Effects Of Ibotenic Acid Lesions Research Articles

Mediodorsal thalamic lesions block the stress-induced inversion of serial memory retrieval pattern in mice

This study examines the effects of ibotenic acid lesions of the mediodorsal nucleus of the thalamus (MD) on serial contextual memory retrieval in non-stress and stress conditions. Independent groups of mice learned two successive contextual serial discriminations (D1 and D2) in a four-hole board. The discriminations differed each by the color and texture of the floor. Twenty-four hours later, memory testing occurred in independent groups of mice on one of the two floors of the initial acquisition session. Half of the subjects received three electric footschocks (0.9 mA, 2 s) 5 min prior to testing. Results showed that (i) stress induced a plasma corticosterone rise of same magnitude in sham-operated and MD-lesioned mice; (ii) non-stressed sham-operated mice accurately remembered D1 but not D2, whereas stressed sham-operated animals remembered D2 but not D1; (iii) non-stressed MD-lesioned mice exhibited a memory retrieval pattern similar to that observed in non-stressed sham-operated mice; (iv) however, the stress-induced inversion of the memory retrieval pattern was not observed in MD animals. The effects of MD lesions on memory retrieval in this task are similar to those observed in earlier studies in prefrontal cortex or amygdala-lesioned mice [Chauveau F, Piérard C, Coutan M, Drouet I, Liscia P, Béracochéa D. Prefrontal cortex or basolateral amygdala lesions blocked the stress-induced inversion of serial memory pattern in mice. Neurobiol Learn Mem 2008;90:395–403]; they are however in sharp contrast with mice exhibiting hippocampal lesions [Chauveau F, Pierard C, Tronche C, Coutan M, Drouet I, Liscia P, et al. The hippocampus and prefrontal cortex are differentially involved in serial memory retrieval in non-stress and stress condition. Neurobiol Learn Mem; in press; Chauveau F, Pierard C, Tronche C, Coutan M, Drouet I, Liscia P, et al. Rapid stress-induced corticosterone rise in the hippocampus reverses serial memory retrieval pattern. Hippocampus; in press]. Overall, the present findings highlight the involvement of the MD in an AMG/PFC system mediating the rapid effects of stress on serial memory retrieval.

Lesions of the medial preoptic area interfere with the display of a conditioned place preference for vaginocervical stimulation in rats.

The present study examined the effect of ibotenic acid lesions of the medial preoptic area (mPOA) on the expression of a conditioned place preference (CPP) for vaginocervical stimulation. Rats with bilateral lesions of the mPOA failed to display the CPP for vaginocervical stimulation shown by rats with sham or incomplete lesions. These findings provide additional support for the role of the mPOA in the neural circuitry underlying the reinforcing effects of female sexual behavior and raise the possibility that the altered pattern of approach and withdrawal behavior observed following lesions of the mPOA may be attributable in part to a diminution of the reinforcing effects of vaginocervical stimulation.

Prefrontal cortex or basolateral amygdala lesions blocked the stress-induced inversion of serial memory retrieval pattern in mice

Previous data from our team have shown that pre-test stress in mice reversed the pattern of memory retrieval in a contextual serial spatial task (CSD; Celerier, A., Pierard, C., Rachbauer, D., Sarrieau, A., & Beracochea, D. (2004). Contextual and serial discriminations: A new learning paradigm to assess simultaneously the effects of acute stress on retrieval of flexible or stable information in mice. Learning and Memory, 11, 196–204). The present study is aimed at determining brain areas which might be critically involved in mediating the stress effect on memory retrieval in the CSD task. For that purpose, we studied hereby the effects of ibotenic acid lesions of either the prefrontal cortex (PFC) or the basolateral amygdala (BLA) in Stressed or Non-Stressed Balb/c mice on memory retrieval in the CSD task. In that task, mice learned two successive spatial discriminations (D1 and D2) within two different internal contexts in a four-hole board. The stressor (electric footshocks) was delivered 5 min before test, occurring 24 h after acquisition. During test, mice were relocated either on the floor of the first or of the second discrimination. Results showed that (i) spatial memory was substantial and remained unaffected both by lesions and stress; (ii) Non-Stressed controls as well as Non-Stressed or Stressed PFC and BLA-lesioned mice remembered accurately D1 but not D2; and (iii) in contrast, Stressed controls accurately remembered D2 but not D1. In parallel to behavioral experiments, we also showed that PFC and BLA lesions did not affect the stress-induced increase of plasma corticosterone levels. All together, PFC and BLA integrity are not necessary for retrieval processes per se; in contrast, the PFC and BLA are critically involved in the mediation of the deleterious stress effects on serial order memory retrieval.

