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Neuroscience Pretest Self Assessment and Review 8th Ed
8th Edition Allan Siegel Digital Instant Download
Author(s): Allan Siegel
ISBN(s): 9781259072352, 1259072355
Edition: 8
File Details: PDF, 14.71 MB
Year: 2013
Language: english
 Notice
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To Carla, whose patience, support, and understanding made this book possible, and to David
Eliahu, Tzipporah Hannah, Matan Dov, Nadav David, Adi Hila, and Eden Chava.
Student Reviewers
Leena Bhatia
Medical Student
Ross University School of Medicine
Class of 2011

Anand Mehta
Medical Student
Ross University School of Medicine
Class of 2011
 Contents
Preface
Introduction

High-Yield Facts
High-Yield Facts in Neuroscience

Gross Anatomy of the Brain

Questions
Answers

Development
Questions
Answers

Anatomical and Functional Properties of Neurons and Muscle

Questions
Answers

The Synapse
Questions
Answers

Neurochemistry/Neurotransmitters
Questions
Answers

The Spinal Cord

Questions
Answers

The Autonomic Nervous System

Questions
Answers

The Brainstem and Cranial Nerves

Questions
Answers

Sensory Systems
Questions
Answers

Anatomy of the Forebrain

Questions
Answers

Motor Systems
Questions
Answers

Higher Functions
Questions
Answers

Bibliography
Index
 Preface
The study of the neurosciences has undergone remarkable growth over the past two decades. To
a large extent, such advancements have been made possible through the development of new
methodologies, especially in the fields of neuropharmacology, molecular biology, and
neuroanatomy. Neuroscience courses presented in medical schools and related schools of health
professions generally are unable to cover all the material that has evolved in recent years. For
this reason, Neuroscience: PreTest Self-Assessment and Review was written for medical students
preparing for licensing examinations as well as for undergraduate students in health professions.
The subject matter of this book is mainly the anatomy and physiology of the nervous system.
Also, an attempt was made to encompass the subjects of molecular and biophysical properties of
membranes, neuropharmacology, and higher functions of the nervous system. Moreover, clinical
correlations for each part of the central nervous system, often using MRI and CT scans, are
presented. Although it is virtually impossible to cover all aspects of neuroscience, the objective
of this book is to include its most significant components as we currently understand them.
The author wishes to express his gratitude to Leo Wolansky, MD, and Alan Zimmer, MD, of
blessed memory, and Michael Schulder, MD, for providing the MRI and CT scans.
 Introduction
Neuroscience: PreTest Self-Assessment and Review, eighth edition, allows medical students to
comprehensively and conveniently assess and review their knowledge of neuroscience. The 500
questions parallel the format and degree of difficulty of the questions found in Step 1 of the
United States Medical Licensing Examination (USMLE). The High-Yield Facts in the beginning
of the book are provided to facilitate a rapid review of the subject. It is anticipated that the reader
will use these High-Yield Facts as a “memory jog” before proceeding through the questions.
Each question in the book is followed by four or more answer options to choose from. In each
case, select the one best response to the question. Each answer is accompanied by a specific
page reference to a text that provides background to the answer, and a short discussion of issues
raised by the question and answer. A bibliography listing all the sources can be found following
the last chapter.
To simulate the time constraints imposed by the licensing exam, an effective way to use this
book is to allow yourself one minute to answer each question in a given chapter. After you finish
going through the questions in the section, spend as much time as you need verifying your
answers and carefully reading the explanations provided. Special attention should be given to the
explanations for the questions you answered incorrectly; however, you should read every
explanation even if you’ve answered correctly. The explanations are designed to reinforce and
supplement the information tested by the questions. For those seeking further information about
the material covered, consult the references listed in the bibliography or other standard medical
texts.
 High-Yield Facts

GROSS ANATOMY OF THE BRAIN

Lateral view of the brain (Fig. 1). The loci of key motor and sensory structures of the cerebral
cortex are indicated in this figure. Anatomical definitions: anterior—toward the front
(rostral end) of the forebrain; posterior—toward the back (caudal end) of the forebrain;
dorsal—toward the superior surface of the forebrain; ventral—toward the inferior surface of
the forebrain. Note that with respect to the brainstem and spinal cord, the terms anterior and
ventral are synonymous; likewise, posterior and dorsal are synonymous. Here, the term
rostral means toward the midbrain, and the term caudal means toward the sacral aspect of
the spinal cord (with respect to embryonic development and folding of the neural tissue). In
Fig. 1, note that rostral and anterior mean the same as caudal and posterior.
 Figure 1
Lateral view of the brain.

Midsagittal view of the brain (Fig. 2). Magnetic resonance image: T2-weighted, high-
resolution, fast-spin echo image.
 Figure 2
Medial view of the central nervous system. (Modified, with permission, from White JS.
USMLE Road Map: Neuroscience. 2nd ed. New York: McGraw-Hill; 2008:10.)

Horizontal (transaxial) view of the brain (Fig. 3). Magnetic resonance image: T2-weighted.
Fast inversion recovery for myelin suppression image.
 Figure 3
Horizontal (transaxial) view of the brain. (Modified, with permission, from Martin JH.
Neuroanatomy:Text and Atlas. 3rd ed. New York McGraw-Hill; 2003:475.)

Frontal view of the brain (Fig. 4). Magnetic resonance image: T2-weighted. Fast inversion
recovery for myelin suppression image.
 Figure 4
Frontal view of the brain. (Modified, with permission, from Martin JH. Neuroanatomy:Text
and Atlas. 3rd ed. New York: McGraw-Hill; 2003:469.)

I. Cerebral cortex and adjoining structures

A. Lateral surface of the brain
1. Frontal lobe
a. Motor functions
(1) Precentral gyrus: primary motor cortex for head region and upper limbs
(2) Premotor cortex: assists in integrating complex motor responses
(3) Broca area: motor speech area
b. Areas regulating cognitive and emotional behavior
(1) Orbital (prefrontal) cortex
2. Parietal lobe
a. Postcentral gyrus: primary somatosensory cortex
b. Inferior and superior parietal lobules: areas mediating complex perceptual
discriminations
c. Inferior parietal lobule and adjoining aspect of the superior temporal gyrus: area
mediating speech perception
d. Spatial reasoning
3. Temporal lobe
a. Primary and secondary auditory receiving areas
4. Occipital cortex
a. Secondary visual receiving areas and region for the integration of visual signals
B. Medial surface of the brain
1. Subcortical structures
a. Corpus callosum: commissure connecting the hemispheres of the cerebral cortex
2. Areas of the cerebral cortex
a. Frontal lobe
(1) Medial prefrontal cortex and anterior cingulate gyrus: regions regulating
intellectual, emotional, and autonomic processes
(2) Medial aspect of the precentral gyrus: region mediating motor functions of the
lower limbs
b. Parietal lobe
(1) Primary and secondary somatosensory receiving areas for the lower limb
c. Occipital lobe
(1) Primary visual cortex
C. Inferior surface of the brain
 1. Frontal lobe: the part of the prefrontal cortex that relates to control of emotional and
autonomic processes
2. Olfactory bulb and cortex: receiving areas for olfactory signals
3. Temporal lobe
a. Superior temporal gyrus: primary auditory receiving area
b. Limbic cortex: pyriform and entorhinal areas; receiving areas for olfactory signals;
also serves as afferent sources of signals to the amygdala and hippocampal
formation
II. Other forebrain structures
A. Ventricular system of the brain: lateral and third ventricles; the most important function
is cerebrospinal fluid formation
B. Septum pellucidum: membranous structure separating the lateral ventricles of the right
and left hemispheres
C. Fornix: fiber pathway that passes in a dorsomedial direction from the hippocampal
formation to the diencephalon
D. Diencephalon
1. Thalamus: large group of nuclei that serve as relays for signals from different regions
of the nervous system to the cerebral cortex
2. Hypothalamus: structure situated below the thalamus; mediates a number of important
visceral functions, such as endocrine and autonomic regulation, control of sexual
behavior, aggression, and feeding and drinking behavior
E. Anterior commissure: connects the olfactory bulbs of each side of the brain; aids in the
integration of olfactory signals
F. Basal ganglia: group of structures, seen best in horizontal and frontal sections, that serve
primarily to regulate motor regions of the cortex
1. Caudate nucleus
2. Putamen
3. Globus pallidus
G. Limbic structures: important group of structures situated mainly within the temporal lobe
that regulate emotional behavior and autonomic and visceral functions associated with
the hypothalamus
1. Amygdala
2. Hippocampal formation
3. Cingulate gyrus
III. Cerebellum and brainstem
A. Cerebellum
1. Attached to the brainstem by three pairs of peduncles (superior, inferior, and middle
cerebellar peduncles) that serve primarily as communicating links between the
cerebellum and the brainstem
2. Anterior, posterior, and flocculonodular lobes: the three lobes of the cerebellum
 3. Vermis: midline structure of the cerebellum, to which the cerebellar hemispheres are
attached
B. Midbrain
1. Superior and inferior colliculus: situated dorsally in the roof of the midbrain (tectum);
mediate visual and auditory functions, respectively
2. Cerebral aqueduct: tubular portion of the ventricular system connecting the third and
fourth ventricles; the aqueduct is surrounded by the periaqueductal gray matter, a
group of compact cells that are continuous with similar cell populations surrounding
the other ventricles
3. Tegmentum: part of the core of the brainstem and a continuation of the pontine and
medullary tegmentum
4. Peduncular region: includes the cerebral peduncle, axons of cortical origin terminating
in the brainstem and spinal cord, and the substantia nigra, a structure functionally
associated with the basal ganglia
C. Pons
1. Tegmentum: core of the brainstem, functionally linked with corresponding regions of
the medulla and midbrain
2. Basilar region: contains descending fiber bundles from the cerebral cortex, in addition
to numerous cells and transversely oriented fibers that communicate with the
cerebellum
3. Fourth ventricle: lies on the dorsal surface of the pons and upper medulla
D. Medulla
1. Open part of the medulla: rostral half of the medulla; contains many different cell
groups, including some cranial nerve nuclei and ascending and descending fiber
bundles
2. Closed part of the medulla: caudal half of the medulla; contains many different cell
and fiber groups, including those of cranial nerves
IV. Cranial nerves
A. Forebrain: cranial nerves I and II
B. Midbrain: cranial nerves III and IV
C. Pons: cranial nerves V to VII
D. Medulla: cranial nerves VIII to X and XII (note that cranial nerve XI is mainly a spinal
nerve but does have a cranial root that functions as a component of cranial nerve X)

