The circumventricular organs form a potential neural pathway for lactate sensitivity: implications for panic disorder

Patients with panic disorder experience panic attacks after intravenous sodium lactate infusions by an as yet unexplained mechanism. Lactate elicits a panic-like response in rats with chronic dysfunction of GABA neurotransmission in the dorsomedial hypothalamus (DMH). The circumventricular organs, organum vasculosum lamina terminalis (OVLT) and subfornical organ (SFO), are potential sites that could detect increases in plasma lactate levels and activate the DMH. To test this, we obtained baseline heart rate (HR) and blood pressure (BP) responses to lactate infusions in rats fit with femoral arterial and venous catheters. Next, unilateral chronic injection cannulae connected to an Alzet infusion pump filled with the GABA synthesis inhibitor L-allylglycine (L-AG) were implanted into the DMH. Another chronic injection cannula was implanted into the region of the OVLT, SFO, or an adjacent control site, the median preoptic area (MePOA). These rats were tested once again with lactate infusions after injection of either artificial cerebrospinal fluid (ACSF) or tetrodotoxin (TTX) into the CVO sites. Injecting TTX into the OVLT completely blocked the lactate-induced response, whereas TTX injections into the SFO or MePOA did not. Also, direct injections of lactate (100 or 500 nl) into the OVLT elicited robust anxiety-like responses in these rats. These results suggest that the OVLT may be the primary site that detects lactate infusions, activating an anxiety-like response in a compromised DMH, and provide the first neuroanatomical basis for lactate response in panic disorder

Panic-prone state induced in rats with GABA dysfunction in the dorsomedial hypothalamus is mediated by NMDA receptors

Rats with chronic inhibition of GABA synthesis and consequently enhanced glutamatergic excitation in the dorsomedial hypothalamus (DMH) develop panic-like responses, defined as tachycardia, tachypnea, hypertension, and increased anxiety as measured by a social interaction (SI) test, after intravenous sodium lactate infusions, a phenomenon similar to patients with panic disorder. Therefore, the present studies tested the role of the postsynaptic NMDA and AMPA type glutamatergic receptors in the lactate-induced panic-like responses in these rats. Rats were fit with femoral arterial and venous catheters and Alzet pumps [filled with the GABA synthesis inhibitor L-allylglycine (L-AG; 3.5 nmol/0.5 microl per hour) or its inactive isomer D-AG] into the DMH. After 4-5 d of recovery only those rats with L-AG pumps exhibited panic-like responses to lactate infusions. Using double immunocytochemistry, we found that rats exhibiting panic-like responses (e.g., L-AG plus lactate) had increased c-Fos immunoreactivity in DMH neurons expressing the NMDA receptor 1 (NR1) subunit, but not those expressing the glutamate receptor 2 and 3 subunits of the AMPA receptors. To confirm this pharmacologically, we tested another group of rats implanted with l-AG pumps with intravenous lactate infusions preceded by injections of either NMDA [aminophosphonopentanoic acid (AP-5) or (+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d]cyclohepten-5,10-imine maleate (MK-801)] or non-NMDA [CNQX or 4-(8-methyl-9H-1,3-dioxolo[4,5-h][2,3]benzodazepin-5-yl)-benzenamine dihydrochloride (GYKI52466)] antagonists into the DMH. Injections of NMDA, but not non-NMDA, antagonists into the DMH resulted in dose-dependent blockade of the tachycardia, tachypnea, hypertension, and SI responses after lactate infusions. These results suggest that NMDA, and not non-NMDA, type glutamate receptors regulate lactate-induced panic-like responses in rats with GABA dysfunction in the DMH

Indiana Clinical and Translational Sciences Institute Metrics

poster abstractThe Indiana Clinical and Translational Sciences Institute (Indiana CTSI) activities are designed to contribute to the achievement of NIH Strategic Goals for the Clinical and Translational Sciences Award program. The Indiana CTSI uses a Logic Model-based system of metrics to provide data to the NIH regarding Indiana CTSI accomplishments. The metrics address achievement of Specific Aims, number of investigators benefitting from Indiana CTSI resources, publications generated from Indiana CTSI-supported activities, and the awarding of pilot grant funds to support the acquisition of findings and data that may support applications for external funding. This poster shows the growth in Indiana CTSI accomplishments over the first three years of the CTSA grant. Conclusions: The Indiana CTSI has increased its contribution to the NIH strategic goals to advance the conduct of clinical and translational sciences through support of investigators, the contribution of new knowledge, and support for pilot grant activity

