Biology subjects

Nair, J.

Publications and source records attributed to Nair, J..

9 recordsLinked to original sources

bioRxiv2026

A number simplex in the human medial temporal lobe

Humans handle numbers nimbly, suggesting a richer neural manifold structure than the prevalent mental number line model. In populations of medial temporal lobe (MTL) neurons in humans performing two simple tasks (dot counting and arithmetic), we find robust neural coding of numerosity that results in high dimensional, simplex-shaped manifolds. This shape affords more flexibility than a linear manifold due to its high shattering dimensionality and expressibility. Dot arrays and Arabic numerals evoked distinct simplicial population codes, yet they were linked by a linearly transferable latent structure within the same task. We find similar simplicial geometry of number representations in large language models (LLMs). Moreover, subjects internally computed arithmetic results were decodable during the calculation period, with decoding accuracy correlating with individual mathematical capacity. Finally, linear transformations of simplicial operand representations modeled the brains conversion of operands into decodable results, suggesting that the brains arithmetic procedures have some resemblance to the attention architecture of LLMs. Together, these findings establish a high dimensional representational foundation for numerical cognition in the brain.

neuroscience↗

bioRxiv2025

Biobanking of Biological Samples at Room Temperature

Biospecimens have become an integral part of life science research, pharma and drug development. There is increased demand for biospecimens from patients with assured quality of collection, processing, and storage. Establishing a biobank with high-quality biospecimens is an expensive aspect due to the requirement of costly freezers and liquid nitrogen facilities. Many studies have explored various storage reagents for biological samples. Still, the need of the hour is the one that can preserve biological samples at ambient room temperature and suitable for diagnosis and research. InstaPRESERVE is an eco/user-friendly solution with long-term sustainable alternative for freezer or liquid nitrogen systems for biobanking. Blood and saliva specimens were collected and stored in InstaPRESERVE at room temperature and conventional storage conditions. The genomics and proteomics analysis of the DNA, RNA, and protein extracted from the -80{degrees}C and InstaPRESERVE stored specimens and fresh specimens indicated that the specimens were well-conserved at room temperature compared to frozen specimens. Innovative technologies and approaches are being evaluated in biobanks for sample integrity, reducing collection, processing, and storage costs, increasing speed and throughput, and reducing energy expenditure. Preserving the biospecimens in InstaPRESERVE at room temperature eliminates expensive storage systems, cold-chain during transportation, and pre-processing requirements. The qualitative and quantitative results of DNA, RNA, and protein ensured stabilized storage for a longer period. The use of InstaPRESERVE as a specimen storage medium is emerging as an alternative in biobanking for specimen storage at room temperature. The existing and proposed biobanks may consider employing InstaPRESERVE as a reliable resource for biospecimens storage.

molecular biology↗

bioRxiv2024

Daily Acute Intermittent Hypoxia Elicits Age & Sex-Dependent Changes in Molecules Regulating Phrenic Motor Plasticity

Acute intermittent hypoxia (AIH) elicits a form of respiratory motor plasticity known as phrenic long-term facilitation (LTF). Repetitive daily AIH (dAIH) exposure enhances phrenic LTF, demonstrating a form of metaplasticity. Two additional factors impacting phrenic LTF are age and sex. For example, moderate AIH-induced phrenic LTF decreases with age in males, but increases in middle-aged females. However, little is known concerning cellular mechanisms of dAIH effects or age-dependent sexual dimorphism in phrenic LTF. Moderate AIH elicits distinct signaling cascades within phrenic motor neurons initiated by 5HT2 receptors (Q pathway) versus adenosine 2A or 5HT7 receptors (S pathway), respectively. The Q and S pathways interact via mutual crosstalk inhibition, a powerful regulator of phrenic LTF. To test the hypothesis that dAIH, age and sex effects on phrenic LTF are associated with differential expression of molecules known to regulate the Q and S pathways, we assessed mRNA of key regulatory molecules in ventral cervical homogenates from spinal segments containing the phrenic motor nucleus from young (3 month) and middle-aged (12 month) male and female Sprague-Dawley rats. Since CNS estrogen levels impact molecules regulating the Q and/or S pathways, mRNA was correlated with serum estradiol. Rats (n=8/group) were exposed to sham (21% O2) or dAIH (15, 1 min episodes of 10.5% inspired O2 per day) for 14 days, and sacrificed 24 hours post-dAIH. mRNA for molecules known to regulate phrenic LTF were assessed via RT PCR, including: brain derived neurotrophic factor (Bdnf); serotonin 2A (Htr2a); 2B (Htr2b); and (Htr7) receptors; adenosine 2a (Adora2a) receptors; exchange protein activated by cAMP (Epac1); p38 MAP kinase [Mapk14 () & Mapk11 ({beta})]; PKA catalytic subunit (Prkaa1); PKA regulatory subunit (Prkar1a); fractalkine (Cx3cl1); phosphodiesterase type 4 (Pde4b); NAPDH-gp91 (Cybb) and p47 (ncf1); and the PKC{delta} isoform (Prkcd). Significantly higher Pde4b, Adora2a, and Prkcd mRNA were found in young and middle-aged females versus age-matched males; Epac1 was elevated, but only in young females (p<0.001). Ncf1 was increased in middle-aged versus young adult rats of both sexes (p<0.01). Ncf1, Cx3cl1, Adora2a and Prkcd mRNA were reduced by dAIH in middle-aged females (p<0.01), but not other groups. Serum estradiol levels positively correlated with Epac1 (r2=0.29, p=0.002), Mapk14 (r2=0.31, p=0.001), Mapk11 (r2=0.20, p=0.014), and Prkar1a (r2=0.20 p=0.013) mRNA. With higher serum estradiol levels, dAIH decreased Mapk14 mRNA (slope difference p=0.001). Thus, age, sex and dAIH preconditioning influence molecules known to regulate the Q and S pathways to phrenic motor facilitation. These novel findings advance our understanding of phrenic LTF, and inform translational research concerning the therapeutic potential of dAIH to treat breathing deficits in individuals of different ages or sex.