BLOOD SUPPLY
I. Brainstem: Vertebral and internal carotid arteries are sources of blood supply to brain.
A. Anterior spinal artery is formed as a branch of vertebral artery and supplies medial
medulla; vertebral artery supplies intermediate region of medulla just lateral to region
supplied by anterior spinal artery; posterior inferior cerebellar artery supplies lateral
aspect of medulla and parts of cerebellum; anterior inferior cerebellar artery supplies
lateral aspect of pons, including region of middle cerebellar peduncle and cerebellum;
superior cerebellar artery supplies region of superior cerebellar peduncle, cerebellum,
and parts of midbrain (Fig. 5).
 Figure 5
The blood vessels of the brain. The circle of Willis is made up of the proximal posterior
cerebral arteries; the posterior communicating arteries; the internal carotid arteries, just
before their bifurcations; the proximal anterior cerebral arteries; and the anterior
communicating artery. The dark areas show common sites of atherosclerosis and occlusion.
(Reproduced, with permission, from Kandel E. Principles of Neural Science. 4th ed. New
York: McGraw-Hill; 2000:1303.)
 B. Basilar artery formed from convergence of vertebral arteries supplies much of the pons.
C. Circle of Willis is formed by proximal branches of posterior cerebral artery, posterior
communicating arteries, a part of internal carotid artery prior to its bifurcation, proximal
part of anterior cerebral artery, and anterior communicating arteries.
D. Anterior cerebral artery supplies rostral part of cerebral cortex and its medial aspect.
E. Middle cerebral artery supplies lateral aspect of cerebral cortex.
F. Posterior cerebral artery supplies the occipital and posterior aspects of parietal cortex and
lateral aspect of midbrain.

DEVELOPMENT
The sulcus limitans divides the alar plate (from which sensory regions of the spinal cord and
brainstem are formed) from a basal plate (from which the motor regions of the spinal cord and
brainstem are formed) (see Table 1).

TABLE 1. DIFFERENTIATION OF THE NEURAL TUBE

 THE NEURON
I. Overview
A. Consists of a cell body, dendrites (which extend from the cell body), and an axon
1. Activation of voltage-gated sodium channels associated with membrane
depolarization.
2. Activation of voltage-gated potassium and chloride channels associated with
membrane hyperpolarization.
3. Temporal events: After information is received from a presynaptic neuron →
depolarization of postsynaptic neuron → action potential is initiated and propagated
down axon from the initial segment.
B. Myelin formation
1. In the peripheral nervous system myelin is produced by numerous Schwann cells.
2. In the central nervous system (CNS) it is produced by an oligodendrocyte wrapping
itself around numbers of neurons.
3. Myelination allows for rapid conduction of action potentials by saltatory conduction
(signals skip along openings in the myelin called nodes of Ranvier), for example, in
the pyramidal tract and medial lemniscus.
4. Damage to myelinated neurons disrupts transmission of neural signals (frequently seen
in autoimmune diseases such as multiple sclerosis; sensory and motor functions are
severely compromised).
5. Poorly myelinated or nonmyelinated neurons (eg, certain pain-afferent fibers to the
spinal cord) are slow conducting.
II. Different components of the neuron
A. Plasma membrane, which forms the external boundary of neuronal cell body and its
processes, consists of a double layer of lipids in which proteins, including ion channels,
are embedded. Inorganic ions enter and leave the neuron through ion channels.
B. Nerve cell body (soma) consists of a mass of cytoplasm, which contains the nucleus and
various organelles.
1. Soma—site of synthesis of most proteins, phospholipids, and other macromolecules.
2. Genetic material of nucleus—consists of deoxyribonucleic acid (DNA) called
chromatin.
3. Nucleus contains a prominent (relatively large) nucleolus—concerned with the
synthesis of ribonucleic acid (RNA).
4. In female, Barr body represents one of two X chromosomes located at inner surface of
nuclear membrane.
5. Cytoplasm contains
a. Nissl substance consists of RNA granules called ribosomes—many ribosomes are
attached to membrane of rough endoplasmic reticulum (RER).
b. Mitochondria—involved in generation of energy.
c. Golgi apparatus—site where proteins are modified, packaged into vesicles, and
 transported to other intracellular locations.
d. Lysosomes—membrane-bound vesicles formed from the Golgi apparatus; contain
hydrolytic enzymes; serve as scavengers in neurons.
e. Cytoskeleton—determines shape of neuron; consists of microtubules,
neurofilaments, and microfilaments.
C. Dendrites—short processes arising from cell body; primary function is to increase
surface area for receiving signals from axonal projections of other neurons.
D. Axon—a single long, cylindrical, and slender process arising usually from the soma. The
axon usually arises from the axon hillock, a small, conical elevation on the soma of a
neuron that does not contain Nissl substance. The first 50 to 100 μm of the axon
emerging from the axon hillock, is known as the initial segment. This segment is the site
where the action potential originates. Axons are either myelinated or unmyelinated. At
their distal ends, the axons branch extensively; their terminal ends, which are mostly
enlarged, are called synaptic terminals.
III. Axonal transport
A. Fast anterograde transport: Precursors of peptide neurotransmitters, lipids, and
glycoproteins, which are necessary to reconstitute the plasma membrane, are carried
from the cell body to the terminals by this mechanism.
B. Slow anterograde axonal transport: Neurofilaments and microtubules are synthesized in
the cell body and are transported by this mechanism to the terminals.
C. Fast retrograde axonal transport: Rapid retrograde transport carries materials from the
nerve terminals to the cell body. Fast retrograde transport is involved in some
pathological conditions. For example, herpes simplex, polio, and rabies viruses, and
tetanus toxin, are taken up by the axon terminals in peripheral nerves and carried to their
cell bodies in the CNS by rapid retrograde transport.
D. Neuroanatomical applications: In anterograde tracing techniques, radioactively tagged
amino acids are taken up by the perikarya of the neurons for protein synthesis and are
then transported anterogradely to their axon terminals. The labeled axons and their
terminals are then visualized by autoradiography. Anterograde transport of carbohydrate-
binding proteins, called lectins, has been used for investigating neuronal connections.
1. Retrograde tracing technique: This procedure involves the microinjection of an
enzyme (eg, horseradish peroxidase [HRP]), fluorescent dyes (eg, Fluoro-Gold),
cholera toxin, or virus at the desired site. The injected substance is taken up by axon
terminals and transported retrogradely into the neuronal cell bodies. The labeled
neurons are then visualized by a chemical reaction. Likewise, fluorescent substances
such as Fluoro-Gold, microinjected at the desired site, are taken up by axon terminals
and transported to the cell bodies, where they are visualized under a fluorescent
microscope.
IV. Types of neurons: multipolar neurons, bipolar neurons, pseudounipolar neurons, and
unipolar neurons. Neurons can also be grouped as principal or projecting neurons (also
known as type I or Golgi type I) and intrinsic neurons (also known as type II or Golgi type
II neurons). Principal neurons (eg, motor neurons in the ventral horn of the spinal cord)
possess very long axons. Intrinsic neurons have very short axons.
 V. Neuroglia (glial cells): These are supporting cells located in the CNS. They are mostly
nonexcitable and are more numerous than neurons. They have been classified into the
following groups: astrocytes (fibrous and protoplasmic), oligodendrocytes, and microglia
and ependymal cells (ependymocytes, choroidal epithelial cells, and tanycytes).
VI. Myelination: Myelinated axons are present in the peripheral nervous system as well as the
CNS. In the peripheral nervous system, Schwann cells provide myelin sheaths around
axons. The myelin sheaths are interrupted along the length of the axons at regular intervals
at the nodes of Ranvier. The action potential becomes regenerated at the uninsulated nodes
of Ranvier. Therefore, the action potential traveling along the length of the axon jumps
from one node of Ranvier to another (saltatory conduction). In the CNS, oligodendrocytes
form the myelin sheaths around neurons. The intervals between adjacent oligodendrocytes
are devoid of myelin sheaths and are called the nodes of Ranvier.
VII. Composition of peripheral nerves: Each peripheral nerve consists of epineurium,
perineurium, endoneurium, and nerve fibers.
VIII. Neuronal injury: Wallerian degeneration refers to the changes that occur distal to the site of
damage on an axon. Initially, the axon swells up and becomes irregular. Later, it is broken
down into fragments and phagocytosed by adjacent macrophages and Schwann cells. When
an axon is damaged, the alterations may be restricted to the proximal segment of the axon
up to the first node of Ranvier. Retrograde degeneration occurs when sectioning of an axon
produces changes in the cell body. If the injury is close to the cell body, the neuron may
degenerate. The cell body swells up due to edema and becomes round in appearance, and
the Nissl substance gets distributed throughout the cytoplasm (chromatolysis). The nucleus
moves from its central position to the periphery due to edema. Transneuronal degeneration
occurs in the CNS when damage to one group of neurons results in the degeneration of
another set of neurons closely associated with the same function.
IX. Recovery of neuronal injury (regeneration): If the damage to the neurons is not severe,
regeneration is possible. However, complete recovery may take as long as 3 to 6 months.
Although sprouting occurs in axons in the CNS, this process ceases within a short time
(about 2 weeks). CNS neuronal function cannot be restored. However, in peripheral nerves,
an axon can regenerate satisfactorily if the endoneurial sheaths are intact. In this situation,
the regenerating axons reach the correct destination, and function may be restored.
X. Neuronal membrane
A. The neuronal membrane, like other cell membranes, consists of a lipid bilayer in which
proteins, including ion channels, are embedded.
B. The lipid bilayer determines the basic structure of the neuronal membrane. The proteins
embedded in it are responsible for most of the membrane functions, serving as specific
receptors, enzymes, and transport proteins.
XI. Permeability of the neuronal membrane
A. The neuronal membrane is permeable to all lipid-soluble substances and some polar
(lipid-insoluble, water-soluble) molecules, provided they are uncharged and small in
volume.
B. The neuronal membrane is impermeable to most polar and charged molecules (even if
they are very small).
 C. Cations and anions contain electrostatically bound water (waters of hydration). The
attractive forces between the ions and the water molecules make it difficult for the ions
to move from a watery environment into the hydrophobic lipid bilayer of the neuronal
membrane.
XII. Carrier proteins (carriers or transporters)
A. When a specific solute binds to a carrier protein, a reversible conformational change
occurs in the protein, which in turn results in the transfer of the solute across the lipid
bilayer of the membrane.
B. When a carrier protein transports a solute from one side of the membrane to the other, it
is called a uniport.
C. A carrier protein that moves one solute in a particular direction and another solute in the
opposite direction is called an antiport.
D. A carrier protein that carries one solute in a particular direction and another solute in the
same direction is called a symport.
XIII. The channel proteins: The channel proteins span the neuronal membrane and contain water-
filled pores. Inorganic ions of suitable size and charge (eg, Na+, K+) can pass through the
pore when it is in open state and thus pass through the membrane.
XIV. Simple diffusion: The substances that pass through the neuronal membrane by simple
diffusion include all lipid-soluble substances and some polar (lipid-insoluble or water-
soluble) molecules (provided they are uncharged and small in volume).
XV. Passive transport (facilitated diffusion): In this type of transport, solutes are transported
across the neuronal membrane without requiring energy.
XVI. Active transport: Some carrier proteins transport certain solutes by active transport (ie, the
solute is moved across the neuronal membrane against its electrochemical gradient). This
type of transport requires coupling of the carrier protein to a source of metabolic energy.
XVII. Intracellular and extracellular ionic concentrations: The concentration of sodium ions is
much greater outside the neuron as compared to that inside the neuron. On the other hand,
the concentration of potassium ions is greater inside the cell than outside (see Table 2).

