Information Processing in the Central Nervous System

162 Chapter 6

how closely does the BOLD signal, and the functional hyperemia it reflects, correlate with neuronal activity? Understanding the answers to these ques- tions is critical to being an informed user of fMRI methods and an informed consumer of fMRI results.

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 sup- porting cells, the nature of their information transactions, and their metabolic costs. Neurons The neuron is the primary information-processing unit of the central nervous cerebral cortex (neocortex) The thin system. Modern stereological evidence has estimated that the brain of an wrapping of cells around the outer average-size adult male human contains some 86 billion neurons, give or take surface of the cerebral hemispheres. It 8 billion. Of these 86 billion neurons, about 16 billion are contained within the has a layered structure, referred to as cerebral cortex, or neocortex, a thin wrapping of cell bodies around the outer cortical columns or cortical layers. surface of the brain. About 69 billion neurons are contained in the cerebellum, cerebellum A large cortical structure at a structure located in the posterior fossa (skull depression) below the cerebral the caudal base of the brain that plays hemispheres that has an important role in controlling movements and other an important role in motor function. functions. (See Figure 1 in Box 6.3 at the end of this chapter; Box 6.3 provides soma The body of a cell; it contains an overview of key concepts in neuroanatomy.) The cerebellum accounts for cytoplasm, the cell nucleus, and only 10% of the size of the brain, but due to its high density of tightly packed organelles. neurons, it contains nearly 80% of the brain’s neurons. dendrite A neuronal process that re- There are many different types of neurons, all of which can generate and ceives signals from other cells. A neu- transmit electrical signals. As in most other cells of the body, the soma (cell ron typically has multiple dendrites, body) of a neuron contains cytoplasm, organelles such as the Golgi apparatus which perform a primarily integrative and mitochondria, and a nucleus containing DNA (Figure 6.2A). Uniquely, function. however, the cell body of a typical neuron gives rise to multiple branch- axon A neuronal process that trans- ing protoplasmic processes called dendrites that vary greatly in number and mits an electrical impulse from the spatial extent. Most neurons also have a single, larger protoplasmic process cell body to the synapse, performing called an axon, which can branch extensively. A useful simplification is that a primarily transmissive function. A neuronal activity can be characterized as either integrative or transmissive. neuron typically has a single axon, Integrative activity occurs when a neuron collects and integrates input from which in some types of neurons can other neurons through connections on its dendrites and soma. Transmissive be extremely long and/or can branch activity profusely. communicates the outcome of the neuron’s integrative processes to other neurons via its axons. integrative activity The collection of The human cerebral cortex has six layers, defined by different composi- inputs from other neurons through dendritic or somatic connections. tions 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 transmissive activity The relaying of neural processing may occur within vertically organized units called columns. the outcome of an integrative process pyramidal cell from one neuron to another, typically One common neuron in the cerebral cortex is the , named for through signals sent via axons. 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 pyramidal cell A common neuronal type of the cerebral cortex. These cells axon that can travel a long distance; the axons of pyramidal cells provide the have a pyramid-shaped soma, exten- principal output from most cortical regions. For example, the axons of layer sive spined dendrites, and are charac- V pyramidal cells in motor cortex form the corticospinal tract that extends terized by a long, branching axon that from the cortical surface of the brain well down into the spinal cord. Other can extend for many centimeters. neurons within the cortical layers contribute to intracortical processing and

(A) (B) Axon of second neuron

Synapse Dendrites Double bouquet Synaptic cleft cell Microtubule

Mitochondrion Nucleus Micro lament Large basket cell Soma Nucleolus Rough endoplasmic Chandelier cell reticulum

Cell membrane

Axon hillock

Myelin

Pyramidal cell

Axon Figure 6.2 Neuron organization and structure. (A) As seen in Axon 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, Axon terminals 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 interneuron A neuron that is connected other neurons, the output from interneurons can both excite and inhibit other locally to other neurons. Interneurons neurons, as will be discussed later in this chapter. participate in local brain circuits, but do not project to distant cortical Glia regions. Along with neurons, glial cells, or glia, are also important cellular constituents glial cells (glia) Brain cells that support of the central nervous system. Glial cells were once thought to greatly exceed the activities of neurons but are not neurons in number. However, research now suggests that the ratio of neurons primarily involved with information to glia is closer to 1:1. The most common glial cells found in the brain are transmission. microglia, oligodendrocytes, and astrocytes. Microglial cells are part of the astrocyte A type of glial cell that regu- brain’s immune system and act as phagocytic scavengers, among several du- lates the extracellular environment. It ties. Oligodendrocytes wrap themselves around the axons of some neurons, is the most prevalent glial cell type in the brain. 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,

