Learning And Memory

Front 1

Second messengers

Back 1

low weight diffusable molecules that are used in signal transduction to relay a signal within a cell. Synthesized or released by specifice enzymatic reactions usually as a result of external signal(NT binding to receptor)which was received by transmembrane receptor and processed by other proteins

Front 2

3 types of second messenger molecules

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1.hydrophobic- diacylglycerol membrane associated and diffuse from plasma membrane into juxtamembrane space where they can reach and regulate membrane associated effector proteins
2.hydrohilic molecules- water soluble molecules, like cAMP,cGMP,Ca, that are located within cytosol
3. Gases- NO, CO, can diffuse both across cytosol and cellular membranes

Front 3

Signal transduction

Back 3

any process by which a cell converts one type of signal or stimulus into another, rapid, usually occurs through second messenger cascade

Front 4

Protein kinases

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enzymes that modify other proteins by chemically adding phosphate groups to them (phosphorylation). This usually results in a functional change in the protein, by changing enzyme activity, cellular location or association with another proteins.

Front 5

Protein phosphatase

Back 5

enzyme that removes phosphate group from ATP reversing regulatory effect

Front 6

Main characteristics of ion channels

Back 6

1. formed of glycoproteins that transverse cell membrane
2.aggregation of subunits
3. ions cross channels by electrical potential or concentration differences

Front 7

What are main second messengers?

Back 7

cAMP, cGMP, Ca, IP3, DAG

Front 8

What are retrograde signals?

Back 8

convey modulation from postsynaptic cell to presynaptic terminal
NO, CO, AA

Front 9

How second messenger mediated events different from directly gated events?

Back 9

can close channels, time course is much longer, directly gated channels (except NMDA receptors) are not affected by voltage and do not contribute to AP

Front 10

What is PKA

Back 10

cAMP dependent protein kinase

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What is PKC

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calcium dependent protein kinase

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2 components of kinases

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regulatory and catalytic

Front 13

Prefrontal cortex main function

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sensory integration, executive motor control, working memory, future planning, affect modulation, attentional regulation

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Psychiatric disorders related to PFC

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schizophrenia and bipolar disorder, anxiety disorders, OCD, addictive disorders, ADHD

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Orbital and medial PFC

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emotional behavior, control of basic drives and response inhibition

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Working memory

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abiltity to hold information in absence of sensory cues in order to guide future behavior

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PFC intrinsic connections

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principal cells: pyramidal neurons
secondary cells: GABA local circuit neurons

Front 18

Function of interneurons

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shape pyramidal cell receptive fields, contribute to orientation and direction tuning, control pyramidal cell firing frequency, regulate synchronous activity states

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PFC extrinsic connections

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major connections: mediodorsal nucleus of thalamus, associative and higher order sensory cortex
other connections: limbic cortex, hippocampus and amygdala, other thalamic areas, midbrain and hypothalamus, basal ganglia (unreciprocated)

Front 20

What is a likely cellular substrate fir working memory?

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sustained firing of PFC neurons during period on which memory is being held, these cells are spatially tuned, i.e have "memory fields"

Front 21

Delayed Response Task

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Has been used to study working memory in monkeys. While a monkey fixes gaze on a central spot, target flashes on screen, then vanishes. During delay of several seconds, monkey keeps a memory of the spot "in mind". When central spot turns off, animal moves its eyes to look where target appeared. Measurements of electrical activity show that certain neurons in PFC react to appearance of target, others hold memory of it in mind and still others fire in preparation for motor response

Front 22

Calcium influx

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sources - NMDA recptors, voltage dependent calcium channels, ER. Acts on transmitter vesicles, VDCC, ER, K channels, PKC, calmodulin

Front 23

G proteins

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always associated with transmitter receptors, g protein activation couples NT binding with second messenger activation (cAMP)

Front 24

Inositol lipid cascade

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activated by G-P and PLC leads IP3 production, which diffuses into cytosol, binds to ER releasing Ca. It also leads to DAG which remains bound to membrane

Front 25

PKC

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PKC is activated by cytosolic calcium and translocate to membrane to bind to DAG

Front 26

Calmodulin

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alternative pathway for PKC activation, activated by Ca, leads to activation of PKC

Front 27

MAP

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mitogen activated protein kinase phosphorylate CREB (cAMP response element binding protein) in the nucleus. CREB binds to CRE ( cAMP response element)m which initiates transcription of immediate early genes (IEGs)

Front 28

Why was aplysia chosen to be model for memory and learning

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Aplysia has about 20,000 neurons in the nervous system consisting of nine ganglia -- four pairs of symmetrical ganglia and one large abdominal ganglion consisting of two lobes

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How does the NMDA channel work?

