Pigeons' memory for number of events: Effects of intertrial interval and delay interval illumination

In Experiment 1, pigeons were trained at a 0-s baseline delay to discriminate sequences of light flashes (illumination of the feeder) that varied in number but not time (2f/4s and 8f/4s). During training, the intertrial interval was illuminated by the houselight for Group Light, but it was dark for Group Dark. Testing conducted with dark delay intervals produced a strong choose-small bias in both groups. All birds then received baseline training with a 5-s dark delay and were subsequently tested at shorter and longer dark delays. A choose-small bias was again observed at delays longer than the training delay, while a choose-large bias occurred at delays shorter than the training delay. Differentiating the ambient chamber illumination during the intertrial interval and the delay interval did not attenuate choose-small or choose-large effects. In Experiment 2, all birds received baseline training with a 5-s illuminated delay and were subsequently tested at shorter and longer illuminated delays. A choose-large bias was observed at delays longer than the training delay, while a choose-small bias occurred at delays shorter than the training delay. In Experiment 3, on intermittent test trials, when the duration of the second flash on small-sample trials was equal to the total flash duration on large-sample trials (i.e., 1600 ms), accuracy fell to approximately chance. These results suggest that pigeons discriminated the sequences of light flashes that varied in number but not in total duration of the sequence by relying on other temporal properties of the sequence rather than by using an event switch to count flashes.     

Learning and memory deficits in mice lacking protease activated receptor-1

The roles of serine proteases and protease activated receptors have been extensively studied in coagulation, wound healing, inflammation, and neurodegeneration. More recently, serine proteases have been suggested to influence synaptic plasticity. In this context, we examined the role of protease activated receptor 1 (PAR1), which is activated following proteolytic cleavage by thrombin and plasmin, in emotionally motivated learning. We were particularly interested in PAR1 because its activation enhances the function of NMDA receptors, which are required for some forms of synaptic plasticity. We examined several baseline behavioral measures, including locomotor activity, expression of anxiety-like behavior, motor task acquisition, nociceptive responses, and startle responses in C57Bl/6 mice in which the PAR1 receptor has been genetically deleted. In addition, we evaluated learning and memory in these mice using two memory tasks, passive avoidance and cued fear-conditioning. Whereas locomotion, pain response, startle, and measures of baseline anxiety were largely unaffected by PAR1 removal, PAR1-/- animals showed significant deficits in a passive avoidance task and in cued fear conditioning. These data suggest that PAR1 may play an important role in emotionally motivated learning.     

Retention interval and intertrial interval in a serial learning or delayed discrimination task

In each of four experiments, rats were provided with the same three-event decreasing series (18-1-0) of 0.045-g food pellets in a runway. Tracking, running fast to 18 pellets and running slow to 1 and 0 pellets, was investigated as a function of the temporal interval elapsing between the events of the series (the retention interval), shifts in retention interval, and number of trials each day (or the intertrial interval), a trial being defined as presentation of each of the three events of the series. Neither retention interval, which varied from 15 s to 30 min in various investigations, nor shifts in retention interval affected tracking when only one trial was given each day. But when more than one daily trial was given, tracking was acquired more slowly and was disrupted by a shift in retention interval from 15 s to 5 min. Tracking was also disrupted by a shift from one to two trials each day. These results indicate that when given one 18-1-0 trial each day, the rat partitions events on a first-event/subsequent-event basis; that little forgetting occurs even at long retention intervals; that somewhat different memories signal events when one or more than one 18-1-0 trial occurs each day; and that retention interval deficits can arise owing to the same or similar memories' signaling different events. The results described limit the generality of three hypotheses suggested in two recent investigations: that as retention interval increases, rats find it increasingly difficult to remember and utilize serial position cues; that tracking in serial tasks is not influenced by number of trials each day; and that there are specific stimuli associated with each retention interval which, when changed, necessarily disrupt performance.     

Working memory deficits in retinoid X receptor gamma-deficient mice

Retinoid signaling has been recently shown to be required for mnemonic functions in rodents. To dissect the behavioral and molecular mechanisms involved in this requirement, we have analyzed the spatial and recognition working memory in mice carrying null mutations of retinoid receptors RARbeta and RXRgamma. Double mutants appeared deficient in spatial working memory as tested in spontaneous alternation in the Y-maze and delayed nonmatch to place (DNMTP) test in the T-maze. These mutant mice did acquire, however, spatial place reference or right/left discrimination tasks in the T-maze set-up, indicating that basic sensorimotor functions, spatial orientation, and motivational factors are unlikely to account for deficits in working memory-sensitive tasks. Double-mutant mice were also deficient in novel object recognition at intermediate, but not short delays. RXRgamma appeared to be the functionally predominant receptor in modulation of the working memory, as RXRgamma, but not RARbeta single null mutant mice exhibited deficits similar to those observed in the double mutants. The mechanism of this modulation is potentially related to functions of RXRgamma in frontal and perirhinal cortex, structures in which we detected RXRgamma expression and which are functionally implicated in working memory processes.     