neuroscience↗

bioRxiv2023

APOE4, Age & Sex Regulate Respiratory Plasticity Elicited By Acute Intermittent Hypercapnic-Hypoxia

RationaleAcute intermittent hypoxia (AIH) is a promising strategy to induce functional motor recovery following chronic spinal cord injuries and neurodegenerative diseases. Although significant results are obtained, human AIH trials report considerable inter-individual response variability. ObjectivesIdentify individual factors (e.g., genetics, age, and sex) that determine response magnitude of healthy adults to an optimized AIH protocol, acute intermittent hypercapnic-hypoxia (AIHH). MethodsAssociations of individual factors with the magnitude of AIHH (15, 1-min O2=9.5%, CO2=5% episodes) induced changes in diaphragm motor-evoked potential amplitude (MEP) and inspiratory mouth occlusion pressures (P0.1) were evaluated in 17 healthy individuals (age=27{+/-}5 years) compared to Sham. Single nucleotide polymorphisms (SNPs) in genes linked with mechanisms of AIH induced phrenic motor plasticity (BDNF, HTR2A, TPH2, MAOA, NTRK2) and neuronal plasticity (apolipoprotein E, APOE) were tested. Variations in AIHH induced plasticity with age and sex were also analyzed. Additional experiments in humanized (h)ApoE knock-in rats were performed to test causality. ResultsAIHH-induced changes in diaphragm MEP amplitudes were lower in individuals heterozygous for APOE4 (i.e., APOE3/4) allele versus other APOE genotypes (p=0.048). No significant differences were observed between any other SNPs investigated, notably BDNFval/met (all p>0.05). Males exhibited a greater diaphragm MEP enhancement versus females, regardless of age (p=0.004). Age was inversely related with change in P0.1 within the limited age range studied (p=0.007). In hApoE4 knock-in rats, AIHH-induced phrenic motor plasticity was significantly lower than hApoE3 controls (p<0.05). ConclusionsAPOE4 genotype, sex and age are important biological determinants of AIHH-induced respiratory motor plasticity in healthy adults. ADDITION TO KNOWLEDGE BASEAcute intermittent hypoxia (AIH) is a novel rehabilitation strategy to induce functional recovery of respiratory and non-respiratory motor systems in people with chronic spinal cord injury and/or neurodegenerative diseases. Since most AIH trials report considerable inter-individual variability in AIH outcomes, we investigated factors that potentially undermine the response to an optimized AIH protocol, acute intermittent hypercapnic-hypoxia (AIHH), in healthy humans. We demonstrate that genetics (particularly the lipid transporter, APOE), age and sex are important biological determinants of AIHH-induced respiratory motor plasticity.

neuroscience↗

bioRxiv2022

GluK2 Q/R editing regulates kainate receptor signalling and synaptic AMPA receptor expression and function.

Q/R editing of the kainate receptor (KAR) subunit GluK2 radically alters properties of recombinant KARs, but the effects in vivo remain largely unexplored. We compared GluK2 editing-deficient mice that express [~]95% unedited GluK2(Q) to wild-type counterparts that express [~]85% edited GluK2(R). At mossy fibre-CA3 (MF-CA3) synapses GluK2(Q) mice displayed enhanced postsynaptic KAR function and increased KAR-mediated presynaptic facilitation, demonstrating heightened ionotropic function. Conversely, there was reduced metabotropic KAR function, assessed by KAR-mediated afterhyperpolarization currents, in GluK2(Q) mice. GluK2(Q) mice had fewer GluA1- and GluA3-containing AMPA receptors (AMPARs) and reduced postsynaptic AMPAR currents at both MF-CA3 and CA1-Schaffer collateral synapses. Moreover, long-term potentiation of AMPAR-mediated transmission at CA1-Schaffer collateral synapses was reduced in GluK2(Q) mice. These findings suggest that GluK2 Q/R editing influences ionotropic/metabotropic balance of KAR signalling to regulate synaptic expression of AMPARs and plasticity.

