Examining the role of insula sub-circuits in attention-guided behavior

About This Grant

PROJECT SUMMARY Deficits in attention are a common cognitive symptom across a range of neuropsychiatric and neurodegenerative disorders, including attention-deficit hyperactivity disorder (ADHD), major depressive disorder (MDD), schizophrenia, and Alzheimer’s disease (AD). The most commonly used test to assess attention deficits in these patient populations is the continuous performance test, or CPT. In humans, a wealth of studies have shown that the insula is consistently activated during tasks that require attention, including the CPT. Numerous other studies have demonstrated that patients with ADHD, MDD, and schizophrenia all have abnormal insula structure and function. These results point to the insula as a critical area of investigation for researchers interested in the pathophysiology of aberrant attentional processing in these disorders. Although the relationship between insula activation and attention is well established, we do not yet have a mechanistic understanding of how the insula contributes to attention. The overall objective of the proposed research is to provide links between insula function at the molecular, cellular, and circuit levels of analysis and behavior during the CPT. We will reach this objective by using a combination of cutting-edge techniques to measure neuronal activity in two projection-specific insula subpopulations (those that send axons to the locus coeruleus, or LC, and those that send axons to the prelimbic cortex, or PrL) during a translational, touchscreen-based rodent analogue of the CPT (the rCPT). In particular, we will pursue the following specific aims: 1) Characterize the molecular identities of LC-projecting and PrL-projecting neurons in the insula, and determine the functional relevance of these two subpopulations to the rCPT; 2) Identify patterns of activity between the LC, PrL, and insula during the rCPT, and; 3) Relate population activity in LC- projecting and PrL-projecting insula neurons to behavior during the rCPT. These data will vertically advance our knowledge of how cellular function in the insula contributes to attention, and will provide critical information about how anatomically distinct insula sub-circuits relate to disparate attentional domains, such as vigilance, impulsivity, and error monitoring in a translationally and clinically-relevant task. Patients with different neuropsychiatric disorders often have domain-specific attentional impairments; knowing which circuits underlie these domains, and how to effectively target them therapeutically, is therefore pivotal for effective treatment of attention symptoms in these disorders. This research, therefore, directly aligns with mission of the NIMH to “transform the understanding and treatment of mental illnesses through basic and clinical research”.