Differences in the neural basis and transcriptomic patterns in acute and persistent pain-related anxiety-like behaviors

Abstract

BackgroundBoth acute and persistent pain is associated with anxiety in clinical observations, but whether the underlying neural mechanisms differ is poorly understood.MethodsWe used formalin or complete Freund’s adjuvant (CFA) to induce acute or persistent pain. Behavioral performance was assessed by the paw withdrawal threshold (PWT), open field (OF), and elevated plus maze (EPM) tests. C-Fos staining was used to identify the activated brain regions. Chemogenetic inhibition was further performed to examine the necessity of brain regions in behaviors. RNA sequencing (RNA-seq) was used to identify the transcriptomic changes.ResultsBoth acute and persistent pain could lead to anxiety-like behavior in mice. The c-Fos expression indicates that the bed nucleus of the stria terminalis (BNST) is activated only in acute pain, whereas the medial prefrontal cortex (mPFC) is activated only in persistent pain. Chemogenetic manipulation reveals that the activation of the BNST excitatory neurons is required for acute pain-induced anxiety-like behaviors. In contrast, the activation of the prelimbic mPFC excitatory neurons is essential for persistent pain-induced anxiety-like behaviors. RNA-seq reveals that acute and persistent pain induces differential gene expression changes and protein–protein interaction networks in the BNST and prelimbic mPFC. The genes relevant to neuronal functions might underline the differential activation of the BNST and prelimbic mPFC in different pain models, and be involved in acute and persistent pain-related anxiety-like behaviors.ConclusionDistinct brain regions and gene expression patterns are involved in acute and persistent pain-related anxiety-like behaviors.

The neurophysiological basis of stress and anxiety - comparing neuronal diversity in the bed nucleus of the stria terminalis (BNST) across species

“…-Caudate nucleus (Torrisi et al, 2015) -Putamen (Avery et al, 2014) -NAc (Torrisi et al, 2015) Behavioural function and dysfunction -Stress induced nociception (Tran et al, 2012) (Acute) pain related behaviors (Myers et al, 2014;Fang et al, 2023) -Anxiety related responses (freezing behaviour) (Kalin et al, 2005) -Sustained anxiety/threat anticipa tion/threat processing (Davis et al, 2010;Alvarez et al, 2011;Grupe et al, 2012;Somerville et al, 2013;Herrmann et al, 2016;Brinkmann et al, 2018;Camilo et al, 2022) (Continued) , 1998;Eiler et al, 2003) -Anxiety like behaviour during withdrawal (Huang et al, 2010) -Arousal (Ju et al, 1989) -Conditioned anxiety/ contextual fear/ sustained anxiety (Sullivan et al, 2004;Vantrease et al, 2022) -Sustained anxiety/threat anticipation/ threat processing (Fellinger et al, 2021) -Pavlovian fear and reward behaviour/learning (Bruzsik et al, 2021;Kaouane et al, 2021) -Regulation of food intake (Wang et al, 2019) -Alcohol-and drug-motivated behaviour (Silberman et al, 2013) -Threat anticipation/evaluation of threatening stimuli (Hoffman et al, 2007) -Behavioural inhibition (Fox et al, 2010) -Social/affiliative behaviour: aggression, mating behaviour, maternal care, social interaction (Jacobs et al, 2023) -Phasic threat processing (Gungor and Paré, 2016;Shackman and Fox, 2016;Klumpers et al, 2017;Brinkmann et al, 2018;…”