Oxytocin, Neural Plasticity, and Social Behavior.

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.

Locus coeruleus activity improves cochlear implant performance.

Cochlear implants (CIs) are neuroprosthetic devices that can provide hearing to deaf people1. Despite the benefits offered by CIs, the time taken for hearing to be restored and perceptual accuracy after long-term CI use remain highly variable2,3. CI use is believed to require neuroplasticity in the central auditory system, and differential engagement of neuroplastic mechanisms might contribute to the variability in outcomes4-7. Despite extensive studies on how CIs activate the auditory system4,8-12, the understanding of CI-related neuroplasticity remains limited. One potent factor enabling plasticity is the neuromodulator noradrenaline from the brainstem locus coeruleus (LC). Here we examine behavioural responses and neural activity in LC and auditory cortex of deafened rats fitted with multi-channel CIs. The rats were trained on a reward-based auditory task, and showed considerable individual differences of learning rates and maximum performance. LC photometry predicted when CI subjects began responding to sounds and longer-term perceptual accuracy. Optogenetic LC stimulation produced faster learning and higher long-term accuracy. Auditory cortical responses to CI stimulation reflected behavioural performance, with enhanced responses to rewarded stimuli and decreased distinction between unrewarded stimuli. Adequate engagement of central neuromodulatory systems is thus a potential clinically relevant target for optimizing neuroprosthetic device use.

Neural circuitry for maternal oxytocin release induced by infant cries.

Oxytocin is a neuropeptide that is important for maternal physiology and childcare, including parturition and milk ejection during nursing1-6. Suckling triggers the release of oxytocin, but other sensory cues-specifically, infant cries-can increase the levels of oxytocin in new human mothers7, which indicates that cries can activate hypothalamic oxytocin neurons. Here we describe a neural circuit that routes auditory information about infant vocalizations to mouse oxytocin neurons. We performed in vivo electrophysiological recordings and photometry from identified oxytocin neurons in awake maternal mice that were presented with pup calls. We found that oxytocin neurons responded to pup vocalizations, but not to pure tones, through input from the posterior intralaminar thalamus, and that repetitive thalamic stimulation induced lasting disinhibition of oxytocin neurons. This circuit gates central oxytocin release and maternal behaviour in response to calls, providing a mechanism for the integration of sensory cues from the offspring in maternal endocrine networks to ensure modulation of brain state for efficient parenting.

Oxytocin neurons enable social transmission of maternal behaviour.

Maternal care, including by non-biological parents, is important for offspring survival1-8. Oxytocin1,2,9-15, which is released by the hypothalamic paraventricular nucleus (PVN), is a critical maternal hormone. In mice, oxytocin enables neuroplasticity in the auditory cortex for maternal recognition of pup distress15. However, it is unclear how initial parental experience promotes hypothalamic signalling and cortical plasticity for reliable maternal care. Here we continuously monitored the behaviour of female virgin mice co-housed with an experienced mother and litter. This documentary approach was synchronized with neural recordings from the virgin PVN, including oxytocin neurons. These cells were activated as virgins were enlisted in maternal care by experienced mothers, who shepherded virgins into the nest and demonstrated pup retrieval. Virgins visually observed maternal retrieval, which activated PVN oxytocin neurons and promoted alloparenting. Thus rodents can acquire maternal behaviour by social transmission, providing a mechanism for adapting the brains of adult caregivers to infant needs via endogenous oxytocin.

Innate and plastic mechanisms for maternal behaviour in auditory cortex.

Infant cries evoke powerful responses in parents1-4. Whether parental animals are intrinsically sensitive to neonatal vocalizations, or instead learn about vocal cues for parenting responses is unclear. In mice, pup-naive virgin females do not recognize the meaning of pup distress calls, but retrieve isolated pups to the nest after having been co-housed with a mother and litter5-9. Distress calls are variable, and require co-caring virgin mice to generalize across calls for reliable retrieval10,11. Here we show that the onset of maternal behaviour in mice results from interactions between intrinsic mechanisms and experience-dependent plasticity in the auditory cortex. In maternal females, calls with inter-syllable intervals (ISIs) from 75 to 375 milliseconds elicited pup retrieval, and cortical responses were generalized across these ISIs. By contrast, naive virgins were neuronally and behaviourally sensitized to the most common ('prototypical') ISIs. Inhibitory and excitatory neural responses were initially mismatched in the cortex of naive mice, with untuned inhibition and overly narrow excitation. During co-housing experiments, excitatory responses broadened to represent a wider range of ISIs, whereas inhibitory tuning sharpened to form a perceptual boundary. We presented synthetic calls during co-housing and observed that neurobehavioural responses adjusted to match these statistics, a process that required cortical activity and the hypothalamic oxytocin system. Neuroplastic mechanisms therefore build on an intrinsic sensitivity in the mouse auditory cortex, and enable rapid plasticity for reliable parenting behaviour.

