Biology subjects

Nagarajan, R.

Publications and source records attributed to Nagarajan, R..

12 recordsLinked to original sources

bioRxiv2026

Astrocytes in the Dentate Gyrus Shift the Equilibrium from Pattern Separation to Pattern Completion and Inhibit Fear Extinction

Pattern separation and pattern completion are core hippocampal computations linked to memory interference and overgeneralization in many neuropsychiatric disorders and to mnemonic discrimination deficits in neurodegenerative conditions. Astrocytes are increasingly recognized as important integrators and modulators of neuronal activity as many studies have shown changes in animal behavior and neural circuits induced by manipulation of astrocytic activity. The role of astrocytes in the dentate gyrus for learning and memory is, however, largely unknown. To investigate the functional significance of astrocytic activity in the dentate gyrus, we expressed the calcium extruding pump hPMCA2w/b (CalEx), resulting in inhibition of astrocytic calcium activity, the Gq-coupled receptor hM3Dq, or the Gi-coupled receptor hM4Di, allowing chronic activation of Gq- and Gi-dependent pathways by a designer drug, in dentate gyrus astrocytes. Our main finding is that inhibition of astrocytic calcium activity by CalEx resulted in improved pattern separation and impaired pattern completion. In -vivo calcium imaging revealed that CalEx expression in astrocytes altered the neuronal activity pattern in dentate gyrus neurons with an overall inhibitory effect. This suggests that in the dentate gyrus astrocytes promote the activity of these neurons. Furthermore, chronic activation of hM4Di resulted in impaired between-session fear extinction while chronic activation of hM3Dq resulted in impaired within-session fear extinction and improved pattern separation learning over multiple days, suggesting that activation of astrocytic activity enhances mechanistically separable forms of fear extinction in a Gq- or Gi-pathway-specific manner. Our findings reveal that dentate gyrus astrocytic calcium shifts the balance between pattern separation and pattern completion towards pattern completion and thus modulates an essential neuronal functional output of the dentate gyrus. Chronic activation of astrocytes inhibits fear extinction, and thus also affects management of memory interference. Our findings imply that astrocytic modulation may be beneficial to treat cognitive deficits in disorders in which overgeneralization is a problem.

neuroscience↗

bioRxiv2026

A Small-Molecule Mitochondrial Complex I Modulator Improves Behavioral and Mitochondrial Dysfunction in Schizophrenia

Weak inhibition of mitochondrial complex I (mtCI) has been shown to have neuroprotective effects in cellular and animal models of Alzheimers and Huntingtons diseases, at least in part by enhancing mitochondrial biogenesis and function. Mitochondrial dysfunction has also been demonstrated in schizophrenia patients and mouse models of schizophrenia. We tested whether weak inhibition of mtCI would ameliorate mitochondrial and behavioral phenotypes in a mouse model of schizophrenia. In mice with four copies of the Gldc gene, 8 weeks of treatment with the weak mtCI inhibitor, the small-molecule tricyclic pyrone compound CP2, reversed spontaneous alternation deficits in the Y maze, startle habituation deficits, and social novelty deficits in the three-chamber social interaction test. Consistent with the mechanism of action, Western blots revealed that CP2 reverses the reduced expression of PGC-1, a master regulator of mitochondrial biogenesis, and of the VDAC1, a primary gatekeeper for the exchange of metabolites, ions, and ATP between mitochondria and the cytosol. These findings suggest that the improvement of mitochondrial function may represent a novel strategy to reverse pathophysiological and behavioral deficits in schizophrenia.

neuroscience↗

bioRxiv2025

Ventral Hippocampal Temporoammonic and Schaffer Collateral Pathways Differentially Control Fear- and Anxiety-Related Behaviors

