Five Neuroscience Graduate Program students successfully defend MSc theses

The Division of Medical Sciences and the Neuroscience Graduate Program (NGP) would like to congratulate Charlotte Copas (Nahirney Lab), Elisa Gonçalves de Andrade (Tremblay Lab), Irene Shkolnikov (Christie Lab), Kaylene Scheil (Caruncho/Kalynchuk Lab), and Patrick Montgomery (Krigolson Lab) on successfully defending their MSc theses. Read on to learn more about each student’s research.

Charlotte Copas
(Nahirney Lab)

“Ultrastructural analysis of synaptic inputs to dopamine neurons in the substantia nigra pars compacta and the ventral tegmental area”

The substantia nigra pars compacta (SNc) and the ventral tegmental area (VTA) are two extremely influential dopamine (DA) output centers that reside in the midbrain. Due to their influential roles in movement execution and reinforcement learning, respectively, there is an extensive body of literature investigating the broad effects of their outputs. However, one question that remains unanswered is how these DA neurons are modulated by their afferent inputs. Previous research shows that glutamate (Glut), acetylcholine (ACh), and γ-aminobutyric acid (GABA) are a few of the major neurotransmitters that modulate the activity of midbrain DA neurons. These findings also suggest that there is a population of terminals that co-localize both ACh and GABA vesicles, implying that DA neurons are under extremely fine-tuned afferent control.

Through her research, Charlotte aimed to describe the morphology of assumed Glut, ACh, and GABA vesicles, and to determine if there is indeed co-localization of ACh and GABA. She also wanted to determine the frequency of this co-localization and investigate whether there is heterogeneity in the prevalence of these inputs between the medial and lateral adult SNc and VTA. Using a combination of confocal and electron microscopy, she was able to offer a glimpse into the regulation of these essential modulatory neurons, adding a small piece of the puzzle to the ongoing investigation concerning basic ultrastructure and normal functioning of the SNc and VTA. 

Charlotte’s work was supported by a Project Grant from the Canadian Institutes of Health Research Project (CIHR; PJT-159548), as well as two UVic Fellowships, the James A. & Laurette Agnew Memorial Scholarship and Memorial Award, and the Vera Allen Travel Award for Medical Sciences.

Elisa Gonçalves de Andrade
(Tremblay Lab)

“Microglia change at the micro- and nano-scopic scales in response to therapeutic focused ultrasound blood-brain barrier modulation”

Treating conditions like Alzheimer’s disease is a challenge, partially due to the specialized protective blood vessels in the brain. These vessels block the entrance of nearly 99 per cent of drugs. Transcranial-focused ultrasound with microbubbles is a technology that could solve this issue by transiently opening this blood-brain barrier in a minimally invasive way. However, it is important to ensure that this technology does not impair normal functioning of the brain (e.g., disrupting the work of microglia, which are cells that protect the brain from danger or damage).

To tackle this challenge, Elisa investigated how the micro- and nanoscopic shape of microglia change in response to focused ultrasound. Using cutting-edge techniques, such as correlative light and scanning electron microscopy, she found that microglia mostly show subtle but diverse changes in their shape after focused ultrasound. Her findings support further application of this technology and indicate that microglia can greatly adapt to changes in the blood-brain barrier.

Elisa’s work is supported by the CIHR, the National Institute of Biomedical Imaging and Bioengineering, the Sunnybrook Health Sciences Centre, and the Natural Sciences and Engineering Research Council of Canada (NSERC). Her work is also supported by Dr. Tremblay’s Canada Research Chair (Tier II) of Neurobiology of Aging and Cognition

Irene Shkolnikov
(Christie Lab)

“Adiponectin Receptor Modulation as a Therapeutic Approach to Fragile X Syndrome”

Fragile X syndrome (FXS) is the most common form of genetically inherited intellectual disability and a leading cause of autism spectrum disorder (ASD), a condition that remains highly stigmatized, poorly understood, and subject to a lack of pharmaceutical treatments.

In her thesis, Irene investigated the molecular causes of ASD in FXS models and explored the use of a novel drug candidate AdipoRon, a synthetic adiponectin receptor agonist. FXS subjects showed alterations in social behaviour / aversion and anxiety-like behaviour, as well as a significant reduction in hippocampal long-term potentiation – a process central to learning and memory. Pilot data suggests that brief, but not prolonged, treatment with AdipoRon may help alleviate these deficits. Future work in the Christie lab will focus on fully understanding the underlying mechanisms of this novel treatment and how it affects ASD in FXS models. This research was funded by the FRAXA Research Foundation.

Kaylene Scheil
(Caruncho / Kalynchuk Lab)

“Time-dependent parallel and synergistic antidepressant-like effects of reelin and ketamine in an animal model of chronic stress”

Depression is the leading cause of global disability, disproportionately affecting females. As approximately 30 per cent of those diagnosed do not respond adequately to first-line treatment, there is a pressing need for novel therapeutics. At the forefront of research for novel therapeutics is ketamine, an N-methyl-d-aspartate receptor (NMDAR) antagonist that has rapid antidepressant effects following a single sub-anesthetic dose. Ketamine can improve traditionally hard-to-treat symptoms (e.g., anhedonia – the inability to feel pleasure – and suicidal ideation), although its use is limited due to side-effects that mimic psychosis symptoms and high abuse potential. Further, ketamine’s exact underlying mechanisms remain unknown.  

Reelin is an extracellular matrix glycoprotein that appears to be downregulated in the hippocampus of patients with depression. Previous work in the Caruncho / Kalynchuk lab has shown that exogenous reelin administration can produce rapid-acting antidepressant-like effects. While the molecular signaling pathway of reelin remains elusive, research indicates that reelin and ketamine may share certain mechanisms of action. Kaylene’s thesis examined the parallel and synergistic antidepressant-like effects of reelin and ketamine in the pursuit of developing a reelin-based therapeutic.  

Kaylene’s work was supported by a CIHR Canada Graduate Scholarship – Master’s, a UVic President’s Research Scholarship, a UVic Faculty of Graduate Studies Award, and several donor scholarships. After successfully defending her thesis, Kaylene started medical school at the University of Calgary.

Patrick Montgomery
(Krigolson Lab)

“Reliability, Attenuation, and Order Effects of EEG Components Across Multiple Assessments”

For his thesis, Patrick used electroencephalography (EEG) to measure neural signals linked to learning and attentional processes. These signals were measured across five sequential assessments and then examined in three distinct analyses. First, the neural signals showed high levels of reliability, supporting any found effects as experimentally driven. Second, Patrick examined order effects as previous studies suggesting a possible carry-over effect from one task to the next. His results indicated no order effects were present, supporting the stimulation of these neural signals without unexpected interactions. Finally, he inspected attenuation of the neural signals across the five sequential testing sessions. Previous research had shown a reduction in signal across a single assessment for both signals of interest. Unexpectedly, Patrick’s results revealed no attenuation for the learning signal and an increase across assessments for the attentional signal when evaluated across sequential assessments. The increasing attentional signal necessitates further investigation as this behaviour is uncharacteristic of this type of signal. Overall, this research expanded on the scientific literature regarding these neural signals, while opening the door to new areas of exploration. 

Patrick’s work was supported by an NSERC Canada Graduate Scholarship – Master’s, a UVic President’s Research Scholarship, and a UVic Graduate Award.