TABLE 2. NEURONAL INTRACELLULAR AND EXTRACELLULAR

CONCENTRATIONS OF SOME IMPORTANT IONS
XVIII. Na+, K+-ATPase
A. The differences in intracellular and extracellular concentrations of different ions are
maintained by Na+, K+-ATPase (also known as Na+, K+ pump), which is located in the
neuronal membrane.
B. It transfers three Na+ ions out of the neuron for every two K+ions that are taken in. A net
outward ionic current is generated because of this unequal flow of Na+ and K+ ions
across the neuronal membrane. Because of the generation of this current, the Na+, K+
pump is said to be electrogenic.
XIX. Ion channels
A. Ion channels are made up of proteins and are embedded in the lipid bilayer of the
neuronal membrane across which they span.
B. Nongated channels: These are always open and control the flow of ions during the
resting membrane potential. Examples include nongated Na+ and K+ channels that
contribute to the resting membrane potential.
C. Gated channels: All gated channels are allosteric proteins. At rest, these channels are
mostly closed; they open in response to different stimuli, for example, change in
membrane potential, ligand binding, or mechanical forces.
D. Voltage-gated channels: They are opened or closed by a change in the membrane
potential. Examples: voltage-gated Na+channels, voltage-gated Ca2+ channels, and
 voltage-gated K+channels.
E. Ligand-gated channels: Opened by noncovalent binding of chemical substances
(transmitters or second messengers) to their receptors on the neuronal membrane.
F. Mechanically gated channels: These channels open by a mechanical stimulus; for
example, channels involved in producing generator potentials of stretch and touch
receptors.
XX. Nernst equation: Can be used to calculate the equilibrium potential of any ion that is
present both inside and outside the cell, where the cell membrane is permeable to that ion.
XXI. Goldman equation: This equation is used to determine the membrane potential when the
membrane is permeable to more than one ion species.

where P is the permeability of the specific ion, i = inside the cell, and o = outside the cell.
XXII. The ionic basis of the resting membrane potential
A. When the neuron is at rest, the potential difference across its membrane is called the
resting membrane potential.
B. In the resting state, a neuron has a more negative charge inside relative to outside.
C. If the neuronal membrane contained only K+ channels, the resting membrane potential
would be determined by the K+ concentration gradient and be equal to the equilibrium
potential for K+ ions (approximately-90 mV).
D. However, neurons at rest are selectively permeable to Na+ ions also. The Na+ ions tend
to flow into the neuron. Due to influx of Na+ ions, the resting membrane potential
deviates somewhat from that of the K+ equilibrium potential, but it does not reach the
equilibrium potential for Na+. The reason for the inability of the neuron to attain a resting
membrane potential closer to the Na+ equilibrium potential is because the number of
open nongated Na+ channels is much smaller than the number of open nongated K+
channels in the resting state of a neuron.
XXIII. The ionic basis of the action potential
A. When a neuron receives an excitatory input, the neuronal membrane is depolarized,
resulting in an opening of some voltagegated Na+ channels and an influx of Na+.
B. The accumulation of positive charges due to influx of Na+promotes further
depolarization of the neuronal membrane.
C. When the membrane potential reaches a threshold level, a large number of voltage-gated
Na+ channels open, and the permeability of Na+ increases during the rising phase of the
action potential. The depolarization continues so that the membrane potential approaches
the Na+ equilibrium potential.
D. The neuron is then repolarized by slow inactivation of voltagegated Na+ channels (which
stops influx of Na+ through these channels) and delayed opening of voltage-gated K+
 channels (which allows increased efflux of K+ through voltage-gated K+channels-
delayed rectifiers). It should be noted that influx of Na+ and efflux of K+ through the
nongated channels continues throughout these events.
XXIV. Propagation of action potentials
A. When a region of the axonal membrane is depolarized sufficiently to reach a threshold,
voltage-gated Na+ channels open, Na+ flows into the axoplasm, and an action potential is
generated in that region.
B. The local depolarization spreads electronically (passively) to an adjacent region, where
an action potential is generated by the opening of voltage-gated Na+ channels and the
influx of Na+ into the axoplasm. The passive spread of voltage along the length of an
axon results in an active regeneration process.
C. In vertebrates, nodes of Ranvier (bare segments of the axonal membrane) are present in
between the segments of the myelin sheath.
D. The passive spread of current can generate an intense current at the nodes of Ranvier due
to the high density of voltage-gated Na+ channels in this area.
E. The action potential propagates along an axon by saltatory conduction (ie, the jumping of
an action potential from one node to another) without decrement.

