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Floyd Bloom Discusses the Messengers of the Mind Commentary | History, Teaching, and Public Awareness Floyd Bloom Discusses the Messengers of the Mind Floyd Bloom Discusses the Messengers of the Mind Teresa Esch Science Writer, The Society for Neuroscience DOI: 10.1523/ENEURO.0076-14.2014 Received: 24 December 2014 Accepted: 24 December 2014 Published: 31 December 2014 Correspondence should be addressed to Teresa Esch, 2307 Rosedown Drive, Reston, Virginia, 20191, United States. E-mail: [email protected]). Cite as: eNeuro 2014; 10.1523/ENEURO.0076-14.2014 Alerts: Sign up at eNeuro.SfN.org to receive customized email alerts when the fully formatted version of this article is published. Accepted manuscripts are peer-reviewed but have not been through the copyediting, formatting, or proofreading process. This article is distributed under the terms of the Creative Commons Attribution License (http:// creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. Copyright © 2014 Society for Neuroscience eNeuro http://eneuro.msubmit.net eN-ICOM-0076-14 Floyd Bloom Discusses the Messengers of the Mind This is a confidential document and must not be discussed with others, forwarded in any form, or posted on websites without the express written consent of eNeuro. 1 Title: Floyd Bloom Discusses the Messengers of the Mind 2 Teresa Esch, Science Writer, The Society for Neuroscience 3 [email protected] 4 Significance Statement: 5 Some of the basic principles of nervous system function that we now take for 6 granted were once topics of great controversy that required decades of research 7 to resolve. One such principle is that neurons communicate via chemicals. In the 8 History of Neuroscience lecture at this year’s meeting of the Society for 9 Neuroscience, Floyd Bloom discussed how this principle came to be accepted by 10 the community. In doing so, he hoped to recognize some of the great minds who 11 contributed to the debate and also to remind young scientists that even great 12 minds can sometimes be wrong. This commentary presents some of the key 13 discoveries highlighted in his talk. 14 15 1 16 The ability of plant alkaloids and animal venoms to affect nervous system 17 function has been known for millennia. People throughout the world have taken 18 advantage of these effects to paralyze prey, kill enemies, keep alert, and enter 19 spiritual states. But an understanding of how neuroactive chemicals work—by 20 affecting synaptic transmission—came about only gradually, beginning in the 21 19th century. As is often the case, many long-held beliefs had to be overturned 22 before this understanding was reached. In his History of Neuroscience lecture at 23 this year’s meeting of the Society for Neuroscience, Floyd Bloom described some 24 of the paradigm shifts that were necessary for people to appreciate chemical 25 neurotransmission and “The Messengers of the Mind.” 26 Bloom reckoned that the journey began in 1844, with Claude Bernard’s studies of 27 curare. Bernard first administered curare to a living frog. Dissecting the frog 28 immediately after it died, he found that the heart was still beating and muscles 29 still contracted when stimulated electrically. From this he concluded that curare 30 paralyzed the frog by poisoning the nerves rather than the muscles (Black, 31 1999). Subsequent experiments on isolated nerve–muscle preparations revealed 32 that if only the nerve was bathed in curare, nerve stimulation continued to cause 33 muscle contraction, whereas if only the muscle was bathed in curare, nerve 34 stimulation did not evoke contraction; yet the curare-bathed muscle contracted if 35 stimulated directly (Bennett, 2001). At that time it was believed that vital spirits 36 flowed through hollow nerve tubes and inflated muscles, causing them to 37 contract. Therefore, Bernard concluded that curare disconnects motor nerves 38 from their cell bodies in the spinal cord. 39 Of course we now know that nerves do not work by pumping vital spirits into 40 muscles. This is largely thanks to the work of Emil du Bois-Reymond, who 41 studied the electrical properties of tissues. He proposed that nerve cells stimulate 42 muscles electrically, but he acknowledged that they might instead use chemicals. 43 For this, du Bois-Reymond is credited with being the first to propose chemical 44 neurotransmission. 45 The next step in the journey was led by John Newport Langley, starting in 1885. 46 By using nicotine to stimulate sympathetic ganglia, Langley was able to map the 47 major pathways of what he named the autonomic nervous system. He went on to 48 use physiological, pharmacological, and anatomical techniques to investigate 49 synapses in the sympathetic nervous system. With his student Thomas Elliott, he 50 found that extracts from the adrenal medulla mimicked the effects of sympathetic 51 nerve stimulation on smooth muscles. He noted, however, that not all cells 52 responded to the extracts, leading him to hypothesize that “receptive substances” 53 present on a cell determined its responsiveness (Langley, 1905). 