Biology subjects

Narayanan, R.

Publications and source records attributed to Narayanan, R..

5 recordsLinked to original sources

bioRxiv2017

Monovalent ions modulate the flux through multiple folding pathways of an RNA pseudoknot

The functions of RNA pseudoknots (PKs), which are minimal tertiary structural motifs and an integral part of several ribozymes and ribonucleoprotein complexes, are determined by their structure, stability and dynamics. Therefore, it is important to elucidate the general principles governing their thermodynamics/folding mechanisms. Here, we combine experiments and simulations to examine the folding/unfolding pathways of the VPK pseudoknot, a variant of the Mouse Mammary Tumor Virus (MMTV) PK involved in ribosomal frameshifting. Fluorescent nucleotide analogs (2-aminopurine and pyrrolocytidine) placed at different stem/loop positions in the PK, and laser temperature-jump approaches serve as local probes allowing us to monitor the order of assembly of VPK with two helices with different intrinsic stabilities. The experiments and molecular simulations show that at 50 mM KCl the dominant folding pathway populates only the more stable partially folded hairpin. As the salt concentration is increased a parallel folding pathway emerges, involving the less stable hairpin structure as an alternate intermediate. Notably, the flux between the pathways is modulated by the ionic strength. The findings support the principle that the order of PK structure formation is determined by the relative stabilities of the hairpins, which can be altered by sequence variations or salt concentrations. Our study not only unambiguously demonstrates that PK folds by parallel pathways, but also establishes that quantitative description of RNA self-assembly requires a synergistic combination of experiments and simulations.\n\nSIGNIFICANCEThe assembly mechanism of RNA, vital to describing their functions, depends on both the sequence and the metal ion concentration. How the latter influences the folding trajectories remains an important unsolved problem. Here, we examine the folding pathways of an RNA pseudoknot (PK) with key functional roles in transcription and translation, using a combination of experiments and simulations. We demonstrate that the PK, consisting of two helices with differing stabilities, folds by parallel pathways. Surprisingly, the flux between them is modulated by monovalent salt concentration. Our work shows that the order of assembly of PKs is determined by the relative stability of the helices, implying that the folding landscape can be controlled by sequence and ion concentration.

biophysics↗

bioRxiv2017

Degeneracy in hippocampal physiology and plasticity

Degeneracy, defined as the ability of structurally disparate elements to perform analogous function, has largely been assessed from the perspective of maintaining robustness of physiology or plasticity. How does the framework of degeneracy assimilate into an encoding system where the ability to change is an essential ingredient for storing new incoming information? Could degeneracy maintain the balance between the apparently contradictory goals of the need to change for encoding and the need to resist change towards maintaining homeostasis? In this review, we explore these fundamental questions with the mammalian hippocampus as an example encoding system. We systematically catalog lines of evidence, spanning multiple scales of analysis, that demonstrate the expression of degeneracy in hippocampal physiology and plasticity. We assess the potential of degeneracy as a framework to achieve the conjoint goals of encoding and homeostasis without cross-interferences. We postulate that biological complexity, involving interactions among the numerous parameters spanning different scales of analysis, could establish disparate routes towards accomplishing these conjoint goals. These disparate routes then provide several degrees of freedom to the encoding-homeostasis system in accomplishing its tasks in an input- and state-dependent manner. Finally, the expression of degeneracy spanning multiple scales offers an ideal reconciliation to several outstanding controversies, through the recognition that the seemingly contradictory disparate observations are merely alternate routes that the system might recruit towards accomplishment of its goals. Against the backdrop of the ubiquitous prevalence of degeneracy and its strong links to evolution, it is perhaps apt to add a corollary to Theodosius Dobzhanskys famous quote and state \"nothing in physiology makes sense except in the light of degeneracy\".\n\nHighlightsO_LIDegeneracy is the ability of structurally distinct elements to yield similar function\nC_LIO_LIWe postulate a critical role for degeneracy in the emergence of stable encoding systems\nC_LIO_LIWe catalog lines of evidence for the expression of degeneracy in the hippocampus\nC_LIO_LIWe suggest avenues for research to explore degeneracy in stable encoding systems\nC_LIO_LIDobzhansky wrote: \"nothing in biology makes sense except in the light of evolution\"\nC_LIO_LIA corollary: \"nothing in physiology makes sense except in the light of degeneracy\"\nC_LI

neuroscience↗

bioRxiv2017

Degeneracy in the robust expression of spectral selectivity, subthreshold oscillations and intrinsic excitability of entorhinal stellate cells

