Paper : 06 Animal Physiology Module : 01 General organization and classification of

Development Team

Principal Investigator : Prof. Neeta Sehgal Department of Zoology, University of Delhi

Co-Principal Investigator : Prof. D.K. Singh Department of Zoology, University of Delhi

Paper Coordinator : Prof. Rakesh Kumar Seth Department of Zoology, University of Delhi

Content Writer : Dr. Anju Jain1, Dr. KP Mishra2, Dr. Sarita Nanda1 1Daulat Ram College, University of Delhi 2 Defence Institute of Physiology and Allied Sciences, Delhi

Content Reviewer : Dr. Tanushri Saxena Shraddhanand College, University of Delhi

Animal Physiology ZOOLOGY General Organization and Classification of neuron

Description of Module

Subject Name ZOOLOGY

Paper Name Zool 006 Animal Physiology

Module Name/Title Organization and Evolution of

Module Id M01: General Organization and Classification of neuron

Keywords Affector, Effector, Neuron, Glial cells, Unipolar, Bipolar, Multipolar, , , , Nissl Bodies, , , , Schwann Cells, Satellite cells, Ependymal cell

Contents 1. Learning Outcomes 2. Introduction 3. Neuron as the Basic Unit of Nervous System 4. Discovery of 5. Classification of neurons 6. Glial Cells: supporting cells 7. Identification of Neurons by Various Techniques 8. Neuronal Stem Cells (NSCs) 9. Conclusion 10. Summary

Animal Physiology ZOOLOGY General Organization and Classification of neuron

1. Learning Outcome

This chapter will help you to learn about the following:  Different parts of the  The characteristics of Neurons  History of discovery of the brain cells  Classification strategies of Neurons  Characteristics of the supporting cells of the brain  The various techniques which are used in study of the brain  The stem cells present in the brain tissue.

2. Introduction

Brain, the most complex part of the body communicates with each and every other body parts through a well-developed and essential electrical wiring known as nervous system which includes both the (CNS) and the peripheral nervous system (PNS). The central nervous system is the main integration and command centre of body and is made up of the and where PNS connects the CNS to different effector organs of body and is divided into two subdivisions, somatic nervous system (SNS) and autonomic nervous system (ANS) (Fig.1). Along with that recent researches also revealed the importance of enteric nervous system (ENS) or intrinsic nervous system as one of the major divisions of the nervous system. It includes a mesh-like system of neurons that mainly governs the function of the gastrointestinal tract. The ENS again includes two plexuses, the submucosal and the myenteric with their own functions.

The cellular building blocks of the entire nervous system are nerve cells, called neurons, and supporting cells called glial cells. The is composed of almost 100 billion of electrically excitable neurons and 10 times as many glial cells (Herculano-Houzel S. 2009). Neurons are specialized for electrical and chemical signaling over long distances. Glial cells, in contrast to nerve cells, are not capable of transmission of electrical signaling; thereby the neuron is the only functional unit of the nervous system. Current evidences

Animal Physiology ZOOLOGY General Organization and Classification of neuron

indicate that the supporting glial cells play an important role in modulation of neuronal activity and developmental processes (Stout et al. 2014).

Nervous system

CNS PNS

Brain Spinal cord SNS ANS

Fig 1. Organisation of the Nervous System: CNS: Central Nervous system, PNS: Peripheral Nervous System, SNS: Sympathetic Nervous System, ANS: Autonomic Nervous System. Source: Self Drawn

3. Neuron as the Basic Unit of Nervous System

A single neuron is mainly made up of three parts: nerve cell body, and (Fig 2). Cell body is also known as perikaryon or and it is constituted by mass of cytoplasm named neuroplasm. Neuroplasm contains a large nucleus, neurofibrils, nissl bodies, mitochondria and Golgi apparatus. Neurofibrils and nissl bodies are found only in neurons, not in other cells. In its mature state, neuron cannot divide due to absence of centrosome. Very few nerve cells are formed after birth. Although recent researches indicate the promising roles of some transcription factor like A to h7 in many aspects of early neurogenesis in the retina (Jusuf et.al. 2012).

