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Papers by Valery Grinevich

Research paper thumbnail of Elevated Oxytocin Receptor Blood Concentrations Predict Higher Risk for, More, and Earlier 24-Month Hospital Readmissions after In-Patient Detoxification in Males with Alcohol Use Disorder

International Journal of Molecular Sciences, Sep 1, 2022

Research paper thumbnail of An analgesic pathway from parvocellular oxytocin neurons to the periaqueductal gray in rats

Nature Communications, Feb 24, 2023

Research paper thumbnail of Oxytocinergic Feedback Circuitries: An Anatomical Basis for Neuromodulation of Social Behaviors

Frontiers in Neural Circuits, Jun 14, 2021

Research paper thumbnail of Oxytocin Signaling in the Lateral Septum Prevents Social Fear during Lactation

Current Biology, Apr 1, 2018

Research paper thumbnail of Evolution of oxytocin pathways in the brain of vertebrates

Frontiers in Behavioral Neuroscience, 2014

Research paper thumbnail of An analgesic pathway from parvocellular oxytocin neurons to the periaqueductal gray in rats

Nature Communications

The hypothalamic neuropeptide oxytocin (OT) exerts prominent analgesic effects via central and pe... more The hypothalamic neuropeptide oxytocin (OT) exerts prominent analgesic effects via central and peripheral action. However, the precise analgesic pathways recruited by OT are largely elusive. Here we discovered a 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 targeted by OT projections are GABAergic. Ex vivo stimulation of parvocellular OT axons in the vlPAG induced local OT release, as measured with OT sensor GRAB. In vivo, optogenetically-evoked axonal OT release in the vlPAG of as well as chemogenetic activation of OTR vlPAG neurons resulted in a long-lasting increase of vlPAG neuronal activity. This lead to an indirect suppression of sensory neuron activity in the spinal cord and strong analgesia in both female and male rats. Altogether, we describe an OT...

Research paper thumbnail of Oxytocin-based therapies for treatment of Prader-Willi and Schaaf-Yang syndromes: evidence, disappointments, and future research strategies

Translational Psychiatry

The prosocial neuropeptide oxytocin is being developed as a potential treatment for various neuro... more The prosocial neuropeptide oxytocin is being developed as a potential treatment for various neuropsychiatric disorders including autism spectrum disorder (ASD). Early studies using intranasal oxytocin in patients with ASD yielded encouraging results and for some time, scientists and affected families placed high hopes on the use of intranasal oxytocin for behavioral therapy in ASD. However, a recent Phase III trial obtained negative results using intranasal oxytocin for the treatment of behavioral symptoms in children with ASD. Given the frequently observed autism-like behavioral phenotypes in Prader-Willi and Schaaf-Yang syndromes, it is unclear whether oxytocin treatment represents a viable option to treat behavioral symptoms in these diseases. Here we review the latest findings on intranasal OT treatment, Prader-Willi and Schaaf-Yang syndromes, and propose novel research strategies for tailored oxytocin-based therapies for affected individuals. Finally, we propose the critical pe...

Research paper thumbnail of 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 proces... more 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 isc...

Research paper thumbnail of A novel analgesic pathway from parvocellular oxytocin neurons to the periaqueductal gray

The hypothalamic neuropeptide, oxytocin (OT), exerts prominent analgesic effects via central and ... more 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)...

Research paper thumbnail of 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 phys... more 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 togeth...

Research paper thumbnail of Oxytocinergic Feedback Circuitries: An Anatomical Basis for Neuromodulation of Social Behaviors

Frontiers in Neural Circuits, 2021

Oxytocin (OT) is a neuropeptide produced by hypothalamic neurons and is known to modulate social ... more Oxytocin (OT) is a neuropeptide produced by hypothalamic neurons and is known to modulate social behavior among other functions. Several experiments have shown that OT modulates neuronal activity in many brain areas, including sensory cortices. OT neurons thus project axons to various cortical and subcortical structures and activate neuronal subpopulations to increase the signal-to-noise ratio, and in turn, increases the saliency of social stimuli. Less is known about the origin of inputs to OT neurons, but recent studies show that cells projecting to OT neurons are often located in regions where the OT receptor (OTR) is expressed. Thus, we propose the existence of reciprocal connectivity between OT neurons and extrahypothalamic OTR neurons to tune OT neuron activity depending on the behavioral context. Furthermore, the latest studies have shown that OTR-expressing neurons located in social brain regions also project to other social brain regions containing OTR-expressing neurons. W...

