Retracted: Nrf2: a novel therapeutic target in fragile X syndrome is modulated by NNZ2566.

Retraction: "Nrf2: a novel therapeutic target in fragile X syndrome is modulated by NNZ2566" by R. M. J. Deacon, M. J. Hurley, C. M. Rebolledo, M. Snape, F. J. Altimiras, L. Farías, M. Pino, R. Biekofsky, L. Glass and P. Cogram. The above article, from Genes, Brain and Behavior, published online on 12th May 2017 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor in Chief, Andrew Holmes and John Wiley & Sons Ltd. The retraction has been agreed as all authors cannot agree on a revised author order, and at least one author continues to dispute the original order. In this case, the original article is being retracted on the grounds that the journal does not have permission to publish. Reference: Deacon, R. M. J., Hurley, M. J., Rebolledo, C. M., Snape, M., Altimiras, F. J., Farías, L., Pino, M., Biekofsky, R., Glass, L. and Cogram, P. (2017), Nrf2: a novel therapeutic target in fragile X syndrome is modulated by NNZ2566. Genes, Brain and Behavior. doi:10.1111/gbb.12373.

Supercurrent in the quantum Hall regime.

A promising route for creating topological states and excitations is to combine superconductivity and the quantum Hall (QH) effect. Despite this potential, signatures of superconductivity in the QH regime remain scarce, and a superconducting current through a QH weak link has been challenging to observe. We demonstrate the existence of a distinct supercurrent mechanism in encapsulated graphene samples contacted by superconducting electrodes, in magnetic fields as high as 2 tesla. The observation of a supercurrent in the QH regime marks an important step in the quest for exotic topological excitations, such as Majorana fermions and parafermions, which may find applications in fault-tolerant quantum computing.

4π-periodic Josephson supercurrent in HgTe-based topological Josephson junctions.

The Josephson effect describes the generic appearance of a supercurrent in a weak link between two superconductors. Its exact physical nature deeply influences the properties of the supercurrent. In recent years, considerable efforts have focused on the coupling of superconductors to the surface states of a three-dimensional topological insulator. In such a material, an unconventional induced p-wave superconductivity should occur, with a doublet of topologically protected gapless Andreev bound states, whose energies vary 4π-periodically with the superconducting phase difference across the junction. In this article, we report the observation of an anomalous response to rf irradiation in a Josephson junction made of a HgTe weak link. The response is understood as due to a 4π-periodic contribution to the supercurrent, and its amplitude is compatible with the expected contribution of a gapless Andreev doublet. Our work opens the way to more elaborate experiments to investigate the induced superconductivity in a three-dimensional insulator.

Cooper pair splitting in parallel quantum dot Josephson junctions.

Devices to generate on-demand non-local spin entangled electron pairs have potential application as solid-state analogues of the entangled photon sources used in quantum optics. Recently, Andreev entanglers that use two quantum dots as filters to adiabatically split and separate the quasi-particles of Cooper pairs have shown efficient splitting through measurements of the transport charge but the spin entanglement has not been directly confirmed. Here we report measurements on parallel quantum dot Josephson junction devices allowing a Josephson current to flow due to the adiabatic splitting and recombination of the Cooper pair between the dots. The evidence for this non-local transport is confirmed through study of the non-dissipative supercurrent while tuning independently the dots with local electrical gates. As the Josephson current arises only from processes that maintain the coherence, we can confirm that a current flows from the spatially separated entangled pair.

CD4⁺ but not CD8⁺ T cells revert the impaired emotional behavior of immunocompromised RAG-1-deficient mice.

