(4ax) Mapping Neurochemistry of the Brain with Near-Infrared Nanosensors and Deep-Brain Microscopy

Research Interests: Neurochemicals underlie neuronal communication, and their imbalance lies at the core of neurodegenerative and psychiatric conditions. One such neurochemical, oxytocin, is a neuropeptide hypothesized to play a central role in social behaviors alongside molecules like dopamine and serotonin. Dysregulation of these molecules are implied in social impairment disorders such as autism spectrum disorder. However, the majority of neurochemicals remain invisible due to the absence of real-time biosensors, hindering our understanding of their release conditions and locations, and how their release may be impaired (and thus treatable) in disorders. Additionally, while it is critical to use social models like prairie voles for social neuroscience studies, genetically encoded techniques are only available for traditional organisms like mice. To address this gap, my goal is to develop a versatile neuroimaging platform based on purely synthetic nanosensors to illuminate neurochemistry in social animals. Leveraging my PhD expertise in nanomaterial engineering and advanced microscopy with my current research in chemical and biomolecular engineering and neuroscience, the objectives of my independent lab are to:

Aim 1: Enable multiplexed imaging by designing nanosensors with distinct fluorescent wavelengths.
Aim 2: Enable in vivo imaging by constructing deep-tissue microscopes.
Aim 3: Image previously invisible neurochemical interactions in social species to uncover their roles in social behaviors and social impairment disorders.

Related Work: My doctoral study at Rice University has focused on engineering optical properties of low-dimensional nanomaterials, including single-walled carbon nanotubes (SWCNTs). I demonstrated that the photoluminescent wavelengths of SWCNTs can be uniquely tuned by purifying their chiralities, or (n, m) types (Dal Forno, Komatsu et al. 2022). I further pioneered techniques to engineer their chemical potential and photophysical properties (Komatsu et al. 2021, Komatsu et al. 2020).

As a Schmidt Science Fellow and Burroughs Wellcome Fund CASI Fellow in the Landry Lab at UC Berkeley, my postdoctoral work focuses on developing nanosensors and applying them to image neuromodulator signaling in the brain. I have developed the first real-time synaptic scale nanosensor for oxytocin, a key neuromodulator for social interactions and autism spectral disorders, based on SWCNTs functionalized with single-stranded DNA (Adams, Komatsu, et al. 2024). I designed a unique DNA sequence that selectively modulates the SWCNT’s fluorescence intensity upon oxytocin interaction, enabling real-time imaging of oxytocin in the brain.

I have also developed a new assay to image oxytocin’s role in social behavior in prairie voles, a rodent species that, unlike nice, exhibit human-like selective affiliation and social monogamy. By conducting the first real-time imaging of oxytocin release in prairie voles, my study revealed altered oxytocin regulation in the absence of receptors. Together with behavioral study indicating reduced selectivity in receptor knockout voles, my research provides molecular insights into oxytocin neurocircuits in social animals for the first time (Komatsu*, Black*, et al. in prep).

Specific Aims: My interdisciplinary trajectory uniquely positions me to bring state-of-art nanomaterial, optical, and chemical engineering to neuroimaging. With the ultimate goal of understanding how neurochemistry affects social interactions in social animals, and aberrations thereof in autism spectrum disorders, the specific aims of my independent research group are the following:

Aim 1: Enable multiplexed imaging by designing nanosensors with distinct fluorescent wavelengths.

Our current oxytocin nanosensor indiscriminately includes several (n, m) types, resulting in a broad and thus fluorescently indiscriminate fluorescence spectrum. These nanosensors only report intensity changes and lack wavelength resolution, preventing differentiation of oxytocin from dopamine or serotonin, thus hindering their concurrent use. To overcome this limitation, my group will develop nanosensors exclusively based on single (n, m) type of SWCNTs, each assigned with distinct, well-separated wavelengths for different neurochemical analytes. This will enable multicolor neurochemical imaging by translating different near-infrared wavelengths into distinct pseudo-colors with my additional advanced in polychromatic near infrared microscopy. Currently, a wide array of fluorescent dyes with distinct colors in the visible range are readily available for multicolor bioimaging. My research program will extend this concept to the near-infrared range, where brain tissues are maximally transparent.

