Biology subjects

Sarkisyan, D.

Publications and source records attributed to Sarkisyan, D..

6 recordsLinked to original sources

bioRxiv2026

A Symmetric Systemic Challenge Elicits a Right-Biased Response Mediated by Vasopressin Signaling

Bilaterian animals exhibit operational (functional) asymmetry--population-level, directional left-right differences in physiology and behavior, including responses to spatially symmetric environmental challenges. Whether such symmetry-to-asymmetry conversion can be driven at the systems level by neurohormonal regulators remains unclear. Here we tested whether a spatially symmetric neuroendocrine challenge--water deprivation (WD)--can elicit a directional left-right physiological response in rats using hindlimb postural asymmetry (HL-PA), a binary readout that quantifies left- versus right-sided hindlimb flexion. Twenty-four hours of WD induced robust HL-PA with right hindlimb flexion, revealed under anesthesia. The asymmetry persisted after complete thoracic spinal cord transection, suggesting that humoral signaling, rather than descending neural commands, may maintain the postural bias. Because dehydration recruits the hypothalamic-neurohypophysial arginine vasopressin (AVP) system, we next tested AVP receptor involvement. Both a V1B antagonist (SSR-149415) and a V1A/V2 antagonist (conivaptan) abolished WD-induced HL-PA, supporting an AVP-dependent mechanism that likely operates at least two anatomical sites. AVP signaling may involve pituitary V1B-dependent endocrine output and spinal V1A actions; consistent with the latter, expression of AVP V1A receptors is right-biased in lumbar spinal cord. Together, these findings identify WD as a symmetric systemic challenge capable of imposing a directional peripheral set-point, and implicate vasopressin signaling in symmetry breaking and left-right physiological regulation. Visual summary O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=133 SRC="FIGDIR/small/708998v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@10d6b3corg.highwire.dtl.DTLVardef@1fb4b5aorg.highwire.dtl.DTLVardef@11003c0org.highwire.dtl.DTLVardef@66671c_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2026

Hypothalamic asymmetry in hemisphere-specific neuroendocrine signaling

Brain lesions classically cause contralateral sensorimotor and postural deficits, attributed to the decussation of descending neural pathways. However, recent findings reveal that, beyond neural mechanisms, contralateral effects can also be mediated by the neuroendocrine system via humoral pathways. This raises the possibility that the brain regulates left- and right-sided peripheral processes through hypothalamic neurohormones released into the bloodstream. For such spatially targeted endocrine signaling to occur, hemisphere-specific neural activity must be encoded into side-specific hormonal output--requiring a lateralized organization of hypothalamic neuroendocrine systems. Here, we report molecular asymmetries in the rat hypothalamus that support this mechanism. Transcriptomic analysis revealed asymmetric expression of eleven neurohormonal genes, including Gnrh1, Cck, and Trh, along with distinct left-right side-specific gene co-expression networks. Chemogenetic stimulation of Arg-vasopressin neurons in vasopressin-hM3Dq-mCherry transgenic rats produced generalized changes in these networks--predominantly in the right hypothalamus--suggesting that hypothalamic neurohormonal circuits function as integrated, lateralized ensembles. Stereological analysis revealed asymmetric coordination of vasopressin neurons within the paraventricular nucleus, with the left rostral region decoupled from the right rostral and caudal subregions. Functionally, gonadotropin-releasing hormone, cholecystokinin-8, and thyrotropin-releasing hormone--administered intracisternally in rats with complete spinal cord transection--elicited side-specific peripheral responses, measured as hindlimb postural asymmetry in a binary left-right output model. These neurohormonal effects were therefore transmitted via the humoral route. These findings suggest that multiple hypothalamic neurohormones and their integrated networks are asymmetrically organized, and that their lateralization may be necessary for hemisphere-specific hormonal regulation of peripheral systems.

neuroscience↗

bioRxiv2023

Bipartite left-right sided endocrine system: processing of contralateral effects of brain injury

The crossed descending neural tracts set a basis for contralateral effects of brain injury. In addition, the left-right side-specific effects of the unilateral brain lesions may be mediated by neurohormones through the humoral pathway as discovered in animals with disabled descending motor tracts. We here examined if counterparts of the endocrine system that convey signals from the left and right brain injuries differ in neural and molecular mechanisms. In rats with completely transected cervical spinal cords a unilateral injury of the hindlimb sensorimotor cortex produced hindlimb postural asymmetry with contralateral hindlimb flexion, a proxy for neurological deficit. The effects of the left and right side brain lesions were differently inhibited by antagonists of the {delta}-, {kappa}- and {micro}-opioid receptors suggesting differential neuroendocrine control of the left-right side-specific hormonal signaling. Bilateral deafferentation of the lumbar spinal cord eliminated hormone-mediated effects of the left-side brain injury but not the right-side lesion suggesting their afferent and efferent mechanisms, respectively. Analysis of gene-gene co-expression patterns identified the left and right side-specific gene regulatory networks that were coordinated across the hypothalamus and lumbar spinal cord through the humoral pathway. The coordination was ipsilateral and perturbed by brain injury. These findings suggest that the neuroendocrine system that conveys left-right side-specific hormonal messages from injured brain is bipartite, contributes to contralateral neurological deficits through asymmetric neural mechanisms, and enables ipsilateral coordination of molecular processes across neural areas along the neuraxis. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=173 HEIGHT=200 SRC="FIGDIR/small/546857v2_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@1d0ad6org.highwire.dtl.DTLVardef@b273f8org.highwire.dtl.DTLVardef@1dbac79org.highwire.dtl.DTLVardef@118599c_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2022