An imbalanced immune system has long been known to influence a variety of mood disorders including anxiety, obsessive-compulsive disorders and depression. In this study, we sought to model the impact of an immunocompromised state on these emotional behaviors using RAG-1⁻/⁻ mice, which lack T and B cells. We also investigated the relative contribution of CD4⁺ or CD8⁺ T cells to these manifestations using RAG-1⁻/⁻/OT-II and RAG-1⁻/⁻/OT-I transgenic mice, respectively. Our results show that RAG-1⁻/⁻ mice present a significant increase in digging and marble-burying activities compared with wild-type mice. Surprisingly, these anxiety-like behaviors were significantly reverted in RAG-1⁻/⁻/OT-II but not RAG-1⁻/⁻/OT-I transgenic mice. Immunodepletion experiments with anti-CD4 or anti-CD8 in C57/BL6 mice or repopulation studies in RAG-1⁻/⁻ mice did not reproduce these findings. Microarray analysis of the brain of RAG-1⁻/⁻ and RAG-1⁻/⁻/OT-II mice revealed a significantly different gene fingerprint, with the latter being more similar to wild-type mice than the former. Further analysis revealed nine main signaling pathways as being significantly modulated in RAG-1⁻/⁻ compared with wild-type mice. Taken together, these results suggest that life-long rather than transient immunodeficient conditions influence the emotional behaviors in mice. Most interestingly, these effects seem to correlate with a specific absence of CD4⁺ rather than CD8⁺ T cells. Validation of these findings in man might provide new clues on the mechanism by which early life immune modulation might impact mood response in adults and provide a further link between immune and emotional well-being.

[The effect of a caudal hippocampus lesion on learning in a Morris water maze in bank voles (Clethrionomys glareolus)].

A bilateral cytotoxic lesion of the caudal hippocampus (about 1/3 of the whole hippocampus, which is insufficiently studied) influences learning of bank voles (Clethrionomys glareolus) in the Morris water maze. This effect has been estimated in this paper. A version of the test intended to measure long-term spatial memory was used. The lesion was shown to exert an influence on the learning dynamics by slowing it down, as well as to reduce the accuracy of platform location memorizing at early stages of training. The data obtained indicate the involvement of this area in control of spatial learning in rodents.

Naked mole-rats: behavioural phenotyping and comparison with C57BL/6 mice.

Naked mole-rats (NMR) live underground in large eusocial colonies in East Africa. They are extremely long-lived, some individuals having a lifespan of over 30 years. This has attracted research into longevity and possibly neurodegenerative disorders. However, very little is known about their basic behaviour, particularly in tests commonly used to characterise the behaviour of the laboratory rat and mouse, for which there is an enormous database. Recently the authors carried out comprehensive behavioural phenotyping on NMRs, comparing them on most tasks directly with C57BL/6 mice, the strain for which there is the largest behavioural database. The NMR colony had been obtained from the wild originally, but housed in an animal facility for about two years. Large inter-species differences in behaviour were seen between the mice and the NMRs. The latter had generally poor sensorimotor function, including cutaneous sensation, strength and even grasp reflexes. They were often reluctant to enter or head-dip into small holes that mice readily entered. Their vision (generally considered to be very poor) was sufficient to distinguish the two zones of a light-dark box. Although, as expected, the NMRs were capable of burrowing and digging, when individually housed they did not shred cotton material to make nests. Shredding was seen in a colony cage containing a queen, but no nests were made there even when a nesting box was provided. In cognitive testing, although, unlike mice and rats, they did not spontaneously alternate in a T-maze, they learnt rewarded alternation and a cued position task well. This study demonstrates how behaviour uniquely reflects the natural environment in which these unusual animals have evolved and live, and provides baseline data for future work.

Electrically tuned spin-orbit interaction in an InAs self-assembled quantum dot.

Electrical control over electron spin is a prerequisite for spintronics spin-based quantum information processing. In particular, control over the interaction between the orbital motion and the spin state of electrons would be valuable, because this interaction influences spin relaxation and dephasing. Electric fields have been used to tune the strength of the spin-orbit interaction in two-dimensional electron gases, but not, so far, in quantum dots. Here, we demonstrate that electrical gating can be used to vary the energy of the spin-orbit interaction in the range 50-150 µeV while maintaining the electron occupation of a single self-assembled InAs quantum dot. We determine the spin-orbit interaction energy by observing the splitting of Kondo effect features at high magnetic fields.

