Thalamic reticular impairment underlies attention deficit in Ptchd1Y/− mice

Developmental disabilities, including attention-deficit hyperactivity disorder (ADHD), intellectual disability (ID), and autism spectrum disorders (ASD), affect one in six children in the USA. Recently, gene mutations in patched domain containing 1 (PTCHD1) have been found in ∼1% of patients with ID and ASD. Individuals with PTCHD1 deletion show symptoms of ADHD, sleep disruption, hypotonia, aggression, ASD, and ID. Although PTCHD1 is probably critical for normal development, the connection between its deletion and the ensuing behavioural defects is poorly understood. Here we report that during early post-natal development, mouse Ptchd1 is selectively expressed in the thalamic reticular nucleus (TRN), a group of GABAergic neurons that regulate thalamocortical transmission, sleep rhythms, and attention. Ptchd1 deletion attenuates TRN activity through mechanisms involving small conductance calcium-dependent potassium currents (SK). TRN-restricted deletion of Ptchd1 leads to attention deficits and hyperactivity, both of which are rescued by pharmacological augmentation of SK channel activity. Global Ptchd1 deletion recapitulates learning impairment, hyper-aggression, and motor defects, all of which are insensitive to SK pharmacological targeting and not found in the TRN-restricted deletion mouse. This study maps clinically relevant behavioural phenotypes onto TRN dysfunction in a human disease model, while also identifying molecular and circuit targets for intervention.Simons Foundation Autism Research Initiative (Grant 307913)National Institutes of Health (U.S.) (Grant R01MH097104)National Institute of Mental Health (U.S.) (Grant R01MH097104)National Institutes of Health (U.S.) (Grant R01MH107680

State-Dependent Architecture of Thalamic Reticular Subnetworks

Behavioral state is known to influence interactions between thalamus and cortex, which are important for sensation, action, and cognition. The thalamic reticular nucleus (TRN) is hypothesized to regulate thalamo-cortical interactions, but the underlying functional architecture of this process and its state dependence are unknown. By combining the first TRN ensemble recording with psychophysics and connectivity-based optogenetic tagging, we found reticular circuits to be composed of distinct subnetworks. While activity of limbic-projecting TRN neurons positively correlates with arousal, sensory-projecting neurons participate in spindles and show elevated synchrony by slow waves during sleep. Sensory-projecting neurons are suppressed by attentional states, demonstrating that their gating of thalamo-cortical interactions is matched to behavioral state. Bidirectional manipulation of attentional performance was achieved through subnetwork-specific optogenetic stimulation. Together, our findings provide evidence for differential inhibition of thalamic nuclei across brain states, where the TRN separately controls external sensory and internal limbic processing facilitating normal cognitive function.National Institute of Neurological Disorders and Stroke (U.S.) (NIH Pathway to Independence Career Award K99 NS 078115)Brain & Behavior Research Foundation (Young Investigator Award)National Institutes of Health (U.S.) ( Transformative R01 Award TR01-GM10498)National Institutes of Health (U.S.) (Grant R01-MH061976

Design and Fabrication of Ultralight Weight, Adjustable Multi-electrode Probes for Electrophysiological Recordings in Mice

The number of physiological investigations in the mouse, mus musculus, has experienced a recent surge, paralleling the growth in methods of genetic targeting for microcircuit dissection and disease modeling. The introduction of optogenetics, for example, has allowed for bidirectional manipulation of genetically-identified neurons, at an unprecedented temporal resolution. To capitalize on these tools and gain insight into dynamic interactions among brain microcircuits, it is essential that one has the ability to record from ensembles of neurons deep within the brain of this small rodent, in both head-fixed and freely behaving preparations. To record from deep structures and distinct cell layers requires a preparation that allows precise advancement of electrodes towards desired brain regions. To record neural ensembles, it is necessary that each electrode be independently movable, allowing the experimenter to resolve individual cells while leaving neighboring electrodes undisturbed. To do both in a freely behaving mouse requires an electrode drive that is lightweight, resilient, and highly customizable for targeting specific brain structures. A technique for designing and fabricating miniature, ultralight weight, microdrive electrode arrays that are individually customizable and easily assembled from commercially available parts is presented. These devices are easily scalable and can be customized to the structure being targeted; it has been used successfully to record from thalamic and cortical regions in a freely behaving animal during natural behavior.Simons FoundationNational Institute of Neurological Disorders and Stroke (U.S.) (NIH Pathway to Independence Career Award)National Institutes of Health (U.S.

