Acquisition Of Two-way Active Avoidance Research Articles

Orexin/hypocretin treatment restores hippocampal-dependent memory in orexin-deficient mice

Orexin A is produced in neurons of the lateral, perifornical and dorsomedial regions of the lateral hypothalamic area, which then project widely throughout the central nervous system to regulate arousal state, sleep-wake architecture, energy homeostasis and cognitive processes. Disruption of orexin signaling leads to sleep disturbances and increased body mass index, but recent studies also indicate that orexin neuron activation improves learning and memory. We hypothesized that hippocampal orexin receptor activation improves memory. To test this idea, we obtained orexin/ataxin-3 (O/A3) mice, which become deficient in orexin neurons by about 12 weeks of age. We first measured hippocampal orexin receptor 1 (OX1R) gene expression and protein levels, then tested acquisition and consolidation of two-way active avoidance (TWAA) memory, a hippocampal-dependent learning and memory task. Finally, we determined if exogenous intra-hippocampal OXA treatment could reverse cognitive impairment (as determined by TWAA) in OA/3 mice. We showed that OX1R mRNA expression and protein levels were significantly elevated in O/A3 mice, indicating the potential for preserved orexin responsiveness. The O/A3 mice were significantly impaired in TWAA memory vs. control mice, but OXA treatment (both acute and chronic) reversed these memory deficits. These results demonstrate that orexin plays an important role in hippocampal-dependent consolidation of two-way active avoidance memory, and orexin replacement can rescue the cognitive impairment.

Neonatal handling enduringly decreases anxiety and stress responses and reduces hippocampus and amygdala volume in a genetic model of differential anxiety: Behavioral-volumetric associations in the Roman rat strains

The hippocampus and amygdala have been proposed as key neural structures related to anxiety. A more active hippocampus/amygdala system has been related to greater anxious responses in situations involving conflict/novelty. The Roman Low- (RLA) and High-avoidance (RHA) rat lines/strains constitute a genetic model of differential anxiety. Relative to RHA rats, RLA rats exhibit enhanced anxiety/fearfulness, augmented hippocampal/amygdala c-Fos expression following exposure to novelty/conflict, increased hippocampal neuronal density and higher endocrine responses to stress. Neonatal handling (NH) is an environmental treatment with long-lasting anxiety/stress-reducing effects in rodents. Since hippocampus and amygdala volume are supposed to be related to anxiety/fear, we hypothesized a greater volume of both areas in RLA than in RHA rats, as well as that NH treatment would reduce anxiety and the volume of both structures, in particular in the RLA strain. Adult untreated and NH-treated RHA and RLA rats were tested for anxiety, sensorimotor gating (PPI), stress-induced corticosterone and prolactin responses, two-way active avoidance acquisition and in vivo 7 T 1H-Magnetic resonance image. As expected, untreated RLA rats showed higher anxiety and post-stress hormone responses, as well as greater hippocampus and amygdala volumes than untreated RHA rats. NH decreased anxiety/stress responses, especially in RLA rats, and significantly reduced hippocampus and amygdala volumes in this strain. Dorsal striatum volume was not different between the strains nor it was affected by NH. Finally, there were positive associations (as shown by correlations, factor analysis and multiple regression) between anxiety and PPI and hippocampus/amygdala volumes.

Association between prepulse inhibition of the startle response and latent inhibition of two-way avoidance acquisition: A study with heterogeneous NIH-HS rats

This study presents the first evaluation of the associations between responses in two paradigms related to schizophrenia in the genetically heterogeneous NIH-HS rat stock. NIH-HS rats are a stock of genetically heterogeneous animals that have been derived from eight different inbred strains. A rotational breeding schedule has been followed for more than eighty generations, leading to a high level of genetic recombination that makes the NIH-HS rats a unique tool for studying the genetic basis of (biological, behavioral, disease-related) complex traits. Previous work has dealt with the characterization of coping styles, cognitive and anxiety/fear-related profiles of NIH-HS rats. In the present study we have completed their characterization in two behavioral models, prepulse inhibition (PPI) and latent inhibition (LI) of the two-way active avoidance response, that appear to be related to schizophrenia or to schizophrenia-relevant symptoms. We have found that these rats display PPI for each of the four prepulse intensities tested, allowing their stratification in high, medium and low PPI subgroups. When testing these three subgroups for LI of two-way active avoidance acquisition it has been observed that the LowPPI and MediumPPI subgroups present impaired LI, which, along with the fact that the HighPPI group presents significant LI, allows us to hypothesize that responses in these two paradigms are somehow related and that selection of NIH-HS rats for Low vs HighPPI could make a promising animal model for the study of clusters of schizophrenia-relevant symptoms and their underlying neurobiological mechanisms.

