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Neuronal diversity and convergence in a visual system developmental atlas

Özel, Mehmet Neset; Simon, Félix; Jafari, Shadi; Holguera, Isabel; Chen, Yen-Chung; Benhra, Najate; El-Danaf, Rana Naja; Kapuralin, Katarina; Malin, Jennifer Amy; Konstantinides, Nikolaos; Desplan, Claude
Deciphering how neuronal diversity is established and maintained requires a detailed knowledge of neuronal gene expression throughout development. In contrast to mammalian brains1,2, the large neuronal diversity of the Drosophila optic lobe3 and its connectome4-6 are almost completely characterized. However, a molecular characterization of this neuronal diversity, particularly during development, has been lacking. Here we present insights into brain development through a nearly complete description of the transcriptomic diversity of the optic lobes of Drosophila. We acquired the transcriptome of 275,000 single cells at adult and at five pupal stages, and built a machine-learning framework to assign them to almost 200 cell types at all time points during development. We discovered two large neuronal populations that wrap neuropils during development but die just before adulthood, as well as neuronal subtypes that partition dorsal and ventral visual circuits by differential Wnt signalling throughout development. Moreover, we show that the transcriptomes of neurons that are of the same type but are produced days apart become synchronized shortly after their production. During synaptogenesis we also resolved neuronal subtypes that, although differing greatly in morphology and connectivity, converge to indistinguishable transcriptomic profiles in adults. Our datasets almost completely account for the known neuronal diversity of the Drosophila optic lobes, and serve as a paradigm to understand brain development across species.
PMID: 33149298
ISSN: 1476-4687
CID: 4662932

Myosin V Regulates Spatial Localization of Different Forms of Neurotransmitter Release in Central Synapses

Maschi, Dario; Gramlich, Michael W; Klyachko, Vitaly A
Synaptic active zone (AZ) contains multiple specialized release sites for vesicle fusion. The utilization of release sites is regulated to determine spatiotemporal organization of the two main forms of synchronous release, uni-vesicular (UVR) and multi-vesicular (MVR). We previously found that the vesicle-associated molecular motor myosin V regulates temporal utilization of release sites by controlling vesicle anchoring at release sites in an activity-dependent manner. Here we show that acute inhibition of myosin V shifts preferential location of vesicle docking away from AZ center toward periphery, and results in a corresponding spatial shift in utilization of release sites during UVR. Similarly, inhibition of myosin V also reduces preferential utilization of central release sites during MVR, leading to more spatially distributed and temporally uniform MVR that occurs farther away from the AZ center. Using a modeling approach, we provide a conceptual framework that unites spatial and temporal functions of myosin V in vesicle release by controlling the gradient of release site release probability across the AZ, which in turn determines the spatiotemporal organization of both UVR and MVR. Thus myosin V regulates both temporal and spatial utilization of release sites during two main forms of synchronous release.
PMCID:8081987
PMID: 33935678
ISSN: 1663-3563
CID: 4865912

Resting-State fMRI to Identify the Brain Correlates of Treatment Response to Medications in Children and Adolescents With Attention-Deficit/Hyperactivity Disorder: Lessons From the CUNMET Study

