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Stress peptides sensitize fear circuitry to promote passive coping.

ABSTRACT: Survival relies on optimizing behavioral responses through experience. Animals often react to acute stress by switching to passive behavioral responses when coping with environmental challenge. Despite recent advances in dissecting mammalian circuitry for Pavlovian fear, the neuronal basis underlying this form of non-Pavlovian anxiety-related behavioral plasticity remains poorly understood. Here, we report that aversive experience recruits the posterior paraventricular thalamus (PVT) and corticotropin-releasing hormone (CRH) and sensitizes a Pavlovian fear circuit to promote passive responding. Site-specific lesions and optogenetic manipulations reveal that PVT-to-central amygdala (CE) projections activate anxiogenic neuronal populations in the CE that release local CRH in response to acute stress. CRH potentiates basolateral (BLA)-CE connectivity and antagonizes inhibitory gating of CE output, a mechanism linked to Pavlovian fear, to facilitate the switch from active to passive behavior. Thus, PVT-amygdala fear circuitry uses inhibitory gating in the CE as a shared dynamic motif, but relies on different cellular mechanisms (postsynaptic long-term potentiation vs. presynaptic facilitation), to multiplex active/passive response bias in Pavlovian and non-Pavlovian behavioral plasticity. These results establish a framework promoting stress-induced passive responding, which might contribute to passive emotional coping seen in human fear- and anxiety-related disorders.

SUBMITTER: Pliota P

PROVIDER: S-EPMC6169733 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Stress peptides sensitize fear circuitry to promote passive coping.

Pliota Pinelopi P Böhm Vincent V Grössl Florian F Griessner Johannes J Valenti Ornella O Kraitsy Klaus K Kaczanowska Joanna J Pasieka Manuel M Lendl Thomas T Deussing Jan M JM Haubensak Wulf W

Molecular psychiatry 20180614 2

Survival relies on optimizing behavioral responses through experience. Animals often react to acute stress by switching to passive behavioral responses when coping with environmental challenge. Despite recent advances in dissecting mammalian circuitry for Pavlovian fear, the neuronal basis underlying this form of non-Pavlovian anxiety-related behavioral plasticity remains poorly understood. Here, we report that aversive experience recruits the posterior paraventricular thalamus (PVT) and cortico ...[more]

PMID: 29904149

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Project description:Fear conditioning is an established model for investigating posttraumatic stress disorder (PTSD). However, symptom triggers may vaguely resemble the initial traumatic event, differing on a variety of sensory and affective dimensions. We extended the fear-conditioning model to assess generalization of conditioned fear on fear processing neurocircuitry in PTSD. Military veterans (n=67) consisting of PTSD (n=32) and trauma-exposed comparison (n=35) groups underwent functional magnetic resonance imaging during fear conditioning to a low fear-expressing face while a neutral face was explicitly unreinforced. Stimuli that varied along a neutral-to-fearful continuum were presented before conditioning to assess baseline responses, and after conditioning to assess experience-dependent changes in neural activity. Compared with trauma-exposed controls, PTSD patients exhibited greater post-study memory distortion of the fear-conditioned stimulus toward the stimulus expressing the highest fear intensity. PTSD patients exhibited biased neural activation toward high-intensity stimuli in fusiform gyrus (P<0.02), insula (P<0.001), primary visual cortex (P<0.05), locus coeruleus (P<0.04), thalamus (P<0.01), and at the trend level in inferior frontal gyrus (P=0.07). All regions except fusiform were moderated by childhood trauma. Amygdala-calcarine (P=0.01) and amygdala-thalamus (P=0.06) functional connectivity selectively increased in PTSD patients for high-intensity stimuli after conditioning. In contrast, amygdala-ventromedial prefrontal cortex (P=0.04) connectivity selectively increased in trauma-exposed controls compared with PTSD patients for low-intensity stimuli after conditioning, representing safety learning. In summary, fear generalization in PTSD is biased toward stimuli with higher emotional intensity than the original conditioned-fear stimulus. Functional brain differences provide a putative neurobiological model for fear generalization whereby PTSD symptoms are triggered by threat cues that merely resemble the index trauma.

Project description:Structural brain studies of adult post-traumatic stress disorder (PTSD) show reduced gray matter volume (GMV) in fear regulatory areas including the ventromedial prefrontal cortex (vmPFC) and hippocampus. Surprisingly, neither finding has been reported in pediatric PTSD. One possibility is that they represent age-dependent effects that are not fully apparent until adulthood. In addition, lower-resolution MRI and image processing in prior studies may have limited detection of such differences. Here we examine fear circuitry GMV, including age-related differences, using higher-resolution MRI in pediatric PTSD vs healthy youth. In a cross-sectional design, 3 T anatomical brain MRI was acquired in 27 medication-free youth with PTSD and 27 healthy non-traumatized youth of comparable age, sex, and IQ. Voxel-based morphometry was used to compare GMV in a priori regions including the medial prefrontal cortex and amygdala/hippocampus. Compared with healthy youth, PTSD youth had reduced GMV but no age-related differences in anterior vmPFC (BA 10/11, Z=4.5), which inversely correlated with PTSD duration. In contrast, although there was no overall group difference in hippocampal volume, a group × age interaction (Z=3.6) was present in the right anterior hippocampus. Here, age positively predicted hippocampal volume in healthy youth but negatively predicted volume in PTSD youth. Within the PTSD group, re-experiencing symptoms inversely correlated with subgenual anterior cingulate cortex (sgACC, Z=3.7) and right anterior hippocampus (Z=3.5) GMV. Pediatric PTSD is associated with abnormal structure of the vmPFC and age-related differences in the hippocampus, regions important in the extinction and contextual gating of fear. Reduced anterior vmPFC volume may confer impaired recovery from illness, consistent with its role in the allocation of attentional resources. In contrast, individual differences in sgACC volume were associated with re-experiencing symptoms, consistent with the role of the sgACC in fear extinction. The negative relationship between age and hippocampal volume in youth with PTSD may suggest an ongoing neurotoxic process over development, which further contributes to illness expression. Future studies employing a longitudinal design would be merited to further explore these possibilities.

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Stress peptides sensitize fear circuitry to promote passive coping.

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Stress peptides sensitize fear circuitry to promote passive coping.

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