Microgravity (MG) is one of the main problems that astronauts have to cope with during space missions. Long-duration space travel can have detrimental effects on human neurophysiology. Despite scientific efforts, these effects are still insufficiently investigated. Animal earth-based analogs are used to investigate potential nervous system associated perturbations that might occur during prolonged space missions. Hindlimb unloading, Tail suspension and Pelvic suspension models are currently used in MG studies. Loss of homeostasis of certain biological pathways in the nervous system can lead to the functioning and expression of receptors/genes, and the release and functioning of neurotransmitters and neuronal membrane ion channels into specific brain regions. The potential impact of MG on molecular mechanisms linked to neurophysiology through animal earth-based analogs is reviewed. The effect of molecular signalling pathways on the decline of neuronal connectivity and cognitive and neuroplasticity function under MG simulated conditions will be studied. The role of biomarkers including neurotransmitters, genes or receptors will be highlighted in the healthy and MG-affected brain. MG-mediated neurodegenerative mechanisms linked to learning and memory impairment will be highlighted. This review depicts the current rodent models applied to simulate MG ground based approaches and investigates the MG induced changes in the nervous system. The neuropathological profile of the above animal MG ground-based models can be comparable to the effects of ageing, anxiety and other neurological disorders. The advantages and limitations of the existing approaches are discussed. MG induced neurophysiology outcomes can be extrapolated to study other clinical applications.