This question assumes one has a layout. I don't. I have plans for a pike with a layout set in Pueblo Colorado.
Inspired by the V&O, I went the freelance route back in the 1970s with my Pine Ridge and North River. I came up with back stories, a made up geography requiring the railroad engineers to grade the track through the area. Made a layout design from that. I developed logos and paint schemes for locos and cars. Standard station and other track side structure designs, the whole 9 yards. Spent probably 10 years on it. What happened? I found myself making more and more concessions to either era, or geography, or occasionally even common sense. With each self justification for whatever it was I "wanted to do at the moment) the freelance became less and less V&O like and more and more like a little kids "train board" clown show.
So I switched to prototype. Couldn't decide which so I switched prototypes several times (CB&Q -> GN -> NP -> Hill Lines (there goes the slipery slope again) then finally back to my roots of AT&SF. Modeling in Pueblo prototypically also gives me the presence of D&RGW, C&S, C&W, Mopac, and Rock Island.
I've only made 1 concession that puts me into the "protolance" category. In my world, the 1880
"Treaty of Boston" went in more in favor of the Santa Fe and they got to keep the hanging bridge of the Royal Gorge that they built, but Rio Grande still has trackage rights. This way I can bring the transcon passenger trains through Pueblo.