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Figure 6.3 An astrocyte (green) showing its protoplasmic end-feet processes in contact with blood vessels (red). (Pho- tograph courtesy of Dr. S. A. Fisher, University of California Santa Barbara; prepared by G. Luna and P. Keeley.)

concentration gradient A difference specialized regions where the membranes of two cells touch—that allow small in the density of a substance across molecules and ions to pass from one astrocyte to another without those mole- space. Substances diffuse along cules entering the extracellular milieu. Such gap junctions thus allow molecular concentration gradients from areas messages to pass along connected astrocytes. Recent studies have suggested of high concentration to areas of low that astrocytes may play an important role in synaptic transmission and the concentration. creation of new synapses, as we will soon describe. ion channel A pore in the membrane of a cell that allows passage of particular Neuronal membranes and ion channels ions under certain conditions. Neuronal integration and transmission both depend on the properties of neu- ligand-gated ion channel An ion chan- ronal membranes, which are lipid bilayers that separate the internal contents nel that opens or closes in response to of neurons from the external milieu. An important role of neuronal mem- binding of chemical signals (ligands). branes is to restrict the flow of chemical substances into and out of neurons. The ligand is often a neurotransmitter When substances are allowed to diffuse freely, they diffuse from areas of high molecule. 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

(A) (B) Figure 6.4 Ion channels and pumps. (A) Ion channels allow particular ions to diffuse across membranes along Na+ concentration gradients. Channels may be opened by the actions of particular molecules, or they may open K+ when the voltage difference across the membrane Outside reaches a threshold. (B) Pumps move ions across membranes against their concentration gradients, usually at Lipid Neuronal bilayer membrane a cost of energy supplied by ATP. The very important pump depicted here transports sodium out of the cell Inside while bringing potassium into the cell. ATP

ADP

Ion channel Sodium-potassium pump

molecule binds with a specific receptor on the neuron’s surface mem- voltage-dependent ion channel An brane. This metabotropic binding activates so-called second messen- ion channel that opens or closes in gers within the cell, and these second-messenger molecules initiate response to changes in membrane biochemical cascades that can open ion channels and/or activate other potential. molecular machinery within the cell. pump A transport system that moves • Voltage-gated ion channels open not in response to second messengers ions across a cell membrane against their concentration gradients. or a bound ligand, but rather when the electrical potential difference across the membrane reaches a particular threshold. sodium–potassium pump A transport system that removes three sodium • Finally, some receptors are both ligand- and voltage-gated. For example, ions from within a cell while bringing the NMDA (N-methyl-D-aspartate) receptor is activated by glutamate. two potassium ions into the cell. 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.

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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1 Action potential Myelin travels down axonaxon.

Axon

2 Action potential depolarizes presynaptic membrane, opening voltage-dependent Ca2+ ion channels.

Ca2+ 3 Ca2+ ows into cell, causing vesicles to fuse 3 with presynaptic Vesicles (store membrane. neurotransmitters) 4 Neurotransmitter (e.g., glutamate) is released into synapse. Presynaptic membrane 5 Neurotransmitter binds with receptors on postsynaptic ion channels, opening them.

Synaptic Glutamate cleft

Neurotransmitter Electrode molecules

Na+ Postsynaptic membrane

Dendrite + + + Local 6 Ions (e.g., Na ) ow + + + EPSP into postsynaptic cell, Ion channel + 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. Huettel 3e fMRI, Sinauer Associates HU3e06.05.ai Date Jun 26 2014 Version 5 Jen

