UWM’s Fred Helmstetter presents “How Does Memory Work?”


So we study memory
and we were interested in how it’s formed and stored. Memory is central to our sense of self. It’s how we accumulate experience and become who we are. While we may tend to view
memories as intangible, they have a specific, physical substrate. That’s what my students and
I are interested in studying. So why do we care about memory? Well, it’s an important
basic science questions and it’s really very interesting, but it’s also fundamental
to an understanding of who we are and how our brains function. We make assumptions about how
our memory works all the time, but these assumptions can have
rather serious consequences. The reliance on eyewitness
testimony, for example, in our judicial system
is one example of this. We also wanna know how to
fix memory when it breaks. People are deeply affected
when our memory doesn’t work the way it’s suppose to. While we see a gradual decrease in memory as a function of normal aging, memory impairment is often an early sign of neurodegenerative disorders
like Alzheimer’s Disease. As we get older as a population, this is becoming a real crisis in need of effective interventions. Losing your memory is bad,
but we can also have problems if we remember too much. Current work on Post Traumatic
Stress Disorder suggests that here strong
emotional memories related to trauma can’t be suppressed
or stored in some way that defies regulation. So there’s as much interest
in erasing memories that we don’t want as there
is in preserving memories that we do. So the first key point that
I want you to walk away with is that each of your memories
represents a physical change in your brain. Brain cells called neurons
are plastic or changeable, and your experiences drive neural activity that induce storage of
memory traces in the brain. The change can become
essentially permanent, allowing you to store
information for your whole life. (audience laughing) So, about 86 billion
neurons in adult brain with an average of over
10,000 complex connections to other cells. How do we go about finding
the needle in the haystack? The answer is to leverage the strength of experimental psychology with tools from molecular biology,
genetics, and imaging. We can narrow the search
because we know a little bit about patients and people
with brain lesions. We know some areas are
particularly important, but there’s no single
memory center in the brain. Memory takes many forms, and the circuits that you use to remember
how to ride a bicycle are very different from the circuits that you’re gonna use to find your car when you leave tonight. We could also monitor brain function while people perform a memory task. In our experiments, we measure a signal that tells us how hard the
cells in the brain are working, and use this as our way
to figure out which parts of the brain are important. This is a very popular type of study, but there are real limitations with this for getting down to the nuts and bolts of what’s actually happening in the brain. If we focus on one brain area, we can use genetic strategies
to label or tag groups of cells that encode a particular memory. Since active cells express different genes than cells that are not active. So we create two memories. Maybe two different mazes for the animal and then take the brain out
and look at where the signal for one set of cells active at time A and one set of cells at time B might be. That’s fine, but that’s kind
of a correlational procedure. What can we do to actually infer cause and effect relationships? What if we could control the activity of the cells that encode a memory? It turns out that we can do that. There’s a couple of techniques
that we can use to do that. One really popular one
now is called optogenetics where we put in a transgene
that makes the cells express a light sensitive ion channel. Once they express this channel,
we can shine laser light of different wavelengths onto the cells and turn them on or off at will. Several recent experiments have supported the idea that activating
a particular population of neurons in this way will
actually cause an animal to retrieve an established
memory and behave accordingly. The real action in
memory is at the synapse, or the connection, the
communication, between cells. We have 86 billion neurons. We have 86 trillion synapsis
which makes the brain, sorry Paul, the most powerful
supercomputer in the world. (audience laughing) So we’ve known for a long time that training, learning,
changes synaptic physiology and it changes synaptic structure. So this idea of synaptic
plasticity is central to our understanding of learning. There’s various ways
that we can measure this. But the key to synaptic plasticity is the altered gene expression
and subsequent changes in local protein synthesis
that happens in neurons. These new proteins allow for alternations in both cellular structure
and cellular function. Now we looked at protein
synthesis in my lab since 1990s, but we’ve recently started to focus more on a related process
called Protein Degradation. You probably didn’t know that
your cells have a biological garbage disposal called the
Ubiquitin-Proteasome System ,or UPS for short, who’s job it is to break down and get rid of proteins that are toxic or no longer needed. The system does a lot
of basic housekeeping and protein homeostasis,
but we’ve recently shown that the activity generated when you learn turns on this system. If we prevent the system from turning on, we prevent the storage of memory. So the idea is that before
you can strengthen a synapse, you have to break it
down and destabilize it. This destabilization is what the UPS does. This is critical for our understanding, not only of memory
formation but of forgetting and memory modification. The UPS is also interesting
for other reasons because one thing that we’ve noticed is that Protein Degradation or a decrease in protein
degradation is part of the normal, cellular aging process. Alzheimer’s Disease partially involves and inability of cells
to clear toxic proteins. So we did a few experiments
to look at this. We looked at young rats versus old rats and we found that young
rats have good memory and normal UPS function, whereas old rats have poor memory and depressed UPS function. Importantly, the rate of protein clearance actually predicted the memory impairments in the old rats, so that’s kind of cool. But really, what we wanna be able to do is target the system for interventions. We’ve tried a couple of ways
to upregulate UPS activity to fix the memory problem. We haven’t had any success yet, but right now we’re trying
this promising, new technique of gene editing to
actually reprogram the UPS, make old neurons look like new neurons and maybe fix the memory problem. So the last thing I wanna
say is that non of this work would be possible without UWM PhD students and post-doctoral fellows. I’ve had some great
students over the years, and they keep me excited and
they do all the hard work. My final thought is, support
federal research funding because federal research
funding enables us to do this kind of work, and
it also is gonna allow us to have a prosperous and happy future. Thank you. (audience applauding)

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