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Local modulation by presynaptic receptors controls neuronal communication and behaviour

Nature Reviews Neuroscience volume 23, pages 191–203 (2022)Cite this article

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Abstract

Central nervous system neurons communicate via fast synaptic transmission mediated by ligand-gated ion channel (LGIC) receptors and slower neuromodulation mediated by G protein-coupled receptors (GPCRs). These receptors influence many neuronal functions, including presynaptic neurotransmitter release. Presynaptic LGIC and GPCR activation by locally released neurotransmitters influences neuronal communication in ways that modify effects of somatic action potentials. Although much is known about presynaptic receptors and their mechanisms of action, less is known about when and where these receptor actions alter release, especially in vivo. This Review focuses on emerging evidence for important local presynaptic receptor actions and ideas for future studies in this area.

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Fig. 1: Presynaptic ionotropic and metabotropic receptor control of neuronal communication in cortico-basal ganglia circuitry.
Fig. 2: Approaches to observe and manipulate presynaptic activity in vivo.

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References

  1. Fioravante, D. & Regehr, W. G. Short-term forms of presynaptic plasticity. Curr. Opin. Neurobiol. 21, 269–274 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Kupferschmidt, D. A., Juczewski, K., Cui, G., Johnson, K. A. & Lovinger, D. M. Parallel, but dissociable, processing in discrete corticostriatal inputs encodes skill learning. Neuron 96, 476–489.e5 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Mohebi, A. et al. Dissociable dopamine dynamics for learning and motivation. Nature 570, 65–70 (2019). This study provides important evidence that somatic and local control of NAc DA release contributes to distinct aspects of behaviour.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Kandel, E. R., Koester, J. D., Mack, S.H., Siegelbaum, S. A. Principles of Neural Science 6th edn (McGraw Hill, 2021).

  5. Lu, H. C. & Mackie, K. Review of the endocannabinoid system. Biol. Psychiatry Cogn. Neurosci. Neuroimaging 6, 607–615 (2021).

    PubMed  Google Scholar 

  6. Brundege, J. M. & Dunwiddie, T. V. Metabolic regulation of endogenous adenosine release from single neurons. Neuroreport 9, 3007–3011 (1998).

    CAS  PubMed  Google Scholar 

  7. Lovatt, D. et al. Neuronal adenosine release, and not astrocytic ATP release, mediates feedback inhibition of excitatory activity. Proc. Natl Acad. Sci. USA 109, 6265–6270 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Spudich, J. L., Yang, C. S., Jung, K. H. & Spudich, E. N. Retinylidene proteins: structures and functions from archaea to humans. Annu. Rev. Cell Dev. Biol. 16, 365–392 (2000).

    CAS  PubMed  Google Scholar 

  9. Latek, D., Modzelewska, A., Trzaskowski, B., Palczewski, K. & Filipek, S. G protein-coupled receptors — recent advances. Acta Biochim. Pol. 59, 515–529 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Betke, K. M., Wells, C. A. & Hamm, H. E. GPCR mediated regulation of synaptic transmission. Prog. Neurobiol. 96, 304–321 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Hauser, A. S., Attwood, M. M., Rask-Andersen, M., Schioth, H. B. & Gloriam, D. E. Trends in GPCR drug discovery: new agents, targets and indications. Nat. Rev. Drug Discov. 16, 829–842 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Oldham, W. M. & Hamm, H. E. Structural basis of function in heterotrimeric G proteins. Q. Rev. Biophys. 39, 117–166 (2006).

    CAS  PubMed  Google Scholar 

  13. Yim, Y. Y., Zurawski, Z. & Hamm, H. GPCR regulation of secretion. Pharmacol. Ther. 192, 124–140 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Nestler, E.J. & Duman, R.S. in Basic Neurochemistry: Molecular, Cellular and Medical Aspects 6th edn (eds Siegel, G.J. et al.) 335–346 (Lippincott, Williams & Wilkins, 1999).

  15. Kofuji, P. & Araque, A. G-Protein-coupled receptors in astrocyte–neuron communication. Neuroscience 456, 71–84 (2021).

    CAS  PubMed  Google Scholar 

  16. Herlitze, S. et al. Modulation of Ca2+ channels by G-protein βγ subunits. Nature 380, 258–262 (1996).

    CAS  PubMed  Google Scholar 

  17. Ikeda, S. R. Voltage-dependent modulation of N-type calcium channels by G-protein βγ subunits. Nature 380, 255–258 (1996).

    CAS  PubMed  Google Scholar 

  18. Logothetis, D. E., Kurachi, Y., Galper, J., Neer, E. J. & Clapham, D. E. The βγ subunits of GTP-binding proteins activate the muscarinic K+ channel in heart. Nature 325, 321–326 (1987).

    CAS  PubMed  Google Scholar 

  19. Zhu, X. & Birnbaumer, L. G protein subunits and the stimulation of phospholipase C by Gs-and Gi-coupled receptors: lack of receptor selectivity of Gα16 and evidence for a synergic interaction between Gβγ and the α subunit of a receptor activated G protein. Proc. Natl Acad. Sci. USA 93, 2827–2831 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Schicker, K. W., Dorostkar, M. M. & Boehm, S. Modulation of transmitter release via presynaptic ligand-gated ion channels. Curr. Mol. Pharmacol. 1, 106–129 (2008).

    CAS  PubMed  Google Scholar 

  21. Borroto-Escuela, D. O. et al. Understanding the role of GPCR heteroreceptor complexes in modulating the brain networks in health and disease. Front. Cell Neurosci. 11, 37 (2017).

    PubMed  PubMed Central  Google Scholar 

  22. Gaitonde, S. A. & Gonzalez-Maeso, J. Contribution of heteromerization to G protein-coupled receptor function. Curr. Opin. Pharmacol. 32, 23–31 (2017).

