Loss of the parkinsonism-associated protein FBXO7 in glutamatergic forebrain neurons in mice leads to abnormal motor behavior and synaptic defects.

Mutations in PARK15, which encodes for the F-box protein FBXO7 have been associated with Parkinsonian Pyramidal syndrome, a rare and complex movement disorder with Parkinsonian symptoms, pyramidal tract signs and juvenile onset. Our previous study showed that systemic loss of Fbxo7 in mice causes motor defects and premature death. We have also demonstrated that FBXO7 has a crucial role in neurons as the specific deletion in tyrosine hydroxylase-positive or glutamatergic forebrain neurons leads to late-onset or early-onset motor dysfunction, respectively. In this study, we examined NEX-Cre;Fbxo7fl/fl mice, in which Fbxo7 was specifically deleted in glutamatergic projection neurons. The effects of FBXO7 deficiency on striatal integrity were investigated with HPLC and histological analyses. NEX-Cre;Fbxo7fl/fl mice revealed an increase in striatal dopamine concentrations, changes in the glutamatergic, GABAergic and dopaminergic pathways, astrogliosis and microgliosis and little or no neuronal loss in the striatum. To determine the effects on the integrity of the synapse, we purified synaptic membranes, subjected them to quantitative mass spectrometry analysis and found alterations in the complement system, endocytosis and exocytosis pathways. These neuropathological changes coincide with alterations in spontaneous home cage behavior. Taken together, our findings suggest that FBXO7 is crucial for corticostriatal projections and the synaptic integrity of the striatum, and consequently for proper motor control.

The murine ortholog of Kaufman oculocerebrofacial syndrome protein Ube3b regulates synapse number by ubiquitinating Ppp3cc.

Kaufman oculocerebrofacial syndrome (KOS) is a severe autosomal recessive disorder characterized by intellectual disability, developmental delays, microcephaly, and characteristic dysmorphisms. Biallelic mutations of UBE3B, encoding for a ubiquitin ligase E3B are causative for KOS. In this report, we characterize neuronal functions of its murine ortholog Ube3b and show that Ube3b regulates dendritic branching in a cell-autonomous manner. Moreover, Ube3b knockout (KO) neurons exhibit increased density and aberrant morphology of dendritic spines, altered synaptic physiology, and changes in hippocampal circuit activity. Dorsal forebrain-specific Ube3b KO animals show impaired spatial learning, altered social interactions, and repetitive behaviors. We further demonstrate that Ube3b ubiquitinates the catalytic γ-subunit of calcineurin, Ppp3cc, the overexpression of which phenocopies Ube3b loss with regard to dendritic spine density. This work provides insights into the molecular pathologies underlying intellectual disability-like phenotypes in a genetically engineered mouse model.

Uncoupling the widespread occurrence of anti-NMDAR1 autoantibodies from neuropsychiatric disease in a novel autoimmune model.

Autoantibodies of the IgG class against N-methyl-D-aspartate-receptor subunit-NR1 (NMDAR1-AB) were considered pathognomonic for anti-NMDAR encephalitis. This view has been challenged by the age-dependent seroprevalence (up to >20%) of functional NMDAR1-AB of all immunoglobulin classes found in >5000 individuals, healthy or affected by different diseases. These findings question a merely encephalitogenic role of NMDAR1-AB. Here, we show that NMDAR1-AB belong to the normal autoimmune repertoire of dogs, cats, rats, mice, baboons, and rhesus macaques, and are functional in the NMDAR1 internalization assay based on human IPSC-derived cortical neurons. The age dependence of seroprevalence is lost in nonhuman primates in captivity and in human migrants, raising the intriguing possibility that chronic life stress may be related to NMDAR1-AB formation, predominantly of the IgA class. Active immunization of ApoE-/- and ApoE+/+ mice against four peptides of the extracellular NMDAR1 domain or ovalbumin (control) leads to high circulating levels of specific AB. After 4 weeks, the endogenously formed NMDAR1-AB (IgG) induce psychosis-like symptoms upon MK-801 challenge in ApoE-/- mice, characterized by an open blood-brain barrier, but not in their ApoE+/+ littermates, which are indistinguishable from ovalbumin controls. Importantly, NMDAR1-AB do not induce any sign of inflammation in the brain. Immunohistochemical staining for microglial activation markers and T lymphocytes in the hippocampus yields comparable results in ApoE-/- and ApoE+/+ mice, irrespective of immunization against NMDAR1 or ovalbumin. These data suggest that NMDAR1-AB of the IgG class shape behavioral phenotypes upon access to the brain but do not cause brain inflammation on their own.

