Flexible Multielectrode Arrays for Tonic and Phasic Serotonin Electrochemical Detection in the Brain

Project Summary
Simultaneous multi-site measurements of tonic and phasic serotonin (5-hydroxytryptamine, 5-HT) dynamics
across different brain regions are of utmost importance to clarify the roles that 5-HT plays in anxiety, depression,
and impulse control disorders. Chronic sampling across multiple weeks is critical to investigate the 5-HT
variations during neurological transitions and to understand the efficacy of specific pharmacological treatments.
Despite their values, in vivo multi-site chronic measurements of 5-HT are limited by the capability of the existing
technologies. For example, microdialysis measures the tonic 5-HT level with slow temporal resolution, while fast
scan cyclic voltammetry (FSCV) at carbon fiber microelectrodes (CFEs) can only detect phasic 5-HT release.
These experiments are currently performed one site at a time, while 5-HT dynamics are complex and differ in
different brain regions or different loci of the same region, requiring high resolution multisite measurements.
Additionally, to the best of our knowledge, no chronic 5-HT detection with such technique have been shown.
Here, we propose to develop an implantable carbon-based multielectrode array on ultra-thin flexible substrate
(C-Flex-MEA) for integrated phasic and tonic measurements of 5-HT dynamics from different brain locations. To
achieve our goal: first, we will optimize a pattern transfer technique that allows for the integration of glassy carbon
(GC) microelectrode arrays and interconnections on ultra-thin flexible polymeric substrate. The resulting C-Flex-
MEAs will allow for multi-site FSCV detection of phasic 5-HT release. Second, we will incorporate the poly(3,4-
ethylenedioxythiophene)/functionalized carbon nanotube (PEDOT/CNT) coating on selected GC
microelectrodes of the same MEAs, to achieve multi-site detection of tonic 5-HT concentrations using square
wave voltammetry. Combining the superior electrochemical stability of the carbon electrodes and
interconnections with the excellent biocompatibility of a miniaturized thin-film flexible device, the C-Flex-MEA
presents ideal properties for in vivo neurochemical sensing for both tonic and phasic 5-HT measurements, also
promoting seamless tissue integration. Our Specific Aim 1 focuses on fabrication and in vitro optimization of the
C-Flex-MEA with the goal of meeting the criteria in detection sensitivity, selectivity, and stability. Specific Aim 2
focuses on acute and chronic in vivo testing of multi-site sensing performance of the C-Flex-MEAs in mouse
brain, and implant biocompatibility. The acute testing will guide the probe design and fabrication to minimize
insertion injury and validate 5-HT sensing. The completion of the chronic experiments will allow us to determine
the sensor’s lifetime and understand the abiotic and biotic factors that affect the stability of the sensor over time.
Successful completion of this project will produce an unprecedented platform to study the specific implications
of the different 5-HT dynamics in neurological and psychiatric disorders.

Grant Number: 5R21MH128803-02
NIH Institute/Center: NIH
Principal Investigator: Elisa Castagnola