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162 Chapter 6
how closely does the BOLD signal, and the functional hyperemia it reflects,
correlate with neuronal activity? Understanding the answers to these questions is critical to being an informed user of fMRI methods and an informed
consumer of fMRI results.
Information Processing in the Central
Nervous System
In this chapter, we will explore the links between neuronal activity, energy
consumption, cerebral metabolism, and blood flow. We begin by describing
the foundation of information processing in the brain: the neurons and supporting cells, the nature of their information transactions, and their metabolic
costs.
Neurons
cerebral cortex (neocortex) The thin
wrapping of cells around the outer
surface of the cerebral hemispheres. It
has a layered structure, referred to as
cortical columns or cortical layers.
cerebellum A large cortical structure at
the caudal base of the brain that plays
an important role in motor function.
soma The body of a cell; it contains
cytoplasm, the cell nucleus, and
organelles.
dendrite A neuronal process that receives signals from other cells. A neuron typically has multiple dendrites,
which perform a primarily integrative
function.
axon A neuronal process that transmits an electrical impulse from the
cell body to the synapse, performing
a primarily transmissive function. A
neuron typically has a single axon,
which in some types of neurons can
be extremely long and/or can branch
profusely.
integrative activity The collection of
inputs from other neurons through
dendritic or somatic connections.
transmissive activity The relaying of
the outcome of an integrative process
from one neuron to another, typically
through signals sent via axons.
pyramidal cell A common neuronal
type of the cerebral cortex. These cells
have a pyramid-shaped soma, extensive spined dendrites, and are characterized by a long, branching axon that
can extend for many centimeters.
The neuron is the primary information-processing unit of the central nervous
system. Modern stereological evidence has estimated that the brain of an
average-size adult male human contains some 86 billion neurons, give or take
8 billion. Of these 86 billion neurons, about 16 billion are contained within the
cerebral cortex, or neocortex, a thin wrapping of cell bodies around the outer
surface of the brain. About 69 billion neurons are contained in the cerebellum,
a structure located in the posterior fossa (skull depression) below the cerebral
hemispheres that has an important role in controlling movements and other
functions. (See Figure 1 in Box 6.3 at the end of this chapter; Box 6.3 provides
an overview of key concepts in neuroanatomy.) The cerebellum accounts for
only 10% of the size of the brain, but due to its high density of tightly packed
neurons, it contains nearly 80% of the brain’s neurons.
There are many different types of neurons, all of which can generate and
transmit electrical signals. As in most other cells of the body, the soma (cell
body) of a neuron contains cytoplasm, organelles such as the Golgi apparatus
and mitochondria, and a nucleus containing DNA (Figure 6.2A). Uniquely,
however, the cell body of a typical neuron gives rise to multiple branching protoplasmic processes called dendrites that vary greatly in number and
spatial extent. Most neurons also have a single, larger protoplasmic process
called an axon, which can branch extensively. A useful simplification is that
neuronal activity can be characterized as either integrative or transmissive.
Integrative activity occurs when a neuron collects and integrates input from
other neurons through connections on its dendrites and soma. Transmissive
activity communicates the outcome of the neuron’s integrative processes to
other neurons via its axons.
The human cerebral cortex has six layers, defined by different compositions of neuron density and types (see Figure 3 in Box 6.3). Within this cortical
structure, inputs and outputs tend to be stratified to the different layers, and
neural processing may occur within vertically organized units called columns.
One common neuron in the cerebral cortex is the pyramidal cell, named for
the shape of its soma (Figure 6.2B). A typical pyramidal cell has extensive
dendrites that are studded with spines. The pyramidal cell also has a large
axon that can travel a long distance; the axons of pyramidal cells provide the
principal output from most cortical regions. For example, the axons of layer
V pyramidal cells in motor cortex form the corticospinal tract that extends
from the cortical surface of the brain well down into the spinal cord. Other
neurons within the cortical layers contribute to intracortical processing and
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From Neuronal to Hemodynamic Activity 163
(A)
(B)
Axon of second neuron
Synapse
Dendrites
Double bouquet
cell
Synaptic cleft
Microtubule
Mitochondrion
Nucleus
Nucleolus
Microfilament
Large basket cell
Soma
Rough endoplasmic
reticulum
Chandelier cell
Cell membrane
Axon hillock
Myelin
Pyramidal cell
Axon
Axon terminals
Axon
Figure 6.2 Neuron organization and structure. (A) As seen in
this stylized depiction, neurons are organized into three basic
parts. Dendrites integrate signals coming from other neurons
via small gaps known as synapses. The soma, or cell body,
contains the nucleus and organelles that support metabolic
and structural properties of the neuron. Changes in the membrane potential of the neuron are signaled to other neurons
by action potentials that travel along its axon. (B) Neurons
come in a variety of shapes as indicated in this drawing from
DeFilepe and Fariñas (1992). The large neuron in the center is
a pyramidal cell, the principal output cell type of the cerebral
cortex. The smaller neurons are different kinds of interneurons,
which facilitate intracortical processing.
