Advanced approaches for selective investigation of neuronal function and circuitry: the future of developing novel therapeutic strategies in neuropharmacology?
Abstract
Recent advances in neuroscience techniques and methods ushered in a new era in the research of neuronal function with unprecedented selectivity and temporal resolution. One of the main characteristics of these technical advances is the ability to selectively target and/or modulate specific neuronal subpopulations and circuits in both healthy and diseased brains. Although initially designed as tools to help researchers better understand the mechanisms underlying neuronal activity and complex behaviors, these novel approaches may also accelerate the process of drug discovery in many areas of neuroscience, and some may even potentially serve as novel therapeutic strategies. The application of different electrophysiological techniques is still considered essential in studying ion channel function and pharmacology, as well as network-level changes in brain activity. The cutting-edge methods for investigation of brain function include opto- and chemogenetics in freely behaving animals; both approaches enable highly selective control of neuronal activity using either a light stimulation (optogenetics) or a chemical ligand (chemogenetics) in both loss- and gain-of-function experiments. In this review paper, we aim to summarize recent scientific evidence on the state-of-the-art and provide information on these advances, taking into account both academic and pharmaceutical industry points of view.
References
1. Song C, Knöpfel T. Optogenetics enlightens neuroscience drug discovery. Nat Rev Drug Discov. 2016;15(2):97-109.
2. Vázquez-Guardado A, Yang Y, Bandodkar AJ, Rogers JA. Recent advances in neurotechnologies with broad potential for neuroscience research. Nat Neurosci. 2020;23(12):1522-36.
3. Ozawa A, Arakawa H. Chemogenetics drives paradigm change in the investigation of behavioral circuits and neural mechanisms underlying drug action. Behav Brain Res. 2021;406:113234.
4. Hong G, Lieber CM. Novel electrode technologies for neural recordings. Nat Rev Neurosci. 2019;20(6):330-45.
5. Yang W, Yuste R. In vivo imaging of neural activity. Nat Methods. 2017;14(4):349-59.
6. Daou I, Tuttle AH, Longo G, Wieskopf JS, Bonin RP, Ase AR, et al. Remote optogenetic activation and sensitization of pain pathways in freely moving mice. J Neurosci. 2013;33(47):18631-40.
7. Roy DS, Arons A, Mitchell TI, Pignatelli M, Ryan TJ, Tonegawa S. Memory retrieval by activating engram cells in mouse models of early Alzheimer’s disease. Nature. 2016;531(7595):508-12.
8. Navabpour S, Kwapis JL, Jarome TJ. A neuroscientist’s guide to transgenic mice and other genetic tools. Neurosci Biobehav Rev. 2020;108:732-48.
9. Tye KM, Prakash R, Kim SY, Fenno LE, Grosenick L, Zarabi H, et al. Amygdala circuitry mediating reversible and bidirectional control of anxiety. Nature. 2011;471(7338):358-62.
10. Parnaudeau S, O’Neill PK, Bolkan SS, Ward RD, Abbas AI, Roth BL, et al. Inhibition of mediodorsal thalamus disrupts thalamofrontal connectivity and cognition. Neuron. 2013;77(6):1151-62.
11. Roy DS, Zhang Y, Aida T, Choi S, Chen Q, Hou Y, et al. Anterior thalamic dysfunction underlies cognitive deficits in a subset of neuropsychiatric disease models. Neuron. 2021;109(16):2590-603.
12. Neher E, Sakmann B. Single-channel currents recorded from membrane of denervated frog muscle fibres. Nature. 1976;260:799-802.
13. Edwards FA, Konnerth A, Sakmann B, Takahashi T. A thin slice preparation for patch clamp recordings from neurones of the mammalian central nervous system. Pflügers Archiv. 1989;414:600-12.
14. Obergrussberger A, Friis S, Brüggemann A, Fertig N. Automated patch clamp in drug discovery: major breakthroughs and innovation in the last decade. Expert Opin Drug Discov. 2021;16(1):1-5.
15. Namer B, Schmidt D, Eberhardt E, Maroni M, Dorfmeister E, Kleggetveit IP, et al. Pain relief in a neuropathy patient by lacosamide: Proof of principle of clinical translation from patient-specific iPS cell-derived nociceptors. EBioMedicine. 2019;39:401-8.