The role of KIBRA in reconstructive episodic memory.

BACKGROUND: In order to retrieve episodic past events, the missing information needs to be reconstructed using information stored in semantic memory. Failures in these reconstructive processes are expressed as false memories. KIBRA single nucleotide polymorphism (rs17070145) has been linked to episodic memory performance as well as an increased risk of Alzheimer's disease and post-traumatic stress disorder (PTSD). METHODS: Here, the role of KIBRA rs17070145 polymorphism (male and female CC vs. CT/TT carriers) in reconstructive episodic memory in the Deese-Roediger-McDermott (DRM) paradigm was investigated in N = 219 healthy individuals. RESULTS: Female participants outperformed males in the free recall condition. Furthermore, a trend towards a gender x genotype interaction was found for false recognition rates. Female CT/TT carriers exhibited a lower proportion of false recognition rates for associated critical lures as compared to male CT/TT. Additionally, an association between KIBRA rs17070145 genotype, familiarity and recollection based recognition performance was found. In trials with correct recognition of listed items CT/TT carriers showed more "remember", but fewer "know" responses as compared to CC carriers. DISCUSSION AND CONCLUSION: Our findings suggest that the T-allele of KIBRA rs17070145 supports recollection based episodic memory retrieval and contributes to memory accuracy in a gender dependent manner. Findings are discussed in the context of the specific contribution of KIBRA related SNPs to reconstructive episodic memory and its implications for cognitive and emotional symptoms in dementia and PTSD.

Cognitive, emotional and social phenotyping of mice in an observer-independent setting.

Based on the intellicage paradigm, we have developed a novel cognitive, emotional and social phenotyping battery that permits comprehensive standardized behavioral characterization of mice in an experimenter-independent social setting. Evaluation of this battery in a large number of male and female C57BL/6 wildtype mice, tested in >20 independent cohorts, revealed high reproducibility of the behavioral readouts and may serve as future reference tool. We noticed robust sex-specific differences in general activity, cognitive and emotional behavior, but not regarding preference for social pheromones. Specifically, female mice revealed higher activity, decreased sucrose preference, impaired reversal and place-time-reward learning. Furthermore, female mice reacted more sensitively than males to reward-withdrawal showing a negative emotional contrast/Crespi-effect. In a series of validation experiments, we tested mice with different pathologies, including neuroligin-3 deficient mice (male Nlgn3y/- and female Nlgn3+/-) for autistic behavior, oligodendrocyte-specific erythropoietin receptor knockout (oEpoR-/-) mice for cognitive impairment, as well as mouse models of renal failure (unilateral ureteral obstruction and 5/6 nephrectomy) and of type 2 diabetes (ApoE-/-) - for delineating potentially confounding effects of motivational factors (thirst, glucose-craving) on learning and memory assessments. As prominent features, we saw in Nlgn3 mutants reduced preference for social pheromones, whereas oEpoR-/- mice showed learning deficits in place or reversal learning tasks. Renal failure led to increased water intake, and diabetic metabolism to enhanced glucose preference, limiting interpretation of hereon based learning and memory performance in these mice. The phenotyping battery presented here may be well-suited as high-throughput multifaceted diagnostic instrument for translational neuropsychiatry and behavioral genetics.

