PhD Exit Seminar for Soroush Darvish-Ghane (Martin lab)

Anterior Cingulate Cortex Dopaminergic Modulation of Ionotropic Transmission and Dopaminergic Homeostasis in Mice with Inflammatory Pain

Abstract

The Anterior cingulate cortex (ACC) is a cortical brain region critical for processing acute and chronic pain. Anatomical studies indicate bidirectional connectivity between the ACC and ventral tegmental area (VTA) as nodes within the mesocortical dopaminergic pathway. Evidence suggests that the release of dopamine (DA) in the ACC may have analgesic properties. DA modulates behaviour and synaptic transmission by signalling through D1- and D2-like receptors with distinct downstream pathways. D1 receptors (D1R) in the medial prefrontal cortex (mPFC) promote neuronal excitability and learning. Thus, a D1R mechanism in the ACC may influence pain perception and chronic pain development. Initially, we sought to characterize the function of the D1R subtype in the ACC on modulation of excitatory transmission and pain-related behaviour. In this regard, we characterized behaviour in a CRISPR/Cas9 mediated somatic knockout of the D1Rs in all neuronal subtypes of the ACC and we find enhanced mechanical sensitivity without affecting locomotion and anxiety. Further, I used patch-clamp electrophysiology on ACC slices from mice and found that D1R agonists inhibit AMPAR currents in the ACC. Paradoxically, co-application of D1R antagonists with D1R agonists produced robust synergistic depression of AMPAR currents in the ACC, demonstrating an overall inhibitory role for D1R ligands.

Since pain potentiates ACC neurons, this may, cause activation of the VTA to release DA in target areas, including the ACC. Thus, pain-induced DA release may activate feedback mechanisms and pathways to modulate the sensory and affective components of pain. In this regard, the overarching goal of this thesis was to explore the role of ACC dopaminergic signalling and homeostatic function in response to inflammatory injury. One of the main parameters of ACC dopaminergic homeostasis included the effect of DA on the balance of excitation and inhibition (E/I) in the ACC. In the central nervous system, glutamate and GABA neurotransmitters mediate the E/I balance in pyramidal neurons. E/I balance is paramount for neuronal information processing, whereas an imbalance has been observed in neuropathological states. In addition, I have demonstrated that DA modulation inhibits both glutamatergic and GABAergic transmission in the ACC neurons through a postsynaptic G-protein mechanism. However, in mice with chronic inflammatory pain, we observed decreased dopaminergic mediated inhibition of AMPAR-mediated excitatory currents. Dopaminergic homeostasis of the ACC was further analyzed by examining the expression levels of DA receptors and neurotransmitter concentraion in the ACC and striatum. In mice with chronic inflammation of peripheral extremities, DA receptor expression was enhanced three- and four-days post-CFA treatment. These results demonstrate that inflammation changes DAR protein expression and signalling in the ACC. These results demonstrate pain-induced activity-dependent changes of mesocortical dopaminergic pathways. Whether these activity-dependent changes in DA function enhance or alleviate unpleasantness of pain remains to be investigated.

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Join Zoom Meeting

Tuesday, November 30th, 2021 at 2:00 pm

https://utoronto.zoom.us/j/83304741051

Host: Loren Martin (lj.martin@utoronto.ca)

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