THE SYNAPSE AND NEUROTRANSMITTERS

The binding of the neurotransmitter to the receptor molecule is determined by the postsynaptic
receptor, which serves a gating function for particular ions. The receptor is responsible for
opening or closing ligand-gated channels regulated by noncovalent binding of compounds such
as neurotransmitters. The neurotransmitter is contained in presynaptic vesicles and released onto
the postsynaptic terminal, causing activation of the receptor, which in turn produces postsynaptic
potentials.
The sequence of events in synaptic transmission is as follows: transmitter synthesis → release
of transmitter into synaptic cleft → binding of transmitter to postsynaptic receptor → removal of
transmitter.
Major excitatory transmitters include substance P, acetylcholine, and excitatory amino acids.
Major inhibitory transmitters include GABA, enkephalin, and glycine. Disruption of
neurotransmitter function can lead to different diseases of the nervous system. For example,
when antibodies are formed against the acetylcholine receptor at the neuromuscular junction,
transmission is disrupted, and the autoimmune disease called myasthenia gravis occurs. This
disorder manifests with symptoms such as weakness and fatigue of the muscles.
I. Synaptic transmission
A. Characteristics of electrical transmission
1. Current generated by an impulse in one neuron spreads to another neuron through a
pathway of low resistance. Such a pathway has been identified at gap junctions.
2. Current generated by voltage-gated channels at the presynaptic neuron flows directly
into the postsynaptic neuron. Therefore, transmission at such a synapse is very rapid
(<0.1 ms).
 3. Electrical transmission is not very common in the CNS.
B. Characteristics of chemical transmission
1. At chemical synapses, the pre-and postsynaptic cells are separated by synaptic clefts,
which are fluid-filled gaps (about 20-40 nm). The presynaptic terminal contains
synaptic vesicles, which are filled with several thousand molecules of a specific
chemical substance, the neurotransmitter.
2. When an action potential depolarizes the presynaptic nerve terminal, the permeability
to Ca2+ increases, and Ca2+ enters the terminal. These events cause the vesicles to fuse
with the cytoplasmic membrane and then release the neurotransmitter into the synaptic
cleft (exocytosis).
II. Characteristics of receptors: They consist of membrane-spanning proteins. The recognition
sites for the binding of the chemical transmitter are located on the extracellular components
of the receptor. The binding of the neurotransmitter to its receptor results in opening or
closing of ion channels on the postsynaptic membrane or activation of a second messenger
cascade.
III. Characteristics of ion channels
A. Indirectly gated ion channel: In this type of channel, the ion channel and the recognition
site for the transmitter (receptor) are separate. This type of receptor is called a
metabotropic receptor. When a transmitter binds to the receptor, a guanosine-5′-
triphosphate (GTP)-binding protein (G-protein) is activated, which in turn activates a
second messenger system. The second messenger can either act directly on the ion
channel to open it or activate an enzyme that will open the channel by phosphorylating
the channel protein. Activation of this type of channel elicits slow synaptic actions that
are long lasting (seconds or even minutes).
B. Directly gated ion channel: In this type of ion channel, several protein subunits (4 or 5)
are arranged in such a way that the recognition site for the neurotransmitter is part of the
ion channel. This type of receptor is called an ionotropic receptor. A transmitter binds to
its receptor and brings about a conformational change, which results in the opening of
the ion channel. Receptors of this type usually bring about fast synaptic responses lasting
for only a few milliseconds.
C. Directly gated synaptic transmission at a peripheral synapse (nerve-muscle synapse): At
the neuromuscular junction, the axons of motor neurons whose cell bodies are located in
the CNS innervate skeletal muscle fibers. As the motor axon reaches a specialized region
on the muscle membrane called the end plate, it loses its myelin sheath and gives off
several fine branches. Many varicosities (swellings), called synaptic boutons, are present
at the terminals of these branches. The presynaptic boutons contain the synaptic vesicles
containing acetylcholine. When the motor axon is stimulated, an action potential reaches
the axon terminal and depolarizes the membrane of the presynaptic bouton, which results
in the opening of the voltage-gated Ca2+ channels. Influx of Ca2+ into the terminal
promotes fusion of the vesicle with the terminal membrane and subsequent release of
acetylcholine by exocytosis. Acetylcholine acts on the nicotinic cholinergic receptors
located at the crest of the junctional folds to produce an end plate potential (EPP). The
amplitude of the EPP is large enough (about 70 mV) to activate the voltage-gated Na+
channels in the junctional folds and generate an action potential, which then propagates
 along the muscle fiber and brings about muscle contraction.
D. Directly gated transmission at a central synapse: A synaptic potential that excites a
postsynaptic cell in the CNS is called an excitatory postsynaptic potential (EPSP). This
EPSP is generated by the opening of directly gated ion channels, which permit influx of
Na+ and efflux of K+. If the depolarization produced by the EPSP is large enough, the
membrane potential of the axon hillock of the spinal motor neuron is raised to a firing
threshold, and an action potential results. A synaptic potential that inhibits a postsynaptic
cell in the CNS system is called an inhibitory postsynaptic potential (IPSP). An IPSP
usually hyperpolarizes the neuronal membrane.
IV. Diseases affecting chemical transmission at the nerve-muscle synapse
A. Myasthenia gravis: This is an autoimmune disease in which the number of functional
nicotinic acetylcholine receptors is reduced by an antibody. This results in muscular
weakness. The symptoms include weakness of eyelids, eye muscles, oropharyngeal
muscles, and limb muscles. Antibodies, probably produced by T and B lymphocytes,
against the acetylcholine receptors are present in the serum of such patients.
Acetylcholinesterase-inhibiting drugs (eg, neostigmine) can reverse the muscle
weakness.
B. Lambert-Eaton syndrome: In this disorder, antibodies are developed to voltage-gated
Ca2+ channels on presynaptic terminals. The loss of voltage-gated Ca2+ channels impairs
the release of acetylcholine from the nerve terminals. Standard treatment consists of
administration of guanidine and calcium gluconate, which elicit or facilitate
acetylcholine release from the presynaptic nerve terminals.
V. Major classes of neurotransmitters (see Table 3)