Indiana Biobank (IB)

poster abstractThe Indiana Biobank (IB) was established in July 2010 as a conduit in the new era of personalized medicine to serve the needs of the Indiana research communities and to make an impact on Hoosier health. The overall objective of the Indiana Biobank is to create a collection of high quality biospecimens that are well annotated and linked to the electronic health record, genomic and proteomic data, to provide to the research community to carry out translational research. The ability to successfully do research and translate to the clinical setting is greatly facilitated by the availability of an extensive biorepository of biological samples, with accompanying clinical and genomic data, procured from patients at IU Health, Wishard and other clinical venues throughout Indiana

Etiology, triggers and neurochemical circuits associated with unexpected, expected, and laboratory-induced panic attacks

Panic disorder (PD) is a severe anxiety disorder that is characterized by recurrent panic attacks (PA), which can be unexpected (uPA, i.e., no clear identifiable trigger) or expected (ePA). Panic typically involves an abrupt feeling of catastrophic fear or distress accompanied by physiological symptoms such as palpitations, racing heart, thermal sensations, and sweating. Recurrent uPA and ePA can also lead to agoraphobia, where subjects with PD avoid situations that were associated with PA. Here we will review recent developments in our understanding of PD, which includes discussions on: symptoms and signs associated with uPA and ePAs; Diagnosis of PD and the new DSM-V; biological etiology such as heritability and gene×environment and gene×hormonal development interactions; comparisons between laboratory and naturally occurring uPAs and ePAs; neurochemical systems that are associated with clinical PAs (e.g. gene associations; targets for triggering or treating PAs), adaptive fear and panic response concepts in the context of new NIH RDoc approach; and finally strengths and weaknesses of translational animal models of adaptive and pathological panic states

Using Social Network Analysis Tools to Visualize and Analyze Collaboration in Use of CTSA Resources and Publications

poster abstractTo garner baseline data to determine whether or not the Indiana Clinical and Translational Sciences Institute (Indiana CTSI) was achieving collaboration across disciplines and institutions, the Indiana CTIS Tracking and Evaluation (T&E) Program compiled data regarding the utilization of resources across different Indiana CTSI programs and Project Development Teams (PDT) and data for the authors, departments, and institutional affiliations of Indiana CTSI peer reviewed publications. The Indiana CTSI T&E used a social networking tool, NodeXL, and data garnered to create a visualization of utilization of resources and publications co-authorship. The analysis showed the mean number of contacts with different resources per investigator was 1.37; every targeted program and PDT was shown to be linked to another. For publications analysis, 64 papers were identified with a total of 195 authors from the four Indiana CTSI member institutions. Sixty-nine of the authors were ICTSI investigators. However, 126 authors were non Indiana CTSI investigators although residing at partner institutions. Most surprising was that 140 authors were from 58 non-Indiana CTSI institutions. Conclusion: Baseline data indicates interdisciplinary and inter-institutional collaboration is already taking place

Role of medial hypothalamic orexin system in panic, phobia and hypertension

Orexin has been implicated in a number of physiological functions, including arousal, regulation of sleep, energy metabolism, appetitive behaviors, stress, anxiety, fear, panic, and cardiovascular control. In this review, we will highlight research focused on orexin system in the medial hypothalamic regions of perifornical (PeF) and dorsomedial hypothalamus (DMH), and describe the role of this hypothalamic neuropeptide in the behavioral expression of panic and consequent fear and avoidance responses, as well as sympathetic regulation and possible development of chronic hypertension. We will also outline recent data highlighting the clinical potential of single and dual orexin receptor antagonists for neuropsychiatric conditions including panic, phobia, and cardiovascular conditions, such as in hypertension