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CONTRIBUTORS

Daniel L. Alkon
Blanchette Rockefeller Neurosciences Institute, Morgantown, West Virginia, USA
Raül Andero
Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine,
and Yerkes National Primate Research Center, Atlanta, Georgia, USA
Amy F.T. Arnsten
Department of Neurobiology, Yale University School of Medicine, New Haven,
Connecticut, USA
Fabricio Ballarini
Instituto de Biologı́a Celular y Neurociencias “Prof. E. De Robertis”, Consejo Nacional de
Investigaciones Cientı́ficas y Técnicas de Argentina, Facultad de Medicina, Universidad de
Buenos Aires, Buenos Aires, Argentina
P.J. Banks
School of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom
Z.I. Bashir
School of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom
Antoine Besnard
Harvard Stem Cell Institute, Harvard Medical School, Center for Regenerative Medicine,
Massachusetts General Hospital, Boston, Massachusetts, USA
Anna Beyeler
Department of Brain and Cognitive Sciences, Picower Institute for Learning and Memory,
Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
Johannes Bohacek
Brain Research Institute, Medical Faculty of the University of Zürich, and Department of
Health Sciences and Technology, Swiss Federal Institute of Technology, Brain Research
Institute Zürich, Switzerland
M.W. Brown
School of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom
Jocelyne Caboche
INSERM, UMRS 952; CNRS, UMR7224, Physiopathologie des Maladies du Système
Nerveux Central, and UPMC University Paris 6, Paris, France
Victoria S. Cavener
Vanderbilt Brain Institute, Vanderbilt University School of Medicine, Nashville, Tennessee,
USA
Dennis C. Choi
Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine,
and Yerkes National Primate Research Center, Atlanta, Georgia, USA

xi
xii Contributors

Roger J. Colbran
Department of Molecular Physiology and Biophysics; Vanderbilt Brain Institute, and
Vanderbilt-Kennedy Center for Research on Human Development, Vanderbilt University
School of Medicine, Nashville, Tennessee, USA
Sabrina Davis
CNRS, Centre de Neurosciences Paris-Sud, and Centre de Neurosciences Paris-Sud, Univ
Paris-Sud, UMR 8195, Orsay, France
Christine A. Eckhardt
Department of Brain and Cognitive Sciences, Picower Institute for Learning and Memory,
Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
Wambura C. Fobbs
Laboratory of Neural Systems, Decision Science, Learning and Memory, Neurobiology and
Behavior Program, Psychology Department, University of Washington, Seattle,
Washington, USA
Katharina Gapp
Brain Research Institute, Medical Faculty of the University of Zürich, and Department of
Health Sciences and Technology, Swiss Federal Institute of Technology, Brain Research
Institute Zürich, Switzerland
Thu N. Huynh
Center for Neural Science, New York University, New York, USA
Nidhi Jalan-Sakrikar
Department of Molecular Physiology and Biophysics, Vanderbilt University School of
Medicine, Nashville, Tennessee, USA
Lu E. Jin
Department of Neurobiology, Yale University School of Medicine, New Haven,
Connecticut, USA
Zafar U. Khan
Laboratory of Neurobiology at CIMES and Department of Medicine at Faculty of
Medicine, University of Málaga, Málaga, Spain
Eric Klann
Center for Neural Science, New York University, New York, USA
Serge Laroche
CNRS, Centre de Neurosciences Paris-Sud, and Centre de Neurosciences Paris-Sud, Univ
Paris-Sud, UMR 8195, Orsay, France
Joseph E. LeDoux
Center for Neuroscience, New York University, and Emotional Brain Institute, Nathan
Kline Institute for Psychiatric Research, Orangeburg, New York, USA
Isabelle M. Mansuy
Brain Research Institute, Medical Faculty of the University of Zürich, and Department of
Health Sciences and Technology, Swiss Federal Institute of Technology, Brain Research
Institute Zürich, Switzerland
Contributors xiii

Elisa Martı́n-Montañez
Laboratory of Neurobiology at CIMES, and Department of Pharmacology at Faculty of
Medicine, University of Málaga, Málaga, Spain
Marı́a Cecilia Martı́nez
Instituto de Biologı́a Celular y Neurociencias “Prof. E. De Robertis”, Consejo Nacional de
Investigaciones Cientı́ficas y Técnicas de Argentina, Facultad de Medicina, Universidad de
Buenos Aires, Buenos Aires, Argentina
Sheri J.Y. Mizumori
Laboratory of Neural Systems, Decision Science, Learning and Memory, Neurobiology and
Behavior Program, Psychology Department, University of Washington, Seattle,
Washington, USA
Diego Moncada
Instituto de Biologı́a Celular y Neurociencias “Prof. E. De Robertis”, Consejo Nacional de
Investigaciones Cientı́ficas y Técnicas de Argentina, Facultad de Medicina, Universidad de
Buenos Aires, Buenos Aires, Argentina, and Neurophysiology of Learning and Memory
Research Group, Leibniz-Institut für Neurobiologie, Magdeburg, Germany
E. Chris Muly
Atlanta Department of Veterans Affairs Medical Center, Decatur; Department of
Psychiatry and Behavioral Sciences, Emory University, Atlanta, and Division of
Neuropharmacology and Neurological Diseases, Yerkes National Primate Research
Center, Atlanta, Georgia, USA
Irene Navarro-Lobato
Laboratory of Neurobiology at CIMES, and Department of Medicine at Faculty of Medicine,
University of Málaga, Málaga, Spain
Kerry J. Ressler
Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine;
Yerkes National Primate Research Center, Atlanta, Georgia, and Howard Hughes Medical
Institute, Chevy Chase, Maryland, USA
Emanuela Santini
Center for Neural Science, New York University, New York, USA
Hillary C. Schiff
Center for Neuroscience, New York University, New York, USA
Robert M. Sears
Center for Neuroscience, New York University, New York, USA
Brian C. Shonesy
Department of Molecular Physiology and Biophysics, Vanderbilt University School of
Medicine, Nashville, Tennessee, USA
Miao-Kun Sun
Blanchette Rockefeller Neurosciences Institute, Morgantown, West Virginia, USA
Kay M. Tye
Department of Brain and Cognitive Sciences, Picower Institute for Learning and Memory,
Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
xiv Contributors

Alexandra Veyrac
CNRS, Centre de Neurosciences Paris-Sud, and Centre de Neurosciences Paris-Sud, Univ
Paris-Sud, UMR 8195, Orsay, France
Haydée Viola
Instituto de Biologı́a Celular y Neurociencias “Prof. E. De Robertis”, Consejo Nacional de
Investigaciones Cientı́ficas y Técnicas de Argentina, Facultad de Medicina, and
Departamento de Fisiologı́a, Biologı́a Molecular y Celular, Facultad de Ciencias Exactas y
Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
E.C. Warburton
School of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom
Bisrat T. Woldemichael
Brain Research Institute, Medical Faculty of the University of Zürich, and Department of
Health Sciences and Technology, Swiss Federal Institute of Technology, Brain Research
Institute Zürich, Switzerland
PREFACE

Life is all memory, except for the one present moment that goes by you so quickly
you hardly catch it going.
Tennessee Williams

Memory is central to our conceptualization of who we are as individuals.

