Biology subjects

Narayanan, R.

Publications and source records attributed to Narayanan, R..

At least 37 records · Page 2Linked to original sources

bioRxiv2023

Cell-free chromatin from dying cells trigger an immune response via the cGAS-STING pathway

It is long established that cell death and immune response are closely related, although the nature of this relationship has remained unclear. We earlier reported that cell-free chromatin particles (cfChPs) released from the billions of cells that die in the body every day to enter into the blood circulation, or those that are released locally from dying cells, can readily enter into healthy cells to induce DNA damage and activate inflammatory cytokines. In this study we investigated whether cfChPs from dying cells might be the missing link between cell death and immune response. We treated human lymphocytes with cfChPs isolated from sera of healthy individuals or with cfChPs released from hypoxia-induced dying lymphocytes. We observed that cfChPs from both sources readily entered into lymphocytes to accumulate in their nuclei within 2 h. This was associated with marked activation of CD69 and release of inflammatory cytokines, as well as of p-STING and cGAS expression. The addition of the STING protein inhibitor H151 to the cfChPs treated cells abolished the release of inflammatory cytokines. These findings lead us to suggest that cfChPs from dying cells are the critical triggers of immune response which act via cGAS-STING pathway.

immunology↗

bioRxiv2022

Transgenic mice overexpressing mutant TDP-43 show aberrant splicing of autism associated gene Zmynd11 prior to onset of motor symptoms

Mutations in TDP-43 are known to cause Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD). TDP-43 binds to and regulates splicing of several RNA including Zmynd11. Zmynd11 is a transcriptional repressor and a potential E3 ubiquitin ligase family member, known for its role in neuron and muscle differentiation. Mutations in Zmynd11 have been associated with autism with significant developmental motor delays, intellectual disability, and ataxia. Here, we show that Zmynd11 is aberrantly spliced in the brain and spinal cord of transgenic mice overexpressing a mutant human TDP-43 (A315T), and that these changes occur before the onset of motor symptoms.

neuroscience↗

bioRxiv2022

Cross-strata co-occurrence of ripples with theta-frequency oscillations in the hippocampus of foraging rats

Background and motivationBrain rhythms have been postulated to play central roles in animal cognition. A prominently reported dichotomy of hippocampal rhythms, driven primarily by historic single-strata recordings, assigns theta-frequency oscillations (4-12 Hz) and ripples (120-250 Hz) to be exclusively associated with preparatory and consummatory behaviors, respectively. However, due to the differential power expression of these two signals across hippocampal strata, reports of such exclusivity require validation through simultaneous multi-strata recordings and cross-strata analysis of these oscillatory patterns. MethodologyWe assessed co-occurrence of theta-frequency oscillations with ripples in multi-channel recordings of extracellular potentials across hippocampal strata from foraging rats. We detected all ripple events from an identified stratum pyramidale (SP) channel based on rigorous thresholds relating to the spectro-temporal and spatial characteristics of ripples. We then defined theta epochs based on theta oscillations detected from each of the different channels spanning the SP to the stratum lacunosum-moleculare (SLM) through the stratum radiatum (SR). We calculated the proportion of ripples embedded within theta epochs. ResultsWe found [~]20% (across rats) of ripple events (in SP) to co-occur with theta epochs identified from SR/SLM channels, defined here as theta ripples. All characteristics of theta ripples were comparable with ripples that occurred in the absence of theta oscillations. Furthermore, the power of theta oscillations in the immediate vicinity of theta ripples was similar to theta power across identified theta epochs, together validating the identification process of theta ripples. Strikingly, when theta epochs were instead identified from the SP channel, such co-occurrences were significantly lower in number. The reduction in the number of theta ripples was consequent to progressive reduction in theta power along the SLM-SR-SP axis. We assessed the behavioral state of rats during ripple events and found most theta ripples to occur during immobile periods. We confirmed that across sessions and rats, the theta power observed during exploratory theta epochs was comparable with theta power during immobile theta epochs. In addition, the progressive reduction in theta power along the SLM-SR-SP axis was common to both exploratory and immobile periods. Finally, we found a strong theta-phase preference of theta ripples within the third quadrant [3{pi}/2-2{pi}] of the associated theta oscillation. ImplicationsOur analyses provide direct quantitative evidence for the occurrence of ripple events nested within theta oscillations in the rodent hippocampus. These analyses emphasize that the prevalent dichotomy about the manifestation of theta-frequency oscillations and ripples needs to be reevaluated, after explicitly accounting for the differential stratum-dependent expression of these two oscillatory patterns. The prevalence of theta ripples expands the potential roles of ripple-frequency oscillations to span the continuum of encoding, retrieval, and consolidation, achieved through interactions with theta oscillations.

