Failure of impulse control epitomizes many psychiatric diseases. Patients with autism spectrum disorders (ASDs), which are characterized chiefly by socio-communicative abnormalities and stereotypic/repetitive behaviors, commonly exhibit increased impulsivity1?3. A convergence of evidence across humans and mouse models has implicated the nucleus accumbens (NAc) as one source of cognitive impairments4. The NAc is composed primarily of medium spiny neurons, which are sub-divided based on their expression of Drd1a (D1- MSNs) or Drd2 (D2-MSNs) dopamine receptors, and parvalbumin-positive (PV+) interneurons that restrain and sculpt MSN activity through strong synaptic inhibition5. Although the NAc represents a critical node for integrating cognitive information6, its complex cellular organization has made studying its role in cognition and disease traditionally intractable. The first goal of this proposal is to use modern optogenetic tools in behaving mice to monitor (Aim 1) and modulate (Aim 2) PV+ interneurons within the NAc to elucidate their role in impulse control. To accomplish this, I will employ the five- choice serial reaction time task (5-CSRTT), which assays an array of cognitive processes, including instrumental learning, visuo-spatial attention, and impulse control7. My preliminary data using the 5-CSRTT point to a specific role of NAc PV+ interneurons for counteracting impulsive behavior. To study the microcircuitry of the NAc in disease, I will examine mice harboring a genetic deletion of neuroligin- 3 (Nlgn3), an important post-synaptic molecule for synapse development and maintenance8,9. Highly penetrant Nlgn3 mutations have been identified in human patients with ASDs10 and Nlgn3 mutant mice reproduce behavioral outcomes that parallel human symptomatology11. My sponsor has recently identified dysregulated inhibitory signaling within the NAc of Nlgn3 mutant mice12. I have collected additional preliminary data demonstrating increased impulsive behavior of Nlgn3 mutant mice in the 5-CSRTT. Thus, the second goal of this proposal is to apply the same imaging and modulation techniques to characterize and reverse the behavioral and pathophysiological features of Nlgn3 mutant mice (Aim 3). Based off my preliminary findings, I predict that reduced PV+ interneuron activity underlies the impulsivity phenotype of Nlgn3 mutant mice and optogenetically activating these cells will correct this loss of impulse control.
Cognitive impairments epitomize many psychiatric diseases, including autism spectrum disorders (ASDs). Using state-of-the-art optogenetic tools, this proposal aims to elucidate the specific cell-level contributions of the nucleus accumbens in impulse control and impairments of a mouse model of ASDs. This knowledge can advance our understanding of the brain and better inform the development of therapeutics for ASDs.