    CAS  PubMed  Google Scholar 

  23. Briggs, C. A., Gopalakrishnan, M. in Comprehensive Medicinal Chemistry II Vol. 2 (ed. Kubinyi, H.) 877–918 (Elsevier, 2007).

  24. Jun, S. B., Ikeda, S. R., Sung, J. E. & Lovinger, D. M. Ethanol induces persistent potentiation of 5-HT3 receptor-stimulated GABA release at synapses on rat hippocampal CA1 neurons. Neuropharmacology 184, 108415 (2021).

    CAS  PubMed  Google Scholar 

  25. Koyama, S., Matsumoto, N., Kubo, C. & Akaike, N. Presynaptic 5-HT3 receptor-mediated modulation of synaptic GABA release in the mechanically dissociated rat amygdala neurons. J. Physiol. 529, 373–383 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Kramer, P. F., Twedell, E. L., Shin, J. H., Zhang, R. & Khaliq, Z. M. Axonal mechanisms mediating γ-aminobutyric acid receptor type A (GABA-A) inhibition of striatal dopamine release. eLife 9, e55729 (2020). This study elegantly demonstrates presynaptic mechanisms by which ionotropic GABAA receptors and nAChRs regulate DA release in the striatum.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Assous, M. Striatal cholinergic transmission. Focus on nicotinic receptors’ influence in striatal circuits. Eur. J. Neurosci. 53, 2421–2442 (2021).

    PubMed  PubMed Central  Google Scholar 

  28. Sacaan, A. I., Dunlop, J. L. & Lloyd, G. K. Pharmacological characterization of neuronal acetylcholine gated ion channel receptor-mediated hippocampal norepinephrine and striatal dopamine release from rat brain slices. J. Pharmacol. Exp. Ther. 274, 224–230 (1995).

    CAS  PubMed  Google Scholar 

  29. Cachope, R. et al. Selective activation of cholinergic interneurons enhances accumbal phasic dopamine release: setting the tone for reward processing. Cell Rep. 2, 33–41 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Mateo, Y. et al. Endocannabinoid actions on cortical terminals orchestrate local modulation of dopamine release in the nucleus accumbens. Neuron 96, 1112–1126.e5 (2017). This study demonstrates complex cannabinoid-mediated presynaptic regulation of DA release in the NAc and its effects on reinforcement behaviour.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Threlfell, S. et al. Striatal dopamine release is triggered by synchronized activity in cholinergic interneurons. Neuron 75, 58–64 (2012).

    CAS  PubMed  Google Scholar 

  32. Zhou, F. M., Liang, Y. & Dani, J. A. Endogenous nicotinic cholinergic activity regulates dopamine release in the striatum. Nat. Neurosci. 4, 1224–1229 (2001).

    CAS  PubMed  Google Scholar 

  33. Exley, R. et al. Striatal dopamine transmission is reduced after chronic nicotine with a decrease in α6-nicotinic receptor control in nucleus accumbens. Eur. J. Neurosci. 38, 3036–3043 (2013).

    PubMed  Google Scholar 

  34. Exley, R., McIntosh, J. M., Marks, M. J., Maskos, U. & Cragg, S. J. Striatal α5 nicotinic receptor subunit regulates dopamine transmission in dorsal striatum. J. Neurosci. 32, 2352–2356 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Partridge, J. G., Apparsundaram, S., Gerhardt, G. A., Ronesi, J. & Lovinger, D. M. Nicotinic acetylcholine receptors interact with dopamine in induction of striatal long-term depression. J. Neurosci. 22, 2541–2549 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Augustin, S. M. & Lovinger, D. M. Functional relevance of endocannabinoid-dependent synaptic plasticity in the central nervous system. ACS Chem. Neurosci. 9, 2146–2161 (2018).

    CAS  PubMed  Google Scholar 

  37. Collins, A. L. et al. Nucleus accumbens cholinergic interneurons oppose cue-motivated behavior. Biol. Psychiatry 86, 388–396 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Kaiser, S. & Wonnacott, S. α-Bungarotoxin-sensitive nicotinic receptors indirectly modulate [3H]dopamine release in rat striatal slices via glutamate release. Mol. Pharmacol. 58, 312–318 (2000).

    CAS  PubMed  Google Scholar 

  39. Morgenstern, N. A., Isidro, A. F., Israely, I. & Costa, R. M. Pyramidal tract neurons drive feed-forward excitation of striatum through cholinergic interneurons. Preprint at bioRxiv https://doi.org/10.1101/2020.12.14.422716 (2020).

    Article  Google Scholar 

  40. Tanimura, A., Du, Y., Kondapalli, J., Wokosin, D. L. & Surmeier, D. J. Cholinergic interneurons amplify thalamostriatal excitation of striatal indirect pathway neurons in Parkinson’s disease models. Neuron 101, 444–458.e6 (2019).

    CAS  PubMed  Google Scholar 

  41. Falcon-Moya, R. & Rodriguez-Moreno, A. Metabotropic actions of kainate receptors modulating glutamate release. Neuropharmacology 197, 108696 (2021).

    CAS  PubMed  Google Scholar 

  42. Atwood, B. K., Lovinger, D. M. & Mathur, B. N. Presynaptic long-term depression mediated by Gi/o-coupled receptors. Trends Neurosci. 37, 663–673 (2014). This review details mechanisms by which presynaptic GPCR activation exerts long-lasting effects on the strength of synaptic transmission at various CNS synapses.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Gothert, M. Role of autoreceptors in the function of the peripheral and central nervous system. Arzneimittelforschung 35, 1909–1916 (1985).

