Impairments in effort-related aspects of motivation can result in psychiatric symptoms that are seen across several patient populations. The severity of effort-related symptoms is highly correlated with problems in social function, employment, and treatment outcomes. The neural basis of effort-related dysfunctions are still being characterized, nevertheless, considerable evidence implicates nucleus accumbens (NAc) dopamine (DA), basal ganglia and related corticolimbic circuitry. My graduate and postdoctoral training thus far have provided me with extensive experience monitoring changes in DA transmission in healthy and states of amotivation through use of microdialysis and voltammetry approaches. However, to better understand the circuit architecture of the NAc, I propose to learn whole cell electrophysiology and awake behaving optogenetic approaches under the primary mentorship of Drs. Jeff Conn and Erin Calipari to round out my training and have the necessary skills to produce high impact publications and successful R01 submissions. Recent studies have shown the importance of NAc D1- and D2-medium spiny neurons (MSNs) and their projections in the regulation of goal directed behavior. A crucial regulator of MSN activity and DA release is the muscarinic acetylcholine (mACh) M1 receptor. Our preliminary data demonstrates that selective activators of M1 increase motivated behavior, an effect which may be mediated, in part, by increased excitability of D1-MSNs in the NAc lateral (NAcLat) shell subregion. Interestingly, the regulatory role of M1 on NAc microcircuitry has not yet been investigated. In the mentored K-phase of this Award, I will focus on the modulatory role of M1 on D1-MSNs in NAc shell subregions and subsequent effects of activation or inhibition of D1-MSNs in effort-related choice behavior. The innovative combination of these tools will enable me to understand the actions of M1 on D1- MSNs, and how this action drives allocation of effort-related choice behavior. In the independent phase (R00), I will use these techniques to study individual differences in work output, which may lead to the development of individualized medicine. Together, the proposed studies will elucidate the role of M1 on NAc microcircuitry, which will expand our basic understanding of the neural circuits underlying effort-related choice behavior and may lead to the development of novel therapeutic avenues. In summary, the research proposed in this Pathway to Independence Award will illuminate the neural mechanisms involved in allocation of effort, while simultaneously preparing me to develop a fully independent research program capable of integrating a wide range of circuit based and behavioral approaches to dissect the neurobiology of motivational dysfunctions.
While motivational dysfunctions are one of the most common psychiatric symptoms in general medicine, current treatment options are limited; thus, there is an unmet clinical need to develop potential therapeutics through investigation of putative mechanisms in animal models. Dysregulation of dopaminergic signaling and medium spiny neurons (MSNs) in the nucleus accumbens (NAc) have been linked to amotivation. The current proposal will provide evidence for guiding novel treatment development by investigating precisely how the muscarinic acetylcholine M1 receptor regulates NAc circuit architecture and influences effort-related choice behavior through interactions with D1-MSNs that project to the midbrain.
