Dietary omega-3 deficiency exacerbates inflammation and reveals spatial memory deficits in mice exposed to lipopolysaccharide during gestation.

Maternal immune activation (MIA) is a common environmental insult on the developing brain and represents a risk factor for neurodevelopmental disorders. Animal models of in utero inflammation further revealed a causal link between maternal inflammatory activation during pregnancy and behavioural impairment relevant to neurodevelopmental disorders in the offspring. Accumulating evidence point out that proinflammatory cytokines produced both in the maternal and fetal compartments are responsible for social, cognitive and emotional behavioral deficits in the offspring. Polyunsaturated fatty acids (PUFAs) are essential fatty acids with potent immunomodulatory activities. PUFAs and their bioactive derivatives can promote or inhibit many aspects of the immune and inflammatory response. PUFAs of the n-3 series ('n-3 PUFAs', also known as omega-3) exhibit anti-inflammatory/pro-resolution properties and promote immune functions, while PUFAs of the n-6 series ('n-6 PUFAs' or omega-6) favor pro-inflammatory responses. The present study aimed at providing insight into the effects of n-3 PUFAs on the consequences of MIA on brain development. We hypothesized that a reduction in n-3 PUFAs exacerbates both maternal and fetal inflammatory responses to MIA and later-life defects in memory in the offspring. Based on a lipopolysaccharide (LPS) model of MIA (LPS injection at embryonic day 17), we showed that n-3 PUFA deficiency 1) alters fatty acid composition of the fetal and adult offspring brain; 2) exacerbates maternal and fetal inflammatory processes with no significant alteration of microglia phenotype, and 3) induces spatial memory deficits in the adult offspring. We also showed a strong negative correlation between brain content in n-3 PUFA and cytokine production in MIA-exposed fetuses. Overall, our study is the first to address the deleterious effects of n-3 PUFA deficiency on brain lipid composition, inflammation and memory performances in MIA-exposed animals and indicates that it should be considered as a potent environmental risk factor for the apparition of neurodevelopmental disorders.

Impact of Early Consumption of High-Fat Diet on the Mesolimbic Dopaminergic System.

Increasing evidence suggest that consumption of high-fat diet (HFD) can impact the maturation of brain circuits, such as during adolescence, which could account for behavioral alterations associated with obesity. In the present study, we used behavioral sensitization to amphetamine to investigate the effect of periadolescent HFD exposure (pHFD) in rats on the functionality of the dopamine (DA) system, a central actor in food reward processing. pHFD does not affect responding to an acute injection, however, a single exposure to amphetamine is sufficient to induce locomotor sensitization in pHFD rats. This is paralleled by rapid neurobiological adaptations within the DA system. In pHFD-exposed animals, a single amphetamine exposure induces an increase in bursting activity of DA cells in the ventral tegmental area (VTA) as well as higher DA release and greater expression of (tyrosine hydroxylase, TH) in the nucleus accumbens (NAc). Post-synaptically, pHFD animals display an increase in NAc D2 receptors and c-Fos expression after amphetamine injection. These findings highlight the vulnerability of DA system to the consumption of HFD during adolescence that may support deficits in reward-related processes observed in obesity.

A role for anterior thalamic nuclei in contextual fear memory.

Understanding the neural processes that govern the attribution of a predictive value to environmental stimuli is a major issue in behavioural neuroscience. The main strategy to explore this question has been the use of Pavlovian fear conditioning paradigms. While a majority of studies have focussed on the specific role of the hippocampus and amygdala in contextual versus cued fear, very few studies examined the potential role of subcortical limbic areas. Among those, the anterior thalamic nuclei (ATN) connect to both the hippocampus and the amygdala and also to the cingulate region which is known to support fear-related activity. Here, we show that rats sustaining ATN lesions exhibit a specific impairment following context but not tone conditioning. ATN lesions slowed down acquisition without preventing normal freezing behaviour when rats were reexposed to the conditioning context 24 h later. However, ATN rats exhibited poor retrieval of contextual but not cued fear when assessed 3 weeks after conditioning. In addition, extinction was faster in ATN rats and spontaneous recovery of contextual fear was impaired by the lesions. These deficits indicate that contextual fear memories established in the absence of the ATN are not robust. Collectively, these findings support an involvement of the ATN in the circuits underlying contextual fear memory.

Bilateral lesions of the entorhinal cortex differentially modify haloperidol- and olanzapine-induced c-fos mRNA expression in the rat forebrain.

