Biology subjects

Paul, A.

Publications and source records attributed to Paul, A..

82 records · Page 5Linked to original sources

bioRxiv2019

Effects of genetic variability of CYP2D6 on neural substrates of sustained attention during on-task activity

The polymorphic drug-metabolizing enzyme CYP2D6, which is responsible for the metabolism of most psychoactive compounds, is expressed not only in the liver, but also in the brain. The effects of its marked genetic polymorphism on the individual capacity to metabolize drugs are well known, but its role in metabolism of neural substrates affecting behavior personality or cognition, suggested by its CNS expression, is a long-standing unresolved issue. To verify earlier findings suggesting a potential effect on attentional processes, we collected functional imaging data while N=415 participants performed a simple task in which the reward for correct responses varied. CYP2D6 allelic variants predicting higher levels of enzymatic activity level were positively associated with cortical activity in occipito-parietal areas as well as in a right lateralized network known to be activated by spatial attentional tasks. Reward-related modulation of activity in cortical areas was more pronounced in poor metabolizers. In conjunction with effects on reaction times, our findings provide evidence for reduced cognitive efficiency in rapid metabolizers compared to poor metabolizers in on-task attentional processes manifested through differential recruitment of a specific neural substrate.

pharmacology and toxicology↗

bioRxiv2019

Signals of anticipation of reward and of mean reward rates in the human brain

Theoretical models of dopamine function stemming from reinforcement learning theory have emphasized the importance of prediction errors, which signal changes in the expectation of impending rewards. Much less is known about the effects of mean reward rates, which may be of motivational significance due to their role in computing the optimal effort put into exploiting reward opportunities. Here, we used a reinforcement learning model to design three functional neuroimaging studies and disentangle the effects of changes in reward expectations and mean reward rates, showing recruitment of specific regions in the brainstem regardless of prediction errors. While changes in reward expectations activated ventral striatal areas as in previous studies, mean reward rates preferentially modulated the substantia nigra/ventral tegmental area, deep layers of the superior colliculi, and a posterior pontomesencephalic region. These brainstem structures may work together to set motivation and attentional efforts levels according to perceived reward opportunities.

neuroscience↗

bioRxiv2019

Nf1 deletion results in depletion of the Lhx6 transcription factor and a specific loss of parvalbumin+ cortical interneurons

Neurofibromatosis-1 (NF-1) is a monogenic disorder caused by mutations in the NF1 gene, which encodes the protein, Neurofibromin, an inhibitor of Ras GTPase activity. While NF-1 is often characterized by cafe-au-lait skin spots and benign tumors, the mechanisms underlying cognitive changes in NF-1 are poorly understood. Cortical GABAergic interneurons (CINs) are implicated in NF-1 pathology but cellular and molecular changes to CINs are poorly understood. We deleted Nf1 from the medial ganglionic eminence (MGE), which gives rise to both oligodendrocytes and CINs that express somatostatin and parvalbumin. Loss of Nf1 led to a persistence of immature oligodendrocytes that prevented later born oligodendrocytes from occupying the cortex. Moreover, PV+ CINs were uniquely lost, without changes in SST+ CINs. We discovered that loss of Nf1 results in a graded decrease in Lhx6 expression, the transcription factor necessary to establish SST+ and PV+ CINs, revealing a mechanism whereby Nf1 regulates a critical CIN developmental milestone.

neuroscience↗

bioRxiv2019

Release of stem cells from quiescence reveals multiple gliogenic domains in the adult brain

Quiescent neural stem cells (NSCs) in the adult ventricular-subventricular zone (V-SVZ) have a regional identity and undergo activation to generate neurons. The domains for gliogenesis are less explored. Here we show that Platelet-Derived Growth Factor Receptor beta (PDGFR{beta}) is expressed by adult V-SVZ NSCs that generate olfactory bulb interneurons and glia with slow baseline kinetics. Selective deletion of PDGFR{beta} in adult V-SVZ NSCs leads to their release from quiescence uncovering multiple domains in the septal wall for oligodendrocyte and astrocyte formation. Unexpectedly, we identify a novel intraventricular oligodendrocyte progenitor inside the brain ventricles. Together our findings reveal different NSC spatial domains for gliogenesis in the adult V-SVZ that are largely quiescent under homeostasis and may have key functions for brain plasticity.

neuroscience↗

bioRxiv2018

Diversity of GABAergic interneurons and diversification of communication modules in cortical networks

The phenotypic diversity of cortical GABAergic neurons is likely necessary for their functional versatility in shaping exquisite spatiotemporal dynamics of circuit operations underlying cognitive processes. Deciphering the logic of this diversity requires overcoming the technical challenge of quantitative and comprehensive analysis of multi-modal cell features as well as the conceptual challenge of formulating a framework of neuronal identity that reflects biological mechanisms and principles. In the past few years, advances in high-throughput single cell analyses began to generate unprecedented datasets on interneuron transcriptomes, morphology and electrophysiology that drive their classification. Recent studies suggest that cardinal interneuron types can be defined by their synaptic communication properties encoded in key transcriptional signatures - a conceptual framework that integrates across phenotypic features and captures neuronal input-output properties elemental to circuit operation. This definition may further facilitate understanding the appropriate granularity of neuron types toward building a biologically-grounded and operationally useful interneuron taxonomy.

neuroscience↗

bioRxiv2018

Quantitative mapping of triacylglycerol chain length and saturation using broadband CARS microscopy

