Agent-based modeling of the central amygdala and pain using cell-type specific physiological parameters

Abstract

The amygdala is a brain area involved in emotional regulation and pain. Over the course of the last 20 years, multiple researchers have studied sensory and motor connections within the amygdala in trying to understand the ultimate role of this structure in pain perception and descending control of pain. A number of investigators have been using cell-type specific manipulations to probe the underlying circuitry of the amygdala. As data have accumulated in this research space, we recognized a critical need for a single framework to integrate these data and evaluate emergent system-level responses. In this manuscript, we present an agent-based computational model of two distinct inhibitory neuron populations in the amygdala, those that express protein kinase C delta (PKCδ) and those that express somatostatin (SOM). We utilized a network of neural links to simulate connectivity and the transmission of inhibitory signals between neurons. Type-specific parameters describing the response of these neurons to noxious stimuli were estimated from published physiological and immunological data as well as our own wet-lab experiments. The model outputs an abstract measure of pain, which is calculated in terms of the cumulative pro-nociceptive and anti-nociceptive activity across neurons in both hemispheres of the amygdala. Results demonstrate the ability of the model to produce changes in pain that are consistent with published studies and highlight the importance of several model parameters. In particular, we found that the relative proportion of PKCδ and SOM neurons within each hemisphere is a key parameter in predicting pain and we explored model predictions for three possible values of this parameter. We compared model predictions of pain to data from our earlier behavioral studies and found areas of similarity as well as distinctions between the data sets. These differences, in particular, suggest a number of wet-lab experiments that could be done in the future.

Identification and characterization of genetic risk shared across 24 chronic pain conditions in the UK Biobank

“…Evidence for central processes beyond local pathophysiology has been accumulating, including recent studies demonstrating that chronic pain is best conceptualized as a combination of biopsychosocial factors that may lead to a variety of pain conditions [21, 125, 75, 20, 124, 16]. Studies in rodents have identified neuroinflammation- and neuroplasticity-related changes in brain pathways that mediate persistent pain behavior in animal models of different pain modalities [143, 96, 91, 27, 6, 122, 52, 5, 37, 87]. Neuroimaging studies have identified common brain systems involved in musculoskeletal pain [79, 68, 17, 44, 67, 61, 90], IBS [106, 4], orofacial pain [2], neuropathic pain [95, 100, 139], and postsurgical pain [47].…”

Synaptic plasticity in two cell types of central amygdala for regulation of emotion and pain

“…Previous studies have mostly used the expression of a specific neurochemical marker for the base of cell type identification in amygdala. These markers include SOM, PKCδ, CRF, neurotensin and tachykinin ( Li et al, 2013 ; Hunt et al, 2017 ; McCullough et al, 2018 ; Wilson et al, 2019 ; Li and Sheets, 2020 ; Miller Neilan et al, 2021 ). For example, PBN has been shown to project to both SOM-expressing [SOM(+)] and CRH(+) CeA cells ( Li and Sheets, 2020 ); optical activation of PKCδ(+) or CRH(+) CeA cells increases pain response whereas optical activation of SOM(+) CeA cells decreases pain response under pain conditions ( Wilson et al, 2019 ; Mazzitelli et al, 2021 ; Chen et al, 2022 ).…”

“…Increasing evidence indicates that there are functionally distinct types of cells in CeA that mediate differential effects on pain ( Wilson et al, 2019 ; Li and Sheets, 2020 ; Neugebauer et al, 2020 ; Miller Neilan et al, 2021 ). These previous studies primarily focus on CeA cells that express different neurochemical profiles of somatostatin (SOM), protein kinase C-delta (PKCδ) or corticotropin-releasing hormone (CRF) in regulation of pain.…”

Integration of Adenylate Kinase 1 with Its Peptide Conformational Imprint

“…There is a growing interest in and need for artificial enzymes [ 1 , 2 ]. Although researchers have explored many experimental and computational methods for elucidating the chemical mechanisms of enzymes, most of these sophisticated methods are for noninvasive observation [ 3 ]. To study the catalytically competent state of an enzyme, researchers routinely use a substrate or inhibitor as an interloper to bind the active site [ 3 ].…”

“…Although researchers have explored many experimental and computational methods for elucidating the chemical mechanisms of enzymes, most of these sophisticated methods are for noninvasive observation [ 3 ]. To study the catalytically competent state of an enzyme, researchers routinely use a substrate or inhibitor as an interloper to bind the active site [ 3 ]. Notable exceptions to this reliance on substrates and inhibitors involve the use of mechanical force or miniaturized tweezers [ 4 , 5 ].…”