Animal Physiology ZOOLOGY General Organization and Classification of neuron

Fig 2: Structure of Neuron showing soma, dendrites and axon. The cell body is nucleated and the axon ends in . The axon can be wrapped by Schwann cells to form sheath. Source: Creative Commons

Soma: it is the head of the neuronal cell (Fig. 3). It has nucleus and the cytoplasm which is also called neuroplasm. It contains organelles as the mitochondria, Golgi apparatus, endoplasmic reticulum, secretory granules, ribosomes and polysomes. Is the watery and salty fluid with a potassium-rich solution inside the cell containing enzymes responsible for the metabolism of the cell. Nucleus helps to form RNA which can be transcribed into proteins. Dendrites are projections arising from soma which help to receive messages from other neurons. Its membrane has several receptors which can interact with receptors. Nissl bodies are granular bodies found in the neurons which are formed by rough endoplasmic reticulum and ribosomes. They are site of synthesis of proteins. The neuro fibrils are the cytoskeleton elements like intermediate filaments, microtubules and microfilaments (Fig. 4) which maintain the shape of the neuron as well as help in transport of neurotransmitters.

Axons: are long/short projections from the soma which carry messages away from the head of the neuron. The axons are either myelinated or non-myelinated. Myelin sheath is made up of oligodendrocytes in the CNS and Schwann cells (they were discovered by

Animal Physiology ZOOLOGY General Organization and Classification of neuron

Theodor Schwann) in the PNS arranged in concentric layers. They are rich in glycolipids. They help in fast conductance of electric activity. It forms the outermost layer of the nerve fiber in the. In case of peripheral nervous system neurolemma is the outermost layer. It serves protective functions for peripheral nerve fibers during regeneration. After nerve injury neurolemma forms a regeneration tube through which the growing axon reestablishes its original connection. There are gaps in these covering which are called as Nodes of Ranvier. The is point of attachment axon with the soma.

Synapses are point of contact between one neuron and other. The can be of two types: Electrical and Chemical. The electrical synapses pass on the electrical activity from one cell to another by passage of ions. On the other hand, in the chemical the message is passed on by transmission of neurotransmitters released by the pre-synaptic membrane which act on the post synaptic membrane. They can either excite or inhibit the activity.

Fig 3. The details of internal structure of soma. It contains nucleus, nucleolus, cytoplasm and dendrites. The cytoplasm contains endoplasmic reticulum, mitochondria, golgi apparatus, Nissl bodies, cytoskeleton elements .Source: Creative Commons

Animal Physiology ZOOLOGY General Organization and Classification of neuron

Fig 4: Different type of cytoskeleton elements like Microtubules, Intermediate filaments, Actin filaments present in dendrites and axons. These elements are associated with proteins like MAP, Tau and GFAP etc which help in maintaining their structure and function. Source: Creative Commons.

4. Discovery of Neurons

The history of discovery of neurons is given in Table1.

Table 1: Important findings in neuronal history.

Name Time period Discovery Christian Gottfried Ehrenberg 1795–1876 Neurons as cells in the Valentin 1836 -1863 Nucleus and nucleolus of neurons. Purkinje 1837 Neurons in the .

Animal Physiology ZOOLOGY General Organization and Classification of neuron

Discovery of continuous network in Joseph Gerlach 1820-1886 brain known as the "reticulum”. A method of staining of neurons by Camillo Golgi 1873 hardening nervous cells. Henry Pickering Bowditch 1840-1911 Nerve impulse transmission

5. Classification of neurons

The brain's diverse function is mainly due to tremendous regional specialization. Different brain areas contain neurons with special shapes, physiological properties, and connections. There are four major methods of classification of neurons (Fig. 5) a. Structural b. Functional c. Based on neurotransmitter secreted by them. d. Electrophysiological

Fig 5: Different methods of classification of neurons in the nervous system. Source: Self Drawn

a. Structural classification of neuron: (Fig. 6) An amazing diversity of shapes and sizes is highly observed in neuronal cells which is responsible for functional differentiation among the cells. Branching off the cell body of neurons are the dendrites, which is just like antennae picking up signals from other neurons. Another long projection of neuron, that conducts electrical impulses away from cell body, is

Animal Physiology ZOOLOGY General Organization and Classification of neuron

known as Axon. The structural classification of neurons mainly depends upon the number of dendrites present on the cell body.

