Effects of Caloric Restriction on Spatial Object Recognition Memory, Hippocampal Neuron Loss and Neuroinflammation in Aged Rats.

Age-related neurobiological changes significantly affect hippocampal structure and function, such that the main cognitive impairments associated with aging are related to the integrity of this brain structure, including the deterioration in spatial object recognition (SOR) memory. Previous studies have shown that intrinsic factors such as neuroinflammation, as well as lifestyle factors such as diet, can affect aging-associated brain functions and cognitive performance. In this regard, caloric restriction (CR) produces beneficial effects on health and life expectancy, although its ability to slow down age-dependent effects on cognitive decline and hippocampus (HPC) functioning remains unclear. Therefore, we set out to evaluate the effects of CR on SOR memory in aged male Wistar rats, as well as those on hippocampal neuron loss, neurogenesis and inflammation. The data show that CR in aged rats attenuates the decline in SOR memory, age-associated hippocampal neuron loss, and age-dependent microglial activation. Furthermore, we found a significant reduction in neurogenesis in the dentate gyrus of the old animals relative to adult rats. These findings support the positive effect of CR on SOR memory, suggesting that it dampens hippocampal neuronal loss and reduces proinflammatory activity.

Effects of caloric restriction on monoaminergic neurotransmission, peripheral hormones, and olfactory memory in aged rats.

Aging is associated with a reduced ability to identify and discriminate scents, and olfactory dysfunction has been linked to preclinical stages of neurodegenerative diseases in humans. Moreover, emerging evidence suggests that smell-driven behaviors are regulated by hormones like insulin or leptin, and by metabolic parameters like glucose, which in turn may influence monoaminergic neurotransmission in brain areas related to cognition. Several studies have suggested that dietary interventions like caloric restriction (CR) can mitigate the age-induced decline in memory by modifying metabolic parameters and brain monoaminergic levels. The present study explored the effects of CR on age-dependent olfactory memory deficits, as well as their relationship with peripheral leptin, insulin and glucose levels, and brain monoamines. To this end, aged rats (24-months-old) fed on a CR diet or with ad libitum access to food, and adult rats (3-4 months), were trained in an odor discrimination task (ODT). The peripheral plasma levels of insulin, leptin, and glucose, and of monoamines and metabolites/precursors in brain areas related to olfactory learning and memory processes, such as the striatum and frontal cortex (FC), were determined. The data obtained indicated that CR attenuated the age-dependent decline in olfactory sensitivity in old animals fed ad libitum, which was correlated with the performance in ODT retention trial, as well as with leptin plasma levels. CR enhanced dopamine levels in the striatum, while it attenuated the age-related decline in serotonin levels in the striatum and FC. Such findings support a positive effect of CR on age-dependent olfactory sensitivity decline and dysfunctions in brain monoamine levels.

Caloric restriction modulates the monoaminergic and glutamatergic systems in the hippocampus, and attenuates age-dependent spatial memory decline.

The beneficial effects of caloric restriction (CR) on health and life expectancy are well documented, although its ability to slow down age-dependent cognitive decline and the underlying biochemical changes remains unclear. Therefore, the aim of this study was to investigate the effects of CR on spatial memory in aged Wistar rats, as well as on monoaminergic and glutamatergic neurotransmission in the hippocampus (HPC). As such, animals maintained on different dietary regimes were trained in the Morris Water Maze (MWM): old rats (24-27 months) maintained on a 30% CR diet from four months of age, old rats (24-27 months) with unrestricted access to food (Ad Libitum); and adult rats (3-4 months) with Ad Libitum access to food. As well as their performance in the spatial memory task, monoamine levels, and NMDA and AMPA receptor subunit expression in the HPC were also assessed in these rats, as was the plasma corticosterone as a measure of the pituitary-adrenal response to stress. Accordingly, it appears that CR attenuates the spatial memory decline in aged rats and the age-associated decrease in the serotonin metabolite 5-HIAA, as well as the expression of the GluA1 and GluA2 AMPA receptor subunits in the HPC. In addition, CR augments the noradrenaline in this structure, although it did not modify the age-associated increase in plasma corticosterone levels. These findings support the positive effect of CR on spatial memory, suggesting that enhancing monoaminergic and glutamatergic neurotransmission in the HPC may help improve learning and memory in aged animals.

