We used functional magnetic resonance imaging (fMRI) to investigate the relation between left and right prefrontal cortex (PFC) and task complexity in episodic memory. In Experiments 1A, 1B, and 1C, left PFC activity (and, in Experiment 1C, right PFC as well) was greater for source identification than for old/new recognition, indicating that left PFC is likely to be recruited when specific features of episodic memories are considered. In Experiment 2, we found greater activity in PFC areas more medial or more ventral to those found in Experiments 1A-1C in successive recognition relative to forced-choice recognition, indicating that the regions of PFC recruited depend on the nature of the task complexity. Furthermore, Experiment 2 provided evidence consistent with the hypothesis that increased processing complexity may require interhemispheric interaction. In Experiments 1A, 1C, and 2, increased task complexity also increased activity in anterior cingulate (ACC), consistent with the idea that ACC interacts with PFC to control processing during remembering.
The prefrontal cortex is one of the latest regions of the neocortex to develop, in both phylogeny and ontogeny. In the primate, the prefrontal cortex is anatomically divided into three major sectors: medial, orbital (or inferior), and dorsolateral. The dorsolateral sector is the association cortex of the convexity of the frontal lobe. Phylogenetically and ontogenetically, this part of the prefrontal cortex is the one to develop last and most. It is the neural substrate of the higher cognitive functions that reach their maximum development in the human brain. The most general and distinctive function of the dorsolateral prefrontal cortex is the temporal organization of goal-directed actions. In the human, this role extends to the domains of speech and reasoning. Two temporally symmetrical and mutually complementary cognitive functions—one retrospective and the other prospective—support that general prefrontal function of temporal organization: (1) active short-term memory, also called working memory; (2) prospective or preparatory set. The dorsolateral prefrontal cortex interacts with other cortical and subcortical structures in those two time-bridging functions at the basis of the temporal organization of behavior.
the next to the last sentence should read as follows:The attentional facilitation is transient, in most cases absent with a cue-mask SOA of 250 msec.
Ovariectomized rats were trained to discriminate discrete sound sequences that varied in time or number. On time trials, the number of sounds was held constant at four, and the duration of the sound sequences was either 2 or 8 sec. On number trials, the duration of the sound sequence was a constant 4 sec, and the number of sounds was two or eight. After reaching criterion, half the rats received injections of 17-β-estradiol 3-benzoate (8 µg per kg bodyweight) for a period of 2 weeks. In Experiment 1, estradiol treatment significantly decreased both the number of training trials completed and discrimination accuracy. For the ovariectomized control rats, the psychophysical functions for time and number had properties that were consistent with those in the previous literature. For the ovariectomized estradiol-treated rats, the psychophysical functions were initially flatter, but as time since estradiol exposure increased, they approached those of control rats. The points of subjective equality were equivalent for estradiol-treated and control rats, and both groups performed with higher accuracy on time trials than on number trials. In Experiment 2, prefeeding the rats before a session decreased the number of trials completed but had no significant effect on discrimination accuracy. Therefore, estradiol’s effect on the accuracy of time and number discriminations in Experiment 1 was not due to its effect on food motivation. These findings are discussed in terms of the internal clock model, their relation to studies of spatial processing, and implications for human health.
Numerous brain lesion and functional neuroimaging studies have suggested that the dorsolateral and frontopolar prefrontal regions are involved in complex cognitive processes subserving thought and memory. However, previously proposed functional subdivisions of prefrontal function have concentrated predominantly on posterior prefrontal cortex, including the dorsolateral, ventral, and medial regions. Far less consideration has been given to characterizing the psychological processes mediated by the frontopolar cortex. Here we review published neuroimaging studies of reasoning and episodic memory, two domains in which the frontopolar cortex has been frequently activated. The results suggest that dorsolateral prefrontal cortex is involved when externally generated information is being evaluated, whereas the frontopolar cortex becomes recruited when internally generated information needs to be evaluated. A hierarchical model of prefrontal function is proposed in which dorsolateral and frontopolar regions are serially recruited as a reasoning or memory task requires evaluation of internally generated information.
