Sex-specific expression of distinct serotonin receptors mediates stress vulnerability of adult hippocampal neural stem cells in mice.

Women are more vulnerable to stress and have a higher likelihood of developing mood disorders. The serotonin (5HT) system has been highly implicated in stress response and mood regulation. However, sex-dependent mechanisms underlying serotonergic regulation of stress vulnerability remain poorly understood. Here, we report that adult hippocampal neural stem cells (NSCs) of the Ascl1 lineage (Ascl1-NSCs) in female mice express functional 5HT1A receptors (5HT1ARs), and selective deletion of 5HT1ARs in Ascl1-NSCs decreases the Ascl1-NSC pool only in females. Mechanistically, 5HT1AR deletion in Ascl1-NSCs of females leads to 5HT-induced depolarization mediated by upregulation of 5HT7Rs. Furthermore, repeated restraint stress (RRS) impairs Ascl1-NSC maintenance through a 5HT1AR-mediated mechanism. By contrast, Ascl1-NSCs in males express 5HT7R receptors (5HT7Rs) that are downregulated by RRS, thus maintaining the Ascl1-NSC pool. These findings suggest that sex-specific expression of distinct 5HTRs and their differential interactions with stress may underlie sex differences in stress vulnerability.

Anterior cingulate cortex projections to the dorsal medial striatum underlie insomnia associated with chronic pain.

Chronic pain often leads to the development of sleep disturbances. However, the precise neural circuit mechanisms responsible for sleep disorders in chronic pain have remained largely unknown. Here, we present compelling evidence that hyperactivity of pyramidal neurons (PNs) in the anterior cingulate cortex (ACC) drives insomnia in a mouse model of nerve-injury-induced chronic pain. After nerve injury, ACC PNs displayed spontaneous hyperactivity selectively in periods of insomnia. We then show that ACC PNs were both necessary for developing chronic-pain-induced insomnia and sufficient to mimic sleep loss in naive mice. Importantly, combining optogenetics and electrophysiological recordings, we found that the ACC projection to the dorsal medial striatum (DMS) underlies chronic-pain-induced insomnia through enhanced activity and plasticity of ACC-DMS dopamine D1R neuron synapses. Our findings shed light on the pivotal role of ACC PNs in developing chronic-pain-induced sleep disorders.

Synthesis of graded CdS1-xSex nanoplatelet alloys and heterostructures from pairs of chalcogenoureas with tailored conversion reactivity.

A mixture of N,N,N'-trisubstituted thiourea and cyclic N,N,N',N'-tetrasubstituted selenourea precursors were used to synthesize three monolayer thick CdS1-xSex nanoplatelets in a single synthetic step. The microstructure of the nanoplatelets could be tuned from homogeneous alloys, to graded alloys to core/crown heterostructures depending on the relative conversion reactivity of the sulfur and selenium precursors. UV-visible absorption and photoluminescence spectroscopy and scanning transmission electron microscopy electron energy loss spectroscopy (STEM-EELS) images demonstrate that the elemental distribution is governed by the relative precursor conversion kinetics. Slow conversion kinetics produced nanoplatelets with larger lateral dimensions, behavior that is characteristic of precursor conversion limited growth kinetics. Across a 10-fold range of reactivity, CdS nanoplatelets have 4× smaller lateral dimensions than CdSe nanoplatelets grown under identical conversion kinetics. The difference in size is consistent with a rate of CdSe growth that is 4× greater than the rate of CdS. The influence of the relative sulfide and selenide growth rates, the duration of the nucleation phase, and the solute composition on the nanoplatelet microstructure are discussed.

Long-term optical imaging of the spinal cord in awake, behaving animals.