Ibotenic acid lesions of the medial preoptic area disrupt the expression of partner preference in sexually receptive female rats

The present study evaluated the effects of ibotenic acid lesions of the medial preoptic area (mPOA) on the display of partner preference in ovariectomized, estrogen- and progesterone-primed rats. Preference for a sexually vigorous male or an estrous female rat was determined in one of two conditions: unlimited physical access to the stimulus rats ( Contact condition) or access that was limited to olfactory, auditory and visual cues ( No-contact condition). Lesions of the mPOA reduced the male preference, social preference, and arena crossings, independent of test condition. However, the reduction in male preference following mPOA lesions was most pronounced during tests with unlimited physical access. These results suggest that the mPOA may be involved in integrating somatosensory signals from coital stimulation with the motor responses associated with the appetitive aspects of female sexual behavior.

Prolonged initiation latency in Morris water maze learning in rats with ibotenic acid lesions to medial striatum: effects of systemic and intranigral muscimol administration

The contribution of the rat striatonigral GABAergic system to spatial navigation was investigated in this study. We first tested the effects of ibotenic acid lesions of the striatum on place navigation performance in Morris water maze. Medial but not lateral striatal lesions produced a significant increase of escape latency, and this deficit was clarified as mainly caused by a marked increase of initiation latency rather than of thigmotaxis time (experiment 1). Next we tested the effects of systemic (0.5 mg/kg) and intranigral (2.0 ng/side) administrations of muscimol, a GABA receptor agonist, on the place navigation deficits produced by medial striatal lesions. Systemic muscimol administration significantly ameliorated the increase of initiation latency, while intranigral administration was not sufficiently effective (experiment 2). The results suggest that neural circuits containing medial striatal neurons play an essential role in place navigation performance probably through some movement preparation processes that precede movement execution, and the GABAergic system may be involved in this initiation process, although whether it is the striatonigral GABAergic system that is involved remains unclear.

Effects of ibotenic acid lesions of the mediodorsal thalamus on memory: relationship with emotional processes in mice

The effects of ibotenic acid lesions of the mediodorsal nucleus of the thalamus (MD) on memory and fear reactivity in mice were studied. In the first experiment, MD subjects were submitted to a behavioral design allowing to study the relationship between memory and anxiety [Krazem A, Borde N, Beracochea D. Effects of diazepam and beta-CCM on working memory in mice: relationship with emotional reactivity. Pharmacol Biochem Behav 2001;68:235–44; Beracochea D, Krazem A, Jaffard R. Methyl beta carboline-3-carboxylate reverses the working memory deficits induced either by chronic alcohol consumption or mammillary body lesions in mice. Psychobiology 1995;23:52–8]. In a second experiment, MD-lesioned subjects were submitted to a GO/NOGO temporal alternation task involving two intertrial intervals (ITIs: 0 and 30 s). Lesioned subjects exhibited large bilateral mediodorsal thalamic lesions with small damage into the centromedial thalamic nucleus. In the first experiment, MD-lesioned animals performed normally a sequential alternation task involving fixed ITIs over seven successive trials (5 or 30 s); in contrast, MD-lesioned subjects exhibited deficits in the sequential task involving the same but mixed ITIs (30–5 s versus 5–30 s) the deficit being observed for the last trials of the series, regardless the ITIs used. MD lesions increased fear reactivity in an elevated-plus maze, and scores of anxiety were negatively correlated with performance in the mixed alternation schedule. The second experiment involving non spatial information extended results of the first experiment in showing that the deficit of MD-lesioned animals was not dependent on the ITIs separating trials. Overall, our data show that MD-lesioned subjects exhibit a cognitive impairment characterized by a difficulty to maintain an alternation rule in situations involving procedural variance, and this deficit could stem primarily from an increase of fear reactivity.

