Reduced avoidance coping in male, but not in female rats, after mild traumatic brain injury: Implications for depression.

Although there is evidence that traumatic brain injury (mTBI) induces emotional sequelae in rats, it is unclear whether the phenotype is reminiscent of major depressive disorder (MDD) or posttraumatic stress disorder (PTSD). Three behavioral protocols with oppositional indicators for MDD or PTSD were assessed: acoustic startle responses (ASRs), eyeblink conditioning, and instrumental escape/avoidance (E/A) learning. Female and male rats were exposed to lateral fluid percussion injury (LFPi) consistent with mild TBI (mTBI) or sham (SHAM) surgery. Experiment 1 suggested that the acquisition of the classically conditioned eyeblink responses was unaffected by mTBI infemale and male rats. In Experiment 2, male and female mTBI rats acquired instrumental escape responses similar to their SHAM counterparts. Avoidance expression of female mTBI rats did not differ appreciably from female SHAM rats. However, male mTBI rats expressed avoidance at a lower rate than male SHAM rats over training. Poor coping in male rats emerged with repeated exposure to stress, suggesting that depressive behaviors in mTBI develop over time and with continued demand from stress. Severely attenuated ASRs were evident in female and male mTBI rats compared to respective SHAM rats throughout testing across the two experiments. Overall, signs among the three bidirectional assessments during the subacute period after mTBI were more indicative of MDD-like, than PTSD-like sequelae.

Startle suppression after mild traumatic brain injury is associated with an increase in pro-inflammatory cytokines, reactive gliosis and neuronal loss in the caudal pontine reticular nucleus.

Mild traumatic brain injury (mTBI) can produce somatic symptoms such as headache, dizziness, fatigue, sleep disturbances and sensorimotor dysfunction. Sensorimotor function can be measured by tests such as the acoustic startle reflex (ASR), an evolutionarily conserved defensive response to a brief yet sharp acoustic stimulus. mTBI produces a long-lasting suppression of ASR in rodents and humans; however, the mechanism of this suppression is unknown. The present study examined whether inflammatory processes in the brainstem (particularly the caudal pontine reticular nucleus, PnC) could account for the suppression of ASR after mTBI, because the PnC is an essential nucleus of the ASR circuit. Furthermore, while inflammation after mTBI is commonly observed in brain regions proximal to the site of impact (cortex and hippocampus), the effects of mTBI in brainstem structures remains largely understudied. The present study demonstrated a suppression of ASR one day after injury and lasting at least three weeks after an mTBI, replicating previous findings. Within the PnC, transient elevations of IL-1ß and TNF-α mRNA were observed at one day after injury, while IL-1α mRNA exhibited a delayed increase at three weeks after injury. Reactive gliosis (via IBA-1-ir for microglia and GFAP-ir for astrocytes) were also observed in the PnC, at one day and seven days after injury, respectively. Finally, the number of giant neurons (the major functional cell population in the PnC) was decreased three weeks after injury. The results indicate that glial activation precedes neuronal loss in the PnC, and correlates with the behavioral suppression of the ASR. The results also raise implications for brainstem involvement in the development of post-traumatic symptoms.

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

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.

Long-lasting suppression of acoustic startle response after mild traumatic brain injury.

Acoustic startle response (ASR) is a defensive reflex that is largely ignored unless greatly exaggerated. ASR is suppressed after moderate and severe traumatic brain injury (TBI), but the effect of mild TBI (mTBI) on ASR has not been investigated. Because the neural circuitry for ASR resides in the pons in all mammals, ASR may be a good measure of brainstem function after mTBI. The present study assessed ASR in Sprague-Dawley rats after mTBI using lateral fluid percussion and compared these effects to those on spatial working memory. mTBI caused a profound, long-lasting suppression of ASR. Both probability of emitting a startle and startle amplitude were diminished. ASR suppression was observed as soon as 1 day after injury and remained suppressed for the duration of the study (21 days after injury). No indication of recovery was observed. mTBI also impaired spatial working memory. In contrast to the suppression of ASR, working memory impairment was transient; memory was impaired 1 and 7 days after injury, but recovered by 21 days. The long-lasting suppression of ASR suggests long-term dysfunction of brainstem neural circuits at a time when forebrain neural circuits responsible for spatial working memory have recovered. These results have important implications for return-to-activity decisions because recovery of cognitive impairments plays an important role in these decisions.

Damage of GABAergic neurons in the medial septum impairs spatial working memory and extinction of active avoidance: effects on proactive interference.

The medial septum and diagonal band (MSDB) are important in spatial learning and memory. On the basis of the excitotoxic damage of GABAergic MSDB neurons, we have recently suggested a role for these neurons in controlling proactive interference. Our study sought to test this hypothesis in different behavioral procedures using a new GABAergic immunotoxin. GABA-transporter-saporin (GAT1-SAP) was administered into the MSDB of male Sprague-Dawley rats. Following surgery, rats were trained in a reference memory water maze procedure for 5 days, followed by a working memory (delayed match to position) water maze procedure. Other rats were trained in a lever-press avoidance procedure after intraseptal GAT1-SAP or sham surgery. Intraseptal GAT1-SAP extensively damaged GABAergic neurons while sparing most cholinergic MSDB neurons. Rats treated with GAT1-SAP were not impaired in acquiring a spatial reference memory, learning the location of the escape platform as rapidly as sham rats. In contrast, GAT1-SAP rats were slower than sham rats to learn the platform location in a delayed match to position procedure, in which the platform location was changed every day. Moreover, GAT1-SAP rats returned to previous platform locations more often than sham rats. In the active avoidance procedure, intraseptal GAT1-SAP impaired extinction but not acquisition of the avoidance response. Using a different neurotoxin and behavioral procedures than previous studies, the results of this study paint a similar picture that GABAergic MSDB neurons are important for controlling proactive interference.