Advances in optical imaging approaches and fluorescent biosensors have enabled an understanding of the spatiotemporal and long-term neural dynamics in the brain of awake animals. However, methodological difficulties and the persistence of post-laminectomy fibrosis have greatly limited similar advances in the spinal cord. To overcome these technical obstacles, we combined in vivo application of fluoropolymer membranes that inhibit fibrosis; a redesigned, cost-effective implantable spinal imaging chamber; and improved motion correction methods that together permit imaging of the spinal cord in awake, behaving mice, for months to over a year. We also demonstrate a robust ability to monitor axons, identify a spinal cord somatotopic map, conduct Ca2+ imaging of neural dynamics in behaving animals responding to pain-provoking stimuli, and observe persistent microglial changes after nerve injury. The ability to couple neural activity and behavior at the spinal cord level will drive insights not previously possible at a key location for somatosensory transmission to the brain.

A few-layer covalent network of fullerenes.

The two natural allotropes of carbon, diamond and graphite, are extended networks of sp3-hybridized and sp2-hybridized atoms, respectively1. By mixing different hybridizations and geometries of carbon, one could conceptually construct countless synthetic allotropes. Here we introduce graphullerene, a two-dimensional crystalline polymer of C60 that bridges the gulf between molecular and extended carbon materials. Its constituent fullerene subunits arrange hexagonally in a covalently interconnected molecular sheet. We report charge-neutral, purely carbon-based macroscopic crystals that are large enough to be mechanically exfoliated to produce molecularly thin flakes with clean interfaces-a critical requirement for the creation of heterostructures and optoelectronic devices2. The synthesis entails growing single crystals of layered polymeric (Mg4C60)∞ by chemical vapour transport and subsequently removing the magnesium with dilute acid. We explore the thermal conductivity of this material and find it to be much higher than that of molecular C60, which is a consequence of the in-plane covalent bonding. Furthermore, imaging few-layer graphullerene flakes using transmission electron microscopy and near-field nano-photoluminescence spectroscopy reveals the existence of moiré-like superlattices3. More broadly, the synthesis of extended carbon structures by polymerization of molecular precursors charts a clear path to the systematic design of materials for the construction of two-dimensional heterostructures with tunable optoelectronic properties.

Superatom Regiochemistry Dictates the Assembly and Surface Reactivity of a Two-Dimensional Material.

The area of two-dimensional (2D) materials research would benefit greatly from the development of synthetically tunable van der Waals (vdW) materials. While the bottom-up synthesis of 2D frameworks from nanoscale building blocks holds great promise in this quest, there are many remaining hurdles, including the design of building blocks that reliably produce 2D lattices and the growth of macroscopic crystals that can be exfoliated to produce 2D materials. Here we report the regioselective synthesis of the cluster [trans-Co6Se8(CN)4(CO)2]3-/4-, a "superatomic" building block designed to polymerize and assemble into a 2D cyanometalate lattice whose surfaces are chemically addressable. The resulting vdW material, [Co(py)4]2[trans-Co6Se8(CN)4(CO)2], grows as bulk single crystals that can be mechanically exfoliated to produce flakes as thin as bilayers, with photolabile CO ligands on the exfoliated surface. As a proof of concept, we show that these surface CO ligands can be replaced by 4-isocyanoazobenzene under blue light irradiation. This work demonstrates that the bottom-up assembly of layered vdW materials from superatoms is a promising and versatile approach to create 2D materials with tunable physical and chemical properties.

Superatomic solid solutions.

In atomic solids, substitutional doping of atoms into the lattice of a material to form solid solutions is one of the most powerful approaches to modulating its properties and has led to the discovery of various metal alloys and semiconductors. Herein we have prepared solid solutions in hierarchical solids that are built from atomically precise clusters. Two geometrically similar metal chalcogenide clusters, Co6Se8(PEt3)6 and Cr6Te8(PEt3)6, were combined as random substitutional mixture, in three different ratios, in a crystal lattice together with fullerenes. This does not alter the underlying crystalline structure of the [cluster][C60]2 material, but it influences its electronic and magnetic properties. All three solid solutions showed increased electrical conductivities compared with either the Co- or Cr-based parent material, substantially so for two of the Co:Cr ratios (up to 100-fold), and lowered activation barriers for electron transport. We attribute this to the existence of additional energy states arising from the materials' structural heterogeneity, which effectively narrow transport gaps.

Precursor reaction kinetics control compositional grading and size of CdSe1-x S x nanocrystal heterostructures.

