Compartmental Neuropeptide Release Measured Using a New Oxytocin Sensor (original) (raw)
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Oxytocin Intranasal Administration Affects Neural Networks Upstream of GNRH Neurons
Journal of molecular neuroscience : MN, 2017
The last decade has witnessed a surge in studies on the clinical applications of intranasal oxytocin as a method of enhancing social interaction. However, the molecular and cellular mechanisms underlying its function are not completely understood. Since oxytocin is involved in the regulation of hypothalamic-pituitary-gonadal axis by affecting the gonadotropin-releasing hormone (GNRH) system, the present study addressed whether intranasal application of oxytocin has a role in affecting GNRH expression in the male rat hypothalamus. In addition, we assessed expression of two excitatory (kisspeptin and neurokinin B) and two inhibitory (dynorphin and RFamide-related peptide-3) neuropeptides upstream of GNRH neurons as a possible route to relay oxytocin information. Here, adult male rats received 20, 40, or 80 μg oxytocin intranasally once a day for 10 consecutive days, and then, the posterior (PH) and anterior hypothalamus (AH) dissected for evaluation of target genes. Using qRT-PCR, we ...
Oxytocin Modulation of Neural Circuits
Current Topics in Behavioral Neurosciences
Oxytocin is a hypothalamic neuropeptide first recognized as a regulator of parturition and lactation which has recently gained attention for its ability to modulate social behaviors. In this chapter, we review several aspects of the oxytocinergic system, focusing on evidence for release of oxytocin and its receptor distribution in the cortex as the foundation for important networks that control social behavior. We examine the developmental timeline of the cortical oxytocin system as demonstrated by RNA, autoradiographic binding, and protein immunohistochemical studies, and describe how that might shape brain development and behavior. Many recent studies have implicated oxytocin in cognitive processes such as processing of sensory stimuli, social recognition, social memory, and fear. We review these studies and discuss the function of oxytocin in the young and adult cortex as a neuromodulator of central synaptic transmission and mediator of plasticity.
Evoked Axonal Oxytocin Release in the Central Amygdala Attenuates Fear Response
Neuron, 2012
The hypothalamic neuropeptide oxytocin (OT), which controls childbirth and lactation, receives increasing attention for its effects on social behaviors, but how it reaches central brain regions is still unclear. Here we gained by recombinant viruses selective genetic access to hypothalamic OT neurons to study their connectivity and control their activity by optogenetic means. We found axons of hypothalamic OT neurons in the majority of forebrain regions, including the central amygdala (CeA), a structure critically involved in OT-mediated fear suppression. In vitro, exposure to blue light of channelrhodopsin-2-expressing OT axons activated a local GABAergic circuit that inhibited neurons in the output region of the CeA. Remarkably, in vivo, local blue-light-induced endogenous OT release robustly decreased freezing responses in fear-conditioned rats. Our results thus show widespread central projections of hypothalamic OT neurons and demonstrate that OT release from local axonal endings can specifically control region-associated behaviors.
Frontiers in Molecular Neuroscience, 2022
In the last 10 years, it has become increasingly clear that large numbers of axon collaterals extend from the oxytocin (OXT) hypothalamic axons, especially the parvocellular components, to other brain regions. Consequently, the OXT signaling system forms, like other monoamine axons, a rich functional network across several brain regions. In this manuscript, we review the recently indicated higher order G-protein coupled heteroreceptor complexes of the oxytocin receptor (OXTR), and how these, via allosteric receptor-receptor interactions modulate the recognition, signaling, and trafficking of the participating receptor protomers and their potential impact for brain and behavior. The major focus will be on complexes of the OXTR protomer with the dopamine D2 receptor (D2R) protomer and the serotonin 2A (5-HT2AR) and 2C (5-HT2CR) receptor protomers. Specifically, the existence of D2R-OXTR heterocomplexes in the nucleus accumbens and the caudate putamen of rats has led to a postulated function for this heteromer in social behavior. Next, a physical interaction between OXTRs and the growth hormone secretagogue or ghrelin receptor (GHS-R1a) was demonstrated, which consequently was able to attenuate OXTR-mediated Gαq signaling. This highlights the potential of ghrelintargeted therapies to modulate oxytocinergic signaling with relevance for appetite regulation, anxiety, depression, and schizophrenia. Similarly, evidence for 5-HT2AR-OXTR heteromerization in the pyramidal cell layer of CA2 and CA3 in the dorsal hippocampus and in the nucleus accumbens shell was demonstrated. This complex may offer new strategies for the treatment of both mental disease and social behavior. Finally, the 5-HT2CR-OXTR Frontiers in Molecular Neuroscience 01 frontiersin.org Borroto-Escuela et al. 10.3389/fnmol.2022.1055344 heterocomplexes were demonstrated in the CA1, CA2, and CA3 regions of the dorsal hippocampus. Future work should be done to investigate the precise functional consequence of region-specific OXTR heteromerization in the brain, as well across the periphery, and whether the integration of neuronal signals in the brain may also involve higher order OXTR-GHS-R1a heteroreceptor complexes including the dopamine (DA), noradrenaline (NA) or serotonin (5-HT) receptor protomers or other types of G-protein coupled receptors (GPCRs).
