Behavioural learning depends on the brain's capacity to respond to instructive experience and is often enhanced during a juvenile sensitive period. How instructive experience acts on the juvenile brain to trigger behavioural learning remains unknown. In vitro studies show that forms of synaptic strengthening thought to underlie learning are accompanied by increased stability, number and size of dendritic spines, the major site of excitatory synaptic transmission in the vertebrate brain1-7. In vivo imaging studies in sensory cortical regions reveal that these structural features can be affected by disrupting sensory experience and that spine turnover is elevated during sensitive periods for sensory map formation8-12. These observations support two hypotheses: 1) the increased capacity for behavioural learning during a sensitive period is associated with enhanced spine dynamics on sensorimotor neurons important to the learned behaviour; 2) instructive experience rapidly stabilizes and strengthens these dynamic spines. Here we tested these hypotheses using two-photon in vivo imaging to measure spine dynamics in zebra finches, which learn to sing by imitating a tutor song during a juvenile sensitive period13,14. Spine dynamics were measured in the forebrain nucleus HVC, the proximal site where auditory information merges with an explicit song motor representation15-19, immediately before and after juvenile finches first experienced tutor song20. Higher levels of spine turnover prior to tutoring correlated with a greater capacity for subsequent song imitation. In juveniles with high levels of spine turnover, hearing a tutor song led to the rapid (~24h) stabilization, accumulation and enlargement of dendritic spines in HVC. Moreover, in vivo intracellular recordings made immediately before and after the first day of tutoring revealed robust enhancement of synaptic activity in HVC. These findings suggest behavioural learning results when instructive experience is able to rapidly stabilize and strengthen synapses on sensorimotor neurons important to the control of the learned behaviour.Investigating structural correlates of song learning requires repeated imaging of dendritic structure as a juvenile bird learns to sing. We used lentivirus-GFP constructs to fluorescently Users may view, print, copy, download and text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#termsCorrespondence and requests for materials should be addressed to R.M. (mooney@neuro.duke.edu). Supplementary Information accompanies the paper Author ContributionsT.F.R. and R.M. designed the study and wrote the manuscript. T.F.R. and K.A.T. collected and analyzed the imaging and behavioural data. T.F.R. and M.E.K. designed the lentiviral construct and M.E.K. made the lentivirus. T.F.R and R.M. collected the electrophysiological data. HHS Public Access Author ManuscriptAuthor Manuscript Author ManuscriptAu...

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Summary Hearing loss prevents vocal learning and causes learned vocalizations to deteriorate, but how vocalization-related auditory feedback acts on neural circuits that control vocalization remains poorly understood. We deafened adult zebra finches, which rely on auditory feedback to maintain their learned songs, to test the hypothesis that deafening modifies synapses on neurons in a sensorimotor nucleus important to song production. Longitudinal in vivo imaging revealed that deafening selectively decreased the size and stability of dendritic spines on neurons that provide input to a striatothalamic pathway important to audition-dependent vocal plasticity, and changes in spine size preceded and predicted subsequent vocal degradation. Moreover, electrophysiological recordings from these neurons showed that structural changes were accompanied by functional weakening of both excitatory and inhibitory synapses, increased intrinsic excitability, and changes in spontaneous action potential output. These findings shed light on where and how auditory feedback acts within sensorimotor circuits to shape learned vocalizations.

Animals vocalize only in certain behavioral contexts, but the circuits and synapses through which forebrain neurons trigger or suppress vocalization remain unknown. Here, we used transsynaptic tracing to identify two populations of inhibitory neurons that lie upstream of neurons in the periaqueductal gray (PAG) that gate the production of ultrasonic vocalizations (USVs) in mice (i.e. PAG-USV neurons). Activating PAG-projecting neurons in the preoptic area of the hypothalamus (POAPAG neurons) elicited USV production in the absence of social cues. In contrast, activating PAG-projecting neurons in the central-medial boundary zone of the amygdala (AmgC/M-PAG neurons) transiently suppressed USV production without disrupting non-vocal social behavior. Optogenetics-assisted circuit mapping in brain slices revealed that POAPAG neurons directly inhibit PAG interneurons, which in turn inhibit PAG-USV neurons, whereas AmgC/M-PAG neurons directly inhibit PAG-USV neurons. These experiments identify two major forebrain inputs to the PAG that trigger and suppress vocalization, respectively, while also establishing the synaptic mechanisms through which these neurons exert opposing behavioral effects.

Songbirds use auditory feedback to learn and maintain their songs, but how feedback interacts with vocal motor circuitry remains unclear. A potential site for this interaction is the song premotor nucleus HVC, which receives auditory input and contains neurons (HVCX cells) that innervate an anterior forebrain pathway (AFP) important to feedback-dependent vocal plasticity. Although the singing-related output of HVCX cells is unaltered by distorted auditory feedback (DAF), deafening gradually weakens synapses on HVCX cells, raising the possibility that they integrate feedback only at subthreshold levels during singing. Using intracellular recordings in singing zebra finches, we found that DAF failed to perturb singing-related synaptic activity of HVCX cells, although many of these cells responded to auditory stimuli in non-singing states. Moreover, in vivo multiphoton imaging revealed that deafening-induced changes to HVCX synapses require intact AFP output. These findings support a model in which the AFP accesses feedback independent of HVC.DOI:http://dx.doi.org/10.7554/eLife.01833.001

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9Animals vocalize only in certain behavioral contexts, but the circuits and synapses through 10 which forebrain neurons trigger or suppress vocalization remain unknown. Here we used 11 transsynaptic tracing to identify two populations of inhibitory neurons that lie upstream of 12 neurons in the periaqueductal gray that gate the production of ultrasonic vocalizations in mice 13 (i.e., PAG-USV neurons). Activating PAG-projecting neurons in the preoptic hypothalamus 14 (POAPAG neurons) elicited USV production in the absence of social cues. In contrast, activating 15 PAG-projecting neurons in the extended amygdala (EAPAG neurons) transiently suppressed USV 16 production without disrupting non-vocal social behavior. Optogenetics-assisted circuit mapping 17 in brain slices revealed that POAPAG neurons directly inhibit PAG interneurons, which in turn 18 inhibit PAG-USV neurons, whereas EAPAG neurons directly inhibit PAG-USV neurons. These 19 experiments identify two major forebrain inputs to the PAG that trigger and suppress 20 vocalization, respectively, while also establishing the synaptic mechanisms through which these 21 neurons exert opposing behavioral effects. 22 23

Humans are extraordinarily social, and social isolation has profound effects on our behavior, ranging from increased social motivation following short periods of social isolation to increased anti-social behaviors following long-term social isolation. Mice are frequently used as a model to understand how social isolation impacts the brain and behavior. While the effects of chronic social isolation on mouse social behavior have been well studied, much less is known about how acute isolation impacts mouse social behavior and whether these effects vary according to the sex of the mouse and the behavioral context of the social encounter. To address these questions, we characterized the effects of acute (3-day) social isolation on the vocal and non-vocal social behaviors of male and female mice during same-sex and opposite-sex social interactions. Our experiments uncovered pronounced effects of acute isolation on social interactions between female mice, while revealing more subtle effects on the social behaviors of male mice during same-sex and opposite-sex interactions. Our findings advance the study of same-sex interactions between female mice as an attractive paradigm to investigate neural mechanisms through which acute isolation enhances social motivation and promotes social behavior.