Developmental differences in memory for temporally neutral and temporally tagged information

Forty children (ages 7 and 11 years) listened to stories and then answered questions about temporally neutral and temporally tagged information appearing in them (e.g., “Linda is smart” vs “Linda ate an apple”). Number of presentations and free recall of the stories were manipulated to study age-related changes in the effects of additional processing on memory for the two kinds of information. Older children exhibited overall better memory, but with additional processing that difference was larger for temporally neutral than for temporally tagged information. The observed interactions among age, additional processing, and kind of information demonstrated the importance of the distinction between temporally neutral and temporally tagged information for developmental studies of memory for prose.     

Kv4.2 knockout mice have hippocampal-dependent learning and memory deficits

Kv4.2 channels contribute to the transient, outward K(+) current (A-type current) in hippocampal dendrites, and modulation of this current substantially alters dendritic excitability. Using Kv4.2 knockout (KO) mice, we examined the role of Kv4.2 in hippocampal-dependent learning and memory. We found that Kv4.2 KO mice showed a deficit in the learning phase of the Morris water maze (MWM) and significant impairment in the probe trial compared with wild type (WT). Kv4.2 KO mice also demonstrated a specific deficit in contextual learning in the fear-conditioning test, without impairment in the conditioned stimulus or new context condition. Kv4.2 KO mice had normal activity, anxiety levels, and prepulse inhibition compared with WT mice. A compensatory increase in tonic inhibition has been previously described in hippocampal slice recordings from Kv4.2 KO mice. In an attempt to decipher whether increased tonic inhibition contributed to the learning and memory deficits in Kv4.2 KO mice, we administered picrotoxin to block GABA(A) receptors (GABA(A)R), and thereby tonic inhibition. This manipulation had no effect on behavior in the WT or KO mice. Furthermore, total protein levels of the α5 or δ GABA(A)R subunits, which contribute to tonic inhibition, were unchanged in hippocampus. Overall, our findings add to the growing body of evidence, suggesting an important role for Kv4.2 channels in hippocampal-dependent learning and memory.     

Chronic treatment with haloperidol induces deficits in working memory and feedback effects of interval timing

Normal participants (n=5) having no experience with antipsychotic drugs and medicated participants (n=5) with clinical experience with chronic low doses of haloperidol (3-10 mg/day for 2-4 months) in the treatment of neuroses were evaluated for the effects of inter-trial interval (ITI) feedback on a discrete-trials peak-interval timing procedure. Feedback was presented during the ITI in the form of a histogram showing the distribution of the responses participants made on the previous trial plotted on a relative time scale. As feedback concerning the accuracy and precision of a reproduced duration (e.g., 7- and 14-s visual signals) became more remote in time, reproduced intervals gradually lengthened in duration. This rightward horizontal shift in peak time increased as a function of the probability of feedback and was enhanced by chronic treatment with haloperidol in a manner that was proportional to the duration of the signal. Our data suggest a gradual change in the underlying representation of the signal duration as a function of the remoteness of ITI feedback that is dependent upon both changes in working memory and the speed of the internal clock used to time durations in the seconds-to-minutes range.     

Relative durations of conditioned stimulus and intertrial interval in conditioned suppression.

The effects of the relative durations of the conditional stimulus and the intertrial interval on bar pressing during a conditioned-suppression procedure were examined as a function of two additional variables--type of operant baseline schedule and rate of shock presentation. In Experiment 1, response suppression was compared across components of a multiple fixed-ratio, random-ratio, fixed-interval, random-interval schedule, at relative conditioned-stimulus/intertrial-interval durations of 1/1, 1/4, and 1/9. In Experiment 2, relative conditioned-stimulus/intertrial-interval duration (1/5, 3/3, or 5/1) was manipulated across groups, while shock frequency (2, 6, or 10 shocks/hr) was manipulated within groups. In both experiments, suppression during the signal was virtually complete at all relative durations. Responding was also suppressed during the intertrial interval, but that suppression varied as a function of experimental manipulations. In Experiment 1, intertrial-interval response rates were higher when relative signal duration was 1/9 than when it was 1/1, although both relative signal duration and shock frequency, which covaried, could have contributed to the difference. In Experiment 2, the patterning of response rates between successive shocks was affected by relative duration, absolute rates during the intertrial interval varied as a function of shock frequency, and differences between suppression during the signal and suppression during the intertrial interval were affected by both relative duration and shock frequency. The data support an analysis based upon relationships between shock-correlated and intertrial-interval stimuli and, as assessed by the relative-delay-to-reinforcement metric, are comparable to results that have been reported from experiments using similar manipulations under the autoshaping paradigm.     

