Molecular and Cellular Signaling - Martin Beckerman

532 21. Learning and Memory

amygdala, and the prefrontal cortex that encompasses the nonmotor portions of the frontal lobe.

The most striking feature of cells in the two systems is the prominence of dopamine-releasing neurons. Neurons in the ventral tegmental area and in the substantia nigra contain large numbers of dopamine-releasing neurons. When stimulated by drugs these neurons elevate the extracellular dopamine levels in the nucleus accumbens and striatum. Dopamine promotes reinforcement, in which behavioral responses linked to rewards increase in frequency over time. In the drug-reward circuits, dopamine functions as the reward signal in response to the taking of drugs such as cocaine, and also as a stimulant of reward-seeking behavior.

21.15 Drug Addiction May Be an Aberrant Form of Synaptic Plasticity

Drug addiction appears to be an aberrant form of synaptic plasticity, in which circuits involved in LTP and LTD are altered. Glutamate and dopamine work together in the VTA to promote addiction (Figure 21.15). Addictive drugs such as nicotine act in at least three different ways in the VTA. They bind to nicotinic acetylcholine receptors (nAChRs) on dopamine-releasing cells triggering the release of dopamine. They also bind to nAChRs on presynaptic terminals of glutamate-releasing cells resulting in an increased release of glutamate. The glutamate, in turn, triggers an increased production of dopamine by dopamine-releasing cells receiving

FIGURE 21.15. Schematic representation of a portion of the VTA-NAc drug-reward circuitry: Shown is a representative VTA dopamergic neuron whose axon projects into the nucleus accumbens and releases dopamine there. As explained in the text, the dopamine release is regulated and, under the influence of nicotine, potentiated by a GABAergic neuron and by a glutamergic neuron, here depicted as located in the VTA. Also included in the figure is the action of amphetamines and cocaine on the dopamine transporter (DAT).

the glutamate signals. The effect of the glutamate is to prolong the release of dopamine results in an LTP-like potentiation of synaptic transmission and increase in duration of the reward signal. (When nAChRs found on dopamergic neurons in the VTA bind nicotine they depolarize the membrane. The nAChRs located on presynaptic terminals enhance glutamate release, thus stimulating further dopamine release. When NMDA receptors are present, long-term potentiation of synaptic transmission is produced.) Thirdly, nicotine binds to GABA-releasing cells, which for a while throttle back the actions of dopamine-releasing cells, but desensitization turns this off over time, further promoting addictive effects of the drug.

A definition of synaptic plasticity useful in discussions of drug addiction is one describing it as the ability of circuits and systems to modify their responses to a stimulus brought on by prior stimulation, either of the same type or of an associated form. The connections between drug addiction and synaptic plasticity have been studied most intensively in the ventral tegmental area and the nucleus accumbens. Opiates and nicotine exert their influences through interactions with neurons of the VTA, while cocaine and amphetamines act on neurons of the NAc. As indicated in Figure 21.15, cocaine and amphetamines impede the ability of the dopamine transporter (DAT) to take up dopamine from the extracellular spaces. Homeostatic regulation is lost and the dopamine levels become excessive.

Neurons in the prefrontal cortex send and receive signals from VTA and NAc neurons, and these regions are the locus of feelings of pleasure associated with drug addiction. The networks in these areas serve as the core of the brain’s reward circuitry. Again, a key element in this reward circuitry, that is, a feature that is common to all forms of drug abuse, is the elevation of dopamine levels leading to pleasurable sensations.

21.16 In Reward-Seeking Behavior, the Organism

Predicts Future Events

To survive an organism must be able to decide between alternative responses whenever it is searching for food or water, or avoiding danger, or seeking a mate. In reward-driven behavior a positive reinforcement is supplied to behavioral acts in order to strengthen future response to the associated stimuli. Reward-driven behavior is a type of learning, quite like the Hebbian form, in which a stimulus is paired with a reward or a punishment. This kind of learning is called predictive learning, the classical example of which is Pavlov’s experiments with dogs.

Pairing a reward/punishment with a stimulus does not always result in learning. There is a second requirement: Some element of uncertainty or novelty must be present. More formally, there must be some discrepancy, or error, between the reinforcement predicted by the stimulus and the actual reinforcement. If this reinforcement error is zero there is no learn-

534 21. Learning and Memory

ing since everything turns out as expected. The dopamine release can be regarded as a teaching signal that triggers an increased alertness whenever something interesting or unexpected has occurred. In doing so, it strengthens connections between neurons leading to LTP and drug addiction.

References and Further Reading

General References

Bear MF, Connors BW, and Paradiso MA [2001]. Neuroscience: Exploring the Brain (2nd ed.) Baltimore, MD: Lippincott, Williams and Wilkins.

