The discovery of central monoamine neurons gave volume transmission to the wired brain

Abstract

The dawn of chemical neuroanatomy in the CNS came with the discovery and mapping of the central dopamine, noradrenaline and 5-hydroxytryptamine neurons by means of transmitter histochemistry using the Falck–Hillarp formaldehyde fluorescence technique in the early 1960s. Our mapping of the central monoamine neurons was continued and further established with tyrosine hydroxylase, dopa decarboxylase and dopamine-beta-hydroxylase immunohistochemistry in collaboration with Menek Goldstein and Tomas Hökfelt. During recent years an evolutionary constraint in the nuclear parcellation of the DA, NA and 5-HT neurons was demonstrated in the order Rodentia and other mammals. The abundant existence of global monoamine varicose nerve terminal networks synthesizing, storing and releasing monoamines in various parts of the CNS, including the release of DA by tubero-infundibular DA neurons as a prolactin inhibitory factor from the external layer of the median eminence into the portal vessels and the appearance of extraneuronal DA fluorescence after, e.g., treatment with amphetamine in nialamide pretreated rats (Falck–Hillarp technique) were also remarkable observations. These observations and others like the discovery of transmitter–receptor mismatches opened up the possibility that monoamines were modulating the wired brain, built up mainly by glutamate and GABA neurons, through diffusion and flow in the extracellular fluid of the extracellular space and in the CSF. This transmission also involved long-distance channels along myelinated fibers and blood vessels and was called volume transmission (VT). The extracellular space (ECS), filled with a 3D matrix, plays a fundamental role in this communication. Energy gradients for signal migration in the ECS are produced via concentration, temperature and pressure gradients, the latter two allowing a flow of the ECF and CSF carrying the VT signals. The differential properties of the wiring transmission (WT) and VT circuits and communication channels will be discussed as well as the role of neurosteroids and oxytocin receptors in volume transmission leading to a new understanding of the integrative actions of neuronal–glial networks. The role of tunneling nanotubes with mitochondrial transfer in CNS inter alia as part of neuron–glia interactions will also be introduced representing a novel type of wiring transmission. The impact of the technicolour approach to the connectome for the future characterization of the wired networks of the brain is emphasized.

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.