are thus called interneurons. Although the output from pyramidal cells excites
other neurons, the output from interneurons can both excite and inhibit other
neurons, as will be discussed later in this chapter.
Glia
Along with neurons, glial cells, or glia, are also important cellular constituents
of the central nervous system. Glial cells were once thought to greatly exceed
neurons in number. However, research now suggests that the ratio of neurons
to glia is closer to 1:1. The most common glial cells found in the brain are
microglia, oligodendrocytes, and astrocytes. Microglial cells are part of the
brain’s immune system and act as phagocytic scavengers, among several duties. Oligodendrocytes wrap themselves around the axons of some neurons,
forming a myelin sheath that helps speed the transmission of information.
Astrocytes, the most numerous glial cells in the brain, play an important
role in mediating the relationship between neuronal activity and vascular activity. They are named for their star-shaped appearance, the result of numerous
protoplasmic processes extending from the cell body (Figure 6.3). These processes make contact with blood vessels and can cover much of the surface of
intracortical arterioles and capillaries, as we will see in the last section of this
chapter. Astrocytes are coupled to adjacent astrocytes by gap junctions—small,
interneuron A neuron that is connected
locally to other neurons. Interneurons
participate in local brain circuits,
but do not project to distant cortical
regions.
glial cells (glia) Brain cells that support
the activities of neurons but are not
primarily involved with information
transmission.
astrocyte A type of glial cell that regulates the extracellular environment. It
is the most prevalent glial cell type in
the brain.
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164 Chapter 6
Figure 6.3 An astrocyte (green) showing its protoplasmic
end-feet processes in contact with blood vessels (red). (Photograph courtesy of Dr. S. A. Fisher, University of California
Santa Barbara; prepared by G. Luna and P. Keeley.)
concentration gradient A difference
in the density of a substance across
space. Substances diffuse along
concentration gradients from areas
of high concentration to areas of low
concentration.
ion channel A pore in the membrane of
a cell that allows passage of particular
ions under certain conditions.
ligand-gated ion channel An ion channel that opens or closes in response to
binding of chemical signals (ligands).
The ligand is often a neurotransmitter
molecule.
specialized regions where the membranes of two cells touch—that allow small
molecules and ions to pass from one astrocyte to another without those molecules entering the extracellular milieu. Such gap junctions thus allow molecular
messages to pass along connected astrocytes. Recent studies have suggested
that astrocytes may play an important role in synaptic transmission and the
creation of new synapses, as we will soon describe.
Neuronal membranes and ion channels
Neuronal integration and transmission both depend on the properties of neuronal membranes, which are lipid bilayers that separate the internal contents
of neurons from the external milieu. An important role of neuronal membranes is to restrict the flow of chemical substances into and out of neurons.
When substances are allowed to diffuse freely, they diffuse from areas of high
concentration to areas of low concentration. That is, they move along a concentration gradient until an equilibrium is reached. Neuronal membranes prevent
free diffusion, but they have embedded proteins that form pores, or ion channels, through which ions such as sodium (Na+), chloride (Cl–), potassium (K+),
and calcium (Ca2+) can diffuse (Figure 6.4A). (Note that an ion can have either
a negative charge, an anion, from having gained one or more electrons, or it
can have a positive charge, a cation, from having lost one or more electrons.)
Ion channels are selective, in that some ions can pass through a specific channel and others cannot. Furthermore, channels have gating mechanisms that
can close or open the channel to ion traffic in response to molecular signals.