Five temporal aspects of the production of a conditioned response (CR) have been documented. Most of these phenomena were demonstrated using short-delay conditioning procedures, which are appropriate for eyeblink CRs. Relatively less is known about temporal aspects of CR production in longer delay conditioning procedures, which are common, for example, in studies of fear conditioning. Here, we show through computer simulations that our circuit-level model of fear conditioning predicts that these five time-domain phenomena should also be witnessed in longer delay conditioning procedures, provided that a suitable behavioral or neural probe is used. We explain how and why these phenomena emerge naturally from this general type of circuit-level model, which relies on intrinsic neuronal dynamics for time-domain computations, and we point out that the model furnishes a computational platform for Pavlov's original notion of a slowly spreading "wave of excitation." In accordance with Pavlov's thinking, these Various temporal phenomena are captured using a contiguity-driven learning mechanism.
The clomipramine (CLI) model of depression was used to examine whether exercise has antidepressant-like effects. Male Sprague-Dawley pups were injected with CLI-HCl (40 mg/kg/day) from age 8 to 21 days. At age 4 weeks, rats were assigned to one of five conditions: (1) sedentary; (2) 24-h access to an activity wheel; (3) sedentary + imipramine-HCl (10 mg/kg/twice daily) during the last 10 days of the experiment; (4) wheel running + imipramine; (5) daily treadmill running. At age 16 weeks, rats underwent sex behavior testing. The rate of copulation was lower in the sedentary CLI-treated group than in the saline controls. Reductions in measures of sexual arousal and levels of monoamines were consistent with the CLI model of depression but were smaller than expected. Wheel runners had more frequent mounts, intromissions, and ejaculations relative to the other groups. Norepinephrine levels in brain frontal cortex were higher in all running groups and the imipramine group relative to the sedentary CLI and saline groups. Radioligand [125I] binding density (BMax) of β-adrenoceptors in frontal cortex was lower for the wheel running, imipramine, and wheel running + imipramine groups. Activity wheel running equaled imipramine treatment for increasing norepinephrine and decreasing BMax, and it exceeded imipramine treatment for increasing male copulatory performance. We conclude that activity wheel running favorably influences several hallmark pharmaco-physiological and behavioral measures of an antidepressant effect but did not alter sexual arousal, a surrogate measure of anhedonia. The weaker than expected effects of CLI treatment indicate that the generalizability of the CLI model requires further elucidation using convergent behavioral, biochemical, and pharmacological measures.
In order to investigate the respective roles of dorsal and ventral parts of the medial prefrontal cortex (mPFC) on a delayed alternation task, the acquisition of which is disrupted by large mPFC lesions (Winocur, 1991), rats with circumscribed lesions to the anterior cingulate (ACd) or the prelimbic-infralimbic (PL-IL) cortex were compared. As was predicted, ACd lesions severely impaired performance, and an analysis of the results suggests an involvement of this region in sequencing temporally ordered behavior. On the other hand, PL-IL lesions had no effect, a finding that was in contrast with previous evidence that PL-IL lesions induced delay-dependent deficits on a similar task (Delatour & Gisquet-Verrier, 1999). However, an important difference between the tasks related to the scheduling of critical delays. Whereas in the previous experiment, delay intervals were increased progressively in a block design, variable intertrial intervals were a constant feature of training in the present Experiment 1. In Experiment 2, rats with PL-IL lesions were administered Delatour and Gisquet-Verrier's (1999) alternation task, but modified to incorporate Winocur's (1991) variable-interval procedure that required less response adjustment. Under these conditions, the PL-IL group performed normally, as in Experiment 1. Taken together, the results provide evidence that the PL-IL cortex is implicated in processes that support attentional mechanisms and behavioral flexibility. Overall, the present results support the general hypothesis of subregionalization of mPFC functions.
Previous work has suggested that the hippocampus (HPC) is not a functionally homogenous structure, because lesions of the septal pole have been found to produce more of a deficit in spatial navigation. To investigate whether this dissociation extends to configural-relational learning, we tested rats with dorsal or ventral HPC lesions in a modified version of the Morris water task and in a discriminative context-conditioning paradigm. Results indicated that dorsal HPC lesions were more efficient in impairing performance in the spatial navigation task but that ventral HPC lesions also had some effect. However, no differences between groups were found in the nonspatial context-conditioning task. Both lesion groups acquired discriminative freezing at a rate identical to that of the controls, but lesioned animals could not acquire preference for the safe environment even after three pairings with shock. Thus, comparison of multiple cues with different emotional valence requires integration along the septotemporal axis of the HPC. Reviewing previous studies, we conclude that although the dorsal HPC pole is more efficient than the ventral in supporting spatial navigation, the dissociation is not absolute. We also hypothesize that physiological activity along the longitudinal axis of the HPC might have particular behavioral relevance. Theoretical implications of this hypothesis are considered.