    CAS  PubMed  Google Scholar 

  44. Nolan, S. O. et al. Direct dopamine terminal regulation by local striatal microcircuitry. J. Neurochem. 155, 475–493 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Cragg, S. J. & Greenfield, S. A. Differential autoreceptor control of somatodendritic and axon terminal dopamine release in substantia nigra, ventral tegmental area, and striatum. J. Neurosci. 17, 5738–5746 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Anzalone, A. et al. Dual control of dopamine synthesis and release by presynaptic and postsynaptic dopamine D2 receptors. J. Neurosci. 32, 9023–9034 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Bello, E. P. et al. Cocaine supersensitivity and enhanced motivation for reward in mice lacking dopamine D2 autoreceptors. Nat. Neurosci. 14, 1033–1038 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Shin, J. H., Adrover, M. F., Wess, J. & Alvarez, V. A. Muscarinic regulation of dopamine and glutamate transmission in the nucleus accumbens. Proc. Natl Acad. Sci. USA 112, 8124–8129 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Foster, D. J. et al. Antipsychotic-like effects of M4 positive allosteric modulators are mediated by CB2 receptor-dependent inhibition of dopamine release. Neuron 91, 1244–1252 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Lewis, R. G. et al. Dopaminergic control of striatal cholinergic interneurons underlies cocaine-induced psychostimulation. Cell Rep. 31, 107527 (2020).

    CAS  PubMed  Google Scholar 

  51. Kharkwal, G. et al. Parkinsonism driven by antipsychotics originates from dopaminergic control of striatal cholinergic interneurons. Neuron 91, 67–78 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Threlfell, S. et al. Striatal muscarinic receptors promote activity dependence of dopamine transmission via distinct receptor subtypes on cholinergic interneurons in ventral versus dorsal striatum. J. Neurosci. 30, 3398–3408 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Shin, J. H., Adrover, M. F. & Alvarez, V. A. Distinctive modulation of dopamine release in the nucleus accumbens shell mediated by dopamine and acetylcholine receptors. J. Neurosci. 37, 11166–11180 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Yee, J. et al. Muscarinic acetylcholine receptors in the nucleus accumbens core and shell contribute to cocaine priming-induced reinstatement of drug seeking. Eur. J. Pharmacol. 650, 596–604 (2011).

    CAS  PubMed  Google Scholar 

  55. Soares-Cunha, C. et al. Nucleus accumbens microcircuit underlying D2-MSN-driven increase in motivation. eNeuro 5, ENEURO.0386-18.2018 (2018).

    PubMed  PubMed Central  Google Scholar 

  56. Johnson, K. A., Mateo, Y. & Lovinger, D. M. Metabotropic glutamate receptor 2 inhibits thalamically-driven glutamate and dopamine release in the dorsal striatum. Neuropharmacology 117, 114–123 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Kupferschmidt, D. A. & Lovinger, D. M. Inhibition of presynaptic calcium transients in cortical inputs to the dorsolateral striatum by metabotropic GABAB and mGlu2/3 receptors. J. Physiol. 593, 2295–2310 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Scofield, M. D. et al. The nucleus accumbens: mechanisms of addiction across drug classes reflect the importance of glutamate homeostasis. Pharmacol. Rev. 68, 816–871 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Caprioli, D., Justinova, Z., Venniro, M. & Shaham, Y. Effect of novel allosteric modulators of metabotropic glutamate receptors on drug self-administration and relapse: a review of preclinical studies and their clinical implications. Biol. Psychiatry 84, 180–192 (2018).

    CAS  PubMed  Google Scholar 

  60. Johnson, K. A. & Lovinger, D. M. Presynaptic G protein-coupled receptors: gatekeepers of addiction? Front. Cell Neurosci. 10, 264 (2016).

    PubMed  PubMed Central  Google Scholar 

  61. Pehrson, A. L. & Moghaddam, B. Impact of metabotropic glutamate 2/3 receptor stimulation on activated dopamine release and locomotion. Psychopharmacology 211, 443–455 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. D’Souza, M. S., Liechti, M. E., Ramirez-Nino, A. M., Kuczenski, R. & Markou, A. The metabotropic glutamate 2/3 receptor agonist LY379268 blocked nicotine-induced increases in nucleus accumbens shell dopamine only in the presence of a nicotine-associated context in rats. Neuropsychopharmacology 36, 2111–2124 (2011).

    PubMed  PubMed Central  Google Scholar 

  63. Johnson, K. A., Voyvodic, L., Loewinger, G. C., Mateo, Y. & Lovinger, D. M. Operant self-stimulation of thalamic terminals in the dorsomedial striatum is constrained by metabotropic glutamate receptor 2. Neuropsychopharmacology 45, 1454–1462 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Araque, A., Castillo, P. E., Manzoni, O. J. & Tonini, R. Synaptic functions of endocannabinoid signaling in health and disease. Neuropharmacology 124, 13–24 (2017). This review details functional roles of presynaptic CB1 receptors in normal brain functions and in disease states.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Foster, D. J. et al. M5 receptor activation produces opposing physiological outcomes in dopamine neurons depending on the receptor’s location. J. Neurosci. 34, 3253–3262 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Pancani, T. et al. M4 mAChR-mediated modulation of glutamatergic transmission at corticostriatal synapses. ACS Chem. Neurosci. 5, 318–324 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Dobbs, L. K. et al. Dopamine regulation of lateral inhibition between striatal neurons gates the stimulant actions of cocaine. Neuron 90, 1100–1113 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Gremel, C. M. et al. Endocannabinoid modulation of orbitostriatal circuits gates habit formation. Neuron 90, 1312–1324 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Covey, D. P., Mateo, Y., Sulzer, D., Cheer, J. F. & Lovinger, D. M. Endocannabinoid modulation of dopamine neurotransmission. Neuropharmacology 124, 52–61 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Wang, H. & Lupica, C. R. Release of endogenous cannabinoids from ventral tegmental area dopamine neurons and the modulation of synaptic processes. Prog. Neuropsychopharmacol. Biol. Psychiatry 52, 24–27 (2014).