These gating mechanisms can be grouped into several categories:
•Ligand-gated ion channels depend on the actions of specific “messenger
molecules,” or ligands, that bind to receptor proteins. For example, ligand-gated ionotropic channels open when a messenger molecule, such
as a neurotransmitter, binds to (ligates) a receptor on the exterior of the
channel. Ligand-gated metabotropic channels open when a messenger
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From Neuronal to Hemodynamic Activity 165
(A)
Figure 6.4 Ion channels and pumps. (A) Ion channels
(B)
Na+
K+
Lipid
bilayer
Outside
Neuronal
membrane
ATP
Inside
allow particular ions to diffuse across membranes along
concentration gradients. Channels may be opened by
the actions of particular molecules, or they may open
when the voltage difference across the membrane
reaches a threshold. (B) Pumps move ions across membranes against their concentration gradients, usually at
a cost of energy supplied by ATP. The very important
pump depicted here transports sodium out of the cell
while bringing potassium into the cell.
ADP
Ion channel
Sodium-potassium pump
molecule binds with a specific receptor on the neuron’s surface membrane. This metabotropic binding activates so-called second messengers within the cell, and these second-messenger molecules initiate
biochemical cascades that can open ion channels and/or activate other
molecular machinery within the cell.
•Voltage-gated ion channels open not in response to second messengers
or a bound ligand, but rather when the electrical potential difference
across the membrane reaches a particular threshold.
•Finally, some receptors are both ligand- and voltage-gated. For example,
the NMDA (N-methyl-D-aspartate) receptor is activated by glutamate.
However, the channel is blocked by a magnesium (Mg2+) ion that is
ejected when the local membrane is depolarized. Once the Mg2+ is
cleared by the voltage change, the channel admits both Na + and Ca2+
into the neuron.
voltage-dependent ion channel An
ion channel that opens or closes in
response to changes in membrane
potential.
pump A transport system that moves
ions across a cell membrane against
their concentration gradients.
sodium–potassium pump A transport
system that removes three sodium
ions from within a cell while bringing
two potassium ions into the cell.
Although an open channel can allow ions to diffuse passively down their
concentration gradients, membranes also contain pumps that can transport
ions across the membrane against the ions’ concentration gradients, thereby
maintaining or restoring an unequal distribution of some ions ( Figure 6.4B).
One of the most important pumps is the sodium–potassium pump, which uses
a transporter molecule that forces three sodium ions out of the cell and brings
two potassium ions into the cell. The net result of the action of the sodium–potassium pump and other transporters, along with the selective permeability of
the membrane channels to different ions, is that a neuron at rest has a greater
concentration of K+ inside its membrane and a greater concentration of Na+,
Ca2+, and Cl– outside its membrane. Any transient change in the permeability
of the membrane will cause an influx (movement into the cell) or efflux (movement out of the cell) of these ions as the system eliminates the concentration
gradient and establishes equilibrium.
The diffusion of substances through channels down their concentration
gradients requires only kinetic energy from heat, but the operation of pumps
requires cellular sources of energy. For example, one turn of the sodium–potassium pump requires the energy of one molecule of adenosine triphosphate,
or ATP, which is converted to adenosine diphosphate, or ADP. (We will have
more to say about ATP later in this chapter, when we discuss cerebral metabolism.) Consider the analogy of a water tower in which holes in the bottom of
the reservoir allow the water to pass into pipes descending below. Here, the
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166 Chapter 6
1 Action potential
travels down axon.
axon
Myelin
Axon
2 Action potential depolarizes
presynaptic membrane,
opening voltage-dependent
Ca2+ ion channels.
Ca2+
Vesicles (store
neurotransmitters)
3 Ca2+ flows into cell,
causing vesicles to fuse
3 with presynaptic
membrane.
4 Neurotransmitter
(e.g., glutamate) is
released into synapse.
Presynaptic
membrane
5 Neurotransmitter binds
with receptors on postsynaptic ion channels,
opening them.
Synaptic
cleft
Glutamate
Neurotransmitter
molecules
Electrode
Na+
Postsynaptic
membrane
Dendrite
+
Ion channel
+
+ +
+ +
+
+ + + + +
+ + + +
Local
EPSP
6 Ions (e.g., Na+) flow
into postsynaptic cell,
changing its potential.
7 The resulting potential
change is known as an
EPSP or IPSP.
Figure 6.5 An action potential leads to the release of neurotransmitters at a
synapse.
