Skip to main content Accessibility help
×
Hostname: page-component-8448b6f56d-gtxcr Total loading time: 0 Render date: 2024-04-18T10:08:43.019Z Has data issue: false hasContentIssue false

15 - The neural substrates of anxiety

from Part VII - Affective illness

Published online by Cambridge University Press:  19 January 2010

Simon Killcross
Affiliation:
Cardiff University, Cardiff, UK
Maria A. Ron
Affiliation:
Institute of Neurology, London
Trevor W. Robbins
Affiliation:
University of Cambridge
Get access

Summary

Introduction

The aim of this chapter is to try to bring together some of the recent advances in the study of the neural substrates of fear and anxiety in laboratory animals to form a coherent overview that will facilitate comparisons between these basic studies and clinical investigations. The advances made in the study of animal models of anxiety over the past decade are little short of remarkable, especially in the field of conditioned fear. We may now with some confidence map out likely neural mechanisms from the level of functional systems to the cellular and molecular details. We know much of which neuroanatomical areas, neural projections, neurotransmitter systems and receptors are involved in the acquisition and expression of a number of fear-related behaviours.

This is fine progress indeed, but often begs the question of direct relevance to clinical applications. To what extent is the study of conditioned fear and anxiety in animals easily translated into the neuropsychiatric domain? There are several approaches to answering this question. One might suggest that clinical anxiety does indeed reflect a specific neuropathology in a specific behavioural system that is well described at the neurobiological and behavioural level (e.g. patterns of defensive behaviour; Rodgers 1997). This approach values certain forms of animal model over others (e.g. ethological vs. conditioning-based models), and to a certain degree adheres to the suggestion that anxiety reflects a pathological state of a perfectly normal fear system.

Type
Chapter
Information
Publisher: Cambridge University Press
Print publication year: 2003