    PubMed  PubMed Central  Google Scholar 

  71. Wenzel, J. M. & Cheer, J. F. Endocannabinoid regulation of reward and reinforcement through interaction with dopamine and endogenous opioid signaling. Neuropsychopharmacology 43, 103–115 (2018).

    CAS  PubMed  Google Scholar 

  72. Narushima, M. et al. Tonic enhancement of endocannabinoid-mediated retrograde suppression of inhibition by cholinergic interneuron activity in the striatum. J. Neurosci. 27, 496–506 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Uchigashima, M. et al. Subcellular arrangement of molecules for 2-arachidonoyl-glycerol-mediated retrograde signaling and its physiological contribution to synaptic modulation in the striatum. J. Neurosci. 27, 3663–3676 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Castillo, P. E., Younts, T. J., Chavez, A. E. & Hashimotodani, Y. Endocannabinoid signaling and synaptic function. Neuron 76, 70–81 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Katona, I. et al. Distribution of CB1 cannabinoid receptors in the amygdala and their role in the control of GABAergic transmission. J. Neurosci. 21, 9506–9518 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Katona, I. et al. Presynaptically located CB1 cannabinoid receptors regulate GABA release from axon terminals of specific hippocampal interneurons. J. Neurosci. 19, 4544–4558 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Marsicano, G. et al. The endogenous cannabinoid system controls extinction of aversive memories. Nature 418, 530–534 (2002).

    CAS  PubMed  Google Scholar 

  78. Younts, T. J. & Castillo, P. E. Endogenous cannabinoid signaling at inhibitory interneurons. Curr. Opin. Neurobiol. 26, 42–50 (2014).

    CAS  PubMed  Google Scholar 

  79. Andrasi, T. et al. Differential excitatory control of 2 parallel basket cell networks in amygdala microcircuits. PLoS Biol. 15, e2001421 (2017).

    PubMed  PubMed Central  Google Scholar 

  80. Freund, T. F. Interneuron diversity series: rhythm and mood in perisomatic inhibition. Trends Neurosci. 26, 489–495 (2003).

    CAS  PubMed  Google Scholar 

  81. LeDoux, J. E. & Pine, D. S. Using neuroscience to help understand fear and anxiety: a two-system framework. Am. J. Psychiatry 173, 1083–1093 (2016).

    PubMed  Google Scholar 

  82. Gunduz-Cinar, O. The endocannabinoid system in the amygdala and modulation of fear. Prog. Neuropsychopharmacol. Biol. Psychiatry 105, 110116 (2021).

    CAS  PubMed  Google Scholar 

  83. Gunduz-Cinar, O. et al. Convergent translational evidence of a role for anandamide in amygdala-mediated fear extinction, threat processing and stress-reactivity. Mol. Psychiatry 18, 813–823 (2013).

    CAS  PubMed  Google Scholar 

  84. Gunduz-Cinar, O. et al. Fluoxetine facilitates fear extinction through amygdala endocannabinoids. Neuropsychopharmacology 41, 1598–1609 (2016).

    CAS  PubMed  Google Scholar 

  85. Steenkamp, M. M., Blessing, E. M., Galatzer-Levy, I. R., Hollahan, L. C. & Anderson, W. T. Marijuana and other cannabinoids as a treatment for posttraumatic stress disorder: a literature review. Depress Anxiety 34, 207–216 (2017).

    PubMed  Google Scholar 

  86. Rabinak, C. A. et al. Cannabinoid modulation of corticolimbic activation to threat in trauma-exposed adults: a preliminary study. Psychopharmacology 237, 1813–1826 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Chavez-Noriega, L. E. & Stevens, C. F. Increased transmitter release at excitatory synapses produced by direct activation of adenylate cyclase in rat hippocampal slices. J. Neurosci. 14, 310–317 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Weisskopf, M. G., Castillo, P. E., Zalutsky, R. A. & Nicoll, R. A. Mediation of hippocampal mossy fiber long-term potentiation by cyclic AMP. Science 265, 1878–1882 (1994).

    CAS  PubMed  Google Scholar 

  89. Capogna, M., Gahwiler, B. H. & Thompson, S. M. Presynaptic enhancement of inhibitory synaptic transmission by protein kinases A and C in the rat hippocampus in vitro. J. Neurosci. 15, 1249–1260 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Trudeau, L. E., Emery, D. G. & Haydon, P. G. Direct modulation of the secretory machinery underlies PKA-dependent synaptic facilitation in hippocampal neurons. Neuron 17, 789–797 (1996).

    CAS  PubMed  Google Scholar 

  91. Hikima, T., Garcia-Munoz, M. & Arbuthnott, G. W. Presynaptic D1 heteroreceptors and mGlu autoreceptors act at individual cortical release sites to modify glutamate release. Brain Res. 1639, 74–87 (2016).

    CAS  PubMed  Google Scholar 

  92. Levey, A. I. et al. Localization of D1 and D2 dopamine receptors in brain with subtype-specific antibodies. Proc. Natl Acad. Sci. USA 90, 8861–8865 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Ding, S., Li, L. & Zhou, F. M. Nigral dopamine loss induces a global upregulation of presynaptic dopamine D1 receptor facilitation of the striatonigral GABAergic output. J. Neurophysiol. 113, 1697–1711 (2015).

    CAS  PubMed  Google Scholar 

  94. Clark, M. & Bracci, E. Dichotomous dopaminergic control of ventral pallidum neurons. Front. Cell Neurosci. 12, 260 (2018).