We report a method to control the composition and microstructure of CdSe1-x S x nanocrystals by the simultaneous injection of sulfide and selenide precursors into a solution of cadmium oleate and oleic acid at 240 °C. Pairs of substituted thio- and selenoureas were selected from a library of compounds with conversion reaction reactivity exponents (k E) spanning 1.3 × 10-5 s-1 to 2.0 × 10-1 s-1. Depending on the relative reactivity (k Se/k S), core/shell and alloyed architectures were obtained. Growth of a thick outer CdS shell using a syringe pump method provides gram quantities of brightly photoluminescent quantum dots (PLQY = 67 to 90%) in a single reaction vessel. Kinetics simulations predict that relative precursor reactivity ratios of less than 10 result in alloyed compositions, while larger reactivity differences lead to abrupt interfaces. CdSe1-x S x alloys (k Se/k S = 2.4) display two longitudinal optical phonon modes with composition dependent frequencies characteristic of the alloy microstructure. When one precursor is more reactive than the other, its conversion reactivity and mole fraction control the number of nuclei, the final nanocrystal size at full conversion, and the elemental composition. The utility of controlled reactivity for adjusting alloy microstructure is discussed.

Pretreatment brain connectivity during positive emotion upregulation predicts decreased anhedonia following behavioral activation therapy for depression.

BACKGROUND: Neurobiological predictors of antidepressant response may help guide treatment selection and improve response rates to available treatments for major depressive disorder (MDD). Behavioral activation therapy for depression (BATD) is an evidence-based intervention designed to ameliorate core symptoms of MDD by promoting sustained engagement with value-guided, positively-reinforcing activities. The present study examined pre-treatment task-based functional brain connectivity as a predictor of antidepressant response to BATD. METHODS: Thirty-three outpatients with MDD and 20 nondepressed controls completed a positive emotion regulation task during fMRI after which participants with MDD received up to 15 sessions of BATD. We used generalized psychophysiological interaction analyses to examine group differences in pre-treatment functional brain connectivity during intentional upregulation of positive emotion to positive images. Hierarchical linear models were used to examine whether group differences in functional connectivity predicted changes in depression and anhedonia over the course of BATD. RESULTS: Compared to controls, participants with MDD exhibited decreased connectivity between the left middle frontal gyrus and right temporoparietal regions during upregulation of positive emotion. Within the MDD group, decreased connectivity of these regions predicted greater declines in anhedonia symptoms over treatment. LIMITATIONS: Future studies should include comparison treatments and longitudinal follow-up to clarify the unique effects of BATD on neural function and antidepressant response. CONCLUSIONS: Results are consistent with previous work showing BATD may be particularly effective for individuals with greater disturbances in brain reward network function, but extend these findings to highlight the importance of frontotemporoparietal connectivity in targeting symptoms of low motivation and engagement.

Two-Dimensional Fullerene Assembly from an Exfoliated van der Waals Template.

Two-dimensional (2D) materials are commonly prepared by exfoliating bulk layered van der Waals crystals. The creation of synthetic 2D materials from bottom-up methods is an important challenge as their structural flexibility will enable chemists to tune the materials properties. A 2D material was assembled using C60 as a polymerizable monomer. The C60 building blocks are first assembled into a layered solid using a molecular cluster as structure director. The resulting hierarchical crystal is used as a template to polymerize its C60 monolayers, which can be exfoliated down to 2D crystalline nanosheets. Derived from the parent template, the 2D structure is composed of a layer of inorganic cluster, sandwiched between two monolayers of polymerized C60 . The nanosheets can be transferred onto solid substrates and depolymerized by heating. Electronic absorption spectroscopy reveals an optical gap of 0.25 eV, narrower than that of the bulk parent crystalline solid.

An Adeno-Associated Virus-Based Toolkit for Preferential Targeting and Manipulating Quiescent Neural Stem Cells in the Adult Hippocampus.