Pereira-Sanchez, Victor; Franco, Alexandre R; de Castro-Manglano, Pilar; Fernandez-Seara, Maria A; Vallejo-Valdivielso, Maria; Díez-Suárez, Azucena; Fernandez-Martinez, Miguel; Garcia de Eulate, M Reyes; Milham, Michael; Soutullo, Cesar A; Castellanos, Francisco X
Neuroimaging research seeks to identify biomarkers to improve the diagnosis, prognosis, and treatment of attention-deficit/hyperactivity disorder (ADHD), although clinical translation of findings remains distant. Resting-state functional magnetic resonance imaging (R-fMRI) is increasingly being used to characterize functional connectivity in the brain. Despite mixed results to date and multiple methodological challenges, dominant hypotheses implicate hyperconnectivity across brain networks in patients with ADHD, which could be the target of pharmacological treatments. We describe the experience and results of the Clínica Universidad de Navarra (Spain) Metilfenidato (CUNMET) pilot study. CUNMET tested the feasibility of identifying R-fMRI markers of clinical response in children with ADHD undergoing naturalistical pharmacological treatments. We analyzed cross-sectional data from 56 patients with ADHD (18 treated with methylphenidate, 18 treated with lisdexamfetamine, and 20 treatment-naive patients). Standard preprocessing and statistical analyses with attention to control for head motion and correction for multiple comparisons were performed. The only results that survived correction were noted in contrasts of children who responded clinically to lisdexamfetamine after long-term treatment vs. treatment-naive patients. In these children, we observed stronger negative correlations (anticorrelations) across nodes in six brain networks, which is consistent with higher across-network functional segregation in patients treated with lisdexamfetamine, i.e., less inter-network interference than in treatment-naive patients. We also note the lessons learned, which could help those pursuing clinically relevant multidisciplinary research in ADHD en route to eventual personalized medicine. To advance reproducible open science, our report is accompanied with links providing access to our data and analytic scripts.
PMCID:8635006
PMID: 34867544
ISSN: 1664-0640
CID: 5110082

Immunohistological Examination of AKT Isoforms in the Brain: Cell-Type Specificity That May Underlie AKT's Role in Complex Brain Disorders and Neurological Disease

Levenga, Josien; Wong, Helen; Milstead, Ryan; LaPlante, Lauren; Hoeffer, Charles A
Protein kinase B (PKB/AKT) is a central kinase involved in many neurobiological processes. AKT is expressed in the brain as three isoforms, AKT1, AKT2, and AKT3. Previous studies suggest isoform-specific roles in neural function, but very few studies have examined AKT isoform expression at the cellular level. In this study, we use a combination of histology, immunostaining, and genetics to characterize cell-type-specific expression of AKT isoforms in human and mouse brains. In mice, we find that AKT1 is the most broadly expressed isoform, with expression in excitatory neurons and the sole detectable AKT isoform in gamma-aminobutyric acid ergic interneurons and microglia. By contrast, we find that AKT2 is the sole isoform expressed in astroglia and is not detected in other neural cell types. We find that AKT3 is expressed in excitatory neurons with AKT1 but shows greater expression levels in dendritic compartments than AKT1. We extend our analysis to human brain tissues and find similar results. Using genetic deletion approaches, we also find that the cellular determinants restricting AKT isoform expression to specific cell types remain intact under Akt deficiency conditions. Because AKT signaling is linked to numerous neurological disorders, a greater understanding of cell-specific isoform expression could improve treatment strategies involving AKT.
PMCID:8223503
PMID: 34296180
ISSN: 2632-7376
CID: 4948632

Cell Type-Specific Membrane Potential Changes in Dorsolateral Striatum Accompanying Reward-Based Sensorimotor Learning

Sippy, Tanya; Chaimowitz, Corryn; Crochet, Sylvain; Petersen, Carl C H
The striatum integrates sensorimotor and motivational signals, likely playing a key role in reward-based learning of goal-directed behavior. However, cell type-specific mechanisms underlying reinforcement learning remain to be precisely determined. Here, we investigated changes in membrane potential dynamics of dorsolateral striatal neurons comparing naïve mice and expert mice trained to lick a reward spout in response to whisker deflection. We recorded from three distinct cell types: (i) direct pathway striatonigral neurons, which express type 1 dopamine receptors; (ii) indirect pathway striatopallidal neurons, which express type 2 dopamine receptors; and (iii) tonically active, putative cholinergic, striatal neurons. Task learning was accompanied by cell type-specific changes in the membrane potential dynamics evoked by the whisker deflection and licking in successfully-performed trials. Both striatonigral and striatopallidal types of striatal projection neurons showed enhanced task-related depolarization across learning. Striatonigral neurons showed a prominent increase in a short latency sensory-evoked depolarization in expert compared to naïve mice. In contrast, the putative cholinergic striatal neurons developed a hyperpolarizing response across learning, driving a pause in their firing. Our results reveal cell type-specific changes in striatal membrane potential dynamics across the learning of a simple goal-directed sensorimotor transformation, helpful for furthering the understanding of the various potential roles of different basal ganglia circuits.
PMCID:8788857
PMID: 35330797
ISSN: 2633-8823
CID: 5220452