Publisher Correction: Innate and plastic mechanisms for maternal behaviour in auditory cortex.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Diverging roles for Lrp4 and Wnt signaling in neuromuscular synapse development during evolution.

Motor axons approach muscles that are prepatterned in the prospective synaptic region. In mice, prepatterning of acetylcholine receptors requires Lrp4, a LDLR family member, and MuSK, a receptor tyrosine kinase. Lrp4 can bind and stimulate MuSK, strongly suggesting that association between Lrp4 and MuSK, independent of additional ligands, initiates prepatterning in mice. In zebrafish, Wnts, which bind the Frizzled (Fz)-like domain in MuSK, are required for prepatterning, suggesting that Wnts may contribute to prepatterning and neuromuscular development in mammals. We show that prepatterning in mice requires Lrp4 but not the MuSK Fz-like domain. In contrast, prepatterning in zebrafish requires the MuSK Fz-like domain but not Lrp4. Despite these differences, neuromuscular synapse formation in zebrafish and mice share similar mechanisms, requiring Lrp4, MuSK, and neuronal Agrin but not the MuSK Fz-like domain or Wnt production from muscle. Our findings demonstrate that evolutionary divergent mechanisms establish muscle prepatterning in zebrafish and mice.

Plasticity of cortical excitatory-inhibitory balance.

Synapses are highly plastic and are modified by changes in patterns of neural activity or sensory experience. Plasticity of cortical excitatory synapses is thought to be important for learning and memory, leading to alterations in sensory representations and cognitive maps. However, these changes must be coordinated across other synapses within local circuits to preserve neural coding schemes and the organization of excitatory and inhibitory inputs, i.e., excitatory-inhibitory balance. Recent studies indicate that inhibitory synapses are also plastic and are controlled directly by a large number of neuromodulators, particularly during episodes of learning. Many modulators transiently alter excitatory-inhibitory balance by decreasing inhibition, and thus disinhibition has emerged as a major mechanism by which neuromodulation might enable long-term synaptic modifications naturally. This review examines the relationships between neuromodulation and synaptic plasticity, focusing on the induction of long-term changes that collectively enhance cortical excitatory-inhibitory balance for improving perception and behavior.

Oxytocin enables maternal behaviour by balancing cortical inhibition.

Oxytocin is important for social interactions and maternal behaviour. However, little is known about when, where and how oxytocin modulates neural circuits to improve social cognition. Here we show how oxytocin enables pup retrieval behaviour in female mice by enhancing auditory cortical pup call responses. Retrieval behaviour required the left but not right auditory cortex, was accelerated by oxytocin in the left auditory cortex, and oxytocin receptors were preferentially expressed in the left auditory cortex. Neural responses to pup calls were lateralized, with co-tuned and temporally precise excitatory and inhibitory responses in the left cortex of maternal but not pup-naive adults. Finally, pairing calls with oxytocin enhanced responses by balancing the magnitude and timing of inhibition with excitation. Our results describe fundamental synaptic mechanisms by which oxytocin increases the salience of acoustic social stimuli. Furthermore, oxytocin-induced plasticity provides a biological basis for lateralization of auditory cortical processing.

Neuromodulation of maternal circuits by oxytocin.

Motherhood in mammals involves tremendous changes throughout the body and central nervous system, which support attention and nurturing of infants. Maternal care consists of complex behaviors, such as nursing and protection of the offspring, requiring new mothers to become highly sensitive to infant needs. Long-lasting neural plasticity in various regions of the cerebral cortex may enable the perception and recognition of infant cues, important for appropriate caregiving responses. Recent findings have demonstrated that the neuropeptide oxytocin is involved in a number of physiological processes, including parturition and lactation and dynamically shaping neuronal responses to infant stimuli as well. Here, we review experience-dependent changes within the cortex occurring throughout motherhood, focusing on plasticity of the somatosensory and auditory cortex. We outline the role of oxytocin in gating cortical plasticity and discuss potential mechanisms regulating oxytocin release in response to different sensory stimuli.

