats without altering food intake, body weight or food motivation in lean or obese, female or male rats. Conclusion Taken together, these results indicate that SuM potently contributes to ingestive and Motivated Behavior control; an effect contingent on sex, diet/homeostatic energy balance state and Behavior of interest. These data also extend the map of brain sites directly responsive to GLP-1 agonists, and highlight key differences in the role that GLP-1R play in interconnected and neighboring nuclei.
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GLP-1 modulates the supramammillary nucleus-lateral hypothalamic neurocircuit to control ingestive and Motivated Behavior in a sex divergent manner
Elsevier, 2019Co-Authors: Lorena López-ferreras, Jennifer E Richard, Kim Eerola, Olesya T Shevchouk, Devesh Mishra, Fredrik H. Nilsson, Matthew R. Hayes, Karolina P SkibickaAbstract:Objective: The supramammillary nucleus (SuM) is nestled between the lateral hypothalamus (LH) and the ventral tegmental area (VTA). This neuroanatomical position is consistent with a potential role of this nucleus to regulate ingestive and Motivated Behavior. Here neuroanatomical, molecular, and Behavior approaches are utilized to determine whether SuM contributes to ingestive and food-Motivated Behavior control. Methods: Through the application of anterograde and retrograde neural tract tracing with novel designer viral vectors, the current findings show that SuM neurons densely innervate the LH in a sex dimorphic fashion. Glucagon-like peptide-1 (GLP-1) is a clinically targeted neuro-intestinal hormone with a well-established role in regulating energy balance and reward Behaviors. Here we determine that GLP-1 receptors (GLP-1R) are expressed throughout the SuM of both sexes, and also directly on SuM LH-projecting neurons and investigate the role of SuM GLP-1R in the regulation of ingestive and Motivated Behavior in male and female rats. Results: SuM microinjections of the GLP-1 analogue, exendin-4, reduced ad libitum intake of chow, fat, or sugar solution in both male and female rats, while food-Motivated Behaviors, measured using the sucrose Motivated operant conditioning test, was only reduced in male rats. These data contrasted with the results obtained from a neighboring structure well known for its role in motivation and reward, the VTA, where females displayed a more potent response to GLP-1R activation by exendin-4. In order to determine the physiological role of SuM GLP-1R signaling regulation of energy balance, we utilized an adeno-associated viral vector to site-specifically deliver shRNA for the GLP-1R to the SuM. Surprisingly, and in contrast to previous results for the two SuM neighboring sites, LH and VTA, SuM GLP-1R knockdown increased food seeking and adiposity in obese male rats without altering food intake, body weight or food motivation in lean or obese, female or male rats. Conclusion: Taken together, these results indicate that SuM potently contributes to ingestive and Motivated Behavior control; an effect contingent on sex, diet/homeostatic energy balance state and Behavior of interest. These data also extend the map of brain sites directly responsive to GLP-1 agonists, and highlight key differences in the role that GLP-1R play in interconnected and neighboring nuclei. Keywords: GLP-1, Supramammillary, Lateral hypothalamic area, Body weight, Operant conditionin
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ghrelin directly targets the ventral tegmental area to increase food motivation
Neuroscience, 2011Co-Authors: Karolina P Skibicka, Caroline Hansson, Mayte Alvarezcrespo, P A Friberg, Suzanne L DicksonAbstract:Ghrelin, a circulating orexigenic stomach-derived hormone, has recently been implicated in extra-homeostatic feeding, increasing food reward and food-Motivated Behavior. The precise target site(s) for ghrelin's effects on food reward have yet to be elucidated. The neurocircuitry underpinning food-Motivated Behavior involves, in particular, the dopamine cells of the ventral tegmental area (VTA) that project to the nucleus accumbens (NAcc). Ghrelin stimulation in both of these mesolimbic reward areas increases chow intake. Here we sought to determine if ghrelin acts directly within these mesolimbic reward areas to increase food reward/motivation in studies that combine feeding Behavior, pharmacology, and neuroanatomy. We found that Motivated Behavior for a sucrose reward, assessed in an operant conditioning paradigm in rats, was increased when ghrelin was microinjected directly into the VTA but not into the NAcc. By contrast, ghrelin administration to both areas increased the free feeding of chow. Importantly, in a state of overnight food restriction, where endogenous levels of ghrelin are increased, ghrelin receptor (GHS-R1A) blockade in the VTA was sufficient to decrease the motivation to work for a sugar reward. Blockade of the GHS-R1A in VTA or NAcc was not sufficient to reduce fasting-induced chow hyperphagia. Taken together our data identify the VTA but not the NAcc as a direct, necessary, and sufficient target site for ghrelin's action on food motivation.