Preexisting Serum Autoantibodies Against the NMDAR Subunit NR1 Modulate Evolution of Lesion Size in Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: Recently, we reported high seroprevalence (age-dependent up to >19%) of N-methyl-d-aspartate-receptor subunit NR1 (NMDAR1) autoantibodies in both healthy and neuropsychiatrically ill subjects (N=4236). Neuropsychiatric syndrome relevance was restricted to individuals with compromised blood-brain barrier, for example, apolipoprotein E4 (APOE4) carrier status, both clinically and experimentally. We now hypothesized that these autoantibodies may upon stroke be protective in individuals with hitherto intact blood-brain barrier, but harmful for subjects with chronically compromised blood-brain barrier. METHODS: Of 464 patients admitted with acute ischemic stroke in the middle cerebral artery territory, blood for NMDAR1 autoantibody measurements and APOE4 carrier status as indicator of a preexisting leaky blood-brain barrier was collected within 3 to 5 hours after stroke. Evolution of lesion size (delta day 7-1) in diffusion-weighted magnetic resonance imaging was primary outcome parameter. In subgroups, NMDAR1 autoantibody measurements were repeated on days 2 and 7. RESULTS: Of all 464 patients, 21.6% were NMDAR1 autoantibody-positive (immunoglobulin M, A, or G) and 21% were APOE4 carriers. Patients with magnetic resonance imaging data available on days 1 and 7 (N=384) were divided into 4 groups according to NMDAR1 autoantibody and APOE4 status. Groups were comparable in all stroke-relevant presenting characteristics. The autoantibody+/APOE4- group had a smaller mean delta lesion size compared with the autoantibody-/APOE4- group, suggesting a protective effect of circulating NMDAR1 autoantibodies. In contrast, the autoantibody+/APOE4+ group had the largest mean delta lesion area. NMDAR1 autoantibody serum titers dropped on day 2 and remounted by day 7. CONCLUSIONS: Dependent on blood-brain barrier integrity before an acute ischemic brain injury, preexisting NMDAR1 autoantibodies seem to be beneficial or detrimental.

Fast cerebellar reflex circuitry requires synaptic vesicle priming by munc13-3.

Munc13-3 is a member of the Munc13 family of synaptic vesicle priming proteins and mainly expressed in cerebellar neurons. Munc13-3 null mutant (Munc13-3 (-/-)) mice show decreased synaptic release probability at parallel fiber to Purkinje cell, granule cell to Golgi cell, and granule cell to basket cell synapses and exhibit a motor learning deficit at highest rotarod speeds. Since we detected Munc13-3 immunoreactivity in the dentate gyrus, as reported here for the first time, and current studies indicated a crucial role for the cerebellum in hippocampus-dependent spatial memory, we systematically investigated Munc13-3 (-/-) mice versus wild-type littermates of both genders with respect to hippocampus-related cognition and a range of basic behaviors, including tests for anxiety, sensory functions, motor performance and balance, sensorimotor gating, social interaction and competence, and repetitive and compulsive behaviors. Neither basic behavior nor hippocampus-dependent cognitive performance, evaluated by Morris water maze, hole board working and reference memory, IntelliCage-based place learning including multiple reversals, and fear conditioning, showed any difference between genotypes. However, consistent with a disturbed cerebellar reflex circuitry, a reliable reduction in the acoustic startle response in both male and female Munc13-3 (-/-) mice was found. To conclude, complete deletion of Munc13-3 leads to a robust decrease in the acoustic startle response. This readout of a fast cerebellar reflex circuitry obviously requires synaptic vesicle priming by Munc13-3 for full functionality, in contrast to other behavioral or cognitive features, where a nearly perfect compensation of Munc13-3 deficiency by related synaptic proteins has to be assumed.

