Hippocampal injections of amyloid beta-peptide 1-40 impair subsequent one-trial/day reward learning

The injection of amyloid beta-peptide (Abeta) into rat CNS has been reported to induce cellular neuropathology. The present study investigated whether multiple intrahippocampal injections of Abeta 1-40 would impair one-trial/day reward learning 14 days later. Twenty-four male Sprague-Dawley rats, 3-4 months old, were injected with either Abeta 1-40 or distilled water into seven hippocampal sites bilaterally. Ten rats received 3 nmol Abeta 1-40 in 2 microl of distilled water per injection site, while 14 rats received distilled water alone. Following a 9-day recovery period, rats were gradually food deprived to 82% of their initial body weight. Fourteen days after the intrahippocampal injection, all rats received an initial training trial and three subsequent daily retention trials. Rats receiving Abeta 1-40 were significantly impaired on the second retention trial in terms of accuracy (number of unbaited alleys entered) and on the second and third retention trials in terms of speed (reciprocal of latency to reward). Histological analysis showed that Abeta 1-40 injections produced significant neuronal loss and gliosis. Abeta 1-40 immunoreactivity persisted locally at the injection site and in macrophages 2 weeks following the hippocampal injections. These effects appear to be sequence-specific; rats receiving Abeta 1-42 with a scrambled peptide sequence did not differ significantly from rats receiving distilled water alone in retention of the learning task or degree of histological damage.     

Effects of BIM-22015, an analog of ACTH4-10, on functional recovery after frontal cortex injury.

Male rats, 90-100 days old, with frontal cortex lesions were given either subcutaneous sterile water (SW) as a vehicle control or 1, 10, or 100 micrograms of BIM-22015 every other day for 20 days. Brain-injured subjects tested in the Morris water maze with either 10 micrograms BIM-22015 or SW took significantly more trials than sham-operated rats to locate a submerged platform eight consecutive times within 60 s. The animals given 1 or 100 micrograms BIM-22015 took significantly fewer trials to reach criterion than brain-injured animals in the other drug treatment groups. On a percentage of savings, measured 8 days after reaching criterion, the brain-injured subjects given 1, 10, or 100 micrograms BIM-22015 did not differ from sham-operated rats. In contrast, the brain-injured animals given SW took longer to find the submerged platform than they did during the initial training. To assess long-term effects of the ACTH analog treatment, rats were trained on a delayed spatial alternation task 30 days after receiving the last injection. On this task, brain-injured rats treated with the 10-micrograms dose performed significantly better than those given sterile water. Acetylcholinesterase (AChE)-labeled neurons counted in the nucleus basalis magnocellularis indicated that rats with frontal cortex damage given the 10-micrograms treatment did not differ from the sham controls and had significantly more AChE-positive neurons than injured counterparts treated with SW or 100 micrograms.     

Cholinergic modulation of the hippocampus during encoding and retrieval

The present experiments were aimed at determining whether acetylcholine (ACh) plays a role in encoding and retrieval of spatial information using a modified Hebb-Williams maze. In addition, the present experiments tested two computational models of hippocampal function during encoding and retrieval using a maze sensitive to hippocampal disruption. Thirty male, Long-Evans rats served as subjects. Chronic cannulae were implanted bilaterally into the CA3 (n=26) and CA1 (n=5) subregions of the hippocampus. Rats were tested using a modified Hebb-Williams maze. In the first experiment, rats were injected with either saline or scopolamine hydrobromide 10 min before testing for each day. The number of errors made per day per group was used as the measure of learning. Encoding was assessed by the average number of errors made on the first five trials of Day 1 compared to the last five trials of Day 1, whereas the average number of errors made on the first five trials of Day 2 compared to the last five trials of Day I was used to assess retrieval. No deficit was found for the saline group. The scopolamine group showed a deficit in encoding, but not retrieval. In the second experiment, rats were injected with either saline or physostigmine 10 min before testing each day. In contrast to the scopolamine groups, the physostigmine group showed a deficit in retrieval, but not encoding. To test whether the retrieval deficit was due to a disruption in storage or gaining access to the information two groups of rats received either saline on Day 1 and physostigmine on Day 2 or physostigmine on Day 1 and saline on Day 2. In addition, one group received physostigmine immediately after testing on Day 1. Data indicate that physostigmine causes a disruption of retrieval by means of a disruption in consolidation process. In conclusion, the cholinergic antagonist, scopolamine, disrupts encoding in both CA3 and CA1 subregions of the hippocampus. Furthermore, the cholinesterase inhibitor, physostigmine, boosts ACh action during a time when cholinergic levels need to decline for proper consolidation.     

