Hypothermia is potently neuroprotective, but the molecular basis of this effect remains obscure and the practical challenges of cooling have restricted its clinical use. This thesis was borne on the premise that considerable therapeutic potential may lie in a deeper understanding of the neuronal physiology of cooling. Rodent studies indicate that hypothermia can elicit preconditioning wherein a subtoxic stress confers resistance to an otherwise lethal injury. This cooling-induced tolerance requires de novo protein synthesis – a fundamental arm of the cold-shock response, for which data in human neurons is lacking. Since cooling protects the human neonatal brain, experiments herein address the molecular effects of clinicallyrelevant cooling using functional, maturationally-comparable cortical neurons differentiated from human pluripotent stem cells (hCNs). Several core hypothermic phenomena are explored, with particular scrutiny of neuronal tau, since this protein is modified extensively in brains that are resistant to injury. Mild-to-moderate hypothermia produces an archetypal cold-shock response in hCNs and protects them from oxidative and excitotoxic stress. Principal features of human cortical tau development are recapitulated during hCN differentiation, and subsequently reversed by cooling, returning tau transcriptionally and post-translationally to an earlier foetallike state. These findings provide the first evidence of cold-stress-mediated ontogenic reversal in human neurons. Furthermore, neuroprotective hypothermia induces mild endoplasmic reticulum (ER) stress in hCNs, with subsequent activation of the unfolded protein response (UPR). Reciprocal modulation of both tau phosphorylation and the ER-UPR cascade suggests that cold-induced hyperphosphorylation of tau and ER-hormesis (preconditioning) represent significant components of hypothermic neuroprotection. Cooling thus modifies proteostatic pathways in a manner that supports neuronal viability. Historically, hypothermic preconditioning has been limited to the acute injury setting, and tau hyperphosphorylation is an established hallmark of chronic neural demise. More recently however, preconditioning has been proposed as a target for neurodegenerative disease and neuroprotective roles of phospho-tau have emerged. To date, hypothermia has protected hCNs against oxidative, excitotoxic and ER stress, all of which have been implicated in traumatic as well as degenerative processes. This ‘cross-tolerance’ effect places exponential value on the molecular neurobiology of cooling, with the potential to extract multiple therapeutic targets for an unmet need.