Inactivation of ceramide synthase 6 in mice results in an altered sphingolipid metabolism and behavioral abnormalities.

The N-acyl chain length of ceramides is determined by the specificity of different ceramide synthases (CerS). The CerS family in mammals consists of six members with different substrate specificities and expression patterns. We have generated and characterized a mouse line harboring an enzymatically inactive ceramide synthase 6 (CerS6KO) gene and lacz reporter cDNA coding for ß-galactosidase directed by the CerS6 promoter. These mice display a decrease in C16:0 containing sphingolipids. Relative to wild type tissues the amount of C16:0 containing sphingomyelin in kidney is ∼35%, whereas we find a reduction of C16:0 ceramide content in the small intestine to about 25%. The CerS6KO mice show behavioral abnormalities including a clasping abnormality of their hind limbs and a habituation deficit. LacZ reporter expression in the brain reveals CerS6 expression in hippocampus, cortex, and the Purkinje cell layer of the cerebellum. Using newly developed antibodies that specifically recognize the CerS6 protein we show that the endogenous CerS6 protein is N-glycosylated and expressed in several tissues of mice, mainly kidney, small and large intestine, and brain.

Pathologic and phenotypic alterations in a mouse expressing a connexin47 missense mutation that causes Pelizaeus-Merzbacher-like disease in humans.

Gap junction channels are intercellular conduits that allow diffusional exchange of ions, second messengers, and metabolites. Human oligodendrocytes express the gap junction protein connexin47 (Cx47), which is encoded by the GJC2 gene. The autosomal recessive mutation hCx47M283T causes Pelizaeus-Merzbacher-like disease 1 (PMLD1), a progressive leukodystrophy characterized by hypomyelination, retarded motor development, nystagmus, and spasticity. We introduced the human missense mutation into the orthologous position of the mouse Gjc2 gene and inserted the mCx47M282T coding sequence into the mouse genome via homologous recombination in embryonic stem cells. Three-week-old homozygous Cx47M282T mice displayed impaired rotarod performance but unchanged open-field behavior. 10-15-day-old homozygous Cx47M282T and Cx47 null mice revealed a more than 80% reduction in the number of cells participating in glial networks after biocytin injections into oligodendrocytes in sections of corpus callosum. Homozygous expression of mCx47M282T resulted in reduced MBP expression and astrogliosis in the cerebellum of ten-day-old mice which could also be detected in Cx47 null mice of the same age. Three-month-old homozygous Cx47M282T mice exhibited neither altered open-field behavior nor impaired rotarod performance anymore. Adult mCx47M282T expressing mice did not show substantial myelin alterations, but homozygous Cx47M282T mice, additionally deprived of connexin32, which is also expressed in oligodendrocytes, died within six weeks after birth and displayed severe myelin defects accompanied by astrogliosis and activated microglia. These results strongly suggest that PMLD1 is caused by the loss of Cx47 channel function that results in impaired panglial coupling in white matter tissue.

Insights into conscious cognitive information processing.

For over a century, the neuro- and pathophysiological, behavioral, and cognitive correlates of consciousness have been an active field of theoretical considerations and empirical research in a wide range of modern disciplines. Conscious cognitive processing of information cannot be observed directly, but might be inferred from step-like discontinuities in learning performance or sudden insight-based improvements in problem solving behavior. It is assumed that a sudden step of knowledge associated with insight requires a creative reorganization of mental representations of task- or problem-relevant information and the restructuration of the task, respectively problem to overcome an cognitive dead-end or impasse. Discontinuities in learning performance or problem solving after an insight event can be used as time-tags to capture the time window in which conscious cognitive information processing must have taken place. According to the platform theory of conscious cognitive information processing, the reorganization and restructuration processes, require the maintenance of task- or problem-relevant information in working memory for the operation of executive functions on these mental representations. Electrophysiological evidence suggests that the reorganization and restructuration processes in working memory, that precede insight-based problem solutions are accompanied by an increase in the power of gamma oscillations in cortical areas including the prefrontal cortex. Empirical evidence and theoretical assumptions argue for an involvement of gap junction channels and connexin hemichannels in cortical gamma-oscillations and working memory processes. Discontinuities in learning or problem solving performance might be used as time-tags to investigate the implication of gap junction channels and hemichannels in conscious cognitive processing.