The contribution of attention to learning was examined in delay, trace, discrimination, and discrimination reversal eyeblink conditioning in young healthy adults. Participants performed either single- or two-cued conditioning paradigms with three levels of distraction: no distraction (full attention), concurrently watching a silent movie, or concurrent verbal shadowing. Conditioning for single-cue delay and trace conditioning paradigms was unaffected by the level of distraction. Conditioning for the two-cue paradigms of discrimination and discrimination reversal was reduced greatly when attention was divided. Silent movie watching allowed for some acquisition (CRs to the CS+) but no discrimination (differential responses to CS+ vs. CS−). Verbal shadowing eliminated both acquisition and discrimination. These results indicate that, in the human, attention makes a critical contribution to the successful acquisition of two-cue eyeblink conditioning tasks that require discrimination and discrimination reversal.
Rats with large amygdala lesions (Experiment 1) were compared with sham controls on a conditional discrimination task that allowed assessment of occasion-setting learning. A saccharin solution was paired with lithium chloride in one context, but with saline in a second context. All the groups learned to suppress fluid consumption in the first, relative to the second, context. Sham lesioned rats, but not amygdala-lesioned rats, also showed a large aversion to the first context on a choice test. Shamlesioned Pavlovian control groups, given direct pairings of Context 1 with lithium chloride and of Context 2 with saline, showed large aversions to Context 1, whereas similarly trained amygdala-lesioned rats did not avoid the context associated with lithium chloride. Rats with discrete lesions of either the central nucleus or the basolateral nucleus (Experiment 2) of the amygdala were not impaired on the conditional discrimination task but did show deficits on the place choice test. The data from amygdala-lesioned rats in the present study support previous behavioral data in suggesting that the aversive properties of contextual cues, as acquired through Pavlovian conditioning, are neither necessary nor sufficient for occasion-setting learning.
In the present investigation, we explored the effects of alternating sensory stimuli of two modalities on habituation to those stimuli. The subjects in two control groups participated in 25 trials in which they were exposed to either cutaneous (stimulation of supraorbital nerve) or acoustic (white noise burst) stimuli with a 5-sec interstimulus interval (ISI). The subjects in the experimental group participated in 50 trials in which they were exposed to alternating cutaneous and acoustic stimuli at 2.5-sec ISIs. Habituation in the experimental group, in which the cutaneous stimulus was alternated with acoustic stimuli, was expected to be more rapid than habituation in the control groups, in which the cutaneous stimulus was presented alone, due to the indirect stimulation of the supraorbital nerve by the eyeblinks was elicited by each acoustic stimulus. As predicted, alternating cutaneous and acoustic stimuli enhanced habituation to the cutaneous stimulus. Habituation to the acoustic stimulus was not increased by the interpolation of cutaneous stimuli. These results support the hypothesis that blinking to an acoustic stimulus will generate cutaneous stimuli that interact with direct cutaneous stimulation to engage modulatory processes.
In the present experiments, we examined the effects of posttraining and preretention intra-amygdala infusion of the anesthetic lidocaine on memory consolidation and expression in a food conditioned place preference (CPP) task. In two separate experiments, for 4 alternating days, food deprived adult male Long-Evans rats were given access to food or no access to food during confinement for 30 min to one of two compartments in a place preference apparatus. On Day 9, the rats were given a 20-min test session and allowed access to all compartments of the apparatus. No food was present on the test day, and the amount of time spent in each compartment of the apparatus was recorded. On the test day, rats receiving saline immediately after previous training, or immediately prior to testing, spent more time in the compartment that was previously paired with food, demonstrating a food conditioned place preference (CPP). Posttraining infusion of lidocaine (2% solution, 0.5 µl/side) into the basolateral amygdala blocked acquisition, indicating that this structure is necessary for memory consolidation processes that mediate a food CPP. In contrast, immediate pretest infusion of lidocaine into the basolateral amygdala had no effect on expression of a food CPP. Taken together, the findings suggest a modulatory role for the basolateral amygdala in memory consolidation processes that underlie reward-related learning in a food CPP task.