Large anisotropy of the spin-orbit interaction in a single InAs self-assembled quantum dot.

The anisotropy of the spin-orbit interaction (SOI) is studied for a single uncapped InAs self-assembled quantum dot holding just a few electrons. The SOI energy is evaluated from anticrossing or SOI-induced hybridization between the ground and excited states with opposite spins. The magnetic angular dependence of the SOI energy falls on an absolute cosine function for azimuthal rotation, and a cosinelike function for tilting rotation. Furthermore, the SOI energy is quenched for a specific magnetic field vector. The angular dependence of SOI is found to compare well with calculation of Rashba SOI in a two-dimensional harmonic potential.

Tunneling spectroscopy of Andreev energy levels in a quantum dot coupled to a superconductor.

The coupling of a quantum dot with a BCS-type superconducting reservoir results in an intriguing system where low energy physics is governed by the interplay of two distinct phases, singlet and doublet. In this Letter we show that the spectrum of Andreev energy levels, which capture the properties of the two phases, can be detected in transport measurements with a quantum dot strongly coupled to a superconducting lead and weakly coupled to a normal metal lead. We observe phase transitions between BCS singlet and degenerate magnetic doublet states when the quantum dot chemical potential is tuned with an electrostatic gate, in good qualitative agreement with numerical renormalization group calculations.

Burrowing: a sensitive behavioural assay, tested in five species of laboratory rodents.

In the burrowing test, mice or rats spontaneously empty a tube filled with food pellets, gravel or other substances. The test is extremely simple to perform, the apparatus is inexpensive and readily constructed. It exploits a natural rodent behaviour, provides quantitative data under controlled laboratory conditions, and has proved extremely sensitive to prion disease in mice (Mus musculus), cytokines in rats (Rattus norvegicus), lipopolysaccharide in mice and rats, strain differences and brain lesions in mice. However, it has not been used in other, less common, laboratory species, and might, e.g. be useful in detecting scrapie infection in hamsters (Mesocricetus auratus), a commonly used species in prion disease research. Therefore, the present study systematically investigated burrowing behaviour in five rodent species, using five different burrowing substrates. It also enquired whether rats are unique among rodents in showing little burrowing of food pellets, yet burrow gravel and other earth-like substrates vigorously. The results showed that all the species (rats, mice, hamsters and gerbils (Meriones unguiculatus)), except one (Egyptian spiny mice, Acomys cahirinus, which does not dig burrows in the wild) burrowed earth-like substrates well. However, laboratory mice were the only species that burrowed food pellets vigorously, without prior exposure to other substrates. These results show that burrowing, with an appropriate substrate, can be used as a simple behavioural test in many rodent species. It is an excellent detector of neurobehavioural toxicity with applications in many areas of research, especially when long-term behavioural monitoring is required, e.g. to track changes in chronic disease models.

Aged Tg2576 mice are impaired on social memory and open field habituation tests.

In a previous publication [Deacon RMJ, Cholerton LL, Talbot K, Nair-Roberts RG, Sanderson DJ, Romberg C, et al. Age-dependent and -independent behavioral deficits in Tg2576 mice. Behav Brain Res 2008;189:126-38] we found that very few cognitive tests were suitable for demonstrating deficits in Tg2576 mice, an amyloid over-expression model of Alzheimer's disease, even at 23 months of age. However, in a retrospective analysis of a separate project on these mice, tests of social memory and open field habituation revealed large cognitive impairments. Controls showed good open field habituation, but Tg2576 mice were hyperactive and failed to habituate. In the test of social memory for a juvenile mouse, controls showed considerably less social investigation on the second meeting, indicating memory of the juvenile, whereas Tg2576 mice did not show this decrement.As a control for olfactory sensitivity, on which social memory relies, the ability to find a food pellet hidden under wood chip bedding was assessed. Tg2576 mice found the pellet as quickly as controls. As this test requires digging ability, this was independently assessed in tests of burrowing and directly observed digging. In line with previous results and the hippocampal dysfunction characteristic of aged Tg2576 mice, they both burrowed and dug less than controls.

