Biology subjects

Grinevich, V.

Publications and source records attributed to Grinevich, V..

At least 19 recordsLinked to original sources

bioRxiv2026

Chemogenetic activation of hypothalamic oxytocin neurons reorients face exploration toward the eyes in macaques

Oxytocin (OT) shapes social behavior across species. However, in humans and non-human primates, its effects have been studied mainly through exogenous administration, despite uncertainty about the extent to which peripherally administered OT reaches the brain and limited control over the neural pathways it engages. To overcome these limitations, we developed a chemogenetic approach targeting the endogenous OT system by selectively activating OT neurons in the paraventricular nucleus (PVN) and supraoptic nucleus (SON) of macaques using excitatory DREADDs. We combined this approach with digit-tracking, a non-invasive, calibration-free assay of face exploration in freely moving animals. In this task, subjects explored blurred face images through a finger-controlled viewing window, providing a proxy for gaze exploration and enabling behavioral assessment of OT neuron activation. DREADD-mediated activation redirected ongoing face exploration toward the eyes at the expense of non-face regions, increasing the consistency of eye-directed exploration and the time spent inspecting the eyes once reached. Immunohistochemical analysis confirmed selective DREADD expression in OT neurons of the PVN and SON. These findings provide the first causal evidence in primates that hypothalamic OT neurons regulate social visual orienting by increasing exploration of the eyes, thereby linking a hallmark effect of intranasal OT administration to defined central OT pathways and establishing chemogenetic access to this system in freely behaving macaques.

neuroscience↗

bioRxiv2026

Autism-risk gene mutations convergently disrupt sexually dimorphic oxytocin circuits to lower social engagement

Autism arises from diverse genetic risk factors, yet how they converge to produce core symptoms and contribute to its sex bias remains unestablished. Oxytocin increases sociability in multiple murine autism models, presenting an opportunity to identify a potentially shared mechanistic basis across etiologies. Here we show that spontaneous social investigation triggers overlapping patterns of aberrant functional connectivity across social and sensory brain regions in two knockout (KO) mouse models, which are rescued by oxytocin. We also report that, during social investigation, wildtype mice exhibit sexually dimorphic oxytocin release and neuronal activity dynamics in the nucleus accumbens and the amygdala. These patterns are disrupted in both KO models, but can be restored by sex- and circuit-specific stimulation of endogenous oxytocin release, accompanied by enhanced social engagement. These findings identify impaired oxytocin recruitment of sexually dimorphic social circuits as a convergent consequence of autism-risk gene mutations that may underlie low sociability.

animal behavior and cognition↗

bioRxiv2025

Sex-specific regulation of social play in juvenile rats by oxytocin neurons in the hypothalamus and oxytocin signaling in the nucleus accumbens

Social play is a rewarding behavior shown across juvenile mammalian species and is important for the development of social competency throughout the lifespan. The neuropeptide oxytocin (OXT) regulates various social behaviors and is being used in clinical trials to improve social competency. However, the role of OXT in juvenile social play is largely unknown. To address this gap, we determined the involvement of hypothalamic OXT-producing neurons in the supraoptic nucleus (SON) and paraventricular nucleus (PVN), PVNOXT projections to the nucleus accumbens (NAc), and OXT signaling within the NAc, in the regulation of social play in juvenile male and female rats. We found that neither chemogenetic stimulation of SONOXT cell bodies nor PVNOXT projections to the NAc altered the expression of juvenile social play but instead increased social investigation. However, chemogenetic stimulation of PVNOXT cell bodies as well as intra-NAc infusion of OXT decreased social play in males without an effect in females. Lastly, social play duration correlated negatively with the proportion of activated NAcOXTR neurons, an effect driven by males. Together, these findings suggest that distinct OXT neuronal populations modulate different forms of social behavior and that PVNOXT neurons and NAc-OXT signaling sex-specifically modulate social play behavior.