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From Neuronal to Hemodynamic Activity 167
gravity gradient is analogous to a concentration gradient, and the holes are
analogous to open ion channels. Water will move through the holes and run
through the pipes down the gravity gradient without the need for additional
energy. The situation is quite different, however, if we want to return the water
to the tower. Active pumping against the gravity gradient is now required,
and the pump requires energy to operate.
While this analogy is instructive, it is incomplete. Because ions have electrical charge, their unequal distribution also results in a resting electrical
potential difference between the inside and outside of the membrane; that is,
neurons are electrically polarized. For neurons, the inside of the cell is about
–40 to –70 mV relative to the outside of the cell. Part of this negative resting
potential is due to protein anions within the neuron that are too large to exit
the cell through ion channels. Thus, the movement of ions across a membrane
is governed by both chemical and electrical gradients. The movements of ions
across the membranes and the resulting changes in membrane potentials are
the generators of synaptic transmission.
Synapses: Information transmission between neurons
In stylized form, information processing within a neuron begins with input
from other neurons at synapses; leads to integrative activity in the dendrites
and soma, where the neuron receives information from hundreds or even
thousands of other neurons; and ends with transmissive activity associated
with changes in their membrane potentials along long axons. A distinction
is sometimes drawn between “wired” and “volume” modes of information
transmission between neurons. Wired transmission does not, of course, involve
wires, but refers to the transmission of information at specialized junctions
called synapses, where a thickening of a terminal axon process from one neuron (the presynaptic terminal) is physically apposed to a postsynaptic membrane of the dendrite or soma of another neuron (the postsynaptic membrane)
(Figure 6.5). In pyramidal and some other neurons, the postsynaptic membranes of dendrites are located on the spines. These presynaptic and postsynaptic membranes typically are separated by a small space, the synaptic cleft,
into which chemical messengers called neurotransmitters are released from the
presynaptic element and subsequently influence activity in the postsynaptic
membrane. In a relatively small number of specialized electrical synapses,
the presynaptic and postsynaptic membranes are in physical contact, and
electrical signaling events can cross membranes without intervening chemical messengers. A neuron may have hundreds or even many thousands of
synapses on its dendrites and soma. It has been estimated that there are 100
to 150 trillion synapses in the human brain.
Volume transmission occurs when the presynaptic membrane is not apposed
to an obvious postsynaptic membrane. Rather, the chemicals released by the
presynaptic membrane diffuse into the extracellular space and may then affect cells that are distant from the release site—something more typical of
hormonal communication. Whereas wired transmission can be fast (occurring
over milliseconds), volume transmission is slow, and may have modulatory
effects that persist for many seconds or even minutes. The targets of volume
transmission may be other neurons, or they may be glia or blood vessels.
Figure 6.5 introduced the concept of the synapse in terms of two neurons
exchanging information. Now we can expand the concept to include three
components in what is known as the tripartite synapse (Figure 6.6). Besides
the presynaptic membrane at the terminus of an axon and the postsynaptic
membrane on the dendrite or soma of the receiving neuron, the organization
membrane potential The difference in
electrical charge between the inner
and outer surfaces of a cell membrane,
the result of a difference in the distribution of ions.
wired transmission The transmission
of information from one neuron to a
closely apposed neuron across a synaptic cleft. Often used synonymously
with synaptic transmission.
synapse A junction between neurons
where the presynaptic process of an
axon is apposed to the postsynaptic
process of a dendrite or cell body.
synaptic cleft A gap between presynaptic and postsynaptic membranes.
neurotransmitters Chemicals released
by presynaptic neurons that travel
across the synaptic cleft to influence
receptors on postsynaptic neurons.
volume transmission The transmission
of an information-carrying signal molecule such as a neurotransmitter from
a presynaptic cell into intercellular
space. The molecule can travel some
distance and have long-lasting effects.
tripartite synapse A synapse formed by
a presynaptic axon and a postsynaptic dendrite, with the addition of the
astrocytic process that ensheathes and
modulates the synapse.
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168 Chapter 6
glutamate The most common excitatory
neurotransmitter in the brain.
depolarization A change in the cell
membrane potential caused by admitting positive charge into the cell and
thus reducing its negative resting
potential.
excitatory postsynaptic potential
(EPSP) A depolarization of the postsynaptic cell membrane.
synaptic plasticity A change in the
strength of a synapse as a consequence
of functional activation.
excitotoxicity Damage or death of neurons caused by excess concentrations
of glutamate and other substances.
