Panic results in unique molecular and network changes in the amygdala that facilitate fear responses
| Autor: | A.R. Abreu, Stephanie D. Fitz, Amy D. Dietrich, L. Ver Donck, M Ceusters, Izabela F Caliman, Anantha Shekhar, Philip L. Johnson, Erik T. Dustrude, Jodi L. Lukkes, Andrei I. Molosh, J M Kent, William A. Truitt |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Male Poison control Glutamic Acid Receptors Metabotropic Glutamate Amygdala behavioral disciplines and activities Synaptic Transmission Article Extinction Psychological Rats Sprague-Dawley 03 medical and health sciences Cellular and Molecular Neuroscience Glutamatergic GABA 0302 clinical medicine mental disorders medicine Animals Molecular Biology Metabotropic glutamate 2 receptors business.industry Basolateral Nuclear Complex Panic disorder Panic Brain Extinction (psychology) Fear amygdala medicine.disease humanities Frontal Lobe Rats Optogenetics Psychiatry and Mental health Inhibition Psychological 030104 developmental biology medicine.anatomical_structure Fear extinction perifornical hypothalamus panic attacks Metabotropic glutamate receptor 2 medicine.symptom business Neuroscience 030217 neurology & neurosurgery Basolateral amygdala |
| Zdroj: | Molecular psychiatry |
| ISSN: | 1476-5578 |
| Popis: | Recurrent panic attacks (PAs) are a common feature of panic disorder (PD) and post-traumatic stress disorder (PTSD). Several distinct brain regions are involved in the regulation of panic responses, such as perifornical hypothalamus (PeF), periaqueductal gray, amygdala and frontal cortex. We have previously shown that inhibition of GABA synthesis in the PeF produces panic-vulnerable rats. Here, we investigate the mechanisms by which a panic-vulnerable state could lead to persistent fear. We first show that optogenetic activation of glutamatergic terminals from the PeF to the basolateral amygdala (BLA) enhanced the acquisition, delayed the extinction and induced the persistence of fear responses 3 weeks later, confirming a functional PeF-amygdala pathway involved in fear learning. Similar to optogenetic activation of PeF, panic-prone rats also exhibited delayed extinction. Next, we demonstrate that panic-prone rats had altered inhibitory and enhanced excitatory synaptic transmission of the principal neurons, and reduced protein levels of metabotropic glutamate type 2 receptor (mGluR2) in the BLA. Application of an mGluR2-positive allosteric modulator (PAM) reduced glutamate neurotransmission in the BLA slices from panic-prone rats. Treating panic-prone rats with mGluR2 PAM blocked sodium lactate (NaLac)-induced panic responses and normalized fear extinction deficits. Finally, in a subset of patients with comorbid PD, treatment with mGluR2 PAM resulted in complete remission of panic symptoms. These data demonstrate that a panic-prone state leads to specific reduction in mGluR2 function within the amygdala network and facilitates fear, and mGluR2 PAMs could be a targeted treatment for panic symptoms in PD and PTSD patients. |
| Databáze: | OpenAIRE |
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