Delia L. Tio

The glossopharyngeal nerve as a novel pathway in immune-to-brain communication: relevance to neuroimmune surveillance of the oral cavity.

Glossopharyngeal afferents may be the neural channel by which immune challenge of the posterior oral cavity conveys information to the brain. If this is the case, then bilateral transection of the glossopharyngeal nerves (GLOx) should disrupt this communication. Injection of lipopolysaccharide (LPS) or interleukin (IL)-1beta into the soft palate (ISP) of sham-operated rats induced a dose-related febrile response. GLOx significantly attenuated the febrile response induced by ISP injection of both LPS and IL-1beta. In contrast, GLOx did not affect the febrile response when LPS or IL-1beta were injected intraperitoneally, indicating that the effect of GLOx is not systemic. These results provide experimental evidence for a novel neural pathway for immune-to-brain communication.

Heightening of the stress response during the first weeks after a mild traumatic brain injury.

The effects of a mild traumatic brain injury range from white matter disruption to affective disorders. We set out to determine the response to restraint-induced stress after a mild fluid-percussion injury (FPI), an experimental model for brain injury. Hypothalamic-pituitary-adrenal (HPA) axis regulation of corticosterone (CORT) and adrenocorticotropic hormone (ACTH) was determined during the first post-injury weeks, which corresponds to the same time period when rehabilitative exercise has been shown to be ineffective after a mild FPI. Adult male rats underwent either an FPI or sham injury. Additional rats were only exposed to anesthesia. HPA regulation was evaluated by measuring the effects of dexamethasone (DEX) treatment on CORT and ACTH. Tail vein blood was collected following 30-min restraint stress, at post-injury days (PID) 1, 7 and 14, prior to (0 min) and at 30, 60, 90 and 120 min after stress onset. Results from these studies indicate that the stress response was significantly more pronounced after FPI in that CORT and ACTH restraint-induced increases were more pronounced and longer lasting compared to controls. DEX suppression of CORT and ACTH was observed in all groups, suggesting that stress hyper-responsiveness after mild FPI is not attributable to reduced sensitivity of CORT feedback regulation. The increased sensitivity to stressful events in the first two post-injury weeks after a mild FPI may have a negative impact on early rehabilitative therapies.

Injury severity differentially affects short- and long-term neuroendocrine outcomes of traumatic brain injury.

Having reported that traumatic brain injury (TBI), produced by moderate lateral controlled cortical impact (CCI), causes long-term dysregulation of the neuroendocrine stress response, the aim of this study was to assess short- and long-term effects of both moderate and mild CCI on stress-induced hypothalamic-pituitary-adrenal (HPA) function. TBI was induced to the left parietal cortex in adult male rats with a pneumatic piston, at two different impact velocities and compression depths to produce either a moderate or mild CCI. Controls underwent sham surgery without injury. Commencing at one week after recovery from surgery, rats were exposed to stressors: 30-min restraint (days 7, 34, and 70) or 15-min forced swim (days 21 and 54). Tail vein blood was analyzed for corticosterone (CORT) content by radioimmunoassay. On days 7 and 21, the stress-induced HPA responses were significantly attenuated by both mild and moderate CCI. Significant attenuation of the CORT response to stress persisted through day 70 after moderate CCI. In contrast, stress-induced CORT levels on days 34, 54, and 70 were significantly enhanced after mild CCI. Differential effects of injury severity were also observed on motor function in a forelimb test on post-injury day 12 and on cortical lesion volume and hippocampal cell loss at day 70, but not on working memory in a radial maze on day 15. The differing short- and long-term stress-induced HPA responses may be mediated by differential effects of moderate and mild CCI on the efficiency of glucocorticoid negative feedback or signaling among hypothalamic and extrahypothalamic components of the neuroendocrine stress-response system.

