RE: Manipulating Memories: Instantly Eliminate a Fear
This is interesting and not really surprising given the role of the NMDA receptor in the formation of memories. I used to work in a similar kind of lab doing trace and delay fear conditioning with rats looking at the function of the dorsal vs ventral hippocampus and the formation of long-term memories. Adding the emotional component (fear) engages the amygdala but we cannot discount the role of the hippocampus in the creation and extinction of memories. We must also keep in mind that in the development of new therapies that the targeting of such medications is extremely difficult as much of these brain studies require a direct infusion of the agent directly into the brain area.
Given that NMDA receptors are ubiquitous, an agent that blocks them all in the brain would cause widespread problems, especially in the formation of new memory, and for long-term potentiation to occur.
At the end of the day what this paper basically shows is that the NMDA receptor is key for the formation of new memories and for the extinction of old. The question that is debated, and I am from this camp, is that extinction is considered a learned behavior rather than forgetting the original learned behavior. This is why it is easy to slip back into old habits because while you may have extinguished the behavior the connections are not completely gone and can be rebuilt since they were not disassembled, but only weakened through long term depression.
Happy to talk more about this if anyone is interested as it was the topic of my thesis and played into my former work on schizophrenia drug and animal model development in my former life.
oh and my thesis was examining protein expression in dorsal vs ventral hippocampus (amygdala and parietal cortex as controls) in both trace and delay conditioning models. Basically I was trying to show a protein expression difference in these two brain areas as my lab had proven it behaviorally through using excitotixc lesions and then through temporary inactivation using musicmol directly infused into these sites
http://www.rci.rutgers.edu/~totto/Yoon%20&%20Otto%202007.pdf
http://www.rci.rutgers.edu/~totto/Czerniawski%20et%20al%202009.pdf
Yeah, this is super interesting work! Thanks for sharing, i've already started a string of open tabs combing through your references. I am very interested in memory and spent a lot of time reading eletro-physiology papers last year, so I love to see a good hippocampus paper!!
You are spot on. I am interested in what your thesis might have consisted of. Did you happen to do work on ketamine? I am close with a handful of researchers who have studied ketamine's selective antagonism of NMDAs and others who have studied it as a model for mimicking schizophrenia (something I don't really think it necessarily does a very good job of personally). Ketamine has also been used for its NMDA affects in treating PTSD, based on the principals touched upon in this post.
This post is geared towards a broad population who might not be familiar with neuroanatomy, let alone molecular or genetic players. But I am much more interested in Neuroscience from a molecular perspective and would be super excited to make posts along those lines if there are interested readers!
Thanks so much!
So its funny you mention ketamine. I use it in my clinical practice for a few applications. 1. Conscious sedation for procedures, especially in children. 2. headache treatment refractory to my migraine cocktail 3. chemical control of agitated patients. I'm not a psychiatrist but I have been seeing ketamine in the literature being reported for PTSD and depression. I find it to be a fascinating medication due to its differing effects at different concentrations.
See this post by Reuben
http://emupdates.com/2013/12/25/the-ketamine-brain-continuum/
In regards to your question about my model development. I used mice and its hard obviously to make a mouse schizophrenic. We used PCP and looked at their hyperactivity as measured by bean breaks in a plastic cage with lasers to quantify how "psychotic" they were.
Schizophrenia needs something more dopamine specific that hits the areas where schizophrenics have their anatomic and physicologic problems.
One of the models I was working on fit for autism better than schizophrenia due to the way it affected neuronal migration in its knockdown form. I wrote it up for an NIH grant but then graduated and went and did bioscience enterprise instead of staying for a PhD. I hoped the PI I gave it to would've taken it under advisement but alas nothing came of it. I looked at that molecule and also GAD expression as its not only over stimulation but also under suppression by GABA in many of these circuits in the CNS, glycine in PNS.
I'm starting a medical toxicology fellowship this summer so geeking out over molecular pharma is what I'll be doing professionally for the next 2 years! Lets get nerdy!
Yeah, ketamine has seen some super vast use recently. The compounding pharmacy that I used to work for started getting scripts for it to be used for such a diverse set of reasons, and like you say very specific dosages. Its there is some very exciting research on its treatment for long term depression! Ill be sure to check out the link later tonight when I have a moment.
That sounds like some super interesting work you have done. Sounds like you combine a good blend of techniques for your research. I am always slow to think of a pharmacological, or genetic intervention as being a perfect model, but the research along the way seems to bear many fruits!
Thanks so much for your post, great to find some other molecular-pharma enthusiasts on here! Congrats on your fellowship, I am envious of your experience (being a mere senior undergrad)!