Examining the relationship between blast-induced mild traumatic brain injury and posttraumatic stress-related traits.

Emerging evidence suggests that mild traumatic brain injury (mTBI) resulting from blast exposure may contribute to the occurrence of posttraumatic stress disorder (PTSD) and related affective sequelae, such as anxiety and depression. Many studies have used survey techniques to describe blast exposure leading to comorbid mTBI and related persistent postconcussive symptoms (PPCS) with PTSD in military populations. Despite this, there is a lack of literature that examines possible biological mechanisms by which blast exposure contributes to the development of PTSD sequelae. This Mini-Review addresses the current literature on potential neurophysiological changes that may contribute to PTSD-like traits as a result of a single or multiple exposures to blast events. Evidence from clinical blast-induced mTBI populations and animal models of blast-induced mTBI was evaluated with an emphasis on behavioral and physiological symptoms similar to those seen in PTSD populations and models. From the analysis, we propose potential mechanisms that merit further investigation for better understanding of how blast exposures may produce a higher rate of comorbid PPCS, PTSD, and affective phenomena. An improved understanding of PTSD-like outcomes resulting from blast exposure will ultimately help facilitate the development of future treatments and contribute to a better understanding of PTSD sequelae that develop from physical trauma.

Anterograde amnesia induced by hyperthermia in rats.

Anterograde amnesia (AA), forgetting of events that occur following a traumatic episode, has recently been demonstrated by using a mild decrease in temperature (hypothermia) as the amnestic agent. However, no data currently exist to indicate if an increase in body temperature (hyperthermia) might affect memory processing in a similar manner. Experiments 1 and 2 demonstrated that increasing the colonic body temperature of the rat to 3-4 degrees C or more above normal during avoidance training produced a significant retention loss when the test occurred 24 hr after training. Slight hyperthermia to 1-2 degrees C above normal did not impair retention. In Experiment 3, AA resulting from an elevation in temperature was reversed by reheating "amnestic" subjects just prior to the 24-hr test. By rapidly reversing hyperthermia immediately after the training trial with a cooling procedure, Experiment 4 demonstrated that hyperthermia-induced AA was not the result of retrograde influences of the heating treatment. Implications of these results are discussed in terms of possible retention deficits which could conceivably follow environmental heat stress or fever hyperthermia resulting from bacterial infection.

Administration of dexamethasone prior to training blocks ACTH-induced recovery of an extinguished avoidance response.

Pretest administration of ACTH has been shown to produce recovery of an extinguished avoidance response. Presumably this effect is found because endogenous ACTH is a component of the original training memory. However, another possible explanation of this finding is that administration of the peptide acts as a novel stimulus that "disinhibits" the extinguished response. In order to test this "disinhibitory" hypothesis of ACTH-induced recovery of an extinguished avoidance response, some subjects were given dexamethasone 2 hr prior to training and extinction. This synthetic glucocorticoid is effective in blocking endogenous release of ACTH. Thus, ACTH should not be a component of the training memory in subjects given dexamethasone prior to training and extinction but would be a relatively novel stimulus condition at testing. Pretest administration of ACTH was found to be effective in alleviating performance deficits induced by extinction only for subjects given saline prior to training and extinction. Administration of ACTH had no effect on the avoidance responding of subjects given dexamethasone. These findings suggest that pretest administration of ACTH affects retrieval processes rather than acts as a disinhibitor.

Tyrosine ameliorates a cold-induced delayed matching-to-sample performance decrement in rats.

