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History of Neuroscience, a brief accountThe brain is often, correctly, mentioned as the most complex organ in our body, the last terra incognita, that has challenged many great minds over the centuries. It was early on (BC) considered as the site of intelligence (Hippocrates) or as an organ important for cooling of the blood (Aristotle). The knowledge of some brain structures was already recognized in Egypt (BC), but more detailed descriptions of the animal nervous system were first offered by the Greek physician Galen (130-210 AD): the structures of the human brain not until the 16th century, by the Flemish anatomist Andreas Vesalius. During the 19th century the role of electricity for nervous system function was discovered by Luigi Galvani, an Italian physician, the first indication of an 'electric' brain. A major breakthrough occurred during the late 1880’s, when the combined efforts of two gifted scientists resulted in a detailed description of the nervous system as seen in the microscope, a description that still is valid. It was Camillo Golgi who developed a silver impregnation method that visualized, for the first time, all morphological features of a neuron: the cell body, dendrites and the axon with its ramifications and nerve endings. And it was Ramon y Cajal who in a monumental work used the Golgi method, painstakingly drawing the details of the built-up of the many differently shaped neuron types in the different brain regions and peripheral nerve structures (Figure 1), virtually exactly as we know them today using other methods, like immunohistochemistry (Figure 2). And moreover, Cajal interpreted his drawings to suggest function: he unequivocally defined the entity “neuron”. He stated that it is not part of a huge syncytium, that is nerve cells are not a continuum (the “reticular theory”), but neurons are individual units that are connected to each other at certain points later by Charles Scott Sherrington (Nobel Prize (N.P.) 1923) called synapses. And the nerve impulse travels via dendrites and cell soma into the axon terminating at the synapses. Cajal is often still celebrated as the greatest ever neuroscientist. Golgi and Cajal shared the N.P. in 1906. In fact, one can follow much of the progress in the neuroscience field with the help of relevant N.Ps. They can be divided into such awarding discoveries directly related to the nervous system, and those that indirectly have been of immense importance for this topic, e.g. the imaging methods. Many N.Ps. have recognized mechanisms associated with discrete neural functions, but only rarely with more general functions, like attention, mood and sleep, as well as with dysfunctions, such as mental and neurological illnesses. We will here follow the development in neuroscience on the basis of N.Ps. awarded in this sphere. Unless otherwise stated, it is the N.P. in Physiology or Medicine Many basic characteristics of nervous system, mainly focusing on peripheral nerves, eventually single axons, were defined: reflexes, adaptation processes, active inhibition and the propagation of nerve impulses. These discoveries, based on new methods and instrumentation, were made by outstanding neurophysiologists: Sherrington and Edgar Adrian (N.P. 1932) as well as Joseph Erlanger and Herbert Gasser (N.P. 1944). This work culminated in the studies by Alan Hodgkin and Andrew Huxley (N.P. 1963) who were able to measure currents by introducing a minute voltage clamp electrode inside the lumen of the axon of the very large nerve of the squid. In this way they could show the ionic mechanisms underlying the action potential travelling along the nerve. Still the “Hodgkin and Huxley equation” (theory, model) is a ground pillar for understanding nervous system physiology. Not until 2003 were some molecules, 'channels', associated with these fundamental events awarded with the N.P. (Peter Agre and Roderick MacKinnon).
Figure 2. Immunohistochemical staining of the Homer scaffolding protein 3 (HOMER3) protein in the Purkinje cells in cerebellum, showing the dendritic tree, cell bodies and the initial section of the axon projecting through the granular layer.
This model is true also for events at the synapse, that is when information is transferred from one to another neuron, a transfer that can result in excitation or inhibition. This was shown by Sir John Eccles, the third Awardee of the 1963 N.P., who also reported the first identified neurotransmitter in the central nervous system, acetylcholine (ACh), not starting the exploration of the 'chemical'brain. An ultimate contribution in the electrophysiology field was the introduction of the “patch-clamp” methodology by Erwin Neher and Bert Sakmann (N.P. 1991), which allows analysis of single ion channels and opened up a whole new field in neurobiology. A still indispensable method. Out of the 20162 human protein-coding genes, 132 are classified as voltage-gated ion channels (according to the protein classification) and 104 out of these are detected on RNA level in the human brain. Examples of voltage-gated ion channels with elevated expression levels in brain are HCN1 and KCNB1, both with enhanced expression in brain and retina. KCNC1 and KCND2 are also brain elevated, but also show an increased expression level in cerebellum compared to other brain regions. N.Ps. in the field of physiology have also been awarded for systems-related discoveries, first to Ragnar Granit, Haldan Hartline and George Wald (1967), and to David Hubel and Torsten Wiesel (1981) for processing of visual information in, respectively, the eye and the visual cortex. The latter Prize was shared with Roger Sperry for his work on the functional differences between the right and left cerebral hemisphere. Kart von Frisch, Konrad Lorenz and Nikolaas Tinbergen were awarded for basic principles underlying animal behaviour (1973). The discovery of “place cells” in the hippocampus by John O’Keefe followed by the identification of “grid cells” in the entorhinal