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Cristina Maria Alberini, Ph.D.
Professor of Neural Science
New York University
Dana Grantee: 2016-2022
What is your first childhood memory?
For some, it may be the sunflowers on the wallpaper in the family kitchen. For others, it may be the joy of splashing in the bathtub or playing on a swing. Each memory is unique, based on our personal experience, and each is based on our interactions with the outside world. New research suggests such experience-dependent learning not only archives those experiences but also helps shape our brain development and the way we process memories later in life.
While it’s long been known that our childhood experiences have the power to change brain development, especially harmful events, neuroscientists had thought the brain relied on pre-programmed networks to guide its trajectory—and that complex experiences are memorized only after the brain has reached a certain level of development. But groundbreaking research out of Cristina Alberini’s laboratory at New York University suggests that early life learning establishes key neural networks, which consequently direct our cognitive and emotional development as we grow. Those networks, in turn, can influence the way each person processes their experiences throughout life, as well as how they adapt to their environments as they age. Here, Alberini discusses why we can’t understand memory systems without understanding how they first develop, how experience is at the heart of individuality, and why all experiences matter when it comes to brain development.
What first interested you in studying brain development, especially as it pertains to memory?
I’ve been interested in the neurobiology of memory since the time I was a postdoctoral fellow, when I decided to switch my research interest from immunology to neurobiology. I was fascinated by brain biology, especially the biology of complex brain functions. This then became the overarching interest of my lab, and it has been the focus of our studies for more than 25 years.
Memories are not only essential functions for survival but are also major components of who we are—of our very identity. Also, they significantly contribute to many of our brain functions. In my lab, we have been studying the biological mechanisms of memory formation using adult rodents as models, but, at one point, It became clear to me that we couldn’t understand how memory systems work if we did not understand how they develop. It’s a question that, at the mechanistic level, has been largely overlooked.
The study of biological mechanisms underlying early life memory formation has been mostly limited to models of stressful or traumatic experiences; very few investigations have been done to address the nature of the biology of learning and memory in normal development. Addressing this basic question is fundamental to understand how memories work throughout life, as well as to gain new insights into how neurodevelopmental disorders may occur. The insights we have obtained about the memories formed in early development have been very exciting and have taken us into a completely new way of thinking.
There are two sets of findings I consider transformative. First, when we compared the biological pathways of the brain over different developmental phases, we found that, undoubtedly, the biological composition of the brain regions involved in memory formation and storage is very distinct at different ages. The infant brain is not just a smaller version of the adult brain but a very unique biological and operational system. Therefore, unless we understand the full complexity of this biology, we will not be able to understand how the memory systems work and how they develop their functions. Second, we found that differential biological mechanisms are engaged by the infant brain to form and store memories. These mechanisms also mature the brain. In other words, the development of the brain system involved in memory formation and storage does not occur by default but as the result of experience. These experience-dependent changes are key for enabling and shaping the memory system itself to function both then and later on in life.
What made you think the old notion of pre-programmed developmental networks might not be shaping development in the brain’s memory regions?
There’s been quite a bit of evidence from several fields, like psychology, cognitive science, and psychiatry, suggesting that our earliest experiences shape brain functions throughout life. But those studies couldn’t really answer the question of how this happens. In my lab, we wanted to take a close look at the biology that allows that experiential molding of brain functions during development and for this we used mice and rats. We focused particularly on episodic memories—the memories of places, contexts, and social interactions—formed at early ages, and focused on an age in rodents that corresponds to approximately 2-3 years of age in humans. At these ages, episodic memories are formed but they do not last; they are very rapidly forgotten. This forgetting is believed to be the cause of infantile amnesia, the inability as adults to remember our childhood memories.
It was believed that infantile episodic memories do not last because the brain regions essential for forming these memories, like the hippocampus, are too immature to properly store them. The belief was that this memory system is unable to function at that age. But our studies showed a very different outcome: We found that memories formed at those infantile ages are not lost, only apparently forgotten as they are stored in long-term memory in a latent, non-expressed form. We found that the infantile memories, apparently forgotten, re-emerge very robustly at later ages if certain types of recall are presented. Also, they require the hippocampus to recruit unique types of biological mechanisms to store them in this latent form. Interestingly, these biological mechanisms had previously been discovered as important players of sensory function maturation within the so-called “critical periods,” or the temporal phases in development during which the brain is very sensitive to stimuli, and through these stimuli it matures certain functions and the associated structures. Our biological studies led us to find that learning in infancy matures the hippocampus both biologically and functionally.
This experience-dependent maturation of the brain begged a very important question: Is learning in early development leading to a general maturation of the brain system involved in memory formation, or is the maturation selective for the type of experience encountered? Addressing this question is very important because the answer would tell us if the functions that each individual matures over development is restricted to their gamut of experiences. If this were true, learning and experiences during early development would be basically the orchestra director of the individual’s brain functions. This would have many implications.
With the support of the Dana Foundation, to which I am very grateful, we carried out several sets of studies to address that question. We found that the infantile experiences selectively shape the brain. In other words, our functions and brain structures develop as a result of the types of experiences encountered during these critical periods.
