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Amygdala Function Aplysia: invertebrate model of learning Pre- and post-synaptic mechanisms contribute to memory What are the neural substrates of classical conditioning in mammals?

Watson and baby Albert experiment - Watson concluded that phobias are conditioned responses - When baby Albert first played with the animals he was happy, but when he was shown the animals again one by one, the first one came with a bang. He then feared all the other animals (Even though he had previously got along with them); this is generalisations Two tests of fear conditioning - The most common procedure to evaluate fear conditioning is to use electric shocks - Rat is placed in a sound-attenuating chamber - Its presented with auditory cue, which will evoke a normal response (i.e. one not of fear) - Pair the auditory cue with a mild foot shock, one that is enough to cause a reaction (makes it jump) but its not hard enough to cause damage to skin or tissue - Once the sound (10 second tone) has been presented with the foot shock (half a second), the animal can then be placed back in the chamber to see if its experiencing any fear 1. If the tone stimulus evokes a memory of shock it shows a fear response (i.e. sticks bottom in corner of stage and sits very still; a freeze response) This would be an auditory cue 2. You could also start with the animal in the box and give a foot shock (no tone) and then put the animal in the same box again and see if they freeze This would be a contextual fear conditions For both circumstances we see a conditioned fear response What aspect of the brain were interested in in the context of fear? - The Klver-Bucy Syndrome - An animal has had part of its medial temporal lobe removed (this includes the amygdala) - When the animal is tested it shows interesting changes in behaviour - Animal does not show anger or fear; it approaches inanimate and animate objects without hesitation - Although there are no motor defects it tends to examine them by mouth rather than by the use of the hands - Various tests do not show any impairment in visual acuity or in the ability to localise visually the position of objects in space - By damaging the amygdala the animal no longer shows fear Amygdala - Has a tight neural network - Three main components of interests 1. Central nucleus Main output pathway from hippocampus 2. Lateral nucleus 3. Basolateral nucleus and basal nucleus - You have discrete input pathways; information comes into the amygdala from the sensory cortex and via the thalamus (the main sensory relay) which project to lateral nucleus = input pathway 1. Information in lateral nucleus goes to basolateral nucleus
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2. Information from basolateral nucleus goes to central nucleus 3. Central nucleus projects to whole host of areas in hypothalamus, midbrain and brainstem areas It is via this route that its thought that the amygdala has its main influence over emotional behaviour, respiration rate, sweating, fight or flight Remember, there were two forms of fear conditioning (one involved the tone and one involved the context with shock) 1. In terms of those sensory inputs: information about auditory cues come in from the sensory cortex into lateral nucleus 2. Information about the context/place (spatial information) comes form the hippocampal formation into the basolateral nucleus This information includes foot shock

Outputs of the Central nucleus of the amygdala - Central nucleus lateral hypothalamus BP changes - Central nucleus Parabrachial nucleus (Pons) Respiration changes What mechanism is responsible for forming this association in the amygdala from a neutral event (tone) and the nasty event (shock) - Part of the grounding from the work in Aplysia is that it has reinforced the grounding of LTP Some synaptic process that relies upon the same mechanisms of the induction of long term potentiation could be responsible for the binding of information of the tone and the shock The idea would be that the amygdala should be susceptible to manipulations that change LTP LeDouxs Predictions - LTP should be inducible along amygdala pathways We should see phenomena that look like LTP We can see LTP in the hippocampus - Fear conditioning itself should also elicit similar changes in these pathways (LTP is an artificial procedure; fear conditioning should elicit the same types of changes) What happens to that evoked potential after conditioning? These auditory evoked responses get bigger after pairings with shock In an unpaired trial the signals are the same as the control rat When the tone is followed by foot shock (paired) the response from the amygdala is bigger compared to control When tone is shown alone in conditioned animal the response is still much bigger compared to control rat These are not artificial stimuli, this is a naturally occurring cue = we see something that looks like potentiation - You should see changes in neural activity as a consequence of training Fear conditioning does increase neural activity We see a more rapid increase in neural activity as a consequence of conditioning; the amygdala fires much more rapidly when the tone is presented (whereas it wouldnt fire at all before) This all points to the fact that during fear conditioning, processes occur in the amygdala that change the network activity - Any affect that blocks LTP should block fear conditions
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If the mechanisms are the same as in Aplysia (post-synaptic mechanisms) then mechanisms that block the induction of LTP should also block learning LTP induction requires post-synaptic NMDA receptors (the ones with the Mg ion that gets expelled when membrane is sufficiently depolarised) When the NMDA receptor is activated by Glutamate and the Mg is released, theres massive Ca influx that leads to increase in AMPA receptors AP5 is a drug that can be used to block NMDA receptor (its an antagonist) No increase in Ca receptors No increases in AMPA receptors Blockage of induction of LTP If we infuse AP5 into the basolateral nucleus (of a rat in the contextual shock scenario) of the amygdala we block the acquisition of conditioned freezing This does not change the animals ability to feel the foot chock The same would happen with the auditory cue in other experiments If a drug blocks LTP it will block fear conditioning in animals