The ventral hippocampus plays a crucial role in regulating anxiety- and fear-related behaviors. Previously, we demonstrated that diazepam reduces anxiety-like behavior by inhibiting the dentate gyrus and CA3 principal neurons via 2-GABAARs, while inhibition of CA1 pyramidal neurons is necessary to suppress fear-related responses. This study investigated the role of inputs from ventral CA3 (vCA3) and entorhinal cortex to ventral CA1 (vCA1) in anxiety- and fear-like behavior using bidirectional optogenetic modulations. Adult C57BL/6J male and female mice were subjected to bilateral stereotaxic injection of a viral vector expressing channelrhodopsin or halorhodopsin into vCA3 or into layers II-III of lateral entorhinal cortex, followed by bilateral implantation of fiberoptic ferrules into vCA1. After four weeks of recovery, mice were assessed for anxiety-like behavior in the novel open field, elevated plus maze, and Vogel conflict tests, and by contextual and trace fear conditioning for fear. The behavior of the mice was recorded under laser ON and OFF conditions in all experiments. The activation of vCA3 to vCA1 projections (i.e., Schaffer collateral pathway) increased anxiety- and fear-related behaviors, whereas inhibition reduced such behaviors. In contrast, optogenetic activation or inhibition of EC to vCA1 projections (i.e., temporoammonic pathway) had no effect on anxiety-related behavior but positively or negatively modulated fear-related behavior, respectively. These results suggest that while fear-related behavior is modulated by both inputs to vCA1, modulation of anxiety-related behavior is input-specific for the vCA3 to vCA1 projection. In summary, this study offers mechanistic insights into the complex organization of hippocampal circuitry underlying fear and anxiety. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=183 SRC="FIGDIR/small/690696v1_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@1a3a0d7org.highwire.dtl.DTLVardef@194b96forg.highwire.dtl.DTLVardef@11a62b7org.highwire.dtl.DTLVardef@1471977_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2024

Enhancing tumor-infiltrating T cells with an exclusive fuel source

Solid tumors harbor immunosuppressive microenvironments that inhibit tumor-infiltrating lymphocytes (TILs) through the voracious consumption of glucose. We sought to restore TIL function by providing them with an exclusive fuel source. The glucose disaccharide cellobiose, which is the building block of cellulose, contains a {beta}-1,4-glycosidic bond that that animals (or their tumors) cannot hydrolyze, but microbes have evolved enzymes to catabolize cellobiose into useful glucose. We equipped mouse T cells and human CAR-T cells with two proteins enabling import and hydrolysis of cellobiose and demonstrated that cellobiose supplementation during glucose withdrawal restores key anti-tumor T-cell functions: viability, proliferation, cytokine production, and cytotoxic killing. Engineered T cells offered cellobiose suppress murine tumor growth and prolong survival. Offering exclusive access to a natural disaccharide is a new tool that augments cancer immunotherapies. This approach could be used to answer questions about glucose metabolism across many cell types, biological processes, and diseases.

immunology↗

bioRxiv2023

Assessing the Dose-Dependent Effects of tDCS on Neurometabolites using Magnetic Resonance Spectroscopy

Concurrent transcranial direct current stimulation (tDCS) and proton Magnetic Resonance Spectroscopy (1H MRS) experiments have shown up- or downregulation of neurotransmitter concentration. However, effects have been modest applying mostly lower current doses and not all studies found significant effects. Dose of stimulation might be an important variable in eliciting a consistent response. To investigate dose effects of tDCS on neurometabolites, we placed an electrode over the left supraorbital region (with a return electrode over the right mastoid bone) and utilized an MRS voxel (3x3x3cm) that was centered over the anterior cingulate/inferior mesial prefrontal region which is in the path of the current distribution. We conducted 5 epochs of acquisition, each one with a 9:18min acquisition time, and applied tDCS in the third epoch. We observed significant dose and polarity dependent modulation of GABA and to a lesser degree of Glutamine/Glutamate (GLX) with the highest and reliable changes seen with the highest current dose, 5mA (current density 0.39 mA/cm2), during and after the stimulation epoch compared with pre-stimulation baselines. The strong effect on GABA concentration (achieving a mean change of 63% from baseline, more than twice as much as reported with lower doses of stimulation) establishes tDCS-dose as an important parameter in eliciting a regional brain engagement and response. Furthermore, our experimental design in examining tDCS parameters and effects using shorter epochs of acquisitions might constitute a framework to explore the tDCS parameter space further and establish measures of regional engagement by non-invasive brain-stimulation.

neuroscience↗

bioRxiv2023

A marker chromosome in psychosis identifies glycine decarboxylase (GLDC) as a novel regulator of neuronal and synaptic function in the hippocampus

The biological significance of a small supernumerary marker chromosome that results in dosage alterations to chromosome 9p24.1, including triplication of the GLDC gene encoding glycine decarboxylase, in two patients with psychosis is unclear. In an allelic series of copy number variant mouse models, we identify that triplication of Gldc reduces extracellular glycine levels as determined by optical fluorescence resonance energy transfer (FRET) in dentate gyrus (DG) but not in CA1, suppresses long-term potentiation (LTP) in mPP-DG synapses but not in CA3-CA1 synapses, reduces the activity of biochemical pathways implicated in schizophrenia and mitochondrial bioenergetics, and displays deficits in prepulse inhibition, startle habituation, latent inhibition, working memory, sociability and social preference. Our results thus provide a link between a genomic copy number variation, biochemical, cellular and behavioral phenotypes, and further demonstrate that GLDC negatively regulates long-term synaptic plasticity at specific hippocampal synapses, possibly contributing to the development of neuropsychiatric disorders.