Quiescent neural stem cells (qNSCs) with radial morphology are the only proven source of new neurons in the adult mammalian brain. Our understanding of the roles of newly generated neurons depends on the ability to target and manipulate adult qNSCs. Although various strategies have been developed to target and manipulate adult hippocampal qNSCs, they often suffer from prolonged breeding, low recombination efficiency, and non-specific labeling. Therefore, developing a readily manufactured viral vector that allows flexible packaging and robust expression of various transgenes in qNSCs is a pressing need. Here, we report a recombinant adeno-associated virus serotype 4 (rAAV4)-based toolkit that preferentially targets hippocampal qNSCs and allows for lineage tracing, functional analyses, and activity manipulation of adult qNSCs. Importantly, targeting qNSCs in a non-Cre-dependent fashion opens the possibility for studying qNSCs in less genetically tractable animal species and may have translational impact in gene therapy by preferentially targeting qNSCs.

Single-crystal-to-single-crystal intercalation of a low-bandgap superatomic crystal.

The controlled introduction of impurities into the crystal lattice of solid-state compounds is a cornerstone of materials science. Intercalation, the insertion of guest atoms, ions or molecules between the atomic layers of a host structure, can produce novel electronic, magnetic and optical properties in many materials. Here we describe an intercalation compound in which the host [Co6Te8(PnPr3)6][C60]3, formed from the binary assembly of atomically precise molecular clusters, is a superatomic analogue of traditional layered atomic compounds. We find that tetracyanoethylene (TCNE) can be inserted into the superstructure through a single-crystal-to-single-crystal transformation. Using electronic absorption spectroscopy, electrical transport measurements and electronic structure calculations, we demonstrate that the intercalation is driven by the exchange of charge between the host [Co6Te8(PnPr3)6][C60]3 and the intercalant TCNE. These results show that intercalation is a powerful approach to manipulate the material properties of superatomic crystals.

Attenuation of Frontostriatal Connectivity During Reward Processing Predicts Response to Psychotherapy in Major Depressive Disorder.

There are few reliable predictors of response to antidepressant treatments. In the present investigation, we examined pretreatment functional brain connectivity during reward processing as a potential predictor of response to Behavioral Activation Treatment for Depression (BATD), a validated psychotherapy that promotes engagement with rewarding stimuli and reduces avoidance behaviors. Thirty-three outpatients with major depressive disorder (MDD) and 20 matched controls completed two runs of the monetary incentive delay task during functional magnetic resonance imaging after which participants with MDD received up to 15 sessions of BATD. Seed-based generalized psychophysiological interaction analyses focused on task-based connectivity across task runs, as well as the attenuation of connectivity from the first to the second run of the task. The average change in Beck Depression Inventory-II scores due to treatment was 10.54 points, a clinically meaningful response. Groups differed in seed-based functional connectivity among multiple frontostriatal regions. Hierarchical linear modeling revealed that improved treatment response to BATD was predicted by greater connectivity between the left putamen and paracingulate gyrus during reward anticipation. In addition, MDD participants with greater attenuation of connectivity between several frontostriatal seeds, and midline subcallosal cortex and left paracingulate gyrus demonstrated improved response to BATD. These findings indicate that pretreatment frontostriatal functional connectivity during reward processing is predictive of response to a psychotherapy modality that promotes improving approach-related behaviors in MDD. Furthermore, connectivity attenuation among reward-processing regions may be a particularly powerful endophenotypic predictor of response to BATD in MDD.

Survey of antipsychotic medication curriculum content in Australian university nursing programmes.

Antipsychotic medication has long been one of the first-line interventions for people with serious mental illness, with outcomes including reductions in symptoms and relapse rates. More recently, however, questions have been raised about the efficacy of antipsychotic medications, especially in light of their side-effect profile. Such questions have implications for the nurses administering antipsychotic medications, particularly in relation to their knowledge of the antipsychotic medication, its efficacy, and side-effect profile. Also important is the education of nursing students about antipsychotic medications, their use, and management. The present study reports findings of research that explored current curriculum content concerning psychopharmacological treatment in Australian undergraduate and postgraduate nursing programmes. Using a survey design, the research examined the content and modes of delivery of this content to gauge how well students are prepared for administering antipsychotic medication to people with serious mental illness. Findings of the research suggested the need for improvement in preparing nursing students to administer antipsychotic medication, including indications, contraindications, as well as recognition and management of side-effects.