neuroscience↗

bioRxiv2022

Plasticity manifolds and ion-channel degeneracy govern circadian oscillations of neuronal intrinsic properties in the suprachiasmatic nucleus

Motivation and methodsThe suprachiasmatic nucleus (SCN) is the master circadian clock of the mammalian brain that sustains a neural code for circadian time through oscillations in the firing rate of constituent neurons. These cell-autonomous oscillations in intrinsic properties are mediated by plasticity in a subset of ion-channels expressed in SCN neurons and are maintained despite widespread neuron-to-neuron variability in ion channel expression profiles. How do SCN neurons undergo stable transitions and maintain precision in intrinsic properties spanning the day-night cycle if several ion channels change concomitantly in a heterogeneous neuronal population? Here, we address this important question using unbiased stochastic searches on the parametric and the plasticity spaces using populations of SCN models, each explored for multiple valid transitions spanning one complete circadian cycle (day-to-night followed by night-to-day transitions). ResultsOur analyses provided three fundamental insights about the impact of heterogeneities on the circadian oscillations of SCN intrinsic properties. First, SCN neurons could achieve signature electrophysiological characteristics (day-like or night-like) despite pronounced heterogeneity in ion channel conductances, with weak pairwise correlations between their conductance values. This ion-channel degeneracy precluded the need to maintain precise ionchannel expression profiles for achieving characteristic electrophysiological signatures of SCN neurons, thus allowing for parametric heterogeneities despite functional precision. Second, it was not essential that specific conductances had to change by precise values for obtaining valid day-to-night or night-to-day transitions. This plasticity degeneracy, the ability of disparate combinations of ion-channel plasticity to yield the same functional transition, confers flexibility on individual neurons to take one of several routes to achieve valid transitions. Finally, we performed nonlinear dimensionality reduction analyses on the valid plasticity spaces and found the manifestation of a low-dimensional plasticity manifold in day-to-night transitions, but not in night-to-day transitions. These observations demonstrated that the concomitant changes in multiple ion channels are not arbitrary, but follow a structured plasticity manifold that provides a substrate for stability in achieving stable circadian oscillations. ImplicationsOur analyses unveil an elegant substrate, involving a synthesis of the degeneracy and the plasticity manifold frameworks, to effectuate stable circadian oscillations in a heterogeneous population of SCN neurons. Within this framework, the ability of multiple ion channels to change concomitantly provides robustness and flexibility to effectively achieve precise transitions despite widespread heterogeneities in ion-channel expression and plasticity.

neuroscience↗

bioRxiv2022

Ion-channel degeneracy and heterogeneities in the emergence of complex spike bursts in CA3 pyramidal neurons

Complex spike bursting (CSB) is a characteristic electrophysiological signature exhibited by several neurons and has been implicated in neural plasticity, learning, perception, anesthesia, and active sensing. Here, we address the question of how pronounced intrinsic and synaptic heterogeneities affect CSB, with hippocampal CA3 pyramidal neurons (CA3PN) as a substrate where CSB emergence and heterogeneities are well-characterized. We randomly generated 12,000 unique models and found 236 valid models that satisfied 11 characteristic CA3PN measurements. These morphologically and biophysically realistic valid models accounted for gating kinetics and somato-dendritic expression profiles of 10 active ion channels. This heterogeneous population of valid models was endowed with broad distributions of underlying parameters showing weak pair-wise correlations. We found two functional subclasses of valid models, intrinsically bursting and regular spiking, with significant differences in the expression of calcium and calcium-activated potassium conductances. We triggered CSB in all 236 models through different intrinsic or synaptic protocols and observed considerable heterogeneity in CSB propensity and properties spanning models and protocols. Finally, we employed virtual knockout analyses and showed that synergistic interactions between intrinsic and synaptic mechanisms regulated CSB emergence and dynamics. Specifically, although there was a dominance of calcium and calcium-activated potassium channels in the emergence of CSB, individual deletion of none of the several ion channels or N-methyl-D-aspartate receptors resulted in the complete elimination of CSB across all models. Together, our analyses critically implicate ion-channel degeneracy in the robust emergence of CSB and other characteristic signatures of CA3PNs, despite pronounced heterogeneities in underlying intrinsic and synaptic properties.