γ−aminobutyric acid (GABA) One
of the most important inhibitory
neurotransmitters.
hyperpolarization A change in the cell
membrane potential caused by admitting negative change into the cell and
thus increasing its negative resting
potential.
inhibitory postsynaptic potential
(IPSP) A hyperpolarization of the
postsynaptic cell membrane.
of the tripartite synapse includes an astrocytic process that makes contact
with neurons and surrounds the synapse. It has been estimated that a single
astrocyte can envelop as many as 1 million synapses and can contact many
blood vessels, placing astrocytes in a strategic position to influence the interaction between neurons and blood vessels.
In the next section, we describe an example of a tripartite synapse that
involves glutamate, the most common neurotransmitter in the brain, estimated
to be released at some 90% of synapses.
Synaptic potentials and action potentials
When a signal travels down the axon to the synapse, the presynaptic terminal
experiences that signal as a decrease in its membrane potential and opens a
voltage-gated ion channel that is selective for Ca2+ (see Figure 6.6). Calcium
enters the presynaptic terminal and initiates a molecular process whereby
small fluid-filled sacs called vesicles encapsulate the glutamate molecules,
migrate to the presynaptic membrane, and release the glutamate into the
synaptic cleft. The glutamate molecules then diffuse across the synaptic cleft
and attach to different glutamatergic receptors on the postsynaptic membrane,
resulting in the opening ionotropic, metabotropic, and NMDA channels. These
newly opened ion channels allow Na+ to move down its concentration gradient and through the postsynaptic membrane into the target neuron. The influx
of positive Na+ ions decreases the electrical potential between the inside and
outside of the membrane near the channel. This local depolarization of the
postsynaptic cell membrane is referred to as an excitatory postsynaptic potential (EPSP); thus, glutamate is known as an excitatory neurotransmitter. The
NMDA channel also admits Ca2+ into the cell when a particular membrane
threshold is reached. The positive Ca2+ ion also depolarizes the membrane.
Once admitted to the postsynaptic neuron, however, Ca2+ acts as a second
messenger, activating molecular machinery in the cell that may change the
responsiveness of the postsynaptic membrane to future signals. Thus, the
NMDA channel plays an important role in synaptic plasticity.
Astrocytes play important roles in synapses (see Figure 6.6B). As Na+
enters the postsynaptic neuron, K+ exits and accumulates in the extracellular
space. Nearby astrocytes absorb the excess K+ and shuttle it away through
gap junctions that connect adjacent astrocytes. Glutamate released by the
presynaptic neuron is also actively taken up from the extracellular space by
excitatory amino acid transporters on the surface membranes of astrocytes.
Overstimulation by glutamate can damage neurons, a process called excitotoxicity. In another process, glutamate–glutamine recycling, the astrocyte converts
the glutamate to glutamine (which does not stimulate neurons) and returns
the glutamine to the presynaptic neuron, where it can be safely converted
back into glutamate. Glutamate also directly stimulates metabotropic receptors on the membrane surface of astrocytes—a fact to which we will return
later, when we discuss the local control of blood flow.
Not all neurotransmitters excite, or depolarize, the postsynaptic membrane.
Other neurotransmitters, such as γ-aminobutyric acid (GABA), interact with other
receptors to open Cl– or K+ channels. Both the influx of the negatively charged
Cl– into the neuron and the efflux of the positively charged K+ out of the neuron
result in a net increase in the resting potential in the vicinity of these newly
opened channels. This local hyperpolarization of the neuronal membrane is referred to as an inhibitory postsynaptic potential, or IPSP; thus, GABA is known as
an inhibitory neurotransmitter. GABA is released by some types of inhibitory
interneurons, known as GABA inhibitory interneurons. We will encounter these
neurons later in our discussion of the regulation of blood flow.
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From Neuronal to Hemodynamic Activity
(A)
Astrocyte
process
Dendritic spine
(postsynaptic cell)
(B)
Axon terminal
(presynaptic cell)
Postsynaptic density
Astrocyte
process
K+ channel
Figure 6.6 The tripartite synapse. (A) An electron micrograph of the tripartite synapse depicting the presynaptic axon (green) from one neuron filled with vesicles
containing the excitatory neurotransmitter glutamate.
