Background & Aims
The biological need for social interaction is an evolutionarily conserved trait across social species that is reinforced by reward processing pathways in the brain. Pain has been shown to be a potent modulator of social engagement and behavioral sequence selection. Additionally, social interactions can cause idiopathic changes in pain perception depending on the social context. However, there is a notable lack of research on the neurological mechanisms underlying the interaction of social reward with analgesia processing, with even fewer studies investigating the dynamic, and often individual, changes in social behavioral expression caused by pain. My research aims to fill this gap by combining a novel volitional social self-administration procedure with single-cell resolution in-vivo recordings of cellular ensembles before and after sciatic nerve ligation in mice.
Methods
Male and female mice were trained in social-self administration (SSA) which occurs in operant chambers where mice lever-press for access to their social partner during eight, 48-minute once-daily sessions. Following acquisition of SSA, mice underwent a spared nerve injury (SNI) or sham surgery. Mice were then placed back in the social administration task either immediately following injury – immediate social intervention –, or at five days post injury –delayed social intervention – to evaluate the effects of acute and persistent neuropathic pain on social behavior. von Frey testing for mechanical allodynia occurred throughout social testing. A second cohort of mice that acquired SSA received unilateral stereotaxic injections of GCaMP6s into NAc and were implanted with a gradient-index (GRIN) lens over the site of injection. Following recovery from GRIN lens implantation (4-6 weeks), miniscope and behavioral recordings occurred on the first and last day of the SSA task pre and post SNI.
Results
We found that mice exhibit differential pain and social behavioral profiles dependent on sex and whether they received immediate or delayed access to volitional social interaction. We identified a critical recovery window, where male and females with access to volitional social access early in their pain progression show reduced allodynia compared to male and females who receive social access later in their pain progression. Male mice in both the immediate and delayed social intervention groups respond more for social access following injury compared to their pre-injury baseline response rates and sham males. However, only the immediate intervention group displays reduced allodynia. In contrast, immediate social access female mice maintain elevated levels of social responding compared to the delayed social access females who demonstrated phenotypes typical of social withdrawal and high pain sensitivity on the von Frey test. We also identified differential neuron activity patterns.
Conclusions
Here I describe dynamic, sex-dependent social adaptations to persistent pain that cause transient changes in allodynia. Through single cell resolution miniature microscopy, I have characterized how cellular ensemble dynamics shift during social behavior because of pain, and how reflexive allodynia shifts as a result of social intervention. The pain responsive ensembles identified through miniscope recordings will provide more precise targets for subsequent investigation and therapeutic intervention of underlying neural mechanisms dysregulated by prolonged pain states.
References
1. Psychological and neural mechanisms of the affective dimension of pain. Science (1979) 288, 1769-1772 (2000).
2. Comorbidities and chronic neuropathic pain. Pain Medicine vol. 5 (2004).
3. Pain-induced aggression and changes in social behavior in mice. Aggress Behav 47, (2021).
4. Pain-induced negative affect is mediated via recruitment of the nucleus accumbens kappa opioid system. Neuron 102, 564-573. (2019)
5. Social pain and physical pain: shared paths to resilience. Pain Manag 6, 63 (2016).
Presenting Author
Carlee Toddes
Poster Authors
Topics
- Mechanisms: Psychosocial and Biopsychosocial