Paced mating behavior in the female rat following lesions of three regions responsive to vaginocervical stimulation

The present study examines the effects of ibotenic acid lesions of the medial amygdala, the bed nucleus of the stria terminalis and the medial preoptic area on the display of paced mating behavior in female rats. Lesions of either the medial amygdala or the bed nucleus of the stria terminalis have no effect on the display of paced mating behaviors in ovariectomized, hormone-primed rats. In contrast, lesions of the medial preoptic area significantly lengthen contact-return latencies following intromissions and ejaculations and increase withdrawal from the male following intromissions. The present study demonstrates that the medial amygdala and the bed nucleus of the stria terminalis are not involved in the behavioral responses accompanying paced mating behavior, whereas the medial preoptic area is a critical component of the neural circuit mediating paced mating behavior as well as other appetitive aspects of mating.

Effects of ibotenic acid lesions of the dorsal hippocampus on contextual fear conditioning in mice: comparison with mammillary body lesions

The goals of the present study were to determine if ibotenic acid lesions of the dorsal hippocampus (dHPC) or of mammillary body (MB) of the hypothalamus would induce similar contextual conditioning deficit in a fear-conditioning paradigm, previously developed in mice [Eur. J. Neurosci. 12 (2000) 2575]. Results showed that ibotenic acid lesions of the dHPC or of the MB both induced severe deficits on contextual conditioning but spared auditory conditioning, as compared to controls. This study provides direct evidence for an involvement of dHPC neurones in contextual fear conditioning and is first to demonstrate an involvement of the MB in the mediation of contextual fear conditioning.

Excitotoxic lesions of the medial prefrontal cortex attenuate fear responses in the elevated-plus maze, social interaction and shock probe burying tests

Previous research investigating the effects of medial prefrontal cortex (MPFC) lesions on fear- and anxiety-related behavior has yielded an inconsistent body of findings. Behavioral studies have reported increases, decreases, and no effect on anxiety. In addition, many studies are complicated by the use of lesioning techniques that destroy fibers of passage, and the use of conditioned fear tests, which may introduce the confounding effects of learning and memory. Therefore, the present study examined the effects of ibotenic acid lesions of the MPFC (including prelimbic, infralimbic and anterior cingulate) on three wide-ranging and well-validated behavioral assays of anxiety: the elevated plus maze (EPM), social interaction (SI) and the shock-probe tests (SP). In the EPM test, lesioned rats showed a significantly higher percentage of open arm entries and open arm time than controls. In a version of the SI test sensitive to anxiolytic effects, lesioned rats were found to spend a significantly greater amount of time in active interaction with a conspecific; while another version of the SI test sensitive to anxiogenic effects did not show any differences between lesioned and non-lesioned controls. In the SP test, lesioned rats exhibited significantly lower rates of burying. In contrast, retention of shock probe avoidance was not affected. No effects of lesions on measures of locomotor activity or shock reactivity were found. The concordant anxiolytic-like effects found in the three behavioral assays strongly suggests a general reduction in fear responsiveness in MPFC lesioned rats.

Effects of hippocampal lesions in overshadowing and blocking procedures.

The effects of ibotenic acid lesions of the hippocampus on overshadowing and blocking were examined in a Pavlovian appetitive conditioning experiment with rats. In a standard test of performance to the overshadowed or blocked target stimulus, sham-lesioned rats displayed both of these stimulus-selection phenomena. Rats with hippocampal lesions showed normal blocking, but no overshadowing. Subsequent inhibitory learning about the target stimulus was slower after overshadowing or blocking procedures than after a control procedure in sham-lesioned rats, but not in lesioned rats. These results suggest that exposure to these procedures can induce hippocampally mediated losses in conditioned stimulus associability (learning rate parameter), even when those losses are not a major determinant of the stimulus-selection effects themselves.