: Unipolar neurons have a single axon but contain no Dendron. Unipolar neurons are commonly seen in insect’s brain, where the cell body of the neuron is located at the peripheral region of brain and is inactive. Another is pseudounipolar type that contains an axon which has two branches. Pseudounipolar neurons are actually variations of bipolar neurons in that initially they have two processes which fuse during their development into one short common axon. Primary sensory neurons, located in the dorsal root of spinal nerves and the semilunar ganglions of the trigeminal nerves are the major examples of .  Bipolar neurons: Bipolar neurons have an axon and a single dendrite. Bipolar cells mainly act as sensory neurons in the transmission of special senses like olfaction, taste and hearing.  : Multipolar neurons contain several dendrites. It is the most common type of neurons present in CNS and includes and motor neurons. A special type of multipolar neuron, known as pyramidal neuron is found in some areas of brain including hippocampus, and the amygdala. The main structural features of the neuron include conic shaped cell body, after which the neuron is named. Pyramidal neurons are majorly present in the corticospinal tract.

Animal Physiology ZOOLOGY General Organization and Classification of neuron

Fig.6: Structural classification of Neurons. Source: Self Drawn

The mechanism underlying the development of these four different morphological types is not well known. Although some transcription factors are thought to be important in this aspect. Recent researches in Drosophila indicate that transcription factor Dar1 is responsible for determination of morphology of multipolar neuron. (Wang et al.2015).Presence of Dar1 develops multipolar neurons where loss of dar1 gradually converts multipolar neurons into the bipolar or unipolar.

b. Functional classification of neuron: (Fig 7,8) Functionally neurons are classified as sensory neurons, motor neurons, or interneurons.  Sensory neuron or afferent neuron: Sensory neurons are cells of nervous system responsible for converting external stimuli from the organism's environment into internal electrical impulses as sensory information (e.g. the dorsal root cell). In response to a sensory input, peripheral sensory neuron (a first-order sensory neuron) conducts an electrical impulse that travels down the nerve fiber to the central nervous system. In sensory neurons an external stimulus may alters the permeability of cation channels present in the nerve endings, that in-turn generates a depolarizing current (receptor potential). Receptor potential if sufficient in magnitude, generates action potential in the sensory neuron. The axon diameter of a particular sensory neuron determines the

Animal Physiology ZOOLOGY General Organization and Classification of neuron

conduction speed of action potential. A first order sensory neuron may activate a second- or third-order neuron or a motor neuron. The sensory division carries sensory information to the CNS that includes "special senses" of touch, smell, hearing, taste and sight. It also carries senses of pain, body position (proprioception) and a variety of other visceral sensory information. The neurotrophins family of polypeptide growth factors are very much important in regulation of development of sensory neurons GDNF promotes the survival of parasympathetic, sympathetic, proprioceptive, enteroceptive, and cutaneous sensory neurons.  Motor neuron or efferent neuron: Motor neuron (or motoneuron) is the nerve cell along which electrical impulses pass from the brain or spinal cord to a gland, muscle or any other target area (for example neurons in the autonomic nervous system). Motor neurons are classified in three major types, somatic motor neurons (that send their axon to skeletal muscles), special visceral motor neurons (which innervate branchial muscles) and general visceral motor neurons (that innervate cardiac muscle and smooth muscles). According to position motor neurons are again classified into two major group, and . Electrical impulse in the upper motor neuron travels from the cerebral cortex to the spinal cord. Nerve impulse then travels in the lower motor neuron that carries it from the spinal cord to the . Acetylcholine acts as a major neurotransmitter in motor neuron signaling.  : Interneurons are the neurons that connect various neurons within the brain and spinal cord and are very much important in neural circuits. Oscillatory activity of neuron and adult brain neurogenesis is dependent on interneurons present in the circuit. GABAergic interneurons with their axons present near the subgranular zone (SGZ) neurogenic niche can potentially exert functional impact on neurogenesis of adult brain (Bergström et al. 2014.).

Animal Physiology ZOOLOGY General Organization and Classification of neuron

Fig 7: Functional Classification of Neurons. Source: Self drawn

Fig 8: Functional Classification of neuron depicted in reflex arc. Source: Self Drawn

c. Classification based on neurotransmitter secretion: In the nervous system, electrical or chemical signal from a neuron passes to another through a specialized structure known as synapse. Neurotransmitters are endogenous chemical messengers that enable neurotransmission by transmitting signals across a . Neurotransmitters are stored and released from synaptic vesicles present in presynaptic neurons and secreted in