Lesions of the entorhinal cortex are now an accepted model for mimicking some of the neuropathological aspects of schizophrenia, since evidence has accumulated for the presence of cytoarchitectonic abnormalities within this cortex in schizophrenic patients. The present study was undertaken to address the functional consequences of bilateral entorhinal cortex lesions on antipsychotic-induced c-fos expression. After a 15-day recovery period, the effect of a typical antipsychotic, haloperidol (1 mg/kg), on c-fos mRNA expression was compared with that of an atypical one, olanzapine (10 mg/kg), in both sham-lesioned and entorhinal cortex-lesioned rats. In sham-lesioned rats, both haloperidol and olanzapine induced c-fos expression in the caudal cingulate cortex, dorsomedial and dorsolateral caudate-putamen, nucleus accumbens core and shell and lateral septum. In addition, olanzapine, but not haloperidol, increased c-fos expression within the central amygdala. In entorhinal cortex-lesioned rats, haloperidol-induced c-fos expression was markedly reduced in most areas. In contrast, the olanzapine-induced c-fos expression was not altered in the nucleus accumbens shell and lateral septum of the lesioned rats. These findings reveal that entorhinal cortex lesions affect c-fos expression in a compound- and regional-dependent manner. Our results further emphasize the importance of the exploration of the mechanisms of action of antipsychotic drugs in the context of an associated cortical pathology.

Acquired equivalence and distinctiveness of cues: II. Neural manipulations and their implications.

Neural manipulations were used to examine the mechanisms that underlie the acquired equivalence and distinctiveness of cues in rats. Control rats and those with excitotoxic lesions of either the hippocampus (HPC) or entorhinal cortex (EC) acquired the following conditional discrimination: In Contexts A and B, Stimulus X-->food and Stimulus Y-->no food, and in Contexts C and D, Y-->food and X-->no food. Rats then received many food pellets in A but not in C. After this treatment, control rats showed more magazine activity in B than in D--an acquired equivalence-distinctiveness effect. This effect was also evident in HPC rats but not in EC rats. These results indicate that changes in stimulus distinctiveness are dissociable from the process of conditional learning.

Basolateral amygdala lesions disrupt latent inhibitionin rats.

Latent inhibition (LI) refers to the retardation of acquisition of conditioned responding produced by repeated non-reinforced preexposure to the conditioned stimulus (CS) prior to its pairing with the unconditioned stimulus (US) during conditioning. LI has recently been shown to depend upon the integrity of temporal lobe structures, including regions of the hippocampal formation such as the entorhinal cortex. The present study investigated the effects of excitotoxic lesions of another temporal lobe structure, the basolateral nucleus of the amygdala (BLA), on LI. LI was studied in a within-subjects appetitive conditioning preparation in which an auditory CS was paired with food US. In this procedure, preexposure to the CS results in slower acquisition of magazine approach behaviour. Lesions of the BLA reduced the effect of preexposure, disrupting LI. This result suggests that the BLA can play a crucial role in LI. The possible involvement of interactions between BLA and entorhinal cortex in LI is discussed.

Excitotoxic lesions of the hippocampus leave sensory preconditioning intact: implications for models of hippocampal function.

Learning about contextual cues is markedly disrupted in rats with hippocampal lesions. One analysis of this disruption is that it reflects a general failure to form associations between the elements of complex events. A straightforward prediction of this analysis is that sensory preconditioning will be disrupted by hippocampal lesions. This prediction was assessed by presenting rats with flavored solutions composed of 2 elements (A and X) before X was paired with an injection of the emetic, lithium chloride. A subsequent test revealed that rats were less willing to consume Solution A than they were to consume a control solution, B. This was true of rats with sham lesions and those with excitotoxic lesions of hippocampus. These findings fail to support the proposition that the hippocampus-dependent deficit in contextual conditioning is due to a general disruption to the process of associating the elements of complex events.

Restoration of latent inhibition by olanzapine but not haloperidol in entorhinal cortex-lesioned rats.

RATIONALE: Latent inhibition (LI) refers to the decrease in conditioned response induced by the repeated non-reinforced pre-exposure to the conditioned stimulus before its pairing with the unconditioned stimulus during the conditioning stage. LI has been considered as a relevant animal model for the study of the biological bases of schizophrenia. LI has recently been demonstrated to depend on the integrity of the entorhinal cortex, as lesioning of this area disrupted LI. OBJECTIVES: The present study aimed to verify whether the classical neuroleptic haloperidol and/or the atypical antipsychotic olanzapine would prevent the effect of entorhinal cortex lesioning. METHODS: LI was studied in an off-baseline conditioned emotional response (CER) paradigm in which a tone is paired with a footshock. Entorhinal cortex lesions were produced by the electrolytic method. After a recovery period, both lesioned and control rats received either haloperidol (0.3 mg/kg), olanzapine (0.3 mg/kg) or vehicle before both the pre-exposure and conditioning stages of the experiment. RESULTS: In control rats, pre-exposure to the tone induced LI, which was affected by neither haloperidol nor olanzapine. Lesioning of the entorhinal cortex produced a deficit of LI, which was restored by olanzapine but not by haloperidol. CONCLUSIONS: This result suggests a dissociation of the anatomical and pharmacological targets of the two drugs. The possible involvement of dopamine D3 receptors in the effects of olanzapine is discussed.