Lipid droplets (LDs) are highly dynamic organelles that store neutral lipids, primarily triacylglycerols (TAGs), and are found in many cell types. While their primary function is to store excess energy, LDs are also modified in different disease states and during developmental processes. In many cases, not only the presence, but also the composition, of LDs can be equally important. In humans, LD composition has been linked to diseases such as type 2 diabetes; in plants and yeast, LD composition is relevant for engineering these organisms into biological factories in, e.g., algal bioenergy or food oil production. Therefore, lipid analysis of biological LDs with high speed and accuracy in situ is a very active area of research. Here we present an approach for in situ, quantitative TAG analysis using label-free, coherent Raman microscopy to decipher LD TAG composition in different biochemically complex samples. Our method allows direct visualization of inter-LD compositional heterogeneity of physiological quantities - TAG chain length and number of C=C bonds - with sub-micrometer spatial resolution within 5-100 milliseconds. Combined with virtually no sample preparation, this approach should enable rapid and accurate TAG LD analysis for a variety of applications.

bioengineering↗

bioRxiv2018

Translational regulation of Syngap1 by FMRP modulates NMDAR mediated signalling

SYNGAP1, a Synaptic Ras-GTPase activating protein, regulates synapse maturation during a critical developmental window. Heterozygous mutation in SYNGAP1 (SYNGAP1+/-) has been shown to cause Intellectual Disability (ID) in children. Recent studies have provided evidence for altered neuronal protein synthesis in a mouse model of Syngap1+/-. However, the molecular mechanisms behind the same is unclear. Here, we report the reduced expression of a known translation regulator, FMRP, during a specific developmental period in Syngap1+/- mice. Our results demonstrated that FMRP interacts with and regulates the translation of Syngap1 mRNA. We further show that, during development, reduced translation of FMRP and this decrease in FMRP leads to a compensatory increase of Syngap1 translation in Syngap1+/-. These developmental changes are reflected in the altered response of eEF2 phosphorylation downstream of NMDA receptor signalling. We propose a cross-talk between FMRP and SYNGAP1 mediated signalling which can also explain the compensatory effect of impaired signalling observed in Syngap1+/- mice.

neuroscience↗

bioRxiv2018

Cognate T and B cell interaction and association of Follicular helper T cells with B cell responses in Vibrio cholerae O1 infected Bangladeshi adults

Vibrio cholerae O1 can cause life threatening diarrheal disease if left untreated. A long lasting immune response, producing 3-5 years of protection from subsequent, symptomatic disease following natural infection, is mediated by B cell mediated humoral immunity. T cells can play critical roles in inducing such immunity. However, the mechanism of T cell dependent B cell maturation and whether a key sub-population of T cells are involved is not well established in cholera. We hypothesized that a specific population of T cells, follicular helper T (Tfh) cells, are involved in B cell maturation following cholera; we used flow cytometry, culture and colorimetric assays to address this question. We found that V. cholerae infection induces significant increase in circulating Tfh cells expressing B cell maturation associated protein CD40L early in disease. The increased Tfh cells expressing CD40L recognize cholera toxin most prominently, with lessened responses to two antigens tested, V. cholerae membrane preparation (MP) and Vibrio cholerae cytolysin (VCC). We further showed that early induction of Tfh cells and CD40L was associated with later memory B cell responses to same antigens. Lastly, we demonstrated in vitro that Tfh cells isolated after cholera can stimulate class switching of cocultured, isolated B cells from patients with cholera, leading to production of the more durable IgG antibody isotype. These studies were conducted on circulating Tfh cells; future studies will be directed at examining role of Tfh cells during cholera directly in the gut mucosa of biopsied samples, at the single cell level if feasible.

immunology↗

bioRxiv2017

Transcriptional Architecture of Synaptic Communication Delineates Cortical GABAergic Neuron Identity

Understanding the organizational logic of neural circuits requires deciphering the biological basis of neuron type diversity and identity, but there is no consensus on defining a neuron type. We analyzed single cell transcriptomes of anatomically and physiologically characterized cortical ground truth populations and conducted a computational genomic screen for transcription profiles that distinguish them. We discovered that cardinal GABAergic neuron types are delineated by a transcriptional architecture that encodes their synaptic communication patterns. This architecture comprises 6 categories of ~40 gene families including cell adhesion molecules, transmitter-modulator receptors, ion channels, signaling proteins, neuropeptides and vesicular release components, and transcription factors. Combinatorial expression of select members across families shapes a multi-layered molecular scaffold along cell membrane that may customize synaptic connectivity patterns and input-output signaling properties. This molecular genetic framework of neuronal identity integrates cell phenotypes along multiple axes and provides a foundation for discovering and classifying neuron types.

neuroscience↗

bioRxiv2017

Addressing the looming identity crisis in single cell RNA-seq

Single cell RNA-sequencing technology (scRNA-seq) provides a new avenue to discover and characterize cell types, but the experiment-specific technical biases and analytic variability inherent to current pipelines may undermine the replicability of these studies. Meta-analysis of rapidly accumulating data is further hampered by the use of ad hoc naming conventions. Here we demonstrate our replication framework, MetaNeighbor, that allows researchers to quantify the degree to which cell types replicate across datasets, and to rapidly identify clusters with high similarity for further testing. We first measure the replicability of neuronal identity by comparing more than 13 thousand individual scRNA-seq transcriptomes, then assess cross-dataset evidence for novel pyramidal neuron and cortical interneuron subtypes identified by scRNA-seq. We find that 24/45 cortical interneuron subtypes and 10/48 pyramidal neuron subtypes have evidence of replication in at least one other study. Identifying these putative replicates allows us to re-analyze the data for differential expression and provide lists of robust candidate marker genes. Across tasks we find that large sets of variably expressed genes can identify replicable cell types and subtypes with high accuracy, indicating many of the transcriptional changes characterizing cell identity are pervasive and easily detected.

bioinformatics↗