Animal Physiology ZOOLOGY General Organization and Classification of neuron

synaptic cleft. Acetylcholine (ACh) is the first known neurotransmitter discovered in 1921 by Otto Loewi, a German pharmacologist. Neurotransmitters act directly after binding with the postsynaptic ligand binding ion channel receptors. Some important neurotransmitters are Acetylcholine, Glutamate, gamma-Aminobutyric acid, Dopamine, Serotonin, Norepinephrine, Epinephrine. The neurons are classified as Cholinergic neuron, Glutamatergic neuron, GABAergic neuron, Dopaminergic neuron, Serotonergic neuron, Noradrenergic/Norepinephrinergic neuron and Adrenergic/epinephrinergic neuron. Their functions are summarised in Table 2.  Cholinergic neuron: A cholinergic neuron is a nerve cell which mainly uses acetylcholine (ACh) as its own neurotransmitter to send messages. Cholinergic neurons are very much important in CNS functioning during both wakefulness and rapid eye movement sleep. Cholinergic neurons also play important role in memory and cognitive functions of brain. There is dysfunction as well as loss of basal forebrain cholinergic neurons during earliest pathological events of Alzheimer's disease (AD). Cholinergic neurons are also very much important in normal aging as there are beadlike swellings and thickening of axon within the cholinergic fibres that often form clusters during normal aging (Nyakas et al. 2011). The cholinergic innervations of the suprachiasmatic nucleus (SCN) of hypothalamus is important in regulation of mammalian circadian system.  Glutamatergic neuron: Glutamatergic neuron is defined as a neuron that uses glutamate as its neurotransmitter. It is an important excitatory neuron present in the CNS. Glutamatergic neurons are important in memory and learning. Glutamate binds with three different kinds of receptors known as AMPA receptors, N-methyl-D-aspartate receptor (NMDA) receptors, and metabotropic glutamate receptors. In some abnormal conditions glutamate may behave as neurotoxins and may induce impaired cognition.  GABAergic neuron: GABAergic neuron that secrete gamma-Aminobutyric acid (also called GABA) is the chief inhibitory neuron present in the mammalian central nervous system. It plays role in reducing neuronal excitability and thereby protects the entire nervous system. Regulation of muscle tone is the major function of GABAergic neuron (Watanabeet al. 2002). Cerebellum region of brain contains a special kind of GABAergic neuron known as Purkinje cells, or Purkinje neurons. Purkinje neurons show

Animal Physiology ZOOLOGY General Organization and Classification of neuron

two distinct forms of electrophysiological property which includes simple spikes and complex spikes.  Dopaminergic neuron: Dopaminergic neurons secret dopamine and are very few in number. But these neurons play an important role in motor control, motivation, and arousal. These neurons also play an important role in lower-level functions including lactation, sexual gratification.  Serotonergic neuron: Serotonergic neuron is defined as a neuron that uses serotonin as its neurotransmitter. The Raphe nuclei contains serotonergic neurons that is the principal source of serotonin release in the brain. According to recent research low level of serotonin can cause severe depression thereby it has role in maintenance of mood and Mental health.  Adrenergic neuron: Adrenergic neurons are secondary neurons of the sympathetic nervous system. Adrenergic nerve fibres are responsible for increase in heart rate and decrease in digestion; it also controls the sweat glands in the dermal layer of skin.  Noradrenergic neuron: Another important type of neuron is noradrenergic neurons that comprise the postganglionic neurons of the sympathetic nervous system. Noradrenergic neurons play an important role in the control of body fluid metabolism (Antunes-Rodrigues, et al. 2004). Many available drugs exhibit their effects by neither interacting with nor epinephrine systems in the brain or body.

Table 2: Neurotransmitters with function

Type of neurons Nature Physiological action Cholinergic neurons Excitatory Enhanced cognition, Arousal, muscular movement Glutamatergic neuron Excitatory Memory, Learning GABAergic neuron Inhibitory Sleep Dopaminergic neuron, Excitatory and inhibitory Mood, learning, memory serotonergic neuron Excitatory Mood and mental health Noradrenergic neuron Excitatory Heart, Intestine, Body fluid Noradrenergic neurons Excitatory Heart, Intestine

Animal Physiology ZOOLOGY General Organization and Classification of neuron

d. Classification of neurons based on Electrophysiological property (Modern idea about classification): The modern method of neuron classification is according to their electrophysiological characteristics.  Tonic firing type: Most neurons that have been studied have spontaneous electrical activity. Neurons that are typically constantly active are called tonic or regular spiking. Tonic firing is very much common in sensory and cortical neurons that typically occur without presynaptic input. It can be viewed as background activity. Na + and K+ channels may have an important role in such activity. Very high levels of catecholamine may also induce increased tonic firing.  Phasic or bursting type: Another important type of neuron is Phasic or bursting type that fire in bursts. The burst of electrical spikes are mainly observed in dopaminergic neurons and is facilitated by NMDA receptor. Removal of NMDA receptor from the dopaminergic neurons decreases the magnitude of fire bursts.  Fast firing type: Some neurons are special for their fast firing rate including neurons in vestibular, auditory circuits as well as some cortical and basal ganglia neurons. The baseline firing rate in such kind of neuron is 30–100 Hz. Studies showed that these neurons express high levels of sodium channels.