    PubMed  PubMed Central  Google Scholar 

  95. Wang, W. et al. Regulation of prefrontal excitatory neurotransmission by dopamine in the nucleus accumbens core. J. Physiol. 590, 3743–3769 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Flood, M. D., Moore-Dotson, J. M. & Eggers, E. D. Dopamine D1 receptor activation contributes to light-adapted changes in retinal inhibition to rod bipolar cells. J. Neurophysiol. 120, 867–879 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Evans, G. J. & Morgan, A. Regulation of the exocytotic machinery by cAMP-dependent protein kinase: implications for presynaptic plasticity. Biochem. Soc. Trans. 31, 824–827 (2003).

    CAS  PubMed  Google Scholar 

  98. Seino, S. & Shibasaki, T. PKA-dependent and PKA-independent pathways for cAMP-regulated exocytosis. Physiol. Rev. 85, 1303–1342 (2005).

    CAS  PubMed  Google Scholar 

  99. Lambe, E. K. & Aghajanian, G. K. Hypocretin (orexin) induces calcium transients in single spines postsynaptic to identified thalamocortical boutons in prefrontal slice. Neuron 40, 139–150 (2003).

    CAS  PubMed  Google Scholar 

  100. Marek, G. J. & Aghajanian, G. K. 5-HT2A receptor or α1-adrenoceptor activation induces excitatory postsynaptic currents in layer V pyramidal cells of the medial prefrontal cortex. Eur. J. Pharmacol. 367, 197–206 (1999).

    CAS  PubMed  Google Scholar 

  101. Marek, G. J. & Zhang, C. Activation of metabotropic glutamate 5 (mGlu5) receptors induces spontaneous excitatory synaptic currents in layer V pyramidal cells of the rat prefrontal cortex. Neurosci. Lett. 442, 239–243 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Mahler, S. V. et al. Chemogenetic manipulations of ventral tegmental area dopamine neurons reveal multifaceted roles in cocaine abuse. J. Neurosci. 39, 503–518 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Chanaday, N. L. & Kavalali, E. T. Presynaptic origins of distinct modes of neurotransmitter release. Curr. Opin. Neurobiol. 51, 119–126 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Peng, K. et al. Mechanisms underlying enhancement of spontaneous glutamate release by group I mGluRs at a central auditory synapse. J. Neurosci. 40, 7027–7042 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Kushmerick, C. et al. Retroinhibition of presynaptic Ca2+ currents by endocannabinoids released via postsynaptic mGluR activation at a calyx synapse. J. Neurosci. 24, 5955–5965 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Marek, G. J. Interactions of hallucinogens with the glutamatergic system: permissive network effects mediated through cortical layer V pyramidal neurons. Curr. Top. Behav. Neurosci. 36, 107–135 (2018).

    CAS  PubMed  Google Scholar 

  107. Delille, H. K., Mezler, M. & Marek, G. J. The two faces of the pharmacological interaction of mGlu2 and 5-HT2A — relevance of receptor heterocomplexes and interaction through functional brain pathways. Neuropharmacology 70, 296–305 (2013).

    CAS  PubMed  Google Scholar 

  108. Atasoy, D. & Sternson, S. M. Chemogenetic tools for causal cellular and neuronal biology. Physiol. Rev. 98, 391–418 (2018).

    CAS  PubMed  Google Scholar 

  109. Lynagh, T. & Lynch, J. W. An improved ivermectin-activated chloride channel receptor for inhibiting electrical activity in defined neuronal populations. J. Biol. Chem. 285, 14890–14897 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Slimko, E. M., McKinney, S., Anderson, D. J., Davidson, N. & Lester, H. A. Selective electrical silencing of mammalian neurons in vitro by the use of invertebrate ligand-gated chloride channels. J. Neurosci. 22, 7373–7379 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Roth, B. L. DREADDs for neuroscientists. Neuron 89, 683–694 (2016). This review provides fundamental information on the development and application of DREADDs for advancing knowledge of circuit-specific GPCR-mediated neuromodulation in behaving animals.

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Magnus, C. J. et al. Chemical and genetic engineering of selective ion channel–ligand interactions. Science 333, 1292–1296 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Adamantidis, A. et al. Optogenetics: 10 years after ChR2 in neurons — views from the community. Nat. Neurosci. 18, 1202–1212 (2015). This review provides diverse perspectives on the ways in which optogenetics-based approaches have influenced the study of brain circuitry.

    CAS  PubMed  Google Scholar 

  114. Campbell, E. J. & Marchant, N. J. The use of chemogenetics in behavioural neuroscience: receptor variants, targeting approaches and caveats. Br. J. Pharmacol. 175, 994–1003 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Mahler, S. V. et al. Designer receptors show role for ventral pallidum input to ventral tegmental area in cocaine seeking. Nat. Neurosci. 17, 577–585 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Lemos, J. C. et al. Enhanced GABA transmission drives bradykinesia following loss of dopamine D2 receptor signaling. Neuron 90, 824–838 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Stachniak, T. J., Ghosh, A. & Sternson, S. M. Chemogenetic synaptic silencing of neural circuits localizes a hypothalamus → midbrain pathway for feeding behavior. Neuron 82, 797–808 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Vardy, E. et al. A new DREADD facilitates the multiplexed chemogenetic interrogation of behavior. Neuron 86, 936–946 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Lichtenberg, N. T. et al. Basolateral amygdala to orbitofrontal cortex projections enable cue-triggered reward expectations. J. Neurosci. 37, 8374–8384 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Cuzon Carlson, V. C., Gremel, C. M. & Lovinger, D. M. Gestational alcohol exposure disrupts cognitive function and striatal circuits in adult offspring. Nat. Commun. 11, 2555 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Kim, J. M. et al. Light-driven activation of β2-adrenergic receptor signaling by a chimeric rhodopsin containing the β2-adrenergic receptor cytoplasmic loops. Biochemistry 44, 2284–2292 (2005).