Spatial learning in the genetically heterogeneous NIH-HS rat stock and RLA-I/RHA-I rats: Revisiting the relationship with unconditioned and conditioned anxiety

To characterize learning/memory profiles for the first time in the genetically heterogeneous NIH-HS rat stock, and to examine whether these are associated with anxiety, we evaluated NIH-HS rats for spatial learning/memory in the Morris water maze (MWM) and in the following anxiety/fear tests: the elevated zero-maze (ZM; unconditioned anxiety), a context-conditioned fear test and the acquisition of two-way active avoidance (conditioned anxiety). NIH-HS rats were compared with the Roman High- (RHA-I) and Low-Avoidance (RLA-I) rat strains, given the well-known differences between the Roman strains/lines in anxiety-related behavior and in spatial learning/memory. The results show that: (i) As expected, RLA-I rats were more anxious in the ZM test, displayed more frequent context-conditioned freezing episodes and fewer avoidances than RHA-I rats. (ii) Scores of NIH-HS rats in these tests/tasks mostly fell in between those of the Roman rat strains, and were usually closer to the values of the RLA-I strain. (iii) Pigmented NIH-HS (only a small part of NIH-HS rats were albino) rats were the best spatial learners and displayed better spatial memory than the other three (RHA-I, RLA-I and NIH-HS albino) groups. (iv) Albino NIH-HS and RLA-I rats also showed better learning/memory than the RHA-I strain. (v) Within the NIH-HS stock, the most anxious rats in the ZM test presented the best learning and/or memory efficiency (regardless of pigmentation). In summary, NIH-HS rats display a high performance in spatial learning/memory tasks and a passive coping strategy when facing conditioned conflict situations. In addition, unconditioned anxiety in NIH-HS rats predicts better spatial learning/memory.

Nucleus accumbens core lesions enhance two-way active avoidance

The majority of work examining the nucleus accumbens core (NAc) has focused on functions pertaining to behaviors guided by appetitive outcomes. These studies have pointed to the NAc as being critical for motivating behavior toward desirable outcomes. For example, we have recently shown that lesions of the NAc impaired performance on a reward-guided decision-making task that required rats to choose between differently valued rewards. Unfortunately, much less is known about the role that the NAc plays in motivating behavior when aversive outcomes are predicted. To address this issue we asked if NAc lesions impact performance on a two-way active avoidance task in which rats must learn to shuttle back and forth in a behavioral training box in order to avoid a footshock predicted by an auditory tone. Although bilateral NAc lesions initially impaired reward-guided decision-making, we found that the same lesions improved acquisition and retention of two-way active avoidance.

Coping style and stress hormone responses in genetically heterogeneous rats: Comparison with the Roman rat strains

The purpose of the present study was to evaluate for the first time the stress-induced hypothalamus–pituitary–adrenal (HPA), adrenocorticotropic hormone (ACTH), corticosterone and prolactin responses of the National Institutes of Health genetically heterogeneous rat stock (N/Nih-HS rats) in comparison with responses of the relatively high and low stress-prone Roman Low- (RLA-I) and High-Avoidance (RHA-I) rat strains. The same rats were also compared (experiment 1) with respect to their levels of unconditioned anxiety (elevated zero-maze test), novelty-induced exploratory behavior, conditioned fear and two-way active avoidance acquisition. In experiment 2, naive rats from these three strains/stocks were evaluated for “depressive-like” behavior in the forced swimming test. N/Nih-HS and RLA-I rats showed significantly higher post-stress ACTH, corticosterone and prolactin levels than RHA-I rats. N/Nih-HS rats also presented the highest context-conditioned freezing responses, extremely poor two-way avoidance acquisition and very low novelty-induced exploratory behavior. Experiment 2 showed that, compared to RHA-I rats, N/Nih-HS and RLA-I rats displayed significantly less struggling (escape-directed) and increased immobility responses in the forced swimming test. Factor analysis of data from experiment 1 showed associations among behavioral and hormonal responses, with a first factor comprising high loadings of elevated zero-maze variables and lower loadings of conditioned fear, two-way avoidance acquisition and hormonal measures, while a second factor mainly grouped conditioned fear and two-way avoidance acquisition with novelty-induced exploration and post-stress prolactin. Thus, regarding their anxiety/fearfulness, passive coping style, “depressive-like” and stress-induced hormonal responses the N/Nih-HS rats resemble the phenotype profiles of the relatively high-anxious and stress-prone RLA-I rat strain.

