Biology subjects

Murugan, M.

Publications and source records attributed to Murugan, M..

16 recordsLinked to original sources

bioRxiv2026

Projection populations form a dorsoventral gradient of reward representations in the lateral septum

Several decades ago, the septal region was identified as the most dependable location of intracranial self-stimulation (ICSS) in the brain, but the neural substrates that mediate septal self-stimulation are still unknown. One part of the septal region, the lateral septum (LS), contributes to a number of motivated behaviors and may promote reward-seeking. However, the LS contains different anatomical subregions, complicating the characterization of its reward representations. We examine the responses of LS neurons along its dorsoventral axis using cellular resolution calcium imaging during an operant assay. We find that a greater proportion of neurons are excited in response to sucrose reward in the dorsal LS, while a greater proportion are inhibited in response to sucrose reward in the ventral LS. Additionally, we identify two distinct LS projection populations, one to the nucleus accumbens (NAc) and another to the bed nucleus of the stria terminalis (BNST), which are located in the dorsal and ventral regions of the LS, respectively. These two projection populations also have opposing reward responses and their corresponding optogenetic manipulation supports ICSS. These findings demonstrate how LS projection populations contribute to its functional heterogeneity, especially as it pertains to reward-seeking behavior.

neuroscience↗

bioRxiv2025

The Intermediate CA1 and CA3 Subfields of the Hippocampus Differentially Encode Social Recognition

Social recognition requires linking information about others to the spatial contexts in which they are encountered, a computation thought to engage the hippocampus. Although this process depends on coordinated activity across the hippocampal network, how specific subfields differentially contribute to social recognition remains unclear. Of particular interest are the intermediate CA1 (iCA1) and CA3 (iCA3) subfields, which have both been shown to be causally involved in social recognition. Historically, the dense feed-forward projections from CA3 to CA1 led to the view that these subfields form a hierarchical circuit, with CA1 primarily integrating and refining computations from CA3. However, recent causal manipulations of the iCA1 and iCA3 have revealed distinct and separable contributions to approach and avoidance behavior, suggesting functional specialization across the subfields. This functional divergence raises the possibility that iCA1 and iCA3 might differentially encode social recognition information. To test this possibility, we performed one-photon calcium imaging in freely behaving mice to record endogenous activity from the iCA1 and iCA3 during a novel behavioral paradigm that disentangles social identity from spatial position. Notably, we found that iCA3 neurons more robustly discriminated between novel and familiar conspecifics, while iCA1 neurons more strongly encoded spatial position. These results identify the iCA3 as a key locus for social novelty encoding and suggest a functional division of labor within the hippocampus, in which stable spatial frameworks in the iCA1 anchor flexible, context-dependent social representations in the iCA3 that support adaptive social memory.

neuroscience↗

bioRxiv2025

Comparative gene editing reduces dopamine receptor levels across rodent species

Translational challenges in neuroscience originate from species-specific differences that limit the generalizability of experimental findings. Comparative approaches can help distinguish conserved from species-specific mechanisms, but their application has been limited by the lack of molecular tools beyond traditional model organisms, complicating direct comparisons of conserved and divergent mechanisms of neural function. This gap is particularly evident for the dopaminergic system, a key regulator of motivated behaviors across species and the principal pharmacological target for current psychotherapies. Building on our recent development of comparative gene editing, we here present an adeno-associated virus-mediated CRISPR/Cas9 strategy to reduce in vivo dopamine receptors D1 and D2 levels across the rodent phylogeny. Using this approach, we achieved specific reduction of receptor levels in three rodent species (house mouse, prairie vole, and Syrian hamster), which we demonstrate with radioactive ligand binding assays. This toolkit expands the reach of comparative gene editing approaches, enabling functional investigation of the dopaminergic system across rodent species. Thereby, it supports comparative neuroscience by facilitating the identification of conserved versus species-specific neural mechanisms with enhanced translational potential.

neuroscience↗

bioRxiv2025

Non-overlapping social and food reward representations in the basolateral amygdala