TABLE 3. MAJOR CLASSES OF NEUROTRANSMITTERS

 A. Small-molecule neurotransmitters: acetylcholine, excitatory amino acids (glutamate,
aspartate), inhibitory amino acids (GABA, glycine), catecholamines (dopamine,
norepinephrine, epinephrine), indoleamines (serotonin), imidazoleamines (histamine),
and purines (adenosine)
B. Large-molecule neurotransmitters: opioid peptides (eg, dynorphin, endomorphins,
enkephalins, nociceptin), substance P
VI. Steps in neurotransmitter release
A. Depolarization of the presynaptic terminal
B. Ca2+ entry into the terminal
 C. Fusion of vesicles containing the neurotransmitters with the presynaptic terminal
membrane
D. Release of the neurotransmitter into the synaptic cleft
VII. Individual neurotransmitters
A. Acetylcholine
1. Synthesis
a. Choline present in the plasma enters the nerve terminal by active transport.
b. Acetylcholine is synthesized in the cytoplasm from choline and acetylcoenzyme-A
by choline acetyltransferase.
c. Acetylcholine is transported into vesicles and stored there.
2. Release and removal
a. Acetylcholine is released into the synaptic cleft.
b. It is hydrolyzed by acetylcholinesterase.
3. Distribution
a. The basal forebrain constellation, including the basal nucleus of Meynert
b. Cholinergic neurons in the dorsolateral tegmentum of the pons
4. Physiological and clinical considerations
a. Cholinergic neurons have been implicated in the regulation of forebrain activity and
sleep-wakefulness cycles.
b. In Alzheimer disease, there is a dramatic loss of cholinergic neurons in the basal
nucleus of Meynert.
B. Glutamate
1. Synthesis
a. Glucose enters the neuron and undergoes glycolysis in the cytoplasm to generate
pyruvic acid, which enters into the mitochondria. In the mitochondria, pyruvic acid
generates an acetyl group that combines with coenzyme-A present in the
mitochondria to form acetylcoenzyme-A.
b. The acetyl group is regenerated from acetylcoenzyme-A; it enters the Krebs cycle
in the mitochondria.
c. Alpha-ketoglutaric acid, generated in the Krebs cycle, is transaminated to form
glutamate.
d. Glutamate released into the synaptic cleft is recaptured by neuronal-type and glial-
type Na+-coupled glutamate transporters.
e. In the nerve terminal, glutamate is repackaged into vesicles.
f. In the glial cell, glutamate is converted to glutamine by the enzyme glutamine
synthetase. Glutamine in the glial cells is then transported into the neighboring
nerve terminals and converted to glutamate, which is then packaged into vesicles.
2. Release and removal: Glutamate is taken up by a high-affinity sodium-dependent
reuptake mechanism into the nerve terminals and glial cells.
 3. Physiological and clinical considerations
a. Glutamate has been implicated as a transmitter in several circuits in the brain.
b. Alteration in glutamate levels has been implicated in Huntington chorea and
amyotrophic lateral sclerosis (ALS).
c. Prolonged stimulation of neurons by excitatory amino acids results in neuronal
death or injury. This effect is known as excitotoxicity.
C. GABA
1. Synthesis: It is formed by alpha-decarboxylation of L-glutamate. This reaction is
catalyzed by L-glutamic acid-1-decarboxylase (GAD), which is present almost
exclusively in GABAergic neurons.
2. Release and removal
a. In the brain, after its release, GABA is taken up into presynaptic terminals as well
as glia.
b. Most of GABA is metabolized by the enzyme GABA-oxoglutarate transaminase
(GABA-T) to yield glutamate and succinic semialdehyde.
3. Physiological and clinical considerations
a. GABA is found in high concentrations in the brain and spinal cord; it is an
inhibitory transmitter in many brain circuits.
b. Alteration of GABAergic circuits has been implicated in neurological disorders like
epilepsy, Huntington chorea, Parkinson disease, senile dementia, Alzheimer
disease, and schizophrenia.
c. Barbiturates act as agonists or modulators on postsynaptic GABA receptors; they
are used to treat epilepsy and anxiety.
d. Valproic acid (dipropylacetic acid) is an anticonvulsant. It inhibits GABA-
transaminase, an enzyme that metabolizes GABA, and thus increases GABA levels
in the brain. Since epileptic seizures can be facilitated by lack of neuronal
inhibition, increase in the inhibitory transmitter GABA is helpful in terminating
them.
D. Glycine
1. Synthesis
a. In the nerve tissue, serine is formed from glucose via the intermediates 3-
phosphoglycerate and 3-phosphoserine.
b. Glycine is formed from serine by the enzyme serine trans-hydroxymethylase.
2. Release and removal: After its release, glycine is taken up by neurons via an active
sodium-dependent mechanism involving specific membrane transporters.
3. Distribution: Glycine is found in all body fluids and tissue proteins in substantial
amounts. It is not an essential amino acid, but it is an intermediate in the metabolism
of proteins, peptides, and bile salts. It is also a neurotransmitter in the CNS.
4. Physiological and clinical considerations
a. Glycine has been implicated as a neurotransmitter in the spinal cord, the lower
brainstem, and perhaps the retina.
 b. Mutations of genes coding for some of the membrane transporters needed for
removal of glycine result in hyperglycinemia, a devastating neonatal disease
characterized by lethargy, seizures, and mental retardation.
E. Catecholamines
1. Dopamine
a. Synthesis
(1) Tyrosine enters the neuron by active transport.
(2) Tyrosine is converted into dihydroxyphenylalanine (DOPA) by tyrosine
hydroxylase enzyme. DOPA is converted to dopamine by the enzyme aromatic
L-amino acid decarboxylase (DOPA-decarboxylase). These steps occur in the
cytoplasm.
(3) Dopamine is then actively transported into the storage vesicles.
b. Release and removal
(1) Dopamine released into the synaptic cleft is removed by reuptake into the
presynaptic terminal.
(2) It diffuses into the circulation and is destroyed in the liver by two enzymes:
catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO).
c. Distribution
(1) Substantia nigra: The axons of these neurons ascend rostrally in the nigrostriatal
projection and provide dopaminergic innervation of neurons located in the
corpus striatum (caudate nucleus and putamen).
(2) Ventral tegmental area: This paired area lies adjacent to the substantia nigra, and
the dopaminergic neurons located in this area project to different brain areas via
the following pathways: (a) the mesolimbic pathway and (b) the mesocortical
pathway. In the mesolimbic pathway, the axons of the dopaminergic neurons
supply limbic structures (ie, amygdala, septal area, hippocampal formation) and
the nucleus accumbens (ventral striatum). In the mesocortical pathway, the
axons of the dopaminergic neurons provide innervation to the frontal and
cingulate cortex.
(3) Arcuate nucleus of hypothalamus: Dopaminergic neurons in this area project to
the median eminence. They release dopamine directly into the hypophyseal
portal circulation, which then carries the dopamine to the anterior lobe of the
pituitary to inhibit the release of prolactin.
d. Physiological and clinical considerations
(1) Parkinson disease: This disease is characterized by tremor at rest, slowness of
movement (bradykinesia), rigidity of extremities and neck, and an expressionless
face. Dopaminergic neurons located in the substantia nigra are degenerated in
this disease, and the release of dopamine in the caudate putamen is decreased.
Treatment: oral administration of a combination of L-DOPA and carbidopa
(Sinemet). (Carbidopa inhibits DOPA-decarboxylase and reduces
decarboxylation of L-DOPA in peripheral tissues, enabling greater
concentrations of L-DOPA [precursor to dopamine] to reach the brain.)
 (2) Psychotic disorders: Many adult psychotic disorders, including schizophrenia,
are believed to involve increased activity at dopaminergic synapses. Many drugs
that are effective in the treatment of these disorders are believed to mediate their
