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Ultrafast Detection and Quantification of Brain Signaling Molecules with Carbon Fiber Microelectrodes Carbon fiber microelectrodes provide the ideal platform for performing ultrafast, selective measurements of electroactive brain molecules. This article highlights the current status of the use of carbon fiber microelectrodes in neurochemical measurements, outlining the most cutting edge findings and technological advances in amperometry and fast-scan cyclic voltammetry. Rinchen D. Lama,† Karl Charlson,† Arun Anantharam,‡ and Parastoo Hashemi*,† †
Department of Chemistry, Wayne State University, Detroit, Michigan 48202, United States Department of Biology, Wayne State University, Detroit, Michigan 48202, United States selectivity. Finally, these species are present in low concentrations; hence, the probe must display high sensitivity. Carbon fiber microelectrodes are minimally invasive, robust, stable, and biocompatible and have favorable surface kinetics. When coupled with electrochemical detection techniques, these unique properties can fulfill the Four S’s. This article features the most current advances in electrochemistry at carbon fiber microelectrodes.
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MICROELECTRODES FOR DIRECT NEUROTRANSMITTER DETECTION Neurotransmitters are the brain’s chemical messengers.1 These are usually small molecules that are stored in discrete intracellular packages known as vesicles. Electrochemical impulses arriving at the cell terminal trigger neurotransmission by causing fusion of vesicles with the cell membrane. During a process known as exocytosis, the contents of the vesicle are released into the synapse. The neurotransmitter relays a message by interacting with specific receptors on a receiving cell. To cease neurotransmission, these molecules are removed from the synapse by transporters and enzymes. Transporters are selective membrane-bound proteins that reuptake neurotransmitters with high affinity. Enzymes catalytically inactivate the neurotransmitters both in and out of the cell. Monoamines are a fundamental class of transmitters, and many of them are electroactive. This means that they can be electrochemically detected at carbon fiber microelectrodes directly implanted into the brain. Neurotransmission, hence, can be studied quantitatively in terms of their chemical fluctuations. Important members of the monoamines are catecholamines, such as dopamine and norepinephrine and indolamines, such as serotonin and histamine. These molecules are inextricably involved in Alzheimer’s and Parkinson’s diseases and in emotional and reward processes. To investigate these disorders on a synaptic level it is critical to measure within milliseconds, the time scale of neurotransmission. There are currently two main ultrafast electrochemical approaches with carbon fiber microelectrodes that can achieve this: amperometry and fast-scan cyclic voltammetry (FSCV). Amperometry. In amperometry, the microelectrode is held or pulsed usually at a potential more positive than the known
T
he brain is a chemically intricate organ, overseeing our bodily functions, thoughts, emotions, and behaviors. Advancements in public health and medicine promise us longer, healthier lives than our parents. However, diseases of old age that target the brain, such as Alzheimer’s and Parkinson’s, are increasingly diagnosed and remain largely untreatable. Moreover, reports of mood disorders and substance abuse, arguably due to modern societal and environmental stressors, are surging. Now, more than ever, there is a need for effective prevention and treatment of these disorders. Understanding the underlying chemistry of the brain is the key to this. Directly probing the brain’s chemicals requires a unique toolkit. An appropriate analytical technique should adhere to four criteria: size, speed, selectivity, and sensitivity. We refer to these as the Four S’s. First, the brain’s chemical communication junctions, synapses, span only 10−100 nm; as the tissue surrounding these sites must be intact to observe their chemistry, the size of the detection device is crucial. Second, because chemical events in the brain occur on a rapid (millisecond) time scale, the resolution of the probe must have sufficient speed to match this. Third, as there are chemically similar species in the synapse, the technique must have a high degree of chemical discrimination and thus good © 2012 American Chemical Society
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peak potential for substrate oxidation. The resulting current quantifies the substrate. Amperometry enables the most dynamic measurements, limited only by the resistance of the electrode’s microenvironment and the capacitance of the double layer around the electrode.2 Constant Potential Amperometry. Because microelectrodes can be fashioned into a variety of shapes, they can be placed very close to, if not flush with cells in vitro. Hence, specific events associated with even a single cell can be studied when the electrode is held at a constant potential. The most fundamental application of amperometry is in the study of exocytosis. Although not all in the brain, adrenal chromaffin, adrenal PC12, and mast cells can be used as models to study exocytosis.3−6 From adrenal chromaffin cells, amperometry detects reproducible “spike” transients. Amatore and colleagues have recently highlighted the importance of local pH changes, as a consequence of the technique itself, when interpreting these signals.7 Wightman and colleagues have recently shown that this process is modulated by specialized receptors.5 Moreover, they have shown that amperometry can distinguish between signals arising from unselective electrical stimulations (cells vs peripheral nerves).8 One frontier in amperometry is investigating the underlying physiological mechanisms of disease. A parallel frontier is developing novel amperometric technologies to facilitate a more sophisticated analysis of these mechanisms. Haynes and colleagues have undertaken an in-depth series of studies to look at the effects of nanoparticles found in modern consumer goods on exocytosis.4,9 In particular, the group