12 research outputs found
Deletion of Glucocorticoid Receptors in Forebrain GABAergic Neurons Alters Acute Stress Responding and Passive Avoidance Behavior in Female Mice
No full textThe glucocorticoid receptor (GR) is critically involved in regulation of stress responses [inhibition of the hypothalamic-pituitary-adrenal (HPA) axis], emotional behavior and cognition via interactions with forebrain corticolimbic circuity. Work to date has largely focused on GR actions in forebrain excitatory neurons; however, recent studies suggest a potential role mediated by interneurons. Here, we targeted GR deletion in forebrain GABAergic neurons, including the cortical interneurons, using a Dlx5/6-Cre driver line to test the role of forebrain interneuronal GR in HPA axis regulation and behavior. Our data indicate that GR deletion in GABAergic neurons causes elevated corticosterone stress responsiveness and decreased cross-over latencies in a passive avoidance task in females, but not males. Dlx5/6-Cre driven gene deletion caused loss of GR in interneurons in the prefrontal cortex (PFC) and hippocampus, but also in select diencephalic GABAergic neurons (including the reticular thalamic nucleus and dorsomedial hypothalamus). Our data suggest that GR signaling in interneurons is differentially important in females, which may have implications for GR-directed therapies for stress-related affective disease states
Diet-Induced Obese Mice Retain Endogenous Leptin Action
No full textSummaryObesity is characterized by hyperleptinemia and decreased response to exogenous leptin. This has been widely attributed to the development of leptin resistance, a state of impaired leptin signaling proposed to contribute to the development and persistence of obesity. To directly determine endogenous leptin activity in obesity, we treated lean and obese mice with a leptin receptor antagonist. The antagonist increased feeding and body weight (BW) in lean mice, but not in obese models of leptin, leptin receptor, or melanocortin-4 receptor deficiency. In contrast, the antagonist increased feeding and BW comparably in lean and diet-induced obese (DIO) mice, an increase associated with decreased hypothalamic expression of Socs3, a primary target of leptin. These findings demonstrate that hyperleptinemic DIO mice retain leptin suppression of feeding comparable to lean mice and counter the view that resistance to endogenous leptin contributes to the persistence of DIO in mice
Disruption of Glucagon-Like Peptide 1 Signaling in Sim1 Neurons Reduces Physiological and Behavioral Reactivity to Acute and Chronic Stress
No full textOrganismal stress initiates a tightly orchestrated set of responses involving complex physiological and neurocognitive systems. Here, we present evidence for glucagon-like peptide 1 (GLP-1)-mediated paraventricular hypothalamic circuit coordinating the global stress response. The GLP-1 receptor (Glp1r) in mice was knocked down in neurons expressing single-minded 1, a transcription factor abundantly expressed in the paraventricular nucleus (PVN) of the hypothalamus. Mice with single-minded 1-mediated Glp1r knockdown had reduced hypothalamic-pituitary-adrenal axis responses to both acute and chronic stress and were protected against weight loss associated with chronic stress. In addition, regional Glp1r knockdown attenuated stress-induced cardiovascular responses accompanied by decreased sympathetic drive to the heart. Finally, Glp1r knockdown reduced anxiety-like behavior, implicating PVN GLP-1 signaling in behavioral stress reactivity. Collectively, these findings support a circuit whereby brainstem GLP-1 activates PVN signaling to mount an appropriate whole-organism response to stress. These results raise the possibility that dysfunction of this system may contribute to stress-related pathologies, and thereby provide a novel target for intervention
Presentation_1_Deletion of Glucocorticoid Receptors in Forebrain GABAergic Neurons Alters Acute Stress Responding and Passive Avoidance Behavior in Female Mice.pdf
No full textThe glucocorticoid receptor (GR) is critically involved in regulation of stress responses [inhibition of the hypothalamic-pituitary-adrenal (HPA) axis], emotional behavior and cognition via interactions with forebrain corticolimbic circuity. Work to date has largely focused on GR actions in forebrain excitatory neurons; however, recent studies suggest a potential role mediated by interneurons. Here, we targeted GR deletion in forebrain GABAergic neurons, including the cortical interneurons, using a Dlx5/6-Cre driver line to test the role of forebrain interneuronal GR in HPA axis regulation and behavior. Our data indicate that GR deletion in GABAergic neurons causes elevated corticosterone stress responsiveness and decreased cross-over latencies in a passive avoidance task in females, but not males. Dlx5/6-Cre driven gene deletion caused loss of GR in interneurons in the prefrontal cortex (PFC) and hippocampus, but also in select diencephalic GABAergic neurons (including the reticular thalamic nucleus and dorsomedial hypothalamus). Our data suggest that GR signaling in interneurons is differentially important in females, which may have implications for GR-directed therapies for stress-related affective disease states.</p
Enhanced Glucose Control Following Vertical Sleeve Gastrectomy Does Not Require a β-Cell Glucagon-Like Peptide 1 Receptor
