Dysregulated levels of neuromodulators and other chemical signals may contribute to behavioral characteristics of autism spectrum disorder (ASD). Yet previous studies have often examined only one or a few signals, and typically provide a static description of signal levels in the brain or in the cerebrospinal fluid (CSF) that bathes all neurons. In reality, brain tissues and CSF contain hundreds of signals that can exhibit dynamic changes across states ranging from quiet waking to arousal in social and non-social situations. For example, decreases in central and peripheral vasopressin levels are strongly implicated in ASD, and intranasal delivery of vasopressin is a promising treatment for ASD in early trials. However, two major challenges have impeded progress in improving therapies for optimal delivery of vasopressin and other neuromodulatory signals. Specifically, we lack the ability to accurately (i) track and (ii) control multiple neuromodulatory signals in real time in the brain.

In this project, Mark Andermann and colleagues plan to address the first challenge using novel methods they are developing for multiplexed, quantitative imaging of multiple optical sensors of neuromodulators and chemical signals implicated in ASD. These include acetylcholine, adenosine, corticotropin-releasing factor, dopamine, histamine, melatonin, norepinephrine, oxytocin, serotonin, somatostatin, vasoactive intestinal peptide and vasopressin. The team will address the second challenge by developing closed-loop delivery of signals to the brain in a genetic mouse model of ASD, Magel2 heterozygous mice, that exhibit dysfunction in secretory granules and have been shown to exhibit reduced levels of brain vasopressin and other neuropeptides. They will initially focus on controlled tracking and augmentation of vasopressin and then expand to tracking and controlling multiple signals simultaneously.

This proposal offers a novel, holistic framework for the dynamic study and control of dozens of neuromodulators and peptides in mouse models of ASD. Together, these achievable aims provide a roadmap for rational open- and closed-loop tracking and control of combination drug therapies delivered intranasally or intracerebroventricularly via the CSF.