The effects of neonatal lesions in the amygdala or ventral hippocampus on social behaviour later in life

Disruption of normal social behaviour is seen in psychiatric neurodevelopmental disorders like schizophrenia or autism. In a rat model of neurodevelopmental disorders we investigated the social behavioural changes after damage of limbic brain areas, at two early stages of life. The effects of ibotenic acid lesions made on day 7 or 21 of life in the amygdala (AM) ((baso)lateral/medical) or ventral hippocampal area on social play behaviour, social behaviour unrelated to social play behaviour early in life, and social behaviour in adulthood were assessed. Lesions of the AM, but not lesions of the ventral hippocampal area, resulted in decreased social play behaviour, and no differences were found between lesions made on day 7 or 21 of life. Social behaviour unrelated to social play behaviour early in life and in adulthood was decreased in animals lesioned in the AM on day 7 but not in animals lesioned on day 21 of life. This effect was particularly present in animals with an additional lesion in the medial nuclei of the AM. Lesions in the ventral hippocampal area did not affect social behaviour. It is concluded that the AM is an important structure for social play behaviour. The effects on social behaviour that are dependent on the day of lesioning (day 7 vs. 21) are an indication of a neurodevelopmental deficit of structures connected to the (medial part) of the AM.

Effects of ibotenic acid lesions of the nucleus accumbens on paced mating behavior in the female rat.

Effects of ibotenic acid lesions of the nucleus accumbens on paced mating behavior in the female rat.

Effects of ibotenic acid lesions of the nucleus accumbens on paced mating behavior in the female rat.

The present study investigated the role of the nucleus accumbens (NAcc) in paced mating behavior in female rats. A sexually receptive female rat will approach and withdraw from a sexually active male, thereby controlling the timing of the receipt of sexual stimulation (e.g., mounts, intromissions, ejaculations). In this study, ibotenic acid lesions in the NAcc core increased the likelihood that a female rat would withdraw from a male rat after a mount but did not affect contact return latency or sexual receptivity. Ibotenic acid lesions in the NAcc shell did not affect paced mating behavior or sexual receptivity. The results suggest that the NAcc core plays a role in suppressing withdrawal behavior in response to less intense mating stimulation.

The effects of ibotenic acid lesions of the medial and lateral prefrontal cortex on latent inhibition, prepulse inhibition and amphetamine-induced hyperlocomotion

Hypofunction of prefrontal cortical regions, such as dorsolateral and orbital regions, has been suggested to contribute to the symptomatology of schizophrenia. In the rat, the medial and the lateral prefrontal cortices are considered as homologs of the primate dorsolateral and orbital prefrontal cortices, respectively. The present study investigated in rats the effects of lesions of the medial and lateral prefrontal cortices on latent inhibition, prepulse inhibition and amphetamine-induced activity. These paradigms are known to be modulated by the mesolimbic dopaminergic system, a system that has been suggested to be involved in the symptomatology of schizophrenia. Latent inhibition and prepulse inhibition are disrupted in schizophrenic patients as well as in rats treated with amphetamine. Amphetamine-induced activity was tested under dim light (low stress) and bright light (high stress) because stressful situations selectively increase mesocortical dopamine activity. Lateral prefrontal cortex lesioned animals did not differ in their behavior from control animals in any of the paradigms used in this study. Medial prefrontal cortex lesions did not affect latent inhibition but increased prepulse inhibition. In the amphetamine-induced activity experiment, prior to drug administration, open field locomotion was reduced under bright illumination for all lesion groups. After amphetamine administration, medial prefrontal cortex lesions attenuated the hyperlocomotor effect of the drug under the dim light condition and potentiated it under the bright light condition. The results indicate that medial and lateral prefrontal cortex can be functionally differentiated by their involvement in the modulation of behavior requiring mesocorticolimbic dopamine activation. The results in amphetamine induced activity suggest that the behavioral outcomes associated with medial prefrontal cortex depend on the background (stress) against which the evaluation is made. The results also support the notion that prepulse inhibition may be a better model than latent inhibition of the symptoms of schizophrenia associated with dysfunctional prefrontal activity.

