Panic results in unique molecular and network changes in the amygdala that facilitate fear responses

Abstract

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.

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

“…This is similar to PD patients who are reported to have normal acquisition of conditioned fear, but show greater resistance to extinguishing those conditioned fear responses (Michael et al, 2007). In the same study, we also determined that panic-prone state is associated with altered network properties of reduced inhibition and enhanced excitation in the BLA, along with disruptions of select GABA and glutamate genes expressions in the BLA and CeA (Molosh et al, 2018; also see Figure 1).…”

“…Such pre-clinical evidence suggests that chronic activation of ORX neurons in the PeF could lead to altered fear network in the amygdala as a key factor in developing persistent fear responses and development of phobia. This concept was further confirmed by supportive human clinical data from a post-hoc analysis of a proof-of-concept depression clinical trial investigating the efficacy of the mGluR2 PAM compound where in the subset of participants with comorbid panic disorder, treatment with this mGluR2 PAM resulted in complete remission of panic symptoms (Molosh et al, 2018).…”

“…In a recent study (Molosh, 2018), we demonstrated that panic-prone rats with chronic disinhibition of PeF neurons demonstrate delayed extinction of conditioned fear. This is similar to PD patients who are reported to have normal acquisition of conditioned fear, but show greater resistance to extinguishing those conditioned fear responses (Michael et al, 2007).…”

“…Thus, ORX receptor antagonists may represent a potential therapeutic option for the treatment of panicrelated disorders as well as some forms of hypertension. (Molosh, 2018). 1b.…”

“…Particularly, expression of metabotropic glutamate type 2 receptor (mGluR2) gene was significantly reduced in the CeA of panic-prone rats. Treating such panic-prone rats with a selective mGluR2 positive allosteric modulator (PAM) blocked the panic-responses following 0.5M NaLac and normalized fear extinction deficits (Molosh et al, 2018). Such pre-clinical evidence suggests that chronic activation of ORX neurons in the PeF could lead to altered fear network in the amygdala as a key factor in developing persistent fear responses and development of phobia.…”