Organization, anatomy and cellular components of the peripheral nervous system

conducting researches with regard to the development of new treatment approaches, a fundamental knowledge about the structural and functional context of the nervous system is essential.

The vertebrates’ nervous system can be divided into the central nervous system (CNS) and peripheral nervous system (PNS) (López-Cebral et al., 2017). The CNS can be further subdivided into the brain, the spinal cord and the optic, olfactory, and auditory systems. Technically, the auditory system consists of a central part, reaching from the cochlear nucleus to the primary auditory cortex, and a peripheral part, including the outer, middle, and inner ear with the vestibulocochlear nerve as part of the PNS (Kollmeier, 2008). In addition to the integration and coordination of signals from the periphery, the CNS generates excitatory stimuli to the PNS that connects the CNS with the peripheral organs (Tian et al., 2015). The PNS consists of three parts:

the somatic nervous system (SNS, figure 1), the autonomic nervous system (ANS), and the enteric nervous system (ENS). The motoric or efferent part of the SNS is formed by the axon of one neuron of which soma is located either in the anterior horn of the spinal cord, in case of spinal nerves, or in the motor nuclei of the brainstem, in case of cranial nerves. These motor neurons conduct the excitatory signals that reach the spinal cord or brainstem nuclei to the skeletal muscles. Likewise, the sensory or afferent part of the SNS is formed by the axon of one neuron, but of which soma is not located directly within the CNS, but within a ganglion located close to it. For the spinal nerves these ganglia correspond to the dorsal root ganglia. Interestingly, for the cranial nerves, there are two other structures, harboring soma of first order sensory neurons, namely the trigeminal ganglion, located near the apex of the petrous part of the temporal bone, and the mesencephalic nucleus of the trigeminal nerve, located within the brainstem (Capra and Wax, 1989; Luo and Li, 1991). Sensory neurons conduct sensation from the periphery to the posterior horn of the spinal cord or, in cases of cranial nerves, to sensory nuclei of the trigeminal nerve in the brainstem to be further processed (Catala and Kubis, 2013). The ANS, which can be subdivided into the sympathetic and parasympathetic system, is responsible for the regulation of involuntary body functions sustaining body homeostasis. By innervating smooth muscles of viscera and blood vessels as well, as exocrine and endocrine glands, the ANS regulates vegetative

Introduction

parameters, e.g. breathing, blood flow, heartbeat, body temperature, and digestion (McCorry, 2007; Catala and Kubis, 2013; Kenney and Ganta, 2014). The ENS is located in the wall of the esophagus, stomach, and the intestine. It is also influenced by the sympathetic and parasympathetic nervous system, but carries an autonomous function as well. By regulating intestinal motility, absorption, secretion, immunological functions, and gastrointestinal blood supply, the ENS determines the digestion (Furness et al., 2014; Rao and Gershon, 2016).

A peripheral nerve accommodates four layers of connective tissue: Endoneurium, perineurium, epineurium, and mesoneurium (Gonzalez-Perez et al., 2013; Dahlin and Wiberg, 2017; López-Cebral et al., 2017). The endoneurium, which surrounds a single nerve fiber is made of longitudinally oriented collagen fibrils and contains microvessels. A bundle of nerve fibers is covered by the perineurium that is formed by oblique, circular, and longitudinally oriented collagen fibrils as well as perineurial cells, which display epitheloid myofibroblasts, providing the majority of tensile strength to the peripheral nerve. The epineurium covers the entire nerve trunk, but may also separate nerve fascicles by internal extension. By facilitating gliding between the fascicles, the epineurium displays a structure important for motion. The mesoneurium represents an interface, made of a loose layer of connective tissue, differentiating the epineurium from the adjacent tissue, which allows gliding of the whole nerve (Schmidt and Leach, 2003;

Tian et al., 2015; Antoniadis, 2017). Peripheral nerves underlie an extrinsic and intrinsic blood flow (Weerasuriya and Mizisin, 2011). Extrinsic vessels originate from surrounding large arteries and veins, reach the epineurium and ramify to support nerve fascicles. Intrinsic vessels, that reach the endoneurium, are crucial for processes of regeneration as they provide supportive molecules when the blood-nerve barrier (BNB), which is formed by endoneurial microvessels and the perineurium, gets disrupted upon injury (Weerasuriya and Mizisin, 2011; López-Cebral et al., 2017).

Depending on the composition of fiber qualities, peripheral nerves can be either motor, sensory, or mixed nerves. As the conductive unit of the nerve, a nerve fiber is formed by an axon and Schwann cells (SCs), which represent the neuroglia of the PNS (Tian et al., 2015). Large nerve fibers, with a diameter of > 1.5 µm, are myelinated by membranes of adjacent SCs, which are concentrically wrapped around the axon’s segment (Antoniadis, 2017). These wrappings are periodically interrupted by the so called nodes of Ranvier permitting fast, saltatory signal conduction (Dahlin and Wiberg, 2017; López-Cebral et al., 2017). In contrast to that, small nerve

Introduction

fibers, with a diameter of < 1.5 µm are grouped and enwrapped by the membrane of a single, non-myelinating SC, forming the so called Remak bundles (Weerasuriya and Mizisin, 2011).

This structure leads to a slow signal transmission along the axon (Antoniadis, 2017).

On the cellular level the nervous system hosts two types of cells: Neurons and neuroglial cells. A neuron is composed of two types of neurites, namely an axon, conducting electrical impulses away from the cell body, and dendrites, conducting electrical impulses to the cell body. The second component of the neuron is displayed by the cell body or soma, which contains a nucleus, as well as organelles (Tian et al., 2015; López-Cebral et al., 2017). Dependent on the number of dendrites, neurons can be classified into multipolar (= more than two dendrites), bipolar (= one dendrite), unipolar (= one extension), and pseudounipolar (= one extension that divides into one axonal and one dendritic extension) neurons (Waxenbaum and Varacallo, 2019). Neuroglial cells are supporting cells with the ability to divide. In contrast, neurons are usually regarded as post-mitotic cells, which do not undergo cell division. While astrocytes, oligodendrocytes and microglia, which term the resident macrophages of the brain and spinal cord, can be found in the CNS, the neuroglia of the PNS is represented by SCs, which myelinate and ensheath nerve fibers of the PNS, as mentioned above (Tian et al., 2015).

Introduction

Figure 1. Organization and anatomy of the peripheral nervous system. The spinal cord, as part of the central nervous system, includes the grey matter and the surrounding white matter. The peripheral nervous system connects the central nervous system with the periphery. Neuron somas of the motoric or efferent part are located in the anterior horn of the spinal cord. These motor neurons conduct efferent signals via their axons from the spinal cord through the ventral roots to the peripheral skeletal target muscles. Somas of sensory neurons are located in the dorsal root ganglia. Sensory neurons conduct afferent signals of sensation from the periphery, e.g. mechanoreceptors of the skin and muscle spindles, though the dorsal roots to the posterior horn of the spinal cord.