The ability to consider and appraise positively valenced stimuli in the environment, such as food and social interaction, to guide appropriate action is important for survival of most animals. Several studies have compared how food and social rewards are represented in different regions involved in reward processing and found either overlapping or distinct representations. In the basolateral amygdala (BLA) there seems to be opposing evidence for both shared and unique encoding of social and nonsocial stimuli. In our recent work, we found that the medial prefrontal cortex (mPFC), a region reciprocally connected to the BLA, has distinct social and food representations using a novel self-paced two-choice assay. Given the BLA and mPFCs differing roles in reward processing, it is important to understand how these two nodes may differ in their encoding reward types within the same assay. To resolve how the BLA encodes social and food information, we recorded the activity of individual BLA neurons in female and male mice during a two-choice social-sucrose operant task. We found that BLA neurons robustly and distinctly respond to social and food reward. In contrast to the mPFC, BLA neurons did not show a bias towards social reward responsiveness and instead showed equal social/sucrose representation, in males, or a sucrose reward bias, in females. BLA neurons were sensitive to internal state - water deprivation increased the proportion of sucrose reward responsive neurons. Additionally, sucrose reward responsive BLA neurons were differentially sensitive to reward omissions, such that neurons that were excited by sucrose reward were more sensitive to reward omissions compared to those inhibited by reward. Together, these findings demonstrate distinct, heterogeneous response profiles within the BLA to social and food rewards, in a manner different from the mPFC.

neuroscience↗

bioRxiv2025

Omicron Subvariants Infection Kinetics and Nirmatrelvir Efficacy in Transgenic K18-hACE2 Mice

The persistent evolution of SARS-CoV-2 has led to the emergence of antigenically distinct Omicron subvariants exhibiting increased transmissibility, immune evasion, and altered pathogenicity. Among these, recent subvariants like JN.1, KP.3.1.1, and LB.1 possess unique antigenic and virological features, underscoring the need for continued surveillance and therapeutic evaluation. As vaccines and commercial monoclonal antibodies show reduced effectiveness against these variants, the role of direct-acting antivirals, such as Nirmatrelvir, targeting conserved viral elements like the main protease inhibitor, becomes increasingly crucial. In this study, we investigated the replication kinetics, host immune responses, and therapeutic susceptibility of three recently circulating Omicron subvariants in the K18-hACE2 transgenic mouse model, using the SARS-CoV-2 parent WA1/2020 strain as a reference. Omicron subvariants exhibited a marked temporal shift in viral infection kinetics characterized by an early lung viral titer peak ([~]7-8 Log PFU) at 2 days post-infection (dpi), followed by a decline (1-3 Log PFU) by 4 dpi. Pulmonary cytokine and chemokine responses (GM-CSF, TNF-, IL-1{beta}, IL-6) showed an earlier increase in subvariant-infected mice compared to a gradual response in WA1/2020 infection. Notably, Nirmatrelvir treatment led to significant reduction in lung viral titers in subvariant-infected mice than in WA1/2020, surpassing its efficacy against the parent strain. These findings highlight that Omicron subvariants infection yields a broad dynamic range in viral burden with minimum variability, while retaining a prominent therapeutic response to Nirmatrelvir. This study provides insights to the emerging subvariants pathogenesis and therapeutic responsiveness, reinforcing the importance of continued variant monitoring and the development of effective countermeasures. ImportanceThe emergence of SARS-CoV-2 Omicron subvariants still poses a significant public health challenge due to their antigenic drift, altered pathogenesis, and immune evasion capabilities. This study comprehensively highlights the distinct replication kinetics, immune responses, and therapeutic susceptibility of the recently circulating Omicron subvariants JN.1, KP.3.1.1, and LB.1 using the K18-hACE2 mouse model. We demonstrate that while these subvariants exhibit altered virological profiles and immune activation patterns compared to the parent WA1/2020 strain, they remain susceptible to Nirmatrelvir which is a direct-acting main protease inhibitor. Notably, Nirmatrelvir demonstrated greater in vivo antiviral efficacy in Omicron subvariant infections than in the ancestral WA1/2020 strain. These findings underscore the enduring therapeutic value of protease-targeting antivirals and emphasize the critical need for ongoing variant-specific preclinical assessments.