16. de Greef BT, Merkies IS, Geerts M, Faber CG, Hoeijmakers JG. Efficacy, safety, and tolerability of lacosamide in patients with gain-of-function NaV1.7 mutation-related small fiber neuropathy: study protocol of a randomized controlled trial–the LENSS study. Trials. 2016;17:1-8.
17. Steinmetz NA, Koch C, Harris KD, Carandini M. Challenges and opportunities for large-scale electrophysiology with Neuropixels probes. Curr Opin Neurobiol. 2018;50:92-100.
18. Buzsáki G, Buhl DL, Harris KD, Csicsvari J, Czéh B, Morozov A. Hippocampal network patterns of activity in the mouse. Neuroscience. 2003;116(1):201-11.
19. Buzsáki G. Large-scale recording of neuronal ensembles. Nat Neurosci. 2004;7(5):446-51.
20. Ulyanova AV, Cottone C, Adam CD, Gagnon KG, Cullen DK, Holtzman T, et al. Multichannel silicon probes for awake hippocampal recordings in large animals. Front Neurosci. 2019;13:397.
21. Mendoza G, Peyrache A, Gámez J, Prado L, Buzsáki G, Merchant H. Recording extracellular neural activity in the behaving monkey using a semichronic and high-density electrode system. J Neurophysiol. 2016;116(2):563-74.
22. Dzirasa K, Phillips HW, Sotnikova TD, Salahpour A, Kumar S, Gainetdinov RR, et al. Noradrenergic control of cortico-striato-thalamic and mesolimbic cross-structural synchrony. J Neurosci. 2010;30(18):6387-97.
23. Nagy D, Stoiljkovic M, Menniti FS, Hajós M. Differential effects of an NR2B NAM and ketamine on synaptic potentiation and gamma synchrony: relevance to rapid-onset antidepressant efficacy. Neuropsychopharmacology. 2016;41(6):1486-94.
24. Newson JJ, Thiagarajan TC. EEG frequency bands in psychiatric disorders: a review of resting state studies. Frontiers Hum Neurosci. 2019;12:521.
25. El Mansari M, Sánchez C, Chouvet G, Renaud B, Haddjeri N. Effects of acute and long-term administration of escitalopram and citalopram on serotonin neurotransmission: an in vivo electrophysiological study in rat brain. Neuropsychopharmacology. 2005;30(7):1269-77.
26. Mnie-Filali O, El Mansari M, Espana A, Sànchez C, Haddjeri N. Allosteric modulation of the effects of the 5-HT reuptake inhibitor escitalopram on the rat hippocampal synaptic plasticity. Neurosci Lett. 2006;395(1):23-7.
27. Schulz SB, Heidmann KE, Mike A, Klaft ZJ, Heinemann U, Gerevich Z. First and second generation antipsychotics influence hippocampal gamma oscillations by interactions with 5‐HT3 and D3 receptors. Br J Pharmacol. 2012;167(7):1480-91.
28. Smith SJ. EEG in the diagnosis, classification, and management of patients with epilepsy. J Neurol Neurosurg Psychiatry. 2005;76(Suppl 2):ii2-7.
29. Moshé SL, Perucca E, Ryvlin P, Tomson T. Epilepsy: new advances. Lancet. 2015;385(9971):884-98.
30. Flores FJ, Hartnack KE, Fath AB, Kim SE, Wilson MA, Brown EN, Purdon PL. Thalamocortical synchronization during induction and emergence from propofol-induced unconsciousness. Proc Natl Acad Sci U S A. 2017;114(32):E6660-8.
31. Joksimovic SM, Sampath D, Krishnan K, Covey DF, Jevtovic-Todorovic V, Raol YH, Todorovic SM. Differential effects of the novel neurosteroid hypnotic (3β, 5β, 17β)-3-hydroxyandrostane-17-carbonitrile on electroencephalogram activity in male and female rats. Br J Anaesth. 2021;127(3):435-46.
32. Purdon PL, Sampson A, Pavone KJ, Brown EN. Clinical electroencephalography for anesthesiologists: part I: background and basic signatures. Anesthesiology. 2015;123(4):937-60.
33. Raja SN, Ringkamp M, Guan Y, Campbell JN. Peripheral neuronal hyperexcitability: the “low-hanging” target for safe therapeutic strategies in neuropathic pain. Pain. 2020;161(Suppl 1):S14.
34. Zimmermann K, Hein A, Hager U, Kaczmarek JS, Turnquist BP, Clapham DE, Reeh PW. Phenotyping sensory nerve endings in vitro in the mouse. Nature protocols. 2009;4(2):174-96.
