Jason Snyder

Associate Professor

Relevant Thesis-Based Degree Programs


Graduate Student Supervision

Doctoral Student Supervision

Dissertations completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest dissertations.

Effect of non-invasive neurostimulation on hippocampal plasticity and memory (2023)

Non-invasive stimulation therapies such as electroconvulsive therapy (ECT) or transcranial magnetic stimulation (TMS) are effective therapies for treatment-resistant depression. Although ECT is more efficacious than other treatment options, it is associated with cognitive side effects. By understanding the neurobiological underpinnings of ECT and TMS, we may gain critical insights into both their therapeutic and side effect profiles.In the current project, I used adult hippocampal neurogenesis in mice as a measure of neuroplasticity induced by neurostimulation. First, I directly compared the extent of hippocampal neurogenesis generated acutely by different stimulation modalities, including electroconvulsive shock (ECS), the animal analogue of ECT, and two forms of TMS, the 10Hz repetitive TMS (rTMS) and the intermittent theta burst stimulation (iTBS). I found that ECS increased neurogenesis significantly more than either form of TMS. However, a newer pattern of TMS called intermittent theta burst stimulation (iTBS) showed a greater neurogenic potential than the traditional repetitive TMS (rTMS) when administered acutely and therefore I conducted the first study examining neurogenesis following chronic iTBS. Chronic iTBS application did not affect neurogenesis but altered the new neurons' morphology by increasing the size of pre-synaptic terminals in males. In contrast, chronic ECS induced up to a 2-fold increase in new neuron proliferation and survival, along with an enhancement of dendritic length and pre-synaptic terminal size in both males and females. These findings suggest that the stronger form of stimulation, ECS, is associated with increased neurogenesis, however new neuron addition may not be entirely beneficial. Animals that received chronic ECS were impaired in the performance of an associative memory task. While new neurons support hippocampal functions to improve future cognition, the integration of new neurons may disrupt the existing hippocampal circuit. Although chronic ECS did not decrease the number of developmentally-born neurons, I found that chronic ECS decreased the spine density of developmentally-born neurons in the ventral hippocampus. Overall, this study showed that ECS and TMS had differential effects on adult hippocampal neurogenesis and the ECS-induced neurogenesis may impair cognition by pruning existing synaptic connections.

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Hippocampal neurogenesis and the entorhinal-dentate gyrus circuit under healthy and pathological conditions (2023)

Adult hippocampal neurogenesis involves the addition of new neurons in the dentate gyrus (DG) region beyond the developmental period, creating adult-born neurons that exhibit different intrinsic properties and plasticity than the older developmental population. Afferent connectivity differs between adult-born and developmentally-born neurons (ABNs/DBNs), with maturing ABNs mainly receiving lateral entorhinal cortex (LEC) input, while DBNs receive inputs from both LEC and MEC. The LEC is implicated in early stages of Alzheimer’s disease (AD), with hallmark tau protein pathology developing here before progressing downstream to the DG and other regions. We sought to examine how adult-born neurons interact with other neurons in the DG during learning under healthy conditions and explore how tau pathology in the LEC affects memory performance and downstream DG neurons of different ages. In chapter 2, we examine the impact of silencing a fraction of the ABN population on DG activity using an inhibitory chemogenetic approach during spatial learning in the Morris Water Maze. We found that silencing ABNs led to an increase in activity in the DBNs via labelling with a DNA marker bromodeoxyuridine (BrdU) and immediate early gene Fos. Silencing ABNs did not alter activity in other ABNs nor in inhibitory interneurons. These data indicate that ABNs can exert inhibition during learning on the developmental population, likely through direct monosynaptic connections from ABNs to DBNs. In chapter 3, we explore the impact of tau pathology in the LEC-DG circuit on memory performance and ABNs and DBNs respective structure and function. By injecting a virus that overexpresses human tau into a transgenic mouse with inducible florescent labelling of DBNs and ABNs, we found that tau pathology led to disrupted object recognition memory and altered morphology of ABNs and DBNs similarly. Overall, our data show that manipulating the ABN population can impact overall DG activity, and under a disease model, both ABNs and DBNs are similarly vulnerable to pathological insult. These findings provide insight into the impact of neurogenesis on hippocampal activity and provide evidence for synaptic changes at a circuit-level model of disease that could ultimately be targeted for early intervention before further disease progression.

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Regulation of developmentally-born and adult-born neurons in the dentate gyrus (2019)

The discovery that neurons are added to the adult brain of nearly all mammals examined, including humans, has had profound effects on our understanding of the potential for plasticity in the brain. There has been an overwhelming focus on understanding the unique properties of adult-born neurons, often at the expense of another important cell population: the already present developmentally-born neurons. While the stages and integration of neurons in adulthood have been relatively well characterized, less is known about how developmentally-born cells integrate and survive over time and are regulated by experience. Since the dentate gyrus (DG) is comprised of large numbers of both populations, identifying the properties of these two populations and their relationship is essential for understanding how the dentate gyrus contributes to memory and behaviour. In chapter 2 we show that developmentally-born neurons die in early adulthood, unlike adult-born cells, which are known to remain stable (after reaching maturity). While adult-born neurons are unique during their immature stages, many reports indicate that they may become functionally equivalent to neurons born in early postnatal development once they have reached maturity. These data collectively suggest that adult neurogenesis may serve to replace lost developmentally-born cells. In chapter 3 we show that alternating 4-week blocks of running and memantine, an NMDA antagonist, produces sustained increases in adult neurogenesis in males, while in females interval running increased adult neurogenesis. In chapter 4 the relationship between the two populations was investigated using either neurogenesis-promoting or suppressing treatments during early adulthood. We found that that increasing adult neurogenesis decreases the activity in the DG and specifically in developmentally born neurons, indicating that there is a functional relationship between the two populations, and that adult-born neurons may act to inhibit older neurons. This thesis set out to better describe both the developmentally-born and adult-born neuronal populations and investigate the relationships between these two populations. Collectively, these data hope to clarify whether there are interactions between neurons born throughout the lifespan, which may shape how information is retained in the hippocampus and could prioritize treatments that are aimed at generating new cells vs. preserving older cells.