Envejecimiento y memoria: efectos de la restricción calórica / Caloric restriction and memory during aging

Introducción. El conocimiento de los mecanismos cerebrales involucrados en el proceso de envejecimiento y el deterioro mental podría ser clave para el desarrollo de pautas de conducta que garanticen alcanzar edades avanzadas con la máxima calidad de vida posible y reducir la pérdida cognitiva asociada a la senectud. Objetivo. Describir y analizar diferentes investigaciones con animales y humanos que demuestran que una dieta con restricción calórica aminora el envejecimiento cerebral y el declive cognitivo asociados a la edad. Desarrollo. Desde hace más de 100 años se conoce que la restricción calórica incrementa la longevidad de los animales de laboratorio. Este efecto parece derivar de la disminución de algunos síntomas que acompañan al envejecimiento, como la obesidad, la aparición de tumores cancerígenos y algunas enfermedades metabólicas. Sin embargo, mientras las consecuencias de la restricción calórica sobre la salud están bien determinadas, su capacidad para frenar el declive cognitivo que acompaña al envejecimiento sigue siendo un tema controvertido. La investigación de los efectos de la restricción calórica en animales de laboratorio proporciona los primeros avances para la comprensión de sus efectos beneficiosos en la neurobiología de los procesos cognitivos durante el envejecimiento. Conclusiones. La restricción calórica atenúa el envejecimiento normal o patológico del cerebro y reduce los problemas de memoria asociados a la vejez. La intervención dietética podría convertirse en un método muy eficaz para fomentar una mejor calidad de vida y prevenir el déficit cognitivo que acompaña a la ancianidad

Introduction. To understand the underlying brain mechanisms involved in the aging process and mental deterioration could be key to the development of behavioral patterns that guarantee reaching advanced ages with the highest possible quality of life and reduce the cognitive loss associated with senescence. Aim. To describe and analyze different animal and human studies that demonstrate that a caloric restriction diet may rescue cerebral aging and the cognitive decline associated to aging. Development. For more than 100 years it has been known that caloric restriction extends life span in many laboratory animal. This effect seems to derive from the reduction of age-related symptoms, such as obesity, the onset of cancerous tumors and some metabolic diseases. However, while the consequences of caloric restriction on health are well-established, their ability to reverse age-dependent memory deficits remains a controversial issue. The analyses of the effects of caloric restriction on different animals provides progress for the understanding of its beneficial effects on the neurobiology of cognitive processes during aging. Conclusions. Caloric restriction attenuates the normal or pathological aging of the brain and reduces age-related memory problems. Dietary intervention could become a very effective method to promote a better quality of life and prevent the age-related cognitive deficits

Intra-hippocampal D-cycloserine rescues decreased social memory, spatial learning reversal, and synaptophysin levels in aged rats.

RATIONALE: Aging is characterized by a decrease in N-methyl-D-aspartate receptors (NMDARs) in the hippocampus, which might be one of the factors involved in the age-dependent cognitive decline. D-Cycloserine (DCS), a partial agonist of the NMDAR glycine recognition site, could improve memory deficits associated to neurodegenerative disorders and cognitive deficits observed in normal aging. OBJECTIVES AND METHODS: The aim of the present study was to explore whether DCS would reverse age-dependent memory deficits and decreases in NMDA receptor subunits (GluN1, GluN2A, and GluN2B) and the presynaptic protein synaptophysin in Wistar rats. We investigated the effects of pre-training infusions of DCS (10 µg/hemisphere) in the ventral hippocampus on two hippocampal-dependent learning tasks, the social transmission of food preference (STFP), and the Morris water maze (MWM). RESULTS: The results revealed that infusions of DCS administered before the acquisition sessions rescued deficits in the STFP retention and MWM reversal learning in old rats. DCS also significantly increased the hippocampal levels of synaptophysin in old rats, which correlated with STFP and MWM performance in all tests. Moreover, although the levels of the GluN1 subunit correlated with the MWM acquisition and reversal, DCS did not enhance the expression of such synaptic protein. CONCLUSIONS: The present behavioral results support the role of DCS as a cognitive enhancer and suggest that enhancing the function of NMDARs and synaptic plasticity in the hippocampus may be related to improvement in social memory and spatial learning reversal in aged animals.

Parafascicular thalamic nucleus deep brain stimulation decreases NMDA receptor GluN1 subunit gene expression in the prefrontal cortex.