    CAS  PubMed  Google Scholar 

  122. Airan, R. D., Thompson, K. R., Fenno, L. E., Bernstein, H. & Deisseroth, K. Temporally precise in vivo control of intracellular signalling. Nature 458, 1025–1029 (2009). This study reports the development of chimeric light-activated GPCRs that can be used to investigate the effects of GPCR signalling in defined neuron populations with higher spatial precision than traditional pharmacological approaches and higher temporal precision than can be achieved using DREADDs.

    CAS  PubMed  Google Scholar 

  123. Copits, B. A. et al. A photoswitchable GPCR-based opsin for presynaptic inhibition. Neuron 109, 1791–1809.e11 (2021).

    CAS  PubMed  Google Scholar 

  124. Mahn, M. et al. Efficient optogenetic silencing of neurotransmitter release with a mosquito rhodopsin. Neuron 109, 1621–1635.e8 (2021).

    CAS  PubMed  Google Scholar 

  125. Oh, E., Maejima, T., Liu, C., Deneris, E. & Herlitze, S. Substitution of 5-HT1A receptor signaling by a light-activated G protein-coupled receptor. J. Biol. Chem. 285, 30825–30836 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Konermann, S. et al. Optical control of mammalian endogenous transcription and epigenetic states. Nature 500, 472–476 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Yamada, M., Suzuki, Y., Nagasaki, S. C., Okuno, H. & Imayoshi, I. Light control of the Tet gene expression system in mammalian cells. Cell Rep. 25, 487–500 e486 (2018). This review describes approaches for optical control of gene expression that can be used to alter specific proteins in defined cell populations.

    CAS  PubMed  Google Scholar 

  128. Li, P. et al. Optogenetic activation of intracellular adenosine A2A receptor signaling in the hippocampus is sufficient to trigger CREB phosphorylation and impair memory. Mol. Psychiatry 20, 1481 (2015).

    CAS  PubMed  Google Scholar 

  129. Siuda, E. R. et al. Spatiotemporal control of opioid signaling and behavior. Neuron 86, 923–935 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Jing, M., Zhang, Y., Wang, H. & Li, Y. G-protein-coupled receptor-based sensors for imaging neurochemicals with high sensitivity and specificity. J. Neurochem. 151, 279–288 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Liang, R., Broussard, G. J. & Tian, L. Imaging chemical neurotransmission with genetically encoded fluorescent sensors. ACS Chem. Neurosci. 6, 84–93 (2015).

    CAS  PubMed  Google Scholar 

  132. Labouesse, M. A. & Patriarchi, T. A versatile GPCR toolkit to track in vivo neuromodulation: not a one-size-fits-all sensor. Neuropsychopharmacology 46, 2043–2047 (2021). This article provides practical guidance for experimental applications involving GPCR-based neurotransmitter sensors.

    PubMed  PubMed Central  Google Scholar 

  133. Feng, J. et al. A genetically encoded fluorescent sensor for rapid and specific in vivo detection of norepinephrine. Neuron 102, 745–761.e8 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Jing, M. et al. A genetically encoded fluorescent acetylcholine indicator for in vitro and in vivo studies. Nat. Biotechnol. 36, 726–737 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Marvin, J. S. et al. A genetically encoded fluorescent sensor for in vivo imaging of GABA. Nat. Methods 16, 763–770 (2019).

    CAS  PubMed  Google Scholar 

  136. Patriarchi, T. et al. Ultrafast neuronal imaging of dopamine dynamics with designed genetically encoded sensors. Science 360, eaat4422 (2018).

    PubMed  PubMed Central  Google Scholar 

  137. Sun, F. et al. A genetically encoded fluorescent sensor enables rapid and specific detection of dopamine in flies, fish, and mice. Cell 174, 481–496.e19 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Tanaka, M., Sun, F., Li, Y. & Mooney, R. A mesocortical dopamine circuit enables the cultural transmission of vocal behaviour. Nature 563, 117–120 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Dong, A. H. et al. A fluorescent sensor for spatiotemporally resolved imaging of endocannabinoid dynamics in vivo. Nat. Biotechnol. https://doi.org/10.1038/s41587-021-01074-4 (2021).

    Article  PubMed  Google Scholar 

  140. Kim, H. R. et al. A unified framework for dopamine signals across timescales. Cell 183, 1600–1616.e25 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Inoue, M. et al. Rational engineering of XCaMPs, a multicolor GECI suite for in vivo imaging of complex brain circuit dynamics. Cell 177, 1346–1360.e24 (2019).

    CAS  PubMed  Google Scholar 

  142. Meng, C. et al. Spectrally resolved fiber photometry for multi-component analysis of brain circuits. Neuron 98, 707–717.e4 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Bando, Y., Grimm, C., Cornejo, V. H. & Yuste, R. Genetic voltage indicators. BMC Biol. 17, 71 (2019).

    PubMed  PubMed Central  Google Scholar 

  144. Kannan, M., Vasan, G. & Pieribone, V. A. Optimizing strategies for developing genetically encoded voltage indicators. Front. Cell Neurosci. 13, 53 (2019). This review describes progress and challenges in the development of genetically encoded fluorescent voltage sensors, which have the potential to allow in vivo monitoring of neuronal activity in defined neuron populations.

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Ibanez-Tallon, I. & Nitabach, M. N. Tethering toxins and peptide ligands for modulation of neuronal function. Curr. Opin. Neurobiol. 22, 72–78 (2012).

    CAS  PubMed  Google Scholar 

  146. Bishop, A. C. et al. A chemical switch for inhibitor-sensitive alleles of any protein kinase. Nature 407, 395–401 (2000).