microbiology↗

bioRxiv2025

Organization of brainwide inputs to discrete lateral septum projection populations

The lateral septum (LS) is anatomically positioned to play a critical role in directing information from the hippocampus and cortex to downstream subcortical structures, such as the hypothalamus. In fact, early anatomical tracing studies investigated the organization of hippocampal inputs to the LS and its hypothalamic outputs to begin to understand how its structure might relate to its function. These studies also characterized the cellular anatomy of the LS and the organization of different molecular markers within it. However, relatively little is known about the organization of other, non-hypothalamic projection populations within the LS and what types of input these different projection populations receive. Here, we used retrograde tracing to determine the organization of LS projections to six different brain regions that mediate various social behaviors. We found that these projection populations occupy discrete anatomical compartments within the LS. We then used a monosynaptic rabies tracing strategy to map brainwide inputs to these six discrete LS projection populations and examine how different brain regions innervate them. We identified unique region-dependent patterns of inputs to individual LS projection populations. In particular, we observed differences in cortical, hippocampal and thalamic innervation of the six different LS projection populations, while the hypothalamic inputs were largely similar across projection populations. Thus, this study provides insight into the anatomical connectivity that may underlie the functional heterogeneity of the LS.

neuroscience↗

bioRxiv2024

A ventral hippocampal-lateral septum pathway regulates social novelty preference.

The ability to distinguish strangers from familiar individuals is crucial for the survival of most mammalian species. In humans, an inability to recognize kin and familiar individuals and engage in appropriate behaviors is associated with several types of dementia, including Alzheimers disease. Mice preferentially spend more time investigating a novel individual relative to a familiar individual. Yet, how social novelty related information drives increased investigation of the novel animal remains poorly understood. Recent evidence has implicated the ventral hippocampus (vHPC) as a key node in encoding information about conspecific identity. Of particular interest are vHPC projections to the lateral septum (LS), a region that has been implicated in driving a wide range of motivated social behaviors. In this study using chemogenetics, optogenetics and monosynaptic rabies tracing, we identified a novel vHPC-LS-ventral tegmental area (VTA) pathway that is necessary for mice to preferentially investigate novel conspecifics. Using monosynaptic rabies tracing, we established that LS neurons make direct monosynaptic connections onto dopaminergic neurons in the VTA. Thus, we have identified a potential pathway via which conspecific identity could be transformed to drive motivated social behaviors.

neuroscience↗

bioRxiv2023

Overlapping representations of food and social stimuli in VTA dopamine neurons

Dopamine neurons of the ventral tegmental area (VTADA) respond to food and social stimuli and contribute to both forms of motivation. However, it is unclear if the same or different VTADA neurons encode these different stimuli. To address this question, we performed 2-photon calcium imaging in mice presented with food and conspecifics, and found statistically significant overlap in the populations responsive to both stimuli. Both hunger and opposite-sex social experience further increased the proportion of neurons that respond to both stimuli, implying that modifying motivation for one stimulus affects responses to both stimuli. In addition, single-nucleus RNA sequencing revealed significant co-expression of feeding- and social-hormone related genes in individual VTADA neurons. Taken together, our functional and transcriptional data suggest overlapping VTADA populations underlie food and social motivation.

neuroscience↗

bioRxiv2023

Sex differences in neural representations of social and nonsocial reward in the medial prefrontal cortex.

The reinforcing nature of social interactions is necessary for the maintenance of appropriate social behavior. However, the neural substrates underlying social reward processing and how they might differ based on the sex and internal state of the animal remains unknown. It is also unclear whether these neural substrates are shared with those involved in nonsocial rewarding processing. We developed a fully automated, novel two choice (social-sucrose) operant assay in which mice choose between social and nonsocial rewards to directly compare the reward-related behaviors associated with two competing stimuli. We performed cellular resolution calcium imaging of medial prefrontal cortex (mPFC) neurons in male and female mice across varying states of water restriction and social isolation. We found that mPFC neurons maintain largely non-overlapping, flexible representations of social and nonsocial reward that vary with internal state in a sex-dependent manner. Additionally, optogenetic manipulation of mPFC activity during the reward period of the assay disrupted reward-seeking behavior across male and female mice. Thus, using a novel operant assay, we have identified sex-dependent, non-overlapping neural representations of social and nonsocial reward in the mPFC that vary with internal state and that are essential for appropriate reward-seeking behavior.