neuroscience↗

bioRxiv2022

Stochastic resonance and bifurcations in a heterogeneous neuronal population explain intrinsic oscillatory patterns in entorhinal cortical stellate cells

Stellate cells in the medial entorhinal cortex manifest peri-threshold oscillatory patterns in their membrane voltage. Although different theoretical frameworks have been proposed to explain these activity patterns, these frameworks do not jointly account for heterogeneities in intrinsic properties of stellate cells and stochasticity in ion-channel and synaptic physiology. In this study, we first performed in vitro patch-clamp electrophysiological recordings from rat MEC stellate cells and found pronounced cell-to-cell variability in their characteristic physiological properties. We demonstrate that stochasticity introduced into either a simple nonlinear dynamical system (Hopf bifurcation) or into heterogeneous biophysical models yielded activity patterns that were qualitatively similar to peri-threshold oscillations in stellate cells. We developed five quantitative metrics for identification of valid oscillatory traces and confirmed that these metrics reliably captured the variable amplitude and non-rhythmic oscillatory patterns observed in our electrophysiological recordings. We analyzed traces from a stochastic Hopf bifurcation system for further confirmation on the reliability of these quantitative metrics in detecting oscillatory patterns. Apart from providing confirmation, these analyses provided a key insight about the manifestation of stochastic resonance in the stochastic bifurcation system, but not with theta-filtered noise. We then validated peri-threshold activity patterns obtained from a heterogeneous population of stellate cell models, with each model assessed with multiple trials of different levels and forms of noise (ion-channel, synaptic, and additive) at different membrane depolarizations. Strikingly, the validation process confirmed the manifestation of heterogeneous stochastic bifurcations across all models and revealed the detection of the highest number of valid oscillatory traces at an optimal level of each form of noise. The manifestation of stochastic resonance in this heterogeneous model population explained why intrinsic theta oscillations might not be observed under in vivo conditions where noise levels are typically high. Together, we provide several lines of evidence that demonstrate heterogeneous stochastic bifurcations as a unifying framework that fully explains peri-threshold oscillatory patterns in stellate cells and argue for state-dependence in the manifestation of these oscillations.

neuroscience↗

bioRxiv2021

Dominant role of adult neurogenesis-induced structural heterogeneities in driving plasticity heterogeneity in dentate gyrus granule cells

Neurons and synapses manifest pronounced variability in the amount of plasticity induced by identical activity patterns. The mechanisms underlying such plasticity heterogeneity, implicated in context-specific resource allocation during encoding, have remained unexplored. Here, we employed a systematic, unbiased, and physiologically constrained search to identify the mechanisms behind plasticity heterogeneity in dentate gyrus granule cells. We found that each of intrinsic, synaptic, and structural heterogeneities independently yielded heterogeneous plasticity profiles obtained with two different induction protocols. However, prior predictions about strong relationships between neuronal intrinsic excitability and plasticity emerged only when adult-neurogenesis-induced structural heterogeneities were accounted for. Strikingly, despite the concomitant expression of heterogeneities in structural, synaptic, and intrinsic neuronal properties, similar plasticity profiles were attainable through synergistic interactions among these heterogeneities. Importantly, consequent to strong relationships with intrinsic excitability measurements, we found that synaptic plasticity in the physiological range was achieved in immature cells despite their electrophysiologically-observed weak synaptic strengths. Together, our analyses unveil the dominance of neurogenesis-induced structural heterogeneities in driving plasticity heterogeneity in granule cells. Broadly, these analyses emphasize that the mechanistic origins of and the implications for plasticity heterogeneities need quantitative characterization across brain regions, particularly focusing on context-specific encoding of learned behavior.

