Investigating the neural circuitry involved in the negative affective-motivational component of pain
Project Summary:
Pain is a multifaceted physiological system consisting of a range of sensory, affective and cognitive components. Pain is a widely significant problem, with long lasting (chronic) pain affecting large proportions of the worldwide population. Patients suffering from pain often exhibit anxiety disorders, which can manifest as physical (e.g. tachycardia), behavioural (e.g. avoidance and aggression), cognitive (e.g. unable to cope) or emotional (e.g. panic) symptoms.
Although the sensory component of pain (sensory discrimination and neuronal encoding) is well documented, the neural circuitry involved in the negative emotional components of pain (including anxiety, depression and aversive behaviours) are still unclear. Considering the affective and cognitive aspects of pain are regarded as the most challenging to endure and treat, it is important to explore the relationship between the sensory nociceptive component of pain and central affective-motivational networks.
We have identified a unique rodent model by which selective excitation of a specific sensory neuronal cluster in the dorsal horn of the spinal cord is responsible for driving increased pain related behaviours such as hyperalgesia and allodynia. Reductions in oxygen tension within the spinal cord neural tissue excites this exclusive sensory neural ensemble that expresses the oxygen sensor hypoxia inducible factor1α (HIF1α). Activation of HIF1α alters nociceptive processing and the presentation of pain hypersensitivity. In addition, these rodents also display anxiety like behaviours typifying an alteration in affective emotive cortical processing. This highlights a clear link between dorsal horn sensory neural ascending tracts and the affective and cognitive centres within the brain. There is accumulating evidence that the neural ascending tracts from the spinal cord and cortical projections diverge anatomically and functionally to modulate differing behavioural adaptations such as pain and anxiety. Despite this the intricate interconnections within the nervous system remains to be defined.
This PhD will use virally delivered chemogenetic and optogenetic approaches in transgenic rodent models (ie HIF1α Knockout, HIF1α inducible cre recombinase), in combination with neuronal tracing, transcriptome evaluation and rodent behavioural paradigms (e.g. conditioned place preference) to examine the neural circuitry involved in the negative emotional aspect of pain. Viral vectors will be delivered directly to those neural regions of interest to allow us to deduce the anatomical and functional landscape of this neural network between the dorsal horn and the brain. In addition, these viral vectors allow us to specifically control these neural clusters via light and/or druggable options to examine their role in the modulation of sensory neurophysiology and behavioural phenotypes. This project will allow understanding in how nociception and affective behavioural centres are interconnected in the perception of pain.
Training: The student will be involved with processing behavioural data and rodents tissues from the outlined models in preparation for confocal microscopy and neuroanatomical mapping.