neuroscience↗

bioRxiv2021

Genetic Sex Validation for Sample Tracking in Clinical Testing

BackgroundNext generation DNA sequencing (NGS) has been rapidly adopted by clinical testing laboratories for detection of germline and somatic genetic variants. The complexity of sample processing in a clinical DNA sequencing laboratory creates multiple opportunities for sample identification errors, demanding stringent quality control procedures. MethodsWe utilized DNA genotyping via a 96-SNP PCR panel applied at sample acquisition in comparison to the final sequence, for tracking of sample identity throughout the sequencing pipeline. The 96-SNP PCR panels inclusion of sex SNPs also provides a mechanism for a genotype-based comparison to recorded sex at sample collection for identification. This approach was implemented in the clinical genomic testing pathways, in the multi-center Electronic Medical Records and Genomics (eMERGE) Phase III program ResultsWe identified 110 inconsistencies from 25,015 (0.44%) clinical samples, when comparing the 96-SNP PCR panel data to the test requisition-provided sex. The 96-SNP PCR panel genetic sex predictions were confirmed using additional SNP sites in the sequencing data or high-density hybridization-based genotyping arrays. Results identified clerical errors, samples from transgender participants and stem cell or bone marrow transplant patients and undetermined sample mix-ups. ConclusionThe 96-SNP PCR panel provides a cost-effective, robust tool for tracking samples within DNA sequencing laboratories, while the ability to predict sex from genotyping data provides an additional quality control measure for all procedures, beginning with sample collections. While not sufficient to detect all sample mix-ups, the inclusion of genetic versus reported sex matching can give estimates of the rate of errors in sample collection systems.

genomics↗

bioRxiv2021

Neptune: An environment for the delivery of genomic medicine

PurposeGenomic medicine holds great promise for improving healthcare, but integrating searchable and actionable genetic data into electronic health records remains a challenge. Here, we describe Neptune, a system for managing the interaction between a clinical laboratory and an electronic health record system. MethodsWe developed Neptune and applied it to two clinical sequencing projects that required report customization, variant reanalysis and EHR integration. ResultsNeptune enabled the analysis of data for generation of and delivery to EHR systems of over 15,000 clinical genomic reports. These projects demanded customizable clinical reports that contained a variety of genetic data types including SNVs, CNVs, pharmacogenomics and polygenic risk scores. Two variant reanalysis activities were also supported, highlighting this important workflow. ConclusionsMethods are needed for delivering structured genetic data to EHRs. This need extends beyond developing data formats to providing infrastructure that manages the reporting process itself. Neptune was successfully applied on two high-throughput clinical sequencing projects to build and deliver clinical reports to EHR systems. The software is open and available at https://gitlab.com/bcm-hgsc/neptune.

bioinformatics↗

bioRxiv2021

Genomic Considerations for FHIR; eMERGE Implementation Lessons

Structured representation of clinical genetic results is necessary for advancing precision medicine. The Electronic Medical Records and Genomics (eMERGE) Networks Phase III program initially used a commercially developed XML message format for standardized and structured representation of genetic results for electronic health record (EHR) integration. In a desire to move towards a standard representation, the network created a new standardized format based upon Health Level Seven Fast Healthcare Interoperability Resources (HL7 FHIR), to represent clinical genomics results. These new standards improve the utility of HL7 FHIR as an international healthcare interoperability standard for management of genetic data from patients. This work advances the establishment of standards that are being designed for broad adoption in the current health information technology landscape.

genomics↗

bioRxiv2019

Spinal Microglia Contribute to Sustained Inflammatory Pain via Amplifying Neuronal Activity

