Lecture 9 - Synaptic Organization of the Amygdala PDF

1 LECTURE 10: SYNAPTIC ORGANIZATION OF THE AMYGDALA PROF. JUNIOR STEININGER 2 THE AMYGDALA IS A COLLECTION OF MULTIPLE INTERCONNECTED NUCLEI FOUND IN THE TEMPORAL LOBE 3 CORONAL SECTION OF THE MOUSE AMYGDALA 4 NUCLEI ARE DISTINGUISHED USING HISTOLOGICAL CRITERI...

1 LECTURE 10: SYNAPTIC ORGANIZATION OF THE AMYGDALA PROF. JUNIOR STEININGER 2 THE AMYGDALA IS A COLLECTION OF MULTIPLE INTERCONNECTED NUCLEI FOUND IN THE TEMPORAL LOBE 3 CORONAL SECTION OF THE MOUSE AMYGDALA 4 NUCLEI ARE DISTINGUISHED USING HISTOLOGICAL CRITERIA, SUCH AS DENSITY, SHAPE, SIZE OF CELLS, CHEMICAL SIGNATURES Basolateral complex (BLA) = lateral (La) + basal (B) + accessory basal (AB) Central nucleus (CeA) = lateral + medial subdivision (CeL, CeM) 5 THE PRIMARY AMYGDALAR NUCLEI AND BASIC CIRCUIT CONNECTIONS ARE HIGHLY CONSERVED ACROSS SPECIES 6 THE LIMBIC SYSTEM INCLUDES A NUMBER OF STRUCTURES INVOLVED IN THE EXPRESSION AND EXPERIENCE OF EMOTION 7 LESION STUDIES PROVIDED THE FIRST CLUES TO THE ROLE OF THE AMYGDALA IN BEHAVIOUR Temporal lobe ablations, including the amygdala, led to reduced aggression, fear and defensive behaviours Kluver-Bucy Syndrome Selective amygdala lesions impairs behavioural responses to fear- conditioned stimuli Stimulating the amygdala usually increases state of increased vigilance or attention (anxiety) 8 CASE STUDIES IN HUMANS: PATIENT S.M. HAS A RARE CASE OF SEVERE, YET HIGHLY SELECTIVE, BILATERAL AMYGDALA LESION Loss of fear, indiscriminately friendly Impaired recognition of fearful faces Impaired acquisition of conditioned fear response Declarative memory fine BUT, recent observations show: doesn’t look at eyes when determining facial expressions can induce fear by having S.M. inhale carbon dioxide 9 BRAIN ACTIVITY IN THE AMYGDALA IS GREATEST IN RESPONSE TO FEARFUL FACES THAN NEUTRAL OR HAPPY FACES 10 MAJOR FUNCTIONS OF THE AMYGDALA Emotional processing and recognition Responds to emotional stimuli and facial expressions Historical focus has been on fear and threat, but also involved in positive emotions (intensity/salience is the key) Emotional learning and memory Assigns emotional significance or value to sensory information Evaluates incoming sensory stimuli and triggers adaptive responses Critical roles in Pavlovian and instrumental conditioning Variety of cognitive functions, such as attention, perception and explicit memory Amygdala can trigger release of hormones and/or neuromodulators that would alter cognitive processing 11 AFFERENT INPUTS TO THE AMYGDALA The LA is considered the main gatekeeper of the amygdala, receiving info about the external world from all sensory systems 12 EFFERENT OUTPUTS OF THE AMYGDALA MAJOR OUTPUTS CeA is considered the main output of the amygdala controlling emotional expression and physiological responses But basal nucleus connections with striatum important for instrumental actions IN BLA, ~80% OF 13 NEURONS ARE SPINY GLUTAMATERGIC PRINCIPAL NEURONS Very low levels of spontaneous activity Some intrinsically bursting cells exist, but most are “regular spiking” Commonly observe spike frequency adaptation, of varying degrees 14 WITHIN BLA PROJECTION NEURONS, A LARGE CONTINUUM OF SPIKE FREQUENCY ADAPTATION IS OBSERVED DUE TO THE DIFFERENTIAL EXPRESSION OF VOLTAGE- AND CALCIUMDEPENDENT K+ CONDUCTANCES 15 IN BLA, THE OTHER ~20% OF NEURONS ARE SPARSELY SPINY GABAERGIC LOCAL INTERNEURONS Most interneurons show a “fast-spiking” phenotype At least 5 types of GABAergic interneurons in rodent BLA. Two main classes distinguished by expression of: Parvalbumin (PV+; receive input from BLA) -> FeedBACK inhibition Somatostatin (SOM+; receive input from outside amygdala) -> FeedFORWARD inhibition Regulate principal cells in distinct ways, because they have different inputs and target different postsynaptic domains 16 STIMULATION OF THE EXTERNAL CAPSULE EVOKES A DEPOLARIZING EPSP IN BLA NEURONS THAT IS FOLLOWED BY IPSP Activation of principal neurons activate local interneurons via axon collaterals -> Feedback inhibition The fast component is mediated by GABAA receptors, while