neuroscience↗

bioRxiv2022

Genetic ablation of dentate hilar somatostatin-positive GABAergic interneurons is sufficient to induce cognitive impairment

Aging is often associated with a decline in cognitive function. A reduction in the number of somatostatin-positive (SOM+) interneurons in the dentate gyrus (DG) has been described in cognitively impaired but not in unimpaired aged rodents. However, it remains unclear whether the reduction in SOM+ interneurons in the DG hilus is causal for age-related cognitive dysfunction. We hypothesized that hilar SOM+ interneurons play an essential role in maintaining cognitive function and that a reduction in the number of hilar SOM+ interneurons might be sufficient to induce cognitive dysfunction. Hilar SOM+ interneurons were ablated by expressing a diphtheria toxin transgene specifically in these interneurons, which resulted in a reduction in the number of SOM+/GAD-67+ neurons and dendritic spine density in the DG. C-fos and Iba-1 immunostainings were increased in DG and CA3 but not in CA1. Behavioral testing revealed a reduced recognition index in the novel object recognition test, a reduction in the percentage of correct alternations in the Y maze tests, and increased latencies and path lengths in the learning and the reversal learning phase of the Morris water maze. Our results show that partial genetic ablation of SOM+ hilar interneurons is sufficient to increase activity in DG and CA3, as has been described to occur with aging and to induce an impairment of learning and memory functions. Thus, partial ablation of hilar SOM+ interneurons may be a significant contributing factor to age-related cognitive dysfunction. These mice may also be useful as a cellularly defined model of hippocampal aging.

neuroscience↗

bioRxiv2022

Chronic intermittent propofol attenuates surgery-induced neuroinflammation, apoptosis, and cognitive impairment in aged mice

Surgery may lead to long-lasting cognitive deficits that are referred to as perioperative neurocognitive disorder (NCD), particularly in elderly patients. Currently, no interventions are routinely employed in clinical practice to prevent perioperative NCD. Here we show that perioperative chronic intermittent administration of propofol to aged mice undergoing laparotomy under isoflurane anesthesia effectively blocks the surgery-induced increase in nitrosative stress, increased expression of proapoptotic proteins, microglial activation, and cognitive deficits. By contrast, in the absence of surgery and anesthesia, propofol had little effect on biochemical parameters and led to cognitive improvement only in a subset of behavioral paradigms. The actions of propofol were largely absent in mice lacking the GABAA receptor 5-subunit, indicating that they are mediated by 5-containing GABAA receptors. These results demonstrate that propofol - via 5-containing GABAA receptors that are redistributed to the cell surface membranes in a sustained manner - can attenuate surgery-induced neuroinflammation and postsurgical cognitive deficits.

neuroscience↗

bioRxiv2022

Dissecting the cellular basis of age-related cognitive dysfunction: Chronic chemogenetic inhibition of somatostatin-positive interneurons in the dentate gyrus hilus induces memory impairments

The cellular basis of age-related impairments of hippocampal function is not fully understood. In order to evaluate the role of somatostatin-positive (Sst+) interneurons in the dentate gyrus hilus in this process, we chemogenetically inhibited Sst+ interneurons in the dentate gyrus (DG) hilus. Chronic chemogenetic inhibition (CCI) of these neurons resulted in increased c-Fos staining in the DG hilus, a decrease in the percentage of Gad67- and of Sst-expressing interneurons in the DG, and increased microglial activation in DG, CA3, and CA1. Total dendritic length and spine density were reduced in DG and CA1, suggesting reduced dendritic complexity. Behaviorally, the recognition index in an object recognition task and the percentage of spontaneous alternations in the Y maze were decreased, while in both initial and reversal learning in the Morris water maze the latencies to find the hidden platform were increased, suggesting cognitive dysfunction. Our findings establish a causal role for a reduced function of Sst+ interneurons in the DG hilus for cognitive decline and suggest that this reduced function may contribute to age-related impairments of learning and memory. Furthermore, our CCI mice may represent a cellularly defined model of hippocampal aging. SIGNIFICANCE STATEMENTNeuronal circuits and cellular processes underlying age-related cognitive dysfunction are not well understood. We observed that chronic chemogenetic inhibition of a defined cell type, somatostatin-positive interneurons in the dentate gyrus hilus, which have previously been found to be associated with cognitive dysfunction in aged rodents, is necessary and sufficient to elicit changes in expression of interneuronal markers, an increase in the activity of dentate gyrus granule cells, increased microglial activation across the entire hippocampus and an impairment of learning and memory-related tasks. Thus, inhibition of somatostatin-positive interneurons in the dentate gyrus hilus replicates changes that are also seen with normal aging, representing a novel cellularly defined animal model of hippocampal aging.