neuroscience↗

bioRxiv2022

Robust and durable prophylactic protection conferred by RNA interference in preclinical models of SARS-CoV-2

RNA interference is a natural antiviral mechanism that could be harnessed to combat SARS-CoV-2 infection by targeting and destroying the viral genome. We screened lipophilic small-interfering RNA (siRNA) conjugates targeting highly conserved regions of the SARS-CoV-2 genome and identified leads targeting outside of the spike-encoding region capable of achieving [≥]3-log viral reduction. Serial passaging studies demonstrated that a two-siRNA combination prevented development of resistance compared to a single-siRNA approach. A two-siRNA combination delivered intranasally protected Syrian hamsters from weight loss and lung pathology by viral infection upon prophylactic administration but not following onset of infection. Together, the data support potential utility of RNAi as a prophylactic approach to limit SARS-CoV-2 infection that may help combat emergent variants, complement existing interventions, or protect populations where vaccines are less effective. Most importantly, this strategy has implications for developing medicines that may be valuable in protecting against future coronavirus pandemics.

pharmacology and toxicology↗

bioRxiv2022

Reconstruction and simulation of thalamoreticular microcircuitry

Thalamoreticular circuitry is known to play a key role in attention, cognition and the generation of sleep spindles, and is implicated in numerous brain disorders, but the cellular and synaptic mechanisms remain intractable. Therefore, we developed the first detailed computational model of mouse thalamus and thalamic reticular nucleus microcircuitry that captures morphological and biophysical properties of [~]14,000 neurons connected via [~]6M synapses, and recreates biological synaptic and gap junction connectivity. Simulations recapitulate multiple independent network-level experimental findings across different brain states, providing a novel unifying cellular and synaptic account of spontaneous and evoked activity in both wakefulness and sleep. Furthermore, we found that: 1.) inhibitory rebound produces frequency-selective enhancement of thalamic responses during wakefulness, in addition to its role in spindle generation; 2.) thalamic interactions generate the characteristic waxing and waning of spindle oscillations; and 3.) changes in thalamic excitability (e.g. due to neuromodulation) control spindle frequency and occurrence. The model is openly available and provides a new tool to interpret spindle oscillations and test hypotheses of thalamoreticular circuit function and dysfunction across different network states in health and disease.

neuroscience↗

bioRxiv2020

Sustained postsynaptic kainate receptor activation downregulates AMPA receptor surface expression and induces hippocampal LTD

Here we report that sustained activation of GluK2 subunit-containing kainate receptors leads to AMPA receptor endocytosis and a novel form of long-term depression (KAR-LTDAMPAR) in hippocampal neurons. The KAR-evoked loss of surface AMPA receptors requires KAR channel activity and is occluded by the blockade of PKC or PKA. Moreover, in acute hippocampal slices, kainate invoked LTD of AMPA EPSCs. These data, together with our previously reported KAR-LTPAMPAR, demonstrate that KARs bidirectionally regulate synaptic AMPARs and synaptic plasticity.

neuroscience↗

bioRxiv2018

Basal Forebrain Deep Brain Stimulation Impacts the Regulation of Extracellular Vesicle Related Proteins in the Rat Brain

Extracellular vesicle (EV) signaling has attracted considerable attention in recent years because EVs play a key role in long distance cellular communication functions. EV studies have begun to reveal aspects of physiological and physiopathological regulation in numerous applications, although many areas remain to date largely unexplored. Deep brain stimulation (DBS) has shown remarkable therapeutic benefits of patients with neuropsychiatric disorders, but despite of the long and successful history of use, the mechanisms of action on neural ensemble activity are not yet fully understood. Here we explore how DBS of the basal forebrain impacts EV signaling in the rat brain. We employed differential centrifugations to isolate the EVs prefrontal cortex (PFC), hippocampus and striatum. We then performed quantitative analysis of EV-associated proteins using an MS-based proteomics method. We identified a considerable number of EV-associated proteins are modulated by DBS in three brain regions, some of which have been previously linked with central nervous system disorders. Particularly, neurofilament proteins NFL and NFM were both significantly changed in EVs of PFC, hippocampus and striatum after DBS stimulation compared with controls. The SOD1 protein, associated previously with neurodegenerative diseases, was significantly increased only in PFC. Our study is the first, to our knowledge, to use EV protein analysis to examine DBS effects on brain physiological regulation. Our findings open an entirely new perspective on brain area specific DBS effects.

neuroscience↗