Panglial gap junctional communication is essential for maintenance of myelin in the CNS.

In this study, we have investigated the contribution of oligodendrocytic connexin47 (Cx47) and astrocytic Cx30 to panglial gap junctional networks as well as myelin maintenance and function by deletion of both connexin coding DNAs in mice. Biocytin injections revealed complete disruption of oligodendrocyte-to-astrocyte coupling in the white matter of 10- to 15-d-old Cx30/Cx47 double-deficient mice, while oligodendrocyte-to-oligodendrocyte coupling was maintained. There were no quantitative differences regarding cellular networks in acute brain slices obtained from Cx30/Cx47 double-null mice and control littermates, probably caused by the upregulation of oligodendrocytic Cx32 in Cx30/Cx47 double-deficient mice. We observed early onset myelin pathology, and ∼40% of Cx30/Cx47 double-deficient animals died within 42 to 90 d after birth, accompanied by severe motor impairments. Histological and ultrastructural analyses revealed severe vacuolization and myelination defects in all white matter tracts of the CNS. Furthermore, Cx30/Cx47 double-deficient mice exhibited a decreased number of oligodendrocytes, severe astrogliosis, and microglial activation in white matter tracts. Although less affected concerning motor impairment, surviving double-knock-out (KO) mice showed behavioral alterations in the open field and in the rotarod task. Vacuole formation and thinner myelin sheaths were evident also with adult surviving double-KO mice. Since interastrocytic coupling due to Cx43 expression and interoligodendrocytic coupling because of Cx32 expression are still maintained, Cx30/Cx47 double-deficient mice demonstrate the functional role of both connexins for interastrocytic, interoligodendrocytic, and panglial coupling, and show that both connexins are required for maintenance of myelin.

Ablation of neuronal ceramide synthase 1 in mice decreases ganglioside levels and expression of myelin-associated glycoprotein in oligodendrocytes.

Ceramide synthase 1 (CerS1) catalyzes the synthesis of C18 ceramide and is mainly expressed in the brain. Custom-made antibodies to a peptide from the C-terminal region of the mouse CerS1 protein yielded specific immunosignals in neurons but no other cell types of wild type brain, but the CerS1 protein was not detected in CerS1-deficient mouse brains. To elucidate the biological function of CerS1-derived sphingolipids in the brain, we generated CerS1-deficient mice by introducing a targeted mutation into the coding region of the cers1 gene. General deficiency of CerS1 in mice caused a foliation defect, progressive shrinkage, and neuronal apoptosis in the cerebellum. Mass spectrometric analyses revealed up to 60% decreased levels of gangliosides in cerebellum and forebrain. Expression of myelin-associated glycoprotein was also decreased by about 60% in cerebellum and forebrain, suggesting that interaction and stabilization of oligodendrocytic myelin-associated glycoprotein by neuronal gangliosides is due to the C18 acyl membrane anchor of CerS1-derived precursor ceramides. A behavioral analysis of CerS1-deficient mice yielded functional deficits including impaired exploration of novel objects, locomotion, and motor coordination. Our results reveal an essential function of CerS1-derived ceramide in the regulation of cerebellar development and neurodevelopmentally regulated behavior.

Superior working memory and behavioural habituation but diminished psychomotor coordination in mice lacking the ecto-5'-nucleotidase (CD73) gene.