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Alexander, G E, Crutcher, M D and DeLong, M R (1990). Basal ganglia–thalamocortical circuits: parallel substrates for motor, oculomotor, ‘prefrontal’, and ‘limbic’ functions. Prog Brain Res, 85, 119–46Google Scholar
Amorapanth, P, LeDoux, J E and Nader, K (2000). Different lateral amygdala outputs mediate reactions and actions elicited by a fear-arousing stimulus. Nat Neurosci, 3, 74–9Google Scholar
Applegate, C D, Frysinger, R C, Kapp, B S and Gallagher, M (1982). Multiple unit activity recorded from amygdala central nucleus during Pavlovian heart rate conditioning. Brain Res, 238, 457–62Google Scholar
Balleine, B W (1991). The acquisition of self-stimulation of the medial prefrontal cortex following exposure to escapable or inescapable footshock. Behav Brain Res, 43, 167–74Google Scholar
Balleine, B W and Dickinson, A (1998). Goal-directed instrumental action: contingency and incentive learning and their cortical substrates. Neuropsychopharmacology, 37, 407–19Google Scholar
Balleine, B W and Killcross, A S (1994). Effects of ibotenic acid lesions of the nucleus accumbens on instrumental action. Behav Brain Res, 65, 181–93Google Scholar
Barrett, J E and Vanover, K (1993). 5-HT receptors as targets for the development of novel anxiolytic drugs: models, mechanisms and future directions. Psychopharmacology, 112, 1–12Google Scholar
Beckett, S and Marsden, C A (1997). The effect of central and systemic injection of the 5HT1A receptor agonist 8-OH-DPAT and the 5HT1A receptor antagonist WAY 100635 on periaqueductal grey-induced defence behaviour. J Psychopharmacol, 11, 35–40Google Scholar
Bosker, F, Vrinten, D, Klompmakers, A and Westenberg, H (1997). The effects of a 5-HT1A receptor agonist and antagonist on the 5-hydroxytryptamine release in the central nucleus of the amygdala: a microdialysis study with flesinoxan and WAY100635. N-S Arch Pharmacol, 355, 347–53Google Scholar
Botvinik, M, Nystrom, L E, Fissell, K, Carter, C S and Cohen, J D (1999). Conflict monitoring versus selection-for-action in anterior cingulate cortex. Nature, 402, 179–81Google Scholar
Bouton, M E, Mineka, S and Barlow, D H (2001). A modern learning theory perspective on the etiology of panic disorder. Psychol Rev, 108, 4–32Google Scholar
Bucci, D J, Holland, P C and Gallagher, M (1998). Removal of cholinergic input to rat posterior parietal cortex disrupts incremental processing of conditioned stimuli. J Neurosci, 18, 8038–46Google Scholar
Burns, L H, Robbins, T W and Everitt, B J (1993). Differential effects of excitotoxic lesions of the basolateral amygdala, ventral subiculum and medial prefrontal cortex on responding with conditioned reinforcement and locomotor activity potentiated by intra-accumbens infusions of d-amphetamine. Behav Brain Res, 55, 167–83Google Scholar
Bussey, T J, Everitt, B J and Robbins, T W (1997). Dissociable effects of cingulate and medial prefrontal cortex lesions on stimulus-reward learning using a novel Pavlovian autoshaping procedure in the rat: implications for the neurobiology of emotion. Behav Neurosci, 111, 908–19Google Scholar
Cahill, L (1997). The neurobiology of emotionally influenced memory – implications for the treatment of traumatic memory. Ann NY Acad Sci, 821, 238–46Google Scholar
Cahill, L, Prins, B, Weber, M and McGaugh, J L (1994). β-adrenergic activation and memory for emotional events. Nature, 371, 702–3Google Scholar
Cahill, L, Vazdarjanova, A and Setlow, B (2000). The basolateral amygdala complex is involved with, but is not necessary for, rapid acquisition of Pavlovian ‘fear’ conditioning. Eur J Neurosci, 12, 3044–50Google Scholar
Charney, D S, Woods, S W, Goodman, W K and Heninger, G R (1987). Neurobiological mechanisms of panic anxiety: biochemical and behavioural correlates of yohimbine-induced panic attacks. Am J Psychiatry, 144, 1030–6Google Scholar
Chiba, A A, Bucci, D J, Holland, P C and Gallagher, M (1995). Basal forebrain cholinergic lesions disrupt increments but not decrements in conditioned-stimulus processing. J Neurosci, 15, 7315–22Google Scholar
