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Long-Term Dopamine Neurochemical Monitoring in Primates

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Long-Term Dopamine Neurochemical Monitoring in Primates Long-term dopamine neurochemical monitoring in primates Helen N. Schwerdta,b,c, Hideki Shimazua,b, Ken-ichi Amemoria,b, Satoko Amemoria,b, Patrick L. Tierneya,b, Daniel J. Gibsona,b, Simon Honga,b, Tomoko Yoshidaa,b, Robert Langerc,d, Michael J. Cimac,e, and Ann M. Graybiela,b,1 aMcGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA 02139; bDepartment of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139; cKoch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139; dDepartment of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139; and eDepartment of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139 Contributed by Ann M. Graybiel, November 1, 2017 (sent for review August 4, 2017; reviewed by Richard Courtemanche, Paul W. Glimcher, and Christopher I. Moore) Many debilitating neuropsychiatric and neurodegenerative disor- acute dopamine measurements (5–8), with stable measurements ders are characterized by dopamine neurotransmitter dysregula- only for a few hours. The lack of chronic chemical sensors exists tion. Monitoring subsecond dopamine release accurately and for despite great progress in the chronic electrophysiological re- extended, clinically relevant timescales is a critical unmet need. cording of spike and local field potential activity in behaving Especially valuable has been the development of electrochemical nonhuman primates. Chronic measurements of dopamine will fast-scan cyclic voltammetry implementing microsized carbon fiber aid in the identification of dopamine’s contribution to complex probe implants to record fast millisecond changes in dopamine behaviors degraded in human disorders, and to aid in testing the concentrations. Nevertheless, these well-established methods have clinical feasibility of treatments. Specific hurdles have included only been applied in primates with acutely (few hours) implanted large size, increasing the likelihood of tissue damage and probe sensors. Neurochemical monitoring for long timescales is necessary to degradation, and the lack of infrastructure to allow physical improve diagnostic and therapeutic procedures for a wide range of neurological disorders. Strategies for the chronic use of such sensors probe stability with on-demand movability. have recently been established successfully in rodents, but new Key challenges associated with the chronic use of FSCV derive infrastructures are needed to enable these strategies in primates. from the degraded capacity of long-implanted sensors to detect Here we report an integrated neurochemical recording platform for dopamine due to both biologic and nonbiologic processes (9). monitoring dopamine release from sensors chronically implanted in Neurochemical measurements made from acutely implanted deep brain structures of nonhuman primates for over 100 days, sensors produce minimal scarring due to brevity of contact (i.e., together with results for behavior-related and stimulation-induced interface for several hours). Chronically implanted sensors, dopamine release. From these chronically implanted probes, we however, produce persistent inflammation and scarring around measured dopamine release from multiple sites in the striatum as the sensor, which effectively produces a barrier between the induced by behavioral performance and reward-related stimuli, by sensor and regions of neurochemical release. The carbon fiber direct stimulation, and by drug administration. We further developed (CF) sensors used for FSCV semipermanently adsorb and ac- algorithms to automate detection of dopamine. These algorithms cumulate films of proteins and byproducts of neurotransmitter could be used to track the effects of drugs on endogenous dopamine redox reactions (10), all of which are amplified by inflammation neurotransmission, as well as to evaluate the long-term performance (9). Implant size reductions have been critical to minimize of the chronically implanted sensors. Our chronic measurements demonstrate the feasibility of measuring subsecond dopamine Significance release from deep brain circuits of awake, behaving primates in a longitudinally reproducible manner. Dopamine is an important neurotransmitter governing behav- striatum | voltammetry | neurotransmitters | chronic implants ior and heavily implicated in a large range of neural disorders, including Parkinson’s disease, depression, and related mood and movement disorders. Methods allowing accurate moni- opamine neurotransmission is central to movement, moti- toring of dopamine over long timescales have not been pre- Dvation, and behavioral choice, along with other fundamental