Panic disorder (PD) is a severe anxiety disorder characterized by recurrent panic attacks affecting about 2- 5% of the population and resulting in severe disability in about a third of those subjects. During the previous funding period, using our well established animal model we identified that orexin (hypocretin) neurons within the perifornical-dorsomedial hypothalamic region (PeF/DMH) are one of the key regulators of a coordinated panic response and that patients with panic but not depression symptoms did indeed have high levels of orexin in their cerebrospinal fluid. Little is known about how this disrupted panic regulation leads to many of its debilitating consequences such as chronic anticipatory anxiety and agoraphobia. Therefore, the goal of this competitive renewal (MH 52619-14 to -19) is to elucidate the neural mechanisms involved in how a panic- vulnerable state also leads to increased chronic anxiety and enhanced vulnerability to conditioned fears, avoidance and phobias. The project will have significant impact as we hope that the results of these studies will identify novel therapeutic targets for not only panic attacks, but also their many disabling consequences such as agoraphobia. Specifically, we predict that chronic disinhibition of orexinergic neurons in the PeF/DMH results in disruption of neurotransmission of not only orexin, but also its co-transmitters glutamate and dynorphin, resulting in disrupted network functions in 1) the bed nucleus of the stria terminalis (BNST);2) the central nucleus of the amygdala (CeA);and 3) the infralimbic prefrontal cortex (IL) to delay the extinction of conditioned fear. We will elucidate these mechanisms with behavioral, molecular and electrophysiological endpoints, utilizing pharmacological, gene silencing, optogenetic experiments in both whole animal and slice preparations.
Specific Aim 1 will focus on chronic disinhibition of ORX neurons in the DMH/PeF inducing molecular and network changes in the BNST to decrease GABAergic and enhance glutamatergic neurotransmission to induce a chronic anxiety-like phenotype.
Specific Aim 2 will study the mechanisms within the CeA that result in enhanced acquisition and expression of conditioned fears seen in panic-prone rats, testing if chronic disinhibition of ORX neurons in the DMH/PeF enhances excitation and reduces inhibition, thus facilitating neuronal plasticity in the CeA.
In Specific Aim 3, we propose to stud the mechanisms within the IL which could result in delayed extinction of conditioned fear responses in panic-prone rats. This project is innovative at several level providing a mechanistic model to understand the pathophysiology of PD and its disabling consequences combining the study of whole animal behavior, physiology, and systems level pharmacological and optogenetic manipulations with functional network electrophysiology as well as basic cellular and molecular changes. Finally, at the translational level, the work has already had significant impact in the development of novel therapies for acute panic attacks, but hopefully will provide novel insights into the persistent and hard to extinguish nature of agoraphobia and anticipatory anxiety in patients with panic disorder.
Panic disorder (PD) is a severe anxiety disorder characterized by recurrent panic attacks affecting about 2- 5% of the population and resulting in severe disability in about a third of those patients. Using our well established animal model, we identified that a specific set of brain cells called orexin (hypocretin) neurons are a key regulatos of panic attacks. Therefore, we will study how this chemical pathway also leads to increased chronic anxiety, fears, avoidance and phobias.
|Bonaventure, Pascal; Dugovic, Christine; Shireman, Brock et al. (2017) Evaluation of JNJ-54717793 a Novel Brain Penetrant Selective Orexin 1 Receptor Antagonist in Two Rat Models of Panic Attack Provocation. Front Pharmacol 8:357|
|Federici, Lauren M; Roth, Sarah Dorsey; Krier, Connie et al. (2016) Anxiogenic CO2 stimulus elicits exacerbated hot flash-like responses in a rat menopause model and hot flashes in postmenopausal women. Menopause 23:1257-1266|
|Hickman, Debra L; Fitz, Stephanie D; Bernabe, Cristian S et al. (2016) Evaluation of Low versus High Volume per Minute Displacement CO? Methods of Euthanasia in the Induction and Duration of Panic-Associated Behavior and Physiology. Animals (Basel) 6:|
|Johnson, Philip L; Federici, Lauren M; Fitz, Stephanie D et al. (2015) OREXIN 1 AND 2 RECEPTOR INVOLVEMENT IN CO2 -INDUCED PANIC-ASSOCIATED BEHAVIOR AND AUTONOMIC RESPONSES. Depress Anxiety 32:671-83|
|Bonaventure, Pascal; Yun, Sujin; Johnson, Philip L et al. (2015) A selective orexin-1 receptor antagonist attenuates stress-induced hyperarousal without hypnotic effects. J Pharmacol Exp Ther 352:590-601|
|Johnson, Philip L; Molosh, Andrei; Fitz, Stephanie D et al. (2015) Pharmacological depletion of serotonin in the basolateral amygdala complex reduces anxiety and disrupts fear conditioning. Pharmacol Biochem Behav 138:174-9|
|Molosh, Andrei I; Johnson, Philip L; Spence, John P et al. (2014) Social learning and amygdala disruptions in Nf1 mice are rescued by blocking p21-activated kinase. Nat Neurosci 17:1583-90|
|Koehler, Karl R; Mikosz, Andrew M; Molosh, Andrei I et al. (2013) Generation of inner ear sensory epithelia from pluripotent stem cells in 3D culture. Nature 500:217-21|
|Johnson, Philip L; Fitz, Stephanie D; Engleman, Eric A et al. (2013) Group II metabotropic glutamate receptor type 2 allosteric potentiators prevent sodium lactate-induced panic-like response in panic-vulnerable rats. J Psychopharmacol 27:152-61|
|Molosh, Andrei I; Sajdyk, Tammy J; Truitt, William A et al. (2013) NPY Y1 receptors differentially modulate GABAA and NMDA receptors via divergent signal-transduction pathways to reduce excitability of amygdala neurons. Neuropsychopharmacology 38:1352-64|
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