PTSD and appetite dysregulation: mTOR-dependent modulation of fear memory and satiety circuits

Post-traumatic stress disorder (PTSD) is a complex neuropsychiatric condition characterised by persistent fear-related memories, dysregulated stress responses, metabolic and appetite disturbances. The mechanistic target of rapamycin (mTOR) has emerged as a central hub linking these pathways involved in synaptic plasticity, memory consolidation, metabolic and satiety adaptation. This review explores the multifaceted role of mTOR in PTSD, highlighting its involvement in fear memory persistence, neurotransmission, neuroinflammation, and satiety. Dysregulated mTOR signalling has been linked to aberrant fear extinction, heightened synaptic plasticity, and altered brain metabolism, contributing to PTSD symptoms. mTOR's role in regulating protein synthesis, neuronal excitability, and glucose metabolism underscores its importance as a therapeutic target. Pharmacological modulation of mTOR, through inhibitors such as rapamycin, has shown promise in clinical and animal models for mitigating PTSD-like behaviours and promoting adaptive fear extinction and warrants further translation research for human trials. Additionally, PTSD is associated with widespread metabolic dysfunction, including insulin resistance, altered lipid metabolism, and dopaminergic dysregulation. Given mTOR's role in energy homeostasis, mTOR dysregulation may exacerbate metabolic disturbances observed in PTSD. Therefore, understanding the interplay between mTOR-driven neurobiological and metabolic pathways offers novel insights into prospective treatment strategies for PTSD. This review highlights the potential of mTOR as a key therapeutic target in PTSD, emphasising the need for further research to elucidate the precise molecular mechanisms governing its role in trauma-related disorders. Future studies exploring mTOR and Mitogen-activated protein kinase (MAPK) modulation could be used to restore metabolic balance, normalise appetite regulation, and improve cognitive resilience in individuals with PTSD.