action through the D2-dopamine receptors.
2. Norepinephrine
a. Synthesis
(1) In the noradrenergic neurons, dopamine stored in the vesicles is converted into
norepinephrine by the enzyme dopamine-β-hydroxylase (DBH).
b. Release and removal: Norepinephrine released into the synaptic cleft is removed by
the following mechanisms:
(1) Reuptake-1: Norepinephrine is transported back into the terminal of the
noradrenergic neuron.
(2) Reuptake-2: Norepinephrine is actively transported into the effector cells (about
10%), where it is inactivated primarily by COMT.
(3) Norepinephrine diffuses into the circulation from the synaptic cleft and is
destroyed in the liver by two enzymes, COMT and MAO.
c. Distribution: Noradrenergic neurons are located in the locus coeruleus. These
neurons project to the thalamus, hypothalamus, limbic forebrain structures
(cingulate and parahippocampal gyri, hippocampal formation, amygdaloid
complex), and the cerebral cortex, where norepinephrine modulates a wide variety
of functions associated with these regions.
d. Physiological and clinical considerations
(1) Norepinephrine is released as a transmitter from postganglionic sympathetic
nerve terminals.
(2) It is believed to play a role in psychiatric disorders such as depression.
3. Epinephrine
a. Synthesis
(1) About 10% of norepinephrine stored in the vesicles leaks out into the cytoplasm.
(2) In the adrenergic neuron, it is converted into epinephrine by the enzyme
phenylethanolamine-N-methyl-transferase (PNMT).
(3) The epinephrine thus formed is actively transported into storage vesicles in the
nerve terminal (or chromaffin granules in the adrenal medulla) and stored for
subsequent release.
b. Release and removal: The mechanisms for removal of epinephrine are the same as
those for norepinephrine.
c. Distribution
(1) C1 neurons located in the rostral ventrolateral medulla
(2) C2 neurons located in the nucleus tractus solitarius
d. Physiological and clinical considerations: The function of adrenergic neurons in the
CNS has not been clearly established.
F. Indoleamines
 1. Serotonin (5-hydroxytryptamine [5-HT])
a. Synthesis
(1) Plasma tryptophan enters the brain by an active uptake process and is
hydroxylated at the 5-position by tryptophan hydroxylase to form 5-
hydroxytryptophan.
(2) 5-Hydroxytryptophan is immediately decarboxylated to form serotonin.
Serotonin is then actively taken up and stored in vesicles, where it is ready for
release.
b. Release and removal
(1) Serotonin is removed from the synaptic cleft by reuptake mechanisms.
(2) It is also metabolized by MAO.
c. Distribution
(1) Serotonin-containing neurons are located in the midline or raphe regions of the
medulla, pons, and upper brainstem.
(2) The rostral serotonin-containing cell groups of the dorsal, median, and central
superior raphe project to the diencephalon and telencephalon.
(3) 5-HT neurons in the caudal raphe nuclei project to the spinal cord.
d. Physiological and clinical considerations
(1) Serotonin-containing cells in the raphe regions of the brainstem are believed to
play a role in descending pain-control systems.
(2) Serotonin-containing neurons may play a role in mediating affective processes
such as aggressive behavior and arousal.
(3) Serotonin synthesized in the pineal gland serves as a precursor for the synthesis
of melatonin, which in turn serves as a neurohormone that regulates sleep
patterns.
(4) Serotonin is also believed to play an important role in depression. Fluoxetine
(Prozac) selectively blocks reuptake of serotonin and enhances 5-HT levels in
the brain. It may produce beneficial effects in mental depression via
enhancement of transmission through 5-HT1A receptors.
(5) Sumatriptan (Imitrex), a 5-HT1D receptor agonist, is a vasoconstrictor and has
proved useful in treating migraine headaches.
(6) Some drugs of abuse mediate their effects through serotonin-containing neurons.
For example, “Ecstasy” (3, 4, methylene-dioxy-methamphetamine, or MDMA)
is believed to release 5-HT.
G. Imidazoleamines
1. Histamine
a. Synthesis
(1) Histidine enters the brain by active transport.
(2) It is then decarboxylated by histidine decarboxylase to form histamine.
b. Release and removal
 (1) Histamine utilizes catecholamine uptake processes in certain tissues.
(2) It is metabolized to 1-methylhistamine and imidazole acetic acid.
c. Distribution
(1) The highest density of histamine-containing neurons has been found in the
median eminence and premammillary regions of the hypothalamus.
(2) These neurons project to many areas of the brain and spinal cord.
d. Physiological and clinical considerations: Histamine has been implicated as a
transmitter in the regulation of food and water intake, thermoregulation, autonomic
function, and hormone release.
H. Purines
1. Recently, ATP (adenosine triphosphate) has been implicated as a neurotransmitter.
2. ATP has been implicated in pain mechanisms in the spinal cord.
3. Purinergic transmission has been demonstrated in autonomic neurons innervating the
bladder, vas deferens, and muscle fibers of the heart.
I. Opioid peptides
1. Synthesis
a. β-Endorphin: The pre-propeptide (pre-proopiomelanocortin) is present in the RER
of neurons in the anterior pituitary, the intermediate lobe of the pituitary, and the
arcuate nucleus of the hypothalamus. It is converted into the propeptide
proopiomelanocortin, which is transported to the axon terminal by fast axonal
transport. β-Endorphin is derived from proopiomelanocortin.
b. Enkephalins: The pre-propeptide (pre-proenkephalin A) is present in the RER of
neurons predominantly in the hindbrain. It is converted to the propeptide,
proenkephalin A, which is transported to the axon terminal by fast axonal transport.
Further, proteolytic processing in the terminal results in the generation of active
peptides, methionine, and leucine enkephalin. Both of them are pentapeptides.
c. Dynorphins (1-13): These peptides can be isolated from the pituitary and consist of
C-terminally extended forms of [Leu5]-enkephalin.
2. Release and removal: In the CNS, the action of most of the peptides is terminated by
their degradation due to the presence of peptidases.
3. Physiological and clinical considerations: Opioid peptides have been implicated in
regulating blood pressure, temperature, feeding, and sexual behavior.
J. Tachykinins
1. Substance P is an undecapeptide (11 amino acids) and is present in the substantia
nigra, caudate putamen, amygdala, hypothalamus, and cerebral cortex. Substance P
neurons in the striatum project to the dopamine-containing neurons in the substantia
nigra.
2. Physiological and clinical considerations
a. Substance P has been implicated as one of the transmitters responsible for
mediating pain sensation.
b. Substance P levels are reduced in the substantia nigra in patients suffering from
 Huntington chorea, which is characterized by movement and psychological
disorders.
K. Gaseous neurotransmitters
1. Nitric oxide (NO)
a. Synthesis
(1) Glutamate, released from a presynaptic neuron, acts on N-methyl-D-aspartic acid
(NMDA) receptors located on the postsynaptic neuron; calcium ions enter the
postsynaptic neuron and bind with calmodulin (calcium-binding protein), which
results in the activation of nitric oxide synthase (NOS) (see Table 4).

TABLE 4. ISOFORMS OF NITRIC OXIDE SYNTHASE (NOS)

(2) NOS then generates NO and citrulline from L-arginine.

(3) NO stimulates soluble guanylate cyclase, which results in the formation of
cGMP from GTP. Increased levels of cGMP in the postsynaptic neuron elicit a
physiological response.
b. Physiological and clinical considerations
(1) In the CNS, the role of NO as a transmitter is still under investigation.
(2) The relaxation of blood vessels caused by cholinergic agonists may be mediated
by NO.
VIII. Receptors
A. Ligand-gated or ionotropic receptors, which consist of multimeric proteins directly
linked to ion channels (see Table 5).

