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Recognizing Mendelian causes is crucial in molecular diagnostics and counseling for patients with autism spectrum disorder (ASD). We explored facial dysmorphism and facial asymmetry in relation to genetic causes in ASD patients and studied the potential of objective facial phenotyping in discriminating between Mendelian and multifactorial ASD. In a cohort of 152 ASD patients, 3D facial images were used to calculate three metrics: a computational dysmorphism score, a computational asymmetry score, and an expert dysmorphism score. High scores for each of the three metrics were associated with Mendelian causes of ASD. The computational dysmorphism score showed a significant correlation with the average expert dysmorphism score. However, in some patients, different dysmorphism aspects were captured making the metrics potentially complementary. The computational dysmorphism and asymmetry scores both enhanced the individual expert dysmorphism scores in differentiating Mendelian from non‐Mendelian cases. Furthermore, the computational asymmetry score enhanced the average expert opinion in predicting a Mendelian cause. By design, our study does not allow to draw conclusions on the actual point‐of‐care use of 3D facial analysis. Nevertheless, 3D morphometric analysis is promising for developing clinical dysmorphology applications in diagnostics and training. [ABSTRACT FROM AUTHOR]

F‐doped La0.6Sr0.4Co0.2Fe0.8O3‐x−δFx (LSCFFx, x = 0.05, 0.10, and 0.20) materials are evaluated as oxygen electrodes for solid oxide fuel and electrolyser cell application. Materials have been prepared via low‐temperature topotactic route by fluorination of the parent oxide with polyvinylidene fluorine (PVDF). A decrease in the polarisation resistance (Rp) is observed for the "LSCFFx" symmetric cells. However, the improved electrochemical behavior for the symmetric cells cannot be explained by the presence of fluorine, as post mortem chemical analysis shows that fluorine is absent from the materials after the calcination treatment, contradicting previous results from the literature and calling for deeper understanding. The presence of fluorine is proved to result in a sluggish surface exchange rate compared with the LSCF oxide via pulsed isotopic exchange technique. Despite the absence of fluorine in the fabricated symmetric cell, annealing with PVDF at low temperatures prior to the electrode fabrication is proven to be a beneficial step to improve the electrochemical performance of LSCF material with applications for solid oxide cells. Studies with room temperature X‐ray diffraction, X‐ray photoelectron spectroscopy, and Mössbauer spectroscopy suggest that increased oxygen vacancy concentration, structural disorder and changes in the cobalt/iron valence state distribution are potential explanations for the reduced Rp. [ABSTRACT FROM AUTHOR]

Background: In experimental models of Parkinson's disease (PD), different degrees of degeneration to the nigrostriatal pathway produce distinct profiles of synaptic alterations that depend on progressive changes in N-methyl-D-aspartate receptors (NMDAR)-mediated functions. Repetitive transcranial magnetic stimulation (rTMS) induces modifications in glutamatergic and dopaminergic systems, suggesting that it may have an impact on glutamatergic synapses modulated by dopamine neurotransmission. However, no studies have so far explored the mechanisms of rTMS effects at early stages of PD.Objectives: We tested the hypothesis that in vivo application of rTMS with intermittent theta-burst stimulation (iTBS) pattern alleviates corticostriatal dysfunctions by modulating NMDAR-dependent plasticity in a rat model of early parkinsonism.Methods: Dorsolateral striatal spiny projection neurons (SPNs) activity was studied through ex vivo whole-cell patch-clamp recordings in corticostriatal slices obtained from 6-hydroxydopamine-lesioned rats, subjected to a single session (acute) of iTBS and tested for forelimb akinesia with the stepping test. Immunohistochemical analyses were performed to analyze morphological correlates of plasticity in SPNs.Results: Acute iTBS ameliorated limb akinesia and rescued corticostriatal long-term potentiation (LTP) in SPNs of partially lesioned rats. This effect was abolished by applying a selective inhibitor of GluN2B-subunit-containing NMDAR, suggesting that iTBS treatment could be associated with an enhanced activation of specific NMDAR subunits, which are major regulators of structural plasticity during synapse development. Morphological analyses of SPNs revealed that iTBS treatment reverted dendritic spine loss inducing a prevalence of thin-elongated spines in the biocytin-filled SPNs.Conclusions: Taken together, our data identify that an acute iTBS treatment produces a series of plastic changes underlying striatal compensatory adaptation in the parkinsonian basal ganglia circuit. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Autophagy agonists have been proposed to slow down neurodegeneration. Spermidine, a polyamine that acts as an autophagy agonist, is currently under clinical trial for the treatment of age‐related memory decline. How Spermidine and other autophagy agonists regulate memory and synaptic plasticity is under investigation. We set up a novel mouse model of mild cognitive impairment (MCI), in which middle‐aged (12‐month‐old) mice exhibit impaired memory capacity, lysosomes engulfed with amyloid fibrils (β‐amyloid and α‐synuclein) and impaired task‐induced GluA1 hippocampal post‐translation modifications. Subchronic treatment with Spermidine as well as the autophagy agonist TAT‐Beclin 1 rescued memory capacity and GluA1 post‐translational modifications by favouring the autophagy/lysosomal‐mediated degradation of amyloid fibrils. These findings provide new mechanistic evidence on the therapeutic relevance of autophagy enhancers which, by improving the degradation of misfolded proteins, slow down age‐related memory decline. [ABSTRACT FROM AUTHOR]