Position reversal training in the virginia opossum: Evidence for the acquisition of a learning set

To obtain an estimate of the learning ability of opossums, five tame ones were trained on a series of position reversals to a criterion. With 4 trials per day there was no consistent improvement over a series of 15 reversals. When each daily session was increased to as many trials as needed to reach criterion, errors dropped sharply, indicating the formation of a position learning set. Upon return to 4 trials per day, 3 of 4 animals continued to perform with few errors, showing transfer of learning set. Opossums do more poorly than rats on this task, which is in agreement with the relative phyletic level of the two species.     

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.     

The residual spatial abilities of hippocampally lesioned rats can be enhanced by peripheral sympathetic-adrenal interventions

In order to test the possible effectiveness of peripheral interventions with the adrenergic system for the alleviation of certain disorders that typically follow bilateral hippocampal lesions, rats with bilateral lesions of the hippocampus, the overlying neocortex, or sham operations were tested at two postoperative times in the Morris water maze, a frequently used "spatial task." Half of the animals in all groups were exposed to the adrenergic manipulations, i.e., a chronic, 7-day, systemic bretylium regime (5 mg/kg) and, in addition, a peripheral injection of norepinephrine (4 micrograms/kg) 30 min before the start of each training day. The other half received saline chronically and a single saline injection before each training day. Five days of training were given at each of the two training periods. The first began 7 days after surgery while the second began 33 days after surgery. As expected, the hippocampally lesioned animals were severely impaired in the task. The adrenergic treatment produced enhanced performances in the rats with hippocampal lesions at both training sessions, although the improvement was greatest at the later period. Although the animals receiving the pharmacologic treatment located the general area of the hidden platform better than the saline-treated animals with hippocampal lesions, the treated animals were still impaired, swimming directly to the hidden platform on fewer trials than did animals in the other groups.     

Ontogeny of the adrenal response to (+)-methamphetamine in neonatal rats: the effect of prior drug exposure

We examined the ontogeny of the corticosterone response to (+)-methamphetamine in neonatal rats. In experiment-1, animals were injected with 10 mg/kg of (+)-methamphetamine or saline and plasma corticosterone levels were examined in separate groups 30 or 105 min later on postnatal day (P) 1, 3, 5, 7, 9, 11, 13, 15, 17, or 19. The adrenal response to methamphetamine was best described by a U-shaped function with the nadir of corticosterone release occurring between P7 and P13. Experiment-2 was similar except that the effect of four consecutive days of exposure to (+)-methamphetamine (four times daily at 2 h intervals with 10 mg/kg) was assessed with a single final dose early on the fifth day (i.e. P1-5, 3-7, 5-9, 7-11, 9-13, 11-15, 13-17, 15-19). The 30 min corticosterone response after multiple methamphetamine doses was augmented compared to single exposures, with the exception of the two earliest dosing intervals ending on P5 and P7, where the responses were lower. In addition, at 105 min, the levels of corticosterone were attenuated relative to a single drug administration. With the exception of animals receiving methamphetamine from P15 to P19, thymus weights were unaffected. The data demonstrate that (+)-methamphetamine is a robust activator of corticosterone release in developing animals and this release is extensively modified by age and previous drug exposure.     

Dissociation between conditioned emotional response and extended avoidance performance

The present experiments examined the dissociation between the strength of a shuttlebox avoidance response (AR) and one index of fear of the avoidance CS. Avoidance response strength was indexed by resistance to extinction of the AR and by changes in response latency, and fear of the CS was indexed by the conditioned emotional response (CER) technique. Experiments 1, 2A, and 3A all found that rats trained to a criterion of 27 consecutive avoidance responses (CARs) showed response strength comparable or superior to rats trained to a criterion of 9 CARs. Experiments 2B and 3A demonstrated that rats trained to 27 CARs showed less suppression of bar pressing during the avoidance CS (less CER) than rats trained to 9 CARs. Experiment 3A also found that, when extinguished in the shuttlebox to a moderate criterion (5 consecutive trials without a response) before CER testing, rats trained to 9 CARs showed some, although not complete, loss of CER, whereas rats trained to 27 CARs showed no loss of CER. In Experiment 3B rats that took 1 vs 2 days to reach a criterion of 27 CARs were compared for their AR strength and for their CER. Although rats taking 2 days to reach criterion showed somewhat greater resistance to extinction of the AR than rats reaching criterion in 1 day, this variable had no apparent effect on the CER. Implications of the present results for current theories of avoidance learning are discussed.     