TABLE 5. IONOTROPIC AND METABOTROPIC RECEPTORS FOR DIFFERENT

NEUROTRANSMITTERS

1. Nicotinic acetylcholine receptors (nAChR) are located at the neuromuscular junction

(NMJ) as well as at central neurons. Acetylcholine binds to the α-subunits and opens
the channel to allow influx of Na+ and efflux of K+, leading to overall depolarization
of muscle.
2. NMDA receptor: The activity of this receptor can be altered through the following
binding sites:
a. Transmitter-binding site: L-glutamate and related agonists bind at the transmitter-
binding site and promote opening of a high-conductance channel through which
sodium and calcium ions enter the target cells.
 b. Strychnine-insensitive glycine modulatory site: This site is very important because
unless it is occupied, L-glutamate is ineffective at this receptor.
c. Phencyclidine-binding site: This is located within the channel. Noncompetitive
blockers of the NMDA receptorionophore complex (eg, ketamine) also bind at the
same site.
d. Voltage-dependent magnesium-binding site: The channel associated with an
NMDA receptor is blocked by Mg2+ at normal resting potentials or when the cell is
hyperpolarized. When the cell is depolarized, Mg2+ is dislodged and Na+ and Ca2+
enter, while K+ leaves the cell through the same channel.
3. Kainate receptor: Binding of kainic acid to this ionotropic glutamate receptor results in
the opening of an ion channel, permitting influx of Na+ (but not Ca2+) and efflux of K+
through the same channel; the neuron is thus depolarized.
4. AMPA/quisqualate receptor: AMPA and quisqualic acid are agonists for this
ionotropic glutamate receptor. Binding of these agonists to their receptors results in the
opening of an ion channel, permitting influx of Na+ (but not Ca2+) and efflux of K+;
the neuron is thus depolarized.
5. GABAA receptors: The following major binding sites are present on these receptors:
a. For agonists (eg, GABA, muscimol).
b. For antagonists (eg, bicuculline).
c. For benzodiazepines (eg, diazepam or Valium).
d. For barbiturates.
e. GABA agonists open the chloride channels and thus hyperpolarize the neurons.
Drugs that bind to the benzodiazepine site enhance the electrophysiological effects
of GABA (eg, diazepam or Valium, an anxiolytic drug). Barbiturates bind to
another site and prolong the opening of the chloride channel, also enhancing the
inhibitory effects of GABA.
6. Glycine receptor: Activation of glycine receptors results in an influx of chloride ions
into the neuron, which is then hyperpolarized. Strychnine blocks the glycine receptors.
7. Serotonin receptors: At least 7 families of serotonin receptors have been identified.
Only 5-HT3 receptors are ionotropic receptors. All other subtypes are metabotropic
receptors.
B. Metabotropic receptors
1. They consist of a single protein (monomeric) molecule that usually has 7 membrane-
spanning domains.
2. G-proteins bind to an intracellular loop of these domains.
3. Binding of the neurotransmitter to the receptor results in the replacement of GDP by
guanosine-5’ triphosphate (GTP) on the α-subunit of the G-protein. The activated
GTP-α-subunit complex can have the following results: (1) it can open the ion
channels directly, or (2) it can bind to effector molecules (eg, adenylyl cyclase),
generate second messengers (eg, cAMP) and, later, effectors (eg, protein kinase A),
which then finally phosphorylate the ion channel to open it. Ions flow across the
membrane and a postsynaptic response is elicited.
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Masters Goodwin, Bartlett, Carrington and Scott.
As Maud’s mother inquired when in the seclusion of their own
apartments, “Did you really like it so very much?”
Maud answered laughing, “More than I can express.”
The following morning it was a question, “What would be the
proper costume for breakfast?”
From one of their windows they had a partial view of the lake, but
from the other nothing but tall trees met their eyes. Pines were in
abundance, but there was an occasional hemlock, spruce, birch and
maple.
“It is summer. Would you think that this white organdy would
do?” asked Maud, and the frock, apparently only a cloud of
Valenciennes lace, was held towards her mother.
“Do? I am sure I don’t know what is considered correct for such a
wilderness, but you might not be warm enough. I fancy it is cold
outdoors.”
“I’ll tell you what I’ll wear,” said the young lady presently, for she
had a wonderful conception of color values, and knew what would
look best with her dark eyes, and also what would produce the most
fetching effect, should she be able to induce her mother to walk
among the trees after breakfast. “I am going to put on my crimson
piqué, bodice and all,” for she had several waists that could be worn
with the same skirt, and as her quick eyes looked over the guests at
breakfast, she was not sorry the decision had been against the
organdy.
“All night my dreams were of the entertainment,” said Maud, as,
sitting opposite her mother, she tried to pour the cream into her
coffee. “It is almost too thick to stir. Did you ever see such cream?”
she said.
“I never saw thicker. And this trout is delicious. It would be
singular indeed if I were won to this place. But, Maud, tell me about
your dream, dear.”
“Oh, I dreamed of Titania and Oberon, Queen and King of the
fairies, you know. I could see the airy things moving over the green.
It was Midsummer-Night’s Dream truly, for I dreamed of the pretty
piece, and isn’t this Midsummer?”
“Why, Maud! I fancy you slept well. Perhaps you’ll be surprised to
learn that I too dreamed of our evening’s pleasure.”
“Surprised! Yes, indeed!” and Maud’s eyes sought her mother’s.
“What part did you dream about?”
“I think it is the opening of the second act, when the fairy replies
to Puck,
Over hill, over dale,
Thorough bush, thorough brier,
Over park, over pale,
Thorough flood, thorough fire,
I do wander everywhere.
You remember how it goes, don’t you?”
 “Perfectly; and didn’t that fairy look lovely? I am sure I shall be
glad to know her. But Puck I am not as sure about.”
“Could you pass me the rolls, Maud?”
“Certainly, take that one,” and Maud turned the plate so that her
mother could have a temptingly brown roll.
“And now,” continued her mother, as she contentedly broke the
roll open, “tell me more about your dream.”
“You know towards the close, Oberon and Titania entered with
their train.”
“Do you mean where Oberon sings,
Though the house gives glimmering light,
By the dead and drowsy fire,
Every elf and fairy sprite,
And so on?”
“Yes, those are the very words. And didn’t Titania have a sweet
voice? I hope she’ll sing often. I am sure everybody must enjoy
listening to her. I thought this beautiful:
First rehearse your song by rote,
To each word a warbling note.
Hand in hand with fairy grace,
Will we sing and bless this place.”
As Maud said, “bless this place,” the lady who had welcomed
Maud and her mother the evening before was walking past their
table, and having overheard the words, she stopped.
“Just what I like to hear.” Then mischievously looking at Maud’s
mother. “But I did not expect the woods to have won so much
enthusiasm already, did you?”
 “No, I did not,” and the mother’s lip unbent into a sunny smile.
“But there is no telling what we may both say yet.”
“This fish breakfast has been delicious, and besides everybody
looks rested and cheery.”
“That is just the point; no one can help being rested, because
midnight-oil is unknown here and how can people help being cheery,
when this bracing air is a tonic; And besides we have so many
delightful sports. There are to be charades, and rollicking games,
such as Twirl the Platter, and Going to Jerusalem, this evening, and
to-day there are several things on hand. One is a driving and riding
party. All the young people, with two chaperones, are going over to
the next hotel to dinner. By the way, do you ride?”
And Maud, whose face was flushed with the memory of her many
pleasant hours on horseback, answered, “I could ride almost
forever.”
“Then you are the very young lady we want,” and turning to
Maud’s mother, “I’m to be one of the chaperones. I’ll promise to
bring her home safe. There is a fine saddle-horse waiting to be
ridden, and——a fine young man, who is in despair because every
one but himself has a riding companion. He is a New York lawyer.
May I introduce him?” were her words, as the trio left the breakfast-
room together.
The answer must have been “Yes,” because, an hour later, one
dowager said to another, “Did you hear that new girl, that airish
creature with the golden hair, and sleepy-looking dark eyes, who
came just before supper last evening, has gone off horseback riding
with the one we called ‘the dissatisfied young man?’ He seems to be
perfectly satisfied now. I suppose neither of our daughters was good
enough for him.”
 THE FLOWER-TEST.
The postman rapped at my door, and presently the trim little maid
brought me a big square letter on a tray. I knew that hand. Nobody
but Penelope writes in that scraggly style, plain, too, as a pikestaff,
and easy to read. “Darling Gertrude,” she began, “I am about to
plead for a visit. It seems a little bit of forever since I saw you and I
want you here in my country house where we’ll have time to enjoy
one another, talk of the past and present tenses to our hearts’
content, and perhaps plan a happy future.
“Let me tell you whom you’ll meet: Mr. and Mrs. Burkhardt,—you
remember that sweet little girl bride who succeeded so well in
blinding us—at first; dear old General Bolton, and his youngest
brother, who paints almost as well as he talks; pretty Elsie Sterling
and my cousin Bob. You see I put them together, but so would you if
you could look out of my window and see them now. Bob has just
mounted Elsie on White Baron, and now as I write the words he’s up
on Caper and off they go. Well—we’ll borrow White Baron and Caper
later on, you and I, and perhaps as we canter along side by side we
may feel ourselves back again,—back—how many years? Never
mind, we’ll not count. The years have been happy to us both, I
hope.
“But you’ll come—you must not say no, remember. Cordially your
friend,
“Penelope T. Gerard.”
Indeed I would not say “No.” I would arrange and rearrange my
summer plans to meet Penelope once more.
It was scarce three years since I last saw her. She was then a
bride of but two months and I spent three days with her just as I
was leaving for Germany. During the interval our letters were more
or less frequent, and so in a way we each kept track of the other
and felt as close friends as we had been since our childhood.
So it was with infinite pleasure I wrote an acceptance.
“The Maples” is an unpretending rambling sort of a house, with
piazzas, and “corners,” and nooks where one would least expect
them. There is no rhyme or reason to the architecture, and an
architect would shake his head in sad consternation. However, if he
were told that three generations of Gerards had idled their summers
happily away within and without its walls, and that each owner had
added his share to the original pile, perhaps the exact architect
would turn his critical smile to one of content and count himself
fortunate to be allowed to enter this abode of happiness.
It was a sunny day when I first drove up the long maple-lined
driveway and there on the lawn, close to the entrance, was Penelope
making tea and laughing one of her old merry laughs as the General
stood before her. I suppose he was telling her one of his funny
stories. I don’t know, for of course I only saw them a moment
before the carriage stopped, and once more Penelope and I were
together.
The General had known us both as girls, and soon we were
talking over old faces and scenes, and it seemed as though we had
never been parted. The rest of the party had gone for a long drive
and would not be back until seven o’clock. So we three talked on
and on.
“Oh, it does seem so good to be here, Pen,” I said, and added,
“As I came up the driveway, the first thing I heard was your laugh.
You know how mamma used to like to hear you laugh.”
“Yes, I remember how irrepressible I was. But, Trudy, you too
would have laughed if you’d heard the General hang me.”
“Hang you?”
 “Why, yes. Don’t you know the game?” Then seeing my
bewilderment, she went on. “You must learn it. It’s fine for two
people. Especially when one gets short of subjects to talk about.”
Here General Bolton threw back his head and laughed heartily.
“Short of subjects to talk about! I guess Trudy would as soon believe
the Atlantic had gone dry as to think your nimble tongue was ever
still. No, indeed! On the contrary, Trudy, she was bound she would
make me let out a secret, and I, old fool, would probably have fallen
into her trap, only she warned me by—but never mind how she
warned me, or even that will fail me next time. So I hung her. Yes, I
caught her well.” Then with a chuckle. “Tell her how, Pen, you know
best how, for you know you were hung, and well hung.” And again
he laughed.
“That’s true. But try me again sometime, or rather, I’ll try you and
we’ll see who does the hanging. No, not now, you need not look so
eager.”
“Bah, you’re afraid.”
“No, indeed I am not. Just now however I mean to take Gertrude
and show her where her room is. She has been ever so patient.”
“But, my dear, please explain first about the hanging. It sounds so
sanguinary.”
“Well, it is. Now listen and I’ll explain, and then we’ll go indoors.
‘To hang a person with a word,’ is the name of the game. You take
any word you like in your mind and simply mention the number of
letters it has. The other party has to guess, by letters, without
making twelve misses. If she fails to guess without twelve wrong
guesses, she is hung as I was. That doesn’t seem very clear to you,
I suppose.”
“Well, not exactly.”
“I’ll take a word and show you. Now, General, I did not mean to
give you your battle now. But you may have it if you’re ready.”
 “Steady, fire.”
“All right.” Then she whispered to me the word “Eyelet.”
“Well, I’ll hang you, General Bolton, with a word of six letters.”
“Bah, that’s easy. First, I’ll guess L.”
“Right. It has fourth place.” Then she explained to me, “You have
to tell the position of the letter.”
“M.”
“Wrong. That’s one. You help me keep count, Trudy. Remember,
twelve wrong guesses and I’ve hung him.”
“A.”
“Wrong. That makes two.”
“E.”
“Right. First place.”
“I.”
“Wrong. Three.”
“O.”
“Wrong. You see he’s trying the vowels. How many does that
make?”
“Four.”
“Oh, you girls need not look so jubilant; four doesn’t make much.
I’ll guess U, next.”
“Five,” we both shouted.
“Well, T.”
“Right, and sixth place.”
 “An e, an l, and a t. Let me see. Any n’s in it?”
“No. That makes six. Oh, we have you, General, that is half the
number.”
“The battle is not won yet; no, nor lost yet. Well, I’ll guess G.”
“Seven.”
He looked down at the grass and drummed his fingers on his
knee, then said, “D.”
“Eight.”
“An e, an l, and a t. That’s a queer combination when all the
other vowels are out. Holloa! Is there another e?”
“Yes. Third place.”
“Oh, and another l?”
“Nine.”
“I hope this word is in the English language?”
“Oh, yes. It is English and it is used to-day, but a generation back
it was used more frequently.”
“A generation back! Bah!” and he straightened himself and rising
strode back and forth with his hands clasped back of him. “I have it!
That is, I am pretty certain. Has a y, hasn’t it?”
“Yes—second place.”
“Eyelet!” he shouted. “Bah, you thought you had me. Well, you
almost did. Those pesky vowels were at fault.”
“Never mind, I’ll hang you yet. I have another word in mind. But
not to-day. Come, Gertrude. You see it all now, I guess, and we
must hurry in, or Will and the others will be back before we are
ready for dinner. Good-bye for a time, General. Look to your guns. I
shall be after you again.”