Research paper thumbnail of Oxytocin and vasopressin within the ventral and dorsal lateral septum modulate aggression in female rats

Nature Communications, 2021

In contrast to male rats, aggression in virgin female rats has been rarely studied. Here, we esta... more In contrast to male rats, aggression in virgin female rats has been rarely studied. Here, we established a rat model of enhanced aggression in females using a combination of social isolation and aggression-training to specifically investigate the involvement of the oxytocin (OXT) and arginine vasopressin (AVP) systems within the lateral septum (LS). Using neuropharmacological, optogenetic, chemogenetic as well as microdialysis approaches, we revealed that enhanced OXT release within the ventral LS (vLS), combined with reduced AVP release within the dorsal LS (dLS), is required for aggression in female rats. Accordingly, increased activity of putative OXT receptor-positive neurons in the vLS, and decreased activity of putative AVP receptor-positive neurons in the dLS, are likely to underly aggression in female rats. Finally, in vitro activation of OXT receptors in the vLS increased tonic GABAergic inhibition of dLS neurons. Overall, our data suggest a model showing that septal releas...

Research paper thumbnail of Efficiency of cell-type specific and generic promoters in transducing oxytocin neurons and monitoring their neural activity during lactation

Scientific Reports, 2021

Hypothalamic oxytocin (OXT) and arginine-vasopressin (AVP) neurons have been at the center of sev... more Hypothalamic oxytocin (OXT) and arginine-vasopressin (AVP) neurons have been at the center of several physiological and behavioral studies. Advances in viral vector biology and the development of transgenic rodent models have allowed for targeted gene expression to study the functions of specific cell populations and brain circuits. In this study, we compared the efficiency of various adeno-associated viral vectors in these cell populations and demonstrated that none of the widely used promoters were, on their own, effective at driving expression of a down-stream fluorescent protein in OXT or AVP neurons. As anticipated, the OXT promoter could efficiently drive gene expression in OXT neurons and this efficiency is solely attributed to the promoter and not the viral serotype. We also report that a dual virus approach using an OXT promoter driven Cre recombinase significantly improved the efficiency of viral transduction in OXT neurons. Finally, we demonstrate the utility of the OXT p...

Research paper thumbnail of Social touch promotes interfemale communication via activation of parvocellular oxytocin neurons

Nature Neuroscience, 2020

Research paper thumbnail of Oxytocin Signaling in the Central Amygdala Modulates Emotion Discrimination in Mice

Research paper thumbnail of A Fear Memory Engram and Its Plasticity in the Hypothalamic Oxytocin System

Research paper thumbnail of Oxytocin Signaling in the Lateral Septum Prevents Social Fear during Lactation

Research paper thumbnail of Interplay between Oxytocin and Sensory Systems in the Orchestration of Socio-Emotional Behaviors

Research paper thumbnail of Oxytocin Signaling in Pain: Cellular, Circuit, System, and Behavioral Levels

Behavioral Pharmacology of Neuropeptides: Oxytocin, 2017

Research paper thumbnail of Vasopressin casts light on the suprachiasmatic nucleus

The Journal of physiology, Jan 12, 2017

A subpopulation of retinal ganglion cells expresses the neuropeptide vasopressin. These retinal g... more A subpopulation of retinal ganglion cells expresses the neuropeptide vasopressin. These retinal ganglion cells project predominately to our biological clock, the suprachiasmatic nucleus (SCN). Light-induced vasopressin release enhances the responses of SCN neurons to light. It also enhances expression of genes involved in photo-entrainment of biological rhythms. In all animals, the transition between night and day engages a host of physiological and behavioural rhythms. These rhythms depend not on the rods and cones of the retina, but on retinal ganglion cells (RGCs) that detect the ambient light level in the environment. These project to the suprachiasmatic nucleus (SCN) of the hypothalamus to entrain circadian rhythms that are generated within the SCN. The neuropeptide vasopressin has an important role in this entrainment. Many SCN neurons express vasopressin, and it has been assumed that the role of vasopressin in the SCN reflects the activity of these cells. Here we show that va...