©2014 Sinauer Associates, Inc. This material cannot be copied, reproduced, manufactured or disseminated in any form without express written permission from the publisher. From Neuronal to Hemodynamic Activity 167 gravity gradient is analogous to a concentration gradient, and the holes are membrane potential The difference in analogous to open ion channels. Water will move through the holes and run electrical charge between the inner through the pipes down the gravity gradient without the need for additional and outer surfaces of a cell membrane, energy. The situation is quite different, however, if we want to return the water the result of a difference in the distri- to the tower. Active pumping against the gravity gradient is now required, bution of ions. and the pump requires energy to operate. wired transmission The transmission While this analogy is instructive, it is incomplete. Because ions have elec- of information from one neuron to a trical charge, their unequal distribution also results in a resting electrical closely apposed neuron across a syn- potential difference between the inside and outside of the membrane; that is, aptic cleft. Often used synonymously with synaptic transmission. 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 synapse A junction between neurons potential is due to protein anions within the neuron that are too large to exit where the presynaptic process of an axon is apposed to the postsynaptic the cell through ion channels. Thus, the movement of ions across a membrane process of a dendrite or cell body. is governed by both chemical and electrical gradients. The movements of ions synaptic cleft across the membranes and the resulting changes in membrane potentials are A gap between presynaptic and postsynaptic membranes. the generators of synaptic transmission. neurotransmitters Chemicals released Synapses: Information transmission between neurons by presynaptic neurons that travel across the synaptic cleft to influence In stylized form, information processing within a neuron begins with input receptors on postsynaptic neurons. from other neurons at synapses; leads to integrative activity in the dendrites volume transmission and soma, where the neuron receives information from hundreds or even The transmission of an information-carrying signal mol- thousands of other neurons; and ends with transmissive activity associated ecule such as a neurotransmitter from with changes in their membrane potentials along long axons. A distinction a presynaptic cell into intercellular is sometimes drawn between “wired” and “volume” modes of information space. The molecule can travel some transmission between neurons. Wired transmission does not, of course, involve distance and have long-lasting effects. wires, but refers to the transmission of information at specialized junctions tripartite synapse A synapse formed by called synapses, where a thickening of a terminal axon process from one neu- a presynaptic axon and a postsynap- ron (the presynaptic terminal) is physically apposed to a postsynaptic mem- tic dendrite, with the addition of the brane of the dendrite or soma of another neuron (the postsynaptic membrane) astrocytic process that ensheathes and (Figure 6.5). In pyramidal and some other neurons, the postsynaptic mem- modulates the synapse. branes 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 af- fect 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

©2014 Sinauer Associates, Inc. This material cannot be copied, reproduced, manufactured or disseminated in any form without express written permission from the publisher. 168 Chapter 6 glutamate The most common excitatory of the tripartite synapse includes an astrocytic process that makes contact neurotransmitter in the brain. with neurons and surrounds the synapse. It has been estimated that a single depolarization A change in the cell astrocyte can envelop as many as 1 million synapses and can contact many membrane potential caused by admit- blood vessels, placing astrocytes in a strategic position to influence the inter- ting positive charge into the cell and action between neurons and blood vessels. thus reducing its negative resting In the next section, we describe an example of a tripartite synapse that potential. involves glutamate, the most common neurotransmitter in the brain, estimated excitatory postsynaptic potential to be released at some 90% of synapses. (EPSP) A depolarization of the postsynaptic cell membrane. Synaptic potentials and action potentials synaptic plasticity A change in the When a signal travels down the axon to the synapse, the presynaptic terminal strength of a synapse as a consequence experiences that signal as a decrease in its membrane potential and opens a of functional activation. voltage-gated ion channel that is selective for Ca2+ (see Figure 6.6). Calcium excitotoxicity Damage or death of neu- enters the presynaptic terminal and initiates a molecular process whereby rons caused by excess concentrations small fluid-filled sacs called vesicles encapsulate the glutamate molecules, of glutamate and other substances. migrate to the presynaptic membrane, and release the glutamate into the γ−aminobutyric acid (GABA) One synaptic cleft. The glutamate molecules then diffuse across the synaptic cleft of the most important inhibitory and attach to different glutamatergic receptors on the postsynaptic membrane, neurotransmitters. resulting in the opening ionotropic, metabotropic, and NMDA channels. These hyperpolarization A change in the cell newly opened ion channels allow Na+ to move down its concentration gradi- membrane potential caused by admit- ent and through the postsynaptic membrane into the target neuron. The influx ting negative change into the cell and of positive Na+ ions decreases the electrical potential between the inside and thus increasing its negative resting outside of the membrane near the channel. This local depolarization of the potential. postsynaptic cell membrane is referred to as an excitatory postsynaptic poten- inhibitory postsynaptic potential tial (EPSP); thus, glutamate is known as an excitatory neurotransmitter. The (IPSP) A hyperpolarization of the NMDA channel also admits Ca2+ into the cell when a particular membrane postsynaptic cell 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.