A Thematic Inquiry into the Burnout Experience of Australian Solo-Practicing Clinical Psychologists.

Objective: Burnout is conceptualized as a syndrome that consists of emotional exhaustion, depersonalization, and decreased personal accomplishment. Despite the increased frequency and severity of burnout in the Western world, there is limited published research regarding the experiences of clinical psychologists who have had burnout. The present study examines clinical psychologists' different experiences of burnout in Australia. Design and Methods: In the year 2015, six privately practicing and solo-employed clinical psychologists provided rich qualitative data by participating in semi-structured interviews. Thematic analysis was the method used to analyze clinical psychologists' natural accounts of their burnout experiences. Using NVivo, emerging themes were identified through coding 'first order constructs' and then axial code 'second order constructs.' Findings: Clinical psychologists indicated that their roles are demanding and a diverse range of symptoms, including the enduring effects of burnout, mental stress, fatigue, decreased personal accomplishment, negative affect, depersonalization, reduced productivity and motivation, and insomnia. They identified precursors of burnout, including excessive workload and hours of work, life stresses, mismanaged workload, and transference. Clinical psychologists suggested that protective factors of burnout include knowledge and years worked in direct care, and trusting and long-term relationships. They indicated that the barriers to overcoming burnout include the fallacy that their clients' expectations and needs are more important than their own, the financial cost of working in private practice, contemporary knowledge and inadequate education regarding self-care, and time constraints. Discussion and Conclusion: The findings presented in this study provide psychologists and other health professionals with an insight about the burnout experience and inform professionals of the mental shortcomings of working as a solo-practicing clinical psychologist. Findings from this study should lead to an increased understanding of the complexities of burnout, and ultimately reduced cases of burnout, absenteeism, and staff disengagement.

Transition from Molecular Vibrations to Phonons in Atomically Precise Cadmium Selenide Quantum Dots.

We use micro-Raman spectroscopy to measure the vibrational structure of the atomically precise cadmium selenide quantum dots Cd35Se20X30L30, Cd56Se35X42L42, and Cd84Se56X56L56. These quantum dots have benzoate (X) and n-butylamine (L) ligands and tetrahedral (Td) shape with edges that range from 1.7 to 2.6 nm in length. Investigating this previously unexplored size regime allows us to identify the transition from molecular vibrations to bulk phonons in cadmium selenide quantum dots for the first time. Room-temperature Raman spectra have broad CdSe peaks at 175 and 200 cm-1. Density functional theory calculations assign these peaks to molecular surface and interior vibrational modes, respectively, and show that the interior, surface, and ligand atom motion is strongly coupled. The interior peak intensity increases relative to the surface peak as the cluster size increases due to the relative increase in the polarizability of interior modes with quantum dot size. The Raman spectra do not change with temperature for molecular Cd35Se20X30L30, while the interior peak narrows and shifts to higher energy as temperature decreases for Cd84Se56X56L56, a spectral evolution typical of a phonon. This result shows that the single bulk unit cell contained within Cd84Se56X56L56 is sufficient to apply a phonon confinement model, and that Cd56Se35X42L42, with its 2.1 nm edge length, marks the boundary between molecular vibrations and phonons.

Glymphatic fluid transport controls paravascular clearance of AAV vectors from the brain.

Adeno-associated viruses (AAV) are currently being evaluated in clinical trials for gene therapy of CNS disorders. However, host factors that influence the spread, clearance, and transduction efficiency of AAV vectors in the brain are not well understood. Recent studies have demonstrated that fluid flow mediated by aquaporin-4 (AQP4) channels located on astroglial end feet is essential for exchange of solutes between interstitial and cerebrospinal fluid. This phenomenon, which is essential for interstitial clearance of solutes from the CNS, has been termed glial-associated lymphatic transport or glymphatic transport. In the current study, we demonstrate that glymphatic transport profoundly affects various aspects of AAV gene transfer in the CNS. Altered localization of AQP4 in aged mouse brains correlated with significantly increased retention of AAV vectors in the parenchyma and reduced systemic leakage following ventricular administration. We observed a similar increase in AAV retention and transgene expression upon i.c.v. administration in AQP4-/- mice. Consistent with this observation, fluorophore-labeled AAV vectors showed markedly reduced flux from the ventricles of AQP4-/- mice compared with WT mice. These results were further corroborated by reduced AAV clearance from the AQP4-null brain, as demonstrated by reduced transgene expression and vector genome accumulation in systemic organs. We postulate that deregulation of glymphatic transport in aged and diseased brains could markedly affect the parenchymal spread, clearance, and gene transfer efficiency of AAV vectors. Assessment of biomarkers that report the kinetics of CSF flux in prospective gene therapy patients might inform variable treatment outcomes and guide future clinical trial design.

