Neuropsychiatric disorders affect function in several domains: perception (emotional, sensory), integration (information, emotion, sensations), cognition (working memory, social cognition, attention), motivation (hedonic drive, executive function), and others. The impairment in these brain functions offers possible insight into the symptoms of disorganization, hallucinations, delusions, lack of relatedness, involution, distractedness, and cognitive decline that characterize these disorders. One hypothesis is that some of these dysfunctions appear to result from impaired integration of stimuli among various brain regions. Indeed, how the brain integrates the diversity of external and internal stimuli intoa coherent experience is one of the features that characterize the human experience. Yet, arguably, many of the complex neuropsychiatric disorders such as schizophrenia, autism, bipolar disorder, obsessive-compulsive disorder, and others may be viewed as failure of the brain to appropriately integrate various functions into the seamless whole that many of us take for granted. The integration of stimuli in the brain likely occurs through several mechanisms. Here, we focus on the role of the claustrum (CL) as one potential structure that helps integrate diverse brain functions. Based on its connectivity the CL has been theorized to function in higher order cognitive processing and emotional behaviors1,2. Surprisingly little is known about the CL, but our group became interested in this enigmatic structure due to its dense innervation by serotonergic neurons and its high level of expression of serotonin 2A receptors (Htr2A). We have hypothesized that the Htr2A receptors of the CL is the site of action of hallucinogenic drugs such as LSD (lysergic acid diethylamide) - agents that so potently disrupt normal sensory perception and sense of self. By extension, we have speculated whether CL function may be impaired in neuropsychiatric disorders where integrative functions appear disrupted. Our interest in the CL became more concrete as we developed new experimental tools that we believe can provide new insights into how CL function may be altering behavior. In this exploratory grant, we propose to characterize the anatomy of neuronal circuits originating in the CL and assess how serotonin may be modulating these circuits to control complex emotional and cognitive behaviors.
In Aim 1, we propose to investigate the projections, the location and neuronal types of claustro-cortical circuits defined by the expression of Htr2A. Next we will generate knock-in Cre lines using the Htr2A and Gng2 (a CL-specific gene) promoters as tools to direct gene expression in the CL. We will test whether these tools can be used to ablate CL neurons with diphtheria toxin as the simplest way to target CL function. Lastly, we will answer another important question: is Htr2A signaling in the CL the site of action of hallucinogenic drugs. The tools and results from this study can be used in the future to directly manipulate neuronal activity of the CL and reveal new neural substrates of serotonergic action on emotional and cognitive function.
The putative functions of neural circuits originating in the claustrum (CL) may have considerable relevance for understanding neuropsychiatric disorders such as autism, schizophrenia, anxiety and mood disorders, yet the CL remains poorly understood. The results from this study will help elucidate the anatomy and function of the claustrum and its regulation by serotonin. The findings will inform our understanding of claustral function and the neuronal circuitry underlying emotional and cognitive processes - a key step in designing better treatments and therapeutic interventions for neuropsychiatric disorders.
|McOmish, Caitlin E; Demireva, Elena Y; Gingrich, Jay A (2016) Developmental expression of mGlu2 and mGlu3 in the mouse brain. Gene Expr Patterns 22:46-53|
|Harmon, Jennifer L; Wills, Lauren P; McOmish, Caitlin E et al. (2016) 5-HT2 Receptor Regulation of Mitochondrial Genes: Unexpected Pharmacological Effects of Agonists and Antagonists. J Pharmacol Exp Ther 357:1-9|