(A) Astrocyte Axon terminal Figure 6.6 The tripartite synapse. (A) An electron mi- process (presynaptic cell) crograph 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 sche- matic 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 accu- mulate 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 Dendritic spine Postsynaptic density rise in Ca2+ concentration in the astrocyte as well as (postsynaptic cell) the initiation of calcium waves within the network of connected astrocytes that may play a role in regulating (B) Astrocyte local blood flow. (After Eroglu and Barres, 2010.) K+ channel process Axon

Ca2+

Metabotropic Glu receptor Glu Gln

Postsynaptic density 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,

Huettel 3e HU3e06.06.ai ©2014 Sinauer Associates, Inc. This material cannot be copied, reproduced, manufactured 06/7/14 or disseminated in any form without express written permission from the publisher. Dragon y Media Group 170 Chapter 6 axon hillock A region of the neuronal self-propagating potentials (or dendritic spikes) occur when the membrane cell body located at the emergence of potential reaches a particular threshold voltage, sparking a cascade of opening the axon. Changes in its electrical po- voltage-gated ion channels that moves along the dendrites. tential lead to the generation of action Regardless of whether passively conducted or actively propagated, the potentials. dendritic potentials influence the net polarization of a specialized region of the action potential A self-propagating neuron called the axon hillock, which is located where the axon emerges from wave of depolarization that travels the cell body. If the net depolarization experienced at the axon hillock (i.e., down a neuronal axon. 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 voltage- gated 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. Eventu- ally, 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 es- sentially an analog computation performed on the total spatiotemporal pat- tern 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

©2014 Sinauer Associates, Inc. This material cannot be copied, reproduced, manufactured or disseminated in any form without express written permission from the publisher. From Neuronal to Hemodynamic Activity 171 energy to support what Roy and Sherrington’s 1890 study referred to as the adenosine triphosphate (ATP) A nutritional needs of brain tissue, chiefly through the supply of oxygen and nucleotide containing three phosphate glucose. We know that increased neural activity is associated with increased groups that is the primary energy blood flow (i.e., functional hyperemia). We also know that the fMRI signal source for cells in the human body. is dependent on the magnetic properties of hemoglobin that are related in glycolysis The process of breaking turn to oxygen binding. Thus, if we want to interpret the fMRI signal as an down glucose into other compounds indicator of information processing in the brain, we need to understand the to produce ATP. relationship between metabolism and neuronal activity. aerobic glycolysis The process, consist- ing of glycolysis, the TCA cycle, and the electron transport chain, that Thought Question breaks down glucose in the presence Assume that the brain did indeed have large local stores of energy that of oxygen, resulting in a gain of 36 could support neuronal activity. Based on what you know so far, would ATP molecules. fMRI be possible in such a case? TCA cycle The second step in aerobic glycolysis; it involves the oxidation Adenosine triphosphate (ATP) 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 in- sertion 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 intersti- tial space from capillaries to astrocytes and neurons. Once in the cytoplasm of brain cells, glucose is bro- Glucose ken down through glycolysis, a reaction in which the six-carbon glucose is cleaved into two three-carbon Glycolysis sugars, which are then catabolized through a series 2 ATP of reactions. Glycolysis consumes two ATP mol- 2 Pyruvate ecules but produces four, thus providing a net gain of two ATP molecules. What happens next is depen- Aerobic + 2 O2 Anaerobic dent on whether sufficient oxygen is present (aerobic conditions) or not present (anaerobic conditions). 2 Acetyl-CoA 2 Lactate If oxygen is present, the end product of aerobic glycolysis is the compound pyruvate, which then en- 2 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 hemoglo- TCA bin in the blood to oxidize pyruvate, and a network cycle

Figure 6.7 Anaerobic and aerobic glycolysis. In anaero- 4 CO2 4 O bic glycolysis, glucose is converted to lactate via a fast 2 process that produces two ATP molecules. If oxygen Electron transport chain and oxidative phosphorylation is present, the resulting aerobic processes of the TCA 6 H O cycle and the electron transport chain produce an ad- 2 34 ATP ditional 34 ATP molecules.

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