FOXP2 in the Nucleus Accumbens Regulates Reward Signaling and Social Behavior

Background: Disturbances of speech and language are part of a large variety of neuropsychiatric syndromes including autisms. The complex genetic architecture of these disorders and their speech and language related endophenotypes cause substantial problems in the identification of underlying molecular and neuronal networks. Previously a human mutation in the forkhead-box transcription factor Foxp2 has been identified as the first example of a gene specifically implicated in a speech and language disorder. While the speech endophenotypes have been very instrumental in initial genetic mapping, it has long been suggested that critical roles of FOXP2 might lie further ‘upstream’ than the motor system. Foxp2 is highly conserved in genomic structure and neuronal expression pattern and thought to play important roles in development and/or function of cortical and striatal neuronal circuits. Our previous studies  in Foxp2+/- mice  suggested a close interaction between this transcription factor and the dopaminergic system with potentially important implications for reward associated behavior.  

Objectives: We aimed to study the potential role of Foxp2 in DA signaling, to identify involved neuronal circuits and to dissect developmental from adult functions of Foxp2 in reward associated behavior and social interaction. Finally we explored DA activity dependent Foxp2 transcriptional targets in reward circuits. 

Methods: We used robust neuropharmacological approaches, extensive behavioral analysis,electrophysiology and genomic approaches in Foxp2+/-  and Foxp2 conditonal mutant mice. 

Results: Foxp2^+/- mice exhibit a severely attenuated cocaine-induced hyperlocomotion response and significantly decreased ERK phosphorylation elicited by cocaine compare to Foxp2^+/+. The ERK signaling deficit was specifically detected in the nucleus accumbens (Nac) but not in the dorsal striatum. Foxp2 mRNA and protein level were acutely (1h) downregulated in the NAc but not the dorsal striatum 1h following cocaine.DA signaling in the NAc is particularly implicated in associative reward-relating learning and social behaviors, we employed conditioned place preference (CPP) to cocaine and social interactions paradigms in Foxp2 deficient mice. We observed that CPP and social behaviors areimpaired in Foxp2^+/- mice NAc-specific deletion in adult Foxp2^lox/lox mice recapitulated the impaired cocaine-induced hyperlocomotion response and social interaction deficits found in Foxp2^+/- mice.These alterations were associated with deficits in high frequency stimulation induced LTP at cortico-striatal synapses from cortical projections to the NAc, a key synaptic plasticity mechanism for reward learning. Finally, Nac transcriptome profiling in Foxp2 defincient mice following DA stimulation, identify gene networks underlying the role of Foxp2 on reward processing. 

Conclusions: Our data suggest that Foxp2 in Dopamine 1 receptor expressing medium spiny neurons (MSNs) in the Nac has neuronal activity-dependent functions in DA mediated reward signaling. These results resonate with clinical and imaging studies in autism spectrum disorders (ASD) suggesting that social motivation deficits due to decreased reward value for social stimuli as a key pathomechanism. The decreased salience of social stimuli such as faces is thought to profoundly impair the later development of social cognition and language. In this context our results suggest that exploring Foxp2 regulated gene networks in nucleus accumbens MSNs might provide new insights into conserved molecular and cellular mechanisms of social decision making (SDM) networks.