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The NMDA channel is a Glutamate ionotropic receptor that, at resting potentials, is blocked by Magnesium. Depolarization of the post-synaptic cell kicks out the Mg ion and opens up the channel. The channel is permeable for cations with particularly high permeability for Ca.

Front 30

Invariance principle

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position of every cell in abdominal ganglion is fixed

Front 31

What does release of serotonin do

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increase cAMP - closing of K channels
diacyl glycerol- phosphorylation of Ca channels, increase of Ca
increase vesicle docking. All that increases NT release, larger EPSP on motor neuron

Front 32

Advantages of aplysia

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reduced number of synapses and cells (20.000), large cells, invariance principle

Front 33

Experimental preparations

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1. most intact - abdominal ganglion is externalized through small incision in neck, gill and siphon withdrawal can be triggered and measured behaviorally, identified neurons can be monitored through intracellular electrodes
2.semi intact - sliced preparation, maintained in vitro, piece of tail left, mantle organs as well as tail for modullary input are surgically removed while remaining connected to abd. ganglion, permits accurate intracellular recordings (no hormonal influence, no other gangllia present, which reduces confounding variables (intact reflex behavior)
3. isolated abd. ganglion - only ganglion+ cells (motor and sensory left) - access to all elements in reflex neural circuit. Tactile input simulated by direct stm.of siphon nerve. Tail shock mimicked by stim. of afferent nerve from tail. No behavior, EPSP as measure of behavior, neural analog of learning - electrical stim. instead of natural
4. Most reduced preparation - isolated sensory and motor neurons that have been removed and placed in culture, permits exam. of synapse in complete.

Front 34

LTP definition

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persistent increase in excitatory synaptic efficacy (glutamatergic)

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LTP characteristics

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long lasting, induced rapidly, Hebbian (associative)

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Triggering LTP

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increasing Ca in postsynaptic cell

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Long term depression

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decrease in synaptic efficacy

Front 38

Three phenomena of LTP

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1. Induction - release of glutamate from presynaptic neuron, subsequent activation of postsynaptic AMPA, NMDA and glu receptors, Ca influx to postsynaptic neuron
2.Expression - either increase in NT release, and/or increase in number of synapses, and/or increase in postsynaptic receptors and/or uncovering of silent synapses
3. Maintenance -activation of protein kinases, protein synthesis and gene transcription

Front 39

Hebbian view

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was promoted by Hebb in 1949, suggested that when cell A is active at the same time that another cell B, change can occur so that cell A excites cell B changes.Can explain associative learning at cellular level.

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2 basic principles of LTD and LTP

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1. influx of Ca needed for both LTD and LTP (high-LTP, low-LTD)
2. activation of second messengers (LTP - activation of kinases, LTD - activation of phosphatases)

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What are 2 requirements for LTP to occur

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coincident presynaptic activity and postsynaptic depolarization

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Example of top/bottom approach

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NMCR and GSWR

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Example of bottom/top approach

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LTP/LTD

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3 phases of LTP maintenance

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1. immediate
2. early - 2nd messenger dependent
3.late - RNA and protein synthesis dependent

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Features of habituation

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spontaneous recovery, more rapid habituation every time, rate faster for short ISI, rate faster for weaker stimuli, below zero (behavior not observable, but learning still occurs), specific, dishabituation, haituation of dishabituation

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How do we know late phase is not kinase dependent

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apply H7 (kinase blocker) after 3 hours, LTP will not go down, so during late phase not kinase dependent

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How do we know late phase protein dependent

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anisomyacin blocks protein synthesis, blocks LTP during late phase

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Hypothesis that LTP equals memory makes three predictions

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1. block experiment - agents that block LTP should block memory formation
2.mimic experiment - inducing LTP should cause behavioral change indistinguishable from learned behavior. Saturating LTP should interfere with memory formation.
3. measure experiment- when animmal learns LTP should be observable

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What does habituation do?

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weakened synaptic efficacy, reduced transmitter release, depletion of vesicle pool, decrease of docked vesicle, homosynaptic depression, memory for habituation