In this study, we examined the importance of contingent access to a cocaine-related stimulus in the production of cocaine seeking following extinction of lever responding for cocaine. Rats self-administered cocaine for 2 weeks in daily 3-h sessions under a fixed-ratio 1 schedule. A compound stimulus (tone + light) was presented with each infusion. Following seven daily 3-h extinction sessions, rats were reintroduced to the compound stimulus alone. This stimulus was presented in three ways: (1) contingent on lever pressing, (2) noncontingent, and (3) both contingent and noncontingent. Following 3 more extinction days, rats were again reintroduced to the compound stimulus, yet with contingent access to cocaine. Only the two groups with contingent presentation increased lever responding on the 1st day, while all groups increased responding for cocaine on the 2nd day. The need for contingent access to drug-associated stimuli in the absence of drug to produce drug-seeking behavior may be relevant for studies of neural substrates of relapse.
Lateral prefrontal cortex (LPFC) has previously been associated with both attention and working memory. To study both of these mechanisms, patients with LPFC lesions and age-matched controls were tested on working memory tasks that included an interference condition. On a spatial working memory task, patients were impaired overall relative to controls in both no-interference and interference conditions. There was also a significant correlation between patients' performance and the extent of damage to Area 46. Participants were also tested on a color working memory paradigm, in which they had to remember an object's color, rather than location. LPFC patients were disproportionately impaired in the interference condition of this experiment-namely, when they had to perform an interference task during the delay period of the color working memory task. These results are discussed with respect to previous animal and human studies of attention and working memory.
In ovariectomized (ovx), estradiol (E)-primed rats, progesterone (P) facilitates sexual receptivity within 2–30 min following intravenous (i.v.) administration. Intracerebroventricular infusion of P or the dopamine receptor type 1-like (D1) agonist, SKF38393, increases lordosis in ovx, E-primed rats, and intracellular progestin receptor (PR) blockers attenuate P and SKF38393’s facilitation of lordosis. The present experiments examined whether P can have effects via Dl receptors and compared the onset of P’s and SKF38393’s induction of lordosis following i.v. administration. Ovx rats (N = 20) with i.v. jugular catheters were primed daily with 2 µg E subcutaneously and were pretested for sexual receptivity. In Experiment 1, rats (n = 10) were repeatedly tested for receptivity 3–7, 15, 30, 60, and 120 min following i.v. infusion of P (2 µg), SKF38393 (100 ng), and propylene glycol vehicle (0.2 cc). Progesterone increased postinfusion lordosis at all test times, whereas SKF38393’s increases in lordosis were not statistically significant until 15 min following i.v. infusion, relative to lordosis following vehicle or pretest conditions in Experiment 1. In Experiment 2, rats (n = 15; 5 from Experiment 1, and 10 new subjects) received infusions of the antiprogestin, RU38486, the D1 antagonist, SCH23390, or vehicle followed by a second P or vehicle infusion. Although both RU38486 and SCH23390 blocked the facilitatory effects of P on lordosis, their effects varied. RU38486 completely blocked P’s effects, whereas SCH23390 did not. In Experiment 3, rats (n = 15, from Experiment 2) received infusions of RU38486, SCH23390, or vehicle followed by a second SKF38393 or vehicle infusion. RU38486 and SCH23390 both effectively blocked the facilitatory effects of SKF38393 on lordosis. In Experiment 4, rats (n = 15, from Experiment 3) received i.v. infusions of P, which rapidly and significantly increased the number of super-threshold spikes in the ventral tegmental area, but not in the ventral medial hypothalamus or in the parietal cortex. These data suggest that actions at intracellular progestin receptors do not account for all of P’s effects to facilitate receptivity. Interestingly, although PRs may be involved in P and D1 ligand’s activation of female sexual behavior, D1 receptors are not required for P’s effects. However, i.v. P rapidly and significantly alters neuronal activity in sites with the greatest concentration of dopamine neurons (ventral tegmental area > ventral medial hypothalamus > cortex).