Biological heterogeneities are ubiquitous and play critical roles in the emergence of physiology at multiple scales. Although neurons in layer II (LII) of the medial entorhinal cortex (MEC) express heterogeneities in their channel properties, the impact of such heterogeneities on the robustness of cellular-scale physiology has not been assessed. Here, we performed a 55-parameter stochastic search spanning 9 voltage- or calcium-activated channels to assess the impact of channel heterogeneities on the concomitant emergence of 10 electrophysiological characteristics of LII stellate cells (SCs). We generated 50,000 models and found a heterogeneous subpopulation of 155 valid models to robustly match all electrophysiological signatures. We employed this heterogeneous population to demonstrate the emergence of cellular-scale degeneracy in LII SCs, whereby disparate parametric combinations expressing weak pairwise correlations resulted in similar models. We then assessed the impact of virtually knocking out each channel from all valid models and demonstrate that the mapping between channels and measurements was many-to-many, a critical requirement for the expression of degeneracy. Finally, we quantitatively predict that the spike-triggered average of LII SCs should be endowed with theta-frequency spectral selectivity and coincidence detection capabilities in the fast gamma-band. We postulate this fast gamma-band coincidence detection as an instance of cellular-scale efficient coding, whereby SC response characteristics match the dominant oscillatory signals in LII MEC. The heterogeneous population of valid SC models built here unveils the robust emergence of cellular-scale physiology despite significant channel heterogeneities, and forms an efficacious substrate for evaluating the impact of biological heterogeneities on entorhinal network function.\n\nKEY POINTSO_LIStellate cells (SC) in layer II (LII) of the medial entorhinal cortex express cellular-scale degeneracy in the concomitant manifestation of several of their unique physiological signatures.\nC_LIO_LISeveral disparate parametric combinations expressing weak pairwise correlations resulted in models with very similar physiological characteristics, including robust theta-frequency membrane potential oscillations spanning several levels of subthreshold depolarization.\nC_LIO_LIElectrophysiological measurements of LII SCs exhibited differential and variable dependencies on underlying channels, and the mapping between channels and measurements was many-to-many.\nC_LIO_LIQuantitative predictions point to theta-frequency spectral selectivity and fast gamma-range coincidence detection capabilities in class II/III spike-triggered average of LII SCs, with the postulate for this to be an instance of cellular-scale efficient coding.\nC_LIO_LIA heterogeneous cell population that accounts for both channel and intrinsic heterogeneities in LII SCs, which could be employed by network models of entorhinal function to probe the impact of several biological heterogeneities on spatial navigation circuits.\nC_LI

neuroscience↗

bioRxiv2017

Heterogeneities in afferent connectivity dominate local heterogeneities in the emergence of response decorrelation in the dentate gyrus

The ability of a neuronal population to effectuate response decorrelation has been identified as an essential prelude to efficient neural encoding. To what extent are diverse forms of local and afferent heterogeneities essential in accomplishing such response decorrelation in the dentate gyrus (DG)? Here, we incrementally incorporated four distinct forms of biological heterogeneities into conductance-based network models of the DG and systematically delineate their relative contributions to response decorrelation. We incorporated intrinsic heterogeneities by stochastically generating several electrophysiologically-validated basket and granule cell models that exhibited significant parametric variability, and introduced synaptic heterogeneities through randomized local synaptic strengths. In including adult neurogenesis, we subjected the valid model populations to randomized structural plasticity and matched neuronal excitability to electrophysiological data. We assessed networks comprising different combinations of these three local heterogeneities with identical or heterogeneous afferent inputs from the entorhinal cortex. We found that the three forms of local heterogeneities were independently and synergistically capable of mediating significant response decorrelation when the network was driven by identical afferent inputs. Strikingly, however, when we incorporated afferent heterogeneities into the network to account for the unique divergence in DG afferent connectivity, the impact of all three forms of local heterogeneities were significantly suppressed by the dominant role of afferent heterogeneities in mediating response decorrelation. Our results unveil a unique convergence of cellular- and network-scale degeneracy in the emergence of response decorrelation in the DG, and constitute a significant departure from the literature that assigns a critical role for local network heterogeneities in input discriminability.\n\nSIGNIFICANCE STATEMENTThe olfactory bulb and the dentate gyrus (DG) networks assimilate new neurons in adult rodents, with adult neurogenesis postulated to subserve efficacious information transfer by reducing correlations in neuronal responses to afferent inputs. Heterogeneities emerging from the lateral dendro-dendritic synapses, mediated by locally-projecting neurogenic inhibitory granule cells, are known to play critical roles in channel decorrelation in the olfactory bulb. However, the contributions of different heterogeneities in mediating response decorrelation in DG, comprising neurogenic excitatory granule cells projecting beyond DG and endowed with uniquely divergent afferent inputs, have not been delineated. Here, we quantitatively demonstrate the dominance of afferent heterogeneities, over multiple local heterogeneities, in the emergence of response decorrelation in DG, together unveiling cross-region degeneracy in accomplishing response decorrelation.

neuroscience↗

bioRxiv2017

Spatially dispersed synapses yield sharply-tuned place cell responses through dendritic spike initiation

The literature offers evidence for a critical role of spatially-clustered iso-feature synapses in eliciting dendritic spikes essential for sharp feature selectivity, with apparently contradictory evidence demonstrating spatial dispersion of iso-feature synapses. Here, we reconcile this apparent contradiction by demonstrating that the generation of dendritic spikes, the emergence of an excitatory ramp in somatic voltage responses and sharp tuning of place-cell responses are all attainable even when iso-feature synapses are randomly dispersed across the dendritic arbor. We found this tuning sharpness to be critically reliant on dendritic sodium and transient potassium channels and on N-methyl-D-aspartate receptors. Importantly, we demonstrate that synaptic potentiation targeted to afferents from one specific place field is sufficient to effectuate place-field selectivity even when intrinsically disparate neurons received randomly dispersed afferents from multiple place-field locations. These conclusions proffer dispersed localization of isofeature synapses as a strong candidate for achieving sharp feature selectivity in neurons across sensory-perceptual systems.\n\nO_LSTHighlightsC_LSTO_LISystematic analysis of four synaptic localization profiles for sharp spatial tuning\nC_LIO_LIDendritic spikes are generated even with randomly dispersed iso-feature synapses\nC_LIO_LISharp feature tuning could be achieved even in the absence of synaptic clusters\nC_LIO_LITargeted, yet dispersed, synaptic plasticity sufficient for place-cell emergence\nC_LI

neuroscience↗