Certainly, these data do not exclude the importance of genetics. As with any function, the genetic bases play a role in how the brain develops and does so in an individual manner. However, our experimental work provided clear evidence that early life experiences shapes behaviors throughout life. I believe that this experience-dependent molding of brain functions explains how we all develop as individuals—in other words, it is at the core of our individuality.
Work looking at traumatic experiences, like the ACES study, suggests that negative experiences can shape brain development. How does this experience-dependent brain molding work? And how does it affect function and processing later in life?
Of course, adverse childhood experience selectively mold the brain in a very specific manner. But I would like to stress here that It’s not only traumatic or stressful experiences that mold the brain—but all of our experiences. This implies that an individual who has learned via a gamut of enriched, modulated, and balanced experiences will result in a brain that has molded in a very enriched and adaptive way and will be able to use that adaptability throughout life. If instead, an individual had a history of traumas during early life, their brain will be shaped by these traumas and will therefore respond accordingly throughout life.
This doesn’t mean that changes in the brain and behaviors cannot occur after development or these important critical periods. We know the brain remain plastic throughout life; however, our studies suggest that the fundamental lines and abilities are tracked during development according to individual experiences.
Here is an example that explains the concept I am trying to describe: language learning. Language is also shaped by critical periods. A new language can be learned at any age, but while it is learned effortlessly and efficiently during childhood, it is much harder to lean it after certain ages. The language abilities acquired in childhood or in adulthood have a world of difference. Our work suggests it is the same for complex functions based on episodic learning and memory: the types of experiences encountered in early life shape the way the system will be able to work.
The implications of these findings are many. If there aren’t enough of varied experiences within the critical period temporal window, the ability to process and learn information as an adult will be compromised. This explains why experience deprivation or traumatic experiences in childhood change the way individuals process information and, consequently, greatly increase the possibilities of dysfunctions or maladaptive behaviors later in life. Our results have also implications for many fields other than psychological or psychiatric, such as in education, societies, economies, and politics.
What comes next?
A great deal remains to be known on the mechanistic bases of memories formed in early life and their implications on brain functions. In my lab, some of the questions I would like to address are whether we can visualize physical representations in the brain, such as brain networks, that reflect, at least in part, the activation created by infantile experiences. Can these networks influence behavior throughout life? We have technical tools that allow us to label neurons in the brain of living rodents and tag them, so we can not only visualize them using florescent proteins but also manipulate their functions at different times. We plan to block activity of neurons tagged by an infantile experience and see if the representation is selective and then test whether it affects the retrieval of memories or new learning at later ages, such as in adulthood. These experiments will determine whether the circuitry that was recruited in infancy controls memories and behaviors in adulthood.
The second big question I’d like to address is what is the comprehensive biology of the brain regions involved in the formation and storage of infantile memories? Traditionally, most studies trying to gain biological understanding of memory formation have approached the question using hypothesis-driven approaches. This means focusing on one molecule or one pathway at a time. To understand memory, we need to gain a comprehensive knowledge of its biology and not only of single molecular pathways. To gain this knowledge, we need to use approaches such as “-omic” analyses, which can provide large set of data and reveal the comprehensive biology of a system in an unbiased manner.
My plan is to start with transcription and translation, two major biological processes required for memory formation. I am interested in comparing the profiles of transcription and translation evoked by episodic learning in infant animals or at early developmental ages and to the counterparts regulated in the brain of adult animals.
You work with animals. How can we effectively translate this data from rodent models to our understanding of human memory?
Understanding the biological changes created by learning in rodent models is very likely to inform how human brain and brain functions operate, too. There is extensive evolutionary conservation between rodents and humans both at the genetics and behavioral levels. In fact, the majority of behavioral studies in humans are in line with what we see in animal models, and vice versa. One example, one among many, is the responses found associated to human traumatic experiences such as behavioral inflexibility, compulsive and repetitive behaviors, and other related pathologies. We see the same things in rodents that are exposed to trauma.
These animal models are of fundamental importance for understanding human brain functions because we cannot assess the functional biology of the human brain from dead tissues. Our studies on memory in rodent models will provide key information for testing new hypotheses of childhood memories in humans, both in health and disease. In fact, we already have started collaborations with colleagues studying children.
To add some more detail, our studies in rodents can provide a lot more information about what types of brain regions and circuits are involved in processing human memories. They can also help researchers who study humans address questions about neurodevelopmental disorders and milestones. I strongly believe that there will be a lot of data that will come out of rodent biological investigations of brain development that will provide massive new information about human biology. This biology of critical periods of learning and memory is also likely to provide important clues for building new hypotheses concerning neurodevelopmental disorders and help identifying their core problems—and, as a result, guide us to new ideas about potential interventions.
Bessières B, Travaglia A, Mowery TM, Zhang X, Alberini CM. Early life experiences selectively mature learning and memory abilities. Nature Communications 2020 Jan 31;11(1):628. doi: 10.1038/s41467-020-14461-3. PMID: 32005863; PMCID: PMC6994621.