Differential Effects of Voluntary and Forced Exercise on Stress Responses after Traumatic Brain Injury

Voluntary exercise increases levels of brain-derived neurotrophic factor (BDNF) after traumatic brain injury (TBI) when it occurs during a delayed time window. In contrast, acute post-TBI exercise does not increase BDNF. It is well known that increases in glucocorticoids suppress levels of BDNF. Moreover, recent work from our laboratory showed that there is a heightened stress response after fluid percussion injury (FPI). In order to determine if a heightened stress response is also observed with acute exercise, at post-injury days 0-4 and 7-11, corticosterone (CORT) and adrenocorticotropic hormone (ACTH) release were measured in rats running voluntarily or exposed to two daily 20-min periods of forced running wheel exercise. Forced, but not voluntary exercise, continuously elevated CORT. ACTH levels were initially elevated with forced exercise, but decreased by post-injury day 7 in the control, but not the FPI animals. As previously reported, voluntary exercise did not increase BDNF in the FPI group as it did in the control animals. Forced exercise did not increase levels of BDNF in any group. It did, however, decrease hippocampal glucocorticoid receptors in the control group. The results suggest that exercise regimens with strong stress responses may not be beneficial during the early post-injury period.

Alcohol consumption in traumatic brain injury: attenuation of TBI-induced hyperthermia and neurocognitive deficits.

Clinical and animal studies indicate that hyperthermia during or after traumatic brain injury (TBI) is associated with poor outcome. Alcohol intoxication, a complicating risk factor in many cases of head injury, has been found to both worsen or attenuate posttraumatic neural damage and outcome. The purpose of the present study was to determine whether chronic ethanol consumption would affect TBI-induced hyperthermia and deficits in spatial learning. TBI was produced by cortical contusion injury in adult male rats. We first characterized the TBI-induced febrile response using probes implanted intraperitoneally (ip) or intracerebroventricularly for continuous biotelemetric recording of core body and brain temperatures and locomotor activity. In another experiment, rats, implanted with ip probes, were fed a liquid diet containing ethanol (5% w/v, 35% ethanol-derived calories); control rats were pair-fed the isocaloric liquid diet (P-P). At 14 days after commencement of diet feeding, TBI or sham surgery was performed, and the ethanol-fed rats were divided into two groups: half were transferred to the isocaloric diet (E-P) and the other half remained on the ethanol-containing diet (E-E). TBI produced a significant febrile response in all rats, that persisted for at least 6 days in the E-P and P-P groups but lasted for only 2 days in the E-E group. When tested at 3-4 weeks after TBI, E-E rats required significantly fewer trials than E-P rats to reach criterion in the Morris water maze. In sum, continuous consumption of ethanol before and after TBI attenuated TBI-induced hyperthermia and deficits in spatial learning. Whereas the results suggest that this ethanol regimen may be neuroprotective, a causal relationship between the two outcomes remains to be determined.

Recovery of Stress Response Coincides with Responsiveness to Voluntary Exercise after Traumatic Brain Injury

We have recently shown that there is a heightened stress response after a mild traumatic brain injury (TBI) during the first 2 post-injury weeks. This corresponds to the same post-injury period when exercise does not increase brain-derived neurotrophic factor (BDNF) and autonomic dysfunction becomes evident with exercise. Here we determined stress and autonomic responses to voluntary and forced exercise at a post-injury time window when exercise has been found to elicit beneficial effects. Rats underwent a mild fluid percussion injury and were exercised at post-injury days 28-32 and 35-39. Cardiac and temperature autonomic function were evaluated. Hippocampal tissue was obtained immediately after exercise for analysis of BDNF. In contrast to the sub-acute period, corticosterone and adrenocorticotropic hormone responses to exercise were normalized in the TBI group. Irrespective of injury, forced exercise markedly stimulated the corticotrophic axis and did not increase BDNF. BDNF levels were increased with voluntary exercise in all animals. Rats exposed to forced exercise had lower activity levels during periods of non-exercise. This effect was more pronounced in the TBI rats. Cardiac and temperature autonomic responses to delayed exercise also recuperated. Rats with TBI that underwent forced exercise, however, had higher core body temperatures during experimental manipulations, thus suggesting that exposure to a potent stressor facilitates responsiveness to environmental stimulations.

The febrile response to intraperitoneal lipopolysaccharide: strain and gender differences in rats

The acute-phase febrile responses of the inbred Lewis (LEW) and Fischer 344 (F344) rat strains and their parent Sprague-Dawley (S-D) strain to immune challenge with lipopolysaccharide (LPS) were compared. LEW and S-D males and females displayed a biphasic febrile response with a markedly attenuated second phase in F344 rats. At 2 h after LPS (50 microg/kg), corticosterone was significantly higher in F344 than in LEW rats, but serum interleukin-1beta was higher only in F344 than LEW males. These data suggest that the greater LPS-induced corticosterone response of F344 rats mediates differences between febrile responses of F344 and LEW males and females.