Chua P and Dolan R J (2000). The neurobiology of anxiety and anxiety-related disorders: a functional neuroimaging perspective. In Brain Mapping: The Disorders, ed. J C Mazziotta, A T Toga and R S J Frackowiak, pp. 509–22. San Diego: Academic Press
Cole, B J and Robbins, T W (1987). Dissociable effects of lesions to dorsal and ventral noradrenergic bundle on the acquisition, performance, and extinction of aversive conditioning. Behav Neurosci, 101, 476–88Google Scholar
Coutureau, E, Dix, S L and Killcross, A S (2000). Involvement of the medial prefrontal cortex-basolateral amygdala pathway in fear related behaviour in rats. Eur J Neurosci, 12, 156Google Scholar
Coutureau, E, Dix, S L and Killcross, A S (2001). Functional heterogeneity of the medial prefrontal cortex in fear-related behaviour. Behav Pharmacol, 12, 24Google Scholar
Crawley, J N (1999). Behavioral phenotyping of transgenic and knockout mice: experimental design and evaluation of general health, sensory functions, motor abilities, and specific behavioural tests. Brain Res, 835, 18–26Google Scholar
Damasio A R (1998). The somatic marker hypothesis and the possible functions of the prefrontal cortex. In The Prefrontal Cortex: Executive and Cognitive Functions, ed. A C Roberts, T W Robbins and L Weiskrantz, pp. 36–50. Oxford: Oxford University Press
Davis M (1992). The role of the amygdala in conditioned fear. In The Amygdala: Neurobiological Aspects of Emotion, Memory and Mental Dysfunction, ed. J P Aggleton, pp. 255–306. New York: Wiley-Liss
Davis M (2000). The role of the amygdala in unconditioned and conditioned fear and anxiety. In The Amygdala: A Functional Analysis, ed. J P Aggleton, pp. 213–88. New York: Oxford University Press
Deakin, J F W and Graeff, F G (1991). 5HT and mechanisms of defence. J Psychopharmacol, 5, 301–15Google Scholar
Boer, J A and Westenberg, H G M (1990). Serotonin function in panic disorder: a double blind placebo controlled study with fluvoxamine and ritanserin. Psychopharmacology, 102, 85–94Google Scholar
Deutch A Y and Young C D (1995). A model of the stress-induced activation of the prefrontal dopamine system: coping and the development of post-traumatic stress disorder. In Neurobiological and Clinical Consequences of Stress, ed. M J Friedman, D S Charney and A Y Duetch, pp. 163–75. Philadelphia: Lippincott-Raven
Dix, S L, Coutureau, E and Killcross, A S (2001). Dissociable roles of the nucleus accumbens core and shell in fear-related behaviour in rats. Behav Pharmacol, 12, 30Google Scholar
Everitt, B J and Robbins, T W (1997). Central cholinergic systems and cognition. Annu Rev Psychol, 48, 649–84Google Scholar
Eysenck M W (1992). Anxiety: The Cognitive Perspective. London: Lawrence Erlbaum Associates
Eysenck M W (1997). Anxiety and Cognition: A Unified Theory. Hove: Psychology Press
File, S E, Gonzalez, L E and Andrews, N (1996). Comparative study of pre- and post-synaptic 5-HT1A receptor modulation of anxiety in two ethological animal tests. J Neurosci, 16, 4810–15Google Scholar
Finlay, J M and Abercrombie, E D (1991). Stress induced sensitisation of norepinephrine release in the medial prefrontal cortex. Soc Neurosci Abstr, 17, 151Google Scholar
Flint, J, Corley, R, DeFries, J C et al. (1995). A simple genetic basis for a complex psychological trait in laboratory mice. Science, 269, 1432–5Google Scholar
Frysztak, R J and Neafsey, E J (1994). The effect of medial prefrontal cortex lesions on cardiovascular conditioned emotional responses in the rat. Brain Res, 643, 181–93Google Scholar
Gallagher, M, Graham, P W and Holland, P C (1990). The amygdala central nucleus and appetitive Pavlovian conditioning – lesions impair one class of conditioned behavior. J Neurosci, 10, 1906–11Google Scholar
Gora-Maslak, G, McClearn, G E, Crabbe, J C, Phillips, T JBelknap, J K and Plomin, R (1995). Use of recombinant inbred strains to identify quantitative trait loci in psychopharmacology. Psychopharmacology, 104, 413–24Google Scholar