Effects of environmental and physiological covariates on sex differences in unconditioned and conditioned anxiety and fear in a large sample of genetically heterogeneous (N/Nih-HS) rats

Physiological and environmental variables, or covariates, can account for an important portion of the variability observed in behavioural/physiological results from different laboratories even when using the same type of animals and phenotyping procedures. We present the results of a behavioural study with a sample of 1456 genetically heterogeneous N/Nih-HS rats, including males and females, which are part of a larger genome-wide fine-mapping QTL (Quantitative Trait Loci) study. N/Nih-HS rats have been derived from 8 inbred strains and provide very small distance between genetic recombinations, which makes them a unique tool for fine-mapping QTL studies. The behavioural test battery comprised the elevated zero-maze test for anxiety, novel-cage (open-field like) activity, two-way active avoidance acquisition (related to conditioned anxiety) and context-conditioned freezing (i.e. classically conditioned fear). Using factorial analyses of variance (ANOVAs) we aimed to analyse sex differences in anxiety and fear in this N/Nih-HS rat sample, as well as to assess the effects of (and interactions with) other independent factors, such as batch, season, coat colour and experimenter. Body weight was taken as a quantitative covariate and analysed by covariance analysis (ANCOVA). Obliquely-rotated factor analyses were also performed separately for each sex, in order to evaluate associations among the most relevant variables from each behavioural test and the common dimensions (i.e. factors) underlying the different behavioural responses. ANOVA analyses showed a consistent pattern of sex effects, with females showing less signs of anxiety and fear than males across all tests. There were also significant main effects of batch, season, colour and experimenter on almost all behavioural variables, as well as "sex × batch", "sex × season" and "sex × experimenter" interactions. Body weight showed significant effects in the ANCOVAs of most behavioural measures, but sex effects were still present in spite of (and after controlling for) these "body weight" effects. Factor analyses of relevant variables from each test showed a two-fold factor structure in both sexes, with the first factor mainly representing anxiety and conditioned fear in males, while in females the first factor was dominated by loadings of activity measures. Thus, besides showing consistent sex differences in anxiety-, fear- and activity-related responses in N/Nih-HS rats, the present study shows that females' behaviour is predominantly influenced by activity while males are more influenced by anxiety. Moreover, the results point out that, besides "sex" effects, physiological variables such as colour and body weight, and environmental factors as batch/season or "experimenter", have to be taken into account in both behavioural and quantitative genetic studies because of their demonstrated influences on phenotypic outcomes.

Two-way avoidance acquisition is negatively related to conditioned freezing and positively associated with startle reactions: A dissection of anxiety and fear in genetically heterogeneous rats

The double, fear-driven "passive avoidance/active avoidance" conflict appearing during acquisition of two-way active avoidance, involves high levels of anxiety and a dominant tendency for freezing responses, which in turn run against the appearance of active escape/avoidance behavior. In the present study, by using a large sample genetically heterogeneous (N/Nih-HS) rats, we have tested the hypothesis that rats showing relatively higher levels of context-conditioned freezing (during the initial trials of that task) should show lower efficiency to acquire two-way avoidance behavior, i.e. the prediction that the initial context-conditioned freezing in the shuttle box would be negatively related to avoidance acquisition efficiency. In agreement with such a hypothesis, the results from the three rat subsamples used show that context-conditioned freezing (during the first 5 inter-trial intervals of the 40-trial two-way avoidance session) is negatively correlated (r=-0.34 to r=-0.64, p<0.001) with two-way avoidance acquisition, in a way that subgroups of rats with extremely high or low levels of freezing markedly differ in their avoidance performance: "high freezer" rats show much worse avoidance acquisition than "low freezers". Moreover, the relationships of conditioned freezing and avoidance acquisition with baseline and fear-potentiated startle, as well as with unconditioned anxiety (in the elevated zero-maze test), have also been studied. Taken collectively, the results indicate that: (i) context conditioned freezing is a reliable (and negative) predictor of two-way avoidance acquisition; (ii) baseline and fear-potentiated startle responses show positive associations with avoidance responding, and (iii) unconditioned anxiety in the elevated zero-maze is also negatively associated with two-way avoidance acquisition. Such patterns of associations are considered to be very informative in regard to the search for (common or differential) neural and genetic mechanisms of different forms of (unlearned or learned) anxious or fear responses.

