Small Systems of Neurons

Studies of the snail Aplysia show that small systems of neurons are capable of forms of memory and learning

Eric Kandel

Howard Hugh Medical Institute

Columbia University Undergradute BA in

history and literature from Harvard College

MD at the New York University School of Medicine

Motivation

Humans in a large part are “what we have learned and remembered”.

We are unique in our abilities to acquire new ideas from experience and to retain those ideas in memory.

What changes occur in the brain when we learn and how is this information retained in the brain?

Definitions

Learning is the ability to modify behavior in response to experiences.

Memory is the ability to store that modification over a period of time.

Commonality

Aren’t humans unique in their abilities? Aren’t our abilities to learn, etc… qualitatively different from other organisms?

1. Ethologists (Lorenz, Tinbergen, and Frisch) demonstrated that there are commonalities in animal behavior.

2. Thus, such commonality suggests that their may be some underlying common neuronal mechanisms (example: cellular and molecular similarities between our neurons and synapses).

Approach

In the 1950’s, Eric Kandel became interested in opening up what psychoanalysts had been treating as a “black box”. He wanted to study the behaviors of memory and learning using the modern empirical approaches of biology.

Knowing it was unlikely to make progress studying the complex pattern of interconnections in the human or vertebrate brain, he thought that he could apply a reductionist methodology to the problem of memory and learning.

He chose to work with the marine snail, Aplysia, in the vein of working with model organisms like Drosophila, yeast, bacteria, and bacteriophages.

The Marine Sea Slug: Aplysia

Aplysia made a good candidate for study for a number of reasons.

Small Numbers of Neurons (20,000)

10 Ganglia collections (~2000 cells each)

Large, Visible & Uniquely Pigmented Neurons

Steps in Study of Memory

1. Define a simple behavior that can be modified by learning and that gives rise to memory storage.

2. Identify the cells that compose the neural circuit of the behavior.

3. Locate critical neurons and interconnections that had been modified by the behavior.

4. Analyze the cellular and molecular changes occurring at those neurons and interconnections.

The Simple Behavior:Aplysia’s Defense Reflex

When a weak or moderate stimulus is applied to the siphon, the gill contracts and withdraws into the mantle cavity.

There are two forms of learning associated with this reflex: habituation and sensitization

Habituation

Habituation is a decrease in the strength of a behavioral response that occurs when an initially novel stimulus is presented repeatedly.

This is probably the most wide-spread of all forms of learning.

It allows animals to ignore meaningless stimuli so that they are more likely to attend to meaningful stimuli.

Habituation & Memory

Studies of habituation have provided opportunities for understanding short and long-term memory.

After 1 training session of 10 to 15 stimuli, snails habituate the stimuli but the normal reflex begins to return within an hour and fully returns within a day.

After 4 training session of 10 stimuli each, snails habituate the stimuli and this state lasts for weeks.

Sensitization

Sensitization is more complex than habituation in that the animal has to learn to respond strongly to an otherwise neutral stimulus.

It is the prolonged enhancement of an animal’s preexisting response to a stimulus as a result of the presentation of a second noxious stimulus.

Sensitization Experiment

In this case, Aplysia is given a shock to the tail, and then the gill reflex is induced.

Aplysia respond to the previously innocuous habituated stimuli with a strong gill withdrawal reflex

Distinct Memory Phases

A single shock gives rise to a memory lasting only minutes; no protein synthesis required.

Four or five spaced shocks gives rise to a memory lasting many days; requiring protein synthesis.

Identifying the Cellular Circuit:Aplysia’s Abdominal Ganglion

The Cellular Circuit

The circuit contains 24 mechanoreceptor sensory neurons that innervate the siphon skin.

These sensory neurons make direct monosynaptic connections with 6 gill motor cells.

The sensory neurons also made indirect connection to the gill motor cells through interneurons (excitatory and inhibitory).

This circuit was found to be invariant among individuals studied.

Neuronal Modifications

In 1894, Santiago Ramon y Cajal suggested that memory is stored in the growth of new connections.

Kandel’s research showed that although the connections are invariant, their specific strength is not.

Homosynaptic changes occur in a synapse because of activity in that synapse, while heterosynaptic changes occur in a synapse due to activity in an adjacent modulatory interneuron.

Cellular & Molecular Changes:Short Term Memory (Modular Circuits)

Modulatory interneurons transmit serotonin which acts on the sensory neuron.

Serotonergic receptors cause increases in cyclic AMP (cAMP) and the activation of the cAMP-dependent protein kinase (PKA).

PKA phosphorylates K+ and Ca+ channel proteins, causing a reduction and influx of their associated ions, respectively.

Ionic concentrations cause vesicles containing neurotransmitters to fuse with the pre-synaptic membrane and release their contents.

Thus, the short term sensitization is caused by increases in the amount of neurotransmitter.

Short Term Memory Overview

Short-term memory is a modulation of the strength of an existing synapse, through temporary changes in the amount of neurotransmitter released. This does not require new protein synthesis.

Cellular & Molecular Changes:Long Term Memory

Increased levels of serotonin activates PKA and mitogen-activated protein kinase (MAPK), both of which enter the nucleus.

These kinases activate the transcription factor CREB-1 (cAMP Response Element Binding protein-1) which promotes expression of genes leading to the growth of new synaptic connections. Thus, supporting Cajal’s hypothesis.

One gene produces Ubiquitin Hydrolase which causes the persistent activation of PKA.

Long Term Memory Overview

Long-term memory is a modulation of the strength of an existing synapse, through growth in the number of synapses. This requires new protein synthesis.

http://www.pitt.edu/~super1/lecture/lec14361/001.htm

Eric Kandel, Nobel Lecture, The Molecular Biology of Memory Storage: A Dialog Between Genes and Synapses, December 8, 2000.

Eric Kandel (1979) Small Systems of Neurons, Scientific American