neuroscience↗

bioRxiv2020

Resonating neurons stabilize heterogeneous grid-cell networks

A central theme that governs the functional design of biological networks is their ability to sustain stable function despite widespread parametric variability. Here, we investigated the impact of distinct forms of biological heterogeneities on the stability of a two-dimensional continuous attractor network (CAN) implicated in grid-patterned activity generation. We show that increasing degrees of biological heterogeneities progressively disrupted the emergence of grid- patterned activity and resulted in progressively large perturbations in low-frequency neural activity. We postulated that targeted suppression of low-frequency perturbations could ameliorate heterogeneity-induced disruptions of grid-patterned activity. To test this, we introduced intrinsic resonance, a physiological mechanism to suppress low-frequency activity, either by adding an additional high-pass filter (phenomenological) or by incorporating a slow negative feedback loop (mechanistic) into our model neurons. Strikingly, CAN models with resonating neurons were resilient to the incorporation of heterogeneities and exhibited stable grid-patterned firing. We found CAN networks with mechanistic resonators to be more effective in targeted suppression of low-frequency activity, with the slow kinetics of the negative feedback loop essential in stabilizing these networks. As low-frequency perturbations (1/f noise) are pervasive across biological systems, our analyses suggest a universal role for mechanisms that suppress low- frequency activity in stabilizing heterogeneous biological networks.

neuroscience↗

bioRxiv2020

Spatial information transfer in hippocampal place cells depends on trial-to-trial variability, symmetry of place-field firing and biophysical heterogeneities

The relationship between the feature-tuning curve and information transfer profile of individual neurons provides vital insights about neural encoding. However, the relationship between the spatial tuning curve and spatial information transfer of hippocampal place cells remains unexplored. Here, employing a stochastic search procedure spanning thousands of models, we arrived at 127 conductance-based place-cell models that exhibited signature electrophysiological characteristics and sharp spatial tuning, with parametric values that exhibited neither clustering nor strong pairwise correlations. We introduced trial-to-trial variability in responses and computed model tuning curves and information transfer profiles, using stimulus-specific (SSI) and mutual (MI) information metrics, across locations within the place field. We found spatial information transfer to be heterogeneous across models, but to reduce consistently with increasing degrees of variability. Importantly, whereas reliable low-variability responses implied that maximal information transfer occurred at high-slope regions of the tuning curve, increase in variability resulted in maximal transfer occurring at the peak-firing location in a subset of models. Moreover, experience-dependent asymmetry in place-field firing introduced asymmetries in the information transfer computed through MI, but not SSI, and the impact of activity-dependent variability on information transfer was minimal compared to activity-independent variability. Biophysically, we unveiled a many-to-one relationship between different ion channels and information transfer, and demonstrated critical roles for N-methyl-D-aspartate receptors, transient potassium and dendritic sodium channels in regulating information transfer. Our results emphasize the need to account for trial-to-trial variability, tuning-curve shape and biological heterogeneities while assessing information transfer, and demonstrate ion-channel degeneracy in the regulation of spatial information transfer.

neuroscience↗

bioRxiv2019

Conjunctive changes in two distinct ion channels induce activity-dependent intrinsic plasticity in rat dentate gyrus granule cells

The dentate gyrus (DG) was the first brain region to provide insights about synaptic and intrinsic plasticity. However, the assessment of intrinsic plasticity in DG has been surprisingly limited. We employed whole-cell patch-clamp recordings to explore the impact of behaviorally relevant theta-modulated burst firing, in the absence of synaptic stimulation, on intrinsic properties of rat DG granule cells. We found that theta burst firing induced a significant reduction in sub-threshold excitability and temporal summation, accompanied by an unexpectedly contrasting enhancement of action potential firing rate. We show that conjunctive changes in HCN, inward-rectifier potassium and persistent sodium channels mediated this form of plasticity, which was dependent on calcium influx through L-type calcium channels and inositol trisphosphate receptors. Our results unveil the expression of conjunctive plasticity in multiple channels, responding to the same activity pattern, establishing a plasticity manifold that could concomitantly mediate encoding and homeostasis in DG engram cells.