Intrinsically determined cell death of developing cortical interneurons.

Cortical inhibitory circuits are formed by γ-aminobutyric acid (GABA)-secreting interneurons, a cell population that originates far from the cerebral cortex in the embryonic ventral forebrain. Given their distant developmental origins, it is intriguing how the number of cortical interneurons is ultimately determined. One possibility, suggested by the neurotrophic hypothesis, is that cortical interneurons are overproduced, and then after their migration into cortex the excess interneurons are eliminated through a competition for extrinsically derived trophic signals. Here we characterize the developmental cell death of mouse cortical interneurons in vivo, in vitro and after transplantation. We found that 40% of developing cortical interneurons were eliminated through Bax (Bcl-2-associated X)-dependent apoptosis during postnatal life. When cultured in vitro or transplanted into the cortex, interneuron precursors died at a cellular age similar to that at which endogenous interneurons died during normal development. Over transplant sizes that varied 200-fold, a constant fraction of the transplanted population underwent cell death. The death of transplanted neurons was not affected by the cell-autonomous disruption of TrkB (tropomyosin kinase receptor B), the main neurotrophin receptor expressed by neurons of the central nervous system. Transplantation expanded the cortical interneuron population by up to 35%, but the frequency of inhibitory synaptic events did not scale with the number of transplanted interneurons. Taken together, our findings indicate that interneuron cell death is determined intrinsically, either cell-autonomously or through a population-autonomous competition for survival signals derived from other interneurons.

A Distributed Network for Social Cognition Enriched for Oxytocin Receptors.

Oxytocin is a neuropeptide important for social behaviors such as maternal care and parent-infant bonding. It is believed that oxytocin receptor signaling in the brain is critical for these behaviors, but it is unknown precisely when and where oxytocin receptors are expressed or which neural circuits are directly sensitive to oxytocin. To overcome this challenge, we generated specific antibodies to the mouse oxytocin receptor and examined receptor expression throughout the brain. We identified a distributed network of female mouse brain regions for maternal behaviors that are especially enriched for oxytocin receptors, including the piriform cortex, the left auditory cortex, and CA2 of the hippocampus. Electron microscopic analysis of the cerebral cortex revealed that oxytocin receptors were mainly expressed at synapses, as well as on axons and glial processes. Functionally, oxytocin transiently reduced synaptic inhibition in multiple brain regions and enabled long-term synaptic plasticity in the auditory cortex. Thus modulation of inhibition may be a general mechanism by which oxytocin can act throughout the brain to regulate parental behaviors and social cognition.

Anisomorphic cortical reorganization in asymmetric sensorineural hearing loss.

Acoustic trauma or inner ear disease may predominantly injure one ear, causing asymmetric sensorineural hearing loss (SNHL). While characteristic frequency (CF) map plasticity of primary auditory cortex (AI) contralateral to the injured ear has been detailed, there is no study that also evaluates ipsilateral AI to compare cortical reorganization across both hemispheres. We assess whether the normal isomorphic mirror-image relationship between the two hemispheres is maintained or disrupted in mild-to-moderate asymmetric SNHL of adult squirrel monkeys. At week 24 after induction of acoustic injury to the right ear, functional organization of the two hemispheres differs in direction and magnitude of interaural CF difference, percentage of recording sites with spectrally nonoverlapping binaural activation, and the concurrence of peripheral and central activation thresholds. The emergence of this anisomorphic cortical reorganization of the two hemispheres is replicated by simulation based on spike timing-dependent plasticity, where 1) AI input from the contralateral ear is dominant, 2) reestablishment of relatively shorter contralateral ear input timing drives reorganization, and 3) only AI contralateral to the injured ear undergoes major realignment of interaural frequency maps that evolve over months. Asymmetric SNHL disrupts isomorphic organization between the two hemispheres and results in relative local hemispheric autonomy, potentially impairing performance of tasks that require binaural input alignment or interhemispheric processing.NEW & NOTEWORTHY Mild-to-moderate hearing loss in one ear and essentially normal hearing in the other triggers cortical reorganization that is different in the two hemispheres. Asymmetry of cochlea sensitivities does not simply propagate to the two auditory cortices in mirror-image fashion. The resulting anisomorphic cortical reorganization may be a neurophysiological basis of clinical deficits in asymmetric hearing loss, such as difficulty with hearing in noise, impaired spatial hearing, and accelerated decline of the poorer ear.

Food restriction induces synaptic incorporation of calcium-permeable AMPA receptors in nucleus accumbens.