Exposure to cold stress has been shown to impair short-term, or working, memory which may be related to a reduction in brain catecholamines. Administration of the catecholamine precursor tyrosine may alleviate a cold-stress-induced memory impairment by preventing a deficit in brain catecholamine levels. To test this hypothesis, eight rats performed a delayed matching-to-sample (DMTS) task at an ambient temperature of either 2 degrees C (cold) or 22 degrees C, following intraperitoneal administration of saline or tyrosine (50, 100 or 200 mg/kg). Rats administered saline prior to 22 degrees C exposure demonstrated a characteristic delay gradient in which accuracy decreased as the delay interval between sample and comparison stimuli increased from 1 to 16 s. Consistent with previous research, and relative to 22 degrees C exposure sessions, matching accuracy during 2 degrees C exposure sessions was reduced, which is attributed to the effect of cold on short-term, or working, memory. In particular, during cold exposure sessions matching accuracy was significantly reduced at the longer delay intervals, relative to matching accuracy at 22 degrees C. Additional analysis of cumulative matching errors within sessions showed that during exposure to cold, errors occurred at a constant rate throughout the session, indicating rats' performance was equally debilitated by the stressor over the entire session. During cold exposure sessions, the higher doses of 100 and 200 mg/kg tyrosine significantly improved overall matching accuracy relative to saline, but did not completely reverse the effect of cold exposure, as overall matching accuracy did not increase entirely to levels obtained at 22 degrees C.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic responses to cognitive activity in a cold environment.

Adrenergic responses during physical stress such as cold exposure have been reported to differ from those responses observed during cognitive activity. Both the separate and the combined effects of cold and cognitive activity on catecholamine activity were examined in six male subjects. Alterations in plasma epinephrine and norepinephrine showed different patterns as a function of exposure to a 4 degrees C cold environment, a cognitive performance assessment battery (PAB), and the two conditions combined. Plasma epinephrine was not altered by exposure to cold and only slightly increased by PAB performance when given at 23 degrees C. However, epinephrine was substantially elevated by exposure to combined cold and PAB. Heart rate changes paralleled observed changes in epinephrine. Norepinephrine release was predominantly increased by cold exposure and was not altered by PAB performance.

Acute cold stress leading to elevated corticosterone neither enhances synaptic efficacy nor impairs LTP in the dentate gyrus of freely moving rats.

Exposure to stress has previously been found to impair long-term potentiation (LTP) in the hippocampus. Exposure to stress has also been proposed to induce an LTP-like effect. We examined the effect of acute cold stress on synaptic transmission, neuronal excitability, and LTP induction in the medial perforant path-granule cell synapse of freely moving rats. After obtaining baseline recordings of evoked field potentials at room temperature (23 degrees C), rats were transferred to an environmental cage maintained at 4 degrees C (cold group) or 23 degrees C (control group) and, 90 min later, high-frequency stimulation (HFS) was applied to the medial perforant path. Serum corticosterone measured in trunk blood from rats without implanted electrodes was significantly elevated in cold exposed (28. 7 microg/dl) rats relative to control (6.6 microg/dl). Despite increased corticosterone levels indicative of stress activation, cold exposed rats exhibited LTP of the fEPSP slope and population spike of similar magnitude and time course as controls. In addition, there was no stress-specific effect on the fEPSP slope or population spike and no effect on paired-pulse plasticity. Surprisingly, despite extensive cage acclimation, transferring rats to the environmental cage was associated with a reduction in population spike amplitude and an enhancement in paired-pulse facilitation. The results show that acute cold stress leading to elevated serum corticosterone levels neither induces LTP-like increases in synaptic efficacy nor impairs tetanus-evoked LTP in the dentate gyrus of freely moving rats. Thus, impaired working memory during cold stress is not due to an inability of perforant path synapses to express LTP.

Tyrosine pretreatment alleviates suppression of schedule-controlled responding produced by corticotropin releasing factor (CRF) in rats.

Disruption of performance observed when animals are exposed to physical stressors which deplete brain catecholamines can be alleviated by pretreatment with the catecholamine precursor tyrosine. Central administration of the stress hormone corticotropin releasing factor (CRF) has been shown to affect a variety of behaviors and also to potently increase the release of central catecholamines. Since CRF-induced disruption of behavior may involve CRF-induced depletion of brain catecholamines, the present study examined whether tyrosine would alleviate suppression of schedule-controlled responding in rats resulting from ICV administration of CRF. Administration of CRF (1.0 microgram-10 micrograms) produced dose-dependent suppression of response rate and total number of earned reinforcers in rats responding on a multiple fixed-interval 60 s/fixed-ratio 20 schedule for food reinforcement. Pretreatment with 200 mg/kg tyrosine (IP) administered with ICV saline decreased response rate but did not lower total reinforcers, whereas 400 mg/kg of tyrosine decreased both. Injection of 400 mg/kg tyrosine reduced, but did not completely restore, CRF-induced suppression of behavior. The 200 mg/kg tyrosine dose was less effective in alleviating CRF-induced suppression of performance. These data indicate that pretreatment with the catecholamine precursor tyrosine can partially ameliorate performance decrements resulting from CRF administration.

