The F in memory

"Figure 2. Ephs and ephrins mediate molecular events that may be involved in memory formation. Evidence shows that memory formation involves alterations of presynaptic neurotransmitter release, activation of glutamate receptors, and neuronal morphogenesis. Eph receptors regulate synaptic transmission by regulating synaptic release, glutamate reuptake from the synapse (via astrocytes), and glutamate receptor conductance and trafficking. Ephs and ephrins also regulate neuronal morphogenesis of axons and dendritic spines through controlling the actin cytoskeleton structure and dynamics" (Dines & Lamprecht, 2015, p. 3).
“Figure 2. Ephs and ephrins mediate molecular events that may be involved in memory formation. Evidence shows that memory formation involves alterations of presynaptic neurotransmitter release, activation of glutamate receptors, and neuronal morphogenesis. Eph receptors regulate synaptic transmission by regulating synaptic release, glutamate reuptake from the synapse (via astrocytes), and glutamate receptor conductance and trafficking. Ephs and ephrins also regulate neuronal morphogenesis of axons and dendritic spines through controlling the actin cytoskeleton structure and dynamics” (Dines & Lamprecht, 2015, p. 3).

When thinking about long-term memory formation, most people immediately picture glutamate synapses. Dines & Lamprecht (2015) review the role of a family of little known players, but with big roles in learning and long-term memory consolidation: the ephs and the ephrines.

Ephs (the name comes from erythropoietin-producing human hepatocellular, the cancer line from which the first member was isolated) are transmembranal tyrosine kinase receptors. Ephrines (Eph receptor interacting protein) bind to them. Ephrines are also membrane-bound proteins, which means that in order for the aforementioned binding to happen, cells must touch each other, or at least be in a very very cozy vicinity. They are expressed in many regions of the brain like hippocampus, amygdala, or cortex.

The authors show that “interruption of Ephs/ephrins mediated functions is sufficient for disruption of memory formation” (p. 7) by reviewing a great deal of genetic, pharmacologic, and electrophysiological studies employing a variety of behavioral tasks, from spatial memory to fear conditioning. The final sections of the review focus on the involvement of ephs/ephrins in Alzheimer’s and anxiety disorders, suggesting that drugs that reverse the impairment on eph/ephrin signaling in these brain diseases may lead to an eventual cure.

Reference: Dines M & Lamprecht R (8 Oct 2015, Epub 13 Sept 2015). The Role of Ephs and Ephrins in Memory Formation. International Journal of Neuropsychopharmacology, 1-14. doi:10.1093/ijnp/pyv106. Article | FREE FULLTEXT PDF

By Neuronicus, 26 October 2015

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Stressed out? Blame your amygdalae

amygdala
Clipart: Royalty free from http://www.cliparthut.com. Text: Neuronicus.

Sooner or later, everyone is exposed to high amounts of stress, whether it is in the form losing someone dear, financial insecurity, or health problems and so on. Most of us manage to bounce right up and continue with our lives, but there is a considerable segment of the population who do not and develop all sorts of problems, from autoimmune disorders to severe depression and anxiety. What makes those people more susceptible to stress? And, more importantly, can we do something about it (yeah, besides making the world a less stressful place)?

Swartz et al. (2015) scanned the brain of 753 healthy young adults (18-22 yrs) while performing a widely used paradigm that elicits amygdalar activation (brain structure, see pic): the subjects had to match a face appearing in the upper part of the screen with one of the faces in the lower part of the screen. The faces looked fearful, angry, surprised, or neutral and amygdalae are robustly activated when matching the fearful face. Then the authors had the participants fill out questionnaires regarding their life events and perceived stress level every 3 months over a period of 2 years (they say 4 years everywhere else in the paper minus Methods & Results, which are the sections that count if one wants to replicate; maybe this is only half of the study and they intend to follow-up to 4 years?).

The higher your baseline amygdalar activation, the higher the risk to develop anxiety disorders later on if expossed to life stressors. Yellow = amygdala. Photo credit: https://www.youtube.com/watch?v=JD44PbAOTy8, presumably copyrighted to Duke University.
The higher your baseline amygdalar activation, the higher the risk to develop anxiety disorders later on if expossed to life stressors. Yellow = amygdala. Photo credit: https://www.youtube.com/watch?v=JD44PbAOTy8, presumably copyrighted to Duke University.