Unlearned anxiety predicts learned fear: A comparison among heterogeneous rats and the Roman rat strains

Anxiety-related behaviors were evaluated across five tests in a sample of 277 rats from a genetically heterogeneous stock (N/Nih-HS rats), derived from an eight-way cross of inbred strains, and compared with the performance of RLA-I (high anxious) and RHA-I (low anxious) rats in the same tests. These tests either evoke unlearned (novel-cage activity (NACT), elevated “zero” maze (ZM), baseline acoustic startle response (BAS)) or learned (fear-potentiated startle (FPS), two-way active-shuttle box-avoidance acquisition (SHAV)) anxious/fearful responses. The results overall showed that unlearned anxiety responses/behaviors were predictive of behavior in learned fear (i.e. fear-potentiated startle) and conflict (i.e. two-way active avoidance acquisition) situations. Moreover, it was found that N/Nih-HS rats either resemble RLA-I rat anxiety/fear scores or fall in between those of the RLA-I (high anxious) and the RHA-I (low anxious) rat strains. An additional regression analysis (of N/Nih-HS rat data) showed significant positive influences of (unlearned) baseline startle response, risk assessment (i.e. stretch-attend) behavior and activity (5 min) in a novel cage on SHAV acquisition, while baseline startle and entries into the open section of the elevated ‘zero’ maze test of anxiety were the main variables influencing FPS. This indicates that startle responses may have a facilitating role in the rat's active responses in the two-way active (shuttlebox) avoidance acquisition. The results of this behavioral evaluation of N/Nih-HS rats show that unconditioned anxiety (e.g. in the ZM test) predicts learned fear-related responses (e.g. FPS and SHAV) to some extent, while a positive association is also observed between BAS and SHAV. These findings are discussed in terms of their potential usefulness for present and future neurobehavioral and genetic studies of fearfulness/anxiety.

Unlearned anxiety predicts learned fear: A comparison among heterogeneous rats and the Roman rat strains

Event Abstract Back to Event Unlearned anxiety predicts learned fear: A comparison among heterogeneous rats and the Roman rat strains Regina Lopez-Aumatell1*, Elia Vicens-Costa1, Esther Martinez-Membrives1, Toni Canete1, Gloria Blazquez1, Adolf Tobena1 and Alberto Fernandez-Teruel1 1 Universitat Autònoma de Barcelona, Spain We present the behavioural phenotyping of a large sample of rats from the National Institutes of Health Genetically Heterogeneous Rat Stock (N/Nih-HS), including males and females, and the comparison of their results with the RLA-I (very anxious) and RHA-I (low anxious) rat strains. Rats were tested in several anxiety tests comprising unlearned fear (like the novel-cage activity, the elevated “zero” maze and the baseline acoustic startle response), as well as learned fear/anxiety responses (fear-potentiated startle and two-way active shuttlebox avoidance). The results overall showed that unlearned anxiety responses/behaviour were predictive of behaviour in learned fear (i.e. fear-potentiated startle) and conflict (i.e. two-way active avoidance acquisition) situations. N/Nih-HS rats either resemble RLA-I rat anxiety/fear scores or fall in between those of the RLA-I (high anxious) and the RHA-I (low anxious) rat strains. Regression analysis of the N/Nih-HS rat data show that unconditioned anxiety predicts learned fear to some extent, and point that startle measures may have a facilitating role in the rat’s active responses in the two-way active (shuttlebox) avoidance acquisition. Acknowledgements:Partially supported by EURATools (European Commission Contract no. LSHG-CT-2005-019015) and the Wellcome Trust (R. L-A). Conference: 41st European Brain and Behaviour Society Meeting, Rhodes Island, Greece, 13 Sep - 18 Sep, 2009. Presentation Type: Poster Presentation Topic: Poster presentations Citation: Lopez-Aumatell R, Vicens-Costa E, Martinez-Membrives E, Canete T, Blazquez G, Tobena A and Fernandez-Teruel A (2009). Unlearned anxiety predicts learned fear: A comparison among heterogeneous rats and the Roman rat strains. Conference Abstract: 41st European Brain and Behaviour Society Meeting. doi: 10.3389/conf.neuro.08.2009.09.221 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 11 Jun 2009; Published Online: 11 Jun 2009. * Correspondence: Regina Lopez-Aumatell, Universitat Autònoma de Barcelona, Bellaterra, Spain, regina.lopez@uab.es Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Regina Lopez-Aumatell Elia Vicens-Costa Esther Martinez-Membrives Toni Canete Gloria Blazquez Adolf Tobena Alberto Fernandez-Teruel Google Regina Lopez-Aumatell Elia Vicens-Costa Esther Martinez-Membrives Toni Canete Gloria Blazquez Adolf Tobena Alberto Fernandez-Teruel Google Scholar Regina Lopez-Aumatell Elia Vicens-Costa Esther Martinez-Membrives Toni Canete Gloria Blazquez Adolf Tobena Alberto Fernandez-Teruel PubMed Regina Lopez-Aumatell Elia Vicens-Costa Esther Martinez-Membrives Toni Canete Gloria Blazquez Adolf Tobena Alberto Fernandez-Teruel Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Context conditioned fear and anxiety in the acquisition of two-way active avoidance in the genetically heterogeneous N/Nih rat stock: comparison with the Roman rat strains