The spine of the postsynaptic dendrite (yellow) is indicated, as is the postsynaptic thickening (black and red).
The astrocyte (blue) envelops the synapse. (B) A schematic representation of a tripartite synapse illustrates
three functions of astrocytes that help regulate the
synaptic environment. One such function is regulation
of extracellular concentrations of K+, which can accumulate as a consequence of synaptic activity. Another
is the recycling of glutamate to glutamine. Transporters
on the astrocytes take up glutamate (Glu, green circles)
that has been released by the presynaptic axon (green).
The glutamate is converted to glutamine (Gln) within the
astrocyte and then returned to the presynaptic neuron,
where it is converted back to glutamate. Glutamate can
also directly stimulate the astrocyte through metabotropic glutamate receptors, which can then cause a
rise in Ca2+ concentration in the astrocyte as well as
the initiation of calcium waves within the network of
connected astrocytes that may play a role in regulating
local blood flow. (After Eroglu and Barres, 2010.)
Axon
Ca2+
Metabotropic
Glu receptor
Glu
Postsynaptic
density
169
Gln
Glutamate
uptake
Dendritic
spine
A single EPSP or IPSP, considered by itself, is a transient event; the change
in the neuron’s membrane rapidly returns to equilibrium following removal
of the neurotransmitter, closing of ion channels, and the activation of ion
pumps. However, a single neuron may have thousands of synapses, and thus
can experience a barrage of EPSPs and IPSPs throughout its dendritic trees
and soma. Those incoming potentials combine to influence the membrane
potential of the target neuron in a complex manner. The primary influence
is through passive processes, such that each postsynaptic potential decays
as it travels along the target neuron, with net effects determined by the distance between the synapses, the rate of decay of the polarization over the
length of the dendrite, the relative timing of the postsynaptic potentials, and
the spatial geometry and branching of the dendrite tree. In addition, active,
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170 Chapter 6
axon hillock A region of the neuronal
cell body located at the emergence of
the axon. Changes in its electrical potential lead to the generation of action
potentials.
action potential A self-propagating
wave of depolarization that travels
down a neuronal axon.
self-propagating potentials (or dendritic spikes) occur when the membrane
potential reaches a particular threshold voltage, sparking a cascade of opening
voltage-gated ion channels that moves along the dendrites.
Regardless of whether passively conducted or actively propagated, the
dendritic potentials influence the net polarization of a specialized region of the
neuron called the axon hillock, which is located where the axon emerges from
the cell body. If the net depolarization experienced at the axon hillock (i.e.,
the sum of the spatially weighted depolarizing signals minus the sum of the
spatially weighted hyperpolarizing signals) exceeds a threshold voltage, large
numbers of voltage-gated sodium channels open at the axon hillock, which
results in a large influx of Na+ into the cell. This large depolarization spreads
down the axon by a regenerating process like that of dendritic spikes; that is,
the flow of Na+ at one location depolarizes the membrane and causes voltagegated ion channels to open at a neighboring location, a process that repeats
along the entire axon. The wave of depolarization, known as an action potential,
sweeps down the axon in a self-propagating manner, now independent of the
initial EPSPs and IPSPs on the dendrites and soma that triggered it. Eventually, the nerve impulse will reach the end of the axon, where a presynaptic
terminal forms a synapse with another neuron—thus restarting the cycle of
synapse, dendrites, axon that characterizes neuronal information processing.
Information processing by neurons is the combination of the integrative
and transmissive activity described so far in this section. Integration is essentially an analog computation performed on the total spatiotemporal pattern of EPSPs and IPSPs, each generated at a synapse receiving input from
a different neuron. The output of the computation determines whether or
not the neuron generates an action potential, as well as the rate and timing
of those action potentials. Note that only EPSPs increase the likelihood of
action potentials. Hyperpolarizing IPSPs, in contrast, make action potentials
less likely by making the membrane potential more negative. An EPSP that
might have sufficient strength to depolarize the axon hillock below threshold
when this region is at its normal resting potential may not be able to do so if
the axon hillock were hyperpolarized by a preceding IPSP.