neuroscience↗

bioRxiv2025

Social Touch Suppresses Aggression via Thalamic Mechanisms

Understanding the neural circuitry underlying aggression is critical for both scientific insight and clinical intervention. Here, we identify the posterior intralaminar thalamic nucleus (PIL) as a key node in an anti-aggressive circuit activated by social touch. Using a rodent model, we demonstrate that deprivation of direct physical contact during social isolation leads to heightened aggression. Chemogenetic and optogenetic manipulations reveal that PIL neurons activated by social touch inhibit aggression via excitatory projections to the medial preoptic area (MPOA) of the hypothalamus. This PIL-to-MPOA pathway is suppressed by input from the ventromedial hypothalamic nucleus (VMH). Our findings establish a novel thalamic-hypothalamic circuit that mediates social touch-induced suppression of aggression, offering potential targets for therapeutic intervention in conditions marked by pathological aggression.

neuroscience↗

bioRxiv2025

FOXP1 differentially regulates the development of murine vasopressin and oxytocin magnocellular neurons

The neuropeptides arginine vasopressin (AVP) and oxytocin (OXT) are closely related. As neurohormones, AVP and OXT are mainly produced in magnocellular neurons (MCNs) located in the hypothalamus. Development of both neuron types requires coordinated expression of transcription factors OTP, SIM1, ARNT2 and POU3F2. However, the exact transcription factors involved in the diferential diferentiation of the AVP and OXT lineages are yet unknown. We used a publicly available single-cell RNA-sequencing dataset of the developing mouse hypothalamus to identify gene regulatory networks linked to AVP and OXT neuronal diferentiation. We identified RORA, EBF3, FOXP1, FOXP2, and BCL11B as transcription factors with possible relevance for Avp and Oxt MCN divergence. We then modeled developmental gene expression dynamics using computational cell fate mapping. This revealed enrichment of EBF3 and BCL11B in the Avp lineage, while FOXP1 and FOXP2 are enriched in the Oxt lineage. Next, in silico analysis of Avp and Oxt promoters found predicted binding sites for FOXP1 and FOXP2 in the Oxt promoter, suggesting a role in Oxt MCN diferentiation. Finally, we validated the role of one candidate (FOXP1) with a heterozygous knockout mouse line. Compared to wild-type littermates, we find decreased AVP and OXT neuron abundance, with OXT neurons disproportionally afected.

neuroscience↗

bioRxiv2024

Oxytocin neurons in the paraventricular and supraoptic hypothalamic nuclei bidirectionally modulate food intake

Oxytocin (OT) is a neuropeptide produced in the paraventricular (PVH) and supraoptic (SON) nuclei of the hypothalamus. Either peripheral or central administration of OT suppresses food intake through reductions in meal size. However, pharmacological approaches do not differentiate whether observed effects are mediated by OT neurons located in the PVH or in the SON. To address this, we targeted OT neuron-specific designer receptors exclusively activated by designer drugs (DREADDs) in either the PVH or SON in rats, thus allowing for evaluation of food intake following selective activation of OT neurons separately in each nucleus. Results revealed that DREADDs-mediated excitation of PVH OT neurons reduced consumption of both standard chow and a high fat high sugar diet (HFHS) via reductions in meal size. On the contrary, SON OT neuron activation had the opposite effect by increasing both standard chow and liquid sucrose consumption, with the former effect mediated by an increase in meal size. To further examine the physiological role of OT neurons in eating behavior, a viral-mediated approach was used to silence synaptic transmission of OT neurons separately in either the PVH or SON. Results from these studies revealed that PVH OT neuron silencing significantly increased consumption of HFHS by increasing meal size whereas SON OT neuron silencing reduced chow consumption by decreasing meal size. Collectively these data reveal that PVH and SON OT neurons differentially modulate food intake by either increasing or decreasing satiation signaling, respectively.

neuroscience↗

bioRxiv2024

Oxytocin Gαi signaling-induced amygdala astrocytes processes retraction shapes behavioral stress response

Anticipated reactions to stressful situations are vital for the survival and well-being of organisms, and abnormal reactions are involved in stress-related disorders. The neuropeptide oxytocin is a key modulator ensuring well-adapted stress responses. Oxytocin acts on both neurons and astrocytes, but the molecular and cellular mechanisms mediating stress response remain poorly understood. Here, we focus on the amygdala, a crucial hub that integrates and processes sensory information through oxytocin- dependent mechanisms. Using an acute stress paradigm in mice, genetic and pharmacological manipulations combined with proteomic, morphological, electrophysiological and behavioral approaches, we reveal that oxytocinergic modulation of the freezing response to stress is mediated by transient Gi-dependent retraction of astrocytic processes, followed by enhanced neuronal sensitivity to extracellular potassium in the amygdala. Our findings elucidate a pivotal role for astrocytes morphology- dependent modulation of brain circuits that is required for proper anticipated behavioral response to stressful situations.

