Know the role of the neostriatum in habit learning in humans
In humans, the neostriatum (caudate nucleus and putamen) is essential for the gradual, incremental learning of associations that is characteristic of habit learning.
- learning related plascticity
The marine snail, Aplysia:
- understand the advantages (4) of studying invertebrate nervous systems
- Aplysia’s nervous system is relatively simple (10^5 - 10^6 neurons vs 10^12 in humans)
- Cell bodies are large (up to 1mm): ideal for electrophys and for identifying the circuits critical for specific types of Learning and memory
- Larger neurons are found in the same locations in all aplysia: enables scientists to find them easily
- Aplysia capable of several simple forms of learning
What is Reductionism approach?
studying individual parts of a complex system in order to understand the systems functions:
Behaviour → circuits → neurons → synapses → signalling molecules
know the experimental paradigms for habituation and sensitization of the gill withdrawal reflex (GWR)
- touching the siphon or shock to the tail both result in gill withdrawal reflex
- Repeated shocks elicit long-term memory for withdrawal
- Sensitization of the GWR by applying a noxious stimulus to another part of th body (tail) enhances the withdrawal reflex of both the siphon and the gill
- Spaced repetition converts short-term memory into LTM in aplysia
know the synaptic and molecular mechanisms for short- and long-term
habituation and sensitization of the GWR
- Short-term habituation of the GWR is caused by synaptic depression resulting from reduced presynaptic transmitter release
- STH is caused by reduction of transmitter release at the SN-MN synapse (sensory neuron-motor neuron)
- Habituation = reduction of reflex when a harmless stimulus is repeated
know the synaptic and molecular mechanisms for short- and long-term
habituation and sensitization of the GWR
- Long-term habituation correlates with persistently depressed synapses
- Percentage of sensory neurons making physiologically detectable connections with motor neurons in habituated animals is decreased at 3 points in time after long-term habituation training
know the synaptic and molecular mechanisms for short- and long-term
habituation and sensitization of the GWR
Short-term sensitization = enhancement of EPSPs recorded from motor neurons
- Following shock to the tail, a mild touch to the siphon now elicits a powerful GWR = sensitization
- Interneuron releases serotonin (5-HT)
- increases transmitter release from sensory nn onto motor nn
- = presynaptic facilitation → enhancement of GWR
know the synaptic and molecular mechanisms for short- and long-term
habituation and sensitization of the GWR
What is the molecular mechanism of short-term sensitization; which kinases are involved?
- Pathway One
- serotonin released from facilitating interneuron → G-proteins increase activity of adenylyl cyclase → converts ATP to cAMP
- cAMP binds and activates PKA
- PKA phosphorylates K+ channels
- Prolongs the AP → increasing Ca++ influx → augmenting NT release
- Pathway 2:
- serotonin binds to second class of metabotropic receptor that activates Gq → enhances activity of PLC
- PLC activity → production of diacylglycerol
- activates PKC
- phosphorylates presynaptic proteins → mobilization of vesicles containing glutamate from a reserve
- increases efficiency of NT release
- TWO KINASES INVOLVED:
- PKA - closure of K+ channels
- PK - increase vesicle mobilization
know the signalling mechanisms, kinases, and proteins involved in long-term sensitization - understand the key roles of PKA and MAPK in long-term sensitization
- PKA acts in the cytosol and nucleus
- persistently active after its R subunits are degraded by ubiquitin hydrolase
- phosphorylates other proteins such as CREB, K+ channels and the exocytosis apparatus
- MAPK acts in the nucleus to promote transcription
know the signaling mechanisms, kinases, and proteins involved in long-term sensitization - understand the key roles of PKA and MAPK in long-term sensitization
Long-term sensitization involves Nuclear Transcription (CREB-1) and Protein Synthesis
- Repeated stimulation causes the level of cAMP to rise and persist for several minutes
- Catalytic subunits can then translocate to the nucleus and recruit MAPK
- In the nucleus, PKA and MAPK phosphorylate and activate the cAMP response element-binding (CREB) protein and remove the repressive action of CREB-2 (inhibitor of CREB-1)
- CREB-1 activates several immediate-response genes including a ubiquitin hydrolase necessary for regulated proteolysis of the reg subunit of PKA
- Cleavage of the inhibitory regulatory subunit results in persistent activity of PKA
- Persistent phosphorylation of the substrate proteins of PKA
- Seconde immediate-response gene activated by CREB-1 is C/EBP which acts both as a homodimer and as a heterodimer with activating factor (AF) to activate downstream genes (including elongation factor 1 alpha (EF1alpha) that lead to the growth of new synaptic connections
- understand the structural changes that correlate with long-term habituation & sensitization
- Habituation
- Fewer pre-synaptic terminals
- retraction of synapses
- Fewer pre-synaptic terminals
- Sensitization
- More presynaptic terminals
- new synapses
- More presynaptic terminals
know the experimental paradigm for classical conditioning of the GWR - Unpaired Stimuli
- Intracellular electrodes are inserted into the sensory and motor neurons to record spikes and EPSPs respectively
- UNPAIRED STIMULI:
- Touching siphon and tail shock are not paired together in time
- EPSPs show no facilitation before and after training
- Under these conditions, the size of motor nn EPSP is only weakly facilitated by the tail shock
- in this example the EPSP actually decreases slightly because, despite the tail shock, repeated unpaired stimulation of the siphon leads to synaptic depression
Classical conditioning of the GWR: Paired Stimuli
- siphon is touched immediately prior to shocking the tail
- the siphon sensory neurons are primed to be more responsive to input from the facilitatory interneurons of the unconditioned pathway
- Amplifies the response of the conditioned pathway and restricts the amplification to that pathway
- Recordings of EPSPs in motor nn after training is considerably greater = more vigorous gill withdrawal
- eg mild touch to siphon now elicits powerful gill withdrawal as the animal has learned to associate a siphon stimulus with a harmful stimulus
- From persistent increase in transmitter release at both he SN-MN synapses and the neuromuscular synapses in the gill
What is the difference between homosynaptic and heterosynaptic plasticity?