cortex by May-Britt and Edvard Moser gave us a positioning (GPS) system, explaining how the world is represented within the brain (2014). Interest in chemical signaling, that is neurotransmitters and related molecules, started early in the 20th century. ACh as a transmitter was discovered in an ingenious, classic experiment by Otto Loewi, who called it “Vagusstoff”, because of its origin from the vagus nerve. This was followed up by Sir Henry Dale who found a substance in a fungus which he later identified as ACh. Loewi and Dale shared the N.P. in 1936. Sir Bernard Katz showed that ACh is released from nerve terminals at the neuromuscular junction and described details about the transmission process. Sir Bernhard shared the N.P., in 1970, with Ulf von Euler who discovered noradrenaline as the transmitter of the sympathetic nervous system, and Julius Axelrod who showed that noradrenaline is inactivated by reuptake into the nerve ending. Not until 2013 was the molecular mechanisms underlying transmitter release, the “exocytotic release machinery”, awarded with a N.P., to Thomas Südhof (together with James Rothman and Randy Schekman). Also the N.P. in 2000 focused on chemical transmission: Arvid Carlsson., who discovered dopamine as transmitter, laying the ground for treatment of Parkinson’s Disease; Paul Greengard who described molecules essential for the postsynaptic processing of dopamine stimulation involving phospho- and de-phosphorylation; and Eric Kandel who discovered how memory is formed and retained in Aplysia, and which transmitters are involved. It took a long time until transmitter receptors were awarded, but in 2012 Robert Lefkowitz and Brian Kobilka were awarded the N.P. (Chemistry) for their work on G protein-coupled receptors (GPCRs), that are the targets for some 40% of all prescribed drugs. Earlier Richard Axel and Linda Buck, surprisingly, discovered that the olfactory neurons express around 1,000 (!) GPCRs, recognizing the molecules that allows us to distinguish between different smells (N.P. 2004). Among the 20162 human protein-coding genes, 743 are classified as GPCRs (according to the protein classification) and 242 are expressed in the human brain, based on RNA expression. Examples of brain elevated GPCRs are GPR37L1 and GPR162, while GPRC5C is elevated in pancreas but regionally elevated in cerebellum when comparing the expression levels within the brain (Figure 3). Figure 3. Examples of antibody-based stainings targeting different GPCRs detected at different locations of the human cerebellum. Meanwhile some other important molecules had received attention, and been recognized by a N.P.: the hypothalamic releasing and inhibitory hormones controlling the release of hormones from the anterior pituitary, and thus controlling a large part of the endocrine system (Roger Guillemin and Andrew Schally) (1977). They shared the Prize with Rosalyn Yalow, who described the radioimmunoassay (RIA) method, probably the most used approach to determine levels of virtually all types of molecules in body tissues and fluids, important for all disciplines of biomedicine. Another molecule was nerve growth factor (NGF), that was discovered by Rita Levi-Montalcini, and its structure was reported by Stanley Cohen, who also discovered epidermal growth factor (EGF)(1986). A basic phenomenon, the circadian rythms, had been studies for decades, but the underlying molecules and mechanisms were unknown. They were revealed by Jeffrey Hall, Michael Rosbach and Micheal Young (2017). Perhaps surprisingly, the N.P. has only rarely been awarded to discovery of mechanisms underlying, or treatment of diseases afflicting the nervous system. John Enders, Frederick Robbins and Thomas Weller, discovered the poliomyelitis virus and how to grow it in the laboratory (1954). The N.P. to Arvid Carlsson (2000) was basic understanding, and treating Parkinson’s Disease. In 1976 Baruch Blumberg and Carleton Gajdusek were awarded N.P. for the discovery of the mechanism underlying Kuru, a neurodegenerative disease. Some two decades later Stanley Prusiner received the N.P. for identifying the ‘infectious’ agent causing Creutzfeldt-Jakob disease and “mad cow disease”: prions, self-reproducing protein pathogens, a new 'infectious' mechanism (1997). The 2002 N.P. was awarded for a fundamental and general mechanism: programmed cell death (Sydney Brenner, Robert Horovitz and John Sulston). In addition to these N.Ps. directly associated with neurobiology, the neuroscience field has immensely benefitted from Prizes awarded to discoveries of more general applicability. The live brain, surrounded by a bone 'capsule', was until fairly recently not accessible for analysis, contrasting virtually all other organs, such as liver, lungs and heart. Therefore imaging methods have been invaluable. The X-ray method discovered by Wilhelm Conrad Röntgen (first N.P. Physics, 1901) was generally of immense usefulness but not for brain analysis (the brain does not contain any material absorbing X-rays, except the tiny, brain-embedded epiphysis that in some humans is calcified). However, in 1979 Allan Cormack and Godfrey Hounsfield were awarded the prize for the development of computer assisted tomography (CAT) which supplies pictures of an up-till then undreamed detail. Even more useful was the development of the magnetic resonance imaging (MRI) by Lauterbur and Mansfield (2003). This allows high quality anatomical analysis as well as imaging physiological and pathophysiological processes. There are several variants including functional MRI (fMRI) which is dependent on changes in blood oxygen and localizes differences in brain activity, as well as magnetic resonance spectroscopy for studies of metabolic changes. All in the live brain, all without any surgical intervention. TimelineAs described above, there are numerous discoveries awarded the Nobel Prize that have proven important for the advances in neuroscience, below listed in a timeline table
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