Imitation, social facilitation, and the effects of ACTH 4-10 on rats' bar-pressing behavior

The effects of ACTH 4-10 on rats' imitation learning was examined during the acquisition and extinction of a bar-press response for water reinforcement. Rats were exposed to either a bar-pressing conspecific (OB), an experimentally naive conspecific (ON), or an empty box (OE) during bar-press acquisition. In a factorial design, each rat was then exposed to one of the same three conditions during extinction. An 80 mcg dose of ACTH 4-10 was administered to half of the rats in each group prior to observation. Performance differences during acquisition were generally small, but significant performance differences during extinction were found. Social facilitation was indicated by the finding that rats extinguished in the presence of a conspecific exhibited significantly greater resistance to extinction than rats extinguished in the presence of an empty box. An imitation effect was also found. Rats that observed a bar-pressing conspecific during both acquisition and extinction (group OB-OB) showed significantly greater resistance top extinction than did groups OB-ON, CB-OE, or OE-OE. There were no significant effects of the hormone, however, relative to saline controls.     

Muscimol Induces Retrograde Amnesia for Changes in Reward Magnitude

These experiments examined the effect of the GABA_A, agonist, muscimol (MUS), on memory for changes in reward magnitude. In Experiment 1 rats were trained to run a straight alley for either a large or small food reward. After reaching asymptotic performance rats in the high reward group were shifted to the small food reward. Half the animals received 1.0 or 3.0 mg/kg (ip) of MUS or the equivalent volume of saline immediately after training. Shifted training continued for 3 more days and no further injections were given. Shifted saline animals displayed an increase in response latencies compared to unshifted controls with a sharp peak on the day after the shift. Shifted MUS receiving 1.0 mg/kg performed comparably to shifted saline animals. In contrast, shifted MUS animals receiving 3.0 mg/kg displayed performance comparable to shifted saline animals on the day of the shift but displayed a sharp increase in response latencies on the second day after the shift. These findings indicate that post-training systemic MUS injections delay the peak increase in response latencies and suggest that MUS induces retrograde amnesia for reward reduction. Experiment 2 examined the effect of MUS on the memory of a reward increase. Rats were first trained as in Experiment 1 and rats under the high reward condition were then shifted to the small reward. On the next training session, the large food reward was reinstated. Immediately after the session all animals were injected with saline or 3.0 mg/kg of MUS. The large food reward was continued for the remainder of training and no further injections were given. On the following session, the performance of the shifted saline animals was comparable to that of the unshifted controls while shifted MUS animals displayed significantly higher response latencies. The findings that MUS prevented the reduction in response latencies seen in saline-injected animals suggest that MUS also induces retrograde amnesia for reward increases.     

Rotation of Water in the Morris Water Maze Interferes with Path Integration Mechanisms of Place Navigation

The idea that place navigation in the Morris water maze is implemented by path integration between locations determined by landmark sighting was investigated in a 200-cm-diameter pool in which circular (7.2°/s) motion of water could be induced by tangentially arranged water jets. The rats were trained at 8 trials per day to navigate to an erectable platform which was raised after the rat had spent a criterion time in the target annulus (30 cm in diameter) in the midpoint of the NW quadrant. Asymptotic escape latency of 7 s was reached after 9 days in moving water (n= 8) and after 6 days in stationary water (n= 8). The group overtrained for 13 days in stable water performed well even after it was transferred to moving water. Changing the sense of rotation of water from counterclockwise to clockwise did not affect the asymptotic performance. The above findings show that overtrained rats rely on landmark sighting rather than on path integration. The influence of water movement reappeared when place navigation to a new target (SW) was examined in alternating 2-s periods of light (L) and darkness (D). On the first day, the latencies were 15.2 ± 1.2 and 22.8 ± 1.9 s in stable and moving water, respectively, but dropped to 10 s on the following day. The tracks generated in the L period were more tortuous than those generated in the D period and this difference was more pronounced in moving than in stable water. It is concluded that path integration mechanisms supporting navigation during intervals of darkness are impaired in moving water but that this impairment disappears in overtrained animals.     

