Neurobiology of A. californica

Why Aplysia californica?

Memory formation is a biological process that is not only critical to our every day functioning, but also yields meaning to our lives.  However, understanding memory formation in a human model poses several problems; humans possess endlessly complicated neural circuits and studies on human memory formation pose ethical problems.  Due to these concerns, memory formation and neurobiology are often studied in a simple model organism, a sea slug, Aplysia californica.

Background:

The central nervous system of A californica consists of around 20,000 neurons separated into nine ganglia: two head ganglia, two cerebral ganglia, two pedal ganglia, two buccal ganglia, and a single abdominal ganglia.  While simple, this system does allow for expression of several simple behaviors and the capacity for learning/memory.  Early studies using A californica demonstrated the slugs ability for classical conditioning, sensitization, and habituation (Kandel, 2011.)  Using this knowledge, a reflex called the gill withdrawal reflex was used to study the molecular and cellular level development of learning and memory in A californica.

A dorsal view of Aplysia showing the animals gill (Kandel, 2001)

Sensitization and long-term memory formation:

One of the first discoveries made regarding learning and memory in A californica is that the process underlying the development of long-term memories is similar to that in vertebrates and humans. Acquisition of short-term memories does not require the synthesis of new proteins, while the development of long-term memories, lasting up to weeks, requires the synthesis of new proteins.  The experiment testing the formation of memory in A californica involved using different methods to sensitize the gill withdrawal reflex, namely by altering the frequency of shocks used to sensitize the reflex.   A single shock yielded a very short period of sensitization, lasting perhaps minutes.  However, a different method in which the animal was given four spaced shocks yielded a memory lasting days.   A final scheme in which the animal is shocked four times a day for four days creates an even stronger memory, lasting up to weeks (Frost, 1985.)

Spaced repetition converts short-term memory into long-term memory in Aplysia (Kandel, 2001)

Short-term memory formation in A californica:

Later questions regarding the development of memories in A californica began to investigate the differences in the process that creates long-term memories from the process that creates short-term memories.  This work was completed using cell cultures rather than whole animals; in this model puffs of serotonin were used to simulate the tail shock used previously in the sensitization experiments.   It was found that five spaced puffs of serotonin activated PKA, which binds to MAPK, and both are translocated to the cells nucleus.  Upon entering the nucleus, PKA and MAPK activate a transcriptional cascade creating CREB-1, the cAMP response element binding proteing-1, a protein that binds to a cAMP response element (CRE) in the promoters of target genes (Montarolo, 1986).

The role of CREB in the formation of long-term memory was uncovered in a series of experiments in which the relative levels or CREB and CRE in the cells nucleus were manipulated.  In the first experiment, oligonucleotides carrying the CRE were injected into the cells nucleus, reducing the relative amount of CREB in the nucleus.  This experiment resulted in reduced formation of long-term memories, but not short-term memories (Dash, 1990.)   In later experiments it was shown that simply injecting the phosphorylated form of CREB could initiate the process of long-term memory formation (Bartsch, 1998).

Effects of short- and long-term sensitization on the monosynaptic component of the withdrawal reflex of Aplysia (Kandel, 2001). Click to enlarge

References:

D. Bartsch, A. Casadio, K. A. Karl, P. Serodio, E. R. Kandel, Cell 95, 211 (1998).  PMID: 9790528

P. K. Dash, B. Hochner, E. R. Kandel, Nature 345, 718 (1990)  PMID: 2141668

W. N. Frost, V. F. Castellucci, R. D. Hawkins, E. R. Kandel, Proc. Natl. Acad. Sci. U.S.A. 82, 8266 (1985).  PMID: 16593630

Kandel, E. R. (2001). Neuroscience – The molecular biology of memory storage: A dialogue between genes and synapses. [Review]. Science, 294(5544), 1030-1038.  PMID: 11691980

P. G. Montarolo et al., Science 234, 1249 (1986).  PMID: 3775383

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