Effects of Prenatal Alcohol and Pair Feeding on Lipopolysaccharide-Induced Secretion of TNF-α and Corticosterone

Fetal alcohol exposure (FAE) produces profound alterations in immunological and neuroendocrine functions. The present study examined the effects of FAE on the secretion of tumor necrosis factor (TNF-alpha) and corticosterone following administration of lipopolysaccharide (LPS) in normal (N) adult rats, in adult offspring of dams fed a liquid diet supplemented with ethanol (E), and in pair-fed control offspring (P). LPS-induced TNF-alpha secretion was not affected by either gender or prenatal treatment. In contrast, LPS-induced corticosterone secretion was significantly greater in female than in male rats, and at 60-min post-LPS was significantly higher in E and P, compared to N females. Ovariectomy significantly inhibited LPS-induced TNF-alpha secretion in E, but not in P and N, rats and chronic replacement with 17-beta-estradiol markedly inhibited TNF-alpha secretion in ovariectomized E and N, but not in P, rats. In contrast, ovariectomy reduced the effects of LPS on corticosterone secretion in all groups, and chronic replacement with 17-beta-estradiol reversed this effect. These findings indicate that LPS-induced secretion of corticosterone, but not TNF-alpha, is affected by prenatal manipulations and by gender. In addition, alterations in the hormonal environment in females modulate LPS-induced corticosterone secretion in all prenatal treatment groups, but differentially influence TNF-alpha secretion in rats exposed to alcohol, restricted feeding, or normal diets in utero.

Fetal alcohol exposure attenuates interleukin-1β-induced fever: neuroimmune mechanisms

Central mechanisms for the attenuating effects of fetal alcohol exposure (FAE) on interleukin-1beta (IL-1beta)-induced fever were studied in adult male offspring of dams fed a liquid diet supplemented with ethanol (E), in pair-fed (P) control and in normal (N) offspring. Hypothalamic levels of IL-1 were significantly lower in E than in N rats at 2 h, but not at 4 and 6 h, after intraperitoneal administration of lipopolysaccharide. Fever induced by intracerebroventricular (i.c.v.) IL-1 was significantly lower in E than in N and P rats. In contrast, E rats showed a normal febrile response to i.c.v. prostaglandin-E2. Thus, whereas FAE does not affect central thermoregulatory mechanisms, per se, FAE alters the kinetics of hypothalamic IL-1 production/appearance and decreases the responsiveness of central mechanisms which mediate the febrile response to IL-1.

Injury severity differentially alters sensitivity to dexamethasone after traumatic brain injury.

We have reported differential short- and long-term dysregulation of the neuroendocrine stress response after traumatic brain injury (TBI) produced by controlled cortical impact (CCI). We have now investigated three possible mechanisms for this TBI-induced dysregulation: (1) effects on the sensitivity of negative-feedback systems to glucocorticoids; (2) effects on the sensitivity of pituitary corticotrophs to corticotropin-releasing hormone (CRH); and (3) effects on neuronal loss in the hilar region of the dentate gyrus and in the CA3b layer of the dorsal hippocampus. TBI was induced to the left parietal cortex in adult male rats with a pneumatic piston, at two different impact velocities and compression depths, to produce either moderate or mild CCI. At 7 and 35 days after surgery, the rats were injected SC with the synthetic glucocorticoid analog dexamethasone (DEX; 0.01, 0.10, or 1.00 mg/kg) or saline, and 2 h later were subjected to 30 min of restraint stress and tail vein blood collection. Whereas all doses of DEX suppressed corticosterone (CORT) and adrenocorticotropic hormone (ACTH) responses to stress on both days, CORT and ACTH were significantly more suppressed after 0.01 mg/kg DEX in the moderate TBI group than in the mild TBI or sham groups. At both 7 and 35 days post-TBI, CRH (1.0 and 10.0 microg/kg IP) stimulated CORT and ACTH in all rats, regardless of injury condition. Hippocampal cell loss was greatest at 48 days after moderate TBI. Enhanced sensitivity to glucocorticoid negative feedback and greater hippocampal cell loss, but not altered pituitary responses to CRH, contribute to the short- and long-term attenuation of the neuroendocrine stress response following moderate TBI. The role of TBI-induced alterations in glucocorticoid receptors in limbic system sites in enhanced glucocorticoid feedback sensitivity requires further investigation.