NF1-cAMP signaling dissociates cell type–specific contributions of striatal medium spiny neurons to reward valuation and motor control

Abstract

The striatum plays a fundamental role in motor learning and reward-related behaviors that are synergistically shaped by populations of D1 dopamine receptor (D1R)- and D2 dopamine receptor (D2R)-expressing medium spiny neurons (MSNs). How various neurotransmitter inputs converging on common intracellular pathways are parsed out to regulate distinct behavioral outcomes in a neuron-specific manner is poorly understood. Here, we reveal that distinct contributions of D1R-MSNs and D2R-MSNs towards reward and motor behaviors are delineated by the multifaceted signaling protein neurofibromin 1 (NF1). Using genetic mouse models, we show that NF1 in D1R-MSN modulates opioid reward, whereas loss of NF1 in D2R-MSNs delays motor learning by impeding the formation and consolidation of repetitive motor sequences. We found that motor learning deficits upon NF1 loss were associated with the disruption in dopamine signaling to cAMP in D2R-MSN. Restoration of cAMP levels pharmacologically or chemogenetically rescued the motor learning deficits seen upon NF1 loss in D2R-MSN. Our findings illustrate that multiplex signaling capabilities of MSNs are deployed at the level of intracellular pathways to achieve cell-specific control over behavioral outcomes.

Understanding divergent domestication traits from the whole-genome sequencing of swamp- and river-buffalo populations

“…Additionally, adenylyl cyclase III ( ADYC3 ) was involved in all the pathways mentioned above and regulates the transduction of the physical and emotional signals (e.g. favorite food, soothing and care) into cAMP and eventually acting on the brain reward circuits [ 32 ] (Supplementary Fig. 31).…”

Developmental loss of neurofibromin across distributed neuronal circuits drives excessive grooming in Drosophila

“…These disorders emerge early in development and may involve both dysregulations of developmental processes and alterations in acute signaling/neuronal function in the developed nervous system. Nf1 has been observed to have important functions in adult mice and flies [14,19,27,28], and some phenotypes can be rescued by acute pharmacological treatment in adult animals [65]. Nonetheless, our data suggest that Nf1 loss disrupts a distributed set of microcircuits during a critical developmental window.…”

“…The most well-described biochemical function of Nf1 is its conserved Ras-GAP activity, inhibiting Ras [ 12 , 41 ]. However, it also affects other signaling cascades via direct and putative indirect interactions, such as G protein-coupled receptor signaling and cAMP/PKA regulation [ 16 , 17 , 19 , 27 , 42 – 46 ]. To begin probing the critical downstream effectors regulating the grooming phenotype, we used the Gal4-UAS system to express wild-type and GAP-related domain (GRD) mutant Nf1 transgenes in an Nf1 mutant background.…”

“…Learning deficits in Nf1 mutant mice stem from the loss of the gene in GABAergic inhibitory interneurons but not excitatory neurons or glia [26]. Motor and depression-like phenotypes in a mouse model map to dopamine receptor D1 positive neurons in the striatum [27]. In Drosophila, Nf1 mutants exhibit olfactory learning deficits that map to a subset of neurons in the mushroom bodies, important structures for learning and memory [28].…”

Neurofibromin Structure, Functions and Regulation

“…Recently, neurofibromin was shown to be involved in the dopamine-mediated production of cAMP in a population of striatal neurons (D2-dopamine receptor expressing medium spiny neurons), suggesting a role in motor learning [122].…”