viously reported yet are crucial to enable improved diagnostics behaviors (1, 2). Dysregulation of dopamine occurs in neuro- and therapeutics. We report a technical advance that allowed psychiatric and neurologic disorders, including major depression ’ recording of dopamine from sensors implanted into the brains and Parkinson s disease, impairing quality of life on a daily basis of nonhuman primates for over 100 days. Our integrated (3, 4). Methods to allow accurate in vivo monitoring of dopamine platform enabled monitoring fast changes in dopamine release over extended timescales still have not been technically feasible in response to rewarding stimuli and the administration of for primate brains, however, preventing the possibility of dopamine-related drugs. These findings demonstrate the long- assessing longitudinally the role of this neurotransmitter in term feasibility and reproducibility of neurochemical measure- neurodegeneration and in the modulation of behavior. ments and strengthen their potential translation to human use. Electrochemical fast-scan cyclic voltammetric (FSCV) tech- niques have been shown to provide the optimal overall perfor- Author contributions: H.N.S., H.S., K.-i.A., R.L., M.J.C., and A.M.G. designed research; mance for measuring dopamine neurotransmission at the H.N.S., H.S., K.-i.A., P.L.T., S.H., and A.M.G. performed research; H.N.S., S.A., D.J.G., T.Y., required fast timescales (milliseconds), sensitivity (nanomolar), and A.M.G. analyzed data; and H.N.S., H.S., and A.M.G. wrote the paper. and chemical selectivity. Most such measurements, for technical Reviewers: R.C., Concordia University; P.W.G., New York University; and C.I.M., Brown reasons, have been made from acutely implanted sensors that University. provide a sensitive, minimally scarring interface. Chronic dopa- The authors declare no conflict of interest. mine recording systems have only begun to gain widespread use Published under the PNAS license. (1, 2), and these methods have so far been applied only to ro- 1To whom correspondence should be addressed. Email: [email protected]. dents. There is a great need to establish chronic measurements in This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. primates, for whom to date there are only few reports even of 1073/pnas.1713756114/-/DCSupplemental. 13260–13265 | PNAS | December 12, 2017 | vol. 114 | no. 50 www.pnas.org/cgi/doi/10.1073/pnas.1713756114 Downloaded by guest on September 27, 2021 Acute also be obtained from acute sensors (149% increase, P = 0.028, A Stimulation BC Chronic array from four sites in four sessions in monkeys M1, M2, and M3) (Fig. 2E and Fig. S3). The raclopride administration not only increased stimulation-induced release, but could also be used to increase spontaneous dopamine neurotransmission. This drug Ground Reference was used to monitor and to modulate reproducibly endogenous dopamine neurotransmission. We developed an automated algorithm to identify these transient changes in apparent dopamine concentration ([DA]a) (Fig. 3) to detect such spontaneous dopamine release over extended periods of recording from the chronically implanted sensors. The Striatum SNc/VTA Dopamine fibers A –0.4 2 Fig. 1. Modular platform for chronic neurochemical measurements. (A) Mod- Current (nA) B ular chamber combines usage of acute and chronic systems and targets 1 multiple widespread brain regions. (B) Primate-implantable CF sensor. (Scale 1.3 2 bar, 100 μm.) (C) MRI of chamber grid and targeted striatal sites (purple). 0 (Scale bar, 1 cm.) Voltage (V) Voltage –1 0 brain response (9, 11) and to provide stable long-term use in –0.4 Current (nA) rodents (1, 2). 1 nA -0.2 0.6 1.3 We have developed for nonhuman primate use sensors that Voltage (V) maintain the small rodent-scale footprints (1, 2) (7-μmtipdi- ameter), and we have implemented these in macaque monkeys 0 02 outfitted with a modular chamber interface (12) (Fig. 1 and Fig. S1), Time (s) allowing us to introduce CF sensors and to measure from these C probes both acutely and chronically. This modular implant platform 0.8 Rac 2.5 allowed us to make measurements of dopamine release from mul- cn1 cn2 tiple sites in the striatum [the caudate nucleus (CN) and the puta- 2 men], as well as to identify and manipulate dopamine-containing 0.6 brain regions [substantia nigra pars compacta (SNc) and ventral 1.5 tegmental area (VTA)] that give rise to striatal dopamine-containing 0.4 NEUROSCIENCE inputs. We measured dopamine release in response to direct, con- 1 trollable electrical and pharmacologic stimulation, as well as 0.2 behavior-related and spontaneous dopamine release from the awake 0.5 monkeys for over months-long time periods. We characterized in detail the performance of the chronically
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