ABSTRACT Post-transcriptional gene regulation mediated by microRNAs (miRNAs) is implicated in memory formation; however, the function of miR-92 in this regulation is uncharacterized. The present study shows that training mice in contextual fear conditioning produces a transient increase in miR-92 levels in the hippocampus and decreases several miR-92 gene targets, including: (i) the neuronal Cl- extruding K+Cl- co-transporter 2 (KCC2) protein; (ii) the cytoplasmic polyadenylation protein (CPEB3), an RNA-binding protein regulator of protein synthesis in neurons; and (iii) the transcription factor myocyte enhancer factor 2D (MEF2D), one of the MEF2 genes which negatively regulates memory-induced structural plasticity. Selective inhibition of endogenous miR-92 in CA1 hippocampal neurons, by a sponge lentiviral vector expressing multiple sequences imperfectly complementary to mature miR-92 under the control of the neuronal specific synapsin promoter, leads to up-regulation of KCC2, CPEB3 and MEF2D, impairs contextual fear conditioning, and prevents a memory-induced increase in the spine density. Taken together, the results indicate that neuronal-expressed miR-92 is an endogenous fine regulator of contextual fear memory in mice. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

The transcription factor cAMP response element binding protein (CREB) is a key protein implicated in memory, synaptic plasticity and structural plasticity in mammals. Whether CREB regulates the synaptic incorporation of hippocampal glutamatergic receptors under basal and learning-induced conditions remains, however, mostly unknown. Using double-transgenic mice conditionally expressing a dominant negative form of CREB (CREBS133A, mCREB), we analyzed how chronic loss of CREB function in adult hippocampal glutamatergic neurons impacts the levels of the AMPA and NMDA receptors subunits within the post-synaptic densities (PSD). In basal (naïve) conditions, we report that inhibition of CREB function was associated with a specific reduction of the AMPAR subunit GluA1 and a proportional increase in its Ser845 phosphorylated form within the PSD. These molecular alterations correlated with a reduction in AMPA receptors mEPSC frequency, with a decrease in long-term potentiation (LTP), and with an increase in long-term depression (LTD). The basal levels other major synaptic proteins (GluA2/3, GluN1, GluN2A, and PSD95) within the PSD were not affected by CREB inhibition. Blocking CREB function also impaired contextual fear conditioning (CFC) and selectively blocked the CFC-driven enhancement of GluA1 and its Ser845 phosphorylated form within the PSD, molecular changes normally observed in wild-type mice. CFC-driven enhancement of other synaptic proteins (GluA2/3, GluN1, GluN2A, and PSD95) within the PSD was not significantly perturbed by the loss of CREB function. These findings provide the first evidence that, in vivo, CREB is necessary for the specific maintenance of the GluA1 subunit within the PSD of hippocampal neurons in basal conditions and for its trafficking within the PSD during the occurrence of learning. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Processing of Aβ-precursor protein ( APP) plays an important role in Alzheimer's disease ( AD) pathogenesis. The APP intracellular domain contains residues important in regulating APP function and processing, in particular the 682 YENPTY687 motif. To dissect the functions of this sequence in vivo, we created an APP knock-in allele mutating Y682 to Gly ( APP YG/YG mice). This mutation alters the processing of APP and Trk A signaling and leads to postnatal lethality and neuromuscular synapse defects when expressed on an APP-like protein 2 KO background. This evidence prompted us to characterize further the APP YG/YG mice. Here, we show that APP YG/YG mice develop aging-dependent decline in cognitive and neuromuscular functions, a progressive reduction in dendritic spines, cholinergic tone, and Trk A levels in brain regions governing cognitive and motor functions. These data are consistent with our previous findings linking NGF and APP signaling and suggest a causal relationship between altered synaptic connectivity, cholinergic tone depression and Trk A signaling deficit, and cognitive and neuromuscular decline in APP YG/YG mice. The profound deficits caused by the Y682 mutation underscore the biological importance of APP and indicate that APP YG/YG are a valuable mouse model to study APP functions in physiological and pathological processes. [ABSTRACT FROM AUTHOR]

