Kasia M. Bieszczad

University of California, Irvine

sites.uci.edu/kasiamb/

What does your research focus on?

My primary research interests are in the neurobiology of learning and memory, with a particular focus on the neurobiological processes of information storage in the cerebral cortex. A critical issue in behavioral neuroscience is to find neural substrates that comprise the details of experience that form a memory. We all can identify with the notion that memories have content — they are about something. Yet the field has an incomplete understanding of how the details of “what memories are about” are actually represented in the brain. Therefore, it is also unknown what has happened when memories are lost, as in dementia or in various brain diseases.

My work addresses the issue of neural substrates for the content of memory using a simple auditory model of learning and remembering. It is born in some ways from the famous work of Ivan Pavlov, which showed how animals (just like humans) can associate a particular sound with a forthcoming reward (like dogs hearing bells for food). Such associative learning undoubtedly makes that sound important to the animal. So how does the neural representation of sound signify that particular sound as one that is behaviorally relevant? In other words, where and how is the auditory content of that associative memory represented in the brain?

To answer this question, one must consider what I believe to be the most important and exciting property of neural tissue like the cerebral cortex. That is, its remarkable capacity to change itself as one learns and experiences new things: The brain is plastic. It has turned out over several decades of neurobiological research that plasticity is a fundamental property of neural function that persists from childhood, to adulthood, and throughout a lifetime. At the same time there have been discoveries about areas of the brain that used to be labeled “sensory cortex” in textbooks — that is, scientists thought they had the the strict roles of analyzing the identities of incoming sensory inputs from our eyes, ears, etc. Findings showed that such areas are actually also critical participants in learning and remembering what we see, hear, and so on. For example, right there in primary auditory cortical neurons is plasticity that changes their receptive fields for sound when an adult animal learns that one sound is significant.

My research has built upon foundational work in the primary auditory cortex and auditory learning. We have shown that when animals learn and remember that a sound predicts a reward, auditory representational plasticity occurs in the primary auditory cortex to recruit more neurons for the representation of the behaviorally-significant sound. Memory depends on the reorganization of the representation of sound across neurons in the primary auditory cortex. Moreover, we find that the more cells that are recruited, the stronger the animal’s memory is for that sound. Just imagine then what the neural representation of the sound of your name might be like in your own brain — it is probably being represented in lots of neurons, and will probably be really difficult to ever forget.

What drew you to this line of research and why is it exciting to you?

Musical experience from childhood piano lessons and my training as a classical pianist were likely seeds of a passionate curiosity for the workings of auditory memory and the human brain. That, and I was raised by parents who were both computer scientists. That might seem like an odd reason until I tell you that my father had books everywhere about the human brain and its capacity for dynamic neural networks. These books sat on the shelves of our house in my plain sight and also (probably purposely) within my grasp while he was in the midst of developing his own research in the (then) young field of artificial intelligence. Another influence from my father? His steadfast voice reminding me as I whined with frustration about a new piece of music that my hands could not yet glide through: Remember, Kasia: Practice makes perfect. Practice makes perfect. But why did “practice make perfect”? And how could it be, as I’d read in those books, that a man could forget how to speak without forgetting how to sing?

I have been lucky enough to pursue the ideas I marveled about during childhood with empirical methods founded in biology and neuroscience. The laboratory structure allows a targeted inquiry into the mechanisms of how learning changes neural organization and behavioral function.

This work has all been incredibly exciting, especially because of the endless evidence that the adult brain is so plastic. The more we learn about adult neural plasticity (e.g., the circumstances in which it occurs, how exactly it reorganizes the cortex, and the consequences that neural remodeling has on subsequent behavior) the more this kind of basic science will have direct relevance to and an impact on the clinic. For example, behavioral therapeutic strategies that can alleviate or delay memory deficits that occur as a result of brain dysfunction or disease could be developed with targeted learning paradigms for which we have identified predictable outcomes of neural remodeling. It is my hope that we might one day gain enough of an understanding of the underlying plasticity that produces successful learning and remembering to delay or even treat conditions as devastating as the memory-loss that can occur after a stroke or with Alzheimer’s.

Who were/are your mentors or scientific influences?

The foundation of my career in neuroscience was formed while I was an undergraduate biology major at McGill University in Montreal, Canada. There is a strong neurobiological tradition on campus that permeates the prominent greystone psychology and biology buildings atop the hill on Docteur Penfield Avenue (yes, as in Dr. Wilder Penfield) and in the Montreal Neurological Institute down the road. It stirred the future research scientist in me to know that Penfield, as well as Donald Hebb, Brenda Milner, and those that followed them, made their discoveries while walking those same halls — and dealing with the same icy winters.