Research paper thumbnail of Elevated Oxytocin Receptor Blood Concentrations Predict Higher Risk for, More, and Earlier 24-Month Hospital Readmissions after In-Patient Detoxification in Males with Alcohol Use Disorder

International Journal of Molecular Sciences, Sep 1, 2022

Research paper thumbnail of An analgesic pathway from parvocellular oxytocin neurons to the periaqueductal gray in rats

Nature Communications, Feb 24, 2023

Research paper thumbnail of Oxytocinergic Feedback Circuitries: An Anatomical Basis for Neuromodulation of Social Behaviors

Frontiers in Neural Circuits, Jun 14, 2021

Research paper thumbnail of Oxytocin Signaling in the Lateral Septum Prevents Social Fear during Lactation

Current Biology, Apr 1, 2018

Research paper thumbnail of Evolution of oxytocin pathways in the brain of vertebrates

Frontiers in Behavioral Neuroscience, 2014

Research paper thumbnail of An analgesic pathway from parvocellular oxytocin neurons to the periaqueductal gray in rats

Nature Communications

The hypothalamic neuropeptide oxytocin (OT) exerts prominent analgesic effects via central and pe... more The hypothalamic neuropeptide oxytocin (OT) exerts prominent analgesic effects via central and peripheral action. However, the precise analgesic pathways recruited by OT are largely elusive. Here we discovered a 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 targeted by OT projections are GABAergic. Ex vivo stimulation of parvocellular OT axons in the vlPAG induced local OT release, as measured with OT sensor GRAB. In vivo, optogenetically-evoked axonal OT release in the vlPAG of as well as chemogenetic activation of OTR vlPAG neurons resulted in a long-lasting increase of vlPAG neuronal activity. This lead to an indirect suppression of sensory neuron activity in the spinal cord and strong analgesia in both female and male rats. Altogether, we describe an OT...

Research paper thumbnail of Oxytocin-based therapies for treatment of Prader-Willi and Schaaf-Yang syndromes: evidence, disappointments, and future research strategies

Translational Psychiatry

The prosocial neuropeptide oxytocin is being developed as a potential treatment for various neuro... more The prosocial neuropeptide oxytocin is being developed as a potential treatment for various neuropsychiatric disorders including autism spectrum disorder (ASD). Early studies using intranasal oxytocin in patients with ASD yielded encouraging results and for some time, scientists and affected families placed high hopes on the use of intranasal oxytocin for behavioral therapy in ASD. However, a recent Phase III trial obtained negative results using intranasal oxytocin for the treatment of behavioral symptoms in children with ASD. Given the frequently observed autism-like behavioral phenotypes in Prader-Willi and Schaaf-Yang syndromes, it is unclear whether oxytocin treatment represents a viable option to treat behavioral symptoms in these diseases. Here we review the latest findings on intranasal OT treatment, Prader-Willi and Schaaf-Yang syndromes, and propose novel research strategies for tailored oxytocin-based therapies for affected individuals. Finally, we propose the critical pe...

Research paper thumbnail of 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 proces... more 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 isc...

Research paper thumbnail of A novel analgesic pathway from parvocellular oxytocin neurons to the periaqueductal gray

The hypothalamic neuropeptide, oxytocin (OT), exerts prominent analgesic effects via central and ... more 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)...

Research paper thumbnail of 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 phys... more 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 togeth...

Research paper thumbnail of Oxytocinergic Feedback Circuitries: An Anatomical Basis for Neuromodulation of Social Behaviors

Frontiers in Neural Circuits, 2021

Oxytocin (OT) is a neuropeptide produced by hypothalamic neurons and is known to modulate social ... more Oxytocin (OT) is a neuropeptide produced by hypothalamic neurons and is known to modulate social behavior among other functions. Several experiments have shown that OT modulates neuronal activity in many brain areas, including sensory cortices. OT neurons thus project axons to various cortical and subcortical structures and activate neuronal subpopulations to increase the signal-to-noise ratio, and in turn, increases the saliency of social stimuli. Less is known about the origin of inputs to OT neurons, but recent studies show that cells projecting to OT neurons are often located in regions where the OT receptor (OTR) is expressed. Thus, we propose the existence of reciprocal connectivity between OT neurons and extrahypothalamic OTR neurons to tune OT neuron activity depending on the behavioral context. Furthermore, the latest studies have shown that OTR-expressing neurons located in social brain regions also project to other social brain regions containing OTR-expressing neurons. W...

