Saturday, June 6, 2009

Memory, Emotions, and State-Dependent Learning

What is State Dependent Memory?

Experiments early last century first discovered that memories laid down under the influence of some drugs, especially opiates, were much easier to retrieve under the influence of those same drugs. However, for some while the focus of memory studies was on "memory molecules", in a mistaken analogy to the molecular basis of genetics (DNA).29 By the '70's, however, some work was being done on this subject,3 and by the '90's it was an area of research, if not heavily subscribed.2

Basically, there appear to be a number of drugs that produce this behavior: an animal (and, presumably a person) learning certain things (behaviors and perhaps facts) under the influence of a specific drug will find it harder to recall those memories unless under the same influence. There's some overlap, that is some drugs can substitute for others, while there are combinations of drugs that increase the effect.

There continues to be on-going research in this area, ... although much is behind paywalls,7, 8, 9, 10, 11, 14, 15, 16, 17 and quite a bit seems to be only "ruling out" state-dependent learning as part of the cause of whatever effect it's studying.17, 18, 19, 20, 21, 22 There are papers that (IMO) ought to mention the subject but don't,23, 29 including three whole "special issues" of one periodical.24, 25, 26

I was able to find only two very recent papers on the subject that were open access, one of which is in Iran,13 and the other6 is Arcaine and MK-801 make recall state-dependent in rats by Ana Paula Chiapinotto Ceretta, Keli Camera, Carlos Fernando Mello, and Maribel Antonello Rubin.

Ceretta, A., Camera, K., Mello, C., & Rubin, M. (2008). Arcaine and MK-801 make recall state-dependent in rats Psychopharmacology, 201 (3), 405-411 DOI: 10.1007/s00213-008-1304-7

Researching the NMDA Receptor

In the latter paper a new antagonist for one of the binding sites on the NMDA receptor was tested to see if it induced state-dependent learning effects, and whether it was interchangeable with a better-known antagonist with the same site. The NMDA receptor is one of the "smartest" molecules in the nerve cell membrane, with at least six different binding sites, which can be influenced by a number of endogenous substances, as well as a massive number of drugs and poisons.

Figure 1: the NMDA receptor present the nervous system. Click on image to see full figure and legend. (From Wiki)

This receptor has a single known effect, opening a channel for all types of cations, especially including sodium, potassium, and calcium. However, its effect can be modulated by all of the known binding sites, as well as any number of as-yet unknown sites. It consists of a tetramer of two types (two each) each of which comes in a wide variety of sub-types. It performs a very complex "calculation" based on the activity on all its binding sites, resulting in the actual extent the channel is open: its output. Thus, like the nerve cell itself, this molecule integrates a large input into a single scalar output (as far as we know).

One type of binding site responds to the polyamines putrescine, spermidine, and spermine (10 in Figure 1), a set of chemicals known for a while to have some influence on brain activity.28

In the experiments here,6 rats were "trained" by placing them in a cage with an electrified floor, on a small platform. When they stepped off, they got a shock. They were then dosed with one of the drugs (which interfere with the binding site mentioned above) or a "placebo", and put back in their cages. After a day, they were put back into the cage on the the small platform, and the "latency" before they stepped off onto the (previously electrified) floor was measured.

The results were that either drug administered right after the training interfered with their memory later, in that they stepped off the platform pretty quickly the next day. However, if they were administered a new dose of either drug, they remembered as well as the ones who got "placebos" all around. This is a pretty clear indication of state-dependent learning, and that the two drugs create pretty much the same state.

Memory and Emotional State

While the NMDA receptor is probably the best-known receptor involved in state-dependent learning, there are other receptors involved in memory, and there may be (probably are) many undiscovered binding sites for endogenous molecules that can modulate their activity. This, then, shows that all the necessary mechanisms are present in the body for memory, and everything depending on it, to be somewhat specific to emotional states.

Redefining Emotional State

Back in '97, Candace Pert published Molecules of emotion, the first part of which detailed her adventures with the scientific establishment (of which she was a part) while participating in the discoveries of opiate receptors and the body's natural opiates: endorphins, enkephalins, dynorphins, etc. (Since then she appears to have moved towards the woo-woo area, perhaps because of the money available, or perhaps due to disagreements with part of the more hidebound medical establishment. However, a search of Google Scholar yields 19 scholarly papers published since 1998 (out of 28 total references the extras being books and references in other papers).)