    CAS  PubMed  Google Scholar 

  147. Idevall-Hagren, O., Dickson, E. J., Hille, B., Toomre, D. K. & De Camilli, P. Optogenetic control of phosphoinositide metabolism. Proc. Natl Acad. Sci. USA 109, E2316–E2323 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Biever, A., Donlin-Asp, P. G. & Schuman, E. M. Local translation in neuronal processes. Curr. Opin. Neurobiol. 57, 141–148 (2019).

    CAS  PubMed  Google Scholar 

  149. Kim, E. & Jung, H. Local mRNA translation in long-term maintenance of axon health and function. Curr. Opin. Neurobiol. 63, 15–22 (2020).

    CAS  PubMed  Google Scholar 

  150. Ostrom, R. S., Bogard, A. S., Gros, R. & Feldman, R. D. Choreographing the adenylyl cyclase signalosome: sorting out the partners and the steps. Naunyn Schmiedebergs Arch. Pharmacol. 385, 5–12 (2012).

    CAS  PubMed  Google Scholar 

  151. Howe, M. W. & Dombeck, D. A. Rapid signalling in distinct dopaminergic axons during locomotion and reward. Nature 535, 505–510 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Siciliano, C. A. & Tye, K. M. Leveraging calcium imaging to illuminate circuit dysfunction in addiction. Alcohol 74, 47–63 (2019).

    CAS  PubMed  Google Scholar 

  153. Tewson, P. H., Martinka, S., Shaner, N. C., Hughes, T. E. & Quinn, A. M. New DAG and cAMP sensors optimized for live-cell assays in automated laboratories. J. Biomol. Screen. 21, 298–305 (2016). This article describes the development of fluorescent biosensors for the signalling molecules DAG and cAMP.

    CAS  PubMed  Google Scholar 

  154. Chen, Y., Saulnier, J. L., Yellen, G. & Sabatini, B. L. A PKA activity sensor for quantitative analysis of endogenous GPCR signaling via 2-photon FRET-FLIM imaging. Front. Pharmacol. 5, 56 (2014).

    PubMed  PubMed Central  Google Scholar 

  155. Ma, L. et al. A highly sensitive A-kinase activity reporter for imaging neuromodulatory events in awake mice. Neuron 99, 665–679.e5 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Lee, S. J., Chen, Y., Lodder, B. & Sabatini, B. L. Monitoring behaviorally induced biochemical changes using fluorescence lifetime photometry. Front. Neurosci. 13, 766 (2019). This study demonstrates how in vivo monitoring of a fluorescent reporter of the PKA phosphorylation state can be used to observe intracellular signalling in defined neuron populations during behaviour.

    PubMed  PubMed Central  Google Scholar 

  157. Handler, A. et al. Distinct dopamine receptor pathways underlie the temporal sensitivity of associative learning. Cell 178, 60–75.e19 (2019).

    CAS  PubMed  Google Scholar 

  158. Lee, S. J. et al. Cell-type-specific asynchronous modulation of PKA by dopamine in learning. Nature 590, 451–456 (2021).

    CAS  PubMed  Google Scholar 

  159. Xu, L. et al. Widespread receptor-driven modulation in peripheral olfactory coding. Science 368, eaaz5390 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Buck, L. & Axel, R. A novel multigene family may encode odorant receptors: a molecular basis for odor recognition. Cell 65, 175–187 (1991).

    CAS  PubMed  Google Scholar 

  161. Chess, A., Simon, I., Cedar, H. & Axel, R. Allelic inactivation regulates olfactory receptor gene expression. Cell 78, 823–834 (1994).

    CAS  PubMed  Google Scholar 

  162. Zheng, J. & Zagotta, W. N. Stoichiometry and assembly of olfactory cyclic nucleotide-gated channels. Neuron 42, 411–421 (2004).

    CAS  PubMed  Google Scholar 

  163. Colmers, P. L. W. & Bains, J. S. Presynaptic mGluRs control the duration of endocannabinoid-mediated DSI. J. Neurosci. 38, 10444–10453 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. Castro, D. C. et al. An endogenous opioid circuit determines state-dependent reward consumption. Nature 598, 646–651 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by National Institutes of Health (NIH) grants/projects ZIA AA000416 to D.M.L., R00 AA025403 to K.A.J. and R01 DA022340 to J.F.C.

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Authors and Affiliations

  1. Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA

    David M. Lovinger & Yolanda Mateo

  2. Department of Pharmacology, Uniformed Services University of the Health Sciences, Bethesda, MD, USA

    Kari A. Johnson

  3. Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, USA

    Sheila A. Engi & Mario Antonazzo

  4. Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA

    Joseph F. Cheer

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  1. David M. Lovinger
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  2. Yolanda Mateo
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  3. Kari A. Johnson
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  4. Sheila A. Engi
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  5. Mario Antonazzo
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  6. Joseph F. Cheer
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D.M.L., K.A.J., S.A.E., M.A. and J.F.C. wrote the article, and Y.M. reviewed and edited the manuscript before submission.

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Correspondence to David M. Lovinger.

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Glossary

Gap junctions

Intercellular channels that permit direct cell–cell transfer of ions and small molecules.

Adhesion molecules

Cell surface proteins that mediate the interaction between cells, or between cells and the extracellular matrix.

Synapses

Small gaps between two neurons, through which the two neurons communicate by neurotransmitter release and binding to receptor proteins.

Juxtacrine

A signalling process in which the cell producing the effector molecule (for example, a neurotransmitter or protein) interacts with receptor proteins of an adjacent responding cell, usually needing to be in direct contact or within ~20 μm of each other.

Paracrine

A signalling process in which the cell producing the effector molecule (for example, neurotransmitter, hormone) acts on nearby responding cells, usually involving the diffusion over short distances of the effector molecule.

