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Introduction: My PhD Journey in Neuroscience
The main research project of my PhD centered on the role of the glutamate receptor NMDA in a specific population of neurons in the basal ganglia. This work, conducted between 2010 and 2015 at the Université Libre de Bruxelles, was the cornerstone of my doctoral studies and laid the groundwork for collaborations, presentations, and awards.
In 2010, my presentation of this project earned me first place in my commission, securing a 4-year grant from FRIA/FNRS. Additional funding came through the Van Buren Grant, enabling further exploration and expansion of my research. During this time, I also collaborated with:
- Pierre Vanderhaeghen’s lab, focusing on Alzheimer’s disease models (more details available in Chapter 4).
- Janssen Pharmaceuticals, as part of the Stellar Project, a European initiative uniting scientists to refine protocols for iPSC differentiation.
Beyond my main research, I pursued a second independent project studying the inhibitory role of fast-spiking interneurons (FSIs) on the two populations of medium spiny neurons (MSNs) in the striatum. This side project further enriched my understanding of basal ganglia circuitry.
Highlights of My PhD Experience
- Teaching and Mentorship: I trained students, colleagues, and visiting professors in electrophysiology and imaging techniques, fostering a collaborative research environment.
- International Exposure: I worked at the Collège de France to gain expert input on plasticity protocols, expanding the scope of my work.
- Scientific Outreach: I presented my findings at numerous conferences, including the 11th Meeting of the Belgian Society for Neuroscience in 2015, where I won first prize for the best talk. I also engaged with broader audiences, presenting at the Palais of the King of Belgium to Princess Astrid after securing additional funding.
This period of intense research and collaboration culminated in a deeper understanding of NMDA receptor function and its implications for behavior. Below, I develop the main findings of my PhD research.
NMDA Receptors and Their Role in Shaping Neural Circuits and Behavior
Understanding the brain often feels like untangling a web of impossibly complex connections. However, every so often, a study uncovers a thread that fundamentally changes how we see the whole structure. My work, published in the Journal of Neuroscience in 2016, examined one such thread: NMDA receptors in indirect-pathway medium spiny neurons (iMSNs). This study explored their role in synaptic organization, movement, and behavior—a journey that fused molecular biology, electrophysiology, and behavioral science.
Why NMDA Receptors?
NMDA receptors are well-known for their role in synaptic plasticity, learning, and memory. They function as molecular coincidence detectors, responding only when certain conditions—such as the presence of glutamate and postsynaptic depolarization—are met. This makes them critical for synaptic strengthening, also known as long-term potentiation (LTP).
What was less understood at the time was their role in specific neural pathways. The basal ganglia, a hub for movement and decision-making, are divided into two primary pathways:
- The direct pathway, which facilitates action initiation (displayed in blue in the figure below).
- The indirect pathway, which inhibits competing or unwanted actions (displayed in red).
The focus of this research was the indirect pathway, specifically the role NMDA receptors play in striatopallidal medium spiny neurons (iMSNs) that drive this inhibitory circuitry.
Key Findings
1. Synaptic Connectivity and Plasticity
By conditionally knocking out NMDA receptors in iMSNs, we observed significant disruptions in synaptic connectivity. Specifically:
- Reduced synaptic input: The absence of NMDA receptors resulted in weaker connections between neurons, leading to diminished communication across the circuit.
- Impaired synaptic plasticity: Without NMDA receptors, these neurons lost their ability to adjust synaptic strength, a hallmark of learning and adaptation.
This finding highlighted NMDA receptors as central players in maintaining the structural and functional integrity of the brain’s inhibitory pathways.
2. Behavioral Consequences
The behavioral assays revealed striking impairments:
- Goal-directed learning: Mice lacking iMSN NMDA receptors struggled to adapt their actions based on rewards. This suggests a breakdown in the circuits underlying motivation and decision-making.
- Exploratory behavior: The knockout mice exhibited reduced habituation to new environments, reflecting deficits in learning and memory formation.
- Motor control: These mice showed subtle impairments in motor learning, consistent with the basal ganglia’s role in refining movement. Observe the two videos below (video 1, video 2) for a closer look at the motor behaviors studied in this research.
3. Implications for Disease
These results have broad implications for understanding neurological and psychiatric disorders. Disrupted basal ganglia circuits are implicated in diseases like Parkinson’s, Huntington’s, and addiction. This study suggests that targeting NMDA receptor function within specific pathways could offer new therapeutic avenues.
Summary of Key Observations
| Aspect | Wild-Type Mice | NMDA Receptor Knockout Mice |
|---|---|---|
| Synaptic Input | Normal synaptic connectivity | Reduced connectivity |
| Plasticity | Functional plasticity (LTP) | Impaired plasticity |
| Goal-Directed Behavior | Adaptive learning | Deficient learning |
| Exploratory Behavior | Habituation to new stimuli | Persistently exploratory |
What to Pay Attention To
1. The Role of Inhibitory Circuits
While the direct pathway often takes the spotlight, this study emphasizes the importance of inhibitory circuits in regulating not just movement but cognitive processes like learning and decision-making.
2. A Model for Neurological Disorders
This work provides a framework for studying basal ganglia dysfunctions. For instance:
- In Parkinson’s disease, dopamine loss disrupts both direct and indirect pathways. Understanding the role of NMDA receptors helps clarify how synaptic plasticity breaks down in these conditions.
- In Huntington’s disease, where iMSNs are particularly vulnerable, this study underscores the critical balance NMDA receptors maintain.
3. Experimental Rigor
From conditional knockout models to electrophysiological recordings, the methodological diversity here strengthens the conclusions. The combination of in vitro (brain slice) and in vivo (behavioral) approaches ensures that findings are grounded in both cellular and functional contexts.
Personal Reflections on the Study
What stands out most about this chapter in my career is how it brought together seemingly disparate fields—molecular biology, circuit neuroscience, and behavior—to tell a cohesive story. As someone who has always been fascinated by the intersection of cellular mechanisms and their broader behavioral manifestations, this project was a perfect fit.
This study posed broader questions that continue to intrigue me: To what extent can modulating NMDA receptors or dopamine signaling within basal ganglia pathways restore balance and improve outcomes in movement disorders like Parkinson’s disease?
Closing Thoughts
The basal ganglia may often be seen as the brain’s motor control center, but this work highlights its far-reaching influence on cognition and behavior. NMDA receptors, with their dual role as gatekeepers and amplifiers of synaptic change, are at the heart of this story. Through this study, we take one step closer to understanding how the brain’s intricate circuits shape who we are and how we act.
For anyone delving into neuroscience—or simply curious about how our brains function—I encourage you to think about the balance and interplay of these pathways. Sometimes, it’s the inhibitory circuits, the ones that say “not now,” that hold the key to understanding how we move, learn, and adapt.