Graeff, F G (1994). Neuroanatomy and neurotransmitter regulation of defensive behaviours and related emotions in mammals. Brazil J Med Biol Res, 27, 811–29Google Scholar
Graeff, F G, Guimaraes, F S, Andrade, T G C S and Deakin, J F W (1996). Role of 5HT in stress, anxiety and depression. Pharmacol Biochem Behav, 54, 129–49Google Scholar
Graeff, F G, Viana, M B and Mora, P O (1997). Dual role of 5-HT in defence and anxiety. Neurosci Biobehav Rev, 21, 791–9Google Scholar
Hall, G and Pearce, J M (1979). Latent inhibition of CS during CS-US pairings. J Exp Psychol Anim Behav Process, 5, 31–42Google Scholar
Han, J S, Holland, P C and Gallagher, M (1999). Disconnection of the amygdala central nucleus and substantia innominata/nucleus basalis disrupts increments in conditioned stimulus processing in rats. Behav Neurosci, 113, 143–51Google Scholar
Handley, S L, McBlane, J W, Critchley, M A E and Njunge, K (1993). Multiple serotonin mechanisms in animal models of anxiety – environmental, emotional and cognitive factors. Behav Brain Res, 58, 203–10Google Scholar
Harrison, A A, Everitt, B J and Robbins, T W (1997). Central 5-HT depletion enhances impulsive responding without affecting the accuracy of attentional performance: interactions with dopaminergic mechanisms. Psychopharmacology, 133, 329–42Google Scholar
Hatfield, T and McGaugh, J L (1999). Norepinephrine infused into the basolateral amygdala posttraining enhances retention in a spatial water maze task. Neurobiol Learn Memory, 71, 232–9Google Scholar
Heisler, L K, Chu, H M, Brennan, T J et al. (1998). Elevated anxiety and anti-depressant-like responses in serotonin 5-HT1A receptor mutant mice. Proc Natl Acad Sci USA, 95, 15049–54Google Scholar
Hitchcott, P K and Phillips, G D (1998). Double dissociation of the behavioural effects of R(+) 7-OH-DPAT infusions in the central and basolateral amygdala nuclei upon Pavlovian and instrumental conditioned appetitive behaviours. Psychopharmacology, 140, 458–69Google Scholar
Hodges, H, Green, S and Glenn, B (1987). Evidence that the amygdala is involved in benzodiazepine and serotonergic effects on conditioned responding but not on discrimination. Psychopharmacology, 92, 491–504Google Scholar
Holland, P C and Gallagher, M (1993 a). Effects of amygdala central nucleus lesions on blocking and unblocking. Behav Neurosci, 107, 235–45Google Scholar
Holland, P C and Gallagher, M (1993 b). Amygdala central nucleus lesions disrupt increments, but not decrements, in conditioned-stimulus processing. Behav Neurosci, 107, 246–53Google Scholar
Honey, R C and Ward-Robinson, J (2001). Transfer between contextual conditional discriminations: an examination of how stimulus conjunctions are represented. J Exp Psychol Anim Behav Process, 27, 196–205Google Scholar
Hurley, K M, Hernert, H, Moga, M M and Saper, C B (1991). Efferent projections of the infralimbic cortex of the rat. J Comp Neurol, 308, 249–76Google Scholar
Jinks, A L and McGregor, I S (1997). Modulation of anxiety-related behaviors following lesions of the prelimbic or infralimbic cortex in the rat. Brain Res, 772, 181–90Google Scholar
Kapp B S, Whalen P J, Supple W F and Pascoe J P (1992). Amygdaloid contributions to conditioned arousal and sensory information processing. In The Amygdala: Neurobiological Aspects of Emotion, Memory and Mental Dysfunction, ed. J P Aggleton, pp. 229–54. New York: Wiley-Liss
Kapp, B S, Supple, W F and Whalen, P J (1994). Effects of electrical-stimulation of the amygdaloid central nucleus on neocortical arousal in the rabbit. Behav Neurosci, 108, 81–93Google Scholar
Kelley, A E, SmithRoe, S L and Holahan, M R (1997). Response-reinforcement learning is dependent on N-methyl-D-aspartate receptor activation in the nucleus accumbens core. Proc Natl Acad Sci USA, 94, 12174–9Google Scholar
Killcross A S and Blundell P (2002). Associative representations of emotionally significant outcomes. In Emotional Cognition (Advances in Consciousness Research), ed. S Moore and M Oaksford. John Benjamins: Amsterdam