Motivating adolescents to reduce their fines in a token economy

Adolescents on a 16-bed token economy ward of a state hospital were subjected to four interventions in a seven-phase experiment to reduce the number of fines they received each day. Phase I was a four-week baseline period. Phases II and III were four- and five-week periods, respectively, in which residents were awarded tickets for a weekly $10 lottery each day they were at or below a changing criterion of daily fines. In Phase IV, residents received coupons, exchangeable for money, for days with zero fines. Phase V was a return to baseline. Phase VI was a one-week period in which daily lotteries for $1 were held, with the criterion for receiving a ticket being zero fines on the previous day. Phase VII was a one-week return to baseline. No significant differences in average fines per day, number of residents meeting criteria, or mean number of zero-fine days per week were found across phases. Results are discussed in terms of amount and immediacy of reinforcement, other opportunities to gain money, possible rebelliousness of the residents against the increased aversiveness of fines, and implications for further research.     

Chronic sodium azide treatment impairs learning of the Morris water maze task.

A reduction in the activity of cytochrome oxidase, a respiratory chain enzyme, has been recently identified in mitochondria from blood platelets and postmortem brain tissue from Alzheimer's disease (AD) patients. We have developed an animal model of this deficit in rats by chronic subcutaneous infusion of sodium azide, a selective inhibitor of cytochrome oxidase, delivered via Alzet 2ML4 osmotic minipumps. In previous work, azide-treated rats were impaired in an appetitively motivated spatial learning task, the radial arm maze. In the present investigation, we tested male Sprague-Dawley rats (350-400 g), which were tonically infused with azide or saline, on an aversively motivated spatial task, the Morris water maze. Azide-treated rats were impaired on both acquisition and retention of this task, without showing evidence of a motor impairment. Thus, the present results are consistent with previous findings showing that chronic azide treatment produces a learning and memory deficit. These findings strengthen the hypothesis that azide treatment in rats produces a useful animal model of some aspects of AD.     

Common toads (Bufo arenarum) learn to anticipate and avoid hypertonic saline solutions

Toads (Bufo arenarum) were exposed to pairings between immersion in a neutral saline solution (i.e., one that caused no significant variation in fluid balance), followed by immersion in a highly hypertonic saline solution (i.e., one that caused water loss). In Experiment 1, solutions were presented in a Pavlovian conditioning arrangement. A group receiving a single neutral-highly hypertonic pairing per day exhibited a greater conditioned increase in heart rate than groups receiving either the same solutions in an explicitly unpaired fashion, or just the neutral solution. Paired toads also showed a greater ability to compensate for water loss across trials than that of the explicitly unpaired group. Using the same reinforcers and a similar apparatus, Experiment 2 demonstrated that toads learn a one-way avoidance response motivated by immersion in the highly hypertonic solution. Cardiac and avoidance conditioning are elements of an adaptive system for confronting aversive situations involving loss of water balance.     

Rats' preferences for an analgesic compared to water: an alternative to "killing the rat so it does not suffer"

A common policy in research institutions is to kill rats when they display chronic disabilities or recurrent injuries. These guidelines appear to be derived from an oxymoron that "it's better for a rat to be killed so it does not suffer pain" and from untested assumptions that rats cannot control "pain." In a two-bottle paradigm, 10 rats with a history of brain damage following status epilepticus from a single systemic injection of lithium and pilocarpine were given options to consume freely either tap water or 1 mg/cc of acetaminophen in tap water. During periods of fresh lesions due to persistent gnawing or acute injuries associated with tonic-clonic convulsions, the rats consumed 3 to 10 times the fluid from the bottles containing acetaminophen (equivalent to 5 to 10 extra-strength Tylenol tablets per day for a 70-kg person) relative to periods when no lesions or old lesions were present. These results suggest that rats with chronic injuries sufficient to be terminated according to Animal Care guidelines may be capable of reducing the aversive physiological conditions associated with tissue damage by selecting analgesic treatments.     

