Limbic Crhr1 mediates anxiety-related behaviour and is required for hormonal adaptation to stress

Corticotropin-releasing hormone (CRH) plays a key role in coordinating the responses to a variety of stress-associated stimuli. Recent clinical data implicate CRH in the pathophysiology of human affective disorders. To dissect CRH/Crhr1 central nervous system pathways modulating behaviour from those regulating neuroendocrine function, we generated a conditional knockout mouse line (Crhr1 ^loxP/loxP CaMKIIαCre) in which Crhr1 function is inactivated postnatally in anterior forebrain and limbic brain structures while sparing pituitary expression sites, so as to leave hypothalamic-pituitary-adrenocortical (HPA) system regulation intact. Crhr1 ^loxP/loxP CaMKIIαCre mutants display reduced anxiety while basal activity of the HPA system is normal. In contrast to Crhr1 null mutants, conditional mutants are hypersensitive to stress: ACTH and corticosterone levels remain significantly elevated post-stress. Our data clearly show that limbic Crhr1 is modulating anxiety-related behaviour, and that this effect is independent of HPA system function. Furthermore, we provide evidence for a novel role of limbic Crhr1 in neuroendocrine adaptation to stress.