Killcross, A S and Robbins, T W (1993). Differential effects of intra-accumbens and systemic amphetamine on latent inhibition using an on-baseline, within-subject conditioned suppression paradigm. Psychopharmacology, 110, 449–59Google Scholar
Killcross, A S, Dickinson, A and Robbins, T W (1994). Amphetamine-induced disruptions of latent inhibition are reinforcer mediated: Implications for animal models of schizophrenic attentional dysfunction. Psychopharmacology, 115, 185–95Google Scholar
Killcross, A S, Everitt, B J and Robbins, T W (1997 a). Different types of fear-conditioned behaviour mediated by separate nuclei within the amygdala. Nature, 388, 377–80Google Scholar
Killcross, A S, Everitt, B J and Robbins, T W (1997 b). Symmetrical effects of amphetamine and alpha-flupenthixol on conditioned punishment and reinforcement: contrasts with midazolam. Psychopharmacology, 129, 141–52Google Scholar
LeDoux J E (1992). Emotion and the amygdala. In The Amygdala: Neurobiological Aspects of Emotion, Memory, and Mental Dysfunction, ed. J P Aggleton, pp. 339–52. New York: Wiley-Liss
LeDoux J E (1996). The Emotional Brain: The Mysterious Underpinnings of Emotional Life. New York: Touchstone
Mansbach, R S and Geyer, M A (1988). Blockage of potentiated startle responding in rats by 5-hydroxytryptamine1A receptor ligands. Eur J Pharmacol, 156, 375–83Google Scholar
McDonald, A J (1991). Organisation of amygdaloid projections to the prefrontal cortex and associated striatum in the rat. Neuroscience, 44, 1–14Google Scholar
McDonald, A J (1998). Cortical pathways to the mammalian amygdala. Prog Neurobiol, 55, 257–332Google Scholar
McGaugh J L, Ferry B, Vazdarjanova A and Roozendaal B (2000). Amygdala: role in modulation of memory storage. In The Amygdala: A Functional Analysis, ed. J P Aggleton, pp. 391–423. New York: Oxford University Press
Melia, K R and Davis, M (1991). Effects of septal lesions on fear potentiated startle, and on the anxiolytic effects of buspirone and diazepam. Physiol Behav, 49, 603–11Google Scholar
Miller, E K and Cohen, J D (2001). An integrative theory of prefrontal cortex function. Annu Rev Neurosci, 24, 167–202Google Scholar
Mogenson, G, Jones, D L and Yim, C Y (1984). From motivation to action: functional interface between the limbic system and the motor system. Prog Neurobiol, 14, 69–97Google Scholar
Muir, J L, Dunnett, S B, Robbins, T W and Everitt, B J (1992). Attentional functions of the forebrain cholinergic systems – effects of intraventricular hemicholinium, physostigmine, basal forebrain lesions and intracortical grafts on a multiple-choice serial reaction-time-task. Exp Brain Res, 89, 611–22Google Scholar
Muir, J L, Page, K J, Sirinathsinghji, D J S, Robbins, T W and Everitt, B J (1993). Excitotoxic lesions of basal forebrain cholinergic neurons – effects on learning, memory and attention. Behav Brain Res, 57, 123–31Google Scholar
Muir, J L, Everitt, B J and Robbins, T W (1994). AMPA-induced excitotoxic lesions of the basal forebrain – a significant role for the cortical cholinergic system in attentional function. J Neurosci, 14, 2313–26Google Scholar
Nisenbaum, L K, Zigmund, M J, Sved, A F and Abercrombie, E D (1991). Prior exposure to chronic stress results in enhanced synthesis and release of hippocampal norepinephrine in response to a novel stressor. J Neurosci, 11, 1473–84Google Scholar
Ohman, A and Mineka, S (2001). Fears, phobias and preparedness: toward an evolved module of fear and fear learning. Psychol Rev, 108, 483–522Google Scholar
Parkinson, J A, Olmstead, M C, Burns, L H, Robbins, T W, and Everitt, B J (1999). Dissociation of effects of lesions of the nucleus accumbens core and shell on appetitive Pavlovian approach behaviour and the potentiation of conditioned reinforcement and locomotor activity by d-amphetamine. J Neurosci, 19, 2401–11Google Scholar
Pearce, J M and Hall, G (1980). A model for Pavlovian learning: variations in the effectiveness of conditioned but not of unconditioned stimuli. Psychol Rev, 87, 532–52Google Scholar
Pitkänen A (2000). Connectivity of the rat amygdaloid complex. In The Amygdala: A Functional Analysis, ed. J P Aggleton, pp. 31–115. New York: Oxford University Press