Memories of our childhood, of our experiences, and of our accomplish-
ments are, for all intents and purposes, our identity. Memory allows us to
place ourselves in the context of a family and society, and without a memory
of our past, we could not effectively navigate our present nor plan for our
future. Modern society places increased demands on memory as people are
now called upon to have more information memorized than in centuries
past. Furthermore, modern hygiene and health care have dramatically
lengthened life expectancy over the past century, resulting in an increase
in the number of people with memory impairment. Thus, there is a pressing
and increasing need to identify strategies to optimize and preserve memory
function.
In this volume, recent research is presented and reviewed which has
pushed our understanding of memory processes beyond circuit activity to
the underlying molecular mechanisms. It begins with a review of memory
impairment in aging and disease (Chapter 1) and then examines the role of
individual kinases and transcription factors shown to play a role in memory
processes (Chapters 2–4). The molecular mechanisms of synaptic plasticity
and its role in memory are then considered (Chapters 5–6). The next section
considers the interface between molecules and circuits in different types of
memory processes (Chapters 7–10). The volume concludes with consider-
ations of the contributions of epigenetic studies and optogenetic approaches
to the study of memory and a proposed hypothesis to link molecular synaptic
changes to changes integrated into complex neural circuits (Chapters
11–13). It is our hope that this volume will provide a useful overview to
the current state of knowledge in a rapidly evolving field with tremendous
potential to translate into clinical benefits.
E. Chris Muly and Zafar U. Khan

xv
 CHAPTER ONE

Memory Deficits in Aging and

Neurological Diseases
Zafar U. Khan*,†, Elisa Martín-Montañez*,‡, Irene Navarro-Lobato*,†,
E. Chris Muly},},jj
*Laboratory of Neurobiology at CIMES, University of Málaga, Málaga, Spain
†
Department of Medicine at Faculty of Medicine, University of Málaga, Málaga, Spain
‡
Department of Pharmacology at Faculty of Medicine, University of Málaga, Málaga, Spain
}
Atlanta Department of Veterans Affairs Medical Center, Decatur, Georgia, USA
}
Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, Georgia, USA
jj
Division of Neuropharmacology and Neurological Diseases, Yerkes National Primate Research Center,
Atlanta, Georgia, USA

Contents
1. Introduction 2
2. Memory Loss in Aging 2
2.1 Altered epigenetic regulation 4
2.2 Impaired cytoskeletal dynamics 5
2.3 Dysregulated extracellular matrix activity 6
2.4 Dysfunction of neural networks 6
2.5 Impaired neurotransmitter systems 9
3. Memory Deficit in Alzheimer's Disease 13
3.1 High amyloid-b peptide 13
3.2 Altered tau protein phosphorylation 14
3.3 Degeneration of cholinergic neurons in Alzheimer's disease 14
4. Memory Impairment in Schizophrenia 14
4.1 Altered brain circuits 15
4.2 Abnormal neurotransmitter systems 16
5. Concluding Remarks 17
Acknowledgments 17
References 17

Abstract
Memory is central to our ability to perform daily life activities and correctly function in
society. Improvements in public health and medical treatment for a variety of diseases
have resulted in longer life spans; however, age-related memory impairments have
been significant sources of morbidity. Loss in memory function is not only associated
with aging population but is also a feature of neurodegenerative diseases such as
Alzheimer's disease and other psychiatric and neurological disorders. Here, we focus

Progress in Molecular Biology and Translational Science, Volume 122 # 2014 Elsevier Inc. 1
ISSN 1877-1173 All rights reserved.
http://dx.doi.org/10.1016/B978-0-12-420170-5.00001-5
2 Zafar U. Khan et al.

on current understanding of the impact of normal aging on memory and what is known
about its mechanisms, and further review pathological mechanisms behind the cause of
dementia in Alzheimer's disease. Finally, we discuss schizophrenia and look into abnor-
malities in circuit function and neurotransmitter systems that contribute to memory
impairment in this illness.

1. INTRODUCTION
Intact memory function is critical to carry out daily life activities, such
as managing finances, remembering to take medications, driving, remem-
bering a grandchild’s birthday, and learning to use a new computer. Deficits
in memory function are seen in aging and Alzheimer’s disease but are also
features of other psychiatric and neurological disorders. Mental retardation,
autism, attention deficit disorder, learning disability, schizophrenia, and
depression all have memory components, as do Parkinson’s, Huntington’s,
and other neurodegenerative diseases. It is believed that memory deficits
arise from aberrant activity in neuronal networks and diminished synaptic
activity.1 Active synaptic remodeling is essential for the formation of mem-
ories and is thought to be regulated by many biological events. These
include gene expression, protein translation, protein degradation, cytoskel-
etal dynamics, extracellular matrix interactions, second-messenger signaling,
and neurotransmitter receptor trafficking and function2 (Fig. 1.1). Compro-
mise of one or more of these interrelated biological events can hamper cog-
nitive performance and produce memory loss.

2. MEMORY LOSS IN AGING

Aging differentially affects cognitive and neurological functioning.3,4
In particular, abilities reliant on processing speed such as problem solving,
inhibitory function, working memory, long-term memory, and spatial abil-
ity decline with age.5 Aging can also affect the encoding of new information,
particularly when effortful or strategic processes are required.6 For example,
younger adults benefit from a higher degree of detailed information
processing than older adults, suggesting that older individuals encode the
detail of new information less thoroughly.7 Neuroimaging studies have
shown an age-related decrease in functional activity in the medial temporal
lobes and the prefrontal cortex while encoding new information and that has
subsequently been linked to poorer memory performance.8–10 In general,
Memory Deficits in Aging and Neurological Diseases 3

ptic
Syna ng
m o d eli

ion
re

ss
mi
ns
ra
ot
ur
Neuro

Ne
na
netwo l
rk
Cytos
ke
Extrac leton Cognition
ell Genes
matrix ular
and
Memory

Ep
ige
g ne
lin tic
gna s
Si

Gene
expression

Figure 1.1 Interrelated biological functions that mediate cognition and memory.

episodic memory (conscious recollection of experienced events) declines

with age11–13; however, semantic memory (facts, meanings, concepts, and
knowledge) does not show age-related decline. In fact, semantic memory
increases with age. It has been argued that the difficulties older individuals
experience in word finding and name retrieval are associated more with
problems retrieving this information rather than an actual semantic memory
storage deficit. Also, like semantic memory, implicit or procedural memory
(unconscious automated actions and movements, such as playing a guitar or
riding a bike) is relatively unaffected by aging.11,12,14,15
Recognition memory, which is one of the most studied examples of epi-
sodic memory, is supported by recollection and familiarity. Recollection is
recovery of qualitative information with specific details about a prior event.
However, familiarity is when specific details are not recovered but people
believe that the event has occurred previously and seems very familiar. In
aging, retrieval of information is affected by the degree to which brain effort
is required during processing. Retrieval of familiar recognition memory,
which is relatively simple and lacks contextual details, is less affected by nor-
mal aging than recollection.16,17 Perhaps, because recollection requires
4 Zafar U. Khan et al.

more effortful processing during access to specific details stored in brain.

Typically, familiarity and recollection work together to support recognition
memory; however, older individuals may tend to over rely on familiarity
when experiencing recollection failures. Neuroimaging studies have shown
that reliance on familiarity is a compensatory mechanism for poor recollec-
tion.18 Although performance on tasks of both types of recognition memory
can be sensitive to normal aging, older individuals fare much better on
yes–no or forced-choice simple recognition tasks than on recollection tasks,
suggesting that the information is stored in memory but it is not easily
accessible.16,19,20 Thus, older individuals may properly encode and store
information but struggle when asked to retrieve this information. When rec-
ollection demands are eliminated with a recognition task during perfor-
mance, age effects are attenuated. It is thought that deficits in effortful
memory processes arise primarily due to inefficiency of the frontal lobes
to engage in the self-initiation of strategic processes at both encoding and
retrieval. In the following sections, underlying biological mechanisms asso-
ciated with memory decline during aging are described.