The rodent parafascicular nucleus (PFn) or the centromedian-parafascicular complex of primates is a posterior intralaminar nucleus of the thalamus related to cortical activation and maintenance of states of consciousness underlying attention, learning and memory. Deep brain stimulation (DBS) of the PFn has been proved to restore arousal and consciousness in humans and to enhance performance in learning and memory tasks in rats. The primary expected effect of PFn DBS is to induce plastic changes in target neurons of brain areas associated with cognitive function. In this study, Wistar rats were stimulated for 20mins in the PFn following a DBS protocol that had previously facilitated memory in rats. NMDA and GABAB receptor binding, and gene expression of the GluN1subunit of the NMDA receptor (NMDAR) were assessed in regions related to cognitive functions, such as the prefrontal cortex and hippocampus. The results showed that PFn DBS induced a decrease in NMDAR GluN1 subunit gene expression in the cingulate and prelimbic cortices, but no significant statistical differences were found in the density of NMDA or GABAB receptors in any of the analyzed regions. Taken together, our findings suggest a possible role for the NMDAR GluN1 subunit in the prefrontal cortex in the procognitive actions of the PFn DBS.

D-cycloserine prevents relational memory deficits and suppression of long-term potentiation induced by scopolamine in the hippocampus.

Previous research has demonstrated that systemic D-cycloserine (DCS), a partial agonist of the N-methyl-D-aspartate receptor (NMDAR), enhances memory processes in different learning paradigms and attenuates mnemonic deficits produced by diverse pharmacological manipulations. In the present study two experiments were conducted in rats to investigate whether DCS administered in the hippocampus may rescue relational memory deficits and improve deficient synaptic plasticity, both induced by an intracerebral injection of the muscarinic receptor antagonist scopolamine (SCOP). In experiment 1, we assessed whether DCS would prevent SCOP-induced amnesia in an olfactory learning paradigm requiring the integrity of the cholinergic system, the social transmission of food preference (STFP). The results showed that DCS (10 µg/site) injected into the ventral hippocampus (vHPC) before STFP acquisition compensated the 24-h retention deficit elicited by post-training intra-vHPC SCOP (40 µg/site), although it did not affect memory expression in non-SCOP treated rats. In experiment 2, we evaluated whether the perfusion of DCS in hippocampal slices may potentiate synaptic plasticity in CA1 synapses and thus recover SCOP-induced deficits in long-term potentiation (LTP). We found that DCS (50 µM and 100 µM) was able to rescue SCOP (100 µM)-induced LTP maintenance impairment, in agreement with the behavioral findings. Additionally, DCS alone (50 µM and 100 µM) enhanced field excitatory postsynaptic potentials prior to high frequency stimulation, although it did not significantly potentiate LTP. Our results suggest that positive modulation of the NMDAR, by activation of the glycine-binding site, may compensate relational memory impairments due to hippocampal muscarinic neurotransmission dysfunction possibly through enhancements in LTP maintenance.

D-cycloserine in prelimbic cortex reverses scopolamine-induced deficits in olfactory memory in rats.

A significant interaction between N-methyl-D-aspartate (NMDA) and muscarinic receptors has been suggested in the modulation of learning and memory processes. The present study further investigates this issue and explores whether d-cycloserine (DCS), a partial agonist at the glycine binding site of the NMDA receptors that has been regarded as a cognitive enhancer, would reverse scopolamine (SCOP)-induced amnesia in two olfactory learning tasks when administered into the prelimbic cortex (PLC). Thus, in experiment 1, DCS (10 µg/site) was infused prior to acquisition of odor discrimination (ODT) and social transmission of food preference (STFP), which have been previously characterized as paradigms sensitive to PLC muscarinic blockade. Immediately after learning such tasks, SCOP was injected (20 µg/site) and the effects of both drugs (alone and combined) were tested in 24-h retention tests. To assess whether DCS effects may depend on the difficulty of the task, in the STFP the rats expressed their food preference either in a standard two-choice test (experiment 1) or a more challenging three-choice test (experiment 2). The results showed that bilateral intra-PLC infusions of SCOP markedly disrupted the ODT and STFP memory tests. Additionally, infusions of DCS alone into the PLC enhanced ODT but not STFP retention. However, the DCS treatment reversed SCOP-induced memory deficits in both tasks, and this effect seemed more apparent in ODT and 3-choice STFP. Such results support the interaction between the glutamatergic and the cholinergic systems in the PLC in such a way that positive modulation of the NMDA receptor/channel, through activation of the glycine binding site, may compensate dysfunction of muscarinic neurotransmission involved in stimulus-reward and relational learning tasks.