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Master's Student Supervision

Theses completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest theses.

Investigating the Effects of Silencing the Hippocampus in a Probabilistic Reversal Learning Task (2024)

In the quest for rewards, which can range from food to other incentives, both animals and humans must navigate the inherent uncertainties of their environments. The ability to learn from and adapt to these uncertainties, modifying cognitive strategies for reward acquisition, is crucial. This adaptive process is compromised in various neurological and psychological disorders, including depression, obsessive-compulsive disorder (OCD), Parkinson’s disease, schizophrenia, among others. Traditionally, research has focused on the orbitofrontal cortex (OFC), striatum, and amygdala in forming probabilistic reward associations. Since the hippocampus is a brain region heavily involved in the formation and retrieval of memory, and probabilistic reversal learning is a learning task, we hypothesized that the hippocampus is involved. Emerging evidence, including prior research from our laboratory, suggests that hippocampal neurogenesis plays a role in modulating reward feedback sensitivity, hinting at a more nuanced involvement of the hippocampus in this process.Given the hippocampus' extensive connections with the prefrontal cortex (PFC), amygdala, and striatum, we hypothesized that it might be a critical contributor to probabilistic learning mechanisms. The hippocampus itself is not a monolithic structure. It is differentiated into dorsal and ventral domains, with the dorsal primarily implicated in cognitive tasks such as spatial navigation and the ventral in encoding emotional significance. While historically considered in a dichotomous framework, contemporary studies indicate that both hippocampal regions engage in various learning and memory functions.We employed both pharmacological and chemogenetic techniques to transiently inactivate the dorsal and ventral hippocampus. Pharmacological inactivation yielded observable effects in both regions. Chemogenetic inactivation of the dorsal hippocampus did not yield notable results. However, there were discernible and significant differences between the adeno- associated virus (AAV) treated and control groups. These findings may shed light on the differentiated, yet interrelated, roles of hippocampal regions in learning under uncertainty.Our research demonstrates that pharmacological inactivation of the dorsal and ventral hippocampus lead to changes in perseverative behaviours, deemed Win-Stay, as well as impulsivity. Furthermore, chemogenetic inactivation shows diffuse effects of DREADD treatment versus non-surgical controls. AAV surgery leads to a decrease in performance measures (total reversals) as well as perseverative behaviour.

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Representational drift of contextual fear representations across the brain (2024)

The physical manifestation of memory is an “engram”, the population of neurons activated during a learning experience and, when reactivated, contributes to the process of memory retrieval and subsequent behaviour. Traditionally, it has been believed that neural representations must remain stable to maintain memories. However, memories are dynamic and recent investigations have revealed that neural representations are more fluid than formerly thought. In the hippocampus, neurons previously recruited during an experience show variation through time, a process called representational drift. Memories are distributed across multiple ensembles throughout the brain, and drift has been observed in various brain regions as well. To better understand the stability of neural representations at a broader network level, we sought to characterize the drift of neuronal representations for two identical experiences in brain regions that are involved in perception and memory, and explore how this corresponds to memory organization processes over time.Behavioural results suggest that animals showed increased fear generalization over time. Of the nine brain regions of interest, the vCA1 was shown to reactivate less over time, whereas the RSC reactivated more at remote timepoints. Significant differences in reactivation were observed between the dDG and vDG. Surprisingly, memory representations at recent and remote timepoints were not context-specific, implicating negative effects of aging on memory reactivation and fear generalization.In sum, our findings stand in support of memories being reorganized through systems consolidation over time, where representations are seen to drift in ways that can be predicted by systems consolidation. Further research is needed to delineate the interplay between age, transgenic mice efficacy, and fear generalization.

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Anti-amyloid-beta oligomer antibody increases the survival of newborn hippocampal neurons (2023)

We aimed to investigate the role of cSNK-bearing oligomers in hippocampal neurogenesis disturbances associated with AD and assess the potential of mAb5E3 in mitigating these effects.Aged male and female APPswe/PSEN1ΔE9 AD model mice were treated with mAb5E3 for 6 weeks. The effect of passive immunization on adult hippocampal neurogenesis was determined by quantifying the rate of survival in 4-week-old newborn granule cells by immunohistochemical detection of the DNA marker BrdU. Additionally, we analyzed immediate early gene (IEG) expression to assess changes in dentate network activity in response to spatial learning. Behavioral outcomes were assessed via open field exploration, novel object, and location recognition tasks. We found that mAb5E3 significantly increased the survival of newborn hippocampal neurons. Consistent with the role of newborn neurons in modulating the level of activity in the DG, we found that survival rates were inversely related to IEG expression, such that an increase in neurogenesis was associated with a commensurate decrease in the activity levels within the overall GC population. In the novel object recognition task, we found that mAb5E3-treated mice spent significantly more time exploring the novel object compared to the familiar one. This observed bias exceeding the level expected by chance alone suggests an ability to discriminate previously encountered objects. This study extends the understanding of the role of cSNK-bearing AβOs in AD pathogenesis, providing evidence of their role in AD-related neurogenesis abnormalities. Moreover, our findings further validate the therapeutic potential of mAb5E3, providing additional insight into its mechanism and efficacy.

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