University years

How did we start to study memory?

Coming back to my last semester of my last year of Master’s in Neurobiology, today I will talk about memory and in particular about the first pioneer studies by the neuroscientist and Nobel Laureate Erik Kandel, that wanted to study memory from a neurophysiological point of view and that demonstrated how learning leaves traces in our neurons and nervous circuits.

But let’s start from the beginning and let’s talk about the animal model he used for his studies. At first, Kandel tried to study memory on the hippocampus of monkeys, but he soon realized that to study a complex phenomenon such as memory, he needed a simple model with a well known neuronal circuit. He therefore moved to the Aplysia californica, a 3 kg – 30 cm marine invertebrate (have a look at the picture below) that only has 20.000 neurons that form synapses (which basically are connections in between neurons that allow them to communicate – have a look here for a quick description of what a synapse is) in a simple and well defined way.

Aplysia californica. From seaslugforum.net

Once he had the right model to study memory, Kandel followed up on Pavlov’s experiments (have a look here to get to know who Pavlov was and his experiments), but rather than only observing the behaviours of the animals, he wanted to unravel their neural circuits driving them.

Thanks to the marine slug Aplysia, Kandel discovered that when we learn something we reinforce the connections between neurons and we create new ones, rather than modify the neurons themselves. Moreover, he found out that the remodeling of the synapses is dependent on the modulation of the genic expression: indeed, he demonstrated that our genes are under the control of the environment and, more in general, the experiences we have and the things we learn in our lives.

The first discovery that Kandel made was about the neural circuits of behaviour of the marine slugs: all these slugs, when they eventually learn, some of them faster and some of them slower, use always the same neural circuit composed by the same 30 neurons. This was the discovery that made him think about the synaptic nature of memory. Indeed, if learning involves always the same neurons, then the differences seen in learning and the speed of this process should rely only on the connections between neurons.

The next discovery was about the short and long term memory (STM and LTM): it is known that these slugs ordinarily withdraw the gill after gentle tactile stimulation of the siphon (see picture below for a schematic of this behaviour). Upon repeated stimulation, the gill-withdrawal reflex diminishes in both magnitude and duration. If the habituation experience consists of one training session of relatively few stimulations over a short period of time, then the habituation lasts for only a few hours after the training. On the other hand, if four or more individual training sessions are given, the habituation response can last for several weeks. These two forms of habituation have been interpreted as models of STM and LTM. After physiological and biochemical analysis of this behaviour, he discovered that while for the STM the neurons strengthen the already existing connections in between them, for the LTM neurons create new synapses.

A dorsal view of Aplysia showing
the gill, the animal’s respiratory organ. A light touch to the siphon
with a fine probe causes the siphon to contract and the gill to
withdraw. Here, the mantle shelf is retracted for a better view of the
gill. Modified from behavioralhealth2000.com

From the ‘90s on Kandel started identifying smaller and smaller elements of the genic expression cascade (which means the genes that create the messengers that activate other genes that in turn will create the proteins necessary to activate the next set of genes and so on) of memory that create new synapses. In the last years, his research group discovered the protein CPEB, that is essential for the formation of long term memories. This protein has a peculiar confirmation that, weirdly enough, resembles the one of the prion, the protein responsible for the mad cow disease. Currently, Kandel is studying how CPEB is promoting memory and if it is possible increase/potenziate its effects, in order to find new ways to treat neurodegenerative disease that affect the long and short term memories, such as Alzheimer’s disease.

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