Monique Ernst - One of the best experts on this subject based on the ideXlab platform.
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the triadic model perspective for the study of adolescent Motivated Behavior
Brain and Cognition, 2014Co-Authors: Monique ErnstAbstract:The triadic neural systems model is a heuristic tool, which was developed with the goal of providing a framework for neuroscience research into Motivated Behaviors. Unlike dual models that highlight dynamics between approach systems centered on striatal function and control systems centered on prefrontal cortex, the triadic model also includes an avoidance system, centered on amygdala-related circuits. A first application of this model has been to account for adolescent Behavior.
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neural systems underlying Motivated Behavior in adolescence implications for preventive medicine
Preventive Medicine, 2012Co-Authors: Jessica M Richards, Rista C Plate, Monique ErnstAbstract:Objective Although a time of increased independence and autonomy, adolescence is also a time of vulnerabilities, through increased risk-taking and the emergence of psychopathology. Neurodevelopmental changes during this period may provide a neurobiological basis for this normative rise in deleterious Behaviors. Thus, the objective of this review was to identify neurodevelopmental processes underlying the emergence of risk-taking and psychopathology in adolescence, and discuss implications of these findings for prevention.
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new perspectives on adolescent Motivated Behavior attention and conditioning
Developmental Cognitive Neuroscience, 2011Co-Authors: Monique Ernst, Teresa Daniele, Kyle J FrantzAbstract:Adolescence is a critical transition period, during which fundamental changes prepare the adolescent for becoming an adult. Heuristic models of the neurobiology of adolescent Behavior have emerged, promoting the central role of reward and motivation, coupled with cognitive immaturities. Here, we bring focus to two basic sets of processes, attention and conditioning, which are essential for adaptive Behavior. Using the dual-attention model developed by Corbetta and Shulman (2002), which identifies a stimulus-driven and a goal-driven attention network, we propose a balance that favors stimulus-driven attention over goal-driven attention in youth. Regarding conditioning, we hypothesize that stronger associations tend to be made between environmental cues and appetitive stimuli, and weaker associations with aversive stimuli, in youth relative to adults. An attention system geared to prioritize stimulus-driven attention, together with more powerful associative learning with appetitive incentives, contribute to shape patterns of adolescent Motivated Behavior. This proposed bias in attention and conditioning function could facilitate the impulsive, novelty-seeking and risk-taking Behavior that is typical of many adolescents.
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neurobiology of the development of Motivated Behaviors in adolescence a window into a neural systems model
Pharmacology Biochemistry and Behavior, 2009Co-Authors: Monique Ernst, Russell D Romeo, Susan L AndersenAbstract:Adaptive Motivated Behaviors are at the core of a successful life. Conversely, perturbed Motivated Behaviors are the hallmark of psychiatric disorders. Based on the notion that most psychopathology is developmental in nature, understanding the neural mechanisms that control Motivated Behavior across development and in psychopathology is a critical step for preventing and treating psychiatric diseases. This review focuses on adolescence, which is the critical developmental period that determines the successful passage into adulthood. We first present a heuristic neural systems model of Motivated Behavior (triadic model) that integrates neuroscience theories and the emerging body of functional neuroimaging work on the neurodevelopment of Motivated Behavior. As a key feature of adolescence, social reorientation is particularly emphasized through the presentation of a parallel model of social integration processing network. Although not yet integrated in the triadic model, pubertal changes and their possible contribution to adolescent Motivated Behavior are reviewed. Similarly, given its central role in Motivated actions, the dopamine system is discussed from the perspective of animal studies dedicated to changes of this system across adolescence. This review reveals vast gaps in knowledge about the neurobiology of Motivated Behavior in normally developing individuals, which makes the translation to psychopathology only tentative. However, it provides clear directions for future research.
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a developmental neurobiological model of Motivated Behavior anatomy connectivity and ontogeny of the triadic nodes
Neuroscience & Biobehavioral Reviews, 2009Co-Authors: Monique Ernst, Julie L FudgeAbstract:Adolescence is the transition period that prepares individuals for fulfilling their role as adults. Most conspicuous in this transition period is the peak level of risk-taking Behaviors that characterize adolescent Motivated Behavior. Significant neural remodeling contributes to this change. This review focuses on the functional neuroanatomy underlying Motivated Behavior, and how ontogenic changes can explain the typical Behavioral patterns in adolescence. To help model these changes and provide testable hypotheses, a neural systems-based theory is presented. In short, the Triadic Model proposes that Motivated Behavior is governed by a carefully orchestrated articulation among three systems, approach, avoidance and regulatory. These three systems map to distinct, but overlapping, neural circuits, whose representatives are the striatum, the amygdala and the medial prefrontal cortex. Each of these system-representatives will be described from a functional anatomy perspective that includes a review of their connectivity and what is known of their ontogenic changes.
