Thesis Seminars

Mark Stoessel, MS - PhD Candidate, Neuroscience Graduate Program

Synaptic plasticity allows the central nervous system to incorporate new sensory experiences and information, and its disruption is associated with many neurological and psychiatric disorders. Much recent work has focused on the contribution of non-neuronal central nervous system cells, especially microglia, to synaptic plasticity. Though classically defined by their immune capacities, microglia are vital to many homeostatic processes, including synaptic plasticity of nascent and adult neuronal networks. Despite the emerging consensus that microglial dynamics are critical to brain function during physiological as well as pathological conditions, it is unclear whether these microglial roles and their underlying mechanisms are universal or differ between brain regions. There is a growing body evidence to suggest microglia exhibit a high degree of regional specialization. Cerebellar microglia in particular exhibit unique transcriptional and epigenetic profiles, and distinct functional properties, such as being morphologically less ramified, and less densely distributed than cortical microglia. As a consequence, cerebellar microglia survey less of the parenchyma than cortical microglia but compensate for this by undergoing frequent somatic translocations under homeostatic conditions, a phenomenon not observed in cortex. Despite such differences, cerebellar microglia maintain common microglial functions. Two pathways of interest to cortical microglial mediated synaptic plasticity are purinergic signaling through the P2Y12 receptor and noradrenergic signaling through the β2 adrenergic receptor (β2-AR), both of which have been shown to be critically involved in microglial roles in synaptic remodeling and rapid chemotaxis to sites of injury.

To address this question of regional heterogeneity in microglial signaling we investigated the roles of P2Y12 and β2-AR in cerebellar microglial with a comparison to the known roles of these signaling pathways in cerebral cortex. We desired to understand the contribution of these pathways to the many aspects of microglial function in the adult brain and therefore characterized cerebellar microglial morphology, surveillance, injury response dynamics, gene expression patterns, and contributions to cerebellar learning and plasticity, while manipulating either microglial purinergic or adrenergic signaling. On the whole, our findings suggest that signaling pathways that are present in both cortical and cerebellar microglia may play differential roles in microglial function depending on brain area.

 Jun 12, 2024 @ 1:00 p.m.
 Medical Center | K-207 (2-6408)

Gregory Reilly, MS - PhD Candidate, Neuroscience Graduate Program

Biological sex is a fundamental dimension of internal state that can have deep influences on behavior. Understanding the mechanisms behind these influences can provide insight into how shared neural circuits are tuned to produce sex-specific behavioral variation. Biological sex can influence both short-term behaviors and longer, more persistent forms of behavior known as behavioral states. In C. elegans, persistent motor behavior, called locomotor states, is well-studied in hermaphrodites. On a patch of food, hermaphrodites will switch between two states of foraging and feeding, called roaming and dwelling respectively. However, while some work has examined motor states in males, these remain poorly characterized. Previous work from our lab has demonstrated that male locomotion is sex-specific; the sexual state of muscle tissue and the nervous system is essential for sex differences in speed and body posture. Therefore, biological sex may also similarly influence locomotor states. We trained a supervised machine learning Random Forest model to detect three locomotor states: roaming, dwelling, and tail chase. In addition, we used a dimensionality reduction analysis, Linear Discrimination Analysis (LDA), to compare the overall characteristics of these states. Furthermore, to measure the transition probability between states, we used a Markov model. While both males and hermaphrodites share the locomotor states of roaming and dwelling, the characteristics of these differ by sex- the amount of time spent in each state, state durations, and transitions between states (temporal differences), as well as the linear speed, curvature, and other characteristics (feature differences), have sexual dimorphism. To understand how sex tunes these locomotor states, we manipulated the sex determination pathway to sex reverse the nervous system in both males and hermaphrodites. Interestingly, we found that pan-neuronally feminized males had similar locomotor state characteristics to hermaphrodites; both temporal and state feature sex differences were eliminated in the feminized males. Yet, masculinized hermaphrodites were indistinguishable from their wildtype counterparts indicating that either male-specific neurons or other tissue played a role in mediating these sex differences. To uncover the mechanisms that biological sex leverages to achieve this sex-specific variance in locomotor states, various neuromodulator knockout mutants known to affect locomotor states were tested. PDFR-1 emerged as a strong candidate as it removed differences in both temporal and features of locomotor states. Preliminary data suggests that PDFR-1 signaling may regulate the temporal sex differences through daf-7, a TGF-ß signal. daf-7 knockout mutants appear to maintain differences in state features but both spend similar amounts of time roaming and dwelling. Given that PDFR-1 signaling has been implicated as the mechanism that regulates sexual dimorphism in daf-7 expression in the ASJ neuron, these results remain promising. Together, our results provide a mechanistic framework for understanding how sex-specific neuronal tuning influences behavioral states.

 Jun 14, 2024 @ 10:00 a.m.
 Medical Center | SMD Lg. Aud. (2-6424)