found that when cells are exposed to gold and silver nanoparticles, as found in materials generally considered “nontoxic”, exocytosis is impaired by a kinetics driven mechanism.10 Ewing’s group showed that exocytosis is sensitive to steroids such as estradiols.6 Such endocrine disruptors are increasingly found in drinking water sources.11 While their adverse hormonal and health effects have received significant attention, their neurological impact had not been previously considered. Technological innovations are focusing on coupling amperometry to other analytical techniques. Among these are capillary-micro fluidic devices for determining the contents of individual vesicles,12 transparent electrodes that can be coupled to microscopy,13 and microfabricated devices and arrays that can expand the temporal and spatial measurement dimensions.3,14 Ewing’s group is using a 15-electrode array to electrochemically image dopamine release from a single cell.69 They model this digitally as seen in Figure 1. Here, they create an electrochemical image based on the number of exocytotic events per frame captured across 15 electrodes. The number of events is represented on a color scale. Amperometry is an elegant research tool, vital for studying exocytotic mechanisms from single cells or cell slice preparations. However, because it is performed at constant potentials, selectivity is limited and therefore it adheres best to three S’s. For in vivo studies in complex media, where selectivity is important, chronoamperometry has been developed. High-Speed Chronoamperometry. Chronoamperometry applies a square wave potential to the microelectrode, commonly at 5−25 Hz, between defined potential limits. Each time the step is applied, there is a large nonfaradaic current which decays exponentially. Typically, the current during the last 80% of the step is measured and attributed to
Figure 1. Electrochemical image of a PC12 cell. (A) Activity monitored by independent electrodes (y-axis) over an interval of 200 s (x-axis). Each square corresponds to the exocytotic events integrated over a 10 s period, represented by its color intensity. (B) Number of released dopamine molecules determined by independent electrodes (y-axis) over an interval of 200 s (x-axis). Each square corresponds to the number of released molecules integrated over a 10 s period, represented by its color intensity. Modified from ref 69. Copyright 2012 American Chemical Society
Faradaic processes. In vivo constant potential amperometry cannot distinguish between species, whereas chronoamperometry can provide some distinction. A “snapshot” can be taken of the ratio of the reductive to oxidative current values and used for identification.15 Better selectivity still can be achieved if the analyte under study is exogenously applied onto the electrode surface. Its clearance, then, can be quantitatively studied.16 Chronoamperometry has allowed in-depth studies of transporters17 by assessing their dynamics18 and pharmacokinetics.19 In diseases, chronoamperometry is being used to studying alcoholism,20 drug addiction,21 Parkinson’s disease,22 and depression.23,24 It is particularly important in depression studies because current therapies often target the monoamine transporters. These studies, pioneered by Daws and colleagues, are currently focusing on the nexus between different transporters and how they modulate antidepressant effects.25 Chronoamperometry can effectively study neurotransmitter clearance. For studies of endogenous release and uptake events, it still adheres best to three S’s and more selectivity still is required. FSCV. FSCV at carbon fiber microelectrodes identifies a specific reaction based on distinct oxidative and reductive peak 8097
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responses to different reward types and magnitudes.36,37 A further extension is to study the animal’s decision-making in relation to costs and benefits when seeking rewards.38,39 Cost benefit has further been investigated in humans. Here, behavior was studied in Parkinson’s disease patients where carbon fiber microelectrodes were implanted into the patient’s brains during routine surgery for placement of deep brain stimulation probes. Dopamine release was correlated to specific decision-making tasks performed by the patients.40 While dopamine is aggressively studied in vivo and in behavior, there is increasingly an appreciation for the roles that other electroactive brain molecules play. Expanding the Scope of FSCV. There are several other electrochemically active brain molecules. Variations in the electrochemical detection waveform can allow these to be measured. In invertebrates, octopamine and tyramine are molecules analogous to adrenergic neurotransmitters in mammals. Hence, FSCV is used to study them in simple models of neurotransmission.41 Oxygen and pH give rise to unique cyclic voltammograms,42−44 and glucose can be measured via H2O2 production from enzymes immobilized on carbon fibers.45 These molecules are good indicators of metabolism and could be used to study the energetics of the brain. Serotonin is an important molecule that is coimplicated in many of the same disorders as dopamine. It is particularly important in studies of depression since the most common antidepressants target the serotonin transporter. It has traditionally been challenging to monitor serotonin with FSCV because electro-oxidation of serotonin and its metabolites fouls electrode surfaces. This challenge can be overcome by using thin coatings of Nafion, a cation-exchange polymer, such that serotonin can routinely be monitored in vivo.46 With this method, the effects of antidepressants in the brain of live, anesthetized rodents can be evaluated; an example of this from our laboratory is shown by the FSCV color plots in Figure 3. Simultaneous identification and quantification of serotonin via these color plots has been described in detail46−48 and ultimately leads to construction of [serotonin] vs time as shown in the panel under the color plots. Part A shows electrically stimulated serotonin release and uptake in the mouse brain; and part B shows that this signal is dramatically influenced by escitalopram (common antidepressant