Recently, the striatum has been implicated in the spread of epileptic seizures. As the absence of functional scaffolding protein Bassoon in mutant mice is associated with the development of pronounced spontaneous seizures, we utilized this new genetic model of epilepsy to investigate seizure-induced changes in striatal synaptic plasticity. Mutant mice showed reduced long-term potentiation in striatal spiny neurons, associated with an altered N-methyl-d-aspartate (NMDA) receptor subunit distribution, whereas GABAergic fast-spiking (FS) interneurons showed NMDA-dependent short-term potentiation that was absent in wild-type animals. Alterations in the dendritic morphology of spiny neurons and in the number of FS interneurons were also observed. Early antiepileptic treatment with valproic acid reduced epileptic attacks and mortality, rescuing physiological striatal synaptic plasticity and NMDA receptor subunit composition. However, morphological alterations were not affected by antiepileptic treatment. Our results indicate that, in Bsn mutant mice, initial morphological alterations seem to reflect a more direct effect of the abnormal genotype, whereas plasticity changes are likely to be caused by the occurrence of repeated cortical seizures. [ABSTRACT FROM AUTHOR]

The phosphodiesterase type IV inhibitor rolipram increases cAMP response element-binding protein (CREB) phosphorylation and exerts neuroprotective effects in both the quinolinic acid rat model of Huntington’s disease ( DeMarch et al., 2007 ) and the R6/2 mouse including sparing of striatal neurons, prevention of neuronal intranuclear inclusion formation and attenuation of microglial reaction ( DeMarch et al., 2008 ). In this study, we sought to determine if rolipram has a beneficial role in the altered distribution of CREB binding protein in striatal spiny neurons and in the motor impairments shown by R6/2 mutants. Moreover, we investigated whether rolipram treatment altered the degeneration of parvalbuminergic interneurons typical of Huntington’s disease ( Fusco et al., 1999 ). Transgenic mice and their wild-type controls from a stable colony maintained in our laboratory were treated with rolipram (1.5 mg/kg) or saline daily starting from 4 weeks of age. The cellular distribution of CREB binding protein in striatal spiny neurons was assessed by immunofluorescence, whereas parvalbuminergic neuron degeneration was evaluated by cell counts of immunohistochemically labeled tissue. Motor coordination and motor activity were also examined. We found that rolipram was effective in preventing CREB binding protein sequestration into striatal neuronal intranuclear inclusions, sparing parvalbuminergic interneurons of R6/2 mice, and rescuing their motor coordination and motor activity deficits. Our findings demonstrate the possibility of reversing pharmacologically the behavioral and neuropathological abnormalities of symptomatic R6/2 mice and underline the potential therapeutic value of phosphodiesterase type IV inhibitors in Huntington’s disease. [ABSTRACT FROM AUTHOR]