Kandel ER [2001]. The molecular biology of memory storage: A dialogue between genes and synapses. Science 294: 1030–1038.

Kandel ER, Schwartz JH, and Jessel TM [2000]. Principles of Neural Science (4th edition). Norwalk CT: Appleton and Lange.

Lamprecht R, and LeDoux J [2004]. Structural plasticity and memory. Nature Rev. Neurosci., 5: 45–54.

Synaptic Assembly

Biederer T, et al. [2002]. SynCAM, a synaptic adhesive molecule that drives synapse assembly. Science, 297: 1525–1531.

Dalva MB, et al. [2000]. EphB receptors interact with NMDA receptors and regulate excitatory synapse formation. Cell, 103: 945–956.

Dean C, et al. [2003]. Neurexin mediates the assembly of presynaptic terminals.

Nature Neurosci., 7: 708–716.

Penzes P, et al. [2003]. Rapid induction of dendritic spine morphogenesis by trans- synaptic EphrinB-EphB receptor activation of the Rho GEF Kalirin. Neuron, 37: 263–274.

Takasu MA, et al. [2002]. Modulation of NMDA receptor-dependent calcium influx and gene expression through EphB receptors. Science, 295: 491–495.

The Presynaptic Active Zone

Atwood HL, and Karunanithi S [2002]. Diversification of synaptic strength: Presynaptic elements. Nature Rev. Neurosci., 3: 497–516.

Chen YA, and Scheller RH [2001]. SNARE-mediated membrane fusion. Nature Rev. Mol. Cell Biol., 2: 98–106.

Dobrunz LE, and Stevens CF [1997]. Heterogeneity of release probability, facilitation and depletion at central synapses. Neuron, 18: 995–1008.

Jahn R, Lang T, and Südhof TC [2003]. Membrane fusion. Cell, 112: 519–533.

Rizo J, and Südhof TC [2002]. SNAREs and Munc18 in synaptic vesicle fusion.

Nature Rev. Neurosci., 3: 641–653.

Yoshihara M, and Littleton JT [2002]. Synaptotagmin I functions as a calcium sensor to synchronize neurotransmitter release. Neuron, 36: 897–908.

The Postsynaptic Density

Bredt DS, and Nicoll RA [2003]. AMPA receptor trafficking at excitatory synapses. Neuron, 40: 361–379.

Impey S, Obrietan K, and Storm DR [1999]. Making new connections: Role of ERK MAP kinase signaling in neuronal plasticity. Neuron, 23: 11–14.

Kennedy MB [2000]. Signal-processing machines at the postsynaptic density. Science, 290: 750–754.

Kim JH [2003]. Presynaptic activation of silent synapses and growth of new synapses contribute to intermediate and long-term facilitation in Aplysia. Neuron,40: 151–165.

Kim JH, and Huganir RL [1999]. Organization and regulation of proteins at synapses. Curr. Opin. Cell Biol., 11: 248–254.

Malinow R [2003]. AMPA receptor trafficking and long-term potentiation. Phil. Trans. R. Soc. Lond. B, 358: 7–7–714.

Sheng M, and Kim MJ [2002]. Postsynaptic signaling and plasticity mechanisms. Science, 298: 776–780.

Sweatt JD [2001]. The neuronal MAP kinase cascade: A biochemical signal integration system subserving synaptic plasticity and memory. J. Neurochem., 76: 1–10.

Thomas GM, and Huganir RL [2004]. MAPK cascade signalling and synaptic plasticity. Nature Rev. Neurosci., 5: 173–182.

Ziff EB [1997]. Enlightening the postsynaptic density. Neuron, 19: 1163–1174.

Long-Term Potentiation

Bliss TVP, and Collingridge GL [1993]. A synaptic model of memory: Long-term potentiation in the hippocampus. Nature, 361: 31–39.

Lisman J, Schulman H, and Cline H [2002]. The molecular basis of CaMKII function in synaptic and behavioral memory. Nature Rev. Neurosci., 3: 175–190.

Malenka RC, and Nicoll RA [1999]. Long-term potentiation—A decade of progress? Science, 285: 1870–1874.

McGaugh JL [2000]. Memory—A century of consolidation. Science, 287: 248–251.

Bidirectional Synaptic Plasticity

Abraham WC, and Bear MF [1996]. Metaplasticity: The plasticity of synaptic plasticity. Trends Neurosci., 19: 126–130.

Shouval HZ, Bear MF, and Cooper LN [2002]. A unified model of NMDA recep- tor-dependent bidirectional synaptic plasticity. Proc. Natl. Acad. Sci. USA, 99: 10831–10836.