commercially known as lexapro) administration. Histamine, adenosine, and H 2O2 have similar cyclic voltammograms because their oxidation peaks are positioned on the returning positive scan. Therefore, their identities have been verified pharmacologically.45,48,49 These species play important modulatory roles in the brain; histamine has been shown to modulate serotonin transmission through its receptors,48 H2O2 has been found to modulate dopamine release,50 and adenosine release was found to be altered via glutamate receptors.51 Adenosine release has also been found to modulate pain responses.52 Table 1 compares waveforms and conditions necessary for detecting different species with FSCV. Having the capacity to measure such a large spectrum of molecules necessitates the development of novel technologies that will propel FSCV into uncharted neurochemical territories. Expanding the FSCV Toolbox. One of the major difficulties in detecting some of the species described above has been insufficient sensitivity. This also applies to dopamine in certain brain regions. Therefore, techniques are being developed to
positions. FSCV is a highly selective technique and satisfies all four S’s. FSCV and Dopamine. In the brain, FSCV has overwhelmingly been used to study dopamine neurotransmission. Over the last 30 years, many details of dopamine transmission have been elucidated and FSCV technology has been advanced to the extent that neurochemistry can be studied in freely moving animals. In rats, dopamine levels have been shown to fluctuate with the rats’ behavior.26 The most recent studies are assessing the finer details of dopamine, enabling an elegant reexamination of synaptic transmission. Dopamine release is governed by complex interactions between other modulators27 and intracellular proteins,28 and different dopamine releasing domains identified as “fast” and “slow” have been described by Michael and colleagues.29,30 Figure 2A shows examples of fast
Figure 2. (A) Recordings of electrically stimulated dopamine release in the rat striatum depicting fast-type and slow-type responses. (B) Hybrid responses are obtained when the carbon fiber microelectrode samples both fast and slow domains. Modified with permission from ref 29. Copyright 2011 Blackwell Publishing. Circles represent the start of an electrical stimulation that results in the signal, and triangles represent the end.
and slow responses, and Figure 2B shows a “hybrid” response when both domains are sampled. Circles illustrate the start of an electrical stimulation (that evokes the measured dopamine) and triangles the end. This study highlights how dopamine may modulate different processes with different dynamic requirements. When dopamine systems are targeted with drugs of abuse, such as cocaine, addiction can arise. The actions of cocaine on dopamine kinetics are well-established with FSCV. However, new studies explore the kinetic effects of morphine31 and polydrugs of abuse32 on transporters. Correlations between reward seeking behavior and dopamine levels are best studied in freely moving animals. Prior studies have linked dopamine events to rewards and cues predicting rewards;26 more recently, the regulatory mechanisms underlying this relationship are being unearthed. These include genetic traits that link dopamine release to vulnerability to addiction,33 modulation by different receptors,34 the roles of brain subnuclei,35 and 8098
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neurotransmitters with a temporal resolution of 10−100 ms, there are further efforts to improve this in order to match the temporal strength of amperometry.56 Microfabricated FSCV arrays allow simultaneous measurements on multiple electrodes.57 When decoupled, two or more analytes can be measured.58 Moreover, two electrodes placed in spatially different locations can be used to acquire simultaneous signals. This has been used to measure dopamine and norepinephrine and dopamine and serotonin in two distinct brain regions.59,60 While FSCV is being used in invertebrate models because of their genetic pliability, there has been recent success in applying the method in larger mammals.40,61 In humans specifically, it is beneficial to develop wireless electronics to couple FSCV to signal processing without compromising physical mobility. Garris and colleagues have developed the Wireless Instantaneous Neurotransmitter Concentration System (WINCS), capable of remotely transmitting neurochemical information to analysis systems.62 This technology is particularly useful for real-time neurochemical diagnosis of dopamine levels in patients with Parkinson’s disease. The therapy for advanced stage Parkinsonian patients is deep brain stimulation where the subthalamic nucleus is electrically stimulated. Currently, doctors fine-tune the stimulation parameters based on visual assessment of the patient’s tremor. Instead, a less subjective and more precise neurochemical equivalent can be provided by measuring dopamine release during the stimulation. In the future, this will be incorporated into an automated feedback system whereby the stimulation automatically adjusts to control tremor via a closed-loop system as shown in Figure 4.63 Generally, electrical or pharmacological stimulation of neurotransmitter release is an unselective process. Deisseroth and colleagues have genetically incorporated light sensitive
Figure 3. Top panel: Color plots with potential on y-axis, time on xaxis, and current in false color. (A) Serotonin evoked in mouse substantia nigra, pars reticulata with electrical stimulation of the medial forebrain bundle (onset and duration of stimulation are denoted by the vertical white dashed line and the horizontal blue bar, respectively). (B) Serotonin evoked in the same brain region with the same stimulation bundle (onset and duration of stimulation are denoted by the vertical white dashed line and the horizontal blue bar, respectively) after escitalopram (10 mg kg−1) administration. Bottom panel: [serotonin] vs time extrapolated from the current vs time traces from the color plots A and B (horizontal white dashed lines in the top panel). These have been converted to concentration with standard calibrations.