Research paper thumbnail of Oxytocin and vasopressin within the ventral and dorsal lateral septum modulate aggression in female rats

Nature Communications, 2021

In contrast to male rats, aggression in virgin female rats has been rarely studied. Here, we esta... more In contrast to male rats, aggression in virgin female rats has been rarely studied. Here, we established a rat model of enhanced aggression in females using a combination of social isolation and aggression-training to specifically investigate the involvement of the oxytocin (OXT) and arginine vasopressin (AVP) systems within the lateral septum (LS). Using neuropharmacological, optogenetic, chemogenetic as well as microdialysis approaches, we revealed that enhanced OXT release within the ventral LS (vLS), combined with reduced AVP release within the dorsal LS (dLS), is required for aggression in female rats. Accordingly, increased activity of putative OXT receptor-positive neurons in the vLS, and decreased activity of putative AVP receptor-positive neurons in the dLS, are likely to underly aggression in female rats. Finally, in vitro activation of OXT receptors in the vLS increased tonic GABAergic inhibition of dLS neurons. Overall, our data suggest a model showing that septal releas...

Research paper thumbnail of Efficiency of cell-type specific and generic promoters in transducing oxytocin neurons and monitoring their neural activity during lactation

Scientific Reports, 2021

Hypothalamic oxytocin (OXT) and arginine-vasopressin (AVP) neurons have been at the center of sev... more Hypothalamic oxytocin (OXT) and arginine-vasopressin (AVP) neurons have been at the center of several physiological and behavioral studies. Advances in viral vector biology and the development of transgenic rodent models have allowed for targeted gene expression to study the functions of specific cell populations and brain circuits. In this study, we compared the efficiency of various adeno-associated viral vectors in these cell populations and demonstrated that none of the widely used promoters were, on their own, effective at driving expression of a down-stream fluorescent protein in OXT or AVP neurons. As anticipated, the OXT promoter could efficiently drive gene expression in OXT neurons and this efficiency is solely attributed to the promoter and not the viral serotype. We also report that a dual virus approach using an OXT promoter driven Cre recombinase significantly improved the efficiency of viral transduction in OXT neurons. Finally, we demonstrate the utility of the OXT p...

Research paper thumbnail of Social touch promotes interfemale communication via activation of parvocellular oxytocin neurons

Nature Neuroscience, 2020

Research paper thumbnail of Oxytocin Signaling in the Central Amygdala Modulates Emotion Discrimination in Mice

Research paper thumbnail of A Fear Memory Engram and Its Plasticity in the Hypothalamic Oxytocin System

Research paper thumbnail of Oxytocin Signaling in the Lateral Septum Prevents Social Fear during Lactation

Research paper thumbnail of Interplay between Oxytocin and Sensory Systems in the Orchestration of Socio-Emotional Behaviors

Research paper thumbnail of Oxytocin Signaling in Pain: Cellular, Circuit, System, and Behavioral Levels

Behavioral Pharmacology of Neuropeptides: Oxytocin, 2017

Research paper thumbnail of Vasopressin casts light on the suprachiasmatic nucleus

The Journal of physiology, Jan 12, 2017

A subpopulation of retinal ganglion cells expresses the neuropeptide vasopressin. These retinal g... more A subpopulation of retinal ganglion cells expresses the neuropeptide vasopressin. These retinal ganglion cells project predominately to our biological clock, the suprachiasmatic nucleus (SCN). Light-induced vasopressin release enhances the responses of SCN neurons to light. It also enhances expression of genes involved in photo-entrainment of biological rhythms. In all animals, the transition between night and day engages a host of physiological and behavioural rhythms. These rhythms depend not on the rods and cones of the retina, but on retinal ganglion cells (RGCs) that detect the ambient light level in the environment. These project to the suprachiasmatic nucleus (SCN) of the hypothalamus to entrain circadian rhythms that are generated within the SCN. The neuropeptide vasopressin has an important role in this entrainment. Many SCN neurons express vasopressin, and it has been assumed that the role of vasopressin in the SCN reflects the activity of these cells. Here we show that va...