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. / Thesis / Master of Science (MSc) / Neurogenesis is a process that describes the production of new nerve cells in the brain. It mainly occurs during early life, but persists in a central brain structure responsible for learning and memory, known as the hippocampus, throughout our lives. This active brain structure relies on the function of certain organelles called mitochondria, which are the primary cellular energy producers and promote nerve cell production. Mood disorders, such as anxiety and depression, may result as a consequence of impaired hippocampal neurogenesis. Evidently, people suffering from anxiety and depression turn to cannabis use for management and treatment of their mood disorders. Considering cannabis has been shown to affect neurogenesis and mitochondrial function, our primary objective was to explore its effects on hippocampal neurogenesis by focusing on mitochondrial function, in the context of stress. We demonstrate that components found in cannabis, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), alter the stress-induced changes in mitochondrial functions related to neurogenesis, suggesting that cannabis may play a role in protecting nerve cells.

Initial experiments evaluated the impact of hematocrit on a bird’s ability to adapt to stress and what physiological mechanisms occurred to maintain oxygen carrying capacity (OCC). A final experiment was conducted to obtain proteomic evaluation of protein expression in monocytes of unstressed broilers. In initial experiments, ACTH treatment was applied to hematocrit separated broilers. Experiments evaluated effects of ACTH on broilers with low (19 to 22%, Experiment 1; 18-21%, Experiment 3), high (25 to 28%, Experiment 1; 24 to 27%, Experiment 3) or non-selected hematocrit levels (Experiment 2 and 3). After 4 d of ACTH, all treated birds had significantly increased (P < 0.1) pCO2, HCO3-, and corticosterone levels, indicating as stress raises pCO2, HCO3- must rise to maintain acid base balance. Birds not selected for hematocrit had significant drops in pO2 when given ACTH. Broilers compensate for low OCC through release of red blood cells from storage sites, indicated by decreases in organ hemoglobin and increases in hematocrit and blood hemoglobin when birds are given ACTH. Accelerated red blood cell formation does not appear to occur, because erythropoietin decreases following administration of ACTH to non-selected birds. ACTH induced stress, increased hemoglobin and hematocrit only in birds with low or non-selected hematocrit, suggesting high hematocrit birds prior to stress have an adaptive advantage during stress. Higher hematocrit prior to stress apparently provides ample OCC during stress. Unselected birds appear to require initiation of an inflammatory response to adapt to stress which can be noted by increases in total white blood cell count, monocytes, and heterophils and decreases in lymphocytes. High hematocrit birds appear less susceptible to stress effects by maintaining leukocytes at a constant level, while in non-selected birds lymphocyte percents drop. Proteomics was conducted on avian monocytes to reveal proteins related to immune functions, 3229 proteins were identified, with 46 involved in immune functions of professional antigen presenting cells. This protein data provides a means of comparing monocytes of stressed and unstressed animals in the future. In conclusion, evaluated hematocrit is advantageous in adaptation to stress through maintenance of high OCC, acid base balance and immune cells.

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