Selective lesions of the entorhinal cortex, the hippocampus, or the fimbria-fornix in rats: a comparison of effects on spontaneous and amphetamine-induced locomotion.

Using adult Long-Evans male rats, this experiment compared spontaneous (assessed 15 days and 4.5 months after surgery) and amphetamine-induced (assessed from 4.5 months after surgery onwards; 1 mg/kg, i.p., ten injections, 48 h apart) locomotor activity following N-methyl-D-aspartate lesions of the entorhinal cortex, electrolytic lesions of the fimbria-fornix, or ibotenate lesions of the hippocampus. Sham-operated rats were used as controls. Hippocampal and fimbria-fornix lesions, but not entorhinal-cortex lesions induced diurnal and nocturnal hyperactivity, which was attenuated over time, but only in rats with fimbria-fornix lesions. Amphetamine-induced hyperlocomotion was assessed in a familiar environment. Lesions of the entorhinal cortex potentiated the locomotor effects of amphetamine, but not lesions of the hippocampus or interruption of the axons in the fimbria-fornix pathway. Sensitization appeared to be decreased by fimbria-fornix lesions and to be prevented by hippocampal lesions. Rats with entorhinal-cortex lesions behaved as if they had already been sensitized by the lesion. These results clearly show that lesions of the fimbria-fornix, the hippocampus, and of the entorhinal cortex have different effects on spontaneous and amphetamine-induced hyperactivity, as they also have on learning and memory tasks.

Entorhinal but not hippocampal or subicular lesions disrupt latent inhibition in rats.

Latent inhibition (LI) is the deficit of conditioning resulting from repeated nonreinforced preexposure to a conditioned stimulus before its pairing with an unconditioned stimulus. There are cumulative data showing that large lesions of the hippocampal formation disrupt LI. However, the effects of selective lesions of the different components of the hippocampal formation have never been directly addressed in the same study and conditioning paradigm. The first experiment of the present study aimed at investigating the effects of excitotoxic lesions of the hippocampus, subiculum, or entorhinal cortex on LI in an "off-baseline"-conditioned emotional response procedure. Hippocampus or subiculum lesions had no effect on either LI or conditioning. In contrast, entorhinal cortex lesions disrupted LI without modifying conditioning. In Experiment 2, locomotor activity in a novel environment was assessed in the same rats. Whereas lesions of hippocampus increased locomotor activity, lesions of the subiculum or the entorhinal cortex were devoid of effect. Although both LI and habituation to novel environmental cues are thought to involve interactions between the hippocampal formation and the mesolimbic pathway, these results indicate a functional dissociation between the hippocampus and the entorhinal cortex.

Effects of enriched postoperative housing conditions on spatial memory deficits in rats with selective lesions of either the hippocampus, subiculum or entorhinal cortex.

Long-Evans male, adult rats received selective and bilateral lesions of either the hippocampus, subiculum or lateral entorhinal cortex, and were then housed for 30 days in either enriched or standard conditions. Rats were then tested in the eight-arm radial maze to assess spatial working memory and the strategies that were employed (i.e. pattern of arms visited). Lesions of the hippocampus induced both a working-memory impairment and a loss in the use of allocentric strategies to perform the task. Rats with lesions of the subiculum were also impaired but less than hippocampectomized rats and showed a similar pattern of arm visits as control rats. In contrast with other lesioned rats, rats with lateral entorhinal cortex lesions performed the task like control rats. Postoperative enriched housing conditions (EHC) globally enhanced performance of rats, but did not affect the strategies selected by the rats to solve the task. The beneficial effect of EHC was particularly obvious in rats with lesions of the subiculum. In enriched rats with such lesions, performance was not significantly different from that of control rats housed in standard conditions. The present results indicate that 1) the structures within the hippocampal formation are not similarly involved in spatial learning and memory processes and in the management of navigational demands of the radial maze, and 2) enriched conditions may enhance the spared spatial abilities of some lesioned rats thus promoting functional recovery.