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Unformatted text preview: THE NEUROBIOLOGY OF FEAR AND ANXIETY OUTLINE • Conditional fear – Behavioral assays – Neural substrates • Unconditional ("innate") fear – Behavioral assays – Neural substrates • Anxiety – Behavioral assays – Neural substrates • Social communication of fear FEAR CONDITIONING: A MODEL FOR UNDERSTANDING NEURAL CIRCUITS FOR EMOTIONAL BEHAVIOR FEAR-CONDITIONING: A SPECIAL CASE OF PAVLOVIAN ASSOCIATIVE LEARNING • Animal acquires fear response to both tone (“cue”) and box (“context”) • CR does not recapitulate UR (flight) LeDoux, J.E. (1996) The Emotional Brain J.E. The LeDoux, J.E. (1996) The Emotional Brain J.E. The RATS UNDERGOING FEAR CONDITIONING ACQUIRE FEAR OF BOTH CUE AND CONTEXT DIFFERENT PATHWAYS MEDIATE CUE AND CONTEXTUAL FEAR CONDITIONING Cue test training Context test LeDoux, J.E. (1996) The Emotional Brain J.E. The 1 THE AMYGDALA AND HIPPOCAMPUS CONTROL IMPLICIT vs. EXPLICIT CONTROL vs MEMORY BASIC NEURAL CIRCUITRY OF FEAR CONDITIONING Site of CS-US convergence = Cue conditioning = Context conditioning LA IS A SITE OF CS-US CONVERGENCE AND OF LTP A CAUSAL TEST OF LA PLASTICITY IN FEAR CONDITIONING Maren and Quirk (2004) Nat. Rev. Neurosci. 5: 844 Maren Neurosci EFFECT OF PRE- vs. POST-TRAINING EFFECT vs INACTIVATION OF THE AMYGDALA WITH MUSCIMOL CORTICAL vs. SUB-CORTICAL INPUTS CORTICAL vs TO THE AMYGDALA Subjective (conscious) fear Defensive behaviors 2 CORTICAL AND THALAMIC PATHWAYS LIKELY CARRY CS INFORMATION IN PARALLEL TO THE AMYGDALA thalamus cortex BASIC NEURAL CIRCUITRY OF FEAR CONDITIONING THE AMYGDALA CONTROLS MULTIPLE FEAR-RELATED BEHAVIORS BY PROJECTING TO MANY OTHER BRAIN AREAS Site of CS-US convergence X Site of coordinated output X XX A CHALLENGE TO THE FEAR CONDITIONING MODEL: BILATERAL EXCITOTOXIC LESIONS OF CEA DO NOT ABOLISH CONTEXT OR CUE LEARNING MODEL FOR BYPASS OF CEA chemo CeA CeA Koo et al. (2004) J. Neurosci. 24:7654 Koo et Koo et al. (2004) J. Neurosci. 24:7654 Koo et 3 A CONTRADICTORY PAPER: CeA IS IS INVOLVED IN BOTH ACQUISITION INVOLVED BOTH AND STORAGE OF FEAR LEARNING REVISED CIRCUIT MODEL OF FEAR CONDITIONING PROBLEM1: LA CEA CONNECTION PROBLEM1: Possible solution #1 Direct excitatory projection from CEAl to CEAm? Direct CEAm Day, et al. (1999) JCN 413:113 Paré et al. (2004) J. Neurophysiol. 92: 1-9 Neurophysiol Possible Solution #2 Dis-inhibition via Intercalated Cell Mass Huber et al. (2005) Science 308:245 UNCONDITIONAL ("INNATE") FEAR Paré et al. (2004) J. Neurophysiol. 92: 1-9 Neurophysiol 4 DIFFERENCES IN APPROACHES TO LEARNED vs. INNATE FEAR TO vs • FEAR CONDITIONING • INNATE FEAR – Domain of Experimental Psychology – Highly controlled experimental setting – Highly controlled unimodal stimulus (2 unimodal stimulus kHz tone) – Single behavior typically measured (freezing) – Minimize variability – Domain of neuroethology – Naturalistic experimental setting – Complex stimuli (polymodal or complex polymodal or unimodal) – Multiple behaviors measured – Variable responses RESPONSES OF