Thermal stress modulates temporal patterns of responding on a multiple DRL-FR schedule.

To investigate temporal changes in behavior induced by moderate cold temperatures, rats performing on a multiple differential-reinforcement-of-low-rate (DRL) fixed-ratio (FR) schedule were exposed to ambient temperatures of 2, 8, 16, and 24 degrees C. DRL response rates markedly increased with decreasing cold temperatures, while FR response rates remained unchanged. In addition, as ambient temperatures decreased, the interresponse time (IRT) distribution of DRL responses shifted toward shorter times and short IRT bursts increased. Compared with cold effects, exposure to 38 degrees C heat induced decreases in both DRL and FR response rates which were associated with increases in long IRTs. Decreases in reinforcement frequency was associated only with the DRL schedule in cold, and with both DRL and FR schedules during heat exposures. The distinct effects of cold and heat on both DRL and FR responding suggest that the increases in DRL response rates and shifts in IRT distribution are unique to cold, and are not due to general effects of nonspecific thermal change in the ambient environment.

Hippocampal and body temperature changes in rats during delayed matching-to-sample performance in a cold environment.

In order to study the effects of temperature changes induced by cold stress on working memory, telemetry thermistor probes were implanted into the hippocampal region of the brain and into the peritoneal cavity of rats. Temperatures in these regions were monitored while rats performed on a delayed matching-to-sample (DMTS) task at ambient temperatures of 23 degrees C and 2 degrees C. Matching accuracy was significantly decreased during exposure to 2 degrees C, indicating a marked impairment of short-term or working memory. Temperature in the hippocampus increased 2 degrees C during exposure to 23 degrees C, but only 1 degrees C when the environmental temperature was 2 degrees C. Body temperature showed a similar but less pronounced pattern in that cold exposure attenuated the increase in temperature observed when animals performed the DMTS task. These results suggest that cold-induced impairment of working memory may be associated with subtle temperature changes in the brain.

The effects of preexposure to the drug on state dependent retention.

The present experiment examined whether previous experience with a drug would decrease the potential of the drug to produce state dependent retention (SDR) for a passive avoidance response in rats. In the first experiment, a single injection of sodium pentobarbital (20 mg/kg) given on six consecutive days before the training day slightly reduced, but did not block, pentobarbital-induced SDR. In Experiment Two, four preexposure injections of 5 IU/kg insulin reduced the magnitude of memory loss produced by administration of the hormone prior to training. As with pentobarbital, however, preexposure to insulin did not completely block the amnestic effect of the hormone. A subsequent experiment demonstrated that the decrease in the strength of insulin-induced SDR in insulin preexposed rats was not the result of enhanced acquisition. Collectively, these data indicate that noncontingent preexposure to an amnestic treatment may decrease the magnitude of memory loss that would normally result from the administration of that treatment during training.

Neuropeptide-Y both improves and impairs delayed matching-to-sample performance in rats.

Neuropeptide-Y (NPY) was administered intracerebroventricularly to rats performing on delayed matching-to-sample (DMTS) to determine if NPY modulates short-term (working) memory. Rats administered saline demonstrated a characteristic DMTS delay gradient in which accuracy decreased as the delay interval between sample and comparison stimuli increased from 2 to 8 to 16 seconds. At 8- and 16-second delays, low doses of NPY (0.25 and 0.5 nmol/kg) increased matching accuracy. As doses increased from 1 to 16 nmol/kg, accuracy decreased in a dose- and delay-dependent manner. NPY effects were specific to working memory, since NPY did not affect accuracy of responses to the sample stimulus (reference memory). At higher doses, a greater decline in accuracy occurred when the correct stimulus was on the opposite side from the response on the previous trial compared to accuracy when the previous response was on the same side. These data show NPY may both improve and impair accuracy on DMTS and that some portion of impairment is due to proactive interference resulting from previous trials.