Importantly, information processing requires energy. For example, the influx of Na+ during an action potential causes a change in the local membrane
potential of the neuron, so electrical gradients now oppose the re-entry of
the positively charged K+ into the cell. To return the membrane to its resting
potential, the sodium–potassium pump removes three Na+ ions from within
the cell for every two K+ ions it brings into the cell. The energy that powers
this pump is necessary to make the neuron ready for its next contribution to
information processing. Similarly, nearby astrocytes consume energy when
transporting glutamate and when recycling glutamate to replenish the presynaptic neuron’s glutamate supply. In the next section, we will consider
the energy needs of neurons and astrocytes, with an emphasis on neuronal
information processing.
Cerebral Metabolism: Neuronal Energy
Consumption
As neuroscientists, psychologists, and clinicians, we are interested in using
fMRI to localize changes in neuronal activity that are related to information
processing in the brain. Why, then, is it important to understand energy consumption and metabolism? Local brain activity requires external sources of
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From Neuronal to Hemodynamic Activity 171
energy to support what Roy and Sherrington’s 1890 study referred to as the
nutritional needs of brain tissue, chiefly through the supply of oxygen and
glucose. We know that increased neural activity is associated with increased
blood flow (i.e., functional hyperemia). We also know that the fMRI signal
is dependent on the magnetic properties of hemoglobin that are related in
turn to oxygen binding. Thus, if we want to interpret the fMRI signal as an
indicator of information processing in the brain, we need to understand the
relationship between metabolism and neuronal activity.
Thought Question
Assume that the brain did indeed have large local stores of energy that
could support neuronal activity. Based on what you know so far, would
fMRI be possible in such a case?
Adenosine triphosphate (ATP)
adenosine triphosphate (ATP) A
nucleotide containing three phosphate
groups that is the primary energy
source for cells in the human body.
glycolysis The process of breaking
down glucose into other compounds
to produce ATP.
aerobic glycolysis The process, consisting of glycolysis, the TCA cycle, and
the electron transport chain, that
breaks down glucose in the presence
of oxygen, resulting in a gain of 36
ATP molecules.
TCA cycle The second step in aerobic
glycolysis; it involves the oxidation
of pyruvate. Also known as the citric
acid cycle or the Krebs cycle.
The principal energy currency for cells in the human body is adenosine triphosphate, or ATP. ATP is a nucleotide that contains three phosphate groups. Free
energy is released when the third phosphate group of ATP is removed by the insertion of a water molecule in a reaction called hydrolysis. In body tissues, ATP
can be produced from many substrates, including the sugar glucose, fatty acids,
ketone bodies, and even proteins. Glucose is stored throughout the body in the
form of glycogen. Although there are small stores of glycogen in astrocytes,
the brain requires a continuous supply of glucose and oxygen via the vascular
system to maintain function. Under normal circumstances, the brain extracts
about 10% of the approximately 90 mg/dL of glucose in arterial blood. If a
person’s blood glucose concentration falls below 30 mg/dL, coma may ensue.
The generation of ATP from glucose has three primary steps: glycolysis,
the TCA cycle, and the electron transport chain (Figure 6.7). Glucose transporter molecules move glucose through the interstitial space from capillaries to astrocytes and neurons.
Once in the cytoplasm of brain cells, glucose is broGlucose
ken down through glycolysis, a reaction in which the
six-carbon glucose is cleaved into two three-carbon
Glycolysis
2 ATP
sugars, which are then catabolized through a series
of reactions. Glycolysis consumes two ATP mol2 Pyruvate
ecules but produces four, thus providing a net gain
Aerobic + 2 O2
Anaerobic
of two ATP molecules. What happens next is dependent on whether sufficient oxygen is present (aerobic
2 Acetyl-CoA
2 Lactate
conditions) or not present (anaerobic conditions).
If oxygen is present, the end product of aerobic
glycolysis is the compound pyruvate, which then en2 CO2
ters a reaction called the tricarboxylic acid (TCA) cycle,
also known as the citric acid cycle or the Krebs cycle.
The TCA cycle uses oxygen extracted from hemogloTCA
cycle
bin in the blood to oxidize pyruvate, and a network
Figure 6.7 Anaerobic and aerobic glycolysis. In anaerobic glycolysis, glucose is converted to lactate via a fast
process that produces two ATP molecules. If oxygen
is present, the resulting aerobic processes of the TCA
cycle and the electron transport chain produce an additional 34 ATP molecules.
4 CO2
4 O2
Electron transport chain and oxidative phosphorylation
6 H2 O
34 ATP
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