Inhibition of peripheral TNF can block the malaise associated with CNS inflammatory diseases.

Circulating cytokine levels are elevated in many neuropathologies and may be a cause of the associated malaise and depression. Using a rat model, we demonstrate that sickness behaviors generated by microinjection of IL-1beta into the anterior hypothalamus are adopted by naive recipient animals following plasma transfer. We further show that neutralizing peripheral TNF by etanercept (a p75 TNF receptor/Fc fusion protein) prior to the IL-1beta microinjection inhibits certain IL-1beta-mediated sickness behaviors, such as the depression of open-field activity and reduced glucose consumption. IL-1beta-induced central lesions induce peripheral TNF as part of the acute-phase response, and this appears to be the principal target of the etanercept. Thus behavioral changes induced by CNS lesions may result from peripheral expression of cytokines that can be targeted with drugs which do not need to cross the blood-brain barrier to be efficacious.

Age-dependent and -independent behavioral deficits in Tg2576 mice.

The Tg2576 mouse model of excessive cerebral beta-amyloid deposition is now more than a decade old, yet consensus as to its exact characteristics and utility as a model of Alzheimer's disease is still lacking. Four different cohorts of control and Tg2576 mice, aged approximately 3, 9, 13 and 21 months, were therefore subjected to a battery of tests, principally to assess cognitive and species-typical behaviors. A novel test, the paddling Y-maze, demonstrated an age-dependent deficit in 10 and 14, but not 3 month Tg2576 mice, also in aged (21 month) control mice. However, in many other cognitive tests few Tg2576-related deficits could be shown. This frequently seemed attributable to poor performance of control mice. Tests of species-typical behaviors showed that Tg2576 mice had a deficit in burrowing behavior at all ages. An age-independent deficit was also seen in nest construction, but only when mice were group-housed; most individually housed mice in either group made reasonable nests. Overall, the results suggested that these Tg2576 mice are not a simple, suitable or reliable model for routine screening of treatments for Alzheimer's disease. However, this model might perform better behaviorally on a different genetic background.

Deletion of glutamate receptor-A (GluR-A) AMPA receptor subunits impairs one-trial spatial memory.

Genetically modified mice lacking the glutamate receptor A (GluR-A) subunit of the AMPA receptor (GluR-A-/- mice) display normal spatial reference memory but impaired spatial working memory (SWM). This study tested whether the SWM impairment in these mice could be explained by a greater sensitivity to within-session proactive interference. The SWM performance of GluR-A-/- and wild-type mice was assessed during nonmatching-to-place testing under conditions in which potential proactive interference from previous trials was reduced or eliminated. SWM was impaired in GluR-A-/- mice, both during testing with pseudotrial-unique arm presentations on the radial maze and when conducting each trial on a different 3-arm maze, each in a novel testing room. Experimentally naive GluR-A-/- mice also exhibited chance performance during a single trial of spontaneous alternation. This 1-trial spatial memory deficit was present irrespective of the delay between the sample information and the response choice (0 or 45 min) and the length of the sample phase (0.5 or 5 min). These results imply that the SWM deficit in GluR-A-/- mice is not due to increased susceptibility to proactive interference.

A comparison of the behavior of C57BL/6 and C57BL/10 mice.

Selection of an appropriate animal model is a crucial first step in many research programs. The C57BL/6 (B6) mouse is the most widely used inbred mouse strain in biomedical research; this is particularly so in behavioral studies. However, there are several C57BL substrains, all derived from common ancestors. C57BL/10 (B10) mice are superficially almost identical to B6 mice in appearance and behavior and widely used in inflammation and immunology research, yet rarely in behavioral studies. The present study assessed the comparability of behavioral results from these two strains, to determine whether they could be used interchangeably in future behavioral experiments. The results showed that the behavior of B6 mice clearly differed from that of B10 mice: in tests of cognition, species-typical behaviors, and motor coordination the B6 strain performed better. Consequently, B6 mice will probably remain the preferred choice for behavioral studies. Interpretation of results derived from the B10 strain should take into account its particular behavioral characteristics.