Synaptic activity-dependent phosphorylation of the transcription factor cAMP response element binding protein (CREB) leads to CREB-dependent gene transcription, a process thought to underlie long-term hippocampal synaptic plasticity and memory formation. We previously reported that increasing CREB activity in glutamatergic neurons enhances synaptic plasticity and neuronal excitability. Whether these modifications are sufficient to promote hippocampal-dependent memory formation was not determined. Here, we provide direct evidence that a brief increase in CREB-dependent transcription in either CA1 or DG neurons, using in vivo viral vectors, is sufficient to boost memory for contextual representations, as tested in the contextual fear conditioning task, without affecting motor, pain, or anxiety behaviors. © 2008 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a fatal progressive neuropathy associated with the degeneration of spinal and brainstem motor neurons. Although ALS is essentially considered as a lower motor neuron disease, prefrontal cortex atrophy underlying executive function deficits have been extensively reported in ALS patients. Here, we examine whether prefrontal cortex neuronal abnormalities and related cognitive impairments are present in presymptomatic G93A Cu/Zn superoxide dismutase mice, a mouse model for familial ALS. Structural characteristics of prelimbic/infralimbic (PL/IL) medial prefrontal cortex (mPFC) neurons were studied in 3-month-old G93A and wild-type mice with the Golgi–Cox method, while mPFC-related cognitive operations were assessed using the conditioned fear extinction paradigm. Sholl analysis performed on the dendritic material showed a reduction in dendrite length and branch nodes on basal dendrites of PL/IL neurons in G93A mice. Spine density was also decreased on basal dendrite segments of branch order five. Consistent with the altered morphology of PL/IL cortical regions, G93A mice showed impaired extinction of conditioned fear. Our findings indicate that abnormal prefrontal cortex connectivity and function are appreciable before the onset of motor disturbances in this model. [ABSTRACT FROM AUTHOR]

Reelin-deficient mice have been used to investigate the role of this extracellular protein in cortico-striatal plasticity and striatum-related behaviours. Here we show that a repetitive electrical stimulation of the cortico-striatal pathway elicited long-term potentiation (LTP) in homozygous reeler ( rl/rl) mice, while causing long-term depression in their wild-type (+/+) littermates. The N-methyl-d-aspartic acid (NMDA) receptor antagonistd-(–)-2 amino-5-phosphonopentanoic acid prevented the induction of LTP in ( rl/rl) mice, thus confirming that this form of synaptic plasticity was NMDA receptor-dependent. Interestingly, in the presence of tiagabine, a blocker of γ-aminobutyric acid (GABA) re-uptake system, the probability that ( rl/rl) mice showed LTP decreased significantly, thus suggesting an impaired GABAergic transmission in reeler mutants. Consistent with this view, a decreased density of parvalbumin-positive GABAergic striatal interneurons was found in ( rl/rl) mice in comparison to (+/+) mice. Finally, compatible with their abnormal striatal function ( rl/rl) mice exhibited procedural learning deficits. Our data, showing alterations in cortico-striatal plasticity largely depending on a depressed GABAergic tone, delineate a mechanism whereby the lack of reelin may affect cognitive functions. [ABSTRACT FROM AUTHOR]

This study examines the extent to which simultaneous olfactory discrimination learning increases spine density on hippocampal CA1 pyramidal neurons in C57BL/6J (C57) and DBA/2J (DBA) inbred mice, characterized by spontaneous differences in hippocampal plasticity and hippocampus-related learning. The behavioral data first showed a clear-cut difference in performance between the two strains. C57 mice learned to identify the positively reinforced olfactory cue whereas DBA did not. Both strains, however, similarly acquired the procedural aspects of the task. The morphological analysis performed 24 h post-training revealed that spine density was significantly increased along apical, oblique, and basal dendrites in trained C57 mice compared to trained DBA mice, and to pseudotrained as well as to control cage mice of both strains. These findings confirm the ability of C57 mice to solve hippocampal-dependent tasks and provide the first evidence that simultaneous olfactory discrimination learning elicits spine growth in the mouse hippocampus. In addition, the finding that DBA mice failed to discriminate between the two olfactory cues but were as efficient as C57 mice in learning the procedural aspects of the task outlines that the structural changes observed in the latter strain were independent from any procedural learning component. © 2006 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

The possibility of detecting progressive changes in cognitive function reflecting the spatio-temporal pattern of β-amyloid peptide (Aβ) deposition was investigated in Tg2576 mice overexpressing the human mutant amyloid precursor protein (hAPP). Here, we show that at 7 months of age, Tg2576 mice exhibited a selective deficit in hippocampus-based operations including a defective habituation of object exploration, a lack of reactivity to spatial novelty and a disruption of allothetic orientation in a cross-shaped maze. At 14 months of age, Tg2576 mice displayed a more extended pattern of behavioral abnormalities, because they failed to react to object novelty and exclusively relied on motor-based orientation in the cross-shaped maze. However, an impaired reactivity to spatial and object novelty possibly reflecting age-related attention deficits also emerged in aged wild-type mice. These findings further underline that early cognitive markers of AD can be detected in Tg2576 mice before Aβ deposition occurs and suggest that as in humans, cognitive deterioration progressively evolves from an initial hippocampal syndrome to global dementia because of the combined effect of the neuropathology and aging. [ABSTRACT FROM AUTHOR]