Humoral signaling-mediated effects of unilateral brain injury: differences in the left-right sided afferent responses

Disruption of neural tracts descending from the brain to the spinal cord after brain trauma and stroke causes postural and sensorimotor deficits. We previously showed that unilateral lesion to the sensorimotor cortex in rats with completely transected thoracic spinal cord produced asymmetry in hindlimb posture and withdrawal reflexes. Supraspinal signals to hindlimb muscles may be transmitted through the paravertebral chain of sympathetic ganglia that remain intact after the transection. We here demonstrated that prior transection of the spinal cord at the cervical level that was rostrally to segments with preganglionic sympathetic neurons, did not abolish formation of asymmetry in hindlimb posture and musculo-articular resistance to stretch after unilateral brain injury. Thus not the sympathetic system but humoral signals may mediate the effects of brain injury on the lumbar spinal circuits. The asymmetric responses in rats with transected spinal cords were eliminated by bilateral lumbar dorsal rhizotomy after the left-side brain injury, but resistant to deafferentation after the right-side brain lesion. Two mechanisms, one dependent on and one independent of afferent input may account for asymmetric hindlimb motor responses. Resistance to deafferentation may be due to sustained stretch- and effort-unrelated muscle contractions that is often observed in patients with central lesions. Left-right asymmetry is unusual feature of these mechanisms that both are activated by humoral signals. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=120 SRC="FIGDIR/small/488460v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@14770e6org.highwire.dtl.DTLVardef@1452343org.highwire.dtl.DTLVardef@e1aedorg.highwire.dtl.DTLVardef@9c8ea_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2020

Endocrine signaling mediates asymmetric motor deficits after unilateral brain injury

A paradigm in neurology is that brain injury-induced motor deficits (e.g. hemiparesis and hemiplegia) arise due to aberrant activity of descending neural pathways. We discovered that a unilateral injury of the hindlimb sensorimotor cortex of rats with completely transected thoracic spinal cord produces hindlimb postural asymmetry with contralateral flexion, and asymmetric changes in nociceptive hindlimb withdrawal reflexes and gene expression patterns in lumbar spinal cord. The injury-induced postural effects were abolished by prior hypophysectomy and were mimicked by transfusion of serum from animals with unilateral brain injury. Antagonists of the opioid and vasopressin receptors blocked formation of hindlimb postural asymmetry suggesting that these neurohormones mediate effects of brain injury on lateralized motor responses. Our data indicate that descending neural control of spinal circuits is complemented by a previously unknown humoral signaling from injured brain to the contra- and ipsilesional hindlimbs, and suggest the existence of a body side-specific neuroendocrine regulation in bilaterally symmetric animals.

neuroscience↗

bioRxiv2018

Epigenome-wide meta-analysis of blood DNA methylation and its association with subcortical volumes: findings from the ENIGMA Epigenetics Working Group

DNA methylation, which is modulated by both genetic factors and environmental exposures, may offer a unique opportunity to discover novel biomarkers of disease-related brain phenotypes, even when measured in other tissues than brain, such as blood. A few studies of small sample sizes have revealed associations between blood DNA methylation and neuropsychopathology, however, large-scale epigenome-wide association studies (EWAS) are needed to investigate the utility of DNA methylation profiling as a peripheral marker for the brain. Here, in an analysis of eleven international cohorts, totalling 3,337 individuals, we report epigenome-wide meta-analyses of blood DNA methylation with volumes of the hippocampus, thalamus and nucleus accumbens (NAcc) -three subcortical regions selected for their associations with disease and heritability and volumetric variability. Analyses of individual CpGs revealed genome-wide significant associations with hippocampal volume at two loci. No significant associations were found for analyses of thalamus and nucleus accumbens volumes. CpG sites associated with hippocampus volume were significantly enriched within cancer-related genes and within regulatory elements containing the transcriptionally repressive histone H3K27 tri-methylation mark that is vital for stem cell fate specification. Cluster-based analyses revealed additional differentially methylated regions (DMRs) associated with hippocampal volume. DNA methylation at these loci affected expression of proximal genes involved in in learning and memory, stem cell maintenance and differentiation, fatty acid metabolism and type-2 diabetes. These DNA methylation marks, their interaction with genetic variants and their impact on gene expression offer new insights into the relationship between epigenetic variation and brain structure and may provide the basis for biomarker discovery in neurodegeneration and neuropsychiatric conditions.

genomics↗