I was first introduced to laboratory research while at McGill, where I was remarkably lucky to link my music and neuroscience interests working with Daniel Levitin in his Laboratory for Music Perception, Cognition and Expertise. It was my first glimpse of a working research lab, of how collaborative efforts produce new ideas for experiments and clever ways to conduct them. I also saw first-hand how every lab member was invaluable to the laboratory’s overall function, and that we operated best as a family of sorts. Countless times, Dan stepped in to remind me never to give up, and showed me the routes I could take to achieve my goals and pursue my interests.

Those interests in the neurobiological substrates of auditory perception and cognition led me to Norman Weinberger in the Center for the Neurobiology of Learning and Memory at the University of California, Irvine and its Department of Neurobiology and Behavior. Without a doubt, Norm has been one of the most influential of my mentors in neuroscience. My most valued scientific lesson from Norm? Identify your assumptions. One may hold assumptions that are deeply engrained, and while sometimes difficult to detect, their discovery is essential for the ultimate discovery of truth. This simple rule helps in writing, giving lectures, preparing scientific talks, and designing a research program. Once you realize that you hold your own deep assumptions, it helps you understand your audience(s), your students, your colleagues, and even your reviewers.

I would also not be the research scientist I am today were it not for the Center for the Neurobiology of Learning and Memory and its staff at UC Irvine. The Center’s faculty and laboratories are organized so that next door and down the hall are scientists who share common questions but at various levels of investigation. It is undoubtedly due to my experience there and conversations with the people there that I realized it was feasible to form a future research program that would address the mechanisms of learning and remembering that span the behavioral, neural, molecular, and genetic levels. This echoes again the power of collaborative research, the importance of hearty discussion at scientific meetings, and the value of a collegial family of scientists working towards the same goal to discover truths about the nature of the brain. I am especially thankful to my postdoctoral advisors, Jim McGaugh and Marcelo Wood, from whom I have also learned that it is possible to balance a love for life with a love for science.

What’s your future research agenda?

The discovery that representational plasticity in the sensory cortex is a potential mechanism for the strength of the content of memory might explain why some memories are lost (e.g., if the lack of induction of appropriate forms of plasticity after learning contribute to disease- and injury-related dementias or specific memory loss). However, it also has implications for understanding why some memories are especially intrusive. For example, too great an induction of plasticity that recruits cells to a particular sensory cue may contribute to post-traumatic stress disorder (PTSD) by increasing the potency of specific signals that trigger flashbacks and stress responses. Likewise, cortically over-represented cues could be a neural basis for the likelihood of cue-initiated relapse into drug-seeking behaviors in disorders of addiction. Both of these situations are conditions in which memory detail is exceptionally strong.

A new line of my research I have started with Marcelo Wood at UC Irvine has been to determine whether the formation of particularly strong memories involves potent epigenetic mechanisms that promote plasticity in the primary auditory cortex. In recent years, epigenetics has become a major factor in the field of behavioral neuroscience. While there is strong evidence that epigenetic mechanisms control a developmental form of plasticity that establishes cortical organization, they also appear to have an independent and powerful role in post-mitotic differentiated cells in the adult brain. Epigenetic control of the expression of genes — which is required for experience-dependent plasticity — enables incredibly robust changes in neuronal identity, function, structure, connectivity, and ultimately animal behavior. It will be exciting to see whether the auditory model of learning, memory, and cortical plasticity, in conjunction with epigenetic control can provide a targeted approach to address mechanisms for robust and persistent content in memory. The future may reveal the utility of pharmacological manipulations of epigenetic control on specific behaviors, or even the reversal of enduring disorders of pathologically strong memory, which could extend our understanding of other dimensions of learning, memory, or, ultimately, any specific stimulus-driven behavior.

What publication are you most proud of?

Bieszczad, K. M. & Weinberger, N. M. (2012). Extinction reveals that primary sensory cortex predicts reinforcement outcome. European Journal of Neuroscience, 35, 598–613.

This paper incorporates some of the principles of sensory cortical plasticity that were discovered in the course of my graduate work — it shows the utility of combining questions regarding “factors” of auditory cortical plasticity (i.e., what psychological factors drive the formation of plasticity?) and its “functions” (i.e., what are the behavioral outcomes after having developed plasticity?). This framework led to the discovery a potential neural mechanism for the basic learning effect of behavioral extinction, behavioral recovery after extinction, and even a plausible mechanism for Pavlov’s “below-zero” extinction phenomenon. Most importantly, that these mechanisms were found in a “sensory” area emphasizes how the entire cortex might act in concert to support learning, memory, and cognition.

There is another set of papers in the pipeline that I am excited to have come out this year — these are particularly exciting because we have used brain stimulation techniques to approach causal accounts of a primary cortical role for learning and memory. That is …to be continued.