Neural Circuitry of Stress, Fear, and Anxiety: Focus on Extended Amygdala Corticotropin-Releasing Factor Systems

The extended amygdala (EA) contains subpopulations of “extrahypothalamic” corticotropin-releasing factor (CRF) neurons located in the bed nucleus of the stria terminalis and central nucleus of the amygdala. Based on anatomical, cytoarchitectural, neurochemical, electrophysiological, and hodological characteristics, several heterogeneous subpopulations of EA CRF emerge that impact their functional neural circuitry. EA CRF neurons, through widespread connections with serotonergic, dopaminergic, and noradrenergic brainstem nuclei, modulate behavioral responses to emotionally salient stimuli, arousal, and aspects of addiction. Interconnections between EA CRF neurons and central autonomic control regions regulate cardiovascular function, nociception, ingestion, and gastrointestinal function. The bed nucleus of the stria terminalis CRF neurons are critically positioned to filter limbic inputs, including other EA CRF subpopulations, to modulate various aspects of the hypothalamic–pituitary–adrenal axis. Advances in optogenetics, pharmacogenetics, and single-cell profiling in combination with transgenic rodents will allow researchers to unravel the contribution of these heterogeneous EA CRF neurons in stress-related processes.