Chronic food restriction potentiates behavioral and cellular responses to drugs of abuse and D-1 dopamine receptor agonists administered systemically or locally in the nucleus accumbens (NAc). However, the alterations in NAc synaptic transmission underlying these effects are incompletely understood. AMPA receptor trafficking is a major mechanism for regulating synaptic strength, and previous studies have shown that both sucrose and d-amphetamine rapidly alter the abundance of AMPA receptor subunits in the NAc postsynaptic density (PSD) in a manner that differs between food-restricted and ad libitum fed rats. In this study we examined whether food restriction, in the absence of reward stimulus challenge, alters AMPAR subunit abundance in the NAc PSD. Food restriction was found to increase surface expression and, specifically, PSD abundance, of GluA1 but not GluA2, suggesting synaptic incorporation of GluA2-lacking Ca2+-permeable AMPARs (CP-AMPARs). Naspm, an antagonist of CP-AMPARs, decreased the amplitude of evoked EPSCs in NAc shell, and blocked the enhanced locomotor response to local microinjection of the D-1 receptor agonist, SKF-82958, in food-restricted, but not ad libitum fed, subjects. Although microinjection of the D-2 receptor agonist, quinpirole, also induced greater locomotor activation in food-restricted than ad libitum fed rats, this effect was not decreased by Naspm. Taken together, the present findings are consistent with the synaptic incorporation of CP-AMPARs in D-1 receptor-expressing medium spiny neurons in NAc as a mechanistic underpinning of the enhanced responsiveness of food-restricted rats to natural rewards and drugs of abuse.

Maturation of cortical circuits requires Semaphorin 7A.

Abnormal cortical circuits underlie some cognitive and psychiatric disorders, yet the molecular signals that generate normal cortical networks remain poorly understood. Semaphorin 7A (Sema7A) is an atypical member of the semaphorin family that is GPI-linked, expressed principally postnatally, and enriched in sensory cortex. Significantly, SEMA7A is deleted in individuals with 15q24 microdeletion syndrome, characterized by developmental delay, autism, and sensory perceptual deficits. We studied the role that Sema7A plays in establishing functional cortical circuitry in mouse somatosensory barrel cortex. We found that Sema7A is expressed in spiny stellate cells and GABAergic interneurons and that its absence disrupts barrel cytoarchitecture, reduces asymmetrical orientation of spiny stellate cell dendrites, and functionally impairs thalamocortically evoked synaptic responses, with reduced feed-forward GABAergic inhibition. These data identify Sema7A as a regulator of thalamocortical and local circuit development in layer 4 and provide a molecular handle that can be used to explore the coordinated generation of excitatory and inhibitory cortical circuits.

Activation of corticostriatal circuitry relieves chronic neuropathic pain.

Neural circuits that determine the perception and modulation of pain remain poorly understood. The prefrontal cortex (PFC) provides top-down control of sensory and affective processes. While animal and human imaging studies have shown that the PFC is involved in pain regulation, its exact role in pain states remains incompletely understood. A key output target for the PFC is the nucleus accumbens (NAc), an important component of the reward circuitry. Interestingly, recent human imaging studies suggest that the projection from the PFC to the NAc is altered in chronic pain. The function of this corticostriatal projection in pain states, however, is not known. Here we show that optogenetic activation of the PFC produces strong antinociceptive effects in a rat model (spared nerve injury model) of persistent neuropathic pain. PFC activation also reduces the affective symptoms of pain. Furthermore, we show that this pain-relieving function of the PFC is likely mediated by projections to the NAc. Thus, our results support a novel role for corticostriatal circuitry in pain regulation.

A physiological and behavioral system for hearing restoration with cochlear implants.

Cochlear implants are neuroprosthetic devices that provide hearing to deaf patients, although outcomes are highly variable even with prolonged training and use. The central auditory system must process cochlear implant signals, but it is unclear how neural circuits adapt-or fail to adapt-to such inputs. The knowledge of these mechanisms is required for development of next-generation neuroprosthetics that interface with existing neural circuits and enable synaptic plasticity to improve perceptual outcomes. Here, we describe a new system for cochlear implant insertion, stimulation, and behavioral training in rats. Animals were first ensured to have significant hearing loss via physiological and behavioral criteria. We developed a surgical approach for multichannel (2- or 8-channel) array insertion, comparable with implantation procedures and depth in humans. Peripheral and cortical responses to stimulation were used to program the implant objectively. Animals fitted with implants learned to use them for an auditory-dependent task that assesses frequency detection and recognition in a background of environmentally and self-generated noise and ceased responding appropriately to sounds when the implant was temporarily inactivated. This physiologically calibrated and behaviorally validated system provides a powerful opportunity to study the neural basis of neuroprosthetic device use and plasticity.