neuroscience↗

bioRxiv2024

Like sisters but not twins - vasopressin and oxytocin excite BNST neurons via cell type-specific expression of oxytocin receptor to reduce anxious arousal

Interoceptive signals dynamically interact with the environment to shape appropriate defensive behaviors. Hypothalamic hormones arginine-vasopressin (AVP) and oxytocin (OT) regulate physiological states, including water and electrolyte balance, circadian rhythmicity, and defensive behaviors. Both AVP and OT neurons project to dorsolateral bed nucleus of stria terminalis (BNSTDL), which expresses oxytocin receptors (OTR) and vasopressin receptors and mediates fear responses. However, understanding the integrated role of neurohypophysial hormones is complicated by the cross-reactivity of AVP and OT and their mutual receptor promiscuity. Here, we provide evidence that the effects of neurohypophysial hormones on BNST excitability are driven by input specificity and cell type-specific receptor selectivity. We show that OTR-expressing BNSTDL neurons, excited by hypothalamic OT and AVP inputs via OTR, play a major role in regulating BNSTDL excitability, overcoming threat avoidance, and reducing threat-elicited anxious arousal. Therefore, OTR-BNSTDL neurons are perfectly suited to drive the dynamic interactions balancing external threat risk and physiological needs. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=143 SRC="FIGDIR/small/611656v2_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@2c800forg.highwire.dtl.DTLVardef@18b5cfaorg.highwire.dtl.DTLVardef@85324aorg.highwire.dtl.DTLVardef@a8bb6b_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIExogenous and light-evoked vasopressin (AVP) peptide excites neurons of the bed nucleus of the stria terminalis (BNST) via oxytocin receptor (OTR) in male rats C_LIO_LIAVP excites OTR- and Corticotropin-releasing factor (CRF)-expressing neurons, most of which are classified as Type III neurons of the BNST C_LIO_LIOTR-expressing BNST neurons increase exploration of open spaces and reduce anxious arousal in fear-potentiated startle in male rats C_LIO_LIThe dorsolateral BNST receives vasopressinergic inputs from suprachiasmatic, supraoptic, and paraventricular nuclei of the hypothalamus C_LIO_LIInternal signal-sensitive hypothalamic inputs directly impact BNST excitability via OTR to balance interoceptive signals and defensive behaviors C_LI

neuroscience↗

bioRxiv2024

Oxytocin facilitates social behavior of female rats via selective modulation of interneurons in the medial prefrontal cortex

The hypothalamic neuropeptide oxytocin is best known for its prosocial behavioral effects. However, the precise anatomical and cellular targets for oxytocin in the cortex during social behavior remain elusive. Here we show that oxytocin neurons project directly to the medial prefrontal cortex where evoked axonal oxytocin release facilitates social behaviors in adult female rats. In conjunction, we report that local oxytocin receptor-expressing (OTR+) cells are predominantly interneurons, whose activation promotes social interaction. Notably, this prosocial effect persists even under physiological challenge (hunger), pointing to a dedicated prosocial circuit capable of overriding primary survival drives. We further demonstrate that activation of these OTR+ interneurons inhibits principal cells specifically projecting to the basolateral amygdala, thus providing a putative mechanism of selective oxytocin action in this sociability-promoting cortical network.

neuroscience↗

bioRxiv2023

Impaired oxytocin signaling in the central amygdala in rats with chronic heart failure