The AMPA receptor modulator S18986 in the prelimbic cortex enhances acquisition and retention of an odor-reward association.

Systemic administration of S18986, a positive allosteric modulator of AMPA receptors, improves cognition. The present study further characterizes the drug's memory-enhancing properties and is the first to investigate its intracerebral effects on learning and memory. The results showed that rats receiving a single dose of S18986 (3 µg/site) into the prelimbic cortex, prior to olfactory discrimination acquisition, exhibited significantly shorter latencies and fewer errors to make the correct response, both in the acquisition and two drug-free retention tests. Such findings corroborate the involvement of glutamate receptors in odor-reward learning and confirm the role of the AMPAkine S18986 as a cognitive enhancer.

Learning deficits in an odor reward-task induced by parafascicular thalamic lesions are ameliorated by pretraining D-cycloserine in the prelimbic cortex.

We investigated whether the N-methyl-D-aspartate (NMDA) receptor partial agonist D-cycloserine (DCS) infused into the prelimbic cortex (PLC) would reverse the learning deficits caused by bilateral excitotoxic lesions of the parafascicular nucleus (PFn) in an odor discrimination task (ODT). Rats with PFn lesions received a bilateral infusion of DCS (10 µg/side) into the PLC 20 min before ODT acquisition. The task retention was evaluated in a drug-free test carried out 24 h later. DCS significantly attenuated the PFn lesion-induced deficits as measured by both latency to nose-poke the rewarded odor and number of errors committed during ODT acquisition and retention. Therefore, DCS may be an enhancing memory treatment in animal models of cognitive impairment, such as PFn-lesioned rats. The PFn contribution to learning and memory may possibly be linked to its role in the modulation of glutamatergic PLC activity.

D-cycloserine in the basolateral amygdala prevents extinction and enhances reconsolidation of odor-reward associative learning in rats.

It is well established that D-cycloserine (DCS), a partial agonist of the NMDA receptor glycine site, enhances learning and memory processes. Although the effects of DCS have been especially elucidated in the extinction and reconsolidation of aversive behavioral paradigms or drug-related behaviors, they have not been clearly determined in appetitive tasks using natural reinforcers. The current study examined the effects of pre-retrieval intra-basolateral amygdala (BLA) infusions of DCS on the extinction and reconsolidation of an appetitive odor discrimination task. Rats were trained to discriminate between three odors, one of which was associated with a palatable food reward, and, 20 min prior to extinction learning (experiment 1) or reactivation (experiment 2), they received bilateral intra-BLA infusions of DCS or vehicle. In experiment 1, DCS infusion reduced the rate of extinction learning, weakened extinction retention in a post-extinction test and enhanced reacquisition of the ODT task. In experiment 2, DCS improved subsequent memory expression in the reconsolidation test performed one day after the reactivation session. Such results indicate the involvement of BLA NMDA receptors in odor-food reward associative memory and suggest that DCS may potentiate the persistence or strength of the original memory trace.

Effects of muscarinic receptor antagonism in the basolateral amygdala on two-way active avoidance.

The aim of the present study was to investigate whether the blockade of muscarinic receptors (mRs) in the basolateral amygdala (BLA), which receives important cholinergic inputs related to avoidance learning, affects the consolidation of two-way active avoidance (TWAA). In Experiment 1, adult male Wistar rats were bilaterally infused with scopolamine (SCOP, 20 µg/site) or PBS (VEH) in the BLA immediately after a single 30-trial acquisition session. Twenty-four hours later, avoidance retention was tested in an identical session. Results indicated that scopolamine in the BLA did not affect TWAA performance measured by the number of avoidance responses. Experiment 2 was conducted to test whether such a negative outcome might be due to the occurrence of overtraining during acquisition, which may indeed have a protective effect against scopolamine-induced memory deficits. In this experiment, rats were infused with scopolamine in the BLA immediately after a brief 10-trial acquisition session and tested 24 h later in a 30-trial retention session. The SCOP group showed significantly more avoidances and inter-trial crossings in the retention session than the VEH rats. Together, these results reveal that mRs blockade in the BLA does not disrupt TWAA consolidation and may even enhance avoidance performance when infused after a low number of acquisition trials. Performance factors, such as locomotor activity in the shuttle-box, may account, at least in part, for the facilitative effects of muscarinic antagonism in the BLA.