2.1. Altered epigenetic regulation

Aging leads to the transcriptional downregulation of genes involved in syn-
aptic maintenance and function.21–24 This change in gene expression can
alter neuronal integrity and also destabilize dendritic spines and their synap-
tic organization, which is vital for normal memory processing. Chromatin
remodeling via histone modification and DNA methylation represents two
major mechanisms of epigenetic regulation of gene expression. Chromatin
regulation is critical for controlling the expression of genes that are required
for memory processes,25 as demonstrated by animal studies and the associ-
ation of these modifications with human disorders characterized by intellec-
tual disability.26 It has been shown that epigenetic mechanisms contribute to
reduced gene expression in the brain and that this alteration correlates very
well with cognitive decline in aging.27 For example, in the human prefrontal
cortex, a noticeable downregulation of genes implicated in synaptic plastic-
ity was observed.24 Similar observations were made in the hippocampus of
human and rodent brain.28–30 Therefore, downregulation in the epigenetic
control of gene expression in brain areas implicated in memory processing
during aging can alter synaptic plasticity and memory function.31,32 The
posttranslational modifications of histone chromatin protein, such as
acetylation, ADP-ribosylation, and ubiquitination,33 regulate chromatin
Memory Deficits in Aging and Neurological Diseases 5

remodeling processes to facilitate the genetic DNA availability for transcrip-

tion.33 Most studies of posttranslational modifications are focused on histone
acetylation, which has been shown to play a crucial role in regulating syn-
aptic function and long-term memory formation.34–36 Age-dependent
decline in histone acetylation and resulting disruption of memory-related
target genes are key to the deterioration of memory in rodents.32,37,38 Con-
sistent with these observations, increasing histone acetylation via treatments
with histone deacetylase (HDAC) inhibitors rescues memory deficits asso-
ciated with cognitive aging and other memory disorders.35,39 On the other
hand, methylation modifications of DNA have also been shown to play
important role in regulating gene expression. In a genome-wide study of
aging individuals, substantial decline in DNA methylation was observed
and that this change coincided well with the memory deficit.33,40

2.2. Impaired cytoskeletal dynamics

The neuronal cytoskeleton is composed of microtubules and neurofilaments
that are found throughout dendrites, axons, and cell bodies,41 and of actin
filaments that are specially enriched in spines and growth cones. It is widely
believed that information in the brain can be stored by strengthening or
weakening existing synapses, as well as appearance or disappearance of den-
dritic spines and their synapses. Functional and structural changes at spines
and synapses are considered to be the basis of learning and memory in the
brain.42,43 Numerous studies have demonstrated that the actin cytoskeleton
plays a pivotal role in the formation and elimination, motility and stability,
and size and shape of dendritic spines.44–48 In addition, modulation of actin
dynamics drives the morphological changes in dendritic spines that are asso-
ciated with alteration in synaptic strength.49,50 At synapses, the actin cyto-
skeleton not only contributes to overall structure of synapses but also plays
important roles in synaptic activities that range from organizing the postsyn-
aptic density51 and anchoring postsynaptic receptors52 to facilitating the traf-
ficking of synaptic cargos53 and localizing the translation machinery.54 Thus
actin dynamics are fundamental for normal memory processing, and during
aging, the regulation of the actin cytoskeleton becomes defective.55,56 It has
also been shown that dysregulation of the actin cytoskeleton is associated
with memory disorders.56 Furthermore, impaired synaptic plasticity and
memory deficits in the aging brain have been linked to failure of actin poly-
merization in the spine head57 and to elevated breakdown of cytoskeleton
proteins, such as microtubule-associated protein 2A/B.58
6 Zafar U. Khan et al.

2.3. Dysregulated extracellular matrix activity

The extracellular matrix occupies approximately 20% of the normal adult brain59
andiscomposedofmainlyunbranchedpolysaccharidehyaluronicacidandchon-
droitin sulfate proteoglycans of the lectican family, such as aggrecan, versican,
brevican, and neurocan,60 where hyaluronic acid acts as a backbone to recruit
proteoglycans and glycoproteins into extracellular matrix structures.61–63 In
addition, a variety of other glycoproteins and proteoglycans contribute to extra-
cellular matrix of the brain. These include laminins, tenascins, pentraxins, phos-
phocan, reelin, thrombospondins, and heparan-sulfate proteoglycans. Matrix-
shaping enzymes, like proteases and hyaluronidases, are also found in the brain
matrixstructures.61,63–66 Thecomponentsoftheextracellularmatrixformacon-
densed and stable lattice-like network structure known as perineuronal nets.
These perineuronal nets wrap tightly around the synapses on the cell soma and
proximal dendrites,67–70 serving as ground for various secreted glycoproteins,
lectins, growth factors, and enzymes to modulate dendritic spines through inter-
actionswithreceptorsandotherproteins.Extracellularmatrixorganizationinflu-
ences normal physiology of dendritic spines and synapses, and alterations in the
extracellular matrix composition may underlie abnormal dendritic spine devel-
opment and synaptic plasticity.71,72 Indeed, a large family of hyaluronic acid-
bindingproteoglycanshasbeenshowntoplayanimportantroleinregulatingsyn-
aptic function and plasticity,73 and in the aging brain, the extracellular matrix
activity was found altered.74 Abnormal dendritic spine morphology and/or
altered spine density is a hallmark of many neurological disorders associated with
learning deficits, memory loss, and other cognitive deficits. Many components of
the extracellular matrix can affect dendritic spines and synapses. Therefore, it is
not surprising that the changes in extracellular matrix composition as a result
ofgeneregulationor posttranslationalmodifications of several extracellulargenes
can affect cognitive functions as well. Several extracellular proteins, including
reelin, elastin, thrombospondins, and some proteoglycans, have been implicated
in cognitive deficits seen in several neurological disorders and aging.75–80

2.4. Dysfunction of neural networks

Age-dependent behavioral and cognitive decline is well documented,81–83
and neurophysiological signatures have also been shown to slow with
age.84 Biological explanations for this slowing have generally focused on pro-
cesses, such as age-related reductions in axon myelination,85,86 degradation of
the synaptic network, and slower interactions between networks of neurons,
which would increase the processing time to complete a task.87
Memory Deficits in Aging and Neurological Diseases 7

2.4.1 Imaging of brain structure and function

Studies on normal aging-related changes show that the brain shrinks in
volume. Accumulated data indicate an annual reduction of 0.5–1% in
most brain areas.88 However, the pattern of changes is highly hetero-
geneous. The largest reduction was observed in frontal and temporal
association cortex, areas whose functions are typically associated with
age-related cognitive decline.89–91 The decline in brain volume is prob-
ably not related to neuronal loss, rather, shrinkage of neurons and syn-
aptic spines has been observed during aging. In addition, there is a
reduction of up to 50% in the length of myelinated axons.88 Together,
these results indicate an age-related reduction in the connections
between neurons.
In behavioral studies, aged individuals typically showed decreases in the
activation of left-hemisphere prefrontal cortex during encoding of an epi-
sodic memory; however, during retrieval, a decrease in the activation of
right-hemisphere prefrontal cortex together with increase in left-
hemisphere prefrontal cortex was observed.92 Given that during retrieval,
prefrontal cortex activity of young individuals is mainly associated with right
hemisphere, age-related decrease in the activity of right-hemisphere pre-
frontal cortex coupled with age-related increase in left-hemisphere prefron-
tal cortex activity leads to a more symmetric pattern of prefrontal cortex
activity in aged individuals. Moreover, most of the imaging studies are con-
sistent with the notion that neural activity in prefrontal cortex is more sym-
metric with aging.
Aging is accompanied by cognitive decline, including processing speed
and episodic memory.93–95 However, there exists substantial heterogeneity
in cognitive aging96,97 with some individuals showing minimal or no
effect.98 It is thought that individuals resisting age-related cognitive decline
have maintained brain integrity better99 and are spared from the structural
and functional alterations of brain structures, such as the prefrontal cortex
and the medial temporal lobe, which are associated with cognitive
decline.89–91 The better cognitive performance in aging-resistant individuals
is correlated with increased brain activation, particularly in the prefrontal
cortex,100 which has been interpreted as a compensatory process to maintain
performance. However, prefrontal activity appears not to be sufficient for
the maintenance of cognitive ability during aging. A recent study has found
that preservation of both hippocampus and prefrontal function are important
for the maintenance of good memory function in individuals resisting age-
related cognitive decline.101
8 Zafar U. Khan et al.