RODENTS TO INTACT PREDATORS IS CONTEXT DEPENDENT STIMULI AND RESPONSES FOR UNCONDITIONAL FEAR RESPONSES • Stimuli: – Intact predators – Predator odors – Synthetic odors (PT, TMT) • Responses – – – – Freezing Flight Sheltering Behavioral inhibition NEURAL SUBSTRATES FOR PREDATOR DEFENSES: MEDIAL HYPOTHALAMIC BEHAVIORAL CONTROL COLUMN Defensive nuclei Reproductive nuclei Modified from Swanson, L.W. (2000) Brain Res. 886:113-164 INVOLVEMENT OF HYPOTHALAMIC NUCLEI IN PREDATOR DEFENSES C-fos expression following cat exposure fos expression MEDIAL HYPOTHALAMIC NUCLEI RECEIVE TOPOGRAPHIC PROJECTIONS FROM MEDIAL AMYGDALA Effect of PMd lesion Effect lesion R D * CONTROL Canteras et al. (1997) Brain Res. Bull. 44:297 Canteras et * ** ** Modified from Swanson, L.W. (2000) Brain Res. 886:113-164 5 LESIONS OF MEA BUT NOT CEA DISRUPT BEHAVIORAL RESPONSES TO PREDATOR ODORS Suggestion that the BNST is involved in unconditioned fear Lesions of BNSTa, but not LA/BLA, block freezing responses to synthetic fox feces odor, TMT synthetic Li et al., (2004) Behav. Neurosci. 118:324-332 Li Behav Neurosci TMT and natural predator odor are not behaviorally equivalent stimuli Fendt et al (2003) J. Neurosci. 23:23-28 Fendt Neurosci The posterior, NOT anterior, BST The posterior NOT anterior relays projections from MEA to hypothalamus Domain of most BST lesions McGregor et al (2002) Behav. Brain Res. 129:1-16 McGregor Behav Brain Res •The idea that MEA and BSTa lesions have similar effects on predator The lesions responses is not consistent, because it involves the wrong part of the BST responses not wrong ANXIETY "UNCONDITIONAL/INNATE FEAR" vs. "ANXIETY" Behavioral Assays Stimulus dependent vs. independent Neural substrates BNST vs. Lateral Septum 6 Common behavioral tests of anxiety Light-enhanced vs. fearLight-enhanced vs potentiated acoustic startle potentiated acoustic Testing (measure startle) training 2 kHz 2 kHz 24 hr Tone/shock pairing "fear-potentiated" startle 90 DB white 90 DB white noise burst noise burst Others: light-dark box shock-probe burial (active) light-enhancement of acoustic startle control Gordon and Hen (2004) Ann. Rev. Neurosci. 27:193 Gordon Neurosci Lesions of CeA and BNSTa have Lesions have dissociable effects on light-enhanced vs. fear-potentiated acoustic startle potentiated acoustic lesion "light-enhanced" startle Walker and Davis (1997) J. Neurosci. 17:9375 Concept: CeA and BNST are Concept: and differentially involved in fear vs. "anxiety" AMPA receptor antag. AMPA antag (BLA manipulations affect both) Michael Davis Problem: CEA and BNST anterior are densely interconnected GABA? Dong and Swanson (2004) J. Comp. Neurol. 