II.
Breakfast was more than half over, some mornings later, when in
came Bob and Irving Bolton. A chorus of “Fie, fie,” greeted them,
and Elsie Sterling shook her fingers threateningly as Bob explained,
“Pen, don’t be hard on a fellow. Irving and I talked too late, I
suppose, last night. At any rate I know I should never have turned
up this morning only that he yelled across to me that lunch was
most ready. And then he loitered to help me share the blame of our
lateness. Hey, old fellow?” and he looked across at Irving as he slid
into the vacant place between Elsie and Mrs. Burkhardt.
“You are both rascals, both of you,” growled the General.
“Burkhardt and I have been up hours and have planned the finest
sort of a day for the rest of you ungrateful ones. Shall we tell them,
Burkhardt?”
Before Mr. Burkhardt had a chance to reply, Penelope interposed,
“Let me try and guess.”
“All right, Mrs. Gerard, but you’ll have to try twenty questions or
some such game or you’ll not hit it. It’s a fine scheme.” And Ned
Burkhardt nodded triumphantly while he put a piece of buttered
toast on his wife’s plate.
“I’ll guess just once, and without the help of twenty questions
either. It’s a picnic.”
“Bah!” exclaimed the General. “You overheard, or somebody told
you.”
“Perhaps I did, or perhaps that omnipresent ‘little bird’ chirped it
in my ear. But, at any rate, it’s a fine idea. What say the rest of
you?”
 “Just the thing. Fine,” was the reply.
“How shall we go, Will, and where?”
“Oh, let’s go to Sylvan Grove. It is only ten miles. Let me see. Two
of you can ride horseback.
“Will you and Irving ride, Gertrude? And, Burkhardt, you and
madame and Elsie and Bob might take the buckboard, and we three
old fogies—pardon me, General,—will follow on with the provisions.
Will that suit, Penel?”
“All right. And now let’s get ready. Can you all start in three
quarters of an hour?”
“Yes, indeed.”
Promptly we all sallied forth, and it was a merry party. The air
was perfect, and Irving, Bolton and I cantered on ahead, and finding
ourselves far in advance, we turned and rode across country for a
few miles.
It was a perfect day, and the picnic was a perfect success. At
dinner that night we voted it as the best day yet.
“Well, to-morrow is the golf tournament, you know,” said Will, and
turning to his wife, he added, “Didn’t you say there was a dinner on
too?”
“Oh, yes. I nearly forgot. Dear old Mrs. Preston asked us all to
dinner.” Turning towards me she said, “You remember at our tea, the
day after you came, a white-haired lady accompanied by her
granddaughter?”
“Yes, indeed I do. I think you said she lives in that gray stone
house we passed to-day.”
“Yes, that is the one. It’s a lovely house too—and such china!
Why, Mrs. Burkhardt, she has a willow set that would make your
mouth water. Perhaps we’ll see it.”
 Then turning swiftly, for dinner was over and we were just leaving
the room, “Listen, all of you, please. To-morrow night at Mrs.
Preston’s, and next night nowhere. It is Gertrude’s last night here
and let’s spend it all alone,” and having made her little speech she
slipped her arm around my waist and we went out together.
We passed through one of the French windows, out on the
piazza, and sat there late into the night. Snatches of conversation
came to us again and again, and Mrs. Burkhardt’s sweet soprano as
she and Elsie sang together, while Irving accompanied on the
mandoline. But we, Penelope and I, remained alone, each happy in
the other.
The last night came, as all “last nights” must, and with it, “in
sympathy with our mood,” was the General’s courteous construction,
came a heavy, moaning storm. Will poked the fire and piled on the
logs as though a blizzard were raging without. Finally, he paused
and said, “I guess, Pen, dear, you may have your wish. No one will
disturb our family serenity this night.”
How cosy it seemed and how happy all appeared. Elsie and Mrs.
Burkhardt, Irving and Bob were playing checkers in the next room.
Ned and Penelope were talking about dogs and horses and
comparing their relative intelligence. The General was looking over
some foreign photographs, while Will and I bestowed our attention
on the fire.
“Truly,” spoke General Bolton, “did you ever get up early enough
to see Covent Garden Market in its glory!”
“Oh, General, do you mean to infer absolute laziness, or do you
mean that the gray gloom of London would forbid an early
awakening?”
“Never mind what I inferred. Did you ever go to the market—
early?”
 “Strange as it may seem to you, I did. I went one morning to
Covent Garden Market, and early, about six o’clock, with an English
girl. It was a wonderful sight.”
“See,” he interrupted, “it was this picture of a costermonger with
the palms and ferns that made me ask you.”
“It is very natural—the little donkey, the barrow and all. And how
very cheap the plants and flowers are—why that morning I bought
for sixpence as many moss roses and buds as I could carry.”
“Gertrude, did you ever see that?” And Will gave me a printed slip
that he had been searching for in his pocketbook. It was called the
Floral Test.
“No, but isn’t it good? Let’s ask the others the questions and see
who can answer the most.”
“Come, all you people,” called Will, and he stepped over to the
next room. “Aren’t you tired of checkers? Gertrude has a new game.”
When all were seated around expectantly he said: “Now,
Gertrude, you ask the questions and we’ll reply. It is called,” he
explained, “the Floral Test. She’ll ask questions and we’ll give
answers in the names of flowers.”
“Tell me the name of a maiden, and the color of her hair.”
“Maria-gold,” shouted Irving.
“Good for you, old fellow. How did you know?” questioned Bob.
“O here,” and young Bolton tapped his forehead significantly.
“What adjective fitted her and what was her brother’s name?”
All were silent until Mrs. Burkhardt timidly said, “Is it Sweet-
William?”
 “That’s right. Now try this,—What was his favorite sport in
winter?”
“That’s easy. Snowball,” and Bob threw his handkerchief at Will,
who sharply returned it.
“Ned, what was his favorite instrument?”
“Is it the trumpet?”
“That is right. Can you tell me, Elsie, at what hour he awoke his
father by playing on it?”
“Four o’clock.”
“Yes, and what did his father apply to him?”
“A golden-rod,” two or three shouted.
“What office did his father occupy in the church?”
All seemed puzzled. Finally Elsie said, “Was it elder?”
“Right. What was the young man’s name, and what did he write it
with?”
“That is a poser, Trudy. You’ll have to tell them, I guess,”
suggested Will.
“Jonquil, don’t you see?”
“Bah!” exclaimed the General, while the others laughed.
“Irving, what candy do you usually buy?”
“He doesn’t know,” said Will, “but wait a moment and I’ll show
you some,” and he went to a closet and brought back a box of
buttercups.
“Well, what did John do when he popped the question?”
“Aster,” yelled the General.
 “That is correct, General. See if you can tell what ghastly trophy
he offered her.”
“Oh, that is easy. A bleeding heart.”
“Well, what did she say as John knelt before her?”
“Why, Johnny-jump-up, of course.”
“That’s right. You are fine at this game, General. Can you tell me
what minister married them?”
“Oh, Jack-in-the-Pulpit,” exclaimed Penelope.
“What did she wear in her hair?”
“Bridal-wreath.”
“What flowers bloomed in her cheeks?”
“Roses.”
“What did John say when obliged to leave her for a time?”
“Forget-me-not.”
“That is all. It is a fine game, Will. Where did you find it?”
“Oh, I came across it in a paper, and I know Pen likes that sort of
thing, so I cut it out. But I forgot all about it until you two were
talking over Covent Garden and the early market.”
“I think I can add one to that list of questions,” and Penelope
arose and, drawing me up by the hand, said, “What flower should
we put in the candle tray at night?”
“Poppy,” came the quick reply, and Bob quoted,
The Rock-a-bye lady
From Hush-a-bye street,
The poppies they hang
From her head to her feet.
 “—— oh, I say, Pen,” he called, as we were on the stairs, “what
shall we all do when Gertrude leaves us?”
“Do you mean that as a Floral Test question?”
“Yes.”
“I know what I’ll do, but I don’t know any flower or plant to
describe it.”
“Why, Penelope, we’ll all balsam.”
 HOURS WITH THE POETS.
“Felicia Hemans was an American, born ‘down East’ somewhere; I
think in the same section Nora Perry hails from,” was the startling
announcement uttered in my hearing, by a “sweet girl graduate” of
so short time ago as June, 1892.
“Pardon contradiction,” I called from my end of the library, “but
Felicia Hemans was an Englishwoman, and her birthplace was
Liverpool.”
The surprise the above incident created caused my own thought
to revert to the honored and beloved poets who have so lately left
us, as well as to the mighty revered army, from Chaucer down, who
have more or less an abiding-place in our hearts.
And then followed another thought,—would it not be a wise use
of time for some of us to study the lives and works of these poets,
the minor as well as the more prominent ones, and so save
ourselves from similar ludicrous blunders as the one above given?
And particularly do I appeal to the young girls just out; but even
the busy schoolgirl would have the opportunity if she would only
systematically arrange her work. Afternoon classes might be formed,
or evening ones if preferred; the latter would have the advantages,
as then the big brothers might come. Simple refreshments, too,
would not jar on harmony, but rather tend to sociability. These could
be provided by the hostess, for the girls should take turns in having
the class meet at each house. It would also be found to be a benefit
to have a president and secretary for such a class, or, if an old
person could be gotten, popular and wise enough to take charge,
that would prove still more satisfactory.
It is quite the fashion now to be a member of a dancing class,
why not be a member of a poets’ class, and so take care of your
head as well as your heels? Indeed, classes are the “order of the
day,” for language, music, riding, cooking, wood-carving,
needlework, indeed everything, and the young girls or boys who
may read this sketch certainly want to be into things as well as their
fellows.
In these hours with the poets, take a different poet for each time
the class meets. Before the close of one meeting decide on who will
be the next one taken up. For example, will it be Keats, Saxe, Bayard
Taylor, or Jean Ingelow? That settled, name who will be the one to
give a biographical sketch of the poet. This may be in the form of an
original paper, or read directly from an encyclopedia. Also name two
or more members to read or recite poems from the poet under
consideration. Discussion and criticism should be freely allowed, and
unanswerable questions should be always answered at the next
meeting before entering on the new poet. It would save time to
have the hostess answer the questions left from the week before, as
she could have numerous books at hand, and of necessity would be
present.
Do not say this is too difficult a task. Nothing is too difficult for
those who try.
And do not think such study and hours are unnecessary. If you
do, find out how many of your classmates can at once answer whom
Ben Jonson adopted as his poetical son? He was a pastoral lyrist,
and left behind him thirteen hundred poems. He was a bachelor,
though he lived to be eighty-four years of age. He was born at
Cheapside, London, in 1591, and died in 1674, at Dean Prior, which
living was presented to him, for at times he was very poor. His name
was Robert Herrick.
Or does my reader know that Thomas Gray was a close student of
Dryden, or that the author of the first important body of English
sonnets was the romantic hero, Sir Philip Sidney, and that he died
when but thirty-two years of age, having been conspicuous at the
court of Elizabeth, was a soldier of great promise, a leading
statesman, and has a prominent place in history?
 “THANK YOU!”
“I sent her a basket of fruit for Christmas. The basket was of the
finest Chinese straw, and decorated with handsome pale green satin
ribbon; and the fruit, Bartlett pears, mandarins, and white grapes;
but she has not acknowledged it by either verbal or written thanks.”
“Perhaps she never received it,” was the reply.
“I know that she did, for my daughter called one day and
recognized the basket, which stood on the table in the hall through
which she passed.”
“Well, but you know she is a very busy woman.”
“That is no excuse. People may be ever so busy, but they should
not forget decent courtesy. Indeed, my experience has been that the
busy people are, oftener than otherwise, the most polite people. My
theory is, they do not allow themselves to rust in any direction; duty
should be done, and is done. If an individual cannot take time to
thank a friend for a Christmas gift, next year that friend may not
take time to give one. I am sure it is not the question of time; it is
the question of knowledge or carelessness. There are people who
really don’t know enough to be polite; and others know, but are too
indifferent to take the trouble, forgetting that their conduct reflects
most disagreeably upon themselves. One would think a kind heart
might dictate, if common-sense did not. But I suppose some people
have neither common-sense nor kindness of heart.”
Overhearing the above conversation, the listener was reminded of
a similar instance lately experienced in her own life. A letter had
been written, which had honorably adjusted a money complication
that concerned the gentleman to whom she wrote and a society
which he represented, but did not concern or reflect upon the writer
in the smallest degree excepting for the goodwill she bore her friend,
and yet for this same letter she did not receive one word of thanks—
not even the acknowledgment of its ever having been received. That
it was received was later proved by a printed report that it would
have been impossible to set in order without it.
The examples given are by no means rare and peculiar, but may
be duplicated over and over by every intelligent person. And in this
age of letters, when printed matter was never so reasonable, and
when teachers and schools may be really had “without money and
without price,” when lectures on all topics are inexpensively if not,
indeed, freely given, where is the excuse for knowledge not to be
the power of all? It would almost seem as if even those indifferently
educated could not help but have learned to say “thank you,” or to
acknowledge by pen or voice any accommodation, help, or present.
Blood is sure to tell, and with Emerson we say that “man is
physically as well as metaphysically a thing of shreds and patches,
borrowed unequally from good and bad ancestors.” To those of
gentle blood, rudeness would be impossible. If there are partial
lapses of manner with those looked upon as the refined, the
question is asked, “Where does she get that trait?” and possibly the
answer may be, “Her great-grandmother.” For thus are the sins
visited upon the children of even the third and fourth generations.
The deportment of the real gentleman or woman can never be
unpleasantly criticised. They could not be ungracious, no matter how
hard they should try. If there is ever a question about how far
politeness should extend, err on the side of too much rather than
that of too little. Have too much manner rather than not enough. Be
too profuse in thanks rather than too scant and meagre.
When a gift has been received or a courtesy of any kind shown
you, at once acknowledge it, unless you are too ill so to do, or a
positively important matter prevents. If it is impossible to write to
the one you are indebted to that day, do it the next. But as it is so
easy for most of us to have good intentions, do not put off for to-
morrow what should be done to-day.
 The note should not be long, but heartily and pleasantly worded.
Some people might reflect, “I would not tell a falsehood, and how
can I say I like a thing if I do not?” Or, as happened lately, two
boxes of wild flowers were sent me from California by two little boys,
with a note in one of the boxes containing the words, “Which flowers
got to you best, Pierre’s or mine?” and I was obliged to at once put
both boxes in the fire. Should I write of the sweetness of the
blossoms and the purity and beauty of their coloring? By no means.
But I would not wound the childish hearts by telling of the condition
of the flowers at the time they were received. Remember the
thought that prompted the gift. Dwell on that altogether if you will.
Send a loving message to the donors, and they will never dream you
did not like their offering in the one case or were obliged to burn it
in the other.
After all, remembrance is the sweetest of all earthly gifts. When
the dear ones with whom we journey are no longer here, we will
miss their gentle ministry. May not any one of us then know the
bitterness of remorse, but rather let us hasten to send abundant,
hearty thanks to those who have taken time to think and care for us!
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