Núcleos intralaminares posteriores del tálamo y procesos cognitivos / Posterior intralaminar nuclei of the thalamus and cognitive processes

Introducción. El núcleo parafascicular en las ratas y el complejo centromediano parafascicular en los primates y otros mamíferos constituyen los llamados núcleos intralaminares posteriores (ILp) del tálamo. Al igual que el sistema reticular activador ascendente y el de los ganglios basales-tálamo-cortical, los núcleos ILp forman parte de los sistemas de arousal cerebral. Objetivo. Describir y analizar diferentes investigaciones experimentales con animales y trabajos clínicos en humanos que sugieren que los núcleos ILp podrían formar parte de un sustrato neurofisiológico subcortical relacionado con los procesos de atención, aprendizaje y memoria. Desarrollo. Los estudios de lesión del núcleo parafascicular en ratas y neuropatológicos y de neuroimagen en humanos muestran una relación entre la degeneración de las neuronas de los núcleos ILp y el déficit cognitivo que se observa en diversas tareas de aprendizaje y memoria en animales, en diferentes enfermedades neurológicas y en alteraciones de los estados de consciencia. Conclusiones. Por sus características neuroanatómicas y neurofisiológicas y sus implicaciones funcionales, los núcleos ILp son excelentes candidatos para la investigación de los procesos cognitivos en el ámbito básico de la psicobiología y el clínico de la neurología (AU)

Introduction. The parafascicular nucleus in rats and the centromedian parafascicular complex in primates and other mammals are the so-called posterior intralaminar nuclei (pIL) of the thalamus. Like the ascending reticular activating system and the basal ganglia-thalamocortical circuit, the pIL nuclei are part of the brain arousal systems. Aim. To describe and analyze different animal and human studies suggesting that the pIL could also be part of a neurophysiological subcortical system related to cognitive processes as attention, learning and memory. Development. Both parafascicular nucleus lesion studies in rats and neuropathological and neuroimaging reports in humans, indicate a relationship between the degeneration of pIL neurons and the cognitive deficits observed in learning and memory tasks in animals and also in several human neurological diseases and in consciousness disorders. Conclusions. Considering its neuroanatomical, neurophysiological and functional characteristics, the pIL can be considered excellent candidates for investigating cognitive processes in the field of psychobiology and clinical neurology (AU)

[Posterior intralaminar nuclei of the thalamus and cognitive processes]. / Núcleos intralaminares posteriores del tálamo y procesos cognitivos.

INTRODUCTION: The parafascicular nucleus in rats and the centromedian parafascicular complex in primates and other mammals are the so-called posterior intralaminar nuclei (pIL) of the thalamus. Like the ascending reticular activating system and the basal ganglia-thalamocortical circuit, the pIL nuclei are part of the brain arousal systems. AIM: To describe and analyze different animal and human studies suggesting that the pIL could also be part of a neuro-physiological subcortical system related to cognitive processes as attention, learning and memory. DEVELOPMENT: Both parafascicular nucleus lesion studies in rats and neuropathological and neuroimaging reports in humans, indicate a relationship between the degeneration of pIL neurons and the cognitive deficits observed in learning and memory tasks in animals and also in several human neurological diseases and in consciousness disorders. CONCLUSIONS: Considering its neuroanatomical, neurophysiological and functional characteristics, the pIL can be considered excellent candidates for investigating cognitive processes in the field of psychobiology and clinical neurology.

D-cycloserine in prelimbic cortex enhances relearning of an odor-reward associative task.

We investigated the effects of bilateral infusions in the prelimbic cortex of D-cycloserine (DCS), a partial agonist of the NMDA receptor-associated glycine site. Wistar rats underwent a training session (acquisition, three trials) and a 24-h test (two retention and two relearning trials) of a rapidly learned olfactory discrimination task. Rats infused with DCS (10 microg/site) prior to training exhibited a significant enhancement of performance in such odor-reward task, especially in relearning.

Muscarinic receptor blockade in ventral hippocampus and prelimbic cortex impairs memory for socially transmitted food preference.