Sub-pyrogenic systemic inflammation impacts on brain and behavior, independent of cytokines.

Systemic inflammation impacts on the brain and gives rise to behavioral changes, often referred to as 'sickness behavior'. These symptoms are thought to be mainly mediated by pro-inflammatory cytokines. We have investigated the communication pathways between the immune system and brain following sub-pyrogenic inflammation. Low grade systemic inflammation was induced in mice using lipopolysaccharide (LPS); 1-100 microg/kg to mimic aspects of bacterial infection. Changes in fever, open-field activity, burrowing and consumption of glucose solution were assessed and immune activation was studied in the periphery and brain by measuring cytokine production, and immunohistochemistry to study changes in immune cell phenotype. Sub-pyrogenic inflammation resulted in changes in a species-typical, untrained behavior (burrowing) that depends on the integrity of the hippocampus. Increased expression of cytokines was observed in the periphery and selected regions of the brain which coincided with changes in behavior. However, peripheral neutralization of LPS-induced pro-inflammatory cytokines IL-1beta, IL-6 and TNF-alpha did not abrogate the LPS-induced behavioral changes nor affect CNS cytokine synthesis. In contrast, pretreatment of mice with indomethacin completely prevented LPS-induced behavior changes, without affecting cytokine levels. Taken together, these experiments suggest a key role for prostaglandins, rather than cytokines, in communicating to the brain.

Behavioral phenotyping of mice lacking the K ATP channel subunit Kir6.2.

ATP-sensitive potassium (K(ATP)) channels are expressed in various tissues and cell-types where they act as so-called metabolic sensors that couple metabolic state to cellular excitability. The pore of most K(ATP) channel types is built by Kir6.2 subunits. Analysis of a general Kir6.2 knockout (KO) mouse has identified a variety of different functional roles for central and peripheral K(ATP) channels in situations of metabolic demand. However, the widespread distribution of these channels suggests that they might influence cellular physiology and animal behavior under metabolic control conditions. As a comprehensive behavioral description of Kir6.2 KO mice under physiological control conditions has not yet been carried out, we subjected Kir6.2 KO and corresponding wild-type (WT) mice to a test battery to assess emotional behavior, motor activity and coordination, species-typical behaviors and cognition. The results indicated that in these test situations Kir6.2 KO mice were less active, had impaired motor coordination, and appeared to differ from controls in their emotional reactivity. Differences between KO and WT mice were generally attenuated in test situations that resembled the home cage environment. Moreover, in their home cages KO mice were more active than WT mice. Thus, our results suggest that loss of Kir6.2-containing K(ATP) channels does affect animal behavior under metabolic control conditions, especially in novel situations. These findings assign novel functional roles to K(ATP) channels beyond those previously described. However, according to the widespread expression of K(ATP) channels, these effects are complex, being dependent on details of test apparatus, procedure and prior experience.

GluR-A-dependent synaptic plasticity is required for the temporal encoding of nonspatial information.

Four related experiments studied operant performance of mice on differential reinforcement of low rates of responding (DRL) paradigms. Experiment 1 showed that excitotoxic hippocampal lesions impaired performance of a 10-s DRL schedule (DRL-10). Experiments 2 and 3 showed that GluR-A AMPA receptor subunit knockout mice, which are deficient in CA3-CA1 long-term potentiation (LTP), were markedly impaired at 15 s (DRL-15), but less impaired at DRL-10. Experiment 4 compared DRL-15 performance in mice from the 2 strains from which the GluR-A colony was derived and showed that they did not differ. The results show that GluR-A-containing AMPA receptors are required for normal performance on hippocampus-dependent, nonspatial working memory tasks, consistent with a role for GluR-A in the temporal encoding (what happened when) of nonspatial information.