IEGs are surely not simple activity markers, but reflect "above threshold" significant stimulation e. g. a sensory stimulus like a taste or smell do not elicit IEG expression when familiar but do so when experienced for the first time. So the novelty adds the significance. It does not make sense to alter gene expression for every "normal" signal transmission, but only if something exceeds basal activities like coincidence of stimulation.

There was a recent review from Haruhiko Bito on this http://www.ncbi.nlm.nih.gov/pubmed/24795570 . c-fos and arc appear to mark neurons undergo LTP and should not be used to just reflect activities.

C-Fos is upregulated in response to intrinsic neuronal activity, so looking at its expression would provide you a landscape of what neurons fired recently. Arc is also an activity regulated gene, but our lab typically uses it to determine which neurons are "learning." Arc expression has implications for neurons losing synapses and is a good marker for plasticity occurring within the circuit. Hope this helps!

They may even not distinguish between activity and non-activity. They are very vague markers of 'activity' that work as such in some very specific cells. 

@ John Y Lin

Dear John Y Lin,

Thank you for your recommendation. It does include a very brief summary of regulatory mechanism of IEG, which originated from calcium influx caused by synaptic ativity and neural firing. But this does not really address my question which requires the dissociation of synaptic inputs and intrinsic neuronal acitivty (just thinking of spontaneously firing neurons). And yes I agree, IEG expressions can tell more than activation.

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@ Mike Holter

Dear Mike Holter,

Thank you for highlighting Arc as a marker of 'learning', which can be useful for dissecting neurons in associative learning paradigms.

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@Gabriele Scheler

Dear Gabriele Scheler,

You have many good points, thanks! The IEGs are not supposed to tell you where the activity comes from. But the neuron must know I think.

I also notice from the paper J Y Lin recommended, that C-fos, Arc actually do not work equally across all brain regions; they are somehow regulated in cell-type specific manner.

Besides, the cell's need for IEGs to expression might well varies from short-term stimultation (i.e. fear conditioning), to a long-lasting stimuli (i.e. chronic pain).

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@Adolfo Talpalar

Dear Adolfo Talpalar,

They are valuable and in some cases can be the very powerful tools.

Best wishes

There are not rigorous quantitative biophysical studies separating the contribution of early genes (e. g., c-fos and Arc) to the sub threshold (synaptic transmission) and supra threshold (single or complex action potentials) membrane potential depolarizations, which is the main caveat of that technique. However, I am pretty sure that the neuroscience community would be happy to have such characterization. I guess that one of the principal problems is the background activity correction, which has to be optimized to render higher SNR. 

I do not think anybody really knows what IEGs indicate exactly. Moreover, different IEGs probably indicate different things.Finally, IEG's can behave differently in differrent brain regions. http://www.ncbi.nlm.nih.gov/pubmed/23345235

I think Arc is the best characterized one as Mike Holter mentioned. This SfN poster actually characterized the expression of Arc in the barrel cortex to a AP to expression ratio.

http://www.abstractsonline.com/Plan/ViewAbstract.aspx?sKey=c58bafb0-83b9-43e9-8bda-4e49be3b7674&cKey=5e7d4c3f-0cef-48cc-a786-de6c0cc0a5e8&mKey=8d2a5bec-4825-4cd6-9439-b42bb151d1cf

good luck

IEGs are surely not simple activity markers, but reflect "above threshold" significant stimulation e. g. a sensory stimulus like a taste or smell do not elicit IEG expression when familiar but do so when experienced for the first time. So the novelty adds the significance. It does not make sense to alter gene expression for every "normal" signal transmission, but only if something exceeds basal activities like coincidence of stimulation.

Hi Hadley, thanks for your recommendation. It is interesting that they can detect baseline dVenus fluorescence but not Arc in reporter mouse line.

Hi all, from my past experience I know that also ZIF268 is a good marker especially for the amygdala and the base expression is higher than for instance c-fos in certain brain regions.

Hope this helps.

This is a nice question I would like to know the answer about. I might ask one. Does anyone know if c-fos can be expressed in GABA neurons? I can see c-fos expression in GABA neurons in my expts. But one reviewer says GABA neurons do not express c-fos. Also literature suggests yes. The reviewer really confuses me.

Dear Zhang, there are several studies showing Co localization of cfos and gad65 gfp positive neurons indicating an expression in Gaba neurons. Just Google it and you would receive an answer.

Hope this helps

Dear Stefano Gaburro, To be exact, is ZIF268 a good marker to show changes of amygdala neurons in fear learning or other emotional behavior?

Yes it is. Please look whittle et all Journal of neuroscience 2011

Thank you Stefano. You are right. I have GABA YFP mice, I saw co localization with c-fos. Just want to know why the journal reviewer said GABA neurons do not express c-fos. I rebuttaled it is a mistake. This is a nice forum.

Good luck with that

Thanks Stefano, it is great that  actually I find Whittle has several publications on Zif268.

Take a look at the following papers as they might help you to design experiments to answer some of your questions (certainly not all)...

Functional labeling of neurons and their projections using the synthetic activity–dependent promoter E-SARE-Nature Methods 10, 889–895 (2013) doi:10.1038/nmeth.2559

or 

Neural circuits. Labeling of active neural circuits in vivo with designed calcium integrators. Science. 2015 Feb 13;347(6223):755-60. doi: 10.1126/science.1260922.

http://www.jneurosci.org/content/30/41/13586.abstract

http://www.jneurosci.org/content/28/32/8074.abstract