2.4.2 Synaptic dynamics

Normal brain aging is associated with a decline in cognitive perfor-
mance.102,103 This age-related functional impairment does not involve a loss
of neurons.104,105 Instead, it likely depends on the impairment of synaptic
contacts between axonal boutons and dendritic spines.103,106 Both size
and number of dendritic spines on pyramidal neurons of the cerebral cortex
and hippocampus are affected by aging.103,107–109 It has been shown that the
spine loss in prefrontal cortex is highly selective to long-necked thin spines
and the number of mushroom-shaped spines is stable throughout the life-
time of the animal.110–114 Given that thin spines are highly plastic and
dynamic compared with the mushroom spines, cognitive decline in aging
is likely to be associated with impairment in the plasticity of network activity
that this group of spines supports. Furthermore, alterations in the size and
stability of dendritic spines and axonal boutons in the cortex are related
to weaker synapses in aging brain.115 These weaker synapses are less capable
of short-term plasticity, and therefore the neural circuitry is less adaptable.
By contrast, memory processing in the hippocampus is associated with syn-
aptic stability and the conversion of simple synapses into complex synaptic
structures such as perforated synapses and multisynaptic boutons. Indeed, an
increase in the number of perforated synapses has been associated with the
induction and maintenance of long-term potentiation,116,117 and multi-
synaptic boutons are increased in the hippocampal CA1 area following asso-
ciative learning.118 On the other hand, aging cortical circuits display higher
rates of axonal bouton formation, elimination, and destabilization.119 In
addition, persistent axonal boutons which do not disappear with age and
are believed to encode long-term memory are not affected. These findings
indicate that memory deficits in the aged brain arise not through an inability
to form new synapses but rather through decreased synaptic activity.
It has been shown that despite an age-dependent dendritic spine loss,
patch-clamp recording of synaptic activity revealed an increase in miniature
EPSC frequency restricted to aged animals with preserved memory. In con-
trast, a strong positive relationship between miniature IPSC frequency and
the occurrence of both exploratory behavior and novelty-related memory
deficits was observed.120 The enhanced inhibitory tone was accompanied
by a deficit in activity-driven inhibition, also suggesting an impaired
dynamic range for modulation of inhibition in the cognitively impaired aged
animals. Therefore, functional synaptic imbalance toward inhibitory activity
as a substrate of cognitive impairment in the aged cohort while, in contrast,
an increase in excitatory synaptic tone is observed in aged unimpaired
Memory Deficits in Aging and Neurological Diseases 9

animals. The balance between basal inhibitory and excitatory synaptic tone
may thus define unimpaired from impaired cognitive aging.

2.4.3 Gamma frequency

The current view is that age-dependent cognitive slowing is caused by a
reduction in the speed of neural signaling and slower interactions between
networks of neurons.121 In the brain, neural communication is organized by
gamma oscillations at 30–100 Hz and this gamma frequency activity is the
result of the action of fast-spiking inhibitory neurons,122,123 as well as their
interactions with local excitatory neurons.124,125 The activity of neurons
that are engaged in the same information computation can become dynam-
ically synchronized within the gamma cycle.126–128 Consistent with this
idea, treatment with barbiturates, which widen the gamma period by
increasing the inhibitory GABAA receptor time constant,129 also increases
the behavioral reaction times.130 In aging rats, a reduction in 40–70 Hz
gamma oscillation and an increase of the cortical gamma period have been
shown.121 These reductions were observed in the form of local field poten-
tials, later peaks in fast-spiking neuron autocorrelations, and delays in the
spiking of inhibitory neurons following local excitatory signals. Thus, the
reductions in the strength and efficiency of gamma oscillations may contrib-
ute to the slowing of behavior and cognition during aging.

2.5. Impaired neurotransmitter systems

From patient studies, animal research, pharmacological intervention, and
molecular genetics, brain neurotransmitter systems have long been recog-
nized for their fundamental role in memory and cognitive functions. The
cognitive decline with age is associated with altered function of neurotrans-
mitter systems, including the dopaminergic, glutamatergic, cholinergic, and
serotonergic systems.131

2.5.1 Dopamine
Dopamine is one of the most important neurotransmitters in the brain and
dopaminergic pathways are critical for cognitive functions.132 Postmortem
studies of human aging show that dopaminergic neurons in the substantia
nigra are lost 2–6% per decade,133 a figure that correlates well with the
decrease in striatal dopamine neurotransmitter availability.134 These changes
are accompanied by age-related decrease in dopamine D1135 and D2136
receptors at a rate of 3% per decade. There is also evidence for age-related
loss of other proteins related to dopamine neurotransmission. Molecular
Exploring the Variety of Random
Documents with Different Content
our colonists, both in the islands and on the continent, against the
establishment of episcopacy! That persons of all ranks, from Quebec
down to the two Floridas, are at this time prejudiced, and more than
prejudiced against it, is very notorious; but how will the very thought
of the introduction of Lords Bishops even make them shudder? if
their Lordships should think proper to countenance the expulsion of
such worthy and truly religious students, whilst those who have no
religion at all perhaps, may not only meet with countenance, but
approbation and applause.

Besides, if such proceedings should be continued, (which God

forbid!) what little credit may we suppose will hereafter be given to
future university-testimonials, that the bearers of them have behaved
studiously, soberly, and piously; and how must we in time be put
under a disagreeable necessity of having a new, or at least of
altering some part of our present most excellent ordination-office? As
it now stands, one of the questions proposed to every candidate for
holy orders runs thus: “Do you trust that you are inwardly moved by
the holy ghost?” But if all students are to be expelled that sing
hymns, pray extempore, attend upon, or expound a verse now and
then, in a religious church of England society, should it not rather,
Reverend Sir, be worded thus, namely, “Do ye trust that ye are NOT
inwardly moved by the Holy Ghost to take upon you the office and
administration of the church?”

You will excuse this freedom, Reverend Sir.

Agitur de vitâ et sanguine turni.

Love to God, love to mankind in general, and love to that university,

that alma mater where I had the honour of being educated, and,
what is infinitely more, where I had the happiness of receiving the
witness of the Spirit of God in my heart, all together constrain me.