Sustained anterior cingulate cortex activation during reward processing predicts response to psychotherapy in major depressive disorder.

BACKGROUND: The purpose of the present investigation was to evaluate whether pre-treatment neural activation in response to rewards is a predictor of clinical response to Behavioral Activation Therapy for Depression (BATD), an empirically validated psychotherapy that decreases depressive symptoms by increasing engagement with rewarding stimuli and reducing avoidance behaviors. METHODS: Participants were 33 outpatients with major depressive disorder (MDD) and 20 matched controls. We examined group differences in activation, and the capacity to sustain activation, across task runs using functional magnetic resonance imaging (fMRI) and the monetary incentive delay (MID) task. Hierarchical linear modeling was used to investigate whether pre-treatment neural responses predicted change in depressive symptoms over the course of BATD treatment. RESULT: MDD and Control groups differed in sustained activation during reward outcomes in the right nucleus accumbens, such that the MDD group experienced a significant decrease in activation in this region from the first to second task run relative to controls. Pretreatment anhedonia severity and pretreatment task-related reaction times were predictive of response to treatment. Furthermore, sustained activation in the anterior cingulate cortex during reward outcomes predicted response to psychotherapy; patients with greater sustained activation in this region were more responsive to BATD treatment. LIMITATION: The current study only included a single treatment condition, thus it unknown whether these predictors of treatment response are specific to BATD or psychotherapy in general. CONCLUSION: Findings add to the growing body of literature suggesting that the capacity to sustain neural responses to rewards may be a critical endophenotype of MDD.

Radiation Sensitivity in a Preclinical Mouse Model of Medulloblastoma Relies on the Function of the Intrinsic Apoptotic Pathway.

While treatments that induce DNA damage are commonly used as anticancer therapies, the mechanisms through which DNA damage produces a therapeutic response are incompletely understood. Here we have tested whether medulloblastomas must be competent for apoptosis to be sensitive to radiotherapy. Whether apoptosis is required for radiation sensitivity has been controversial. Medulloblastoma, the most common malignant brain tumor in children, is a biologically heterogeneous set of tumors typically sensitive to radiation and chemotherapy; 80% of medulloblastoma patients survive long-term after treatment. We used functional genetic studies to determine whether the intrinsic apoptotic pathway is required for radiation to produce a therapeutic response in mice with primary, Shh-driven medulloblastoma. We found that cranial radiation extended the survival of medulloblastoma-bearing mice and induced widespread apoptosis. Expression analysis and conditional deletion studies showed that Trp53 (p53) was the predominant transcriptional regulator activated by radiation and was strictly required for treatment response. Deletion of Bax, which blocked apoptosis downstream of p53, was sufficient to render tumors radiation resistant. In apoptosis-incompetent, Bax-deleted tumors, radiation activated p53-dependent transcription without provoking cell death and caused two discrete populations to emerge. Most radiated tumor cells underwent terminal differentiation. Perivascular cells, however, quickly resumed proliferation despite p53 activation, behaved as stem cells, and rapidly drove recurrence. These data show that radiation must induce apoptosis in tumor stem cells to be effective. Mutations that disable the intrinsic apoptotic pathways are sufficient to impart radiation resistance. We suggest that medulloblastomas are typically sensitive to DNA-damaging therapies, because they retain apoptosis competence. Cancer Res; 76(11); 3211-23. ©2016 AACR.