No full textBariatric surgeries, including vertical sleeve gastrectomy (VSG), resolve diabetes in 40–50% of patients. Studies examining the molecular mechanisms underlying this effect have centered on the role of the insulinotropic glucagon-like peptide 1 (GLP-1), in great part because of the ∼10-fold rise in its circulating levels after surgery. However, there is currently debate over the role of direct β-cell signaling by GLP-1 to mediate improved glucose tolerance following surgery. In order to assess the importance of β-cell GLP-1 receptor (GLP-1R) for improving glucose control after VSG, a mouse model of this procedure was developed and combined with a genetically modified mouse line allowing an inducible, β-cell–specific Glp1r knockdown (Glp1rβ-cell-ko). Mice with VSG lost ∼20% of body weight over 30 days compared with sham-operated controls and had a ∼60% improvement in glucose tolerance. Isolated islets from VSG mice had significantly greater insulin responses to glucose than controls. Glp1r knockdown in β-cells caused glucose intolerance in diet-induced obese mice compared with obese controls, but VSG improved glycemic profiles to similar levels during oral and intraperitoneal glucose challenges in Glp1rβ-cell-ko and Glp1rWT mice. Therefore, even though the β-cell GLP-1R seems to be important for maintaining glucose tolerance in obese mice, in these experiments it is dispensable for the improvement in glucose tolerance after VSG. Moreover, the metabolic physiology activated by VSG can overcome the deficits in glucose regulation caused by lack of β-cell GLP-1 signaling in obesity.</jats:p
An integrated safety measurement model : a new perspective for performance measurement
No full textPerformance measurement systems provide an opportunity not only to determine if organisations are effectively delivering their strategy and meeting their vision, but also to enable improvements. In 2009, the NHS implemented the NHS Performance Framework (Department of Health 2009), which has since been altered yearly in line with changing governments and policy alterations. Although originally designed to
be applied to Primary Care Trusts (PCTs) from April 2010, the NHS reform, which seeks the replacement of PCTs with GP Consortia, has rendered the framework
redundant in primary care (Department of Health 2010a). Since then, the NHS Outcomes Framework (Department of Health 2010b) has been published, and focuses on 5 outcome domains that are expected to show national level performance across the whole of the NHS. This high level system has failed to provide a performance picture of any individual service, of which there are many, in
addition to proving reliant on outcome (lagging) indicators which have long been recognised as a poor singular method for measuring performance (Eccles and
Pyburn 1992; Kaplan and Norton 1992). This study advocates service specific performance measurement and the engagement of stakeholders during the design
process to develop leading and lagging indicators of value to the stakeholders. This is in particular with efforts to shift the onus onto patients to maintain health; as is true
of the case management programme, which forms the case study for this research. The case management programme aims to reduce expensive hospital admissions for patients with complex long term conditions (LTCs) (Department of Health 2005). It expects to be able to achieve this by implementing a case management approach to oversee the most at risk patients, to develop an integrated care plan and to empower patients to become actively involved in their care at home. This paper will present the underlying literature that supports the development of a safety measurement model and describes the methodology used to gain validation by a key stakeholder group
Role of ethylene and the APETALA 2/ethylene response factor superfamily in rice under various abiotic and biotic stress conditions
No full textAbstractEthylene, the simplest gaseous plant growth regulator (PGR), controls diverse physiological pathways in plants. Under various stress conditions and during different developmental stages, such as root elongation, leaf and flower senescence, seed germination, tissue differentiation and organ abscission, ethylene biosynthesis is significantly increased. In rice, the internal ethylene concentration is rapidly regulated to a genetically, physiologically and morphologically relevant level under various stresses. Regulation of the ethylene signalling pathway under adverse conditions results in up- and/or down-regulation of the expression of stress-related genes in different families. Transcription factors are proteins that influence and control a number of biological processes under both normal and stress conditions. APETALA 2/ethylene response factor (AP2/ERF) is a transcription factor that is considered to function in stress response pathways in rice. To date, many AP2/ERF genes have been functionally characterised in rice. An understanding of the interactions between the AP2/ERF genes and ethylene-dependent mechanisms may provide new insights to facilitate the enhanced adaptation of rice to stress. In the current review, the structure and function of ethylene in rice under normal and stress conditions are described, and then the general functions of the plant AP2/ERF transcription factors are discussed. In addition, the interactions between the AP2/ERF genes and ethylene pathways under abiotic stresses, including submergence, cold, salinity, drought and heavy metal stresses, as well as those under biotic stresses, are summarised. Although the AP2/ERF genes have been identified, information on the physiological mechanisms of this gene family under stress conditions in rice remains limited. Therefore, further physiological studies must be performed in the future to identify additional features of this crucial gene family