Somatic action potential

A rapid sequence of changes in the membrane voltage of a neuron soma, characterized by a rapid rise in voltage (depolarization) followed by a subsequent decrease (repolarization and hyperpolarization), the consequence of opening Na+ and K+ channels, respectively.

Chemogenetic

A technique that uses genetically engineered receptors and selective ligands to facilitate the study and manipulation of neuronal activity.

Optogenetic

A technique aimed at controlling the physiology of neurons (or other cell types) with light, generally involving genetically encoded light-sensitive cation or anion channels such as channelrhodopsin or halorhodopsin, respectively.

Neuromodulator

A substance that modulates the effectiveness of a neurotransmitter by influencing its release or receptor response to it.

VGCCs

(Voltage-gated calcium channels). Transmembrane proteins sensitive to voltage that, upon activation after depolarization, allow the entry of Ca2+ ions into the cell, further depolarizing membrane voltage and eliciting downstream intracellular effects including neurotransmitter release.

Synaptic plasticity

Activity-dependent modification of the connections between neurons.

Cognitive functions

Mental processes involved in the acquisition of knowledge, manipulation of information, thinking, remembering, decision-making, perception and so on.

Synaptosomes

Isolated synaptic terminals representing mainly the presynaptic portion, and often with an attached postsynaptic membrane, that conserve functional traits of the synapse.

Voltammetric

An electrochemical technique used to measure neurochemicals in the brain by taking advantage of the oxidation and reduction reactions that some molecules, such as catecholamines (for example, dopamine (DA) or norepinephrine), undergo when a specific voltage is applied, as measured by current changes.

Long-term depression

(LTD). A synaptic plasticity process in which a long-lasting reduction in the strength of synaptic transmission is observed after receiving certain types of recurrent synaptic stimulation and/or receptor activation.

Subfields

Regions inside a brain nucleus with distinctive neuronal populations, synapses and neurotransmitters that might have a differential impact on behavioural processes in comparison with neighbouring regions within the same nucleus.

Psychoactive drugs

Substances that when administered can affect mental processes (such as perception), mood and behaviour.

Priming

A protocol to investigate a behavioural response facing a previous stimulus, for example, a priming injection.

Microdialysis

A technique that enables the collection of low-molecular-weight substances (for example, neurotransmitters) from the interstitial space.

Fast-scan cyclic voltammetry

An electrochemical technique where the voltage is rapidly (for example, 400 V s–1) increased and decreased between a maximum and a holding potential repeatedly (for example, 10 Hz), allowing sufficient temporal resolution to study release of neuromodulators including dopamine (DA).

Short-term depression

A transient synaptic plasticity process by which high presynaptic transmission reduces the strength of transmission onto the postsynaptic terminal; considered as a low-pass filter for synaptic information transfer.

Extinction training

A behavioural protocol where the animal learns to eliminate a previously learned association or behaviour (for example, extinction of lever pressing for a drug).

Psychiatric disorders

Behavioural, emotional or cognitive dysfunctions that are not readily controlled by the individual and are related to clinically significant distress or impairment in one or more areas including social, occupational and interpersonal functioning.

Amacrine cells

Retinal interneurons that interact at the second synaptic level of the vertically direct pathways consisting of the photoreceptor–bipolar–ganglion cell chain.

Spontaneous excitatory postsynaptic currents

Spontaneous excitatory postsynaptic currents show the depolarizing flow of ions through postsynaptic ionotropic glutamate receptors in the absence of external stimuli, ultimately increasing the chance of evoking an action potential in the postsynaptic terminal.

DREADDs

(Designer receptor exclusively activated by designer drugs). G protein-coupled receptors engineered to activate different downstream effector pathways in response to a specific ligand, modulating cell physiology and allowing the study of certain biological processes in unrestrained animals and in a cell-specific manner.

Chimeric receptors

Genetically engineered receptors that combine functional elements (for example, binding domains, signalling domains) from different proteins.

Circularly permuted fluorescent protein

(cpFP). Modified fluorescent proteins that respond to conformational changes with changes in fluorescence intensity and can be used for studying various biological processes in living systems.

Bacterial periplasmic binding proteins

(PBPs). Receptors present in bacteria with high ligand affinity that experience drastic conformational changes after the binding of a ligand, rendering them a good protein scaffold for the development of fluorescent biosensors for neurotransmitters and other molecules.

Cre-loxP-based expression

Activation or inactivation of genes when the Cre recombinase is present and active; Cre expression is often driven by a cell type-specific promotor.

Amperometric

An electrochemical method in which the potential applied to a sensing electrode is controlled instrumentally and kept constant. The current produced by oxidation/reduction at the electrode surface is recorded as the analytical signal.

High-performance liquid chromatography

(HPLC). A column chromatography technique that pumps a sample mixture or analyte in a solvent (known as the mobile phase) at high pressure through a column with chromatographic packing material (stationary phase), separating and identifying compounds that are present in any sample that can be dissolved in a liquid in trace concentrations as low as parts per trillion.

Tethered inhibitors

Recombinant proteins engineered to block protein function via a tethered toxin in a specific subcellular compartment, such as the membrane, used to manipulate G protein-coupled receptors and ion channels in a subcellular and cell-specific manner, allowing the study of genetically defined populations in vivo.

Proteomic approaches

The large-scale study of proteins, known as the proteome, encompassing all of the proteins produced and modified by a cell or organism, allowing for the study of the different proteins involved in a process, cell population or cellular compartment.

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Lovinger, D.M., Mateo, Y., Johnson, K.A. et al. Local modulation by presynaptic receptors controls neuronal communication and behaviour. Nat Rev Neurosci 23, 191–203 (2022). https://doi.org/10.1038/s41583-022-00561-0

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