Context conditioned fear and anxiety in the acquisition of two-way active avoidance in the genetically heterogeneous N/Nih rat stock: comparison with the Roman rat strains

Successive positive contrast in one-way avoidance behavior with Roman low-avoidance rats

The inbred Roman High - (RHA-I) and Roman Low-Avoidance (RLA-I) rats, psychogenetically selected for rapid (RHA-I) vs. extremely poor (RLA-I) acquisition of two-way active avoidance, exhibit a lower or a higher level of fearfulness, respectively, that can be observed in many laboratory anxiety models. The present study analyzed the performance of female RLA-I and RHA-I rats in a successive positive contrast situation induced during one-way avoidance learning. Three groups of RLA-I and three of RHA-I rats (1–30, 30–30 and 1–1 groups, the numbers stand for the time spent in the safe compartment during the first and second phase of training) were trained to avoid an electric foot-shock administered in a “danger” compartment, by running from this compartment to a “safe” one. Only RLA-I rats showed a significant positive contrast effect, in such a way that the reinforcement increase from the lower (1 s spent in safety) to the higher reward (30 s) led to a response enhancement, surpassing the performance of rats trained with the low (1–1 s) or the high (30–30 s) reward from the beginning of training. The results are discussed in the context of an opponent process theory based upon the interaction between the motivational strength of fear and the incentive value of relief taking place during one-way avoidance learning.

Electrical stimulation of the pedunculopontine tegmental nucleus in freely moving awake rats: Time- and site-specific effects on two-way active avoidance conditioning

The pedunculopontine tegmental nucleus (PPTg) is involved in the regulation of thalamocortical transmission and of several functions related to ventral and dorsal striatal circuits. Stimulation of the PPTg in anesthetized animals increases cortical arousal, cortical acetylcholine release, bursting activity of mesopontine dopaminergic cells, and striatal dopamine release. It was hypothetized that PPTg stimulation could improve learning by enhancing cortical arousal and optimizing the activity of striatal circuits. We tested whether electrical stimulation (ES) of the PPTg, applied to freely-moving awake rats previously implanted with a chronic electrode, would improve the acquisition and/or the retention of two-way active avoidance conditioning, and whether this effect would depend on the specific PPTg region stimulated (anterior vs posterior) and on the time of ES: just before (pre-training) or after (post-training) each of three training sessions. The treatment consisted of 20 min of ES (0.2 ms pulses at 100 Hz; current intensity: 40–80 μA). The results showed that (1) this stimulation did not induce either any signs of distress nor abnormal behaviors, apart from some motor stereotyped behaviors that disappeared when current intensity was lowered; (2) pre-training ES applied to the anterior PPTg improved the acquisition of two-way active avoidance, (3) no learning improvement was found after either post-training ES of the anterior PPTg, or pre- and post-training ES of the posterior PPTg. The results give support to a role of PPTg in learning-related processes, and point to the existence of functional PPTg regions.

