Role of corticosterone in altered neurobehavioral responses to acute stress in a model of compromised hypothalamic-pituitary-adrenal axis function.

An organism's capacity to cope with stressful experiences is dependent on its ability to appropriately engage central and peripheral systems, such as the hypothalamic-pituitary-adrenal (HPA) axis, to adapt to changing environmental demands. The HPA axis is a primary neuroendocrine mediator of neural and behavioral responses to stress, and dysfunction of this system is linked to increased risk for developing mental health disorders such as depression, anxiety, and post-traumatic stress disorder. However, the mechanisms by which dysregulated HPA function results in abnormal behavioral responses to stress are poorly understood. Here, we tested how corticosterone (CORT)-induced HPA axis disruption affects behavioral responses to stress in male C57BL/6 N mice, and probed correlates of these behaviors in the brain. We show that chronic HPA disruption blunts acute stress-induced grooming and rearing behaviors in the open field test, effects which were accompanied by decreased FOS immunoreactivity in the paraventricular nucleus of the hypothalamus (PVH) and paraventricular nucleus of the thalamus (PVT). Blockade of CORT secretion with metyrapone injection prior to acute stress did not recapitulate the effects of chronic HPA disruption on open field behavior, and acute CORT replacement did not rescue normal behavioral stress responses following chronic HPA disruption. This suggests that under acute conditions, CORT is not necessary for these responses normally, nor sufficient to rescue the deficits of chronic HPA dysregulation. Together, these findings support the hypothesis that chronic HPA dysregulation causes adaptation in stress-related brain circuits and demonstrate that these changes can influence an organism's behavioral response to stress exposure.

State-dependent changes in cortical gain control as measured by auditory evoked responses to varying intensity stimuli.

STUDY OBJECTIVES: Auditory evoked potential (AEP) components correspond to sequential activation of brain structures within the auditory pathway and reveal neural activity during sensory processing. To investigate state-dependent modulation of stimulus intensity response profiles within different brain structures, we assessed AEP components across both stimulus intensity and state. DESIGN: We implanted adult female Sprague-Dawley rats (N = 6) with electrodes to measure EEG, EKG, and EMG. Intermittent auditory stimuli (6-12 s) varying from 50 to 75 dBa were delivered over a 24-h period. Data were parsed into 2-s epochs and scored for wake/sleep state. RESULTS: All AEP components increased in amplitude with increased stimulus intensity during wake. During quiet sleep, however, only the early latency response (ELR) showed this relationship, while the middle latency response (MLR) increased at the highest 75 dBa intensity, and the late latency response (LLR) showed no significant change across the stimulus intensities tested. During rapid eye movement sleep (REM), both ELR and LLR increased, similar to wake, but MLR was severely attenuated. CONCLUSIONS: Stimulation intensity and the corresponding AEP response profile were dependent on both brain structure and sleep state. Lower brain structures maintained stimulus intensity and neural response relationships during sleep. This relationship was not observed in the cortex, implying state-dependent modification of stimulus intensity coding. Since AEP amplitude is not modulated by stimulus intensity during sleep, differences between paired 75/50 dBa stimuli could be used to determine state better than individual intensities.

Cortical evoked responses associated with arousal from sleep.

STUDY OBJECTIVE: To determine if low-level intermittent auditory stimuli have the potential to disrupt sleep during 24-h recordings, we assessed arousal occurrence to varying stimulus intensities. Additionally, if stimulus-generated evoked response potential (ERP) components provide a metric of underlying cortical state, then a particular ERP structure may precede an arousal. DESIGN: Physiological electrodes measuring EEG, EKG, and EMG were implanted into 5 adult female Sprague-Dawley rats. We delivered auditory stimuli of varying intensities (50-75 dBa sound pressure level SPL) at random intervals of 6-12 s over a 24-hour period. Recordings were divided into 2-s epochs and scored for sleep/wake state. Following each stimulus, we identified whether the animal stayed asleep or woke. We then sorted the stimuli depending on prior and post-stimulus state, and measured ERP components. RESULTS: Auditory stimuli did not produce a significant increase in the number of arousals compared to silent control periods. Overall, arousal from REM sleep occurred more often compared to quiet sleep. ERPs preceding an arousal had decreased mean area and shorter N1 latency. CONCLUSION: Low level auditory stimuli did not fragment animal sleep since we observed no significant change in arousal occurrence. Arousals that occurred within 4 s of a stimulus exhibited an ERP mean area and latency had features similar to ERPs generated during wake, indicating that the underlying cortical tissue state may contribute to physiological conditions required for arousal.