Adenosine is an important neuromodulator in the central nervous system involved in the regulation of wakefulness, sleep, learning and memory, fear and anxiety as well as motor functions. Extracellular adenosine is synthesized by the cell-surface ectoenzyme ecto-5'-nucleotidase (CD73) from 5'-adenosine monophosphate. While CD73 is widely expressed throughout the mammalian brain, its specific role for behaviour is poorly understood. We examined spatial working memory, emotional responses, motor coordination and motor learning as well as behavioural habituation in mice with a targeted deletion of CD73. CD73 knockout (CD73-/-) mice exhibit enhanced spatial working memory in the Y-maze and enhanced long-term behavioural habituation in the open field. Furthermore, impaired psychomotor coordination on the accelerating rotarod was found in CD73-/- mice. No changes in motor learning and/or anxiety-like behaviour were evident in CD73-/- mice. Our data provide evidence for a role of CD73 in the regulation of learning and memory and psychomotor coordination. Our results might be important for the evaluation of adenosine neuromodulators as possible treatments to ameliorate cognitive and motor deficits associated with neurodegenerative diseases.

Generalization of beneficial exposure effects to untreated stimuli from another fear category.

Previous research has shown that fear associated with one stimulus often spreads to other stimuli with similar perceptual features as well as across different stimulus categories. Exposure is considered as the most effective intervention to attenuate exaggerated fear. The extent to which exposure treatment effects can generalize to fears not targeted during treatment remains elusive. Previous studies on possible generalization of beneficial effects of exposure used stimuli sharing the same stimulus category and/or stimuli having high perceptual similarity. The current study examined whether exposure treatment generalization can be achieved for untreated stimuli which do not share any perceptual resemblance and belong to a different fear category. An analogue sample of fifty participants with fear of spiders (animal-related fears) and heights (natural environment-related fears) was tested. Participants have been randomly assigned to either an exposure treatment (n = 24) or a control condition (n = 26). Exposure treatment was designed to only target participants' fear of spiders, leaving their fear of heights untreated. Results demonstrated that the effects of exposure treatment generalized to fear of heights, as indicated by a reduction in behavioral avoidance, as well as self-reported acrophobia symptoms. The present study confutes the assumption that generalization of exposure effects to untreated fears is based on perceptual similarity. Clearly, further research is required to determine the decisive factors, in order to expand the generalization effect permanently to any given type of fear.

A fatal alliance: Glial connexins, myelin pathology and mental disorders.

Mature oligodendrocytes are myelin forming glial cells which are responsible for myelination of neuronal axons in the white matter of the central nervous system. Myelin pathology is a major feature of severe neurological disorders. Oligodendrocyte-specific gene mutations and/or white matter alterations have also been addressed in a variety of mental disorders. Breakdown of myelin integrity and demyelination is associated with severe symptoms, including impairments in motor coordination, breathing, dysarthria, perception (vision and hearing), and cognition. Furthermore, there is evidence indicating that myelin sheath defects and white matter pathology contributes to the affective and cognitive symptoms of patients with mental disorders. Oligodendrocytes express the connexins GJC2; mCx47 [human (GJC2) and mouse (mCx47) connexin gene nomenclature according to Söhl and Willecke (2003)], GJB1; mCx32, and GJD1; mCx29 in both white and gray matter. Preclinical findings indicate that alterations in connexin expression in oligodendrocytes and astrocytes can induce myelin defects. GJC2; mCx47 is expressed at early embryonic stages in oligodendrocyte precursors cells which precedes central nervous system myelination. In adult humans and animals GJC2, respectively mCx47 expression is essential for oligodendrocyte function and ensures adequate myelination as well as myelin maintenance in the central nervous system. In the past decade, evidence has accumulated suggesting that mental disorders can be accompanied by changes in connexin expression, myelin sheath defects and corresponding white matter alterations. This dual pathology could compromise inter-neuronal information transfer, processing and communication and eventually contribute to behavioral, sensory-motor, affective and cognitive symptoms in patients with mental disorders. The induction of myelin repair and remyelination in the central nervous system of patients with mental disorders could help to restore normal neuronal information propagation and ameliorate behavioral and cognitive symptoms in individuals with mental disorders.