the slow component is mediated by activation of GABAB receptors IN THE CEA, THE PRINCIPAL CELL TYPE 17 IS GABAERGIC WITH VERY FEW LOCAL-CIRCUIT CELLS CeM neurons have a large soma, sparse dendritic branching, and low to moderate density of dendritic spines CeL neurons resemble MSNs of the striatum, with smaller soma, multiple primary dendrites that branch and have high density of spines Both CeM and CeL show 3 main phenotypes for physiological responses: 18 AFFERENT AND EFFERENT CONNECTIONS OF THE AMYGDALA 19 FOR THE LA INPUTS TO INFLUENCE CEA OUTPUTS, INFORMATION MUST BE ROUTED THROUGH INTRA-AMYGDALA CONNECTIONS THE ORIGINAL (OUTDATED) MODEL ASSUMED INFORMATION FLOWED FROM LA TO CEA 20 FOR THE LA INPUTS TO INFLUENCE CEA OUTPUTS, INFORMATION MUST BE ROUTED THROUGH INTRA- AMYGDALA CONNECTIONS The original (outdated) model assumed information flowed from LA to CeA But LA projects very sparsely and only to CeL 21 FOR THE LA INPUTS TO INFLUENCE CEA OUTPUTS, INFORMATION MUST BE ROUTED THROUGH INTRA-AMYGDALA CONNECTIONS Indirect pathway options to CeM: LA -> BA -> CeM LA -> CeL -> CeM Both the LA and BA nuclei also project to intercalated cells which project to CeM 22 INTERCALATED CELLS FORM DISTINCT CONNECTIONS DEPENDING ON THEIR POSITION, GENERATING FEEDFORWARD INHIBITION 23 INTERCALATED CELL MASSES (ICM) DO NOT FORM A COMPACT NUCLEUS BUT OCCUR AS SMALL DENSELY PACKED CELL CLUSTERS  THE VAST MAJORITY OF 24 INTERCALATED CELLS ARE GABAERGIC They have a small soma and dendritic tree that is restricted to the fiber tract, with a high density of spines. Express very high levels of µ-opioid and DA1 receptors Show regular spiking firing pattern Have high intrinsic excitability due to their very high input resistance and modest spike frequency adaptation, as well as activation of an ADP 25 AUDITORY FEARING CONDITIONING PATHWAYS HAVE BEEN WELLSTUDIED IN THE AMYGDALA 26 SUMMARY OF EVIDENCE IMPLICATING THE AMYGDALA AS AN ESSENTIAL NEURAL CIRCUIT INVOLVED IN FEAR CONDITIONING Amygdala receives information about both the CS and US Lesions attenuate or abolish a variety of fear URs and CRs Electrical/Chemical stimulation of amygdala evokes CR-like responses Reversible inactivation prior to learning blocks acquisition of CR Reversible inactivation after learning blocks expression of CR Amygdala undergoes learning-related changes that strengthen the CS input so that it becomes capable of eliciting CR 27 NOVEL STIMULI ELICIT RESPONSES FROM AMYGDALA NEURONS, BUT RAPIDLY HABITUATE IF STIMULUS IS REPEATED AND IRRELEVANT 28 IF NEUTRAL STIMULI ARE PRESENTED IN ASSOCIATION WITH A SIGNIFICANT EVENT (VIA CONDITIONING) RESPONSE IS POTENTIATED 29 LONG-TERM POTENTIATION (LTP) AS A CELLULAR ANALOG OF ASSOCIATIVE LEARNING 30 LONG-TERM POTENTIATION (LTP) AS A CELLULAR ANALOG OF ASSOCIATIVE LEARNING 31 OPTICAL ACTIVATION OF LA PRINCIPAL CELLS, IN THE ABSENCE OF A PERIPHERAL SHOCK US, PRODUCES FEAR CONDITIONING 32 MODULATION OF AMYGDALA FEAR MEMORIES DURING EXTINCTION Extinction training aims to break the CS-US contingency until the animal no longer shows the conditioned fear response 33 MODULATION OF AMYGDALA FEAR MEMORIES DURING EXTINCTION Infralimbic region of mPFC decreases fear memories by exerting feed- forward inhibition to LA and CeA neurons 34 MODULATION OF AMYGDALA FEAR MEMORIES DURING EXTINCTION Hippocampus is believed to be required for the contextual modulation of extinction 35 AMYGDALA & ANXIETY Human fMRI studies: those with generalized anxiety disorder show abnormal functional connectivity between BLA and CeM Inspired use of optogenetic tools to probe specific projections in mouse amygdala Light-activation of BLA terminals in CeL caused inhibition of CeM neurons and induced reversible reduction in anxiety (and suppression of this pathway increased anxiety) 36 STRUCTURAL/FUNCTIONAL CHANGES IN AMYGDALA ASSOCIATED WITH WIDE VARIETY OF PSYCHIATRIC CONDITIONS IN HUMANS Especially those that involve fear and anxiety PTSD, phobia, and panic disorders Depression Schizophrenia Autism Addiction Alterations in amygdala is correlational at this point, not necessarily causative