(2dq) Illuminating Neurochemical Signaling in the Brain with Near Infrared Nanosensors

Research Interests: My lab will focus on leveraging nanomaterials for the development of neuroimaging tools to advance the understanding and treatment of neurological and psychiatric disorders. Neurochemistry in the brain has been touted the “missing dimension of neurobiology” and its imbalance is at the core of neurodegenerative and psychiatric conditions. However, tools to image neurochemicals selectively at spatial and temporal scales of relevance remain limited. As a faculty member, I will integrate my PhD expertise in fundamental nanomaterials science with my postdoctoral work in neurochemical imaging, where I developed and used synthetic near infrared nanosensors to image oxytocin release in acute brain slices.

My graduate work with Prof. Junichiro Kono at Rice University focused on improving fundamental properties of carbon nanotubes (CNTs) – carbon-based nanomaterials with extraordinary electrical, optical, thermal, and mechanical properties, making them promising for a wide range of applications. However, it has been challenging to preserve their intrinsic properties in practical applications. My PhD work tackled these challenges from three angles:

1. Engineering aligned assemblies: Many applications rely on their assemblies, but random orientation leads to a loss of intrinsic properties. To overcome this, I improved a vacuum filtration technique to produce films of aligned CNTs. Through my work, I discovered that parallel grooves on the surface of filter membranes govern CNT alignment. This knowledge enabled me to engineer grooves on the membrane surface to enhance reproducibility and improve alignment [1].
2. Chirality type purification: CNT properties, such as diameters and optical bandgaps, are determined by chirality, (n, m), where n and m describe the carbon lattice structure. Existing CNT growth methods result in mixtures of various (n, m) types, degrading their fundamental properties. I visited Prof. Kazuhiro Yanagi’s group to learn (n, m) type purification technique with gel chromatography. Combining the 2) (n, m) type enrichment with 1) alignment technique provided deeper understandings of optical processes [2], [3].
3. Chemical potential control: CNTs exhibit unique electronic density of states because of their one-dimensionality, and their electrical and optical properties change drastically depending on the chemical potential. I developed methods to precisely control CNT chemical potentials, including solution-phase doping, vapor-phase doping, and electrolyte gating with ionic liquid. By performing the 3) precise control of chemical potential level on 1) aligned samples, I was able to modify optical properties [4] and achieve a giant thermoelectric power factor, surpassing conventional thermoelectric materials [5].

Overall, during my PhD research I successfully tackled practical challenges of CNTs, leading to significant improvements of their properties in macroscopic assemblies and paving the way for their utilization in future applications.

As a Schmidt Science Fellow under Prof. Markita Landry at University of California, Berkeley, I employ CNTs as optical probes to image oxytocin signaling in the brain. Oxytocin is a neuropeptide believed to play a crucial role in social neurocircuits, yet the lack of real-time biosensors hinders our understanding of its effects on maternal behavior and social interactions. We developed non-genetically encoded near infrared oxytocin nanosensors based on functionalized CNTs (Fig. 1(a)-(c)), which exhibit pharmacological compatibility and subcellular spatial resolution. As the nongenetically encoded nature of these nanosensors enable their use in non-model organisms, my ongoing work includes imaging oxytocin release in transgenic voles lacking the oxytocin receptor, and in social versus solitary voles. Combined with behavioral assessments by the Beery Lab at UC Berkeley, we anticipate our oxytocin nanosensors will clarify the central role of oxytocin in social bonding interactions and aberrations thereof.

As a faculty member, my research program seeks to provide cutting-edge imaging tools that will enhance our understanding of neurochemical activities and aberrations thereof. While my proposal emphasizes tool development to utilizes my strong engineering background, I will actively collaborate with neuroscientists to combine neurochemical imaging with behavioral studies, aiming to provide molecular-level insights into behavior and environmental stimuli.