The news of these young mens expulsion hath made, and will
make the ears of all who have heard, or shall hear of it, to tingle: and
therefore if some do not speak, and use great plainness of speech
too, the very stones would, as it were, cry out against us. In respect
to myself, Reverend Sir, I hope, that in taking the freedom of
troubling you with this, I do not justly incur the censure of acting as a
busy-body in other mens matters. For, whatever other pretences
may be made, such as disqualification in respect to learning, age,
the being of trades, &c. &c. &c. (Nugæ tricæque calendæ) it is
notorious and obvious to all intelligent persons, that the grand cause
of these young mens expulsion was this, namely, that they were
either real or reputed Methodists. An honour this indeed,
unwittingly put on Methodists, whoever or whatever they be; since
scarce any now-a days can pray extempore, sing hymns, go to
church or meeting, and abound in other acts of devotion, but they
must be immediately dubbed Methodists. I say, dubbed Methodists;
for it is not a name given to them by themselves, but was imposed
on them by some of their fellow students and contemporaries in the
university.

I take it for granted, Reverend Sir, that you need not be apprized
that I am one of these Methodists; and blessed be God I have had
the honour of being one of them for about thirty-five years. If this is to
be vile, may I be more vile! If this be my shame, upon the most
mature and serious reflection I really glory in it. But then, lest any
more innocent youths should hereafter suffer barely for the
imputation of a nick-name, give me leave simply and honestly to
inform you, Reverend Sir, and through you the whole university, what
not barely a reputed, but a real Methodist is: “He is one of those
whom God hath chosen in Christ out of mankind, to bring them by
Christ to everlasting salvation, as vessels made to honour;
wherefore they, who be endued with so excellent a benefit of God,
are called according to God’s purpose by his spirit working in due
season: they, through grace, obey the calling; they be justified freely;
and made the sons of God by adoption: they are conformed to the
image of his only begotten Son Jesus Christ; they walk religiously
in good works; and at length, by God’s mercy, they attain everlasting
felicity.” This is the true portrait of a Methodist, drawn at full length,
drawn to the very life, and that too not by an ignorant modern
dauber, but by those good old skilful scriptural limners, Cranmer,
Latimer, Ridley, in the xviith article of our church; an article that
deserves to be written in letters of gold; and yet, for holding of this
very article in its literal grammatical sense, agreeable to his
subscription at the time of matriculation, one of these young
students, as we have been informed, was expelled. If our information
be wrong in this or any other respect, the nation may soon be set
right by an authentic publication of the whole judicial proceedings.

If you should desire, Reverend Sir, a definition of Methodism

itself, as well as of a Methodist, you may easily be gratified. It is no
more nor less than “faith working by love. A holy method of living and
dying, to the glory of God.” It is an universal morality, founded upon
the love of God shed abroad in the heart by the Holy Ghost: or, to
keep to the exact terms made use of in the last collect of our
excellent liturgy, it is “the grace of our Lord Jesus Christ, the love
of God, and the fellowship of the Holy Ghost;” which we cannot go to
church or chapel on Sundays, holidays, or other common days,
without praying, not that it may be driven from, but be with us all
evermore.

If this be enthusiasm, the true Methodists confess themselves to

be enthusiasts. But then, they humbly apprehend, that they cannot
with any just propriety of speech be termed modern enthusiasts; for
it is an enthusiasm which our blessed Lord earnestly insists upon, in
that prayer which he put up when he was about to take his farewel of
his disciples, and which is a pattern of that all-prevailing intercession
which He is now making at the right hand of God, and demands that
all his disciples may be possessed of; “Father, I will that those whom
thou hast given me, may be with me where I am; that they may be
one with me, even as thou, O Father, and I are one: I in them, and
they in me, that they all may be made perfect in one.” An
enthusiasm, with which Peter and John were fired, when Annas the
high-priest, and Caiaphas, and John, and Alexander, and as many
as were of the kindred of the high-priest, seeing their boldness, and
perceiving that they were unlearned and ignorant men, marvelled,
and took knowledge of them that they had been with Jesus. An
enthusiasm, with which the proto-martyr Stephen was filled, when he
cried, “Ye stiff-necked and uncircumcised in heart and ears, ye do
always resist the Holy Ghost.” An enthusiasm, which Ignatius
supposed by some to be one of those little children which the Lord
Jesus took up in his arms, was absorbed in, when he stiles himself a
bearer of God; and for witnessing of which good confession, in order
to cure him of this enthusiasm, he was ordered by Trajan, the
Roman emperor, to be thrown to the lions. An enthusiasm, for which
Cranmer, Ridley, and Latimer, those glorious lights of the
reformation, those excellent compilers of our liturgy, articles, and
homilies, were burnt alive near Baliol college. And, to mention but
one more, too too recent an example, an enthusiasm, for being only
a little tinctured with which, six students, on March 11th, in the year
of our Lord 1768, were publicly expelled in Edmund-Hall chapel.

But think you, Reverend Sir, that this is the way to stop the
progress of this enthusiasm? Or rather, may we not imagine that this
very act of expulsion will be a means of furthering and promoting its
progress far and near? To speak my own thoughts, I am fully
persuaded, that if such unscriptural methods of stopping this
enthusiasm be pursued further, it will be only like cutting off the
Lyrnean head; instead of one, an hundred will spring up.

Indeed, if the picture of modern enthusiasts, drawn up and

presented to the public by your Right Reverend Diocesan, be a just
and proper one, supposing at the same time the Methodists are
thereby referred to, no matter how soon they are banished out of the
university, and out of the church also: for his Lordship is pleased to
tell us “that they act in direct opposition to the perverse pharisees of
old; these ascribed the works of the Holy Ghost to Beelzebub; and it
is no uncommon thing for these modern enthusiasts, adds his
Lordship, to ascribe the works of Beelzebub to the Holy Spirit.”
Surely his Lordship, by these modern enthusiasts, cannot mean
those who apply for holy orders, and profess before men and angels,
that “they are inwardly moved by the Holy Ghost, to take upon them
the office and administration of the church;” when the searcher of
hearts knows that they are moved only by secular views and worldly
hopes of preferment. This is ascribing the works of Beelzebub to the
Spirit of God with a witness: or, to use the words of a no less
learned, though less censorious prelate; I mean the moderate
Bishop Burnet, “it is a committing the horrid crime of Ananias and
Sapphira over again; it is lying, not only unto man, but unto God.”

This is a modern kind of enthusiasm, Reverend Sir, which the

true old Methodists always did, and I trust always will abjure, detest
and abhor. If worldly church preferments had been their aim, some of
them at least might have had worldly ladders enough let down to
them to climb up by: but having received a kind of apostolical
commission at their ordination, when those who profess themselves
lineal successors of the Apostles, said unto them, “Receive ye the
Holy Ghost now committed unto you by the imposition of our hands:”
they would fain keep up and maintain something of the dignity of an
apostolic character; and therefore, without ever so much as
designing to enter into any political cabals, or civil or church factions
whatsoever, without turning to the right hand or the left, or troubling
the world with so much as one single sermon or pamphlet, on the
bare externals of religion; they have endeavoured to have but one
thing in view, namely, to determine to think of nothing, to know
nothing, and to preach of nothing but Jesus Christ, and him
crucified; to spend and be spent for the good of souls, and to glory in
nothing save in the cross of Christ, by whom the world is crucified
unto them and they unto the world.

It is true, by thinking and acting thus, the Methodists have been,

and it is presumed always will be, charged and condemned by men
of corrupt minds, as thinking and acting irregularly and disorderly:
but as such a charge, in the very nature of the thing, supposes a
deviation from some settled standing rule, they would humbly ask,
wherein the irregularity and disorderliness of this way of acting and
thinking doth specifically consist? Is it irregular and disorderly to be
“instant in season and out of season?” Is it irregular and disorderly to
do what every Bishop at the very time of our being ordained priests
positively tells us pertaineth to their office, “to seek after the children
of God, scattered abroad in this naughty world?” Is it irregular and
disorderly after we have established the truth of what we deliver in
our sermons by scripture proofs, further to confirm and illustrate
them by repeated and particular quotations, taken from the liturgy,
articles, and homilies of our established church? Is it irregular and
disorderly to fill her pews, to croud her communion tables, and to
recommend a frequent and constant devout attendance upon her
public offices and services? Or, supposing they should, merely by
caprice or prejudice, be denied the privilege of preaching within the
church, can it be justly termed irregular or disorderly, at least can it
possibly be looked upon as criminal, to preach the same truths, to
make use of the same kind of illustrations, to repeat the self-same
recommendations without the church walls, in the fields, or any other
place whatsoever?

