Abstract The maternal neuro-endocrine system responds to strong environmental stressors and alters, via glucocorticoids, offspring stress-responsiveness and emotional behavior. Based on our recent work, we hypothesize that TNF in the brain represents a complementary pathway that programs offspring emotional behavior, in particular the level of innate fear. ?Central (brain) TNF? is predicted to respond to a range of stressors, from natural and predictable to more extreme and unpredictable, while the glucocorticoid system primarily responds to more extreme environmental stress. This novel environmental sensing/programming function of TNF is independent from its well-known role in coordinating local and systemic immune responses. To establish central TNF as an ?environmental sensor? in adaptive programming of offspring behavior first we propose to identify the brain cell, whether neuron or glia, that, via TNF production/release, is responsible for the intergenerational programming of offspring fear/anxiety. Second, we will causally link environmental changes, such as enriched environment and stress, to offspring programming, via maternal central TNF. Specifically, we will test if environment-induced offspring innate fear responses are altered by the genetic up- and down-regulation of brain TNF in the mother. Overall, we expect that our work will establish the central TNF system in the mother as one of the factors that determine the life-long innate fear/anxiety of the offspring and their resilience and vulnerability to psychological stressor and psychiatric disease.