Disruption of the transient receptor potential channel 5 (TRPC5), a brain-expressed cation channel, causes obesity, maladaptive behavior, and postpartum depression in humans and mice. TRPC5 acts on hypothalamic pro-opiomelanocortin (Pomc) and oxytocin neurons to regulate instinctive behaviors such as feeding, arousal, social interaction, and maternal care. In humans, deletion of *TRPC5* leads to obesity, anxiety, autism, and postpartum depression. Male and female mice harboring a human *TRPC5* mutation exhibit similar phenotypes. Deletion of *Trpc5* from oxytocin neurons in the hypothalamic paraventricular nucleus causes obesity and postpartum depressive behavior in females, while overexpression of *Trpc5* in these neurons reverses these phenotypes. These findings demonstrate that TRPC5 plays a crucial role in mediating innate behaviors essential for survival, including food seeking and maternal care.Disruption of the transient receptor potential channel 5 (TRPC5), a brain-expressed cation channel, causes obesity, maladaptive behavior, and postpartum depression in humans and mice. TRPC5 acts on hypothalamic pro-opiomelanocortin (Pomc) and oxytocin neurons to regulate instinctive behaviors such as feeding, arousal, social interaction, and maternal care. In humans, deletion of *TRPC5* leads to obesity, anxiety, autism, and postpartum depression. Male and female mice harboring a human *TRPC5* mutation exhibit similar phenotypes. Deletion of *Trpc5* from oxytocin neurons in the hypothalamic paraventricular nucleus causes obesity and postpartum depressive behavior in females, while overexpression of *Trpc5* in these neurons reverses these phenotypes. These findings demonstrate that TRPC5 plays a crucial role in mediating innate behaviors essential for survival, including food seeking and maternal care.