Falsification Of The Atmospheric CO2 Greenhouse Effects Within The Frame Of Physics

The atmospheric greenhouse effect, an idea that many authors trace back to the traditional works of Fourier (1824), Tyndall (1861), and Arrhenius (1896), and which is still supported in global climatology, essentially describes a fictitious mechanism, in which a planetary atmosphere acts as a heat pump driven by an environment that is radiatively interacting with but radiatively equilibrated to the atmospheric system. According to the second law of thermodynamics such a planetary machine can never exist. Nevertheless, in almost all texts of global climatology and in a widespread secondary literature it is taken for granted that such mechanism is real and stands on a firm scientific foundation. In this paper the popular conjecture is analyzed and the underlying physical principles are clarified. By showing that (a) there are no common physical laws between the warming phenomenon in glass houses and the fictitious atmospheric greenhouse effects, (b) there are no calculations to determine an average surface temperature of a planet, (c) the frequently mentioned difference of 33 degrees Celsius is a meaningless number calculated wrongly, (d) the formulas of cavity radiation are used inappropriately, (e) the assumption of a radiative balance is unphysical, (f) thermal conductivity and friction must not be set to zero, the atmospheric greenhouse conjecture is falsified.Comment: 115 pages, 32 figures, 13 tables (some typos corrected

Cyclic stretch increases splicing noise rate in cultured human fibroblasts

BACKGROUND: Mechanical forces are known to alter the expression of genes, but it has so far not been reported whether they may influence the fidelity of nucleus-based processes. One experimental approach permitting to address this question is the application of cyclic stretch to cultured human fibroblasts. As a marker for the precision of nucleus-based processes, the number of errors that occur during co-transcriptional splicing can then be measured. This so-called splicing noise is found at low frequency in pre-mRNA splicing. FINDINGS: The amount of splicing noise was measured by RT-qPCR of seven exon skips from the test genes AATF, MAP3K11, NF1, PCGF2, POLR2A and RABAC1. In cells treated by altered uniaxial cyclic stretching for 18 h, a uniform and significant increase of splicing noise was found for all detectable exon skips. CONCLUSION: Our data demonstrate that application of cyclic stretch to cultured fibroblasts correlates with a reduced transcriptional fidelity caused by increasing splicing noise

Molecular understanding of sulphuric acid-amine particle nucleation in the atmosphere

4 pages 359-363 in the print version, additional 7 pages online.Peer reviewe

Coulomb dissociation of N 20,21

Neutron-rich light nuclei and their reactions play an important role in the creation of chemical elements. Here, data from a Coulomb dissociation experiment on N20,21 are reported. Relativistic N20,21 ions impinged on a lead target and the Coulomb dissociation cross section was determined in a kinematically complete experiment. Using the detailed balance theorem, the N19(n,γ)N20 and N20(n,γ)N21 excitation functions and thermonuclear reaction rates have been determined. The N19(n,γ)N20 rate is up to a factor of 5 higher at

The effect of acid-base clustering and ions on the growth of atmospheric nano-particles

The growth of freshly formed aerosol particles can be the bottleneck in their survival to cloud condensation nuclei. It is therefore crucial to understand how particles grow in the atmosphere. Insufficient experimental data has impeded a profound understanding of nano-particle growth under atmospheric conditions. Here we study nano-particle growth in the CLOUD (Cosmics Leaving OUtdoors Droplets) chamber, starting from the formation of molecular clusters. We present measured growth rates at sub-3 nm sizes with different atmospherically relevant concentrations of sulphuric acid, water, ammonia and dimethylamine. We find that atmospheric ions and small acid-base clusters, which are not generally accounted for in the measurement of sulphuric acid vapour, can participate in the growth process, leading to enhanced growth rates. The availability of compounds capable of stabilizing sulphuric acid clusters governs the magnitude of these effects and thus the exact growth mechanism. We bring these observations into a coherent framework and discuss their significance in the atmosphere.Peer reviewe

Thalamic circuit mechanisms link sensory processing in sleep and attention

The correlation between sleep integrity and attentional performance is normally interpreted as poor sleep causing impaired attention. Here, we provide an alternative explanation for this correlation: common thalamic circuits regulate sensory processing across sleep and attention, and their disruption may lead to correlated dysfunction. Using multi-electrode recordings in mice, we find that rate and rhythmicity of thalamic reticular nucleus (TRN) neurons are predictive of their functional organization in sleep and suggestive of their participation in sensory processing across states. Surprisingly, TRN neurons associated with spindles in sleep are also associated with alpha oscillations during attention. As such, we propose that common thalamic circuit principles regulate sensory processing in a state-invariant manner and that in certain disorders, targeting these circuits may be a more viable therapeutic strategy than considering individual states in isolation