The possibility that the inducible 72-kDa heat shock protein (hsp72) is involved in learning-related plasticity mechanisms was investigated in two inbred strains of mice that show spontaneous differences in spatial learning performance as well as an opposite reactivity to stress. Induction of hsp72 after radial maze training was measured by immunoblotting in the hippocampus of C57BL/6 (C57) and DBA/2 (DBA) inbred mice exposed or nonexposed to chronic acoustic stress. In agreement with previous studies, inter-strain differences in radial maze performance were found in nonstressed mice with C57 mice showing the higher scores. Chronic acoustic stress, however, impaired performance in the high-learner C57 strain and improved performance in the low-learner DBA strain. Western blot analysis revealed that post-training expression of hsp72 was low in the condition each strain was showing the higher-performance (nonstressed C57 and stressed DBA) and high in the condition each strain was showing the lower performance (stressed C57 and nonstressed DBA). These findings indicate that expression of hsp72 in the hippocampus varies as a function of the learning performance independently from exposure to chronic acoustic stress. © 2005 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

A prospective study was performed, comparing gallium scintigraphy (67Ga) and positron emission tomography (PET) using fluorine-18 fluorodeoxyglucose (18FDG), to monitor the response of aggressive non-Hodgkin's lymphoma during treatment. 67Ga and 18FDG scans were performed in 26 patients after two cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) therapy. The scans were reviewed independently by four experienced nuclear physicians, who were blinded for the alternative scan technique and follow-up. Eleven out of 26 patients remained free from progression with a mean follow up of 25 ± 5 months, whereas 14 patients relapsed, and one died of lung cancer. Interobserver variation was significantly greater for 67Ga than for 18FDG PET. Some 64% of patients who had a negative early restaging 18FDG PET remained free from progression versus 50% of patients with negative 67Ga scans. Only 25% of patients with a positive PET remained disease free versus 42% of 67Ga-positive patients. Time to progression was associated with 18FDG PET results, but not with those by 67Ga. 18FDG PET had better test characteristics than 67Ga for the evaluation of early response in aggressive non-Hodgkin's lymphoma patients. [ABSTRACT FROM AUTHOR]

Summary background Justification for adjuvant radio-iodine (I-131) therapy in differentiated thyroid cancer (DTC) is purely based on retrospective data. This is true for ablative therapy and even more so for high-dosage adjuvant schedules. Randomized trials on the latter application are considered impossible due to anticipated formidable sample sizes required in a disease with an overall excellent prognosis like DTC. objective To develop and validate a model that could stratify for risk of recurrence, rather than survival, as is usually done in prognostic indices, and secondly, to use this model to estimate the sample size required for a randomized trial. design, patients and results From databases of three large Dutch centres, we identified 342 consecutive patients without known residual DTC after (near-) total thyroidectomy. Using Cox proportional hazards analysis, a model was validated that clearly distinguished risk categories of recurrence using commonly available baseline variables. The model included age, N stage at presentation and T stage in papillary carcinoma. According to this stratification, a subset of patients at substantial risk for relapse (30–40%) was identified. They could be eligible for a trial assessing the impact of high-dose adjuvant I-131 on recurrence rates. Assuming a clinically relevant effect of 30% reduction of relapses, 290 patients would have to be entered in either arm (α 0·05, power 80%). conclusion We conclude that even though a randomized trial on this issue will be difficult to design and conduct, sample size is not the main problem. [ABSTRACT FROM AUTHOR]

Abstract Induction of long-term depression (LTD) in rat striatal slices revealed that this form of synaptic plasticity is coupled to an increased expression of tissue-plasminogen activator (t-PA) mRNA, as detected by the mRNA differential display technique. To further investigate the involvement of this gene in synaptic remodelling following striatal LTD, we recorded electrical activity from mice lacking the gene encoding t-PA (t-PA-KO) and from wild-type (WT) mice. Tetanic stimulation induced LTD in the large majority of striatal neurons recorded from WT mice. Conversely, LTD was absent in a significant proportion of striatal neurons obtained from mice lacking t-PA. Electrophysiological recordings obtained from hippocampal slices in the CA1 area showed that mainly the late phase of long-term potentiation (LTP) was reduced in t-PA-KO mice. Learning and memory-related behavioural abnormalities were also found in these transgenic mice. Disruption of the t-PA gene, in fact, altered both the context conditioning test, a hippocampus-related behavioural task, and the two-way active avoidance, a striatum-dependent task. In an open field object exploration task, t-PA-KO mice expressed deficits in habituation and reactivity to spatial change that are consistent with an altered hippocampal function. Nevertheless, decreased rearing and poor initial object exploration were also observed, further suggesting an altered striatal function. These data indicate that t-PA plays a critical role in the formation of various forms of synaptic plasticity and memory. [ABSTRACT FROM AUTHOR]

