Humans have a lot in common with prairie voles—at least when it comes to mating. Unlike the vast majority of mammalian species, we often enter into monogamous pair bonds. A crucial molecule involved in determining this mating strategy is oxytocin. Popularly known as the “cuddle hormone,” oxytocin is a neuropeptide that plays an ancient role in orchestrating social and reproductive behaviors , and frequently makes headlines because of its ability to influence a variety of interesting behaviors . Until recently, however, it has remained unclear how and where oxytocin is exerting its effects in the brain. Using modern experimental tools, neuroscientists are beginning to develop a more mechanistic understanding of how oxytocin affects specific circuits in the brain.
Female mice display a variety interesting behaviors that depend on their sexual experience. To an experienced female, pup vocalizations are a highly salient sensory stimulus and drive robust maternal behavior—if a mother hears a distress call from a pup that has been separated from the nest, she will quickly locate the lost pup and bring it back. This is not true for virgin females, who rarely display this behavior. However, virgin females can be made to act in a maternal fashion by systemic oxytocin administration, suggesting that oxytocin may be important for the development of this maternal behavior. In a recent study, researchers uncovered a fascinating circuit mechanism by which oxytocin sculpts the auditory system of new mothers in order for this maternal behavior to arise .
As a first clue to where oxytocin may be working to promote pup retrieval behavior, Marlin and colleagues used transgenic mice and immunohistochemistry to visualize where oxytocin receptors are found in the female mouse brain. One interesting location where they were detected, in both experienced mothers and naïve virgin females, was the primary auditory cortex. The receptors were found on both inhibitory interneurons within the auditory cortex and the axon terminals of hypothalamic neurons that secrete oxytocin directly into cortex. Even more intriguing was their finding that receptor expression is lateralized: oxytocin receptors are more densely expressed in the left auditory cortex than in the right, reminiscent of the lateralization of language functions in the human brain.
Next, pharmacology and optogenetics were used to manipulate neural activity in the left vs. right auditory cortex. In virgin females, they found that stimulating oxytocin signaling in the left auditory cortex promoted pup retrieval. In experienced mothers, broad-spectrum inactivation of the left auditory cortex disrupted pup retrieval behavior, but specifically blocking oxytocin signaling had no effect. Why would completely shutting down the primary auditory cortex disrupt behavior, but not disrupting oxytocin signaling specifically? One explanation could be that oxytocin is important for plasticity: in its presence, the circuits of auditory cortex are able to change with experience. These changes may then consolidate into a long-term memory—after that, oxytocin signaling no longer matters.
To study the effects of oxytocin on activity and plasticity, they next recorded electrical activity from auditory cortex neurons. Compared to virgin females, auditory cortical neurons in maternal mice displayed larger and more reliable responses to pup distress calls. They further showed that, in the presence of oxytocin, pup calls rapidly decreased the amount of inhibition in auditory cortex. By temporarily decreasing inhibition, sensory signals can be boosted in a way that promotes synaptic plasticity, potentially resulting in the formation of new memories. Cortical disinhibition is emerging as a common circuit mechanism that the brain uses for associative learning, and has been causally linked to the acquisition of multiple behavioral functions, including conditioned fear and spatial navigation behaviors . Could oxytocin-induced disinhibition lead to a persistent increase in the salience of pup distress calls in the female brain?
By pairing pup distress calls with stimulation of oxytocin signaling, researchers were able to transform how the auditory cortex of virgin females represented pup calls, making it look more like it does in maternal mice. The basic model works like this: oxytocin decreases the level of inhibition in auditory cortex. In this state of disinhibition, auditory cortical neurons are more responsive to pup calls, and the boosted responses induce plasticity. As oxytocin signaling fades, cortical inhibition returns to normal, stabilizing the oxytocin-enhanced responses to pup calls. In this way, the salience of pup calls can be stably enhanced in the maternal brain. This helps makes sense of why disrupting oxytocin signaling fails to disrupt pup retrieval behavior in experienced, maternal females: their auditory cortex had already consolidated the plastic changes needed for responding to pup distress calls
So what’s happening in natural settings? One possible model of how things work is that oxytocin levels in the maternal brain increase in response to hormonal changes during pregnancy, and by sensory cues from pups, such as pheromones. This increase in oxytocin signaling would render circuits in the maternal brain more plastic and better able to learn to respond to signals from pups. Without oxytocin, the brain’s ability to learn to relevance of these specific social cues would be impoverished. If it turns out to be generally true that oxytocin renders animals more sensitive to social cues it could have implications for our understanding of neurodevelopmental disorders such as autism, where individuals seem to lack the ability to assign importance to social cues.
 Garrison JL, Macosko EZ, Bernstein S, Pokala N, Albrecht DR, Bargmann CI. Oxytocin/vasopressin-related peptides have an ancient role in reproductive behavior. Science 338, 540-3 (2012).
 Shen H. Neuroscience: the hard science of oxytocin. Nature | News Feature 522, 410-2 (2015).
 Marlin BJ, Mitre M, D’amour JA, Chao MV, Froemke RC. Oxytocin enables maternal behaviour by balancing cortical inhibition. Nature 520, 499-504 (2015).
 Letzkus JJ, Wolff SB, Luthi A. Disinhibition, a Circuit Mechanism for Associative Learning and Memory. Neuron 88, 264-76 (2015).