- Homosynaptic
- activity in branch A elicits plasticity only in A
- Heterosynaptic
- Activity in branch A elicits plasticity at A and B
How is heterosynaptic plasticity accomplished?
- Experiment:
- single presynaptic sensory nn that contacts 2 postsynaptic motor neurons (A and B)
- 5-pulses of serotonin applied to sensory nn synapse with motor neuron A = long term facilitation at these synapses
- One pulse of serotonin at the motor neuron B synapse = allows it to capure new proteins produced in the cell body in response to the five pules of 5-HT at the other synapse
- 1-pulse produces short-term facilitation which returns to normal after 24 hours
- Pairing the 5-pulses at A with 1 pulse at B = Cell B displays long-term fascilitation because:
- single pulse at B creates a tag = captures proteins synthesized by the sensory neuron
- SYNAPTIC CAPTURE OF LONG TERM FACILITATION
- single pulse at B creates a tag = captures proteins synthesized by the sensory neuron
The mammalian amygdala:
- *- know the experimental procedures for classical fear conditioning**
- know the neural circuitry for consolidation of fear memory
- know the cellular and synaptic mechanisms of fear memory
- understand the roles of PKA and MAPK in fear memory: how do
- Pairs tone with shock
- If animal remembers the association between the tone and the shock then it will freeze = conditioned fear memory
- Contextural memory requires hippocampus and amygdala
- Cued memory requires the amygdala
The mammalian amygdala:
- *- know the experimental procedures for classical fear conditioning : Pairing the CS with US - how to test cued memory**
- know the neural circuitry for consolidation of fear memory
- know the cellular and synaptic mechanisms of fear memory
- understand the roles of PKA and MAPK in fear memory: how do
After pairing, animal is moved to changed box - in this example it is peppermint scented and lacks the metallic grid floor for cued memory test (amygdala dependent)
- see if animal responds to tone
- record time spent frozen
The mammalian amygdala:
- know the experimental procedures for classical fear conditioning
- *- know the neural circuitry for consolidation of fear memory**
- know the cellular and synaptic mechanisms of fear memory
- understand the roles of PKA and MAPK in fear memory: how do
- Tone is captured by the auditory thalamus → auditory cortex → Lateral nucleus
- Shock: Somatosensory thalamus → somatosensory cortex → Lateral nucleus
- Lateral nucleus of the amygdala is the critical site that integrates the CS and the US
- Lateral nucleus → central nucleus → Fear responses
Synaptic potentiation in the _______ occurs during retrieval of cued fear memories
Synaptic potentiation in the lateral nucleus of the amygdala occurs during retrieval of cued fear memories
- tone produces potentiation of EPSE in the LA nucleus
The mammalian amygdala:
- know the experimental procedures for classical fear conditioning
- know the neural circuitry for consolidation of fear memory
- *- know the cellular and synaptic mechanisms of fear memory**
- understand the roles of PKA and MAPK in fear memory: how do they act?
- In the Lateral Nucleus (LA), a tone produces potentiation of EPSP
- the animal freezes when tone is heard = associative fear memory
- LTP in the amygdala requires PKA activation
The mammalian amygdala:
- know the experimental procedures for classical fear conditioning
- know the neural circuitry for consolidation of fear memory
- know the cellular and synaptic mechanisms of fear memory
- *- understand the roles of PKA and MAPK in fear memory: how do they act?**
PKA and MAPK trigger changes in gene transcription through CREB activation and epigenetic regulation