Fear Conditioning

Blair HT, et al. [2001]. Synaptic plasticity in the lateral amygdala: A cellular hypothesis for fear conditioning. Learn. Mem., 8: 229–242.

McKernan MG, and Shinnick-Gallagher P [1997]. Fear conditioning incuces a lasting potentiation of synaptic currents in vitro. Nature, 390: 607–611.

Rogan MT, and LeDoux JE [1996]. Emotion: Systems, cells and synaptic plasticity. Cell, 85: 469–475.

Rogan MT, Stäubli UV, and LeDoux JE [1997]. Fear conditioning induces associative long-term potentiation in amygdala. Nature, 390: 604–607.

Schafe GE, et al. [2001]. Memory consolidation of Pavlovian fear conditioning: A cellular and molecular perspective. Trends Neurosci., 24: 540–546.

Shumyatsky GP, et al. [2002]. Identification of a signaling network in lateral nucleus of the amygdala important for inhibiting memory specifically related to learned fear. Cell, 111: 905–918.

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Drug Addiction

Berke JD, and Hyman SE [2000]. Addiction, dopamine, and ther molecular mechansism of memory. Neuron, 25: 515–532.

Fiorillo CD, Tobler PN, and Schultz W [2003]. Discrete coding of reward probability and uncertainty by dopamine neurons. Science, 299: 1898–1902.

Hyman SE, and Malenka RC [2001]. Addiction and the brain: The neurobiology of compulsion and its persistence. Nature Rev. Neurosci., 2: 6695–703.

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Nestler EJ [2001]. Molecular basis of long-term plasticity underlying addiction.

Nature Rev. Neurosci., 2: 119–128.

Saal D, et al. [2003]. Drugs of abuse and stress trigger a common synaptic adaptation in dopamergic neurons. Neuron, 37: 577–582.

Schultz W, Dayan P, and Montague PR [1997]. A neural substrate of prediction and reward. Science, 275: 1593–1599.

Waelti P, Dickinson A, and Schultz W [2001]. Dopamine responses comply with basic assumptions of formal learning theory, Nature, 412: 43–48.

Problems

21.1 How does the neuron know which synapses to strengthen and which synapses to weaken when making long-term changes involving gene expression and protein synthesis? In a Hebbian type of rule for changing the strength of synapses, only those synapses exhibiting correlated firing are strengthened. Referring back to Figure 21.11(a), only the middle synapse onto cell B is strengthened. The middle synapse must be “tagged” in some fashion or other, so that the results of gene expression can be applied to that synapse alone. How might that be done?

21.2 In a Hebbian type of rule the postsynaptic cell fires an action potential. This is a cell-wide signal that a set of associations has been made. This may be viewed as a strong form of Hebb’s rule. The weak form of the rule would only require postsynaptic membrane depolarization by some amount. In a weaker form of Hebbian rule, an action potential is not required, but rather the convergent signals produce a depolarization. How might action potential information get conveyed to the dendrites to elicit an immediate strengthening of the synapse?

21.3 Several different experimental protocols are utilized in the hippocampal slice preparations. All of these involve pairing of spikes in the preand postsynaptic cells. One of the most effective protocols is that of tetanic stimulations. In the last chapter, at least four different kinds of firing modes were discussed. Which of the different modes of

Problems 537

firing would be most effective in eliciting LTP in vivo and in an adult where strong signaling is needed?

Suggested Reading

Martin KC, and Kosik KS [2002]. Synaptic tagging: Who’s it? Nature Rev. Neurosci., 3: 813–820.

Paulsen O, and Sejnowski TJ [2000]. Neural patterns of activity and long-term synaptic plasticity. Curr. Opin. Neurobiol., 10: 172–179.

540 Glossary

Antagonist A molecule that binds a receptor, but the receptor does not transmit a signal in response to the binding event. Drugs that bind in an antagonistic fashion are known as blockers.

Antibiotic Biomolecules synthesized by fungi and bacteria that kill competing microbes.

Antibodies Receptors synthesized by B cells that recognize and bind antigens.

Antigen (antibody generator) Foreign substance, derived from a pathogen and expressed either on the outer surface of the pathogen or on the surface of an antigen-presenting cell, that triggers the production of antibodies.

Antigenic variation Systematic alterations in the antigens expressed on the outer surface of a pathogen.

Apoptosis Programmed cell death, in which there is an orderly disassembly of the cell that avoids harming neighboring cells. Also called cell suicide.

Apoptosome The major control point for converting internal stress signals into apoptotic responses. It is located just outside the mitochondria and is activated by the release of cytochrome c.

Associative learning Changes in the behavioral response to the weak stimulus that has been paired with a strong (positive or negative) stimulus.

Autocrine A signaling mode in which hormones secreted from a cell act back on the cell releasing them.

