Optogenetic investigations into the role of glutamatergic neurons of the anterior cingulate cortex in sensory and affective components of pain
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Pain consists of sensory-discriminative and affective-motivational components, which can share a reciprocal relationship. The anterior cingulate cortex (ACC) plays an important role in top-down control and the affective component of pain. In-vivo optogenetics is a technique in which light-sensitive proteins, opsins, are used to modulate specific populations of neurons with high temporal control in awake behaving animals. Commonly used opsins are channelrhodopsin-2 (ChR2) and archaerhodopsin (ArchT) to activate or silence neurons, respectively. Optogenetic methodology has been a valuable tool in a wide range of neuroscience fields including pain research. The aims of the work presented in this thesis were to (1) use optogenetics to investigate the role of glutamatergic neurons of the ACC in formalin-evoked nociceptive behaviour in male and female Sprague-Dawley (SD) rats and associated alterations in a marker of neuronal activity (c-Fos) in the spinal cord (2) investigate the role of glutamatergic neurons of the ACC in formalininduced aversive behaviour in male and female SD rats and associated alterations in c-Fos in the ACC due to optogenetic modulation of these neurons (3) investigate the role of glutamatergic neurons of the ACC in distraction-induced analgesia (4) develop biomaterials-based advancements of optogenetic methodology. Optogenetic inhibition (ArchT) of glutamatergic neurons in the ACC abolished formalin-induced conditioned place aversion (F-CPA) in male SD rats, while activation (ChR2) of the same neurons did not significantly affect F-CPA, compared with rats expressing control fluorophores. However, optogenetic activation of glutamatergic neurons in the ACC resulted in decreased nociceptive behaviour at discrete time points during the late stage of the 60-minute formalin trial in males but increased formalin-evoked nociceptive behaviour in female SD rats. The use of either fibrin-hydrogel to deliver opsin-encoding adeno-associated virus or sideemitting optical fibres for the delivery of light during optogenetic stimulation had no significant effect on formalin-evoked nociceptive behaviour in male SD rats, but did result in beneficial effects of increased transgene expression and increased activation of ChR2-expressing neurons in the ACC after optogenetic stimulation, respectively. In conclusion, the work presented herein suggests that glutamatergic neurons of the ACC could play a differential role in the aversive and sensory components of inflammatory pain in rats, in a sex-dependent manner. This thesis also presents beneficial biomaterials-based advancements of optogenetic methodology. These results further our understanding of the role of glutamatergic neurons in the ACC in different components of pain and may facilitate the development of novel therapeutic approaches that focus on alleviating the negative affective element of pain.
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