Jason Snyder

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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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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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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