AimsHeart failure (HF) patients often suffer from cognitive decline, depression, and mood impairments, but the molecular signals and brain circuits underlying these effects remain elusive. The hypothalamic neuropeptide oxytocin (OT) is critically involved in the regulation of mood, and OTergic signaling in the central amygdala (CeA) is a key mechanism controlling emotional responses including anxiety-like behaviors. Based on this, we used in this study a well-established ischemic rat HF model and aimed to study alterations in the hypothalamus-to-CeA OTergic circuit. Methods and ResultsTo study potential HF-induced changes in the hypothalamus-to-CeA OTertic circuit, we combined patch-clamp electrophysiology, immunohistochemical analysis, RNAScope assessment of OTR mRNA, brain region-specific stereotaxic injections of viral vectors and retrograde tracing, optogenetic stimulation and OT biosensors in the ischemic HF model. We found that most of OTergic innervation of the central amygdala (CeA) originated from the hypothalamic supraoptic nucleus (SON). While no differences in the numbers of SONCeA OTertic neurons (or their OT content) was observed between sham and HF rats, we did observe a blunted content and release of OT from axonal terminals within the CeA. Moreover, we report downregulation of neuronal and astrocytic OT receptors, and impaired OTR-driven GABAergic synaptic activity within the CeA microcircuit of rats with HF. ConclusionsOur study provides first evidence that HF rats display various perturbations in the hypothalamus-to-amygdala OTergic circuit, and lays the foundation for future translational studies targeting either the OT system or GABAergic amygdala GABA microcircuit to ameliorate depression or mood impairments in rats or patients with chronic HF.

neuroscience↗

bioRxiv2023

Excitatory neurons in stratum radiatum provide an alternative pathway for excitation flow that escapes perisomatic inhibition

For over half a century, it has been postulated that the internal excitatory circuit in the hippocampus consists of three relay stations. Excitation arrives from the entorhinal cortex to the DG granule cells, is transmitted through the mossy fibers to CA3 pyramidal cells, and is then transmitted through Schaffer collaterals to CA1 pyramidal neurons. In all three structures (DG, CA3 and CA1), the activity of the excitatory neurons involved in the synaptic transmission of excitation are under the control of inhibitory basket neurons that are recruited into network activity via feed-forward and feed-back excitation. However, in the late 90s "stratum radiatum giant cells" were described as a novel type of neuron with the anatomical features of excitatory cells. Since then, the role of these cells in the hippocampal circuitry has not been well understood. Here, using optogenetic and electrophysiological techniques we characterized the functional location of these neurons within the hippocampal network. We show that: (i) the main excitatory drive to giant excitatory neurons in stratum radiatum (ExNR) comes via Schaffer collaterals; (ii) within the CA1 field, ExNR are not directly connected with local pyramidal cells, but provide massive and efficient excitatory input to parvalbumin positive (PV+) interneurons; (iii) ExNR are reciprocally innervated by bistratified cells, but not inhibited by backet interneurons; (iv) the efficiency of ExNR excitation to PV+ interneurons is sufficient for a single ExNR action potential to trigger massive inhibition of downstream CA1 pyramidal cells. Taken together, our data shows that ExNR constitute an alternative pathway of excitation for CA1 interneurons that avoids the burden of perisomatic inhibition.

neuroscience↗

bioRxiv2022

Analysis of the hypothalamic oxytocin system and oxytocin receptor-expressing astrocytes in a mouse model of Prader-Willi syndrome

Prader-Willi syndrome (PWS) is a neurodevelopmental disorder characterized by hyperphagia, obesity, developmental delay and intellectual disability. Studies suggest dysfunctional signaling of the neuropeptide oxytocin as one of the key mechanisms in PWS, and administration of oxytocin via intranasal or systemic routes yielded promising results in both humans and mouse models. However, a detailed assessment of the oxytocin system in mouse models of PWS such as the Magel2-deficient Magel2tm1.Stw mouse, is lacking. In this study, we performed an automated counting of oxytocin cells in the entire paraventricular nucleus of the hypothalamus of Magel2tm1.Stw and wild-type control mice and found a significant reduction in the caudal part, which represents the parvocellular subdivision. In addition, based on the recent discovery that some astrocytes express the oxytocin receptor (OTR), we performed detailed analysis of astrocyte numbers and morphology in various brain regions, and assessed expression levels of the astrocyte marker GFAP, which was significantly decreased in the hypothalamus, but not other brain regions in Magel2tm1.Stw mice. Finally, we analyzed the number of OTR-expressing astrocytes in various brain regions and found a significant reduction in the nucleus accumbens of Magel2tm1.Stw mice, as well as a sex-specific difference in the lateral septum. This study suggests a role for caudal PVN OT neurons as well as OTR-expressing astrocytes in a mouse model of PWS, provides novel information about sex-specific expression of astrocytic OTRs, and presents several new brain regions containing OTR-expressing astrocytes in the mouse brain.