468:277 Davis and Shi (1999) Ann. NY Acad. Sci. 877:281 Involvement of CEA in anxiety as measured by elevated plus maze GABA? Burghardt and Wilson (2005) Neuropsychopharmacology 1-14 Burghardt 1-14 7 AN OLD MODEL: ROLE OF THE SEPTO-HIPPOCAMPAL SYSTEM IN ANXIETY The ventral-lateral septum is strongly activated during stress and anxiety avoidance Plus maze Morphine withdrawal Restraint stress Social defeat Social defeat Noise stress Sheehan et al (2004) Brain Res. Rev. 46:71 J. Gray (1973) LSi and LSv express the type 2 LSi express receptor for CRH, which is implicated in anxiety INFUSION OF UROCORTIN 2 INTO THE LS INCREASES ANXIETY UcnIII Li et al. (2002) J. Neurosci. Li Neurosci 22: 991-1001 Rats exposed to a conditioned fear stimulus or predator emit 22 kHz alarm calls Brudzynski (2005) Behav. Genet. 35:85 Brudzynski Behav Injection of cholinergic agonists into LS elicits 22 kHz USVs Koo et al (2004) J. Neurosci. 24:7654 Koo et 8 Evidence for an involvement of lateral septum in anxiety The ventro-lateral septum is a target of the ventral hippocampus FG Risold and Swanson (1997) Brain Res. Rev. 24:115-195 Risold and Treit et al (1993) Behav. Neurosci. 107: 770-785 Treit Behav Neurosci Lesions of ventral hippocampus reduce anxiety in elevated plus maze POTENTIAL SYSTEMS CONTROLLING CONDITIONED/UNCONDITIONED FEAR AND ANXIETY CENTRAL AMYGDALA-BSTa MEDIAL AMYGDALA-BSTp SEPTO-HIPPOCAMPAL Short-term conditioned fear Cortex/Thalamus LA Predator defenses Longer-term responses MeA CoA BSTa Hypothalamus (LH, PVN) Elevator Lateral Septum (v) BSTp Hypothalamus (AHN, VMHdm, PMd) (AHN, VMHdm PMd Brainstem (PAG) OLFACTORY AVOIDANCE CONDITIONING IN DROSOPHILA CONDITIONING DROSOPHILA Hippocampus (v) AOB/MOB BLA CeAm/l Degroot and Treit (2004) Brain Res. 1001:60 Degroot and (2004) Stress/anxiety CRH Identifying neural substrates for behavior in Drosophila behavior Drosophila "training chamber" "testing chamber" Odor 'B' Odor 'A' "T-maze" Benzer (1976); Tully; Heisenberg Benzer (1976); M. Heisenberg, Nat. Rev. Neurosci. 2003 M. Neurosci 9 VISUALIZATION OF NEURONAL SUBSETS USING GAL4 ENHANCER TRAPS Mushroom body-specific Gal4 lines "reporter" "activator" strain GAL-4 X UAS lacZ or GFP Transgene expressed in Transgene expressed subset of neurons mini white Sakai and Kitamoto (2006) J. Neurobiol. 66:821 Neurobiol TEMPERATURE-SENSITIVE BLOCKADE OF NEUROTRANSMITTER RELEASE USING Shiberets RELEASE Shibere GAL-4 X Transgene expressed in Transgene expressed subset of neurons UAS Disruption of synaptic transmission blocks retrieval but not storage in the mushroom body shits Temperature-sensitive inhibitor of neurotransmitter release INHIBITION OF TRANSMITTER RELEASE AT 29oC NORMAL RELEASE AT 21oC UNCONDITIONED AVOIDANCE IN DROSOPHILA MUSHROOM BODY ABLATION HAS NO AFFECT ON THE RESPONSE TO dSO "Drosophila Stress Drosophila Stress Odorant" (dSO) CO2 10 10 Most olfactory neurons project to both the MB and Lateral horn Distinct neural substrates for learned and innate avoidance in flies and mammals Learned Mushroom Body Innate Lateral Horn Learned Innate LA/CeA/BSTa MeA/BSTp LH/PVN AHN/VMHdm/PMd (auditory) (olfactory) Margulies et al. (2005) Curr. Biol. 15:R700 Margulies Curr Biol "CONDITIONED FEAR" LEARNING IN FLIES Elevator "training chamber" "testing chamber" Odor 'B' Odor 'A' MUSHROOM BODIES "T-maze" Benzer (1976); Tully; Heisenberg Benzer (1976); 11 11 ...
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