Biol/Psy 105: Class 19, Memory

November 3rd, 2014

Critical Questions

1) What evidence supports the dopamine hypothesis of schizophrenia? What type of receptor do anti-psychotic drugs target?

2) What are hIPSCs and how can they be used do develop ‘personalized’ medicine?

3) What is classical conditioning and how do we study it in the fruit fly?

4) What evidence supports a role for cAMP signaling in memory?

5) Why are Aplysia a good system for studying memory?

6) What is the difference between short-term and long term memories?

7) What are LTP and Hebb’s postulate?

8) What is reconsolidation and how can we use it to develop drug treatments?

Psychotic Disorders: Schizophrenia

-Positive and negative symptoms-Positive symptoms generally associated with SCHZD

1) Delusions2) Hallucinations3) Disorganized speech/neologisms

Note: problems of SCZD patients extend beyond specific symptoms

Is this a genetic disorder?

Schizophrenia may involve a number of phases with distinct underlying causes

From CNS spectrums, Eli Lilly

Could this really be multiple disorders????

Common symptom: Persecutions of delusion

Point of discussion: How could a neurological disease lead these symptoms?

Examples from DSM IV:FBI has coordinated its efforts with the local police. Plain-clothes officers follow the patient. At times the surveillance is covert. Satellites are used. Listening devices have been placed in the walls; the telephone is tapped. The patient is followed by cars; headlights blink on and off to indicate that capture is imminent. The food is poisoned. etc etc.

The Dopamine Hypothesis of Schizophrenia

-Dopamine inhibitors ameliorate positive symptoms.

-Dopamine agonists induce schizophrenia like symptoms

What might you predict from this hypothesis?

Beaulieu et al, 2004

What differences do we see between D1R and D2R signaling?

Antipsychotic drugs used to treat SCZD-thorazine: first introduced in 1952-Inhibits D2, D3, D4 receptors

D2 family of Rs is coupled to G-alphai

Currently longer lasting antipsychotics available.HaloperidolRisperidone

Stem cells and neurons can be generated from adult fibroblasts

Petros, Tyson and Anderson 2011

1) Take skin cell2) Induce pluripotent stem cell3) Induce neural progenitor4) Induce specific type of neuron5) Run functional/bioinformatic analysis

Neurons generated from fibroblasts of control and schizophrenic patients

Brennand et al, 2011

We cannot run genomic analysis on patient brains but you can on their own differentiated fibroblasts!

what do we think of this approach?

Class discussion point:

How could hIPSCs help treat individuals with complex neurological disease?

Memories can be permanently seared into our brains

What makes these memories different?

Memory occurs across phyla

Formation of memories involves alteration in neural circuits

1) Changes in connectivity2) Alterations in strength of connectivity (increased synaptic formation)

Memories are what make us human

General Themes of Memory

Memories consist of different phases operationally defined as:

Short-term memory: Labile, protein synthesis independent, due to post-translational modifications

Long-term memory: Stable, protein synthesis dependent, involve structural changes

Ivan Pavlov 1849-19361904 Nobel Prize for Physiology or Medicine

Classical Condition involves the pairing of US and CS

odor B

odor A

shock

Odor Memory

shock

odor

Why olfactory memory?

Classical conditioning in Drosophila

# avoiding odor A - # avoiding odor B

total # of flies

Averaged for both odors

A

A

B

B

naive

learned

50 50

10 90

Mutagenesis

Mutagenesis

d

d

d

PKACDCO

PKAR

Numerous mutants were identified

dunce

rutabagaACGα

cAMP

PDEAMP

Ca2+

Many ‘stupid’ fly mutants have mutations in the cAMP pathway.Some mutants have high cAMP levels, orther have low cAMP levels. How could this be?

Most fly memory genes are highly expressed in the mushroom bodies, suggesting this area is the ‘memory center’

How could you test whether the flies are a mushroom body center?

Circa 1994: Ablation of the mushroom bodies abolishes memory

This has since been confirmed by dozens of complementary studies

Steve de Belle Martin Heisenberg

Proposed criteria for effective study of learning mechanisms

1. Define, in cellular detail, the neural circuitry that is capable of being modified

2. Locate in that neural circuit the critical neurons and interconnections modified by learning

3. Analyze the mechanism of learning on the cellular and molecular levelsErik R. Kandel, 1977

Nobel Prize,2000

Aplysia Californica

Grow to 35 inches Large neurons!Robust behavior!Bites and Inks!

Gill-siphon withdrawl reflex can be habituated or sensitized

A simple memory circuit in Aplysia

1) Touch siphon, shock tail then measure gill withdrawl reflex.Why do ‘Spaced trains’ lead to long-lasting memories?

Gill withdrawl reflex in Aplysia

Distinct mechanisms for short and long-term memories

Short term memory requires PKA activity in the sensory neuron Long-term memory requires CREB-

dependent protein synthesis

Recap: The molecular basis of memory formation

1) Memory involves synaptic plasticity and a strengthening or weakening of synapses

2) Memory/synaptic plasticity can be studied through behavior or electrophysiology

3) Short and long-term memories require cAMP signaling

4) Short term memories are labile, and DO NOT require protein synthesis

5) Long term memories are stable and require CREB-dependent protein synthesis.

How does memory work in more complex organisms?

The formation of memory has a number of distinct phases and involves diverse brain regions

Distinct types of memory rely on different brain regions

Note: Thinking about what we know from HM, we can deduce that declarative memories are consolidated in the hippocampus then transferred to other brain regions

Declarative vs. non-declarative

1973: Bliss and Lomo identify ‘memory trace’ within the brain

Application of neural doctrine: Stimulate a region of the hippocampus and see changes in synaptic strength

Neural circuits are plastic: Neurons can be strengthened

Can be measured in hippocampus through Long Term Potentiation

Hebb’s postulate and the development of synaptic inputs

What if we could put all our memories and processing power on a computer chip?

As we know…..the hippocampus is required for consolidating memories

Memory in humans ins transferred and stored in cortical regions

What experimental evidence do we have supporting this? How could this storage occur over such a long period?

Memories are context dependent

Note: Not only true for drunkenness.Common in many motivation-dependentBehaviors including taste memory.

Reconsolidation of memory as a pathway for disease

Process for reconsolidation1) Memories get stored2) A memory that is recalled becomes labile3) Then memory needs to be restored.

Does this present the capability for therapeutic intervention?

Drugs can be combined with cognitive approaches

propranolol

+

Psychotherapy

Does propranolol treatment lead to altered ‘reconsolidation’ of memory

Daniella Schiller

Who was her father? How did his experience impact her view of the brain?

Why are fear memories important and when can they be detrimental?

How are fear memories studied in mammals?

How are emotional memories different? Why would someone choose not to talk about painful past experience?

What is memory consolidation?

How can false memories be generated?

Describe Joe Ledoux and Karim Nader’s experiments. How did the field treat the work?