Effects of repeated administration of corticotropin-releasing factor on schedule-controlled behavior in rats.

To examine the effects of repeated administration of corticotropin-releasing factor (CRF) on behavior, rats were administered ICV injections of either CRF or saline on alternate days for 10 days prior to performing on a multiple fixed-interval (FI) 60 s/fixed-ratio (FR) 20 schedule for food reinforcement. A daily session consisted of 10 components of each schedule that alternated, starting with the FI component. CRF doses were individually determined for each rat and were either 1.0, 3.0, or 10 micrograms CRF based upon the dose that occasioned more than a 50% reduction in the rate of responding. Acute administration of CRF decreased the rate of responding in both components well below control rates; this decrease in responding was associated with a 20 or 50% decrease in the number of earned reinforcements in the FI and FR components, respectively. With repeated administration, CRF-induced suppression of responding was attenuated, although CRF continued to decrease response rate. Despite the continued reduction in response rate, subsequent CRF injections did not result in a loss of reinforcements in the FI component, whereas rats continued to lose 20% of the reinforcers in the FR component. After an 18-day hiatus in which no CRF was administered, the baseline rate of responding on the multiple schedule increased, in particular in the FI component. When CRF was readministered, response rates were slightly suppressed relative to a reestablished saline control but significantly higher than CRF-induced suppression on the last day of the chronic regimen. These data demonstrate that with repeated administration tolerance develops to CRF-induced suppression of responding in rats.

Repeated exposure to moderate cold impairs matching-to-sample performance.

To study effects of moderate cold (5 degrees C) on complex cognitive performance, subjects were exposed to cold while responding on a conditional discrimination task. The task required a correct choice of which of two simultaneously presented matrices matched a previously presented sample matrix. The effects of task performance in cold and ambient temperatures was examined on three repeated occasions, one pair of conditions per week. Responses accuracy was consistently impaired in each cold session. In addition, choice response latencies lengthened and sample response latencies decreased in all cold exposures. The data show that even moderate cold exposure that does not produce core hypothermia can impair performance of a complex cognitive task and that the magnitude of performance change is not attenuated by a brief series of cold exposures.

Moderate cold exposure shortens evoked potential latencies in humans.

Visual, auditory event-related potentials, and brainstem auditory-evoked responses were recorded in as many as six young male subjects in order to study the effects of moderate cold air exposure on central nervous system functioning. Evoked potentials were recorded during repeated 50-min exposures to air of 4 and 22 degrees C; these levels of exposure resulted in no change in rectal core temperature. Evoked potentials recorded during exposures to 4 degrees air displayed consistently shorter latencies compared to those recorded at 22 degrees, suggesting faster CNS processing of sensory stimuli in the cold. These results are consistent with recent investigations of cold-induced behavioral response changes which indicate that increased arousal may occur with moderate (nonhypothermic) cold exposure.

Effects of mild TBI from repeated blast overpressure on the expression and extinction of conditioned fear in rats.

