Neuronal signature of social novelty exploration in the VTA: implication for Autism Spectrum Disorder

Abstract

Novel stimuli attract our attention, promote exploratory behavior, and facilitate learning. Atypical habituation and aberrant novelty exploration have been related with the severity of Autism Spectrum Disorders (ASD) but the underlying neuronal circuits are unknown. Here, we report that dopamine (DA) neurons of the ventral tegmental area (VTA) promote the behavioral responses to novel social stimuli, support preference for social novelty, and mediate the reinforcing properties of novel social interaction. Social novelty exploration is associated with the insertion of calciumpermeable GluA2-lacking AMPA-type glutamate receptors at excitatory synapses on VTA DA neurons. These novelty-dependent synaptic adaptations only persist upon repeated exposure to social stimuli and sustain social interaction. Global or DA neuron-specific inactivation of the ASD risk gene Neuroligin3 alters both social novelty exploration and the reinforcing properties of social stimuli. These behavioral deficits are accompanied by an aberrant expression of non-canonical GluA2-lacking AMPA-receptors at excitatory synapses on VTA DA neurons and an occlusion of novelty-induced synaptic plasticity. Altogether, these findings causally link impaired novelty exploration in an ASD mouse model to VTA DA circuit dysfunction.All rights reserved. No reuse allowed without permission.

Dopamine neurons projecting to medial shell of the nucleus accumbens drive heroin reinforcement

“…To this end, we injected DAT-Cre mice expressing hSyn-DIO-hM4D(Gi) in VTA DA neurons with CNO 1 hr prior to heroin self-administration ( Figure 4a–b ). This chemogenetic intervention has been shown to be efficient to hyperpolarize DA neurons in acute midbrain slices ( Bariselli et al, 2018 ). Silencing VTA DA neurons in animals where self-administration was well established significantly decreased the number of active lever presses and ensuing heroin infusions ( Figure 4c–e , 223 ± 60 LP for 111 ± 25 infusions dropped to 23 ± 9 LP for 15 ± 6 infusions after 4 days of treatment condition (DAT-Cre + versus DAT-Cre - ) x CNO (present, absent), two-way repeated measures ANOVA and multiple comparison post-hoc Sidack test, *p<0.05, **p<0.005, ****p<0.0001).…”

Dopamine neurons projecting to medial shell of the nucleus accumbens drive heroin reinforcement

“…To this end, we injected DAT-Cre mice expressing hSyn-DIO-hM4D(Gi) in VTA DA neurons with CNO 1 h prior to heroin self-administration (Figure 4a-b). This chemogenetic intervention has been shown to be efficient to hyperpolarize DA neurons in acute midbrain slices (Bariselli et al, 2018). Silencing VTA DA neurons in animals where self-administration was well established significantly decreased the number of active lever presses and ensuing heroin infusions ( Figure 4c-e, 223 ± 60 LP for 111 ± 25 infusions dropped to 23 ± 9 LP for 15 ± 6 infusions after 4 days of treatment condition (DAT-Cre + versus DAT-Cre -) x CNO (present, absent), two-way repeated measures ANOVA and multiple comparison post-hoc Sidack test, *P<0.05, **P<0.005, ****P<0.0001).…”

Sexual representation of social memory in the ventral CA1 neurons

“…Similarly, the ablation of dCA2, which plays a pivotal role in encoding social memory (2,3), leads to nondiscriminative place preference by activating vCA1 social memories, irrespective of the sex of the stimuli. The activation of imperfect social memory, which lacks sex-specific information or high-dimensional features of individual conspecifics, could exert a positive reinforcing effect by unmasking the inherently rewarding nature of social information (44) or by inducing an internal state akin to social novelty, which can elicit conditioned place preferences (45). Although functional connectivity is not fully understood, both the MeA and dCA2 send direct and indirect projections to the vCA1 (4,46,47).…”