Dataset Information

Elucidating an Affective Pain Circuit that Creates a Threat Memory.

ABSTRACT: Animals learn to avoid harmful situations by associating a neutral stimulus with a painful one, resulting in a stable threat memory. In mammals, this form of learning requires the amygdala. Although pain is the main driver of aversive learning, the mechanism that transmits pain signals to the amygdala is not well resolved. Here, we show that neurons expressing calcitonin gene-related peptide (CGRP) in the parabrachial nucleus are critical for relaying pain signals to the central nucleus of amygdala and that this pathway may transduce the affective motivational aspects of pain. Genetic silencing of CGRP neurons blocks pain responses and memory formation, whereas their optogenetic stimulation produces defensive responses and a threat memory. The pain-recipient neurons in the central amygdala expressing CGRP receptors are also critical for establishing a threat memory. The identification of the neural circuit conveying affective pain signals may be pertinent for treating pain conditions with psychiatric comorbidities.

SUBMITTER: Han S

PROVIDER: S-EPMC4512641 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Elucidating an Affective Pain Circuit that Creates a Threat Memory.

Han Sung S Soleiman Matthew T MT Soden Marta E ME Zweifel Larry S LS Palmiter Richard D RD

Cell 20150701 2

Animals learn to avoid harmful situations by associating a neutral stimulus with a painful one, resulting in a stable threat memory. In mammals, this form of learning requires the amygdala. Although pain is the main driver of aversive learning, the mechanism that transmits pain signals to the amygdala is not well resolved. Here, we show that neurons expressing calcitonin gene-related peptide (CGRP) in the parabrachial nucleus are critical for relaying pain signals to the central nucleus of amygd ...[more]

PMID: 26186190

Similar Datasets

Project description:The ability to regulate the emotional response to threat is critical to healthy emotional function. However, the response to threat varies considerably from person-to-person. This variability may be partially explained by differences in emotional processes, such as locus of control and affective state, which vary across individuals. Although the basic neural circuitry that mediates the response to threat has been described, the impact individual differences in affective state and locus of control have on that response is not well characterized. Understanding how these factors influence the neural response to threat would provide new insight into processes that mediate emotional function. Therefore, the present study used a Pavlovian conditioning procedure to investigate the influence individual differences in locus of control, positive affect, and negative affect have on the brain and behavioral responses to predictable and unpredictable threats. Thirty-two healthy volunteers participated in a fear conditioning study in which predictable and unpredictable threats (i.e., unconditioned stimulus) were presented during functional magnetic resonance imaging (fMRI). Locus of control showed a linear relationship with learning-related ventromedial prefrontal cortex (PFC) activity such that the more external an individual's locus of control, the greater their differential response to predictable versus unpredictable threat. In addition, positive and negative affectivity showed a curvilinear relationship with dorsolateral PFC, dorsomedial PFC, and insula activity, such that those with high or low affectivity showed reduced regional activity compared to those with an intermediate level of affectivity. Further, activity within the PFC, as well as other regions including the amygdala, were linked with the peripheral emotional response as indexed by skin conductance and electromyography. The current findings demonstrate that the neural response to threat within brain regions that mediate the peripheral emotional response is modulated by an individual's affective state as well as their perceptions of an event's causality.

Project description:For over a millennium, mind-body interactions have fascinated scientists and doctors for their abilities to shape human perceptions of the external world 1,2. Placebo effects are striking demonstrations of mind-body interactions in which, in the absence of any treatment, a positive expectation of pain relief can reduce or even abolish the experience of pain 3–6. However, despite widespread recognition of the strength of placebo effects and their impact on everyday human experience and clinical trials for new analgesics, the neural circuit basis of the placebo effect has remained a mystery. Here, we show that analgesia from the expectation of pain relief is mediated by a distinct population of rostral anterior cingulate cortex (rACC) neurons that project to the pontine nuclei (rACC→Pn), a pair of brainstem pre-cerebellar nuclei with no established function in pain processing. To do this, we created a behavioral assay that models placebo analgesia by conditioning mice to expect pain relief when moving from a chamber with a heated floor to a second chamber. In this assay, an expectation of pain relief induces an analgesic effect that, like placebo analgesia in humans, is mediated by endogenous opioids. Calcium imaging of neural activity in freely moving mice and electrophysiological studies in cingulate cortical brain slices showed that expectations of pain relief boost the activity of rACC→Pn neurons and potentiate neurotransmission in this pathway. Transcriptomic studies of Pn neurons revealed an unusual abundance of opioid receptors in these cells, further suggesting a role in pain modulation. Selective inhibition of either the rACC→Pn pathway or of opioid-receptor-expressing Pn neurons disrupted placebo analgesia and decreased pain thresholds. Finally, a subset of cerebellar Purkinje cells exhibits activity patterns resembling those of rACC→Pn neurons during pain relief expectation, providing cellular-level evidence of a role for the cerebellum in cognitive pain modulation. Altogether, these findings elucidate longstanding mysteries surrounding the placebo effect by identifying a specific neural pathway that mediates expectation-based pain relief. This discovery opens the possibility of targeting this novel pathway with drugs or neurostimulation methods to treat pain. More broadly, our studies provide a framework for investigating the neural circuit basis of other mind-body interactions beyond those involving pain, and point to prefrontocortical-cerebellar communication as a potential basis for such effects.

Dataset Information

Elucidating an Affective Pain Circuit that Creates a Threat Memory.

Publications

Elucidating an Affective Pain Circuit that Creates a Threat Memory.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure