John R. Thomas

Tyrosine Reverses a Cold-Induced Working Memory Deficit in Humans

Acute exposure to cold stress has been shown to impair short-term, or working, memory, which may be related to reduction in, or disruption of, sustained release of brain catecholamines. Administering a supplemental dose of the catecholamine precursor tyrosine may alleviate cold stress-induced memory impairments by preventing cold-induced deficits in brain catecholamine levels. The present experiment determined whether administration of tyrosine would prevent a cold-induced working memory deficit, using a computer-based delayed matching-to-sample (DMTS) memory task. Eight male volunteers performed the DMTS task for 30 min at an ambient temperature of either 4 degrees C (cold) or 22 degrees C following a 30-min preexposure period and 2 h after ingesting 150 mg/kg of L-tyrosine or placebo. Subjects demonstrated a decline in matching accuracy on the DMTS task as delay interval increased, such that matching accuracy following a 16-s delay between sample and comparison stimuli was lower than that following a delay of 2 or 8 s. Consistent with previous research, and relative to 22 degrees C exposure sessions, matching accuracy during 4 degrees C exposure sessions was reduced significantly following placebo administration, which is attributed to the effect of cold exposure on short-term, or working, memory. Administration of tyrosine significantly improved matching accuracy at the longest delay interval most affected by cold exposure, such that matching accuracy in the cold following tyrosine was at the same level as matching accuracy following placebo or tyrosine administration at 22 degrees C. Tyrosine administered prior to 22 degrees C exposure had no effect on DMTS performance.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

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.

Glucose Attenuates Cold-Induced Impairment of Delayed Matching-to-Sample Performance in Rats,

Administration of glucose has been shown to enhance performance in a variety of test situations in which memory is impaired by some amnestic treatment. In the present study, the effects of glucose were examined on a working-memory deficit produced when rats performed a delayed matching-to-sample (DMTS) task while being exposed to ambient cold air. In the DMTS task, the rats were required to respond on one of two levers cued by an illuminated light above the lever on the front wall of an operant chamber. Following a variable delay ranging from 1 to 16 sec, both lights were illuminated and the rats were required to correctly respond on the lever previously cued for a food reward. They responded on the back wall lever during the delay interval to prevent position bias. Glucose (10–500 mg/kg) or saline, administered (i.p.) in a mixed sequence, were given 1 h before a 75-min session in which the rats performed the DMTS task (180 trials). During test sessions, the ambient air temperature was either 23°C or 2°C. Administration of glucose during exposure to 23°C did not systematically affect matching accuracy or other performance measures. In the rats pretreated with saline, exposure to 2°C produced a downward shift in the delay gradient in that matching accuracy was impaired at all delay intervals when compared with performance at 23°C. Glucose produced dose-dependent improvement of matching accuracy with short, but not long, interpolated delays. Selective modulation of cold-induced impairment of working memory at the short delays suggests that glucose preferentially enhances stimulus acquisition during exposure to cold stress.

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.

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.

Alteration of response patterning by d-amphetamine on repeated acquisition in rats

The acute effects of d-amphetamine on response patterning in a repeated acquisition baseline were investigated with rats. Each session the animals acquired a different four-member response sequence on three levers. Each sequence (trial) completion produced a food pellet. Errors produced a brief timeout that was reset by responses made during the timeout. Acute doses of d-amphetamine (0.5-4.0 mg/kg) and saline were administered 30 min presession. The response patterns analyzed were perseverative responses to a single lever (runs), and a response to each lever in either a left-to-right or right-to-left direction (traverses). The trial position, frequency, and lever location of error and timeout responses that occurred in the context of runs and traverses were studied. In contrast to control sessions, higher doses of d-amphetamine produced increases in the number of error and timeout responses emitted. The majority of these responses occurred as runs; traverse responding did not exceed control levels. Furthermore, the run error and timeout responding tended to occur early in the session and on a single response lever. The results are consistent with the view that d-amphetamine disrupts stimulus control and produces perseverative responding which may account for previous reports of disruption in repeated acquisition tasks following d-amphetamine administration.

Response Patterning in a Repeated Acquisition Baseline with Rats

A response-pattern analysis was performed on data obtained from rats trained on a baseline of repeated acquisition of behavioral chains. The response patterns identified and analyzed were perseverative responses to a single lever (runs) and a response to each lever in either a left-to-right or right-to-left direction (traverses). The analysis indicated that runs and traverses accounted for between 50 and 70% of all error response and between 80 and 100% of all timeout responses. In addition, the number of traverses varied according to the composition of a sequence: higher frequencies occurred when the sequence required a traverse for completion, e.g., LRCL, than when it did not, e.g., LRLC. The differentiation of sequence type, however, was not systematically related to the level of error or timeout responding. The results suggest that the generation and maintenance of response patterns influences control of the repeated-acquisition process.

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.

Repeated Acquisition of Four-Member Response Sequences in Rats

A procedure for studying the repeated acquisition of four-member response sequences in rats was developed. Early in training incorrect responses constituted approximately 60% of the total responses emitted during a session, and no evidence of within-session acquisition was observed After 100 training sessions incorrect responses constituted approximately 25% of total responses and within-session acquisition was observed, as evidenced by runs of up to 14 errorless sequence completions during the latter portions of training sessions. The behavior generated after extended training was similar to behavior maintained by repeated acquisition baselines for pigeons and monkeys in over-all levels of error and in the pattern of within-session acquisition.