54 Another student of Langley’s was Charles Sherrington with whom he investigated 55 the effects of cortical lesions on dogs (Nobel Media, 2014). But Sherrington 56 eventually turned his attention to the spinal cord. That nerve stimulation 57 sometimes caused muscles to relax had been known for some time, but the 58 mechanism was generally assumed to be peripheral. By tracing the afferent and 2 59 efferent pathways between muscles and the spinal cord, Sherrington developed 60 the theory of reciprocal innervation, which tied contraction of a flexor to relaxation 61 of the antagonistic extensor muscle via interneurons in the spinal cord. Central to 62 this theory was the novel hypothesis that there are two types of neurons: 63 excitatory and inhibitory (Sherrington, 1932). 64 One of Sherrington’s early influences was Ramon y Cajal, whom Sherrington first 65 met in Spain while studying the cholera outbreak (Nobel Media, 2014). When 66 Cajal later sent his work describing Golgi staining of the developing nervous 67 system to the Royal Society, the work was passed to Sherrington. Sherrington 68 thus became an early supporter of the neuron doctrine, i.e., that the nervous 69 system is composed of individual cells rather than being a continuous reticulum. 70 The eventual universal acceptance of the neuron doctrine led inevitably to the 71 question of how neurons communicate. 72 Following on the ideas of du Bois-Reymond, many prominent neuroscientists of 73 the day—including John Eccles, Lorente de Nó, Herbert Gasser, and Ralph 74 Gerard—believed that neurons communicated electrically. They thought that the 75 actions of chemicals were too slow to mediate the rapid effects of 76 neurotransmission. But Thomas Elliott, a student of John Langley’s, suggested in 77 1904 that epinephrine might be released by sympathetic nerves (Elliott, 1904). 78 This hypothesis arose from his studies of the effects of adrenalin/epinephrine on 79 the sympathetic nervous system. 80 Elliott’s suggestion was largely ignored by the scientific community, including 81 Langley and even Elliott himself in subsequent articles (Rubin, 2007). But in 82 studying the actions of synthetic biogenic amines, Henry Dale provided more 83 evidence that a catecholamine mediated the effects of sympathetic nerves on 84 their target muscles. Dale also discovered that acetylcholine, which he isolated 85 from ergot fungus, mimicked the effects of parasympathetic nerve stimulation on 86 smooth muscle and were likewise blocked by atropine (Rubin, 2007). But 87 because the compounds he studied were exogenous, their role as endogenous 88 neurotransmitters remained in doubt. 89 Direct evidence for chemical neurotransmission was first published by Otto Loewi 90 in 1921. Performing an experiment that came to him in his sleep (Rubin, 2007), 91 Loewi stimulated the vagus nerve innervating a frog’s heart; this slowed the 92 heartbeat. He then transferred the Ringer’s solution surrounding the vagus nerve 93 and heart to another heart. This slowed the second heart, indicating that the 94 vagus nerve released a transferrable substance, which Loewi called “Vagusstoff” 95 Loewi, 1936). But attempts to replicate the experiment failed for several years 96 because—it was later discovered—the release of acetylcholine (which Vagusstoff 97 was eventually shown to be) varies across species and seasons and is degraded 98 by acetylcholinesterase in the blood. Thus, chemical neurotransmission 99 remained a controversial hypothesis. 3 100 John Eccles was one scientist who persisted in the belief that neurons 101 communicated electrically, not chemically (Eccles, 1948). His mind remained 102 unchanged until after the advent of electrophysiological techniques during World 103 War II. Using such techniques, Stephen Kuffler and Bernard Katz showed that 104 denervated muscle was sensitive to acetylcholine and that acetylcholine 105 mimicked the effects of motor nerve stimulation. (Hunt and Kuffler, 1950). This 106 convinced Eccles that chemical neurotransmission occurred at the 107 neuromuscular junction. Nevertheless, he continued to believe that 108 communication between neurons within the CNS was strictly electrical. This 109 changed when a central feature of his electrical model to explain Sherrington’s 110 reciprocal inhibition was disproved. According to his hypothesis, a motor neuron 111 would be depolarized by input from antagonist muscles. But intracellular 112 recordings showed that the neuron was hyperpolarized, thus disproving the 113 model and leading Eccles to finally accept that chemical neurotransmission 114 occurs in the CNS (Eccles et al. 1954). 115 The universal acceptance of chemical neurotransmission led naturally to the 116 quest to identify other neurotransmitters. In 1958, W.D. Paton published an 117 article in Annual Reviews of Physiology (Paton, 1958) outlining criteria for 118 defining a substance as a neurotransmitter: First, the chemical had to be present 119 in neurons.
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