The two memory engram papers by Steve Ramirez et al focused
on the re-activation of either negative or positive memories in their c-fos-tTa
transgenic mice. Their 2013 paper, “Creating a False Memory in the Hippocampus,”
utilized virus and drug-mediated manipulation to selectively express ChR2 and,
in essence, control a mouse’s memory following context fear conditioning. Their
data show robust effects for selectively inducing a fear response when stimulating
dentate gyrus (DG) cells in a novel context. By labeling specific DG neurons in
context A, optically activating them during context fear conditioning in context
B, then measuring the fear response when re-exposed to context A, Ramirez et al
were able to show that fear memories persisted in the cells labeled only in
context A. In every behavioral experiment, false memories were activated, mimicking
a natural fear response both behaviorally and histologically.
The 2015 paper, titled, “Activating positive memory engrams suppresses
depression-like behavior,” Ramirez et al used the same transgenic mice to
re-activate what they deemed as “positive” behaviors in mice. Instead of testing
the functionality of false memories in fear conditioning, different tests of
stress were used to induce depressive-like behaviors in transgenic mice. The
overall results of this paper showed that re-activation of the “positive” memories
in the c-fos-tTa mice reverse the depression-related behaviors induced by the different
stress tests. These behavioral results were further shown to be mediated by
specific circuitry between the BLA and Nucleus Accumbens. These data imply that
“positive memory cells” in the DG are sufficient to reverse depressive-like
behaviors such as anxiety (NSFT), anhedonia (sucrose preference test) and learned
helplessness (Tail suspension test). Does this mean increased dopamine release?
Given the results of our previous papers, studying the VTA’s role in depressive-like
behaviors, it’s interesting that Ramirez et al decided not to include it in
their study.
Though Ramirez’s 2013 paper, in my opinion, shows very clear data
for the efficacy of their transgenic model, the 2015 paper raises more
questions. Depression is a multi-faceted disorder, so coming to a general result that
activating “positive memories” reverses depressive-like behaviors is much too
simplistic. Ramirez backs up his interpretations with strong data; however, what
is their behavioral paradigm actually showing? To me, exposing male mice to
female mice doesn’t necessarily cause hedonic pleasure. It’s possible that the “positive”
associations these male mice are making with females more of an evolutionary
drive to mate rather than what humans would call a “positive” or “pleasurable”
experience. This raises the question, can high levels of hormones such as
Testosterone override anxiousness, anhedonia and escape behaviors? The paradigm would’ve been much more convincing
to me if the “positive experience cells” were selectively labeled due to the mice
eating extra tasty food. These questions once again challenge the utility of
mouse models of human diseases such as depression.
Hi Whitney,
ReplyDeleteI’m happy you mentioned the exclusion of data on dopamine levels in the 2015 paper, as this was something that slipped my eye when first reading as well. Extended Data Fig 7 shows results of the TST and SPT after administration of a dopamine receptor antagonist cocktail. When given, there was less struggling in the TST than was seen in light-induced mice. Interestingly, mice given saline showed the behavioral effects of optically reactivating a positive engram. They also tested mice who did not receive the antagonist cocktail but rather had a memory activated during the TST or SPT. Even though there were increases in struggle time and preference for sucrose, this single session of activation did not produce lasting antidepressant effects on day 2 of testing. Since that was a relatively short article, perhaps they did even more experiments about dopamine changes in the various positive/neutral/negative experiences and simply didn’t have the space to report them out.
Either way, this definitely relates back most directly to how we and the researchers are defining the “naturally rewarding” experience and whether it equates to pleasure or not. I’m a bit more convinced about the plausibility of the female exposure being equated to a positive experience based on what was shown in Extended Data Fig 1. Male mice in the experimental group spent significantly more time in the target zone where a female-associated object (although what was that actually?) was introduced. This group of female-object paired mice generally had an increased preference time for the target zone compared to the neutral-object paired group.
A final thought I had was how anxiety-related behavior could be modulating these effects. As we have discussed in class several times, depression and anxiety are tightly linked. The authors note that anxiety behaviors may rely more heavily on synaptic pathways with the amygdala and hippocampus (versus the nucleus accumbens as discussed in these articles) which would easily require more studies to confirm. They acknowledge that their manipulations of the dorsal hippocampus likely did not access these pathways and it cannot be interfered what role they exactly should or do play. Regardless, they still have an important conclusion that direct activation of this neuronal processes are promising in how they could be used to correct maladaptive behavior.