Fear and the human amygdala - We can present humans with aversive stimuli; if we put them in a fMRI and look at bold images (i.e. which areas are receiving blood supply); we can present images to humans of happy/sad/disgusted/afraid etc. faces The amygdala lights up (increased bold signal) when humans are presented with angry faces or images of a disturbing emotional scene (e.g. aftermath of car accident) Amygdala lights up to aversive stimuli But this is not always the case - There are interesting variations in the responsiveness of the amygdala to aversive stimuli If male and female participants are shown porn, we see that for men we see activation of hypothalamus and (more importantly) in areas that correspond to amygdala region. When females see same material, they fail to show changes in activity of the amygdala - Age is another factors that can change emotional reactivity and the signal we get from the amygdala In young individuals, when theyre shown emotionally provocative signals (angry faces) there is an increase in the bold signal from the amygdala. This is reversed in older individuals Suggestion of change in nature of circuitry responsible for emotional reactions In older individuals there is a reaction of the insular cortex (this reaction is absent in young people) PTSD - Re-experiencing events (flash backs) - Avoidance behaviour Avoid any stimulation or contextual features that remind them of events that remind them of traumatic experience - Hyperarousal Sensitised reaction to auditory cues to car-backfiring - PTSD patients in a scanner show Reduced activation of the prefrontal cortex and hippocampus Prefrontal cortex is involved in regulating emotional activity Hippocampus has been associated with learning-context-shock associations There is reduced hippocampal volume in PTSD patients Hyper-responsiveness of amygdala - Disordered fear regulations Stress sensitivity Over-consolidation of fear Generalisation of fear cues Impaired extinction of fear memories - PTSD patients show enhanced sensitisation to stress - Over-generalisation of fear association
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Fail to extinguish learned fear There are clear examples of certain NT systems involved in PTSD DA, 5HT, opioid systems are involved in modulating traumatic memories More recent findings: brain derived neurotropic factors (BDNF) has been linked to PTSD and also susceptibility to PTSD There are mutations in genes encoding BDNF that have been linked to psychiatric disorders and susceptibility to PTSD We can uses the tone-context-fear-conditioning paradigms to investigate impact of BDNF mutations in mice (we can knock-in the mutation creating transgenic mice) o Such mice show enhanced anxiety and aberrant BDNF activity in amygdala, prefrontal cortex and hippocampus

Amygdala and Representation of Outcomes - The amygdala is not just involved in processing fearful stimulation - It processes information about events that arent just aversive but also about positive emotional experiences (e.g. being with loved one/receiving present) - Exploring the role of the amygdala in positive events is done by instrumental conditioning (the subject has to work [e.g. pressing a lever] to receive a reward) as opposed to Pavlovian conditioning - Reward is used to stamp in a motor behaviour Skinner ignored that fact that reward was stored in the brain; rewarding stimuli are encoded in the brain! - This kind of learning is often referred to as stimulus-response habits (SR learning) E.g. riding a bike; when you start you fall off, but you learn the second time how to balance yourself You have to physically think about these movements to maintain an upright position. But after a while of training you eventually learn an automated response (you dont have to think about balancing yourself; it becomes subconscious) Usually the conversion of thinking about something to it becoming a habit is due to training. Rats have been trained to pull a chain or press a lever for different types of reward (e.g. lever pressing banana flavoured pellet, chain pulling chocolate flavoured pellet) o To determine whether the animal encoded the flavour Bernard, he devalued the food reward Two ways; he could pair the food reward with making the animal sick, or (more commonly used) he allowed the animal to eat one of the food rewards until it was so bloated that it felt ill After over eating one flavour, the preference for it will decline The rewarding value declines - So you give a rat free access to banana flavoured food pellet, you put it into a conditioning box and it will go for the chain (i.e. chocolate flavour) The animal will perform the instrumental action associated with the non-devalued food action - The animal will prefer to make the instrumental response with the non-devalued food action (i.e. the item you have not just eaten loads of) This is important because this discrimination demonstrates that the animal has encoded not just the fact that its instrumental behaviour has been enforced; but also the sensory features of the reward itself If you lesion the basolateral amygdala this discrimination between instrumental actions is obliterated; they do not show the same sensitivity to reward devaluation
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The devaluation manipulation has done something, but it hasnt been able to operate specifically with respect to the sensory features of the food reward A rat with a basolateral lesion will know that one lever gives banana and one chain gives chocolate; after eating lots of banana a normal rat will go to chocolate, but the rat with the lesion will still feel full and so wont go to either. The rat with the lesion will not be aware that one is chocolate and one is banana (its recalling the fact that it is food). The sensory features of choclatyness and bananyness are not retrieved; the fact that its associated with food is The rats with the lesion fail to discriminate between actions associated with different sensory taste qualities. Controls are aware of chocolatyness and bananyness, but rats with amygdala lesions forget this Normal animals automatically encode not just the fact that reward has occurred, but also the sensory aspect and its hedonic value (whether they like it) The liking of it is tied to the sensory properties of the reward The amygdala encodes specific sensory features of the reward E.g. if my amygdala is intact Id go for that desert after a big meal (even though I feel full because I have information encoded about a specific sensory reward i.e. the specificity is that different taste of the desert). If my amygdala has a basolateral lesion I would lose that specificity and would just feel full and say no more food