Aim 2. Enable in vivo imaging by constructing deep-tissue microscopes and investigating nanosensor to protein interactions.

To understand the spatiotemporal dynamics of chemical activities and how they influence social behaviors, it is crucial to image neurochemicals in the awake and behaving brain. However, no technique currently exists for in vivo imaging of chemical coordination in the brain. My group will develop polychromatic infrared fluorescent microscopy with two-photon excitation. This combination will mitigate photon scattering upon both excitation and emission, leading to an estimated penetration depth exceeding 1 cm, promising for through-skull imaging (without craniotomy) in the long-term. To de-risk this ambitious goal, we will explore a fiber photometry approach in parallel by functionalizing photometry fibers with nanosensors, which will optogenetically induce neurochemical release and monitor the near-infrared fluorescence emitted by the nanosensors. Together, this aim will enable in vivo imaging of neurochemicals with unprecedented penetration depth and subcellular-scale spatial resolution during awake animal behavior.

Aim 3: Image previously invisible neurochemical interactions in social species to uncover their roles in social behaviors and social impairment disorders.

Emerging evidence suggests that complex social behaviors such as bond maintenance and social reward involve more than one neurochemical: bond formation between mates requires both oxytocin and dopamine, and social reward relies on oxytocin-serotonin coordination. Yet, the lack of advanced tools renders the existing evidence indirect, and the spatial and temporal dynamics of these interactions, along with their variations due to environmental factors or disorders, remain poorly understood. To bridge this knowledge gap, my group will leverage tools developed in Aim 1 and 2 to monitor multiple neurochemicals simultaneously in awake and behaving brain.

Specifically, my lab will seek to determine the neurocircuit of peer relationships in prairie voles. Friendship, or ‘peer relationship,’ connections formed with nonreproductive partners, have fundamental consequences for individual health (e.g. human life span), and many neurological conditions (e.g., autism spectral disorders) are associated with deficits in peer relationships. However, despite their importance, most research on social neuroscience has focused on reproductive relationships, leaving the neurobiological mechanisms supporting nonreproductive social relationships elusive. My group will image oxytocin, dopamine, and serotonin simultaneously, in conjunctions with leveraging transgenic voles and applications of receptor antagonists, to identify regions and neurochemicals involved in the peer relationship neurocircuit and chemical coordination within each region.

In sum, my lab will map neurochemistry across species and developmental stages, enabled by the non-genetically encoded nature of my probes. By addressing these fundamental questions, I aspire to advance our understanding and treatment of neurological conditions such as autism spectral disorders and postpartum depression. Importantly, by expanding my nanosensor library, my imaging platform becomes applicable and beneficial for the broader field of bioimaging, where near-infrared capability is vital for maximizing transparency to biological tissues. Over the past decades, discoveries in neuroscience have been propelled by technological advancements in visible fluorescence microscopy, but leaving near infrared wavelengths underutilized. My research program will be a driving force in uncovering the last missing dimension of neurobiology – neurochemistry.

Teaching Interests: My teaching goal is to encourage every student to stay curious and enjoy learning through research-driven teaching approaches like formative assessments and active learning. I actively pursued professional development in teaching techniques by completing the Summer Institute on Scientific Teaching at the UCLA Center for Education Innovation and Learning in the Sciences, earning a certificate as a 2022 Scientific Teaching Fellow. I applied these methods effectively in various teaching roles, including co-instructing the freshman engineering course (ENGR-19) at the UCLA, and grading for Electronic Materials (ELEC 261) at Rice University. I also demonstrated active learning strategies through guest lectures at Ubiquitous and Wearable Computing (ELEC 574) at Rice and at the Southern California Japanese Scholars Forum, utilizing clicker questions and small group discussions. These experiences solidified my belief in the effectiveness of evidence-based teaching for fostering positive student attitudes towards learning, and I am committed to further improving my teaching skills by actively participating in programs at my future institutions. Furthermore, with my interdisciplinary background in applied physics, electrical engineering, and chemical engineering, I am well-prepared to teach a broad range of chemical engineering courses such as thermodynamics and transport processes.