The effects of prenatal exposure to stress and to naltrexone on emotional behaviors were studied in CDI mice during ontogeny and in the adulthood. During ontogeny (a) lower body weights were initially found in pups born by mothers injected with naltrexone; (b) treatments did not affect sensory motor development except in the case of the cliff aversion reflex which occurred earlier in pups prenatally exposed to stress; (c) measures of ultrasonic vocalizations in stressful context showed that the amount of vocalizations emitted by pups born by stressed mothers was significantly higher than that emitted by pups born by naltrexone injected and control mothers (c) an examination of mother-offspring interactions on the very first day of observation indicated a consistent trend in stressed mothers to be more responsive to their pups. In adulthood, ultrasonic calls in courtship after short and long periods of isolation showed a time-dependent decrease of vocalizations in males prenatally exposed to naltrexone. These results indicate that the modification of emotionally evident during early development are directly related to the reactivity of the mothers to the experimental treatment. Moreover, the long-term reduction of ultrasonic vocalization in adult males prenatally exposed to naltrexone shows in these animals a lowered reactivity to stressful contexts which probably results from specific physiological alterations due to the prenatal administration of the opiate antagonist. [ABSTRACT FROM AUTHOR]

An overview of European experience with ketoprofen, a nonsteroidal anti-inflammatory drug (NSAID) with analgesic properties, from the time of its marketing in 1973 until the present is presented. Orally administered ketoprofen (200 mg/day) has been proven effective in treating rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis. Furthermore, several alternate dosage forms, including intramuscular injection for relief of acutely painful conditions, suppositories, two slow-release forms (a sustained-release tablet [IBP 200®] and a controlled-release capsule [Oruvaii®]), and a topical gel for local treatment of certain superficial conditions and minor rheumatologic disease are available. The safety of ketoprofen has also been proven in several European postmarketing surveillance studies and more importantly, by French and British drug monitoring data. Ketoprofen was rated as one of the safest NSAIDs available in the United Kingdom (UK) by the Committee on the Safety of Medicine in 1986. For incidence of gastrointestinal complaints per million prescriptions, ketoprofen ranked seventh among 19 NSAIDs in its first five years of marketing in the UK. Ketoprofen has been associated with a very low incidence of serious renal, hepatic, or cutaneous reactions. Thus ketoprofen, in 15 years of marketed use in Europe, has proven to be an effective anti-inflammatory and analgesic agent with an excellent safety profile and several convenient dosage forms. [ABSTRACT FROM AUTHOR]

Abstract The contribution of the nucleus accumbens shell, the dorsal hippocampus, and the basolateral amygdala to contextual and explicit cue fear conditioning was assessed in C57BL/6 (C57) and DBA/2 (DBA) mice showing differences in processing contextual information associated with consistent but non-pathological variations in hippocampal functionality. Mice from both strains with bilateral ibotenic acid or sham lesions located in each area were introduced in a conditioning chamber and exposed twice to the pairing of a tone (2 × 8 s, 2000 Hz, 80 dB) with a shock (2 s, 0.7 mA). On the following day, mice were first exposed to the training context then to the tone in a different context. Freezing behaviour was scored in all situations. C57 showed more freezing to the context than to the tone whereas DBA showed more freezing to the tone than to the context. In C57, both nucleus accumbens and hippocampal lesions impaired acquisition of contextual fear conditioning but paradoxically improved acquisition of cue fear conditioning, whereas amygdala lesions disrupted performance in every task. In DBA, nucleus accumbens lesions, like amygdala lesions, impaired acquisition of both contextual and cue fear conditioning, whereas hippocampal lesions did not produce any effect. The parallelism between the effect of nucleus accumbens and hippocampus lesions in C57, and between the effect of nucleus accumbens and amygdala lesions in DBA points to a variability in nucleus accumbens function according to the strain specialization to develop context- or cue-based responding. [ABSTRACT FROM AUTHOR]