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Faculty of Graduate Studies

Emily Miller

  • BA&Sc (Quest University Canada, 2020)
Notice of the Final Oral Examination for the Degree of Master of Science

Topic

Neuroanatomical relationship between cannabinoid type-1 receptors and dopamine neurons in the substantia nigra and ventral tegmental area

School of Medical Sciences

Date & location

  • Friday, June 13, 2025
  • 10:00 A.M.
  • Medical Sciences Building, Room 310

Examining Committee

Supervisory Committee

  • Dr. Patrick Nahirney, School of Medical Sciences, ßÉßɱ¬ÁÏ (Supervisor)
  • Dr. Brian Christie, School of Medical Sciences, UVic (Member)
  • Dr. Raad Nashmi, School of Medical Sciences, UVic (Member)

External Examiner

  • Dr. Pedro Grandes, Department of Neurosciences, University of the Basque Country

Chair of Oral Examination

  • Dr. Helena Petrosova, Department of Biochemistry and Microbiology, UVic

Abstract

The substantia nigra pars compacta (SNc), substantia nigra pas reticulata (SNr) and ventral tegmental area (VTA) of the midbrain serve as the primary dopamine (DA) neuron hub of the brain. DA neurons project through distinct pathways—the mesolimbic, mesocortical, and nigrostriatal circuits—regulating critical behaviours such as motor control, motivation, and reward processing. The endocannabinoid system (ECS) is a neuromodulatory network that can influence synaptic transmission, predominantly via the cannabinoid type-1 receptor (CB1R) within the central nervous system. Although CB1Rs are widely distributed across the brain, the midbrain exhibits notably high CB1R expression. CB1Rs are proposed to modulate DA neuron activity by modulating afferent synaptic inputs. Dysregulation of CB1R distribution and function has been implicated in DA-related pathologies, including schizophrenia, Parkinson disease, and substance use disorders, making it a promising target for therapeutic intervention and mechanistic research. Despite growing interest in the DA-ECS interaction, the subcellular localization and density of CB1Rs within the SNc, SNr, and VTA remain poorly characterized. This study employed triple immunofluorescent confocal microscopy to assess the regional distribution of CB1R, tyrosine hydroxylase (TH; a DA neuron marker), and glutamate decarboxylase 67 (GAD67; an inhibitory neuron marker) across the SNc, SNr and VTA. Double pre-embedding immunoelectron microscopy was used to label CB1Rs with gold particles and TH with 3,3'-diaminobenzidine (DAB), enabling ultrastructural visualization via transmission electron microscopy. Micrographs were collected from all three regions and presynaptic terminals synapsing onto TH-positive compartments were traced and analyzed for CB1R labeling. Both immunofluorescent and immunoelectron results demonstrated that CB1Rs are most densely expressed in the SNr, followed by the SNc and VTA, and that CB1Rs preferentially localize to inhibitory presynaptic terminals. These findings suggest that CB1Rs predominantly modulate inhibitory inputs onto DA neurons. A deeper understanding of CB1R distribution and function within DA-rich midbrain regions will advance our knowledge of ECS modulation of DA neurotransmission and may inform the development of novel therapeutic strategies for DA-related disorders.

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