Successive negative contrast in one-way avoidance learning in female roman rats

The inbred RLA (Roman Low-Avoidance) and RHA (Roman High-avoidance) rat strains have been psychogenetically selected for rapid (RHA) vs. extremely poor acquisition (RLA) of two-way active avoidance. As a consequence of this selective breeding, RLA animals exhibit a higher level of emotionality that can be observed in many anxiety models. The present study was conducted in order to analyze the performance of female RLA, RHA and Wistar rats in a behavioral test of anxiety that involves the reduction of the magnitude of an expected reward: the negative contrast effect that is obtained in one-way avoidance learning by reducing the time spent in the safe compartment. To this aim, three groups of animals (30–1/RLA, 30–1/RHA and 30–1/W) were trained to avoid an electric foot-shock administered in a “danger” compartment, by running from this compartment to a “safe” compartment. We observed an impairment of the avoidance response when time spent in the safe compartment was reduced from 30 to 1 s, when 30–1/RLA and 30–1/W groups were compared with control groups that were trained with a constant safe time (1–1/RLA and 1–1/W, respectively). We also obtained significant differences between 30–1/RLA and 30–1/RHA groups in the postshift phase. These results indicate that RLA rats respond more negatively to the frustration triggered by the reduction in time spent in the safe compartment, suggesting that animal models based on negative contrast effects can be useful tools for studying the genetic basis of anxiety.

Effects of electrical stimulation of the nucleus basalis on two-way active avoidance acquisition, retention, and retrieval

This study assessed the role of the nucleus basalis magnocellularis (NBM) in specific memory phases of two-way active avoidance conditioning. We evaluated the effects of NBM electrical stimulation applied during different phases of the avoidance task. Rats were trained in a 30-trial acquisition session, and were tested again 24 and 48 h later. NBM stimulation was applied at different stages of memory formation of the conditioning: (1) immediately before the first training session to determine the effects on acquisition of the two-way avoidance task; (2) immediately after the first training session to evaluate effects on memory consolidation; and (3) immediately before the 24-h retention session to analyze the effects on the retrieval process. NBM stimulation before training significantly improved the acquisition of the task, without affecting subsequent retention at either 24 or 48 h. Stimulation of the NBM immediately after the first training session slightly impaired performance in the 24-h retention session. Stimulation of the NBM immediately before the 24-h retention session did not affect performance in either the 24 or 48-h retention sessions. Therefore, the NBM may play a more important role in acquisition of memory in aversively motivated conditioning tasks than in consolidation or retrieval of such memories. These results are discussed in the context of attention enhancement and cortical and amygdala activation.

Effects of Fimbria Lesions on Trace Two-Way Active Avoidance Acquisition and Retention in Rats

The fimbria-fornix (FF) is the main subcortical input to the hippocampus. It has been shown that FF lesions facilitate performance on a standard-delay two-way active avoidance task (AA2), thought to involve implicit memory. The hippocampal region is required for explicit or relational memory. It has been proposed that the hippocampus and related structures might associate events that are separated in space or time and detect elements shared in common by such discontiguous episodes. Therefore, FF lesions would be expected to impair performance on a trace paradigm, which introduces an interval between the CS (conditioned stimulus) and the US (unconditioned stimulus) and is generally considered a model of explicit memory. We predicted that FF lesions would impair memory in a trace AA2 procedure, while the same lesions would facilitate memory in a standard delay version of the task. To test this hypothesis, two experiments were carried out in 102 male Wistar rats. The first experiment characterized the trace paradigm using this kind of conditioning and demonstrated that control rats were able to acquire and retrieve (24 h and 11 days postacquisition) the association between the CS (tone) and the US (electric foot shock) when a trace interval (5, 10, or 20 s) was interposed between both stimuli. In the second experiment, we investigated the effects of FF electrolytic lesions on the same task using delay and trace (10-s trace interval) paradigms. Surprisingly, FF lesions facilitated the acquisition and the 24-h retention of the AA2 not only on the standart delay paradigm, but also with the trace paradigm. We suggest that facilitative effects could be a result of impairment in contextual learning.

Electrolytic and ibotenic acid lesions of the nucleus basalis magnocellularis interrupt long-term retention, but not acquisition of two-way active avoidance, in rats.