D-Amphetamine-induced behavioral sensitization: implication of a glutamatergic medial prefrontal cortex–ventral tegmental area innervation

Behavioral sensitization to amphetamine is expressed as a progressive enhancement of the behavioral activating effects of the drug when repeated injections are performed as well as a long-lasting hypersensitivity to later environmental or pharmacological challenges. The mesoaccumbens dopamine system has been proposed to be the major candidate so far responsible for the induction and expression of this process, which are dependent on the action of amphetamine in the ventral tegmental area and nucleus accumbens, respectively. The development of this process has been proposed to be the result of an interaction between somatodendritically released dopamine and dopaminergic D 1 receptors localized on different inputs to the ventral tegmental area, including glutamate afferents arising in part from mesocorticolimbic areas such as the medial prefrontal cortex and the amygdala. Three groups of experiments were designed to test the role of each of these components in the behavioral sensitization to amphetamine. First, the intervention of the glutamatergic transmission of the ventral tegmental area in the induction of sensitization to amphetamine was tested. The effects of an N-methyl- d-aspartate antagonist, 3-( R-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid, on the behavioral sensitization induced by amphetamine administered repeatedly in the ventral tegmental area was tested. It was found that the blockade of N-methyl- d-aspartate receptors with 3-( R-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid co-administered with amphetamine in the ventral tegmental area dose-dependently prevented the induction of sensitization. In a second step, the role of the structures which send glutamatergic inputs to the ventral tegmental area in the process of behavioral sensitization was tested. We evaluated the effects of ibotenic acid lesion of the medial prefrontal cortex and the amygdala on behavioral sensitization induced by peripheral or intra-ventral tegmental area administration of amphetamine. We found that ibotenic acid lesion of the medial prefrontal cortex blocked the behavioral sensitization induced by both intra-ventral tegmental area and peripheral treatment with amphetamine. In contrast, ibotenic acid lesion of the amygdala produced no effect on behavioral sensitization induced peripherally or centrally. These experiments confirmed (i) that the ventral tegmental area, where dopaminergic cell bodies are located, is a critical site for the induction of behavioral sensitization, (ii) that this process implicates the glutamatergic transmission in the ventral tegmental area, and (iii) that the medial prefrontal cortex is crucially implicated merely because of its direct glutamatergic inputs on to ventral tegmental area neurons. Together, these results reinforce the view that the behavioral sensitization to amphetamine implicates not only the mesoaccumbens dopaminergic neurons, but also other structures of the mesocorticolimbic system, such as the medial prefrontal cortex and more specifically its glutamatergic component.

Spatial memory impairment in ventral subicular lesioned rats

The present study examined the effects of ibotenic acid lesions of the ventral subiculum (SUB) on the ability of rats to memorize a rewarded alternation test in a T-maze. Results indicated that rats with ibotenic acid lesions (IL) of the ventral subiculum were impaired in postoperative acquisition of the spatial discrimination task, making more errors than the vehicle treated and normal control rats. In addition, all rats, including the IL group of rats, were able to memorize an acquired spatial behaviour. These findings suggest that the SUB play an important role in spatial information processing in rats.

N-methyl-D-aspartate and dopamine receptor involvement in the modulation of locomotor activity and memory processes.

