Investigating the effects of corticosterone and cannabinoids on hippocampal neuroplasticity and mitochondria

Abstract

Hippocampal neurogenesis is linked to the onset, progression and remission of major mood disorder such as anxiety and depression. Neurogenesis is the process by which new neurons are formed in the brain. Mitochondria mediate cellular adaption and provide energy to support growth of new neurons. Chronic stress and mood disorders have been associated with impairments in mitochondrial function and neuronal growth. Individuals experiencing stress and mood disorders reportedly use cannabis as a means to self-medicate. The impacts of cannabis on stress-related effects on hippocampal neurogenesis and mitochondria are vastly unexplored. To investigate these effects we generated an in vitro model of hippocampal neuron stress by treating HT22 cells with corticosterone, the major effector molecule of stress in rodents. We first characterized the impacts of corticosterone on markers of neurogenesis and mitochondrial function in HT22 hippocampal cells. We found that corticosterone decreased gene markers of neurogenesis, mitochondrial biogenesis, content, dynamics and decreased mitochondrial membrane potential. Corticosterone also decreased levels of antioxidant enzymes but did not alter levels of reactive oxygen species (ROS) or elicit lipid peroxidation. We then investigated with potential impacts of cannabis components, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), on corticosterone-induced stress. Individually, THC and CBD decreased markers of neurogenesis, dysregulated mitochondrial dynamics and decreased mitochondrial membrane potential. Interestingly, both THC and CBD increased a marker of mitochondrial biogenesis. Finally, we co-treated HT22 cells with corticosterone and THC or CBD to interrogate the impacts of THC and CBD on corticosterone-induced alterations. Our results indicated THC and CBD had no effect on corticosterone-related reductions in neurogenesis markers or mitochondrial membrane potential. However, THC demonstrated a rescuing effect on a marker of mitochondrial biogenesis and CBD normalized a marker of mitochondrial fission; both of which were decreased with individual corticosterone treatments. This thesis ultimately identifies some of the pathways THC and CBD may impact stress response in relation to neurogenesis and mitochondria.