The finding of the study is this: baseline amygdalar activation can predict who will develop anxiety later on. In other words, if your natural, healthy, non-stressed self has a an overactive amygdala, you will develop some anxiety disorder later on if exposed to stressors (and who isn’t?). The good news is that knowing this, the owner of the super-sensitive amygdalae, even if s/he may not be able to protect her/himself from stressors, at least can engage in some preventative therapy or counseling to be better equipped with adaptive coping mechanisms when the bad things come. Probably we could all benefit from being “better equipped with adaptive coping mechanisms”, feisty amygdalae or not. Oh, well…

Reference: Swartz, J.R., Knodt, A.R., Radtke, S.R., & Hariri, A.R. (2015). A neural biomarker of psychological vulnerability to future life stress. Neuron, 85, 505-511. doi: 10.1016/j.neuron.2014.12.055. Article | PDF | Video

By Neuronicus, 12 October 2015

I can watch you learning

Human Stereotaxic System. Photo credit: The Mind Project
Human Stereotaxic System. Photo credit: The Mind Project

Recording directly form the healthy living human brain has always been a coveted goal of many neuroscientists, thus bypassing the limitations of non-invasive techniques or animal work. But, understandably, nobody would seek or grant approval for inserting an electrode in the healthy living human brain, on moral and ethical grounds. The next best thing is to insert an electrode into the not so healthy living human brain.

Ison, Quiroga, & Fried (2015) got lucky and gained access to 14 patients with intractable epilepsy that had electrodes implanted in their brain to find where the seizure focus is (for possible surgical resection later on). Using these electrodes, they recorded the activity of single neurons within the medial temporal lobe (MTL, a brain area paramount for learning) while the patients performed some simple association tasks. First, they presented images of places, people, and animals to the patients to see “which (if any) of the recorded neurons responded to a picture” (p. 220). When they got a neuron responding to something, they rushed out, did some data and image processing, and after an hour they started the experiment. Which was showing the patient the picture to which the neuron responded to (e.g. Stimulus 1 = patient’s daughter) overimposed on a background that the neuron did not respond to (e.g. Stimulus 2 = the Eiffel tower). After one single trial (although there was some variability), the patients learned the associations (i.e. Stimulus 3 = daughter in front of Eiffel tower) and this learning was mirrored by how the neuron responded. Namely, the neuron increased its activity by 200% to 400% (counted in spikes per second) when shown the previously un-responded to image alone (i.e. Stimulus 2).

Excerpt from Fig. 5 from Ison, Quiroga, & Fried (2015).
Excerpt from Fig. 5 from Ison, Quiroga, & Fried (2015). “Average normalized neural activity (black squares) and behavioral responses (green circles) to the non-preferred stimulus as a function of trial number. Data were aligned to the learning time (relative trial number 0)”, i.e. when they showed the composite image between Stimulus 1 and Stimulus 2. “Note that the neural activity follows the sudden increase in behavioral learning”.

The authors recorded from over 600 neurons from various MTL regions, out of which 51 responded to a Stimulus 1. From these, only half learned, that is, they increased their activity when Stimulus 2 was shown. For the picky specialist, the cells were both Type 1 and Type 2 neurons, located 6 in the hippocampus, 4 in the entorhinal cortex, 11 in the parahippocampal cortex, and 1 in the amygdala. And the authors controlled for familiarity, attentional demands, and other extraneous variables (with some very fancy and hard to follow stats, I might add).

The paper settles an old psychology dispute. Do we learn an association gradually or at once? In other words, do we learn gradually that A and B occur together, or do we learn that the first time we are shown A and B together and the next trials serve just to refine and consolidate the new knowledge? Ison, Quiroga, & Fried (2015) data show that learning happens at once, in an all-or-none fashion.

Reference: Ison, M. J., Quian Quiroga, R., & Fried, I. (1 July 2015). Rapid Encoding of New Memories by Individual Neurons in the Human Brain. Neuron, 87(1): 220-30. doi: 10.1016/j.neuron.2015.06.016. Article | FREE PDF

By Neuronicus, 4 October 2015