Journal of Neuroendocrinology, 2007
Gonadotrophin-releasing hormone (GnRH) neurones constitute the final output pathway of a neuronal network that controls the preovulatory luteinising hormone (LH) surge and ovulation (1-4). The activity of GnRH neurones during the reproductive cycle is clearly influenced by oestrogen (4). However, the functions of oestrogen receptor subtypes in the control of GnRH neurones are not completely understood. It has been shown that GnRH cells express oestrogen receptor b (ERb), but not oestrogen receptor a (ERa) (5-8). Although studies have shown that oestrogen regulates directly the GnRH synthesis through ERb (9), it has been assumed that the positive feedback of steroids may be largely exerted via neural networks that, in turn, control GnRH release. The cells in which oestrogen may convey its positive feedback signal may include several neuronal populations, including noradrenaline, GABA, glutamine, endorphin, neuropeptide Y and, kisspeptin (10-12). A number of experiments show that oxytocin may regulate the GnRH cells, suggesting a possible modulation on LH surge. Oxytocin is synthesised within the supraoptic (SON) and paraventricular (PVN) nuclei of the hypothalamus by magnocellular neurones and is released from the posterior pituitary into the general circulation in response to a variety of environmental stimuli, including suckling and osmotic challenge (13, 14). Oxytocin is also produced in parvocellular neurones that project to the median eminence, brain stem and spinal cord, as well as limbic and olfactory areas (13). Oxytocin
Somatodendritic secretion in oxytocin neurons is upregulated during the female reproductive cycle
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2003
During the female reproductive cycle, hypothalamic oxytocin (OT) neurons undergo sharp changes in excitability. In lactating mammals, bursts of electrical activity of OT neurons result in the release of large amounts of OT in the bloodstream, which causes milk ejection. One hypothesis is that OT neurons regulate their own firing activity and that of nearby OT neurons by somatodendritic release of OT. In this study, we show that OT neuron activity strongly reduces inhibitory synaptic transmission to these neurons. This effect is blocked by antagonists of both adenosine and OT receptors and is mimicked by OT application. Inhibition of soluble N-ethylmaleimide-sensitive factor attachment protein receptor complex formation by tetanus toxin completely blocked the stimulation-induced reduction in inhibitory input, as did the calcium chelator BAPTA. During lactation, the readily releasable pool of secretory vesicles in OT cell bodies was doubled, and calcium currents were upregulated. This...
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 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...
Oxytocin enhances cranial visceral afferent synaptic transmission to the solitary tract nucleus
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2008
Cranial visceral afferents travel via the solitary tract (ST) to contact neurons within the ST nucleus (NTS) and activate homeostatic reflexes. Hypothalamic projections from the paraventricular nucleus (PVN) release oxytocin (OT) to modulate visceral afferent communication with NTS neurons. However, the cellular mechanisms through which OT acts are poorly understood. Here, we electrophysiologically identified second-order NTS neurons in horizontal brainstem slices by their low-jitter, ST-evoked glutamatergic EPSCs. OT increased the frequency of miniature EPSCs in half of the NTS second-order neurons (13/24) but did not alter event kinetics or amplitudes. These actions were blocked by a selective OT receptor antagonist. OT increased the amplitude of ST-evoked EPSCs with no effect on event kinetics. Variance-mean analysis of ST-evoked EPSCs indicated OT selectively increased the release probability of glutamate from the ST afferent terminals. In OT-sensitive neurons, OT evoked an inwa...
Oxytocin-Induced Postinhibitory Rebound Firing Facilitates Bursting Activity in Oxytocin Neurons
Journal of Neuroscience, 2008
During parturition and lactation, neurosecretory oxytocin (OT) neurons in the hypothalamus achieve pulsatile hormone secretion by coordinated bursts of firing that occur throughout the neuronal population. This activity is partly controlled by somatodendritic release of OT, which facilitates the onset and recurrence of synchronized bursting. To further investigate the cellular mechanisms underlying the control exerted by OT on the activity of its own neurons, we studied the effects of the peptide on membrane potential and synaptic activity in OT neurons in hypothalamic organotypic slice cultures. Bath application of low concentrations of OT (Ͻ100 nM) facilitated GABA A receptor-mediated inhibitory transmission through a presynaptic mechanism without affecting membrane potential and excitatory glutamatergic synaptic activity. The facilitatory action of OT on GABAergic transmission was dose-dependent, starting at 25 nM and disappearing at concentrations Ͼ100 nM. As shown previously, higher concentrations of OT (Ͼ500 nM) had the opposite effect, inhibiting GABA A receptors via a postsynaptic mechanism. Surprisingly, OT-mediated facilitation of GABAergic transmission promoted action potential firing in 40% of the neurons. Each action potential occurred at the end of the repolarizing phase of an inhibitory potential. Pharmacological dissection revealed that this firing involved the activation of low-threshold activated calcium channels. Detailed statistical analysis showed that OT-mediated firing upregulated bursting activity in OT neurons. It is thus likely to optimize OT secretion and, as a consequence, facilitate delivery and milk ejection in mammals.