• Development of optical probes for simultaneous monitoring of multiple neurochemicals: Recent evidence suggests that neural circuits often involve the interaction of multiple neurochemicals: social interactions depend on oxytocin and serotonin coordination [6], and serotonin-dopamine imbalances are linked to Parkinson's disease [7]. It is therefore crucial to develop tools to track multiple neurochemicals simultaneously. To achieve this ambitious goal, my lab will pioneer developing sensors based on single (n, m) type, as opposed to the current probes based on several (n, m) types. By harnessing the fluorescence tunability of different (n, m) types, we will concurrently monitor multiple neurochemical analytes, such as using (6,5) for oxytocin and (7,6) for serotonin (Fig. 1(d)). Additionally, my lab will build multiplexed microscopy system that can recognize different infrared wavelengths and image them as different colors.
• Development of probe nanoarrays to achieve synaptic spatial resolution: As neuromodulators are believed to diffuse beyond the synaptic cleft and influence broader neural networks, it is crucial to have sufficient spatial resolution to track their efflux from synapses. However, currently available probes, prepared in a solution phase and randomly adsorbed to acute brain slices, lack synaptic information. Recently, a thin film consisting of randomly oriented dopamine probes demonstrated synaptic resolution in cell cultures [8]. Building upon this concept, my lab will develop nanoarrays of probes by aligning CNTs [1] with deterministically placed functionalization [9] (Fig. 1(e)). The aligned structure will provide superior spatial resolution, and their application to acute brain slices will further elucidate neuromodulator activity when combined with the multiplexed imaging approach.
• Implementation of fiber photometry for in vivo imaging: To fully understand the chemical activity of neural circuits, it is imperative to image neurochemicals in the awake and behaving brain using form factors compatible with existing neurobiological tools. Although current optical probes offer excellent spatial and temporal resolution, their application has been limited to ex vivo In my lab, we will aim to achieve in vivo imaging by integrating fiber photometry. By functionalizing photometry fibers with nanosensors, we can both optogenetically induce neurochemical release and monitor the near-infrared fluorescence emitted by the nanosensors (Fig. 1(f)). Additionally, we will develop a near-infrared fiber photometry setup that enables imaging in freely moving animals, facilitating optical excitation and near-infrared fluorescence monitoring.

My proposed research program aligns seamlessly with my diverse interdisciplinary research experience. By leveraging the unique properties of nanomaterials, my lab will develop of state-of-the-art imaging tools that provide understanding of neurochemical activities and their implications for neurological and psychiatric conditions.

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.

References:
[1] N. Komatsu et al., Nano Lett, vol. 20, no. 4, pp. 2332–2338, (2020).
[2] S. Dal Forno, N. Komatsu et al., Carbon, vol. 186, pp. 465–474, (2022).
[3] M. Wais, FRG Bagsican, N.Komatsu et al., Nano Lett., vol. 23, no. 10, pp. 4448–4455, (2023).
[4] N. Komatsu et al., Adv Funct Mat, vol. 27, no. 11, p. 1606022, (2017).
[5] N. Komatsu et al., Nat. Commun., vol. 12, no. 1, p. 4931, (2021).
[6] G. Dölen et al., Nature, vol. 501, no. 7466, pp. 179–184, (2013).
[7] S. M. Stahl, CNS Spectr., vol. 23, no. 3, pp. 187–191, (2018).
[8] C. Bulumulla et al., eLife, vol. 11, p. e78773, (2022).
[9] Y. Zheng et al., ACS Nano, vol. 15, no. 6, pp. 10406–10414, (2021).

Figure caption:
Figure 1. (a) Chemical communications between synapses play crucial roles in brain functions. (b) Pristine single-wall carbon nanotubes are functionalized with single-stranded a DNA sequence. (c) Near infrared fluorescence intensity of the nanosensors increases upon addition of the target analyte, which was oxytocin in this case. (d) Development nanosensors based on single (n,m) type will enable multiplex neuroimaging. (e) Development of thin films with aligned nanosensors (nanoarrays) will provide synaptic information. (f) in vivo imaging with fiber photometry where the fibers are functionalized with nanosensors for imaging.