Brain and Serum Androsterone Is Elevated in Response to Stress in Rats with Mild Traumatic Brain Injury

Abstract

Exposure to lateral fluid percussion (LFP) injury consistent with mild traumatic brain injury (mTBI) persistently attenuates acoustic startle responses (ASRs) in rats. Here, we examined whether the experience of head trauma affects stress reactivity. Male Sprague-Dawley rats were matched for ASRs and randomly assigned to receive mTBI through LFP or experience a sham surgery (SHAM). ASRs were measured post injury days (PIDs) 1, 3, 7, 14, 21, and 28. To assess neurosteroids, rats received a single 2.0 mA, 0.5 s foot shock on PID 34 (S34), PID 35 (S35), on both days (2S), or the experimental context (CON). Levels of the neurosteroids pregnenolone (PREG), allopregnanolone (ALLO), and androsterone (ANDRO) were determined for the prefrontal cortex, hippocampus, and cerebellum. For 2S rats, repeated blood samples were obtained at 15, 30, and 60 min post-stressor for determination of corticosterone (CORT) levels after stress or context on PID 34. Similar to earlier work, ASRs were severely attenuated in mTBI rats without remission for 28 days after injury. No differences were observed between mTBI and SHAM rats in basal CORT, peak CORT levels or its recovery. In serum and brain, ANDRO levels were the most stress-sensitive. Stress-induced ANDRO elevations were greater than those in mTBI rats. As a positive allosteric modulator of gamma-aminobutyric acid (GABAA) receptors, increased brain ANDRO levels are expected to be anxiolytic. The impact of brain ANDRO elevations in the aftermath of mTBI on coping warrants further elaboration.

Anhedonia following mild traumatic brain injury in rats: A behavioral economic analysis of positive and negative reinforcement

“…32,33,[51][52][53][54] Suppression of ASR was also observed after mTBI, as reported previously. [32][33][34]55 With regard to the main focus of this study, mTBI reduced the hedonic value of avoiding foot shock. In contrast, mTBI did not alter the hedonic value or the motivation to escape foot shock, as neither Q0 nor  were significantly different between sham and mTBI groups.…”

“…All rats were assessed for acoustic startle reflex (ASR) because we previously found suppression of ASR to be a consistent outcome of mTBI following lateral fluid percussion injury. [32][33][34] Assessment of ASR was performed as previously described. 32 ASR was assessed in individual, sound-attenuated chambers, each equipped with an exhaust fan, one speaker to maintain background noise (68dB) and another speaker for delivery of the acoustic stimuli (86, 96, and 102dB; 100 ms).…”

“…We have previously reported a long-lasting suppression of ASR following mTBI after lateral fluid percussion injury. [32][33][34] In the present study, we used ASR suppression as an additional measure of injury. ASR sensitivity and magnitude were evaluated up to 14 days following injury (Figure 1).…”

Metabolomics-Guided Hypothesis Generation for Mechanisms of Intestinal Protection by Live Biotherapeutic Products

“…Aldosterone regulates water and salt retention in the kidney [ 38 ], which is upregulated with the increased production of reactive oxygen species and inflammation [ 39 ]. Similarly, androsterone is one of the downstream metabolites of testosterone, which is shown to be elevated under stress, such as brain injury [ 40 ]. The other three major stress hormones, cortisone [ 41 ], corticosterone [ 42 ], and adrenaline [ 43 ], are well-known to increase blood flow and muscle contraction towards the brain, indicating an amplified and accelerated communication between intestine and brain [ 44 ].…”

Albeit nocturnal, rats subjected to traumatic brain injury do not differ in neurobehavioral performance whether tested during the day or night

“…Moreover, forced, but not voluntary, exercise continuously elevated nocturnal CORT levels in both fluid percussion injured and sham control rats during the first week after injury [27]. Additionally, recent studies suggest that TBI has no effect on basal or foot shock induced CORT levels 34 days after injury [28], thus suggesting a differential CORT stress response conditional on the nature and time of day of the stimulus. Lastly, the decrease in CORT at 21 days may be due to handling over the two weeks of behavioral manipulations [29].…”