35. Dyck PJ. Evaluative procedures to detect, characterize, and assess the severity of diabetic neuropathy. Diabet Med. 1991;8(S2):S48-51.
36. Aminoff MJ, Albers JW. Electrophysiologic techniques in the evaluation of patients with suspected neurotoxic disorders. In Electrodiagnosis in clinical neurology. Churchill Livingstone; 2005; pp. 795-811.
37. Hagbarth KE, Burke D. Microneurography in man. Acta Neurol. 1977;32:30–34.
38. Ackerley R, Watkins RH. Microneurography as a tool to study the function of individual C-fiber afferents in humans: responses from nociceptors, thermoreceptors, and mechanoreceptors. Journal of neurophysiology. 2018;120(6):2834-46.
39. Schmelz M, Forster C, Schmidt R, Ringkamp M, Handwerker HO, Torebjörk HE. Delayed responses to electrical stimuli reflect C-fiber responsiveness in human microneurography. Exp Brain Res. 1995;104:331-6.
40. Boyden ES, Zhang F, Bamberg E, Nagel G, Deisseroth K. Millisecond-timescale, genetically targeted optical control of neural activity. Nat Neurosci. 2005;8(9):1263-8.
41. Knopfel T, Boyden ES. Optogenetics: tools for controlling and monitoring neuronal activity. Amsterdam: Elsevier; 2012.
42. Liu X, Ramirez S, Pang PT, Puryear CB, Govindarajan A, Deisseroth K, Tonegawa S. Optogenetic stimulation of a hippocampal engram activates fear memory recall. Nature. 2012;484(7394):381-5.
43. Nagel G, Ollig D, Fuhrmann M, Kateriya S, Musti AM, Bamberg E, Hegemann P. Channelrhodopsin-1: a light-gated proton channel in green algae. Science. 2002;296(5577):2395-8.
44. Han X, Boyden ES. Multiple-color optical activation, silencing, and desynchronization of neural activity, with single-spike temporal resolution. PloS One. 2007;2(3):e299.
45. Yizhar O, Fenno LE, Davidson TJ, Mogri M, Deisseroth K. Optogenetics in neural systems. Neuron. 2011;71(1):9-34.
46. Kitamura T, Ogawa SK, Roy DS, Okuyama T, Morrissey MD, Smith LM, et al. Engrams and circuits crucial for systems consolidation of a memory. Science. 2017;356(6333):73-8.
47. Roy DS, Kitamura T, Okuyama T, Ogawa SK, Sun C, Obata Y, et al. Distinct neural circuits for the formation and retrieval of episodic memories. Cell. 2017;170(5):1000-12.
48. Nabavi S, Fox R, Proulx CD, Lin JY, Tsien RY, Malinow R. Engineering a memory with LTD and LTP. Nature. 2014;511(7509):348-52.
49. Goshen I, Brodsky M, Prakash R, Wallace J, Gradinaru V, Ramakrishnan C, Deisseroth K. Dynamics of retrieval strategies for remote memories. Cell. 2011;147(3):678-89.
50. Ramirez S, Liu X, Lin PA, Suh J, Pignatelli M, Redondo RL, et al. Creating a false memory in the hippocampus. Science. 2013;341(6144):387-91.
51. Krook-Magnuson E, Armstrong C, Oijala M, Soltesz I. On-demand optogenetic control of spontaneous seizures in temporal lobe epilepsy. Nat Commun. 2013;4(1):1376.
52. Lu Y, Zhong C, Wang L, Wei P, He W, Huang K, et al. Optogenetic dissection of ictal propagation in the hippocampal–entorhinal cortex structures. Nature Commun. 2016;7(1):10962.
53. Paz JT, Huguenard JR. Optogenetics and epilepsy: past, present and future: shedding light on seizure mechanisms and potential treatments. Epilepsy Curr. 2015;15:34-8.
54. Taylor NE, Van Dort CJ, Kenny JD, Pei J, Guidera JA, Vlasov KY, et al. Optogenetic activation of dopamine neurons in the ventral tegmental area induces reanimation from general anesthesia. Proc Natl Acad Sci U S A. 2016;113(45):12826-31.
55. Montgomery KL, Iyer SM, Christensen AJ, Deisseroth K, Delp SL. Beyond the brain: Optogenetic control in the spinal cord and peripheral nervous system. Science translational medicine. 2016;8(337):337rv5.