neuroscience↗

bioRxiv2019

Ion-channel regulation of response decorrelation in a multi-scale model of the dentate gyrus

The dentate gyrus (DG) is uniquely endowed with multiple forms of biological heterogeneities owing to the expression of adult neurogenesis and sparse connectivity, and has been functionally implicated in response decorrelation and pattern separation. Although channel decorrelation could be achieved through synergistic interactions between these heterogeneities, the impact of individual ion channels on channel decorrelation has not been explored. Here, to systematically assess the cascading impact of molecular-scale (ion channel) perturbations on network-scale outcomes (decorrelation), we first quantified the impact of eliminating individual ion channels on single-cell physiology of heterogeneous populations of granule cells (GCs) and basket cells (BCs). Employing virtual knockout simulations involving both populations, we found that the mapping between ion channels and nine distinct physiological measurements was many-to-many. Next, to assess the impact of ion channel elimination on channel decorrelation, we employed a conductance-based multi-scale network model of the DG. This network was endowed with four distinct forms of heterogeneities (intrinsic, synaptic, structural and afferent), with afferent inputs from the entorhinal cortices driven by virtual arena traversal. We show that individual ion channels expressed in GCs govern DG network excitability, and critically regulate the ability of the network to perform channel decorrelation. The impact of eliminating individual ion channels on network excitability and channel decorrelation was differential and variable, with local heterogeneities playing a pivotal role in determining the strength of such impact. Specifically, in the presence of structurally immature neurons in the DG network, the impact of ion channel elimination on channel decorrelation was considerably lower when compared with a network exclusively constructed with structurally mature neurons. Finally, we show that for any given ion channel knockout, the average percentage change in output correlation was invariant to the specific values of input correlation, across different network configurations endowed with disparate structural and afferent heterogeneities. Our analyses emphasizes that the mapping between components and function is many-to-many across scales, and assign critical roles for biological heterogeneities in conferring multi-scale functional robustness in the face of physiological and pathological perturbations.\n\nSIGNIFICANCE STATEMENTThere are precise sets of computation spanning different scales of analyses that drive behavioral states and responses of an animal. Perturbations to components that drive these computations at one scale could result in a cascading effect that alters physiological properties across several scales. Multi-scale computational models that account for biological heterogeneities at each scale are ideal tools to approach this complex problem, where systematic analyses of such cascades could be rigorously accomplished. Here, we systematically assessed the impact of eliminating individual ion channels, first on neuronal intrinsic properties, and consequently on network excitability and response decorrelation. Our results unveil important roles for biological heterogeneities in conferring multi-scale functional robustness in the face of physiological and pathological perturbations, achieved through many-to-many mappings between constitutive components and physiological outcomes.

neuroscience↗

bioRxiv2019

Heterogeneities in intrinsic excitability and frequency-dependent response properties of granule cells across the blades of the rat dentate gyrus

The dentate gyrus (DG), the input gate to the hippocampus proper, is anatomically segregated into three different sectors, namely the suprapyramidal blade, the crest region and the infrapyramidal blade. Although there are well-established differences between these sectors in terms of neuronal morphology, connectivity patterns and activity levels, differences in electrophysiological properties of granule cells within these sectors have remained unexplored. Here, employing somatic whole-cell patch-clamp recordings from the rat DG, we demonstrate that granule cells in these sectors manifest considerable heterogeneities in their intrinsic excitability, temporal summation, action potential characteristics and frequency-dependent response properties. Across sectors, these neurons showed positive temporal summation of their responses to inputs mimicking excitatory postsynaptic currents, and showed little to no sag in their voltage responses to pulse currents. Consistently, the impedance amplitude profile manifested low-pass characteristics and the impedance phase profile lacked positive phase values at all measured frequencies, voltages and for all sectors. Granule cells in all sectors exhibited class I excitability, with broadly linear firing rate profiles, and granule cells in the crest region fired significantly less action potentials compared to those in the infrapyramidal blade. Finally, we found weak pairwise correlations across the 18 different measurements obtained individually from each of the three sectors, providing evidence that these measurements are indeed reporting distinct aspects of neuronal physiology. Together, our analyses show that granule cells act as integrators of afferent information, and emphasize the need to account for the considerable physiological heterogeneities in assessing their roles in information encoding and processing.