neuroscience↗

bioRxiv2022

Control of contextual memory through interneuronal α5-GABAA receptors

{gamma}-aminobutyric acid type A receptors that incorporate 5 subunits (5-GABAARs) are highly enriched in the hippocampus and are strongly implicated in control of learning and memory. Receptors located on pyramidal neuron dendrites have long been considered responsible, but here we report that their selective knockout from either interneurons (5-i-KO) or pyramidal neurons (5-pyr-KO) interferes with the ability of the general anesthetic etomidate to suppress contextual conditioning. Using Ca2+ imaging of CA1 pyramidal neuron activity in freely exploring mice to assess hippocampal function directly, we found that etomidate blocked the development of place cells and spatial engrams in wild type (WT) and 5-pyr-KO mice, but not in 5-i-KO mice. In addition, 5-i-KO mice developed weaker spatial engrams than WT mice under control conditions. These findings show that interneuronal 5-GABAARs serve a physiological role in promoting spatial learning, and that they mediate the suppression of hippocampus-dependent memory by etomidate.

neuroscience↗

bioRxiv2021

Mapping QTLs for phenotypic and morpho-physiological traits related to grain yield under late sown conditions in wheat (Triticum aestivum L.)

The elevating temperature makes heat stress one of the major issues for wheat production globally. To elucidate genetic basis and map heat tolerance traits, a set of 166 doubled haploid lines (DHLs) derived from the cross between PBW3438/IC252874 was used. The population was evaluated under Normal sown (NS) and late sown (LS) conditions, by exposing to heat stress during rabi season. The canopy temperature (CT) showed positive correlations with grain yield, whereas Soil plant analysis development (SPAD) was not significantly correlated and associated with GY in both the normal and late sown conditions. Composite interval mapping (CIM) identified total 12 Quantitative trait loci (QTLs) viz., 2 (Normal sown), 10 (late sown) mapped on linkage groups 1A, 1D, 2B, 2D, 3B, 4D, 5B and 6D, during both the crop seasons 2017-18 and 2018-19. Combining the results of these QTLs revealed a major stable QTL for grain yield (GY) on chromosome 3B with 11.84% to 21.24% explaining phenotypic variance under both sowing conditions. QTL for CT and SPAD was detected on chromosome 1A while QTL for GY on chromosome 3B and 5B. The identified QTLs in the genomic regions could be targeted for genetic improvement and marker assisted selection for heat tolerance in wheat. The tools like SPAD and CT could be exploited to screen the large number of breeding lines.

plant biology↗

bioRxiv2021

Development of the Wheat Practical Haplotype Graph Database as a Resource for Genotyping Data Storage and Genotype Imputation

To improve the efficiency of high-density genotype data storage and imputation in bread wheat (Triticum aestivum L.), we applied the Practical Haplotype Graph (PHG) tool. The wheat PHG database was built using whole-exome capture sequencing data from a diverse set of 65 wheat accessions. Population haplotypes were inferred for the reference genome intervals defined by the boundaries of the high-quality gene models. Missing genotypes in the inference panels, composed of wheat cultivars or recombinant inbred lines genotyped by exome capture, genotyping-by-sequencing (GBS), or whole-genome skim-seq sequencing approaches, were imputed using the wheat PHG database. Though imputation accuracy varied depending on the method of sequencing and coverage depth, we found 93% imputation accuracy with 0.01x sequence coverage, which was only slightly lower than the accuracy obtained using the 0.5x sequence coverage (96.9%). Compared to Beagle, on average, PHG imputation was ~4% (p-value = 0.00027) more accurate, and showed 27% higher accuracy at imputing a rare haplotype introgressed from a wild relative into wheat. The reduced accuracy of imputation with GBS data (90.4%) is likely associated with the small overlap between GBS markers and the exome capture dataset, which was used for constructing PHG. The highest imputation accuracy was obtained with exome capture for the wheat D genome, which also showed the highest levels of linkage disequlibrium and proportion of identity-by-descent regions among accessions in our reference panel. We demonstrate that genetic mapping based on genotypes imputed using PHG identifies SNPs with a broader range of effect sizes that together explain a higher proportion of genetic variance for heading date and meiotic crossover rate compared to previous studies.

genomics↗