56. Bonin RP, De Koninck Y. A spinal analog of memory reconsolidation enables reversal of hyperalgesia. Nat Neurosci. 2014;17(8):1043-5.
57. Prigge M, Rösler A, Hegemann P. Fast, repetitive light-activation of CaV3.2 using channelrhodopsin 2. Channels. 2010;4(3):241-7.
58. Agus V, Di Silvio A, Rolland JF, Mondini A, Tremolada S, Montag K, et al. Bringing the light to high throughput screening: use of optogenetic tools for the development of recombinant cellular assays. Proceedings of the SPIE; March 2015 (Optical Techniques in Neurosurgery, Neurophotonics, and Optogenetics II; Vol. 9305, pp. 258-266).
59. Williams JC, Denison T. From optogenetic technologies to neuromodulation therapies. Sci Transl Med. 2013;5(177):177ps6.
60. Park SI, Brenner DS, Shin G, Morgan CD, Copits BA, Chung HU, et al. Soft, stretchable, fully implantable miniaturized optoelectronic systems for wireless optogenetics. Nat Biotechnol. 2015;33(12):1280-6.
61. Novakovic SD, Kassotakis LC, Oglesby IB, Smith JA, Eglen RM, Ford AP, Hunter JC. Immunocytochemical localization of P2X3 purinoceptors in sensory neurons in naive rats and following neuropathic injury. Pain. 1999;80(1–2):273–282.
62. Stemkowski P, Garcia-Caballero A, Gadotti VM, M'Dahoma S, Huang S, Black SAG, et al. TRPV1 Nociceptor Activity Initiates USP5/T-type Channel-Mediated Plasticity. Cell Rep. 2016;17(11):2901–2912.
63. Li B, Yang XY, Qian FP, Tang M, Ma C, Chiang LY. A novel analgesic approach to optogenetically and specifically inhibit pain transmission using TRPV1 promoter. Brain Res. 2015;1609:12–20.
64. Iyer SM, Montgomery KL, Towne C, Lee SY, Ramakrishnan C, Deisseroth K, Delp SL. Virally mediated optogenetic excitation and inhibition of pain in freely moving nontransgenic mice. Nat Biotechnol. 2014;32(3):274–278.
65. Boada MD, Martin TJ, Peters CM, Hayashida K, Harris MH, Houle TT, et al. Fast-conducting mechanoreceptors contribute to withdrawal behavior in normal and nerve injured rats. Pain. 2014;155(12):2646–55.
66. Valtcheva MV, Copits BA, Davidson S, Sheahan TD, Pullen MY, McCall JG, et al. Surgical extraction of human dorsal root ganglia from organ donors and preparation of primary sensory neuron cultures. Nat Protoc. 2016;11(10):1877–88.
67. Armbruster BN, Li X, Pausch MH, Herlitze S, Roth BL. Evolving the lock to fit the key to create a family of G protein-coupled receptors potently activated by an inert ligand. Proc Natl Acad Sci U S A. 2007;104(12):5163-8.
68. Zhu H, Roth BL. Silencing synapses with DREADDs. Neuron. 2014;82(4):723-5.
69. Ferguson SM, Eskenazi D, Ishikawa M, Wanat MJ, Phillips PE, Dong Y, et al. Transient neuronal inhibition reveals opposing roles of indirect and direct pathways in sensitization. Nat Neurosci. 2011;14(1):22-4.
70. Spaethling JM, Piel D, Dueck H, Buckley PT, Morris JF, Fisher SA, et al. Serotonergic neuron regulation informed by in vivo single-cell transcriptomics. FASEB J. 2014;28(2):771.
71. Kong D, Tong Q, Ye C, Koda S, Fuller PM, Krashes MJ, et al. GABAergic RIP-Cre neurons in the arcuate nucleus selectively regulate energy expenditure. Cell. 2012;151(3):645-57.
72. Guettier JM, Gautam D, Scarselli M, de Azua IR, Li JH, Rosemond E, et al. A chemical-genetic approach to study G protein regulation of β cell function in vivo. Proc Natl Acad Sci U S A. 2009;106(45):19197-202.
73. Garner AR, Rowland DC, Hwang SY, Baumgaertel K, Roth BL, Kentros C, Mayford M. Generation of a synthetic memory trace. Science. 2012;335(6075):1513-6.
74. Bock R, Shin JH, Kaplan AR, Dobi A, Markey E, Kramer PF, et al. Strengthening the accumbal indirect pathway promotes resilience to compulsive cocaine use. Nat Neurosci. 2013;16(5):632-8.