neuroscience↗

bioRxiv2022

Coupling of oxytocin and cholecystokinin pathways in the hypothalamus is required for gut-to-brain homeostatic feeding control

Oxytocin-expressing paraventricular hypothalamic neurons (PVNOT neurons) integrate afferent signals from the gut including cholecystokinin (CCK) to adjust whole-body energy homeostasis. However, the molecular underpinnings by which PVNOT neurons orchestrate gut-to-brain feeding control remain unclear. Here, we show that mice undergoing selective ablation of PVNOT neurons fail to reduce food intake in response to CCK and develop hyperphagic obesity on chow diet. Notably, exposing wildtype mice to a high-fat/high-sugar (HFHS) diet recapitulates this insensitivity towards CCK, which is linked to diet-induced transcriptional and electrophysiological aberrations specifically in PVNOT neurons. Restoring OT pathways in DIO mice via chemogenetics or polypharmacology sufficiently re-establishes CCKs anorexigenic effects. Lastly, by single-cell profiling, we identify a specialized PVNOT neuronal subpopulation with increased {kappa}-opioid signaling under HFHS diet, which restrains their CCK-evoked activation. In sum, we here document a novel (patho)mechanism by which PVNOT signaling uncouples a gut-brain satiation pathway under obesogenic conditions.

neuroscience↗

bioRxiv2022

Oxytocin activity in the Paraventricular and Supramammillary Nuclei of the Hypothalamus is Essential for Social Recognition Memory in Rats

Oxytocin plays an important role in modulating social recognition memory. However, the direct implication of oxytocin neurons of the paraventricular nucleus of the hypothalamus (PVH) and their downstream hypothalamic targets in regulating short- and long-term forms of social recognition memory has not been fully investigated. In this study, we employed a chemogenetic approach to target the activity of PVH oxytocin neurons in male rats and found that specific silencing of this neuronal population led to an impairment in short- and long-term social recognition memory. We combined viral mediated fluorescent labeling of oxytocin neurons with immunohistochemical techniques and identified the supramammillary nucleus (SuM) of the hypothalamus as a target of PVH oxytocinergic axonal projections in rats. We used multiplex fluorescence in-situ hybridization to label oxytocin receptors in the SuM and determined that they are predominantly expressed in glutamatergic neurons, including those that project to the CA2 region of the hippocampus. Finally, we used a highly selective oxytocin receptor antagonist in the SuM to examine the involvement of oxytocin signaling in modulating short- and long-term social recognition memory and found that it is necessary for the formation of both. This study discovered a previously undescribed role for the SuM in regulating social recognition memory via oxytocin signaling and reinforced the specific role of PVH oxytocin neurons in regulating this form of memory.

neuroscience↗

bioRxiv2022

Altered PVN-to-CA2 hippocampal oxytocin pathway and reduced number of oxytocin-receptor expressing astrocytes in heart failure rats

Oxytocinergic actions within the hippocampal CA2 are important for neuromodulation, memory processing and social recognition. However, the source of the OTergic innervation, the cellular targets expressing the OT receptors (OTRs) and whether the PVN-to-CA2 OTergic system is altered during heart failure (HF), a condition recently associated with cognitive and mood decline, remains unknown. Using immunohistochemistry along with retrograde monosynaptic tracing, RNAscope and a novel OTR-Cre rat line, we show that the PVN (but not the supraoptic nucleus) is an important source of OTergic innervation to the CA2. These OTergic fibers were found in many instances in close apposition to OTR expressing cells within the CA2. Interestingly, while only a small proportion of neurons were found to express OTRs ([~]15%), this expression was much more abundant in CA2 astrocytes ([~]40%), an even higher proportion that was recently reported for astrocytes in the central amygdala. Using an established ischemic rat heart failure (HF) model, we found that HF resulted in robust changes in the PVN-to-CA2 OTergic system, both at the source and target levels. Within the PVN, we found an increased OT immunoreactivity, along with a diminished OTR expression in PVN neurons. Within the CA2 of HF rats, we observed a blunted OTergic innervation, along with a diminished OTR expression, which appeared to be restricted to CA2 astrocytes. Taken together, our studies highlight astrocytes as key cellular targets mediating OTergic PVN inputs to the CA2 hippocampal region. Moreover, provides the first evidence for an altered PVN-to-CA2 OTergic system in HF rats, which could potentially contribute to previously reported cognitive and mood impairments in this animal model.

