The discovery of central monoamine neurons gave volume transmission to the wired brain
Introduction
The development of the Falck–Hillarp histochemical fluorescence method for the cellular localization of catecholamines (CA) and 5-hydroxytryptamine (5-HT) (Falck et al., 1962); for review see (Fuxe and Jonsson, 1973) made it possible to create a new field in neuroscience—chemical neuroanatomy. For the first time it became possible to discover and map out transmitter-identified neurons in the CNS, namely the dopamine (DA), noradrenaline (NA) and 5-HT neurons (Anden et al., 1964, Dahlstrom and Fuxe, 1964a, Dahlstrom and Fuxe, 1965, Fuxe, 1963, Fuxe, 1964, Fuxe, 1965a, Fuxe, 1965b) and the CA nerve terminal networks of the hypothalamus were the first to be described (Carlsson et al., 1962). This mapping of peripheral adrenergic neurons and central monoamine neurons was validated and extended by the introduction of immunohistochemistry in peripheral nervous system (Geffen et al., 1969, Hartman and Udenfriend, 1970) and CNS (Fuxe et al., 1970c) research using antibodies against the CA synthesizing enzymes (Goldstein et al., 1971).
It is of interest to read what Cajal (1906) expressed in his Nobel lecture: “With time, techniques will discover some colouration process capable of revealing new and more intimate connections between neurons”. Over the last century it has also become clear that the gain in the brain is in the stain as Floyd Bloom wrote (Bloom, 1991). We have gone from Golgi to the Falck–Hillarp technique and later on to immunocytochemistry and receptor autoradiography leading to the volume transmission (VT) and wiring transmission (WT) theory of intercellular communication in the brain (Agnati and Fuxe, 2000, Agnati et al., 1986, Agnati et al., 1987, Agnati et al., 2006, Fuxe and Agnati, 1991a, Fuxe and Agnati, 2009, Fuxe et al., 1988a, Fuxe et al., 2007a). The introduction of amine fluorescence and immunohistochemistry has extended the Golgi–Cajal and ultrastructural maps of neuronal circuits by obtaining neurochemical maps of these circuits, resulting in knowledge of the chemical signals released by one neuron system to act on other neurons and glial cells. The neurochemical mapping at the cellular and ultrastructural level of central monoamine neurons and opioid peptide neurons and their receptors was of special importance for the development in 1986 of this theory by giving the first basic aspects of the chemical architecture of information handling in the CNS (Agnati et al., 2006, Fuxe and Agnati, 1991a).
“Volume” in VT refers to the volume of the extracellular space (ECS) in the brain filled with extracellular fluid and of the space of brain ventricles filled with cerebrospinal fluid. Thus, VT is an extracellular fluid (ECF) and cerebrospinal fluid (CSF) mediated transmission, and VT signals are chemical signals (like neurotransmitters, modulators, trophic factors, ions, etc.) that move from the source cells to the target cells as a consequence of energy gradients in the VT channels of the ECF and CSF leading to diffusion and convection (Agnati et al., 2006, Fuxe et al., 2007a).
After a brief historical summary of the Falck–Hillarp technique and the discovery of the central monoamine neurons this review gives an update of the VT field with focus on the differential role of several types of chemical signals in VT. It also provides novel aspects on WT with cytoplasmic molecule and organelle transfer including mitochondria in tunneling nanotubes (Rustom et al., 2004) (Gerdes and Carvalho, 2008). The impact on the WT field of the transgenic approaches for combinatorial expression of fluorescent proteins in the CNS is emphasized, since they will clarify the wiring of the CNS (Livet et al., 2007). Thus, we have moved from monoamine fluorescence and immunofluorescence histochemistry to combinatorial and stochastic expression of multiple fluorescent proteins to characterize the wiring of the brain.
Section snippets
The Falck–Hillarp histochemical fluorescence method for the cellular localization of CA and 5-HT
The so-called catecholamine (CA, viz. dopamine [DA], noradrenaline [NA] and adrenaline [A]) and 5-hydroxytryptamine (5-HT) formaldehyde histofluorescence method of Falck and Hillarp (Falck et al., 1962, Fuxe and Jonsson, 1973, Jonsson, 1967) was discovered and developed in 1961/1962. This is no doubt one of the great and revolutionary discoveries in modern neuroscience. The chemical basis of this method was characterized early on by Hillarp, Jonsson, Corrodi and colleagues (see review by Fuxe
The discovery of the central DA, NA and 5-HT neurons
The first central monoamine neurons to be discovered were the tubero-infundibular DA neurons in 1963 and 1964 (Fuxe, 1963, Fuxe, 1964) and the nigrostriatal DA neurons in 1964 (Anden et al., 1964, Anden et al., 1965a, Dahlstrom and Fuxe, 1964a). Then came the discovery in 1965 of the descending bulbo-spinal NA and 5-HT neurons (Dahlstrom and Fuxe, 1965, Nygren and Olson, 1977). In 1966 the ascending locus coeruleus and non-locus coeruleus NA systems were becoming characterized together with the
Development of the volume transmission concept and the general characteristics of volume transmission
The first observations that led us into a mode of communication different from the synaptic one was the appearance of extraneuronal DA fluorescence around midbrain DA nerve cells after amphetamine, a CA releasing drug, treatment in reserpine-nialamide-l-dopa treated rats (Fuxe and Ungerstedt, 1970). Similar observations were made on the 5-HT dorsal raphe nerve cell bodies after treatment with the antidepressant drug chlorimipramine, a 5-HT uptake blocker, in reserpine-nialamide pretreated rats (
Tunneling nanotubes representing channels between cells in the CNS as a possible new type of wiring transmission
‘Tunneling nanotubes’ (TNTs; see Fig. 6) have a diameter of 50–200 nm and a length in the order of several cell body diameters. They are not restricted to pairs of cells but could lead to complex cellular networks (Agnati et al., 2009, Agnati et al., submitted for publication, Baluska et al., 2004, Gerdes et al., 2007, Gerdes and Carvalho, 2008, Rustom et al., 2004). Organelles (endosome-related structures including mitochondria) are uni-directionally transferred via actin-mediated mechanisms at
The novel approach to mapping the connectome: transgenic strategies for combinatorial expression of fluorescent proteins
This year the Nobel Prize of Chemistry was given to Drs Shimomura, Chalfie and Tsien for the discovery of the green fluorescence protein and related applications. I believe this discovery has had and will continue to have a strong impact on Neuroscience. The work of Livet and Lichtman and their colleagues in 2007 and 2008 is highly exciting. Through their work we have moved from the “Golgi method” to “The technicolour approach to the connectome” (Lichtman et al., 2008, Livet et al., 2007). They
Conclusions
It was the discovery of the DA, NA and 5-HT neurons in the mammalian CNS in the 1960s and their characterization in the 1970s that gave the essence of the experimental support for the introduction of the volume transmission theory in 1986 by Agnati et al. (1986). The slow VT taking place via chemical signals in ECF and CSF became another major mode of chemical communication in the CNS side by side with the fast WT and DA, NA and 5-HT neurons were shown to operate mainly via VT. In this way the
Acknowledgements
This work has been supported by the Swedish Research Council (04X-715) and by Marcus and Marianne Wallenberg Foundation.
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