Spatial learning in the rat: impairment induced by the thiol-proteinase inhibitor, leupeptin, and an analysis of [3H]glutamate receptor binding in relation to learning

Rats were given continuous intraventricular infusion of saline or the thiol-proteinase inhibitor leupeptin, via subcutaneously implanted osmotic minipumps, while being trained on a spatial learning water task using spaced trials. Leupeptin caused overnight forgetting during training, but performance eventually reached asymptote in both groups. A retention test conducted 48 h later to assess spatial memory revealed no significant group differences, but did cause, in saline-treated rats only, a disruption of subsequent retraining back to the correct spatial location. The groups showed no differences in Cl-dependent [3H]glutamate receptor binding to hippocampal or entorhinal cortex membranes subsequent to training. In a second experiment, normal rats trained on the same task also showed no differences in Cl-dependent [3H]glutamate binding relative to rats exposed to the water task but given random spatial position training and handled controls. The results are discussed in relation to the hypothesis of Lynch and Baudry (Science (1984) 224, 1057-1063) that a calcium-dependent thiol proteinase is involved in memory formation through its ability to modify glutamate receptor distribution and dendritic spine shape.     

Weight gain in post-seized rats is facilitated by adding aspirin, glucose, or glucose-taurine-acetaminophen to food mush.

Adult male rats were seized with lithium and pilocarpine and administered acepromazine to facilitate survival. After four days (1) 8 mg of acetylsalicylic acid (aspirin), (2) 100 mg taurine-15 mg acetaminophen (Tylenol)-40 mg glucose, (3) 40 mg glucose, or (4) water was added to the food mush daily for 30 days. A fifth group served as non-seized controls. Within one week all pharmacological treatments promoted more weight recovery than food mush only. The rats receiving aspirin (equivalent to 3 tablets/day for humans) showed the greatest early recovery. After 15 days of treatment the pharmacologically treated seized rats had returned to baseline weight and did not differ from normals whereas seized rats given only food mush had not. We suggest inhibiting prostaglandins by anti-inflammatory compounds or stimulating the GABA shunt pathway through enhanced dietary glucose to accelerate weight gain following the significant loss that accompanies brain injury.     

Noradrenergic receptor blockade of the NTS attenuates the mnemonic effects of epinephrine in an appetitive light-dark discrimination learning task

These experiments examined the contribution of noradrenergic neurons in the nucleus of the solitary tract (NTS) in mediating the memory-facilitating effects of epinephrine. In Experiment 1, saline or 0.05 or 0.1 mg/kg of epinephrine was given intraperitoneally (ip) to rats after the second day of training in a light-dark Y-maze discrimination task. On a 20-trial retention test given 2 and 7 days later, the 0.1 mg/kg epinephrine group made significantly more correct responses than controls and required fewer trials to reach criterion. In Experiment 2, phosphate-buffered saline or the noradrenergic antagonist dl-propranolol (0.3 or 1.0 microg/0.5 microl) was infused into the NTS prior to an ip injection of saline or 0.1 mg/kg of epinephrine. The memory-enhancing effects of epinephrine were attenuated by the infusion of 0.3 microg/0.5 microl of dl-propranolol into the NTS. These findings indicate an involvement of NTS noradrenergic neurons in mediating the effects of peripheral epinephrine on memory storage processes.     

Maternal behavior of rats is affected by hormonal condition of pups

Previous research has found that maternal rats discriminate male from female offspring and provide more anogenital licking to males. Two experiments were performed to determine whether this discrimination is based on hormonal condition of young. It was found that 500 micrograms of testosterone, estradiol, or dihydrotestosterone injected on the day of birth into female pups led to their receiving an equivalent amount of maternal anogenital licking as males and significantly more than either oil or untreated females. The different steroids had similar effects. Maternal nonanogenital licking was not affected by sex or hormonal condition of pups, but it was significantly increased by injection per se. Effects on maternal behavior of hormonal condition or neonatal injection of young were apparent 1 and 9 days after injection.     

Sex-dependent effects of neonatally administered morphiceptin and D-ala-D-leu-enkephalin on maze learning in rats

Newborn rats were injected (ip) with morphiceptin [72.7 micrograms/kg (a mu-type opioid receptor agonist)], D-alanine2-D-leucine5-enkephalin [79.4 micrograms/kg (a delta-receptor agonist)], or saline for 7 days after birth. Testing on a complex maze on Day 25 revealed a significant sex-dependent facilitation of performance by the opioid peptides. Peptide-treated females performed better than the males on the first day of training as measured by errors. Opioid treatment increased mortality, as three times as many peptide-treated animals died in comparison to the saline control group. Peptide treatment did not affect locomotor activity measured in an open field. Weight at Day 24 was also affected by the peptide treatment, females and males injected with the opioids being lighter and heavier, respectively, than the control group.