Luis De Lecea - One of the best experts on this subject based on the ideXlab platform.
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lateral hypothalamic control of the ventral tegmental area reward evaluation and the driving of Motivated Behavior
Frontiers in Systems Neuroscience, 2017Co-Authors: Susan M. Tyree, Luis De LeceaAbstract:The lateral hypothalamus plays an important role in many Motivated Behaviors, sleep-wake states, food intake, drug-seeking, energy balance, etc. It is also home to a heterogeneous population of neurons that express and co-express multiple neuropeptides including hypocretin, melanin-concentrating hormone, cocaine- and amphetamine- regulated transcript, and neurotensin. These neurons project widely throughout the brain to areas such as the locus coeruleus, the bed nucleus of the stria terminalis, the amygdala, and the ventral tegmental area. Lateral hypothalamic projections to the ventral tegmental area are believed to be important for driving Behavior due to the involvement of dopaminergic reward circuitry. The purpose of this article is to review current knowledge regarding the lateral hypothalamic connections to the ventral tegmental area and the role they play in driving these Behaviors.
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Lateral Hypothalamic Control of the Ventral Tegmental Area: Reward Evaluation and the Driving of Motivated Behavior
Frontiers Media S.A., 2017Co-Authors: Susan M. Tyree, Luis De LeceaAbstract:The lateral hypothalamus (LH) plays an important role in many Motivated Behaviors, sleep-wake states, food intake, drug-seeking, energy balance, etc. It is also home to a heterogeneous population of neurons that express and co-express multiple neuropeptides including hypocretin (Hcrt), melanin-concentrating hormone (MCH), cocaine- and amphetamine-regulated transcript (CART) and neurotensin (NT). These neurons project widely throughout the brain to areas such as the locus coeruleus, the bed nucleus of the stria terminalis, the amygdala and the ventral tegmental area (VTA). Lateral hypothalamic projections to the VTA are believed to be important for driving Behavior due to the involvement of dopaminergic reward circuitry. The purpose of this article is to review current knowledge regarding the lateral hypothalamic connections to the VTA and the role they play in driving these Behaviors
Peter D Balsam - One of the best experts on this subject based on the ideXlab platform.
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neural substrates underlying effort time and risk based decision making in Motivated Behavior
Neurobiology of Learning and Memory, 2016Co-Authors: Matthew R Bailey, Eleanor H Simpson, Peter D BalsamAbstract:All mobile organisms rely on adaptive Motivated Behavior to overcome the challenges of living in an environment in which essential resources may be limited. A variety of influences ranging from an organism's environment, experiential history, and physiological state all influence a cost-benefit analysis which allows motivation to energize Behavior and direct it toward specific goals. Here we review the substantial amount of research aimed at discovering the interconnected neural circuits which allow organisms to carry-out the cost-benefit computations which allow them to behave in adaptive ways. We specifically focus on how the brain deals with different types of costs, including effort requirements, delays to reward and payoff riskiness. An examination of this broad literature highlights the importance of the extended neural circuits which enable organisms to make decisions about these different types of costs. This involves Cortical Structures, including the Anterior Cingulate Cortex (ACC), the Orbital Frontal Cortex (OFC), the Infralimbic Cortex (IL), and prelimbic Cortex (PL), as well as the Baso-Lateral Amygdala (BLA), the Nucleus Accumbens (NAcc), the Ventral Pallidal (VP), the Sub Thalamic Nucleus (STN) among others. Some regions are involved in multiple aspects of cost-benefit computations while the involvement of other regions is restricted to information relating to specific types of costs.
