system
Given the following post, respond as if you're commenting on Reddit:
human
This seems appropriate for finals.  What, exactly, is mental fatigue?  Why does otherwise simple material become flimsy and difficult after hours of study?

Why is it so much more difficult to understand something after studying the subject for a while?  What, physiologically, is occurring?  Stunted synapses?  What fuel, if any, is being used?  My brain hurts...
gpt
Lots of reasons. 

Metabolite build up at synapses over time. (Though this is lack of sleep more than anything else, one molecule that builds up is adenosine which inhibits learning. Caffeiene is actually an adenosine receptor antagonist which helps overcome this.) 

Another answer is that learning is actually somewhat refractory. There is evidence that spacing learning out, even with something like breaks, helps increase learning. There may be some molecule that is used up and refreshed on this time scale. (I actually partially study this phenomena.) 

Another answer (as to why material gets harder and then you feel much better after sleeping) is that the memory hasn't had time to associate with other similar memories. This means that if you are learning facts which are interconnected, the earlier facts haven't had time (REM sleep) to connect in your cortex to related memories and become more comprehensible. Trying to add in new memories when older memories haven't been placed in a proper frame work makes the new memories even harder to figure out.

Another reason is interference. This is more common when studying several related subjects. Basically as you learn (without sleeping) new memories that are similar to your slightly less new memories (not stored safely in their own very distinct networks, because you didn't sleep) interfere with storage and make it harder to learn both sets of facts.

In summary, drink caffeine, take breaks, don't study two similar subjects, and get proper sleep/don't cram and studying will become easier. 

(I can provide citations if you'd like to know more, or think something isn't on the level.)