In this study we report on the effects of N-methyl-D-aspartate (NMDA)- and dopamine (DA)-receptor manipulation on the modulation of one-trial inhibitory avoidance response and the encoding of spatial information, as assessed with a non-associative task. Further, a comparison with the well-known effects of the manipulation of these two receptor systems on locomotor activity is outlined. It is well assessed that NMDA-receptor blockage induces a stimulatory action on locomotor activity similar to that exerted by DA agonists. There is evidence showing that the nucleus accumbens is involved in the response induced by both NMDA antagonists and DA agonists. We show results indicating a functional interaction between these two neural systems in modulating locomotor activity, with D2 DA-receptor antagonists (sulpiride and haloperidol) being more effective than the D1 antagonist (SCH 23390) in blocking MK-801-induced locomotion. A different profile is shown in the effects of NMDA antagonists and DA agonists in the modulation of memory processes. In one-trial inhibitory avoidance response, NMDA antagonists (MK-801 and CPP) impair the response on test day, while DA agonists exert a facilitatory effect; furthermore, sub-effective doses of both D1 (SKF 23390) and D2 (quinpirole) are able to attenuate the impairing effect in a way similar to that induced by NMDA antagonists. The effects of NMDA- and DA-acting drugs on the response to spatial novelty, as assessed with a task designed to study the ability of animals to react to discrete spatial changes, are in good accord with the effects observed on passive avoidance. The results show that NMDA as well as DA antagonists, at low doses, selectively impair the reactivity of mice to spatial changes. In a last series of experiments, the possible role of NMDA receptors located in the nucleus accumbens was investigated regarding reactivity to spatial novelty. The experiments gave apparently contrasting results: while showing an impairing effect of focal administrations of NMDA antagonists in the nucleus accumbens on reactivity to spatial novelty, no effect of ibotenic acid lesions of the same structure was observed.

Hypothalamic Paraventricular Nucleus Modulates Maternal Aggression in Rats: Effects of Ibotenic Acid Lesion and Oxytocin Antisense

GIOVENARDI, M., M. J. PADOIN, L. P. CADORE AND A. B. LUCION. Hypothalamic paraventricular nucleus modulates maternal aggression in rats: Effects of ibotenic acid lesion and oxytocin antisense. PHYSIOL BEHAV 63(3) 351–359, 1998.—Central oxytocin (OT) appears to be crucial for maternal behavior. OT, through the parvocellular neurons of the hypothalamic paraventricular nucleus (PVN), can exert its physiological and behavioral effects by acting on OT receptors in nonpituitary projections of the PVN. The purpose of the present study was to analyze the role of the PVN and OT on maternal aggressive behavior in two different periods after delivery: on the fifth day (period of high aggressiveness) and on the eighteenth day postpartum (period of low aggressiveness). In the first experiment, ibotenic acid was injected into the PVN in order to lesion the parvocellular neurons. A second experiment was designed to study more specifically the effects of OT using the antisense technique. On the fifth day postpartum, both the PVN lesion by the ibotenic acid and a possible acute reduction of OT synthesis by the antisense administration in that nucleus increased maternal aggressive behavior, while on the eighteenth day postpartum no effect was recorded. We may conclude that central projections of the PVN modulate maternal aggression during a restricted period after delivery, only when lactating females show naturally high levels of aggressive behaviors.

Differential effects of ibotenic acid lesions of the hippocampus and blockade of N-methyl-D-aspartate receptor-dependent long-term potentiation on contextual processing in rats.

Differential effects of ibotenic acid lesions of the hippocampus and blockade of N-methyl-D-aspartate receptor-dependent long-term potentiation on contextual processing in rats.

Differential effects of ibotenic acid lesions of the hippocampus and blockade of N-methyl-D-aspartate receptor-dependent long-term potentiation on contextual processing in rats.

The contextual specificity of appetitive conditioned responding was examined in rats undergoing chronic intracerebroventricular infusion of 15 or 30 mM D-2-amino-5-phosphonopentanoic acid (D-AP5) or with excitotoxic hippocampal lesions. The magnitude of conditioned responding by control rats and rats infused with D-AP5 to a conditioned stimulus (CS) trained in Context A was attenuated when the same stimulus was presented in Context B. By contrast, hippocampal-lesioned rats displayed comparable levels of responding to the CS when presented in either Context A or B. Subsequent in vivo electrophysiological investigations showed that the D-AP5 concentrations were effective in blocking long-term potentiation (LTP) in the dentate gyrus. Results indicate that rats are capable of processing contextual information in the absence of N-methyl-D-aspartate (NMDA) receptor-dependent LTP and demonstrate an important dissociation between the effects of hippocampal lesions and the blockade of NMDA receptors in the hippocampus.