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a novel strategy for dissecting goal directed action and arousal components of Motivated Behavior with a progressive hold down task
Behavioral Neuroscience, 2015Co-Authors: Matthew R Bailey, Rae Silver, Eleanor H Simpson, Greg Jensen, Kathleen Taylor, Chris Mezias, Cait M Williamson, Peter D BalsamAbstract:Motivation serves 2 important functions: It guides actions to be goal-directed, and it provides the energy and vigor required to perform the work necessary to meet those goals. Dissociating these 2 processes with existing Behavioral assays has been a challenge. In this article, we report a novel experimental strategy to distinguish the 2 processes in mice. First, we characterize a novel motivation assay in which animals must hold down a lever for progressively longer intervals to earn each subsequent reward; we call this the progressive hold-down (PHD) task. We find that performance on the PHD task is sensitive to both food deprivation level and reward value. Next, we use a dose of methamphetamine (METH) 1.0 mg/kg, to evaluate Behavior in both the progressive ratio (PR) and PHD tasks. Treatment with METH leads to more persistent lever pressing for food rewards in the PR. In the PHD task, we found that METH increased arousal, which leads to numerous bouts of hyperactive responding but neither increases nor impairs goal-directed action. The results demonstrate that these tools enable a more precise understanding of the underlying processes being altered in manipulations that alter Motivated Behavior.
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a novel strategy for dissecting goal directed action and arousal components of Motivated Behavior with a progressive hold down task
Behavioral Neuroscience, 2015Co-Authors: Matthew R Bailey, Rae Silver, Eleanor H Simpson, Greg Jensen, Kathleen Taylor, Chris Mezias, Cait M Williamson, Peter D BalsamAbstract:Motivation serves two important functions: It guides actions to be goal-directed, and it provides the energy and vigor required to perform the work necessary to meet those goals. Dissociating these two processes with existing Behavioral assays has been a challenge. Here, we report a novel experimental strategy to distinguish the two processes in mice. First we characterize a novel motivation assay in which animals must hold a lever down for progressively longer intervals in order to earn each subsequent reward; we call this the Progressive Hold Down (PHD) task. We find that performance on the PHD task is sensitive to both food deprivation level and reward value. Next, we use a dose of Methamphetamine (METH) 1.0mg/kg, to evaluate Behavior in both the Progressive Ratio (PR) and PHD task. Treatment with METH leads to more persistent lever pressing for food rewards in the PR. In the PHD task, we found that METH increased arousal, leading to numerous bouts of hyperactive responding, but neither increase or impaired goal directed action. The results demonstrate that these tools enable a more precise understanding of the underlying processes being altered in manipulations which alter Motivated Behavior.
Henry H Yin - One of the best experts on this subject based on the ideXlab platform.
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ventral tegmental dopamine neurons control the impulse vector during Motivated Behavior
Current Biology, 2020Co-Authors: Ryan N Hughes, Konstantin I Bakhurin, Elijah A Petter, Glenn D R Watson, Namsoo Kim, Alexander D Friedman, Henry H YinAbstract:The ventral tegmental area (VTA) is a major source of dopamine, especially to the limbic brain regions. Despite decades of research, the function of VTA dopamine neurons remains controversial. Here, using a novel head-fixed Behavioral system with five orthogonal force sensors, we show for the first time that the activity of dopamine neurons precisely represents the impulse vector (force exerted over time) generated by the animal. Distinct populations of VTA dopamine neurons contribute to components of the impulse vector in different directions. Optogenetic excitation of these neurons shows a linear relationship between signal injected and impulse generated. Optogenetic inhibition paused force generation or produced force in the backward direction. At the same time, these neurons also regulate the initiation and execution of anticipatory licking. Our results indicate that VTA dopamine controls the magnitude, direction, and duration of force used to move toward or away from any motivationally relevant stimuli.
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ventral tegmental dopamine neurons control the impulse vector during Motivated Behavior
bioRxiv, 2020Co-Authors: Ryan N Hughes, Konstantin I Bakhurin, Elijah A Petter, Glenn D R Watson, Namsoo Kim, Alexander D Friedman, Henry H YinAbstract:Abstract The Ventral Tegmental Area (VTA) is a major source of dopamine, especially to the limbic brain regions. Despite decades of research, the function of VTA dopamine neurons remains controversial. Here, using a novel head-fixed Behavioral system with five orthogonal force sensors, we show for the first time that distinct populations of VTA dopamine activity precisely represent the impulse vector (force exerted over time) generated by the animal. Optogenetic excitation of VTA dopamine neurons quantitatively determines impulse in the forward direction, and optogenetic inhibition produces impulse in the backward direction. At the same time, these neurons also regulate the initiation and execution of anticipatory licking. Our results indicate that VTA controls the magnitude, direction, and duration of force used to move towards or away from any motivationally relevant stimuli. One Sentence Summary VTA dopamine bidirectionally controls impulse vector and anticipatory Behavior
