Oxytocin, Neural Plasticity, and Social Behavior

Abstract

Oxytocin regulates parturition, lactation, parental nurturing, and many other social behaviors in both sexes. The circuit mechanisms by which oxytocin modulates social behavior are receiving increasing attention. Here, we review recent studies on oxytocin modulation of neural circuit function and social behavior, largely enabled by new methods of monitoring and manipulating oxytocin or oxytocin receptor neurons in vivo. These studies indicate that oxytocin can enhance the salience of social stimuli and increase signal-to-noise ratios by modulating spiking and synaptic plasticity in the context of circuits and networks. We highlight oxytocin effects on social behavior in nontraditional organisms such as prairie voles and discuss opportunities to enhance the utility of these organisms for studying circuit-level modulation of social behaviors. We then discuss recent insights into oxytocin neuron activity during social interactions. We conclude by discussing some of the major questions and opportunities in the field ahead.

Keywords: hypothalamus; maternal care; neural circuits; neuromodulation; social behavior; social bonding.

Figure 1

The mouse oxytocin system. (a) Axonal projections of PVN oxytocin neurons. Panel a adapted from Knobloch et al. (2012), Mitre et al. (2016), and Zhang et al. (2021). (b) Inputs to PVN oxytocin neurons. Panel b adapted from Tang et al. (2020). Abbreviations: A, amygdala; AON, anterior olfactory nucleus; Arc, arcuate nucleus; AuCx, auditory cortex; BLA, basolateral amygdala; BNST, bed nucleus of the stria terminalis; CeA, central nucleus of the amygdala; CPu, caudate putamen; DMH, dorsomedial hypothalamic nucleus; DRG, dorsal root ganglion; GP, globus pallidus; Hb, habenula; InfCx, infralimbic cortex; Ins, insular cortex; LH, lateral hypothalamus; LS, lateral septum; MEA, medial amygdala; mPFC, medial prefrontal cortex; MPOA, medial preoptic area; NAc, nucleus accumbens; OrbCx, orbitofrontal cortex; PAG, periaqueductal gray; PBN, parabrachial nucleus; PH, posterior hypothalamic nucleus; PiCx, piriform cortex; PIL, posterior intralaminar nucleus of the thalamus; PlimCx, prelimbic cortex; PPi, posterior pituitary; PVN, paraventricular nucleus; PVT, paraventricular thalamus; RN, raphe nuclei; SNc, substantia nigra pars compacta; SON, supraoptic nucleus; VTA, ventral tegmental area; ZI, zona incerta.

Figure 2

Receptor autoradiograms illustrating oxytocin receptor binding sites in the forebrain of rat, mouse, and prairie vole. Receptor distribution is conserved in some regions, including the lateral septum (LS), bed nucleus of the stria terminalis (BnST), central nucleus of the amygdala (CeA), and ventromedial nucleus of hypothalamus (VMH). There are species differences for other regions: In rat striatum, oxytocin receptors are restricted to dorsal caudate putamen (CP) and nucleus accumbens shell (NAccSh), whereas oxytocin receptors are abundant throughout prairie vole striatum and not detectable in mouse striatum. Figure adapted from Burbach et al. (2006).

Figure 3

Different modes of oxytocinergic modulation. (a) Proposed mechanism of oxytocin receptor GPCR signaling. A G protein activates PLC to degrade PIP₂ into IP₃ and DAG. Depleting membrane PIP₂ closes KCNQ channels, increasing resistance and depolarizing neurons. DAG activates PKC to phosphorylate spike channels (Tirko et al. 2018). (b, left) In first-order modulation, oxytocin directly depolarizes some principal excitatory cells such as CA2 pyramidal neurons (Tirko et al. 2018). (Middle) In second-order modulation, oxytocin reduces inhibitory transmission by either increasing spontaneous firing or impairing GABA release (Owen et al. 2013). (Right) In third-order modulation, or modulation of modulation, oxytocin receptors on serotoninergic terminals impact serotonin signaling in nucleus accumbens (top) (Dölen et al. 2013), and oxytocin increases VTA dopamine neuron firing but decreases SNc dopamine neuron firing (bottom) (Xiao et al. 2017). Abbreviations: 5-HT, 5-hydroxytryptamine; DAG, diacylglycerol; DAn, dopamine neuron; GABA, γ aminobutyric acid; GPCR, G protein–coupled receptor; IP₃, inositol triphosphate; KCNQ, M-type K⁺ channel; MSN, medium spiny neuron; OXTR, oxytocin receptor; P, phosphorylation; PIP₂, phosphatidylinositol 4,5-bisphosphate; PKC, protein kinase C; PLC, phospholipase C; PVN, paraventricular nucleus of the hypothalamus; SNc, substantia nigra pars compacta; TGOT, [Thr⁴, Gly⁷]-oxytocin; VTA, ventral tegmental area.

Figure 4

Mechanisms of oxytocin modulation enable long-term plasticity. (a) Long-term plasticity of synaptic and spiking responses to mouse infant distress calls is induced in vivo in female virgin left auditory cortex. (Top) Voltage-clamp recordings from cortical neurons are shown before, during, and after pairing oxytocin (red) with pup call (black spectrogram above traces). Excitatory-inhibitory correlation improved over time, and responses to the pup call became more reliable. (Bottom) Two consecutive current-clamp recordings of spiking responses are shown before, during, and after oxytocin pairing via optogenetic stimulation (blue). After pairing, pup calls evoked more spikes with higher temporal precision (Marlin et al. 2015). (b) Oxytocin induces LTD in vitro in mouse nucleus accumbens (blue) unless slices were preincubated with OTA (black) (Dölen et al. 2013). Abbreviations: CTL, control; EPSC, excitatory postsynaptic current; LTD, long-term depression; OTA, oxytocin receptor antagonist.

Figure 5

Single-unit recordings from optically identified PVN oxytocin neurons. (a) Combined recordings of behavior, ultrasonic vocalizations, and neural activity in virgin female rats measure responses of oxytocin neurons in vivo. FSI led to the greatest change in firing rate and synchronous activity in simultaneously recorded oxytocin neurons (Tang et al. 2020). (b) Social interactions between dams and virgins activate virgin PVN oxytocin neurons. (Left) Continuous videography of virgins cohoused for days with dams and litters revealed previously undescribed behavior such as dams shepherding virgins to nests and pups. (Right) Simultaneous in vivo recordings of nine PVN units, including a photo-tagged oxytocin PVN cell (u3), show bursting patterns during a single shepherding episode (middle raster plot) and over dozens of shepherding events (right). Many oxytocin neurons and unidentified cells (e.g., u9) reliably burst during virgin head nest entry (Carcea et al. 2019). Asterisks denote significance level: *p < .05, **p < .01. Abbreviations: CSI, chambered social interaction; FSI, free social interaction; OF, open field; PVN, paraventricular nucleus.