Quirarte, G L, Galvez, R, Roozendaal, B and McGaugh, J L (1998). Norepinephrine release in the amygdala in response to footshock and opioid peptodergic drugs. Brain Res, 808, 134–40Google Scholar
Quirk, G J, Armony, J L and LeDoux, J E (1997). Fear conditioning enhances different temporal components of tone-evoked spike trains in auditory cortex and lateral amygdala. Neuron, 19, 613–24Google Scholar
Quirk, G J, Russo, G K, Barron, J L and Lebron, K (2000). The role of the ventromedial prefrontal cortex in the recovery of extinguished fear. J Neurosci, 20, 6225–31Google Scholar
Robledo, P, Robbins, T W and Everitt, B J (1996). Effects of excitotoxic lesions of the central amygdaloid nucleus on the potentiation of reward-related stimuli by intra-accumbens amphetamine. Behav Neurosci, 110, 981–90Google Scholar
Rodgers, R J (1997). Animal models of ‘anxiety’: where next?Behav Pharmacol, 8, 477–96Google Scholar
Roozendaal, B and McGaugh, J L (1996). Amygdaloid nuclei lesions differentially affect glucocorticoid-induced memory enhancement in an inhibitory avoidance task. Neurobiol Learn Memory, 65, 1–8Google Scholar
Sanger, D J (1992). Increased rates of punished responding produced by buspirone-like compounds in rats. J Pharmacol Exp Therapeut, 254, 420–6Google Scholar
Sarter, M and Bruno, J P (1997). Cognitive functions of cortical acetylcholine: toward a unifying hypothesis. Brain Res Rev, 23, 28–46Google Scholar
Selden, N R W, Everitt, B J, Jarrard, L E and Robbins, T W (1991). Complementary roles for the amygdala and hippocampus in aversive conditioning to explicit and contextual cues. Neuroscience, 42, 335–50Google Scholar
Setlow, B, Roozendaal, B and McGaugh, J L (2000). Involvement of a basolateral amygdala complex-nucleus accumbens pathway in glucocorticoid-induced modulation of memory consolidation. Eur J Neurosci, 12, 367–75Google Scholar
Stanhope, K J and Dourish, C T (1996). Effects of 5-HT1A receptor agonists, partial agonists and a silent antagonist on the performance of the conditioned emotional response test in the rat. Psychopharmacology, 128, 293–303Google Scholar
Swanson, L and Petrovich, G (1998). What is the amygdala?Trends Neurosci, 21, 323–31Google Scholar
Taylor, D P, Eison, M S, Riblet, L A and Vandermaelen, C P (1985). Pharmacological and clinical effects of buspirone. Pharmacol Biochem Behav, 23, 687–94Google Scholar
Thierry, A M, Tassin, J P, Blanc, G and Glowinski, J (1976). Selective activation of mesocortical dopaminergic system by stress. Nature, 263, 242–4Google Scholar
Turri, M G, Datta, S R, DeFries, J, Henderson, N D, and Flint, J (2001). QTL analysis identifies multiple behavioural dimensions in ethological tests of anxiety in laboratory mice. Curr Biol, 11, 725–34Google Scholar
Vazdarjanova, A and McGaugh, J L (1998). Basolateral amygdala is not critical for cognitive memory of contextual fear conditioning. Proc Natl Acad Sci USA, 95, 15003–7Google Scholar
Wilkinson, L S, Humby, T, Killcross, A S, Everitt, B J and Robbins, T W (1996). Dissociations in hippocampal 5HT release following Pavlovian aversive conditioning to discrete and contextual stimuli. Eur J Neurosci, 8, 1479–87Google Scholar
Wilkinson, L S, Humby, T, Killcross, A S, Torres, E M, Everitt, B J and Robbins, T W (1998). Dissociations in dopamine release in medial prefrontal cortex and ventral striatum during the acquisition and extinction of classical aversive conditioning in the rat. Eur J Neurosci, 10, 1019–26Google Scholar

Save book to Kindle

To save this book to your Kindle, first ensure coreplatform@cambridge.org is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about saving to your Kindle.

Note you can select to save to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be saved to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

Available formats
×

Save book to Dropbox

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Dropbox.

Available formats
×

Save book to Google Drive

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Google Drive.

Available formats
×