Developmental sensory experience balances cortical excitation and inhibition.

Early in life, neural circuits are highly susceptible to outside influences. The organization of the primary auditory cortex (A1) in particular is governed by acoustic experience during the critical period, an epoch near the beginning of postnatal development throughout which cortical synapses and networks are especially plastic. This neonatal sensitivity to the pattern of sensory inputs is believed to be essential for constructing stable and adequately adapted representations of the auditory world and for the acquisition of language skills by children. One important principle of synaptic organization in mature brains is the balance between excitation and inhibition, which controls receptive field structure and spatiotemporal flow of neural activity, but it is unknown how and when this excitatory-inhibitory balance is initially established and calibrated. Here we use whole-cell recording to determine the processes underlying the development of synaptic receptive fields in rat A1. We find that, immediately after the onset of hearing, sensory-evoked excitatory and inhibitory responses are equally strong, although inhibition is less stimulus-selective and mismatched with excitation. However, during the third week of postnatal development, excitation and inhibition become highly correlated. Patterned sensory stimulation drives coordinated synaptic changes across receptive fields, rapidly improves excitatory-inhibitory coupling and prevents further exposure-induced modifications. Thus, the pace of cortical synaptic receptive field development is set by progressive, experience-dependent refinement of intracortical inhibition.

Calcium-permeable AMPA receptors in the nucleus accumbens regulate depression-like behaviors in the chronic neuropathic pain state.

Depression is a salient emotional feature of chronic pain. Depression alters the pain threshold and impairs functional recovery. To date, however, there has been limited understanding of synaptic or circuit mechanisms that regulate depression in the pain state. Here, we demonstrate that depression-like behaviors are induced in a rat model of chronic neuropathic pain. Using this model, we show that chronic pain selectively increases the level of GluA1 subunits of AMPA-type glutamate receptors at the synapses of the nucleus accumbens (NAc), a key component of the brain reward system. We find, in addition, that this increase in GluA1 levels leads to the formation of calcium-permeable AMPA receptors (CPARs). Surprisingly, pharmacologic blockade of these CPARs in the NAc increases depression-like behaviors associated with pain. Consistent with these findings, an AMPA receptor potentiator delivered into the NAc decreases pain-induced depression. These results show that transmission through CPARs in the NAc represents a novel molecular mechanism modulating the depressive symptoms of pain, and thus CPARs may be a promising therapeutic target for the treatment of pain-induced depression. More generally, these findings highlight the role of central glutamate signaling in pain states and define the brain reward system as an important region for the regulation of depressive symptoms of pain.

Sucrose ingestion induces rapid AMPA receptor trafficking.

The mechanisms by which natural rewards such as sugar affect synaptic transmission and behavior are largely unexplored. Here, we investigate regulation of nucleus accumbens synapses by sucrose intake. Previous studies have shown that AMPA receptor (AMPAR) trafficking is a major mechanism for regulating synaptic strength, and that in vitro, trafficking of AMPARs containing the GluA1 subunit takes place by a two-step mechanism involving extrasynaptic and then synaptic receptor transport. We report that in rat, repeated daily ingestion of a 25% sucrose solution transiently elevated spontaneous locomotion and potentiated accumbens core synapses through incorporation of Ca(2+)-permeable AMPA receptors (CPARs), which are GluA1-containing, GluA2-lacking AMPARs. Electrophysiological, biochemical, and quantitative electron microscopy studies revealed that sucrose training (7 d) induced a stable (>24 h) intraspinous GluA1 population, and that in these rats a single sucrose stimulus rapidly (5 min) but transiently (<24 h) elevated GluA1 at extrasynaptic sites. CPARs and dopamine D1 receptors were required in vivo for elevated locomotion after sucrose ingestion. Significantly, a 7 d protocol of daily ingestion of a 3% solution of saccharin, a noncaloric sweetener, induced synaptic GluA1 similarly to 25% sucrose ingestion. These findings identify multistep GluA1 trafficking, previously described in vitro, as a mechanism for acute regulation of synaptic transmission in vivo by a natural orosensory reward. Trafficking is stimulated by a chemosensory pathway that is not dependent on the caloric value of sucrose.