neuroscience↗

bioRxiv2022

A novel analgesic pathway from parvocellular oxytocin neurons to the periaqueductal gray

The hypothalamic neuropeptide, oxytocin (OT), exerts prominent analgesic effects via central and peripheral action. Here we discovered a novel subset of OT neurons whose projections preferentially terminate on OT receptor (OTR)-expressing neurons in the ventrolateral periaqueductal gray (vlPAG). Using a newly generated line of transgenic rats (OTR-IRES-Cre), we determined that most of the vlPAG OTR expressing cells being targeted by OT projections are GABAergic in nature. Both optogenetically-evoked axonal OT release in the vlPAG as well as chemogenetic activation of OTR vlPAG neurons results in a long-lasting overall increase of vlPAG neuronal activity. This then leads to an indirect suppression of sensory neuron activity in the spinal cord and strong analgesia. Finally, we describe a novel OT[->]vlPAG[->]spinal cord circuit that seems critical for analgesia in the context of both inflammatory and neuropathic pain. Highlights- We generated a new transgenic knock-in rat line (OTR-IRES-Cre) - A distinct parvOT neuronal population projects to vlPAG but not the SON or spinal cord - OT excites vlPAG OTR neurons which indirectly inhibit SC WDR neurons - This novel parvOT[->]vlPAG[->]SC pathway alleviates nociception but not the affective component of pain

neuroscience↗

bioRxiv2022

Compartmental Neuropeptide Release Measured Using a New Oxytocin Sensor

As a peptide hormone and neuromodulator, oxytocin (OT) plays a critical role in a variety of physiological and pathophysiological processes in both the central nervous system and the periphery. However, the processes that regulate spatial OT release in the brain remain enigmatic. Here, we developed a genetically encoded GPCR activation-based (GRAB) OT sensor called GRABOT1.0. Using this sensor, we directly visualized stimulation-induced OT release from specific compartments of OT neurons in acute brain slices, and discovered that N-type calcium channels predominantly mediate axonal OT release, while L-type calcium channels mediate somatodendritic OT release. In addition, we found that components in the fusion machinery of OT release differ between axon terminals versus somata and dendrites. Finally, we demonstrated the sensor responses to the activation of OT neurons in various brain regions in vivo and revealed region specific OT release during male courtship behavior. Taken together, these results provide key insights regarding the role of compartmental OT release in the control of physiological and behavioral functions.

neuroscience↗

bioRxiv2022

A thalamo-preoptic pathway promoting social touch

Social touch is an important form of communication, it is still unknown how it is processed. Here, we discovered a functional role for a neuronal pathway projecting from the posterior intralaminar thalamic nucleus (PIL) to the medial preoptic area (MPOA) in controlling social contact. Neurons in the PIL and the MPOA were activated by physical contact between female rodents and also by chemogenetic stimulation of PIL neurons. Chemogenetic stimulation of PIL neurons tagged by social contact experience increased direct physical interactions between familiar female rats without affecting other forms of social behavior. Furthermore, selective stimulation of the PIL-MPOA pathway, and the local activation of PIL terminals within the MPOA, elevated direct social contact between the animals suggesting the role of pathway-specific activated cell assemblies. Neurons projecting from the PIL to the MPOA contain the neuropeptide parathyroid hormone 2 (PTH2). The expression of the peptide was induced by social housing, the presence of PTH2 receptor was identified in MPOA neurons, and local injection of PTH2 increased the firing rate of identified preoptic area GABAergic neurons via the PTH2 receptor suggesting that PTH2 acts as a neurotransmitter in the PIL-MPOA pathway. We also found a homologous PIL to MPOA neuronal pathway in the human brain. Altogether, we discovered a direct thalamo-preoptic pathway, which bypasses the cerebral cortex and controls social touch. This pathway originates in neurons expressing PTH2, a neuropeptide recently shown in fish to respond to the social environment. These observations provide evidence for common evolutionary-conserved PTH2-containing social-touch specific engram circuits.

neuroscience↗