The influence of intertrial interval food on extinction and devaluation in chain schedules

The authors exposed pigeons to 2 equal 3-link chains by using variable-interval schedules of reinforcement. An intertrial interval (ITI) bisected by free food separated the chains. After baseline training, the authors presented terminal links in a successive discrimination to devalue 1 terminal link: The authors reinforced responses to 1 terminal link and extinguished responses to the other. The authors then presented full chains in extinction, except that they continued to deliver free food during the midpoint of the ITI. There were 2 principal findings. First, across all extinction conditions, responding decreased but did not extinguish. Second, when extinction testing revealed a terminal link devaluation effect in the 3rd condition, responding to the initial link was affected, but not middle-link responding. Overall, the results suggested that ITI food presentations can exert a substantial effect on responding in 3-link chain schedules, and they appear to influence both the pattern of extinction and devaluation effects.     

Glucose effects on mecamylamine-induced memory deficits and decreases in locomotor activity in mice.

Peripheral glucose administration attenuates the effects of muscarinic cholinergic antagonists on several measures, including spontaneous alternation, inhibitory avoidance, and locomotor activity. The present study examined glucose interactions with mecamylamine, a nicotinic cholinergic antagonist, on these measures. Mecamylamine (5 mg/kg, sc) significantly impaired spontaneous alternation performance. Glucose (100 mg/kg, ip) administered with mecamylamine attenuated the impairment. Treatment with hexamethonium (5 and 10 mg/kg, sc), a peripheral nicotinic blocker, did not impair performance. Pretraining treatment with mecamylamine, but not hexamethonium, significantly reduced later retention latencies on inhibitory avoidance tests. Glucose, administered with mecamylamine prior to training, significantly attenuated the impaired test performance. Mecamylamine, but not hexamethonium, significantly decreased locomotor activity. In contrast to the attenuating effects of glucose on the other measures above, glucose administered with mecamylamine potentiated the decreased locomotor activity. These findings demonstrate that glucose influences the behavioral effects of a nicotinic cholinergic antagonist in a manner generally similar to that of muscarinic cholinergic antagonists, and supports previous evidence that circulating glucose interacts with central cholinergic functions.     

Gadd45b knockout mice exhibit selective deficits in hippocampus-dependent long-term memory

Growth arrest and DNA damage-inducible β (Gadd45b) has been shown to be involved in DNA demethylation and may be important for cognitive processes. Gadd45b is abnormally expressed in subjects with autism and psychosis, two disorders associated with cognitive deficits. Furthermore, several high-throughput screens have identified Gadd45b as a candidate plasticity-related gene. However, a direct demonstration of a link between Gadd45b and memory has not been established. The current studies first determined whether expression of the Gadd45 family of genes was affected by contextual fear conditioning. Gadd45b, and to a lesser extent Gadd45g, were up-regulated in the hippocampus following contextual fear conditioning, whereas Gadd45a was not. Next, Gadd45b knockout mice were tested for contextual and cued fear conditioning. Gadd45b knockout mice exhibited a significant deficit in long-term contextual fear conditioning; however, they displayed normal levels of short-term contextual fear conditioning. No differences between Gadd45b knockout and wild-type mice were observed in cued fear conditioning. Because cued fear conditioning is hippocampus independent, while contextual fear conditioning is hippocampus dependent, the current studies suggest that Gadd45b may be important for long-term hippocampus-dependent memory storage. Therefore, Gadd45b may be a novel therapeutic target for the cognitive deficits associated with many neurodevelopmental, neurological, and psychiatric disorders.     