The interaction between low-frequency stimulation (LFS; 900 stimuli at 10 Hz) of field excitatory postsynaptic potentials (fEPSPs) and paired-pulse facilitation (PPF; 50- and 100-msec interstimulus intervals, ISIs) was investigated in the projection from hippocampal area CA1 to the subiculum. We also investigated whether LTD can be obtained in the subiculum using a stress protocol (previously described to induce LTD effectively in vivo in area CA1 of the hippocampus; Xu, Anwyl, & Rowan, 1997). Finally, we examined the interaction between the stress treatment and PPF. There was no significant difference between fEPSP amplitude measured at 30 min post-LFS (10 Hz) when compared with baseline fEPSP peak amplitude; PPF, however, increased significantly 30 min post-LFS when compared with PPF pre-LFS for both 50-msec and 100-msec intervals. These results indicate that there is a dissociation between single-pulse stimulation and paired-pulse stimulation of the CAl—subiculum pathway. The combined effect of stress and LFS produced a depression in synaptic response of 56.99% at 5 min post-LFS and 10.23% at 30 min post-LFS. Behavioral stress combined with LFS caused a significant decrease in PPF at 30 min poststimulation. At a 50-msec ISI, facilitation is minimal; at a 100-msec ISI, paired-pulse depression occurs. These data suggest that there possibly are previously undescribed mechanisms regulating transmission in this pathway.
In this brief review, we address the cognitive functions of a subregion of the rat frontal cortex, the prelimbic cortex. Growing evidence suggests that the prelimbic cortex is involved in working memory, defined as the temporary storage of information required for its internal manipulation. However, several factors appear to modulate the extent to which prelimbic damage impairs performance in delayed tasks. These factors, which contribute to the overall difficulty of the task, are related to the attentional requirement of the task and to the response selection mechanisms that underlie correct performance. Impairments induced by prelimbic cortical damage are increased when the task requires the rat to consistently focus its attention on the detection of external events and when the learning rule countradicts either spontaneously used or previously learned strategies. This overall pattern of deficit suggests that the prelimbic cortex is not a pure working memory system. Rather, it subtends a wide range of processes that are required for solving difficult problems. Together with anatomical evidence, the existence of functional similarities between the prelimbic cortex of the rat and the dorsolateral prefrontal cortex of primates suggests some homology between these regions across species. Therefore, the rat prelimbic cortex appears to provide a valuable model system for studying the precursors of higher level cognitive processes in nonhuman and human primates.
Two groups of rats were trained to detect brief, unpredictable visual stimuli in attentional paradigms with different response selection requirements. Animals had to hold their heads in a central location for a variable delay and then respond to either the same (same condition) side as or the opposite (opposite condition) side to where the visual stimulus had occurred. Following bilateral excitotoxic lesions of the medial prefrontal cortex (mPFC), rats in the same condition were impaired relative to controls, as revealed by reductions in choice accuracy and speed of responding. In the opposite condition, mPFC-lesioned animals performed at chance and were faster than controls to respond to the target. These results extend previous findings of accuracy deficit in mPFC-lesioned rats in a five-choice serial reaction time task in which the animals are not required to respond to targets from a fixed position. In addition, the finding of a larger deficit in the opposite condition suggests a more prominent role for the mPFC in the selection of difficult, "incompatible" responses relative to easy, "compatible" ones.
In the present investigation, we sought to determine whether glucose could enhance declarative memory in head-injured individuals, as has been shown previously with elderly and Alzheimer's patients who had preexisting memory impairments. Varsity rugby players, both with and without a history of concussions, were given glucose- or saccharin-sweetened beverages and then tested on a series of neuropsychological tests of attention and memory; their blood-glucose levels were monitored. Beverages and tests were administered in a counterbalanced, crossover design, enabling within-subjects comparisons. Previously concussed participants were found to perform slightly worse than participants with no history of concussions (controls) on the preliminary screening interview tests and tests of memory and divided attention given in the saccharin (placebo) condition. Glucose was shown to enhance performance of the previously concussed participants and impair the performance of controls on tests of long-term declarative memory. The effects of glucose on memory appeared to be related to the participants' ability to clear glucose from the blood.