The role of self-efficacy in specific fears.

Low self-efficacy for threatening stimuli and situations has been proposed as an important etiological factor in the development and maintenance of specific phobias. The present study examined the relationships between general self-efficacy (GSE), specific self-efficacy (SSE) and specific fears in a representative sample (n = 717). While GSE was associated with higher self-reported fear and avoidance, SSE (e.g. SSE in the presence of animal-related fear) was more related to specific fears. SSE turned out to be a significant predictor of specific fear even after controlling for trait anxiety, age and gender. Interestingly, the association between SSE and specific fear differed across the different fear categories. Fear and avoidance of blood/injection/injuries showed the highest associations with SSE. In contrast, the association between natural environment-related fear and avoidance and GSE or SSE together was only modest. Exploratory analyses revealed a gender-specific effect on the strength of the association between SSE and specific fears. Women scored higher in animal-related fears and SSE. Our findings support the self-efficacy hypothesis of anxiety disorder development and provide a more detailed insight into the role of GSE and SSE in specific fears and phobias.

Conscious knowledge of CS-UCS contingency information affects extinction retrieval of conditioned disgust responses: Findings from an online de novo disgust conditioning task.

Objective: The present study aimed to establish and develop an online de novo conditioning paradigm for the measurement of conditioned disgust responses. We further explored the effects of explicit instructions about the CS-UCS contingency on extinction learning and retrieval of conditioned disgust responses. Method: The study included a sample of 115 healthy participants. Geometric figures served as conditioned stimuli (CS) and disgust-evoking pictures as unconditioned stimuli (UCS). During disgust conditioning, the CS+ was paired with the UCS (66% reinforcement) and the CS- remained unpaired; during extinction and retrieval, no UCS was presented. Half of the participants (n = 54) received instructions prior to the disgust extinction stating that the UCS will not be presented anymore. 1-2 days or 7-8 days later participants performed a retrieval test. CS-UCS contingency, disgust and valence ratings were used as dependent measures. Results: Successful acquisition of conditioned disgust response was observed on the level of CS-UCS contingency, disgust and valence ratings. While some decline in valence and disgust ratings during the extinction stage was observed, contingency instructions did not significantly affect extinction performance. Retrieval one week later revealed that contingency instructions increased the discrimination of the CSs. Conclusions: Extinction of conditioned disgust responses is not affected by explicit knowledge of the CS-UCS contingencies. However, contingency instructions prior to extinction seem to have a detrimental effect on long-term extinction retrieval.

Do oral contraceptives modulate the effects of stress induction on one-session exposure efficacy and generalization in women?

RATIONALE: The administration of glucocorticoids (GC) as an adjunct to exposure represents a promising strategy to improve one-session exposure outcome in anxiety disorders. It remains to be determined whether similar effects can be induced with the use of acute stress. Furthermore, the possible modulation of exposure effects by hormonal factors (e.g., use of oral contraceptives (OCs)) was not explored so far. OBJECTIVES: We investigated whether acute stress prior to one-session exposure for spider fear affects its efficacy in women using oral contraceptives (OC) relative to free-cycling (FC) women. In addition, effects of stress on generalization of exposure therapy effects towards untreated stimuli were examined. METHODS: Women with fears of spiders and cockroaches were randomly assigned to a Stress (n = 24) or No-Stress (n = 24) condition prior to one-session exposure. Of these 48 participants, 19 women used OC (n = 9 in the Stress, and n = 10 in the No-Stress group). All FC women had a regular menstrual cycle and were tested only in the follicular phase of their menstrual cycle. Pre-exposure stress induction was realized with the socially evaluated cold-pressor test. Exposure-induced changes towards treated and untreated fear stimuli were tested with behavioral approach tests for spiders and cockroaches and subjective fear and self-report measures. RESULTS: Acute stress did not influence exposure-induced reduction in fear and avoidance of the treated stimuli (spiders). Similarly, stress had no effect on the generalization of exposure-therapy effects towards untreated stimuli (cockroaches). Exposure-induced reduction in subjective fear and self-report measures for treated stimuli was less evident in women using OC specifically after pre-exposure stress. Women using OC had higher levels of subjective fear and scored higher in self-report measures at post-treatment (24 h after exposure) and follow-up (4 weeks after exposure). CONCLUSIONS: OC intake may represent an important confounding factor in augmentation studies using stress or GC.

