Stress History Modulates Corticotropin-Releasing Factor Neurons to Establish Resilience

Area of Science:

• Neuroscience
• Stress research
• Depression models

Background:

• Cumulative stress is a significant risk factor for major depressive disorder (MDD).
• However, not all individuals exposed to chronic stress develop MDD, and the mechanisms underlying resilience remain unclear.
• Understanding the emergence of stable resilience is crucial for developing targeted interventions.

Purpose of the Study:

• To investigate the critical period and neural mechanisms underlying the development of resilience to chronic stress.
• To identify specific neuroadaptive changes in the BNSTov that differentiate resilient from susceptible individuals.
• To elucidate the role of corticotropin-releasing factor (CRF) neurons in stress resilience.

Main Methods:

• Utilized a 10-day repeated social defeat stress (RSDS) model in male mice to mimic chronic stress.
• Employed cell-type selective electrophysiology, chemogenetics, optogenetics, and RNA quantification.
• Focused on neuroadaptation within the oval nucleus of the bed nucleus of the stria terminalis (BNSTov).

Main Results:

• A critical divergence point between resilient and susceptible mice occurred between 7 and 10 days of daily stress exposure.
• CRF-expressing neurons (CRF+) in the BNSTov showed sustained increased firing rates in resilient mice, but not susceptible mice, in response to stress.
• This neurophysiological adaptation was self-sustaining and dependent on prior stress history, emerging after 7 critical stress exposures.

Conclusions:

• Resilience to chronic stress involves a novel stress-provoked activation, rather than inhibition, of CRF+ neurons in the BNSTov.
• This activation establishes a neurobiological pathway that enables persistence in the face of adversity.
• The findings highlight a key limbic region and neuronal population critical for developing stress resilience.