Exploring fear engrams to shed light on physical manifestation of memory in the brain

In a world grappling with the complexities of mental health conditions like anxiety, depression, and PTSD, new research from Boston University neuroscientist Dr. Steve Ramirez and collaborators offers a unique perspective. The study, recently published in the Journal of Neuroscience , delves into the intricate relationship between fear memories, brain function, and behavioral responses. Dr. Ramirez, along with his co-authors Kaitlyn Dorst, Ryan Senne, Anh Diep, Antje de Boer, Rebecca Suthard, Heloise Leblanc, Evan Ruesch, Sara Skelton, Olivia McKissick, and John Bladon, explore the elusive concept of fear engrams, shedding light on the physical manifestation of memory in the brain. As Ramirez emphasizes, the initiative was led by Dorst and Senne, with the project serving as the cornerstone of Dorst’s PhD.

Beyond its implications for neuroscience, their research marks significant strides in understanding memory formation and holds promise for advancing our comprehension of various behavioral responses in different situations, with potential applications in the realm of mental health. In this Q&A, Dr. Ramirez discusses the motivations, challenges, and key findings of the study. What motivated you and your research collaborators to study the influence of fear memories on behavior in different environments?

The first thing is that with fear memories, it’s one of the most, if not the most, most studied kind of memory in rodents. It’s something that gives us a quantitative, measurable behavioral readout. So when an animal’s in a fearful state, we can begin looking at how its behavior has changed and mark those changes in behavior as like an index of fear. Fear memories in particular are our point because they lead to some stereotyped behaviors in animals such as freezing in place, which is one of many ways that fear manifests behaviorally in rodents..

So that’s one angle. The second angle being that fear is such a core component of a variety of pathological states in the brain. So including probably especially PTSD, but also including generalized anxiety, for instance, and even certain components of depression for that matter. So there’s a very direct link between a fear memory and its capacity to evolve or devolve in a sense into a pathological state such as PTSD. It gives us a window into what’s going on in those instances as well. We studied fear because we can measure it predictably in rodents, and it has direct translational relevance in disorders involving dysregulated fear responses as well. Can you explain what fear engrams are and how you used optogenetics to reactivate them in the hippocampus?

An engram is this elusive term that generally means the physical manifestation of memory. So, whatever memory’s physical identity is in the brain, that’s what we term an engram. The overall architecture in the brain that supports the building that is memory. I say elusive because we don’t really know what memory fully looks like in the brain. And we definitely don’t know what an engram looks like. But, we do have tips of the iceberg kind of hints that for the past decade, we’ve been able to really use a lot of cutting edge tools in neuroscience to study.

In our lab, we’ve made a lot of headway in visualizing the physical substrates of memories in the brain. For instance, we know that there’s cells throughout the brain. It’s a 3D phenomenon distributed throughout the brain but there’s cells throughout the brain that are involved in the formation of a given memory such as a fear memory and that there’s areas of the brain that are particularly active during the formation of a memory. What were the main findings about freezing behavior in smaller versus larger environments during fear memory reactivation?

It’s thankfully straightforward and science is often anything but. First, if we reactivate this fear memory when the animals are in a small environment, then they’ll default to freezing–they stay in place. This is presumably an adaptive response so as to avoid detection by a potential threat. We think the brain has done the calculus of, can I escape this environment? Perhaps not. Let me sit in a corner and be vigilant and try to detect any potential threats. Thus, the behavior manifests as freezing.

The neat part is that in that same animal, if we reactivate the exact same cells that led to freezing in the small environment, everything is the exact same: the cells that we’re activating, the fear memory that it corresponds to, the works. But, if we do that in a large environment, then it all goes away. The animals don’t freeze anymore. If anything, a different repertoire of behaviors emerge. Basically, they start doing other things that is just not freezing, and that was the initial take home for us, was that they, when we reactivate the fear memory up, or artificially, when we do that in the small environment, they freeze, when we do that in the large environment, they don’t freeze.

What was cool for us about that finding in particular was that it means that these fear memory cells are not hardwired to produce the same exact response every single time they’re reactivated. At some point, the brain determines, “I’m recalling a fear memory and now I have to figure out what’s the most adaptive response.” Were there any challenges or obstacles you encountered during the research process, and how did you overcome them?

There’s a couple. The first is that the behavior, ironically enough, was reasonably straightforward for us to reproduce and to do again and again and again–so that we were convinced that there was some element of truth there. In the second half of the study, and the one that probably takes up the most space in the paper, was figuring out what in the brain is mediating this difference. As we observed, the animals are freezing when we artificially activate a memory in a small environment, and they’re not freezing in the large environment. But, we’re activating the same cells. So, what is different about the animal’s brain […]

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