Changes in object recognition and anxiety-like behaviour in mice expressing a Cx47 mutation that causes Pelizaeus-Merzbacher-like disease.

Pelizaeus-Merzbacher-like disease is characterized by impaired psychomotor development, ataxia, progressive spasticity and mental retardation. It is induced by mutations in the gap junction gene GJC2 that encodes for the gap junction protein connexin 47. Mice bearing a human Cx47M283T missense mutation have been generated as a transgenic mouse model of Pelizaeus-Merzbacher-like disease. Homozygous expression of the mutant connexin 47 gene in oligodendrocytes resulted in a complex and variable neuropathologic phenotype, which was associated with impairments in motor coordination in juvenile, but not adult mice. In the present study, we have investigated anxiety-like behaviour and spatial working memory in juvenile (P23) and adult (3-month-old) Cx47M282T mutant mice. Adult Cx47M282T mice were also evaluated in terms of neuromotor functions and in the novel object recognition test. Juvenile Cx47M282T mutant mice exhibited an increase in anxiety-like behaviour in the open field test, but no changes in spatial working memory performance. No significant changes in anxiety-like behaviour, spatial working memory or neuromotor functions were observed in the adult Cx47M282T mutant mice. However, novel object recognition was significantly impaired in adult Cx47M282T mice. Our results suggest that the expression of the human Cx47M282T mutation in the mouse causes changes in anxiety-like behaviour in juvenile and novel object recognition impairments in adult mice. It appears that the distortion of panglial gap junction coupling in white and grey matter tissue in the Cx47M282T mice is associated with a complex age-dependent behavioural phenotype including changes in psychomotor, emotional and memory functions.

Towards an animal model of consciousness based on the platform theory.

The evolution of intellectual capacities has brought forth a continuum of consciousness levels subserved by neuronal networks of varying complexity. Brain pathologies, neurodegenerative, and mental diseases affect conscious cognition and behavior. Although impairments in consciousness are among the most devastating consequences of neurological and mental diseases, valid and reliable animal models of consciousness, that could be used for preclinical research are missing. The platform theory holds that the brain enters a conscious operation mode, whenever mental representations of stimuli, associations, concepts, memories, and experiences are effortfully maintained (in working memory) and actively manipulated. We used the platform theory as a framework and evaluation standard to categorize behavioral paradigms with respect to the level of consciousness involved in task performance. According to the platform theory, a behavioral paradigm involves conscious cognitive operations, when the problem posed is unexpected, novel or requires the maintenance and manipulation of a large amount of information to perform cognitive operations on them. Conscious cognitive operations are associated with a relocation of processing resources and the redirection of attentional focus. A consciousness behavioral test battery is proposed that is composed of tests which are assumed to require higher levels of consciousness as compared to other tasks and paradigms. The consciousness test battery for rodents includes the following tests: Working memory in the radial arm maze, episodic-like memory, prospective memory, detour test, and operant conditioning with concurrent variable-interval variable-ratio schedules. Performance in this test battery can be contrasted with the performance in paradigms and tests that require lower levels of consciousness. Additionally, a second more comprehensive behavioral test battery is proposed to control for behavioral phenotypes not related to consciousness. Our theory could serve as a guidance for the decryption of the neurobiological basis of consciousness.