The late candid Bishop of Lincoln, I am positive, did not think

such a way of acting altogether so very criminal: for in a charge
given to his clergy some years before his translation to the see of
Salisbury, he told them to this effect, “that they were not to look upon
themselves as ministers of a Plato, a Pythagoras, or any other
heathen philosopher, consequently they were not to entertain their
auditories with mere moral harangues; but that they were to consider
themselves as ministers of Jesus Christ; and therefore if they
would not preach the gospel in the church, they could not be justly
angry if the poor people went out to hear it in a field.” A charge this,
truly worthy of a sober-minded, moderate, wise Bishop of the Church
of England. For even in acting thus seemingly irregular and
disorderly, these modern enthusiasts only copy after the greatest
and brightest examples the world ever saw, and whose examples it
is more than criminal not to follow or copy after. Our blessed Lord,
when denied the use of the synagogues, on seeing the multitude,
went up and chose a mountain for his pulpit, and the heavens for his
sounding board. At other times he sat by the sea-side, nay, went into
a ship and preached, whilst the whole multitude stood on the shore.
When Peter and John, that this kind of enthusiasm might spread no
further among the people, were straitly threatened and commanded
that they should thenceforth speak at all to no man in Christ’s
name, they calmly yet boldly replied unto their threatners and
commanders, “Whether it be right in the sight of God, to hearken
unto you, more than unto God, judge ye: for we cannot but speak
the things which we have seen and heard.” A certain woman, named
Lydia, a seller of purple, had her heart opened when the great
apostle of the Gentiles was preaching and praying by a river-side;
and Dionysius the Areopagite, a woman named Damaris, and
others, believed, and clave unto the same Apostle, from the time
they heard him preach in the midst of Areopagus, or Mars-hill. And
we may suppose he was not less successful when he was obliged
by the angry Jews to preach in the school of one Tyrannus.

I believe you will agree, Reverend Sir, that the venerable Fox and
Bradford did not appear less venerable for preaching at Pauls-cross;
neither did I ever hear that Bishop Latimer was looked upon as
degrading his episcopal character, when he used to preach in
Cotton-Garden Westminster, and King Edward the sixth, that Josiah
of his age, with some of his court, looked out at the palace window to
hear him. And I hereby appeal to the whole university, whether the
Reverend Doctors of divinity, heads of houses, graduates or under-
graduates, ever looked upon it as criminal, or beneath the dignity of
their place and station, to sit out in the open air on St. John Baptist’s
day, to hear a master of arts preach from the stone pulpit in
Maudling-College yard; though, for fear it may be they should give
further sanction to field-preaching, they have lately thought proper to
adjourn into the chapel?

You know, Reverend Sir, who it was, that when those who were
bidden in a regular way refused to come to the wedding-supper,
without asking any one’s leave for so doing, sent forth some
irregulars into the lanes and streets of the city, into the highways and
hedges, with that glorious encouraging commission, not by fines and
imprisonments, not by threats and expulsions, not by killing the body
for the good of the soul, but by filling their mouths with gospel
arguments, backed with the all-powerful energy of the Holy Ghost, to
compel poor, wandering, weary, heavy laden sinners to come in.
Armed with this panoply divine, and, as they think, authorised by the
same Lord, some few of us continue to this day, amongst small and
great, high and low, rich and poor, in church or chapel, in commons,
streets, fields, whensoever or wheresoever divine providence opens
a door, “to testify repentance towards God and faith in our Lord
Jesus Christ;” and this not from contempt of, or in opposition to the
godly admonitions of our ecclesiastical superiors, but because “the
love of Christ constraineth us;” and we think that a wo, a dreadful
wo, awaits us if we preach not the gospel. Not that we are enemies
to a decent or even episcopal consecration, or setting apart
churches and chapels for divine and holy worship: but we are more
indifferent about the reputed outward sanctity of places, because our
Lord, with great solemnity, said unto the woman of Samaria,
“Woman, believe me, the hour cometh when ye shall neither in this
mountain, nor yet at Jerusalem, worship the Father: but the hour
cometh, and now is, when the true worshippers shall worship the
Father in Spirit and in truth.” Hence we infer, that every place is then,
and only then properly called holy, when like the ground around the
burning bush, it is made holy by the divine presence of Him who
spake to Moses out of the bush; or like mount Tabor, which by the
Apostle Peter is called, by way of emphasis, the holy mount,
because himself and James and John, not only had upon that mount
a visible outward manifestation, but also a blessed inward heart-felt
sense of the Redeemer’s excellent glory. It was undoubtedly this
which made Peter to break out into that exclamation: “Master, it is
good for us to be here.” And it was this that warmed, and not only
warmed, but constrained the enraptured Patriarch Jacob, when he
had only the ground for his bed, the stones for his pillow, and the
open firmament for his curtains and furniture, to break forth into that
extatic language, “How dreadful is this place! this is no other than the
house of God, this is the gate of heaven.”

If then, Reverend Sir, for this and such like things we are
accounted irregular and disorderly, we are truly sorry for it: sorry, but
not upon our own accounts, having the testimony of a good
conscience that we act with a single eye, and in direct conformity to
the authority of the word of God: but we are sorry, barely on account
of our impeachers and condemners, especially for those, who being
set apart for the ministerial office, and loaded with ecclesiastical
preferments, preach very seldom, or not at all; or, if they do preach
now and then, preach only as though they were barely reading wall-
lectures, and seldom or ever so much as mention or quote the
homilies of our church, though they have subscribed to an article
which says, that “they contain godly and wholesome doctrine, and
which judges them to be read in churches by the ministers diligently
and distinctly, that they may be understood of the people.” It is to be
feared, that it is owing to such irregularity and disorder as this, that
when our people hear of our articles or homilies quoted by some few
in the pulpit, that they are ready to cry out, “What new doctrine is
this? Thou bringest certain strange things to our ears:” At least if it is
not so at home, I am sure it is abroad. Hence it was that about three
years ago, after I had been preaching to a very large auditory in one
of the most polite places on the continent of America, and in
preaching, as is my usual custom, had strongly been recommending
the book of homilies, numbers were stirred up to go to the stores to
purchase them: but upon enquiring after the book of homilies, the
storekeeper, surprized at the novelty of the word homilies, begged
leave to know what muslins they meant, and whether they were not
hummims.

What a pity therefore is it, Reverend Sir, that the book of

homilies, which ought to be in every hand, and as common as our
common prayer books, should never yet have found a place in the
large catalogue of books given away by the truly laudable society for
promoting christian knowledge, though founded soon after the
glorious revolution. If this be not remedied some way or another, we
shall very soon become disorderly indeed: our pulpits will still
continue to contradict our reading-desks, and we shall never have
the honour of being stiled regular and orderly, till, regardless of
subscriptions, oaths, rubrics, and ordination-offices themselves, our
practices give the lie to our professions, and we seek the fleece not
the flock, and “preach ourselves, and not Christ Jesus the Lord.”