Previous experiments on two-way active avoidance have shown conflicting results after nucleus basalis magnocellularis lesion: disrupting effects with electrolytic lesions and facilitative effects with excitotoxic lesions. To resolve this issue, in this experiment, Wistar rats received pre-training bilateral electrolytic or ibotenic acid lesions and were trained in a massed two-way active avoidance conditioning. In order to test the long-term retention of the learned response, one additional session was conducted 10 days after the acquisition. Results showed that whereas electrolytic lesions did not affect the acquisition, ibotenic acid lesions enhanced it. Retention of active avoidance response was impaired by both electrolytic and ibotenic lesions of the NBM. These results suggest a role of the NBM in the memory consolidation and/or retrieval of two-way active avoidance.

The parafascicular nucleus and two-way active avoidance: effects of electrical stimulation and electrode implantation.

To evaluate whether electrical stimulation of the parafascicular nucleus (PF) can improve short-term (24 h) and/or long-term (21 days) retention of two-way active avoidance, rats were implanted with an electrode at this nucleus (experimental groups) or above it (control groups). After a single 30-trial acquisition session, experimental groups were submitted to a 10-min session of electrical stimulation. Results showed that the simple implantation of an electrode at the posterior PF enhanced by itself the acquisition of two-way active avoidance, in such a way that the subsequent stimulation of this region may have been unable to further improve the performance of the rats. On the other hand, parafascicular stimulation improved the 24-h retention of the task in a site-specific way, since this effect was mainly seen after stimulation of the central PF region. The facilitative effect on 24-h retention could also depend on the level of performance achieved during the acquisition session, because this improvement was only evidenced in poorly learning animals. No effects were found on 21-day retention. The present results confirm the involvement of the PF in learning and memory and the functional heterogeneity of this nucleus.

The effects of radiofrequency lesion or transection of the fimbria–fornix on latent inhibition in the rat

Latent inhibition consists of a decrement in conditioning to a stimulus as a result of its prior non-reinforced pre-exposure. Based on evidence pointing to the involvement of the hippocampus and the nucleus accumbens in latent inhibition disruption, it has been proposed that latent inhibition depends on the integrity of the subicular input to the nucleus accumbens. Since fibers originating in the subiculum and destined for the nucleus accumbens run through the fimbria–fornix, we assessed the effects of radiofrequency lesion or transection of the fimbria–fornix, on latent inhibition. The effectiveness of both lesions was demonstrated by the total disappearance of acetylcholinesterase staining in the hippocampus and of retrogradely labeled cells in the hippocampus/subiculum following the injection of the retrograde tracer biotin–dextran amine into the shell subregion of the nucleus accumbens. Likewise, in accord with previously documented behavioral effects of lesions to the hippocampus and related structures, both lesions increased spontaneous activity and disrupted performance in Morris water maze, and the radiofrequency lesion facilitated the acquisition of two-way active avoidance. In spite of the above, latent inhibition remained unaffected by both fimbria–fornix lesions, indicating that the critical projections subserving latent inhibition are not those traversing the fimbria–fornix from the hippocampus/subiculum to the nucleus accumbens. The implications of these results for the neural circuitry of latent inhibition and the latent inhibition model of schizophrenia are discussed.

Fimbria-fornix cut affects spontaneous activity, two-way avoidance and delayed non matching to sample, but not latent inhibition

Latent inhibition (LI) consists of a decrement in conditioning to a stimulus as a result of its prior nonreinforced preexposure. Based on evidence pointing to the involvement of the hippocampus and the nucleus accumbens (NAC) in LI disruption, it has been proposed that LI depends on the integrity of the subicular input to the NAC. Since fibers originating in the subiculum and destined for the NAC run through the fimbria-fornix, we assessed the effects of fimbria-fornix lesion, made using a knife cut, on LI. In addition, we assessed the effects of the fimbria-fornix cut in three tests known to be sensitive to lesions to the hippocampal region, namely, spontaneous activity, two-way active avoidance and delayed-non-matching-to-sample. In accord with previously documented effects of lesions to the hippocampus and related structures, the fimbria-fornix cut increased spontaneous activity (Experiment 1), facilitated the acquisition of two-way active avoidance (Experiment 3), and produced a delay-dependent deficit in the delayed-non-match-to-sample task (Experiment 4), demonstrating that it disrupted hippocampal functioning. In contrast, LI remained unaffected by the fimbria-fornix cut (Experiment 2), indicating that disruption of subicular input to the NAC is not responsible for the attenuation of LI following non-selective hippocampal lesions. The implications of these results for the neural circuitry of LI are discussed.