neuroscience↗

bioRxiv2019

Robust emergence of sharply tuned place cell responses in hippocampal neurons with structural and biophysical heterogeneities

Hippocampal pyramidal neurons sustain propagation of fast electrical signals and are electrotonically non-compact structures exhibiting cell-to-cell variability in their complex dendritic arborization. In this study, we demonstrate that sharp place-field tuning and several somato-dendritic functional maps concomitantly emerge despite the presence of geometrical heterogeneities in these neurons. We establish this employing an unbiased stochastic search strategy involving thousands of models that spanned several morphologies and distinct profiles of dispersed synaptic localization and channel expression. Mechanistically, employing virtual knockout models, we explored the impact of bidirectional modulation in dendritic spike prevalence on place-field tuning sharpness. Consistent with prior literature, we found that across all morphologies, virtual knockout of either dendritic fast sodium channels or N-methyl-D-aspartate receptors led to a reduction in dendritic spike prevalence, whereas A-type potassium channel knockouts resulted in a nonspecific increase in dendritic spike prevalence. However, place-field tuning sharpness was critically impaired in all three sets of virtual knockout models, demonstrating that sharpness in feature tuning is maintained by an intricate balance between mechanisms that promote and those that prevent dendritic spike initiation. From the functional standpoint of the emergence of sharp feature tuning and intrinsic functional maps, within this framework, geometric variability was compensated by a combination of synaptic democracy, the ability of randomly dispersed synapses to yield sharp tuning through dendritic spike initiation, and ion-channel degeneracy. Our results suggest electrotonically non-compact neurons to be endowed with several degrees of freedom, encompassing channel expression, synaptic localization and morphological micro-structure, in achieving sharp feature encoding and excitability homeostasis.

neuroscience↗

bioRxiv2019

Efficient phase coding in hippocampal place cells

Hippocampal place cells encode space through phase precession, whereby neuronal spike phase progressively advances during place-field traversals. What neural constraints are essential for achieving efficient transfer of information through such phase codes, while concomitantly maintaining signature neuronal excitability specific to individual cell types? We developed a conductance-based model for phase precession in CA1 pyramidal neurons within the temporal sequence compression framework, and defined phase-coding efficiency using information theory. We recruited an unbiased stochastic search strategy to build a model population that exhibited physiologically observed heterogeneities in intrinsic properties. Place-field responses elicited from these models matched signature sub- and supra-threshold place-cell characteristics, including phase precession, sub-threshold voltage ramps, increases in theta-frequency power and firing rate during place-field traversals. Employing this model population, we show that disparate parametric combinations with weak pair-wise correlations resulted in models with similar high-efficiency phase codes and similar excitability characteristics. Mechanistically, the emergence of such parametric degeneracy was dependent on the differential and variable impact of individual ion channels on phase-coding efficiency in different models, and importantly, on synergistic interactions between synaptic and intrinsic properties. Furthermore, our analyses predicted a dominant role for calcium-activated potassium channels in regulating phase precession and coding efficiency. Finally, change in afferent statistics, manifesting as input asymmetry, induced an adaptive shift in the phase code that preserved its efficiency, apart from introducing asymmetry in sub-threshold ramps and firing profiles during place-field traversals. Our study postulates degeneracy as a potential framework to attain the twin goals of efficient temporal coding and robust homeostasis.\n\nSIGNIFICANCE STATEMENTNeuronal intrinsic properties exhibit significant baseline heterogeneities, and change with activity-dependent plasticity and neuromodulation. How do hippocampal neurons encode spatial locations through the precise timings of their action potentials in the face of such heterogeneities? Here, employing a unifying synthesis of the temporal sequence compression, efficient coding and degeneracy frameworks, we show that there are several disparate routes for neurons to achieve high-efficiency spatial information transfer through such temporal codes. These disparate routes were consequent to the ability of neurons to produce precise encoding through distinct structural components, critically involving synergistic interactions between intrinsic and synaptic properties. Our results point to an explosion in the degrees of freedom available to a neuron in concomitantly achieving efficient coding and excitability homeostasis.

neuroscience↗

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↗