Mild traumatic brain injury (mTBI) and post-traumatic stress disorder (PTSD) are pressing medical issues for the Warfighter. Symptoms of mTBI can overlap with those of PTSD, suggesting the possibility of a causal or mediating role of mTBI in PTSD. To address whether mTBI can exacerbate the neurobiological processes associated with traumatic stress, we evaluated the impact of mTBI from a blast overpressure (BOP) on the expression of a conditioned fear. In the rat, conditioned fear models are used to evaluate the emotional conditioning processes that are known to become dysfunctional in PTSD. Rats were first trained on a variable interval (VI), food maintained, operant conditioning task that established a general measure of performance. Inescapable electric shock (IES) was paired with an audio-visual conditioned stimulus (CS) and followed 1day later by three daily exposures to BOP (75kPa). Subsequently, the CS alone was presented once every 7days for 2months, beginning 4days following the last BOP. The CS was presented during the VI sessions allowing a concurrent measure of performance. Treatment groups (n=10, each group) received IES+BOP, IES+sham-BOP, sham-IES+BOP or sham-IES+sham-BOP. As expected, pairing the CS with IES produced a robust conditioned fear that was quantified by a suppression of responding on the VI. BOP significantly decreased the expression of the conditioned fear. No systematic short- or long-term performance deficits were observed on the VI from BOP. These results show that mTBI from BOP can affect the expression of a conditioned fear and suggests that BOP caused a decrease in inhibitory behavioral control. Continued presentation of the CS produced progressively less response suppression in both fear conditioned treatments, consistent with extinction of the conditioned fear. Taken together, these results show that mTBI from BOP can affect the expression of a conditioned fear but not necessarily in a manner that increases the conditioned fear or extends the extinction process.

Antagonism studies with BMY-7378 and NAN-190: effects on 8-hydroxy-2-(di-n-propylamino)tetralin-induced increases in punished responding of pigeons.

The purported serotonin (5-HT)1A antagonists BMY-7378 and NAN-190 were examined in pigeons for their potential to block the effects of the prototypical 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) on punished ("conflict") and unpunished behavior and for their binding affinity at the 5-HT1A receptor site labeled by [3H]-8-OH-DPAT. Although BMY-7378 and NAN-190 both displayed high affinity for the 5-HT1A receptor (IC50 values of 0.8 and 7.5 nM, respectively), their effects, when administered alone, as well as in combination with 8-OH-DPAT, were distinct. 8-OH-DPAT (0.3-3.0 mg/kg) produced large increases in punished responding at doses that did not affect or that decreased unpunished responding. Administration of NAN-190 (1.0-3.0 mg/kg) did not increase punished responding, whereas BMY-7378 (1.0-5.6 mg/kg) slightly increased behavior suppressed by punishment. Pretreatment with BMY-7378 attenuated the rate-increasing effects of 8-OH-DPAT on punished responding; however, these effects were accompanied by dose-dependent enhancement of the rate-decreasing effects of 8-OH-DPAT on unpunished responding. In contrast, NAN-190 blocked the rate-increasing effects of 8-OH-DPAT on punished responding and also reversed the rate-decreasing effects of 8-OH-DPAT on responding that was not punished. Pretreatment with NAN-190 failed to block increases in punished responding produced by 0.1 to 1.0 mg/kg of the benzodiazepine midazolam. These data suggest that NAN-190 may be characterized as an antagonist and BMY-7378 a partial agonist with respect to 5-HT1A-induced behavioral changes observed in the conflict procedure with pigeons.

Cold-induced impairment of delayed matching in rats.

Exposure to moderate, nonhypothermic cold temperature has been reported to affect a variety of behavioral and neural functions. To elucidate the effects of mild cold stress on short-term (working) memory, Long-Evans rats were exposed to an ambient temperature of either 2 degrees or 23 degrees C while performing a delayed matching task. At the beginning of each trial, rats were required to respond on one of two levers cued by a light. Following a delay of 2, 8, or 16 s, a response on the lever previously cued produced food reinforcement. Relative to performance at 23 degrees C, exposure to 2 degrees C occasioned no change in matching accuracy at the 2-s delay, a modest decrement at the 8-s delay, and a larger decrement at the 16-s delay. The cold exposure did not decrease colonic temperature. In addition to accuracy decrements, matching response times were consistently shorter during cold exposures. Cold-induced impairments were absent during removal of the memory component from the task, indicating the observed cold effects on memory were not due to impaired attentional, sensory, or motor processes. These data suggest that mild cold stress may impair active maintenance of information in working memory but not processes related to reference memory.

ACTH produces long-lasting recovery following partial extinction of an active avoidance response.

