We develop a system-level approach to modelling optogenetic-neurons firing behaviour in in-vivo conditions. This approach contains three sub-modules: 1) a Mie/Rayleigh scattering mode of light penetration in tissue; 2) a classic likelihood Poisson spiking train model; 3) a 4-state model of the Channelrhodopsin-2 (ChR2) channel added to a CA3 neuron Hodgkin-Huxley model. We first investigate opto-neurons lightto-spike mechanisms in an in-vivo model: the background noise (synaptic currents) play a dominant role in generating spikes rather than light intensities as for in-vitro conditions (Typically the required light intensity is less than 0.3 mW/mm2 for in-vivo). Then the spiking fidelity is analyzed for different background noise levels. Next, by combining light penetration profiles, we show how neuron firing rates decay as tissue distance increases, for a 2D dimensional cross-section. This preliminary data clearly demonstrate that at given light stimulation protocol, the maximum effected distance in-vivo is 250 μm with small frequency decay rates, while for in-vitro is 50μm with considerable frequency decay rates. Therefore, the developed model can be used for designing sensible light stimulation strategies in-vivo and opto-electronics systems.