6. Glial Cells: supporting cells

Glial cells were discovered were first noticed in 1826 and first named in 1856. Their role was not understood then and they were thought to be just filling up gaps between the neurons. Several scientists proposed several functions like their association with blood vessels (Golgi), their morphological plasticity (Cajal), neurotransmitter uptake and pathology (Virchow). But only recently their functions are proven. Glial cells make up 90 percent of the brain's cells. Glial cells are nerve cells that don't carry nerve impulses. The various glial (meaning "glue") cells perform many important functions, including: digestion of parts of dead neurons, manufacturing myelin for neurons, providing physical and nutritional support for neurons, and more. Types of glial cells include Schwann's Cells, Satellite Cells, Microglia, Oligodendroglia, and Astroglia (Fig 9, Table 3). Neuroglia (meaning “nerve glue”) is another

Animal Physiology ZOOLOGY General Organization and Classification of neuron

type of . These cells guide neurons during fetal development. Following injury, are major regulators of neuronal repair and they are largely responsible for the difference in regeneration capacity between the central and peripheral nervous system. (Jessen, K.R. 2004).

Table 3: Details of location and function of different glial cells present in the nervous system. S.No. Type of glial cells Present in Function CNS/PNS 1. Astrocytes CNS Most abundant cell, Support, Regulate ions, help exchange of material between neurons and capillaries, help to form blood brain barrier. 2. Microglial cells CNS Immune cell, defend against invading microorganism 3. Ependymal CNS Create, secrete and circulate cerebrospinal fluid, Line cavities 4. Oligodendrocytes CNS Wrap and insulate , form insulin sheath 5. Satellite Cells PNS Surround neuronal cell bodies 6. PNS Insulate, help form myelin sheath

Fig 9: Different types of Glial cells present in CNS. Source: Creative Commons 7. Identification of Neurons by Various Techniques

Techniques developed by pioneers of like Cajal Golgi are widely used to describe and categorize the diverse cell population in the nervous system. Golgi staining uses silver

Animal Physiology ZOOLOGY General Organization and Classification of neuron

salt and permits visualization of individual neuron and their processes. As a modern counterpart, fluorescent dye is injected into a neuron to identify the function of the cell. Another method named single –unit recording, measures electro-physiological response of a single neuron using a microelectrode system. Modern electron microscopic technique provides ultimate information about neuronal shape.

8. Neuronal Stem Cells (NSCs):

There are two types of stem cells- one found in the adult brain and other in the Embryo. Embryonic stem cells are pluripotent and can differentiate into any type of cell. The adult brain cells are not pluripotent and can only form brain cells like neurons or glial cells. They are found to replace lost or injured neurons and glial cells and thought to be the cause plasticity in areas of memory and learning. Basically, plasticity refers to increase in the interconnections between cells and cell number in response to a practice or condition. In adult brain, neurons mainly originate from proliferating neural precursors of sub ventricular zone of lateral ventricles and in the sub granular zone of the hippocampus.

9. Conclusion:

This introductory chapter reviews the highly complex structure and different methods of classification of nervous system. The chapter should provide the reader with an appreciation of overall organization of nervous system along with its diverse functions.

10. SUMMARY

 Nervous system is composed CNS and PNS  The cellular building blocks of nervous system are neuron and glial cell.  There are four major methods of classification of neurons.  Structural classification includes unipolar neuron, , multipolar neuron, pseudo unipolar neuron.  Functional classification includes Sensory neuron, motor neuron and interneuron.  Based on NT secretion, neurons are divided into cholinergic, glutamatergic, GABAergic, dopaminergic, serotonergic, noradrenergic and adrenergic types.

Animal Physiology ZOOLOGY General Organization and Classification of neuron

 Electrophysiological classification includes Tonic firing type, Fast firing type, phasic or bursting type.  Techniques like Golgi staining, single – unit recording, electron microscopy is used to categorize neurons.

Animal Physiology ZOOLOGY General Organization and Classification of neuron