75. Li H, Penzo MA, Taniguchi H, Kopec CD, Huang ZJ, Li B. Experience-dependent modification of a central amygdala fear circuit. Nat Neurosci. 2013;16(3):332-9.
76. Silva BA, Mattucci C, Krzywkowski P, Murana E, Illarionova A, Grinevich V, et al. Independent hypothalamic circuits for social and predator fear. Nat Neurosci. 2013;16:1731–33.
77. Mueller JS, Tescarollo FC, Sun H. DREADDs in epilepsy research: network-based review. Front Mol Neurosci. 2022;15:863003.
78. Kahn JB, Port RG, Yue C, Takano H, Coulter DA. Circuit-based interventions in the dentate gyrus rescue epilepsy-associated cognitive dysfunction. Brain. 2019;142(9):2705-21.
79. Desloovere J, Boon P, Larsen LE, Goossens MG, Delbeke J, Carrette E, et al. Chemogenetic seizure control with clozapine and the novel ligand jhu37160 outperforms the effects of levetiracetam in the intrahippocampal kainic acid mouse model. Neurotherapeutics. 2022:1-10.
80. Glauser T, Ben‐Menachem E, Bourgeois B, Cnaan A, Guerreiro C, Kälviäinen R, et al. Updated ILAE evidence review of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia. 2013;54(3):551-63.
81. Kahn JB, Port RG, Anderson SA, Coulter DA. Modular, circuit-based interventions rescue hippocampal-dependent social and spatial memory in a 22q11. 2 deletion syndrome mouse model. Biol Psychiatry. 2020;88(9):710-8.
82. Murphy KC, Jones LA, Owen MJ. High rates of schizophrenia in adults with velo-cardio-facial syndrome. Arch Gen Psychiatry. 1999;56(10):940-5.
83. Eldridge MA, Lerchner W, Saunders RC, Kaneko H, Krausz KW, Gonzalez FJ, et al. Disruption of relative reward value by reversible disconnection of orbitofrontal and rhinal cortex using DREADDs in rhesus monkeys. Nat Neurosci. 2016;19(1):37.
84. Nagai Y, Kikuchi E, Lerchner W, Inoue KI, Ji B, Eldridge MA, et al. PET imaging-guided chemogenetic silencing reveals a critical role of primate rostromedial caudate in reward evaluation. Nat Commun. 2016;7(1):13605.
85. Magnus CJ, Lee PH, Bonaventura J, Zemla R, Gomez JL, Ramirez MH, Hu X, Galvan A, Basu J, Michaelides M, Sternson SM. Ultrapotent chemogenetics for research and potential clinical applications. Science. 2019;364(6436):eaav5282.
86. English JG, Roth BL. Chemogenetics—a transformational and translational platform. JAMA Neurol. 2015;72(11):1361-6.
87. Sternson SM, Bleakman D. Chemogenetics: drug-controlled gene therapies for neural circuit disorders. Cell Gene Ther Insights. 2020;6(7):1079-1094.
88. Finnerup NB, Kuner R, Jensen TS. Neuropathic pain: from mechanisms to treatment. Physiol Rev. 2021;101(1):259-301.
89. Gorshkov K, Aguisanda F, Thorne N, Zheng W. Astrocytes as targets for drug discovery. Drug Discov Today. 2018;23(3):673-80.
90. Habib N, McCabe C, Medina S, Varshavsky M, Kitsberg D, Dvir-Szternfeld R, et al. Disease-associated astrocytes in Alzheimer’s disease and aging. Nat Neurosci. 2020;23(6):701-6.
91. Toker L, Mancarci BO, Tripathy S, Pavlidis P. Transcriptomic evidence for alterations in astrocytes and parvalbumin interneurons in subjects with bipolar disorder and schizophrenia. Biol Psychiatry. 2018;84(11):787-96.
92. Koyama Y. Functional alterations of astrocytes in mental disorders: pharmacological significance as a drug target. Front Cell Neurosci. 2015;9:261.
93. Santello M, Toni N, Volterra A. Astrocyte function from information processing to cognition and cognitive impairment. Nat Neurosci. 2019;22(2):154-66.
94. Adamsky A, Kol A, Kreisel T, Doron A, Ozeri-Engelhard N, Melcer T, et al. Astrocytic activation generates de novo neuronal potentiation and memory enhancement. Cell. 2018;174(1):59-71.