Recent data suggest that ACTH administration produces recovery of an extinguished passive avoidance response at an unusually long injection-to-test interval. The present experiment sought to explore further the durability of recovery by examining the effect of ACTH following extinction of one-way active avoidance. Adult rats were injected with 16 IU ACTH, an equivalent volume of the ACTH vehicle gel, or saline 48 h after a previously learned active avoidance response was partially extinguished. Different groups from each treatment condition were tested 15 min, 24 h, or 7 days after injection. ACTH improved avoidance performance at all injection-to-test intervals relative to saline and vehicle gel injected controls. These data indicate that unlike reversal of other types of performance decrements, in which the effect of ACTH appears to be transient, administration of the hormone following an extinction treatment can produce enduring improvement of avoidance performance.

Acute and chronic effects of corticotropin-releasing factor on schedule-controlled responding and neurochemistry of pigeons.

Key pecking by pigeons was maintained under various schedules of food presentation. Acute i.c.v. administration of corticotropin-releasing factor (CRF) (3.0-30.0 micrograms/kg) decreased responding in both components of a multiple 3-min fixed-interval, 30-response fixed-ratio schedule and under a multiple fixed-ratio schedule in which responding during one component was punished by shock delivery. The rate-decreasing effects of intermediate doses of CRF were blocked by the CRF antagonist alpha-helical CRF9-41 under the multiple fixed-internal fixed-ratio schedule, with 10.0 micrograms/kg of the antagonist producing a more complete reversal than 30.0 micrograms/kg. The rate-reducing effects of 10.0 and 30.0 micrograms/kg of CRF disappeared rapidly when CRF was administered daily, with complete restoration of responding occurring by the 4th day of chronic administration. Acute effects were recovered when CRF administration was discontinued for 7 to 14 days. Analyses of cerebrospinal fluid revealed that behaviorally active doses of CRF produced large, dose-dependent increases in levels of the serotonin metabolite 5-hydroxyindoleacetic acid and in the dopamine metabolites dihydroxyphenylacetic acid and homovanillic acid; smaller increases also occurred in the levels of 3-methoxy-4-hydroxyphenylethylene glycol, the metabolite of norepinephrine. Chronic administration of 30 micrograms/kg of CRF for a 4-day period did not reveal any change in metabolite levels when compared to those obtained after acute administration, with the exception of 3-methoxy-4-hydroxyphenylethylene glycol which approached control levels after chronic CRF. These results indicate that, as is the case with mammals, CRF has potent behavioral and neurochemical activity in avian species and that tolerance occurs rapidly to the behavioral effects.

Behavioral studies with anxiolytic drugs. VI. Effects on punished responding of drugs interacting with serotonin receptor subtypes.

The effects of drugs that bind selectively to different serotonin (5-HT) receptor subtypes were assessed in pigeons. Keypecking was maintained by a multiple fixed-ratio schedule of reinforcement in which responding also was punished during one component. The greatest increases in punished responding were produced by the buspirone analogs BMY 7378 and ipsapirone, which act at the 5-HT1A receptor. RU 24969, with high affinity for both 5-HT1A and 5-HT1B receptors, and 1-(2-methoxyphenyl)piperazine, a 5-HT1 compound, increased punished responding to a lesser extent, as did the 5-HT2 antagonists ketanserin and ritanserin. The 5-HT3 antagonists GR 38032F, ICS 205930 and MDL 72222 showed little systematic effect, and the mixed 5-HT1B/5-HT1C compound 1-(3-chlorophenyl)piperazine produced only decreases in punished responding. Levels of neurotransmitter metabolites in cerebrospinal fluid were assessed across a wide dose range of representative drugs used in the behavioral studies. Levels of the 5-HT metabolite 5-hydroxyindoleacetic acid were decreased significantly by BMY 7378 and ipsapirone, were not changed by ritanserin and were increased at one dose by MDL 72222. The results are consistent with suggestions that decreased 5-HT neurotransmission is involved in the effects of novel nonbenzodiazepine anxiolytics such as buspirone. Behavioral and neurochemical data also indicate that the effects of these drugs on other neurotransmitter systems do not play a significant role in their anxiolytic actions.