Microglia are highly dynamic immune cells of the central nervous system (CNS). Microglial processes interact with neuronal elements constantly on the order of minutes. The functional significance of this acute microglia-neuron interaction and its potential role in the context of pain is still largely unknown. Here, we found that spinal microglia increased their process motility and electrophysiological reactivity within an hour after the insult in a mouse model of formalin-induced acute, sustained, inflammatory pain. Using an ablation strategy to specifically deplete resident microglia in the CNS, we demonstrate that microglia participate in formalin-induced acute sustained pain behaviors by amplifying neuronal activity in the spinal dorsal horn. Moreover, we identified that the P2Y12 receptor, which is specifically expressed in microglia in the CNS, was required for microglial function in formalin-induced pain. Taken together, our study provides a novel insight into the contribution of microglia and the P2Y12 receptor in acute, sustained, inflammatory pain that could be used for potential therapeutic strategies.

neuroscience↗

bioRxiv2019

Choice-selective sequences in cortical inputs to the NAc provide a potential substrate for credit assignment

How are actions linked with subsequent outcomes to guide choices? The nucleus accumbens, which is implicated in this process, receives glutamatergic inputs from the prelimbic cortex and midline regions of the thalamus. However, little is known about whether and how representations differ across these input pathways. By comparing these inputs during a reinforcement learning task in mice, we discovered that prelimbic cortical inputs preferentially represent actions and choices, whereas midline thalamic inputs preferentially represent cues. Choice-selective activity in the prelimbic cortical inputs is organized in sequences that persist beyond the outcome. Through computational modeling, we demonstrate that these sequences can support the neural implementation of reinforcement learning algorithms, both in a circuit model based on synaptic plasticity, and one based on neural dynamics. Finally, we test and confirm predictions of our circuit models by direct manipulation of nucleus accumbens input neurons. Thus, we integrate experiment and modeling to suggest neural solutions for credit assignment.

neuroscience↗

bioRxiv2019

ARBoR: An Identity and Security Solution for Clinical Reporting

MotivationClinical genome sequencing laboratories return reports containing clinical testing results, signed by an Board Certified clinical geneticist, to the ordering physician. This report is often a pdf, but can also be a physical paper copy or a structured data file. The reports are frequently modified and re-issued, due to changes in variant interpretation or clinical attributes. To precisely track report authenticity we developed ARBoR, an application for tracking the lineage of versioned clinical reports even when they are distributed as pdf or paper copies. ARBoR employs a modified blockchain approach and instead of relying on a computationally intensive consensus mechanism for determining authenticity, we allow supervised and digitally signed writes to an encrypted ledger, which is then exactly replicated to many clients.\n\nResultsARBoR was implemented for clinical reporting in the HGSC-CL Clinical Laboratory, initially as part of the NIHs Electronic Medical Record and Genomics (eMERGE) project. To date we have issued 15,205 versioned clinical reports tracked by ARBoR. This system has provided us with a simple and tamper-proof mechanism for tracking clinical reports with a complicated update history.

bioinformatics↗

bioRxiv2017

Combined social and spatial coding in a descending projection from the prefrontal cortex

Social interactions are crucial to the survival and well-being of all mammals, including humans. Although the prelimbic cortex (PL, part of medial prefrontal cortex) has been implicated in social behavior, it is not clear which neurons are relevant, nor how they contribute. We found that the PL contains anatomically and molecularly distinct subpopulations of neurons that target 3 downstream regions that have been implicated in social behavior: the nucleus accumbens (NAc), the amygdala, and the ventral tegmental area. Activation of NAc-projecting PL neurons (PL-NAc), but not the other subpopulations, decreased preference for a social target, suggesting an unique contribution of this population to social behavior. To determine what information PL-NAc neurons convey, we recorded selectively from them, and found that individual neurons were active during social investigation, but only in specific spatial locations. Spatially-specific inhibition of these neurons prevented the formation of a social-spatial association at the inhibited location. In contrast, spatially nonspecific inhibition did not affect social behavior. Thus, the unexpected combination of social and spatial information within the PL-NAc population appears to support socially motivated behavior by enabling the formation of social-spatial associations.

neuroscience↗