In this book she outlines an interesting hypothesis: that since emotions are, at the least, accompanied by hormones that act on the same receptors that these drugs do, perhaps we can put a scientific basis under the idea that its easier to remember things when you're in the same emotional state as when they happened.

I recently discussed the idea of redefining "emotional state" as the total hormonal state of the body: an n-dimensional vector where n is the total number of hormones available and the relative concentration of each hormone represents its contribution to the vector.

Let's see how these two ideas interact: If the emotional state consists of all the hormones in the body, it must involve all the receptors those hormones interact with. Such interaction is probably not one-to-one, although that assumption seems to be built into much current research (IMO).

Of course, this doesn't mean that every possible emotional state has its own memories. In the first place, there are probably only a limited number of binding sites on a limited number of receptors that are involved in this process. However, that doesn't mean that any hormone without such a binding site can't affect memory. The body contains a number of cells that both secrete hormones and express receptors (for the same or other hormones) on their surfaces. As yet, we know very little about how the body computes its emotional state, although we know that there's a good deal of hard (number crunching) calculation by the more traditional central nervous system (CNS), especially the limbic system, and the autonomic nervous system, as well as secretion by cells of many types. Nerve cells do a great deal of secretion, and express a great number of receptors, any or all of which may influence both what/when they secrete hormones and how they perform the calculations more traditionally associated with the nerve cell.

Exploring Emotion-Space

If we consider the n-dimensional space defined by the "emotion vector", we could presumably map out the various areas where memory pretty much crosses over, and those areas where small changes to the internal state tend to create large "fades" in memory. Those wouldn't necessarily correlate with the effects of drugs, which are sort of "random scatter-shot" influences on what evolved as a fairly consistent system. But it seems likely that different natural emotional states will tend to have their own associated memories.

The observed effects of drugs, then, would modify the emotional state, that is the location in (n-dimensional) emotion space, often in unnatural ways, since they could well have effects on receptors in combinations never seen naturally.

If we assume that much of what we consider our personalities consists of memories at the level of the aversion the rats in the featured experiments were trained in, then it makes sense that much of our personality is itself dependent on our emotional state, and that we truly are, in some sense, "different people" when in a different mood or other emotional state.

Indeed, it seems reasonable that many cases of "multiple personality" are nothing but extreme cases of this effect, perhaps involving hormones that lack a strong effect on the more traditional types of "emotion".

It also brings up an interesting possibility regarding drug use: if a person has lots of "aversive" childhood memories, and the use of any drug with "state-dependent learning" effects makes those memories fade, you would expect that any new drug would automatically be pleasurable by contrast with normal life. Perhaps for many people it's not just the actual "mind-altering" effect of the drug that makes it so attractive, but the fact that they are more "distant" from unpleasant memories and associations.

This is important research, with many implications. It reaches into the fundamentals of how our brains create and maintain our personalities and consciousness.

Links (I've mentioned any where I've linked to the abstract, because there's a paywall, and in one case because the full PDF is in Iran and may not always be available everywhere. Not all links are necessarily referenced in the text. Use the back key if you came via clicking a footnote.) (I've included only the links referenced in this leader.)

1. Opiate States of Memory: Receptor Mechanisms

2. The influence of central administration of dopaminergic and cholinergic agents on morphine-induced amnesia in morphine-sensitized mice

3. Amnesic trace locked into the benzodiazepine state of memory

4. The locus coeruleus–noradrenergic system: modulation of behavioral state and state-dependent cognitive processes

5. Nicotine does not produce state-dependent effects on learning in a Pavlovian appetitive goal-tracking task with rats

6. Arcaine and MK-801 make recall state-dependent in rats

7. The dopaminergic system plays a role in the effect of lithium on inhibitory avoidance memory in mice paywall

8. Possible involvement of mu-opioid receptors in effect of lithium on inhibitory avoidance response in mice paywall

9. Repeated administration of histamine improves memory retrieval of inhibitory avoidance by lithium in mice paywall

10. Effects of repeated yohimbine on the extinction and reinstatement of cocaine seeking paywall

11. Morphine-Induced Behavioral Sensitization Increased the mRNA Expression of NMDA Receptor Subunits in the Rat Amygdala paywall

12. Modulation of ethanol state-dependent learning by dorsal hippocampal NMDA receptors in mice paywall

13. Intra-dorsal hippocampal microinjections of lithium and scopolamine induce a cross state-dependent learning in mice abstract. Full text (free) supposedly here, in Iran.