Off-Target Expression of Cre-Dependent Adeno-Associated Viruses in Wild-Type C57BL/6J Mice

Botterill, Justin J; Khlaifia, Abdessattar; Walters, Brandon J; Brimble, Mark A; Scharfman, Helen E; Arruda-Carvalho, Maithe
Adeno-associated viruses (AAVs) are a commonly used tool in neuroscience to efficiently label, trace, and/or manipulate neuronal populations. Highly specific targeting can be achieved through recombinase-dependent AAVs in combination with transgenic rodent lines that express Cre-recombinase in specific cell types. Visualization of viral expression is typically achieved through fluorescent reporter proteins (e.g., GFP or mCherry) packaged within the AAV genome. Although nonamplified fluorescence is usually sufficient to observe viral expression, immunohistochemical amplification of the fluorescent reporter is routinely used to improve viral visualization. In the present study, Cre-dependent AAVs were injected into the neocortex of wild-type C57BL/6J mice. While we observed weak but consistent nonamplified off-target double inverted open reading frame (DIO) expression in C57BL/6J mice, antibody amplification of the GFP or mCherry reporter revealed notable Cre-independent viral expression. Off-target expression of DIO constructs in wild-type C57BL/6J mice occurred independent of vendor, AAV serotype, or promoter. We also evaluated whether Cre-independent expression had functional effects via designer receptors exclusively activated by designer drugs (DREADDs). The DREADD agonist C21 (compound 21) had no effect on contextual fear conditioning or c-Fos expression in DIO-hM3Dq-mCherry+ cells of C57BL/6J mice. Together, our results indicate that DIO constructs have off-target expression in wild-type subjects. Our findings are particularly important for the design of experiments featuring sensitive systems and/or quantitative measurements that could be negatively impacted by off-target expression.Significance StatementAdeno-associated viruses (AAVs) are widely used in neuroscience because of their safety and ease of use. Combined with specific promoters, Cre/loxP, and stereotaxic injections, highly specific targeting of cells and circuits within the brain can be achieved. In the present study, we injected Cre-dependent AAVs into wild-type C57BL/6J mice and found Cre-independent viral expression of AAVs encoding mCherry, GFP, or hM3Dq following immunohistochemical amplification of the fluorescent reporter protein. Importantly, we observed no functional effects of the Cre-independent expression in the hippocampus, as C21 (compound 21) had no detectable effect on double inverted open reading frame (DIO)-hM3Dq-mCherry-infected neurons in C57BL/6J mice. Given the widespread use of DIO recombinant AAVs by the neuroscience community, our data support careful consideration when using DIO constructs in control animals.
PMID: 34785571
ISSN: 2373-2822
CID: 5049132

A Pilot Open-label Study of Aldose Reductase Inhibition with AT-001 (caficrestat) in Patients Hospitalized for COVID-19 Infection: Results from a Registry-based Matched-control Analysis [Meeting Abstract]

Gaztanaga, Juan; Ramasamy, Ravichandran; Schmidt, Ann Marie; Fishman, Glenn; Shendelman, Shoshana; Thangavelu, Karthinathan; Perfetti, Riccardo; Katz, Stuart D.
ISI:000746754900022
ISSN: 0002-8703
CID: 5208602