Dead formalists, and proud self-righteous bigots, may loudly

exclaim and cry out, “the temple of the Lord, the temple of the
Lord, the temple of the Lord are we!” They may not only cry out,
but also cast out; and thinking they thereby do God service, though
most notoriously deficient in their own moral conduct, may plead
conscience, and say, “Let the Lord be glorified.” But to such as
these our Lord once said, “Ye are they that justify yourselves before
men, but God knoweth your hearts.” Like the chief priests, and the
scribes and pharisees of old, they may plead their law; for the breach
of which, these irregulars, as they imagine, ought to be condemned
and suffer; nay, a time may come when they may be permitted to
enforce their clamorous accusations, by urging, as their godly
predecessors once did against our Master, that “we found these
fellows perverting the nation, and forbidding to give tribute unto
Cæsar: but Pilate knew that for envy they delivered Him.” And
though they could plead their loyalty, and say, “If thou let this man
go, thou art not Cæsar’s friend, we have no king but Cæsar;” yet
both our Lord and his Apostles rendered themselves, and strictly
taught all that heard them, to “render unto Cæsar the things that are
Cæsar’s, and unto God the things that are God’s.” Fain would the
Methodists copy after such gloriously divine examples: and blessed
be God, after a trial of near forty years, upon the most severe
scrutiny, their loyalty cannot be justly so much as once called in
question: for, as they fear God, so they dearly love and honour their
King, their rightful sovereign King George; and have been, and
continue to be, steady, invariable friends to the protestant
succession in the illustrious house of Hanover. And if so, supposing
these Methodists should be convicted of acting somewhat irregular,
since it is only the irregularity of preaching and recommending
unfeigned love to God, and, for his great name sake, undissembled,
disinterested loyalty to their King; is it not the interest as well as duty
of civil government, if not to encourage, yet not to oppose them? For
it is certainly a most incontestable truth, that every additional
proselyte to true Methodism, is an additional loyal subject to King
George the Third, whom, with his royal most amiable consort, our
gracious Queen Charlotte, the Methodists with one united voice
earnestly pray, God long to continue to be a nursing father and
nursing mother to our church, and people of every denomination
whatsoever.

Every body is loudly complaining of the badness of our times,

and the degeneracy of our morals. Sinners now proclaim their sin
like Sodom, and the nation hath suffered more than a second deluge
by an innundation of every sin, and every kind of corruption that was
ever committed or practised under heaven: “The whole head is sick,
the whole heart faint; from the crown of the head to the sole of our
feet, we are full of wounds and bruises, and putrifying sores.” Shall
there no man be found then to stand in the gap? None dare to
attempt at least to stem the impetuous torrent? None venture to go
out with their lives in their hand, and cry to a profane, careless, busy
world, “Ho! every one that thirsteth, come ye to the waters.” Can any
considerate, much more can any real good man be so cruel, as even
to wish that the gospel should be confined either to church or
meeting, when there are so many thousands and tens of thousands,
who as to spiritual things, know not their right hand from their left,
and who never go either to church or meeting at all? If some are
called to be settled ministers (and may the great Head of the church
fill all our parish-churches and meeting-houses with true evangelical
pastors!) may not others be called out to be itinerants? Have there
not been presbyters at large, even from the earliest times of
christianity? And if some of a more inferior rank and order should be
qualified, and thrust forth by the great Lord of the harvest, when the
harvest is so great, and the labourers so few, who shall dare to say
to Him, “What dost thou?” Shall our eye be evil because he is good?
If Isaiah was a courtier, was not the Prophet Amos a herdsman? In
the days of Moses, when the Israelites were under a more
immediate divine theocracy, news was brought him, and that too
even by a Joshua, that Eldad and Medad were prophesying in the
camp, without his licence or his ordination; what doth this meek man
of God say? “Enviest thou for my sake? Would to God all the
Lord’s people were prophets.” And in the days of our Lord himself,
his beloved disciple John, before his heart was more enlarged by
divine love, said unto him; “Master, we saw one casting out devils in
thy name, and he followeth not with us, and we forbad him, because
he followeth not with us.” But what said Jesus, that good Shepherd
and Bishop of souls? “Forbid him not.”

Such instances, such striking instances as these, methinks,

should make good men careful not to give way to a narrow, selfish,
bigotted spirit; and caution them against joining with the world in
smiting their fellow-servants, by crying down or speaking slightingly
and reproachfully of a method of preaching and acting, which,
maugre all opposition, for these thirty years last past hath been
blessed and owned of God to the converting of thousands; not to a
bare name, sect, or party, or merely to head or notional knowledge;
but “from darkness unto light, from the power of Satan unto God;”
from holding the mere form, to the true abiding possession and
practice of true scriptural godliness, in heart, lip, and life. But if good
or bad men now dislike, and therefore oppose such an irregular way
of acting, they may be told to their comfort, that their uneasiness on
this account, in all probability, will not be of long continuance; for few
will choose to bid, or offer themselves candidates for such airy
pluralities: to go thus without the camp, bearing all manner of
reproach; to become in this manner; “Spectacles to God, to angels,
and to men;” to sacrifice not only our natural, but spiritual affections
and connections, and to part from those who are as dear to them as
their own souls, in order to pass the Atlantic, and bear the colds and
heats of foreign climes; these are such uninviting things to corrupt
nature, that if we will have but a little patience till a few old weary
heads are laid in the silent grave, these uncommon gospel-meteors,
these field-phenomenas, that seldom appear in the latitude of
England, scarce above once in a century, without the help of any
coercive means, will of themselves soon disappear. They begin to be
pretty well in disrepute already: yet a little while, and in all human
probability they will quite vanish away. But though I am neither a
prophet, nor the son of a prophet, I am greatly mistaken, if in the
Redeemer’s own good time and way, some spiritual phœnix will not
hereafter arise, some blessed gospel-instrument be raised, that shall
make the devil and his three-fold army, “The lust of the flesh, the lust
of the eye, and the pride of life,” to fly before the sound of the gospel
trumpet.

I have dwelt the longer upon this particular, Reverend Sir,

because the present learned Bishop of Gloucester, in his late
volume, intitled, “The Doctrine of Grace,” is pleased to observe more
than once, that he finds fault not so much with the matter, as the
manner of the Methodists preaching. But if by the manner, his
Lordship would have us to understand, not their manner of preaching
in the field, but the manner of their delivery, whether in the church or
field, I would humbly ask his Lordship, if he ever heard any of them
preach? If not, doth our law condemn any man, or any set of men,
unheard? And I would humbly enquire further of his Lordship, and all
others whom it may concern, how they would have them or any
others to preach?

I remember the great Doctor Delany, when I had the honour of

being with him, many years ago, at the Right Reverend Dr. Boulter’s,
then Lord Primate of Ireland, among other hints proper for a young
preacher, gave me to understand, that whenever he went up into a
pulpit, he desired to look upon it as the last time he should ever
preach, or the last time that the people should ever hear him. O that
all preachers, whether within or without doors, however dignified or
distinguished, went always up into their respective pulpits thus
impressed! They would then preach, as Apelles once said he
painted, for Eternity. They would then act the part of true gospel
christian orators, and not only calmly and ♦ coolly inform the
understanding, but by persuasive pathetic address, endeavour to
move the affections, and warm the heart. To act otherwise, bespeaks
a sad ignorance of human nature, and such an inexcuseable
indolence and indifference in the preacher, as must constrain the
hearers, whether they will or not, to suspect, that the preacher, let
him be who he will, only deals in the false commerce of unfelt truths.