Acetylcholine is involved in learning and memory and, particularly, in olfactory tasks, but reports on its specific role in consolidation processes are somewhat controversial. The present experiment sought to determine the effects of blocking muscarinic cholinergic receptors in the ventral hippocampus (vHPC) and the prelimbic cortex (PLC) on the consolidation of social transmission of food preference, an odor-guided relational task that depends on such brain areas. Adult male Wistar rats were bilaterally infused with scopolamine (20 microg/site) immediately after social training and showed impairment, relative to vehicle-injected controls, in the expression of the task measured 24 h after learning. Results indicated that scopolamine in the PLC completely abolished memory, suggesting that muscarinic transmission in this cortical region is crucial for consolidation of recent socially acquired information. Muscarinic receptors in the vHPC contribute in some way to task consolidation, as the rats injected with scopolamine in the vHPC showed significantly lower trained food preference than control rats, but higher than both chance level and that of the PLC-injected rats. Behavioral measures such as social interaction, motivation to eat, neophobia, or exploration did not differ between rats infused with scopolamine or vehicle. Such data suggest a possible differential role of muscarinic receptors in the PLC and the vHPC in the initial consolidation of a naturalistic form of nonspatial relational memory.

Muscarinic transmission in the basolateral amygdala is necessary for the acquisition of socially transmitted food preferences in rats.

We examined the involvement of muscarinic receptors in the basolateral amygdala (BLA) in the social transmission of food preference (STFP) learning by assessing the effects of scopolamine (20 microg/side), injected prior to social training, on a 24-h food-choice test. Muscarinic receptor blockade in the BLA significantly impaired STFP, as shown by the rats' chance preference for the odorized trained food. The present results are consistent with the suggestion that intact cholinergic transmission in the BLA is necessary for acquisition and/or initial consolidation and provide evidence that BLA integrity is part of the underlying circuit of STFP learning.

Induction of c-Fos expression by electrical stimulation of the nucleus basalis magnocellularis.

The present study examined the expression of the immediate-early gene c-fos in different brain regions following a single 20-min session of unilateral electrical stimulation of the nucleus basalis magnocellularis (NBM). Current findings confirm that NBM stimulation provides specific activation of several cortical and subcortical regions closely related to the NBM and involved in learning and memory processes, such as the cingulate, parietal, piriform and perirhinal cortices, dorsal subiculum, and the parafascicular, central lateral and central medial nuclei of the thalamus. In contrast, NBM stimulation did not increase c-Fos expression in some expected areas that receive direct NBM projections such as the entorhinal cortex or amygdala nuclei. Results are discussed in terms of the possibility that NBM electrical stimulation facilitates learning by inducing neural changes related to transcription factors such as c-Fos.

Differential effects of muscarinic receptor blockade in prelimbic cortex on acquisition and memory formation of an odor-reward task.

The present experiments determined the consequences of blocking muscarinic cholinergic receptors of the prelimbic (PL) cortex in the acquisition and retention of an odor-reward associative task. Rats underwent a training test (five trials) and a 24-h retention test (two retention trials and two relearning trials). In the first experiment, rats were bilaterally infused with scopolamine (20 or 5 microg/site) prior to training. Although scopolamine rats showed acquisition equivalent to PBS-injected controls, they exhibited weakened performance in the 24-h retention test measured by number of errors. In the second experiment, rats were injected with scopolamine (20 microg/site) immediately or 1 h after training and tested 24 h later. Scopolamine rats injected immediately showed severe amnesia detected in two performance measures (errors and latencies), demonstrating deficits in retention and relearning, whereas those injected 1 h later showed good 24-h test performance, similar to controls. These results suggest that muscarinic transmission in the PL cortex is essential for early memory formation, but not for acquisition, of a rapidly learned odor discrimination task. Findings corroborate the role of acetylcholine in consolidation processes and the participation of muscarinic receptors in olfactory associative tasks.

Effects of parafascicular excitotoxic lesions on two-way active avoidance and odor-discrimination.

To investigate whether the parafascicular (PF) nucleus of the thalamus is involved in different learning and memory tasks, two experiments were carried out in adult male Wistar rats that were submitted to pre-training bilateral N-methyl-d-aspartate PF infusions (0.15M, pH 7.4; 1.2 microl/side, 0.2 microl/min). In Experiment 1, we evaluated the effects of PF lesions in two identical 30-trial training sessions, separated by a 24-h interval, of a two-way active avoidance conditioning. PF-lesioned rats exhibited impaired performance in both sessions, measured by number of avoidance responses. In Experiment 2, the effects of PF lesions were assessed in a training session (5 trials) and a 24-h retention test (2 retention trials and 2 relearning trials) of an odor-discrimination task. PF lesions did not significantly disrupt the acquisition or the first retention trial, which was not rewarded. However, lesioned animals' performance was clearly affected in subsequent trials, following the introduction of the single non-rewarded trial. Current data are discussed considering evidence that lesions of the PF nucleus affect learning and memory functions mediated by anatomically related areas of the frontal cortex and striatum.