Maternal Choline Supplementation as a Potential Therapy for Down Syndrome: Assessment of Effects Throughout the Lifespan

Powers, Brian E; Velazquez, Ramon; Strawderman, Myla S; Ginsberg, Stephen D; Mufson, Elliott J; Strupp, Barbara J
Maternal choline supplementation (MCS) has emerged as a promising therapy to lessen the cognitive and affective dysfunction associated with Down syndrome (DS). Choline is an essential nutrient, especially important during pregnancy due to its wide-ranging ontogenetic roles. Using the Ts65Dn mouse model of DS, our group has demonstrated that supplementing the maternal diet with additional choline (4-5 × standard levels) during pregnancy and lactation improves spatial cognition, attention, and emotion regulation in the adult offspring. The behavioral benefits were associated with a rescue of septohippocampal circuit atrophy. These results have been replicated across a series of independent studies, although the magnitude of the cognitive benefit has varied. We hypothesized that this was due, at least in part, to differences in the age of the subjects at the time of testing. Here, we present new data that compares the effects of MCS on the attentional function of adult Ts65Dn offspring, which began testing at two different ages (6 vs. 12 months of age). These data replicate and extend the results of our previous reports, showing a clear pattern indicating that MCS has beneficial effects in Ts65Dn offspring throughout life, but that the magnitude of the benefit (relative to non-supplemented offspring) diminishes with aging, possibly because of the onset of Alzheimer's disease-like neuropathology. In light of growing evidence that increased maternal choline intake during pregnancy is beneficial to the cognitive and affective functioning of all offspring (e.g., neurotypical and DS), the addition of this nutrient to a prenatal vitamin regimen would be predicted to have population-wide benefits and provide early intervention for fetuses with DS, notably including babies born to mothers unaware that they are carrying a fetus with DS.
PMCID:8527982
PMID: 34690739
ISSN: 1663-4365
CID: 5042192

Bariatric surgery in a patient with cystinuria

Nemati, M R; Harris, P C; Cogal, A G; Goldfarb, D S
We recently encountered concern about the safety of bariatric surgery for a patient with cystinuria. Bariatric surgery procedures include those that cause malabsorption, like the Roux-en-Y gastric bypass procedure, and restrictive operations, such as the sleeve gastrectomy. These procedures produce beneficial effects on health and life expectancy, though whether kidney stones are prevented, as well as promoted, is not established. Although the importance of body weight to metabolic stone activity in patients with cystinuria is not established, the patient's physicians were concerned about whether any bariatric surgery procedure would affect her ability to drink sufficient quantities of water in order to reduce stone activity. Here we report the experience of a genetically defined patient with cystinuria who underwent a gastric sleeve procedure. In the months after the procedure, she lost 45 kg, though with time she regained 23 kg of that loss. She was able to maintain a urine volume of 4.0 L per day and has had no stone recurrence.XXCopyright
EMBASE:2007625598
ISSN: 2196-5293
CID: 4927892

PHOTACs Enable Optical Control of Protein Degradation

Reynders, Martin; Trauner, Dirk
Proteolysis Targeting Chimeras (PROTACs) are a promising technology to degrade specific target proteins. As bifunctional small molecules, PROTACs induce the ternary complex formation between an E3 ligase and a protein of interest (POI), leading to polyubiquitylation and subsequent proteasomal degradation of the protein in a catalytic fashion. We have developed a strategy to control PROTACs with the spatiotemporal precision of light, which led to light-activated versions, termed PHOTACs (PHOtochemically TArgeted Chimeras). By incorporating an azobenzene photoswitch into the PROTAC, we can reversibly control degradation of the POI, as demonstrated for BRD2-4 and FKBP12. Here, we describe our modular approach and the application of PHOTACs for the optical control of protein levels in detail. PHOTACs hold promise as both research tools and precision pharmaceutics.
PMID: 34432252
ISSN: 1940-6029
CID: 5011132