♦ “cooly” replaced with “coolly”

Were our lawyers, our counsellors, or our players to act thus,

both the bar and the stage would soon be deserted; and therefore
the answer of Mr. Betterton, to a worthy prelate, when he asked him,
“How it came to pass that the clergy, who spoke of things real,
affected the people so little, and the players, who spoke of things
barely imaginary, affected them so much,” is worthy of lasting regard.
“My Lord, says Mr. Betterton, I can assign but one reason, which is,
we players speak of things imaginary as though they were real, and
too many of the clergy speak of things real as though they were
imaginary.” Thus it was in his, and all know it is too much the case in
our time: hence it is, that even on our most important occasions, the
worthy gentlemen concerned in our public charities, generally find
themselves more obliged to the musicians than the preachers, for
the largeness of their collections: and hence, no doubt it is, that upon
our most solemn anniversaries, after long previous notice hath been
given, when some even of our Lords Spiritual do preach, perhaps
not two Lords temporal come to hear them.

Sorry am I, Reverend Sir, to find so true, what a celebrated

orator, in one of his lectures delivered, (if I am not mistaken, in the
University of Oxford) takes the liberty of saying, “That it is to be
feared this is too much the state of the pulpit-elocution in general, in
the Church of England: on which account, there never was perhaps
a religious sect upon earth, whose hearts were so little engaged in
the act of public worship, as the members of that church. To be
pleased, we must feel, and we are pleased with feeling. The
Presbyterians are moved; the Methodists are moved; they go to their
meetings and tabernacles with delight; the very Quakers are moved;
fantastical and extravagant as the language of their emotions is, yet
still they are moved by it, and they love their form of worship for that
reason: whilst much the greater part of the members of the Church
of England, are either banished from it through disgust, or reluctantly
attend the service as a disagreeable duty.” Thus far Mr. Sheridan.

But why go I to the bar or stage to fetch vouchers in defence of

earnestness in heart and action, when speaking for the most High
God, and offering salvation to precious and immortal souls, for
whom the ever-adorable Mediator shed his precious blood. You
know, Reverend Sir, the character given of Bucolspherus, one of the
Reformers, Vividus vultus, vividi oculi, vividæ manus, denique omnia
vivida. You have also heard of a Prophet who was commanded by
the Lord God himself, to smite with his hand, and stamp with his
foot; and gospel-ministers in general are commanded to “cry aloud,
and spare not, and to lift up their voices like trumpets.” But why refer
I even to Reformers or Prophets? Rather let me mention the God
and Saviour of all, even our Lord Jesus Christ; on whose manner
of preaching, the multitudes that followed him, when he came down
from the mount, made this just observation, that “He spake as one
having authority, and not as the scribes.” And after his resurrection,
when beginning at Moses and all the Prophets, he expounded unto
them in all the scriptures the things concerning himself, the two
disciples at Emmaus said one to another, “Did not our hearts burn
within us while he talked with us by the way, and while he opened to
us the scriptures?” And I believe we may venture to affirm, that if
preachers in general spake and opened the scriptures more under
the influence and energy of his blessed Spirit, whether in
consecrated or unconsecrated ground, within or without doors, they
would find their hearers hearts in a degree would burn within them
too.

But I have done.—You will be so good, Reverend Sir, as to

pardon not only the freedom but prolixity of this. I have already
mentioned my motives for writing; and therefore shall now close with
the advice given upon a similar occasion to an ecclesiastical council
by Gamaliel, a doctor of law, and had in reputation among all the
people: “And now I say unto you, refrain from these men, and let
them alone: for if this counsel or work be of men, it will come to
nought; but if it be of God, ye cannot overthrow it: lest haply ye be
found to fight against God.” To this God, and the word of his grace, I
most humbly recommend you and the whole University; and
earnestly praying, that all at all times may have a right judgment
given them in all things, I beg leave to subscribe myself, Reverend
Sir,

Your willing servant for Christ’s sake,

George Whitefield.
 O B S E RVAT I O NS
ON

Select Passages of Scripture.

TURNED INTO

C at e c h e t i c a l
Q u e s t i o n s.
Begun, March 12, 1738.

OBSERVATIONS on Select
Passages of Scripture.
LUKE, Chapter XXIII.

Ver.

8. Q. WHY would not Jesus Christ shew Herod a miracle?

A. Because in all probability, it was only to satisfy his

curiosity that he desired to see one.

Q. What may we learn from Herod’s never having seen

Christ before?
 A. That Christ was no friend to courts; that pomp and
greatness keep thousands from Jesus Christ; and that we
ought therefore rather to thank God for our being in a lower
estate.

12. Q. What may we learn from the friendship made between

Pilate and Herod, by the death of Christ?

A. That Jew and Gentile, by Christ’s death, were to be

united together in one body: Herod being a Jew, and Pontius
Pilate a Gentile.

18. Q. When do we as these Jews did?

A. When we prefer our sins, (which are robbers, because

they rob us of God’s favour) to our Saviour’s service.

26. Q. What may we learn from Simon the Cyrenian’s bearing

the cross?

A. That they who would follow Christ, must follow him by

the way of the cross.

31. Q. What is the meaning of this verse?

A. A good man in scripture is compared to a green fruitful

tree, (See Psalm 1st.) and wicked men to chaff, and are
represented also by a barren fig-tree: the meaning of the verse
therefore seems to be this: If they do this to me, who am a good
man, how will God deal with that wicked people the Jews?

32. Q. Why was Christ crucified with the thieves?

A. To fulfill this saying, “And he was numbered with the

transgressors.” Isaiah liii. 12.

Q. Why between them?

A. As though he was the unworthiest and basest of the three.

34. Q. What may we learn from hence?

A. To pray for our most bitter enemies.

38. Q. Why was the superscription written in Hebrew, Greek,

and Latin?

A. To shew that Jesus Christ was to be the Saviour of all

nations, tribes, and languages.

39. Q. What may we learn from the behaviour of the impenitent

thief?

A. That for the generality, those who live all their lives in sin,
die hardened.

40. Q. What may we learn from the behaviour of the penitent

thief, and Christ’s behaviour towards him?

A. That there is mercy for the worst of sinners, through

Christ the Saviour.

Q. May wicked men draw any reasons from hence, to defer

their repentance till a death-bed?

A. No, by no means.

Q. Why?

A. Because probably this thief had never heard of Christ

before. 2dly, He might not have been so notorious a sinner as is
imagined, though drawn in by surprize or temptation to commit
the crime for which he suffered. 3dly, God converted him, to
honour his Son’s death, that he might in the very agonies
thereof triumph over the devil. 4thly, Because he gave
uncommon instances of his faith: he calls Christ, “Lord,” when
his own disciples had forsook him, when the High-priest,
scribes, and rulers were deriding him, and his own divinity under
 an eclipse: none of which circumstances are applicable to a
wilfully wicked man, that defers repentance till he comes to die.

44. Q. What is the sixth hour?

A. Twelve at noon.

Q. What the 9th?

A. Three in the afternoon.

45. Q. What was the vail of the temple?

A. A curtain that parted the two places, where the Jews and
Gentiles worshipped.

Q. Why was it rent in twain?

A. Because by the death of Christ, the partition wall

between Jew and Gentile was to be broken down.

46. Q. Why did Christ cry with a loud voice?

A. To shew that he died full of vigour.

Q. What may we learn from his calling God, Father?

A. That we are to acknowledge God to be our father, though

under the severest dispensations of his providence.

51. Q. What learn you from hence?

A. That we must not follow a multitude to do evil.

53. Q. Why was it remarked, that Christ’s grave was hewn out
of a rock?

A. Because then it could not be said, that his disciples

digged under, and stole it away.