BW: Is that what is meant by unique molecular signatures?
TJC: Correct. So, there are lots of memories we want to use and then discard because they’re no longer of use. That’s called “working memory.” Other memories — like how you get home at night, your grandma’s birthday or memories you use professionally — you want to keep forever. That’s long-term memory.
For example, I am going to tell you that one of my daughters’ names is Amy. In your brain, this information, or the memory I just put in your head, is less than a second old. It is produced by one thing — changes that are occurring to the existing proteins in your brain. We didn’t have time to turn on your genes, make proteins or grow synapses. We didn’t even have time to alter the structure of old synapses.
Now, if I happen to run into you a year from now, you might say, “Oh yeah! Your daughter’s name is Amy. I had a great aunt named Amy.” The content of the memory is the same, but the mechanisms deployed in the brain to produce, store, and encode will be profoundly different. They require turning on genes. Then those genes make gene products called proteins. Those proteins are then involved in any number of ways in structurally changing the brain.
If you remember the smell of your grandmother’s kitchen — you were probably 4, 5, or 6 years old when that memory was formed that’s a deep memory. We all have olfactory memories. They are a little vague, but they are deep and last a long time because they are part of our developmental history — our cultural history. So, memories exist in a variety of temporal domains, and each memory has its own unique molecular signature mechanism that encodes it.
BW: What about memory recall or memory extinction?
TJC: Extinction is actually a formal term that refers to a kind of memory arising in the context of classical conditioning. You’ve probably heard of Pavlov and his dog. [When Pavlov rang a bell and gave the dog meat powder, after a while the bell started eliciting a salivation response in the animal as if it were a substitute for the meat powder.] We now know that Pavlov’s bell is actually a signal — it serves as predictor for the meat powder.
When Pavlov started ringing the bell in the absence of meat powder, the dog [stopped] salivating. That is what is referred to as extinction. It turns out that extinction is a new kind of learning. It’s not erasing the old learning, the connection is still there, but a new kind of learning has now been overlaid, and so the conditioned response of salivation [was] diminished. It’s typically associated with what’s called “associative learning” (classical conditioning or Pavlovian conditioning).
While in Kandel’s lab my colleagues and I have demonstrated that the Aplysia does show classical conditioning, and it absolutely shows extinction. What that means is that, after conditioning, with repeated delivery of a conditioned stimulus (a touch to the skin) the animal begins to realize that there’s no longer a predictive value to the stimulus. Or, rather, the conditioned stimulus is now beginning to predict the lack of a reward or punishment depending on what you’re using to change the animal’s behavior.
BW: How do you see the cellular changes in the Aplysia?
TJC: A long time ago, we developed what we call a reduced preparation. We can take the animal and open it up in a way in which we can have access to its nervous system, put electrodes inside the neurons and record from them directly. Essentially, we can go into the part of the reflex circuit involved in memory formation.
For instance, we can put electrodes directly into the sensory neurons that actually encode tactile information [in the animal]. So, when I touch the Aplysia’s skin, the sensory neurons are activated, and the animal knows it’s being touched. Just like if you touch your hand, the sensory information from your skin will be transported up through your spinal cord to your brain.
Now we can put electrodes in the motor neurons and literally study the animal while it’s behaving. So, touching the Aplysia can make its tail withdraw — it’s a simple withdrawal reflex. It turns out that the motor and sensory neurons connect directly. This is called a monosynaptic connection, and it allows us to see what changes occur during memory formation in the synapse. Notice that we have just moved from talking about behavior to considering a synaptic analysis.
We can go to yet another level. We can remove the central nervous system and put it in a dish to record the activity of the motor and sensory neurons while they are not connected to the animal. We can also introduce serotonin, a neurotransmitter that is released in response to shock in an intact animal, to study the synapse in the isolated nervous system.
Now we can study the molecular requirements for memory formation by studying different signaling cascades (called “second messenger pathways”) and how they are involved in long-term memory formation. We can see what proteins are involved by blocking protein synthesis and see what genes are involved by blocking their activation. And we can study the molecular requirements for memory formation through this isolated system.
So, we can study the behavior of the animal, the nervous system in the intact animal, the isolated nervous system, and the minimal reflex sensory circuit via sensory and motor neurons in a culture dish. This was begun in Eric Kandel’s lab, so we didn’t develop it, but we certainly take advantage of it all the time. Essentially, we study why, where, and how memory formation occurs, but we are also very interested in when during training is a memory encoded.
BW: What are the drawbacks of using such a simple animal rather than a more complex animal?
TJC: All science is a compromise. I don’t care about Aplysia memory. I care about the memories of my daughters and my grandkids. I’d love to know what’s going on in your brain right now, as you encode the memory of this conversation. We, as scientists, have to make a decision about what level of analysis satisfies us. That’s a personal decision, and “satisfied” is a relative term; we have to decide what makes the biggest contribution to the field and what’s fun for us. For some people, recording neurons is bloody boring — you sit in a dark room for hours — for me, it’s like going to a theme park. I love working at that level of analysis. So, I’d say that the drawback is imbedded into the level at which we choose to work at. I think that all successful scientists find something that is a joy for them to study.
BW: You’ve also authored more than 150 scholarly articles.
TJC: (Laughs) I’d say it’s closer to 200 now, but who’s counting? I also wrote “Behavioral Neurobiology: The Cellular Organization of Natural Behavior” when I was a professor at Yale for a course I developed to study how the brain and behavior work in an animal’s natural environment.
To give you a sense of the approach I took in the book, let me use a metaphor: There are two ways to go to the museum. You can move rather quickly from room to room and try to see every painting, or you can spend time in appreciating a few paintings in depth. My book takes the latter approach and considers about a dozen animals in depth, celebrating the unique skills that evolution has endowed each of these animals to enable them to succeed in their particular ecological and behavioral niche.
This article is updated from its initial publication in Brain World Magazine’s Summer 2014 issue.
