This is a highly collaborative project that aims to understand the anatomical distribution of striatal cholinergic interneurons that in addition to acetylcholine (ACh), also co-transmit glutamate or GABA. Previous literature have reported that this heterogenerous transmission (ACh/Glutamate/GABA) is responsible to differentialy regulate dopamine release across subregions of the striatum and behavior.

Neuronal circuits are an intricate mosaic of diverse cell types, each endowed with specific functions and distinctive sets of synaptic connections. To decipher the driving force behind behaviors, it becomes imperative to scrutinize the roles of these individual cell types within the circuit, investigate how neuromodulatory systems (e.g., dopamine and ACh) regulate their functions, and understand how the environment provides context for the myriad in vivo mechanisms shaping specific behavioral outcomes. To date, however, studies have for the most part been unable to identify the relationship between environmental factors and genetic predispositions that govern the functioning of circuits responsible for specific behaviors. This is a seminal study that will help to 1) identifying the cell types, neuromodulatory mechanisms, and local circuits involved in specific behaviors, 2) determining how these local circuits function together and adapt to environmental contexts during behavior, and 3) understanding how genetic factors can determine susceptibility to develop awry maladaptive circuits during environmental insults. 

The ability to learn Pavlovian associations between environmental cues predicting positive outcomes is critical for survival, motivating adaptive behaviors including approaches toward cues signaling rewards. This cued-motivated behavior is mediated by the nucleus accumbens, and its output activity heavily regulated by dopamine, but also by acetylcholine released from cholinergic interneurons (CINs). Dopamine-acetylcholine balance is critical for the acquisition of stimulus-reward associations. However, CINs also release glutamate and the involvement of CIN-derived acetylcholine and glutamate in the updating of dopaminergic signaling is not understood. 

Here I combine in vivo recordings of dopamine, acetylcholine, and calcium dynamics from D1- and D2-expressing spiny projecting neurons (SPNs) using fiber photometry in mice performing a touchscreen Pavlovian task to understand how these signals operate together in the service of cue-motivated behaviors. This project was recently accepted for publication in Nature Communications! 

Genetic variants of Neuregulin 1 (NRG1) and its neuronal tyrosine kinase receptor ErbB4 are associated with risk for schizophrenia, a neurodevelopmental disorder characterized by excitatory/inhibitory imbalance and dopamine (DA) dysfunction. NRGs have shown to modulate DA levels, suggesting a role for ErbB4 signaling in dopaminergic neuron function. Using genetic, biochemistry, in vivo microdialysis, behavior, and neurochemical approaches, I led this project to demonstrate that ErbB4 in midbrain DAergic axonal projections regulates extracellular DA levels in hippocampus, cortex and striatum, a mechanism relevant to regulate cognitive and motivational behaviors. My findings indicate that direct NRG/ErbB4 signaling in DAergic axonal projections modulates DA homeostasis, and that NRG/ErbB4 signaling contribute to the modulation of behaviors relevant to psychiatric disorders.

Circuit mechanisms in the nucleus accumbens (NAc) and the ventral pallidum (VP) have emerged as important network hubs regulating depressive-like behaviors. I explored the role of cholinergic and GABAergic mechanisms during depressive-like behaviors in rats. Microdialysis coupled with HPLC and micellar electrokinetic chromatography was used to monitor in vivo changes of acetylcholine and GABA in the NAc and VP of rats performing a battery of behavioral tasks inducing low motivation. In addition, I combined molecular a biochemical strategies to record the levels of expression of cholinergic and GABAergic receptors. My findings suggest that altered cholinergic and GABAergic mechanisms underlie a low motivational state, anhedonia and a possible memory mechanism for unpleasant experiences in rodents.

I believe that thanks to the generosity of peers sharing their skills and willingness to do better science, we are better prepared to tackle the ever growing challenges that our society demands from us. 

As such, I cultivate a collaborative atmosphere in my work environment that benefits my community, but also makes science funnier.