14. Implicit motivational states influence memory: Evidence for motive by state-dependent learning in personality paywall

15. Combining Exposure and Pharmacotherapy in the Treatment of Social Anxiety Disorder: A Preliminary Study of State Dependent Learning paywall

16. Ethanol state-dependent memory: involvement of dorsal hippocampal muscarinic and nicotinic receptors paywall

17. Relapse following combined treatment discontinuation in a placebo-controlled trial for panic disorder paywall

18. Memory and psychostimulants: modulation of Pavlovian fear conditioning by amphetamine in C57BL/6 mice

19. Revealing Past Memories: Proactive Interference and Ketamine-Induced Memory Deficits

20. Role of dopamine D3 receptors in the expression of conditioned fear in rats

21. Motor-skill learning in a novel running-wheel task is dependent on D1 dopamine receptors in the striatum

22. β2 Subunit Containing Acetylcholine Receptors Mediate Nicotine Withdrawal Deficits in the Acquisition of Contextual Fear Conditioning

23. Neurobiology of Memory and Anxiety: From Genes to Behavior

24. Clinical Pharmacology of Memory

25. Pathological Changes in Memory Processing

26. Plasticity and Anxiety

27. Putrescine, Spermidine, and Spermine

28. Selective Release of Sperrnine and Spermidine from the Rat Striatum by N-Methyl-D-Aspartate Receptor Activation In Vivo

29. From the Search for a Molecular Code of Memory to the Role of Neurotransmitters: A Historical Perspective


  1. Hi AK,

    Interesting stuff. I surfed in on a fortuitous recommendation from Al Fin's place and will definitely be doing some exploring of your previous posts, as you are posting in an area of science which has developed growing interest/relevance for me.

    With respect to this post, might I suggest a broader, or at least differently emphasized, definition/paradigm of emotion? I've put up an introductory post or three on the subject which might interest you, and I will be working to expand and expound as time permits this summer.

    Glad to have found your blog.


  2. Thanks, Piercello. I'll be reading the posts on your blog over the next few days. I will point out that I'm looking at the functional "technology" behind emotions here, like any network, the behavioral structure implemented by that technology can evolve, and the selective incentives and results may be thought of as being overlaid on the neuro-chemical basis in somewhat the same way as software is "overlaid" on computer hardware.

    What I'm proposing is that the evolving human body has, and had from the beginning, a chemical system that constitutes what we call "emotions". That system is tightly interlinked with computational systems (using neurons) that both react to the current state, and help drive the upcoming state, integrating chemical information with sensory and cognitive.

    I'm trying to keep separate the systems by which the "software" is implemented, and the "software" itself: the specifics of how classical "emotions" work in a socio-cultural sense. Hopefully, the overall system is modular enough that the subjects can be studied semi-independently.

    (Modularity is a subject that I intend to post on, but it's integrally combined with the subject of robustness, both subjects have multiple scholarly books (and O/L pubs) on the subject, and putting the whole thing in context for the non-specialist is a real challenge. I'm working on it, but don't hold your breath.)

  3. This comment has been removed by a blog administrator.

  4. This comment has been removed by a blog administrator.

  5. Thanks a lot!!!!
    So Gooood Page..….
    NIce post

  6. Excellent read, I just passed this onto a colleague who was doing a little research on that. And he actually bought me lunch because I found it for him smile So let me rephrase that: shuan t Thanks for lunch!

  7. Glad to hear it, alene12378.

  8. Hi,

    This is the perfect blog for anyone who wants to know about this topic. You know You definitely put a new spin on a subject. I will bookmark your blog and I am quite sure they will learn lots of new stuff here than anybody else!

  9. Site's character and a great color match .. memeestetigiI will recommend your site to the other platforms.Sacekimi