increase the sensitivity of the carbon fiber surface. These include optimizing electrochemical waveforms53 and modifying the electrode surfaces with carbon nanotubes54 and cationexchange polymers.46,54,55 Moreover, while FSCV can detect
Table 1. Table Comparing Different Waveforms and Conditions Necessary to Detect Various Electroactive Neurochemical Species
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Figure 4. Illustration depicting (A) the implantable wireless neurochemical sampling system consisting of stimulating electrode and neurotransmitter sensors in the thalamic nuclei and (B) the CMOS chip, containing an electrometer and transmitter for transmission of neurochemical data. Modified with permission from ref 63. Copyright 2009 Wiley-Blackwell.
proteins, channel rhodopsins, into specific cell types. As a result, cells can selectively be stimulated with laser light.64 Coupling FSCV to optical stimulations provides selectivity in measurement as well as stimulation. This has been performed in fruit fly larvae,65 mice,66 and rats67 and is disentangling the roles of specific neurotransmitters.
exocytosis using electrophysiological, electrochemical, and advanced optical imaging approaches. Parastoo Hashemi obtained an MSci degree in Chemistry from King’s College, London, with first degree honors. She completed her Ph.D. in the Department of Bioengineering in Imperial College, London, under the supervision of Prof. Martyn Boutelle. During her Ph.D., she developed online neuro-electrochemical analysis systems for human traumatic brain injury patients. She completed her postdoctoral training with Prof. Mark Wightman at the University of North Carolina at Chapel Hill, NC, where she developed novel electrochemical methods for neurotransmitter detection. She is currently an assistant professor in the Department of Chemistry at Wayne State University. Her research interests are to apply ultrasmall, ultrafast electrochemical methods to detecting molecules in biological and environmental systems.
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OUTLOOK Ultrafast microelectrodes are an exciting research, diagnostic, and potentially therapeutic tool to probe essential aspects of brain function. Their remarkable properties, which satisfy the four S’s, size, speed, selectivity, and sensitivity, are being exploited in innovative ways to comprehend the brain’s mechanisms. A more nuanced understanding of brain chemistry and hence brain disease, combined with rapid advancements in the medical field, will allow more efficient, personalized therapy of neurological disorders.
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REFERENCES
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Notes
The authors declare no competing financial interest. Biography Rinchen Lama completed her Bachelor of Science degree in Biology at the University of North Carolina at Chapel Hill, NC, in 2011. Karl Charlson is currently studying towards a Bachelor of Science degree in Biochemistry at Wayne State University, performing an honors thesis under the direction of Prof. Parastoo Hashemi. Arun Anantharam completed undergraduate degrees in Neurosciences and English Literature at Columbia University. He earned his Ph.D. in Biophysics at Cornell University under the direction of Dr. Lawrence Palmer. After a postdoctoral fellowship at the University of Michigan with Drs. Ronald W. Holz and Daniel Axelrod, he joined the faculty of Wayne State University. His laboratory studies the molecular regulation of 8100
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NOTE ADDED AFTER ASAP PUBLICATION This paper was published on the Web on August 23, 2012. Reference 69 was added, and the corrected version was reposted on August 30, 2012. 8101
dx.doi.org/10.1021/ac301670h | Anal. Chem. 2012, 84, 8096−8101
