Atypical habituation and aberrant exploration of novel stimuli have been related to the severity of autism spectrum disorders (ASDs), but the underlying neuronal circuits are unknown. Here we show that chemogenetic inhibition of dopamine (DA) neurons of the ventral tegmental area (VTA) attenuates exploration toward nonfamiliar conspecifics and interferes with the reinforcing properties of nonfamiliar conspecific interaction in mice. Exploration of nonfamiliar stimuli is associated with the insertion of GluA2-lacking AMPA receptors at excitatory synapses on VTA DA neurons. These synaptic adaptations persist upon repeated exposure to social stimuli and sustain conspecific interaction. Global or VTA DA neuron-specific loss of the ASD-associated synaptic adhesion molecule neuroligin 3 alters the behavioral response toward nonfamiliar conspecifics and the reinforcing properties of conspecific interaction. These behavioral deficits are accompanied by an aberrant expression of AMPA receptors and an occlusion of synaptic plasticity. Altogether, these findings link impaired exploration of nonfamiliar conspecifics to VTA DA neuron dysfunction in mice.

SummaryHaploinsufficiency of SHANK3, encoding the synapse scaffolding protein SHANK3, leads to a highly penetrant form of Autism Spectrum Disorder (ASD). How SHANK3 insufficiency affects specific neural circuits and this is related to specific ASD symptoms remains elusive. Here we used shRNA to model Shank3 insufficiency in the Ventral Tegmental Area (VTA) of mice. We identified dopamine (DA) and GABA cell-type specific changes in excitatory synapse transmission that converge to reduce DA neuron activity and generate behavioral deficits, including impaired social preference. Administration of a positive allosteric modulator of the type 1 metabotropic glutamate receptors (mGluR1) during the first postnatal week restored DA neuron excitatory synapse transmission and rescued the social preference defects, while optogenetic DA neuron stimulation was sufficient to enhance social preference. Collectively, these data reveal the contribution of impaired VTA function to social behaviors and identify mGluR1 modulation during postnatal development as a potential treatment strategy.

Social interactions are motivated behaviors that in many species facilitate learning. However, how the brain encodes the reinforcing properties of social interactions remains elusive. Here, using in vivo recording in freely moving mice, we show that dopamine (DA) neurons of the ventral tegmental area (VTA) increase their activity during interactions with an unfamiliar conspecific and display heterogeneous responses. Using a social instrumental task (SIT), we then show that VTA DA neuron activity encodes social prediction error and drives social reinforcement learning. Thus, our findings suggest that VTA DA neurons are a neural substrate for a social learning signal that drives motivated behavior.

No abstract

Accurate tracking and analysis of animal behavior is crucial for modern systems neuroscience. Animals can be easily monitored in confined, well-lit spaces or virtual-reality setups. However, tracking freely moving behavior through naturalistic, three-dimensional (3D) environments remains a major challenge. A closed-loop control that provides behavior-triggered stimuli and thus structures a behavioral task, is also more complicated in free-range settings. Here, we present EthoLoop: a framework for studying the neuroethology of freely roaming animals, including examples with rodents and primates. Combining real-time optical tracking, "on the fly" behavioral analysis with remote-controlled stimulus-reward boxes, allows us to directly interact with free-ranging animals in their habitat. Assembled with off-the-shelf and wireless hardware, we show that this closed-loop optical tracking system can be used to follow the 3D spatial position of multiple subjects in real time, continuously provide close-up views, condition behavioral patterns detected online with deep learning methods and be synchronized with wirelessly acquired neuronal recordings or with optogenetic feedback. Reward or stimulus feedback is provided by battery-powered and remote-controlled boxes that communicate with the tracking system and can be distributed at multiple locations in the environment. The EthoLoop framework enables a new generation of interactive, but well-controlled and reproducible neuroethological studies in large-field naturalistic settings.

Social behaviours characterize cooperative, mutualistic, aggressive or parental interactions that occur among conspecifics. Although the Ventral Tegmental Area (VTA) has been identified as a key substrate for social behaviours, the input and output pathways dedicated to specific aspects of conspecific interaction remain understudied. Here, in male mice, we investigated the activity and function of two distinct VTA inputs from superior colliculus (SC-VTA) and medial prefrontal cortex (mPFC-VTA). We observed that SC-VTA neurons display social interaction anticipatory calcium activity, which correlates with orienting responses towards an unfamiliar conspecific. In contrast, mPFC-VTA neuron population activity increases after initiation of the social contact. While protracted phasic stimulation of SC-VTA pathway promotes head/body movements and decreases social interaction, inhibition of this pathway increases social interaction. Here, we found that SC afferents mainly target a subpopulation of dorsolateral striatum (DLS)-projecting VTA dopamine (DA) neurons (VTADA-DLS). While, VTADA-DLS pathway stimulation decreases social interaction, VTADA-Nucleus Accumbens stimulation promotes it. Altogether, these data support a model by which at least two largely anatomically distinct VTA sub-circuits oppositely control distinct aspects of social behaviour.

Individuals differ in their traits and preferences, which shape their interactions, their prospects for survival and their susceptibility to diseases. These correlations are well documented, yet the neurophysiological mechanisms underlying the emergence of distinct personalities and their relation to vulnerability to diseases are poorly understood. Social ties, in particular, are thought to be major modulators of personality traits and psychiatric vulnerability, yet the majority of neuroscience studies are performed on rodents in socially impoverished conditions. Rodent micro-society paradigms are therefore key experimental paradigms to understand how social life generates diversity by shaping individual traits. Dopamine circuitry is implicated at the interface between social life experiences, the expression of essential traits, and the emergence of pathologies, thus proving a possible mechanism to link these three concepts at a neuromodulatory level. Evaluating inter-individual variability in automated social testing environments shows great promise for improving our understanding of the link between social life, personality, and precision psychiatry – as well as elucidating the underlying neurophysiological mechanisms.

Social interactions motivate behavior in many species, facilitating learning, foraging and cooperative behavior. However, how the brain encodes the reinforcing properties of social interactions remains elusive. Here using in vivo recording in freely moving mice, we show that Dopamine (DA) neurons of the Ventral Tegmental Area (VTA) increase their activity during active interactions with unfamiliar conspecific. Using a social instrumental task, we then show that VTA DA neuron activity signals social reward prediction error and drives social reinforcement learning. Thereby, our findings propose that VTA DA neurons are a neural substrate for a social learning signal driving motivated behavior.the lever zone and in the interaction zone. Friedman test (χ 2 (49) = 61.27, P < 0.0001) followed by Bonferroni-Holm correction.