Auxiliary spice sites Sites where splicing regulators bind. Auxiliary sites located within exons are called exonic splice enhancer (ESE) and exonic splice inhibitory (ESI) sites, depending on which regulatory outcome is supported. Similarly, intronic sites are termed intronic splice enhancer (ISE) and intronic splice inhibitory (ISI) sites.

Bacteriophage Virus that infects bacteria; also called a phage.

Biofilm A bacterial colony formed on exposed surfaces and exhibiting cooperative behavior between members.

Branching morphogenesis Growth, invasion, and proliferation of cells that form branched tubular structures that carry fluids in the vasculature, lungs, kidneys, and mammary glands.

Caspases Proteolytic enzymes that catalyze the cleavage of specific molecules in response to apoptosis signals.

Catch bond A bond that is strengthened by the external forces. The forcedriven enhancements in the lifetime of these bonds allow leukoctytes to be captured by the walls of the blood vessels and begin rolling.

Glossary 541

Caveolae (little caves) Tiny flask-shaped invaginations in the outer leaflet of the plasma membrane that are detergent-insoluble, enriched in glycosphingolipids, cholesterol, and lipid-anchored proteins, and in caveolins, a coatlike material.

Cell adhesion Cell-to-cell and cell-to-ECM attachment mediated by long modular and flexible glycoproteins expressed on opposing surfaces acting as receptors and counterreceptors or ligands.

Cell fate The determination of which tissue or organ a particular cell becomes a member of during embryonic development.

Cell polarity The asymmetric distributions of cellular components that arise during development. In the case of nerve cells it produces striking differences in morphology—axons at one end, dendrites at the other; in epithelial cells it gives rise to apical and basolateral plasma membrane domains.

Central pattern generators Circuits built from small numbers of neurons that are used to drive the rhythmic firing of muscles responsible for activities such as walking and swimming, breathing, and chewing and digesting.

Chaperones Proteins that help other proteins to fold into their native state, shuttle proteins to their correct locations in the cell, prevent unwanted aggregation, and assist in recovering and refolding proteins that have become misfolded due to cellular stresses.

Checkpoints Signaling pathways that ensure that a cell cycle or assembly process does not begin before a prior necessary process is completed.

Chemotaxis The process whereby a unicellular organism senses nutrients and noxious substances in its local environment, and, in response, moves towards the nutrients and away from the harmful chemicals.

Chromatin In eukaryotes, material from which chromosomes are made, consisting of DNA wrapped around proteins called histories.

Chromophore Groups of atoms or molecules that act as pigments, imparting color to the materials in which they reside by absorbing light at some wavelengths and scattering it at others.

Competence The ability of a bacterium to take up exogenous DNA from its environment.

Conjugation A form of horizontal gene transfer in which bacteria establish direct contact with one another; sex pili are formed, and genetic material in the form of plasmid are sent from donor to recipient.

Control point Locations in the cell where environmental and regulatory signals converge, integrate, and convent to cellular responses.

542 Glossary

Cytokines Small signaling proteins synthesized and secreted by leukocytes, most commonly, macrophages and T cells. They convey a variety of instructions to leukocytes and to other cells such as neurons.

responses. It is organized by death receptors at and just below the plasma membrane.

Denatured state The ensemble of states that a newly synthesized protein, or an unfolded protein, populates.

Dephosphorylation The removal catalyzed by protein phosphatases of phosphoryl groups previously added to amino acid side chain hydroxyls on protein substrates by protein kinases.

Desensitization The process whereby a G protein-coupled receptor, or any other receptor, loses its responsiveness to binding by its ligand.

Diffraction Scattering of light by atoms, molecules, and larger objects resulting in departures from rectilinear motion other than reflection or refraction.

Diffusion Thermally driven movement of particles in a fluid from one locale to another produced by random collisions of the particles with the molecules of the fluid.

Distal sites DNA regulatory regions where long-range interactions between regulatory proteins and the basal transcription machinery take place.They may be located upstream of the core promoter,downstream of the core promoter,in between coding regions,and inside introns. Positively acting transcription factors that bind at these sites are called enhancers, while negatively acting transcription factors are referred to as silencers.

Domain fold Stable arrangements of multiple secondary structure elements and of two or more structural motifs into independent folding units.

Efficiency of synaptic transmission Magnitude of the response generated in a postsynaptic neuron when an action potential is generated in the presynaptic neuron.

Electrostatic complementarity The matching of hydrophobic patches, the complementary pairing of hydrogen bond donors and acceptors, and the matching of positive and negative charges of basic and acidic polar residues from one surface to the other of the interface.

Endocrine A signaling mode in which hormones are secreted into the bloodstream and other bodily fluids by specialized cells and travel large distances to reach multiple target cells.