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.

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.

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.

The Temporal Association Cortex Plays a Key Role in Auditory-Driven Maternal Plasticity.

Mother-infant bonding develops rapidly following parturition and is accompanied by changes in sensory perception and behavior. Here, we study how ultrasonic vocalizations (USVs) are represented in the brain of mothers. Using a mouse line that allows temporally controlled genetic access to active neurons, we find that the temporal association cortex (TeA) in mothers exhibits robust USV responses. Rabies tracing from USV-responsive neurons reveals extensive subcortical and cortical inputs into TeA. A particularly dominant cortical source of inputs is the primary auditory cortex (A1), suggesting strong A1-to-TeA connectivity. Chemogenetic silencing of USV-responsive neurons in TeA impairs auditory-driven maternal preference in a pup-retrieval assay. Furthermore, dense extracellular recordings from awake mice reveal changes of both single-neuron and population responses to USVs in TeA, improving discriminability of pup calls in mothers compared with naive females. These data indicate that TeA plays a key role in encoding and perceiving pup cries during motherhood.

Capacities and neural mechanisms for auditory statistical learning across species.

Statistical learning has been proposed as a possible mechanism by which individuals can become sensitive to the structures of language fundamental for speech perception. Since its description in human infants, statistical learning has been described in human adults and several non-human species as a general process by which animals learn about stimulus-relevant statistics. The neurobiology of statistical learning is beginning to be understood, but many questions remain about the underlying mechanisms. Why is the developing brain particularly sensitive to stimulus and environmental statistics, and what neural processes are engaged in the adult brain to enable learning from statistical regularities in the absence of external reward or instruction? This review will survey the statistical learning abilities of humans and non-human animals with a particular focus on communicative vocalizations. We discuss the neurobiological basis of statistical learning, and specifically what can be learned by exploring this process in both humans and laboratory animals. Finally, we describe advantages of studying vocal communication in rodents as a means to further our understanding of the cortical plasticity mechanisms engaged during statistical learning. We examine the use of rodents in the context of pup retrieval, which is an auditory-based and experience-dependent form of maternal behavior.

Sex-Specific Differences in Oxytocin Receptor Expression and Function for Parental Behavior.

Parental care is among the most profound behavior expressed by humans and other animals. Despite intense interest in understanding the biological basis of parental behaviors, it remains unknown how much of parenting is encoded by the genome and which abilities instead are learned or can be refined by experience. One critical factor at the intersection between innate behaviors and experience-dependent learning is oxytocin, a neurohormone important for maternal physiology and neuroplasticity. Oxytocin acts throughout the body and brain to promote prosocial and maternal behaviors and modulates synaptic transmission to affect neural circuit dynamics. Recently we developed specific antibodies to mouse oxytocin receptors, found that oxytocin receptors are left lateralized in female auditory cortex, and examined how oxytocin enables maternal behavior by sensitizing the cortex to infant distress sounds. In this study we compare oxytocin receptor expression and function in male and female mice. Receptor expression is higher in adult female left auditory cortex than in right auditory cortex or males. Developmental profiles and mRNA expression were comparable between males and females. Behaviorally, male and female mice began expressing parental behavior similarly after cohousing with experienced females; however, oxytocin enhanced parental behavior onset in females but not males. This suggests that left lateralization of oxytocin receptor expression in females provides a mechanism for accelerating maternal behavior onset, although male mice can also effectively co-parent after experience with infants. The sex-specific pattern of oxytocin receptor expression might genetically predispose female cortex to respond to infant cues, which both males and females can also rapidly learn.