Cyclophosphamide impairs hippocampus-dependent learning and memory in adult mice: Possible involvement of hippocampal neurogenesis in chemotherapy-induced memory deficits

Cyclophosphamide (CYP) is an anti-neoplastic agent as well as an immunosuppressive agent. In order to elucidate the alteration in adult hippocampal function following acute CYP treatment, hippocampus-related behavioral dysfunction and changes in adult hippocampal neurogenesis in CYP-treated (intraperitoneally, 40 mg/kg) mice (8–10-week-old ICR) were analyzed using hippocampus-dependent learning and memory tasks (passive avoidance and object recognition memory test) and immunohistochemical markers of neurogenesis (Ki-67 and doublecortin (DCX)). Compared to the vehicle-treated controls, mice trained at 12 h after CYP injection showed significant memory deficits in passive avoidance and the object recognition memory test. The number of Ki-67- and DCX-positive cells began to decrease significantly at 12 h post-injection, reaching the lowest level at 24 h after CYP injection; however, this reverted gradually to the vehicle-treated control level between 2 and 10 days. We suggest that the administration of a chemotherapeutic agent in adult mice interrupts hippocampal functions, including learning and memory, possibly through the suppression of hippocampal neurogenesis.     

Age-related memory deficits in rats and mice: enhancement with peripheral injections of epinephrine

Epinephrine peripherally administered to rats and mice immediately following avoidance and/or appetitive training enhances later memory retention in both young and old animals. These findings suggest a possible involvement of peripheral adrenergic systems in memory dysfunctions which accompany aging.     

Schizophrenic tendencies and memory deficits in normals

The report tests the hypothesis that normals who exhibit schizophrenic tendencies are likely to show verbal-memory deficits of the types observed in schizophrenics. Thirty-four middle-aged men were tested using the MMPI 2–7–8 schizophrenic-tendency scales, the Sorting Consistency Task and the Physical Anhedonia Scale. The dependent variables were four memory tests selected on the basis of their known discriminating power and their relevance. The results showed the Schizophrenia (8) and Psychasthenia (7) scales of MMPI, and the Sorting Consistency Task effectively detected memory deficits in normals. When partialling out intelligence, as a measure of general current cognitive functioning, it appeared that one of the deficits reflecting encoding difficulty disappeared. This suggests that normal ‘high-risk’ subjects for schizophrenia show a ‘generalized deficit’, which affects memory in addition to a ‘differential deficit’ in retention. Though tentative, the results can be taken as an indication that ‘high-risk’ subjects indeed show memory deficits and that detecting these deficits requires relatively sensitive tools.     

Working memory deficits, increased anxiety-like traits, and seizure susceptibility in BDNF overexpressing mice

BDNF regulates components of cognitive processes and has been implicated in psychiatric disorders. Here we report that genetic overexpression of the BDNF mature isoform (BDNF-tg) in female mice impaired working memory functions while sparing components of fear conditioning. BDNF-tg mice also displayed reduced breeding efficiency, higher anxiety-like scores, high self-grooming, impaired prepulse inhibition, and higher susceptibility to seizures when placed in a new empty cage, as compared with wild-type (WT) littermate controls. Control measures of general health, locomotor activity, motor coordination, depression-related behaviors, and sociability did not differ between genotypes. The present findings, indicating detrimental effects of life-long increased BDNF in mice, may inform human studies evaluating the role of BDNF functional genetic variations on cognitive abilities and vulnerability to psychiatric disorders.     

Adult mice maintained on a high-fat diet exhibit object location memory deficits and reduced hippocampal SIRT1 gene expression

Mounting evidence has established that diet-induced obesity (DIO) is associated with deficits in hippocampus-dependent memory. The bulk of research studies dealing with this topic have utilized rats fed a high-fat diet as an experimental model. To date, there has been a paucity of research studies that have established whether the memory deficits exhibited in DIO rats can be recapitulated in mice. Moreover, the majority of experiments that have evaluated memory performance in rodent models of DIO have utilized memory tests that are essentially aversive in nature (i.e., Morris water maze). The current study sought to fill an empirical void by determining if mice maintained on a high-fat diet exhibit deficits in two non-aversive memory paradigms: novel object recognition (NOR) and object location memory (OLM). Here we report that mice fed a high-fat diet over 23 weeks exhibit intact NOR, albeit a marked impairment in hippocampus-dependent OLM. We also determined the existence of corresponding aberrations in gene expression within the hippocampus of DIO mice. DIO mice exhibited significant reductions in both SIRT1 and PP1 mRNA within the hippocampus. Our data suggest that mice maintained on a high-fat diet present with impaired hippocampus-dependent spatial memory and a corresponding alteration in the expression of genes that have been implicated in memory consolidation.