Karla Kaun - US grants

PROJECT SUMMARY (See instructions): In this project, we will develop an understanding of the range of clinical symptoms and biological factors (genetics and brain morphometry) that correlate with obsessive-compulsive behavior in autism. Autism is a highly heterogeneous disorder. A significant number of patients do not improve substantially with current treatments. We refer to this group of patients as difficult-to-treat autism (DTT-Autism). Our preliminary data suggest that these patients exhibit obsessive-compulsive behavior (OCB). We will test the central hypothesis that participants with autism with high OCB represent a subtype of difficult-to-treat autism (DTT-Autism) who will have abnormal maturation of frontal-striatal circuitry and genetic susceptibilities analogous to those previously studied in obsessive-compulsive spectrum (OCS) conditions. Capitalizing on recent progress in neuroimaging and genetics in OC spectrum (OCS) disorders, this project will test the hypothesis that autism with OCB will share genetic and brain circuitry changes that have been demonstrated in OCS disorders. We will test the hypothesis that autism with OCB will correlate with abnormalities in frontal-striatal circuitry as is true for OCD and related OCS disorders. We will also look for associations between rare and common variation in OC-related genes and OCB symptoms in autism. Using a combination of approaches including clinical assessment, neuroimaging and genotyping, we will characterize the subtype of autism with OCB. This work is important as it studies a group of autism patients who are in greatest need of treatment development. If our hypotheses about the strong biologic relationship between OC spectrum disorders and autism with OCB are accurate, novel treatments for autism may be drawn from ongoing research in interventions in treatment-refractory OCD.

PROJECT SUMMARY Despite its devastating impact on society, there are few effective treatments currently available for alcohol use disorder. The persistence of memories for the intoxication experience induces cravings, which can trigger relapse to alcohol use in recovering individuals. The neural and molecular mechanisms underlying these memories are complex, and despite recent advances, not well understood. This makes progress in finding pharmacological targets challenging. Investigation of these memories in the fruit fly, Drosophila melanogaster, presents a unique opportunity to gain a comprehensive understanding of the memories for alcohol reward at the level of genes, molecules, neurons and circuits. We propose to: 1) identify and investigate how simple central brain circuits function to form memories of the rewarding experience of alcohol intoxication, 2) compare how these circuits function for different forms of reward memory. Specifically, this research will reveal how dopaminergic microcircuits function to assign the rewarding properties of alcohol to associated cues, and how Notch signaling mediates neuronal plasticity within this circuit. This will be informative for understanding basic neural and molecular mechanisms underlying memory formation in addition to investigating how alcohol co-opts the brain's natural reward-related memory mechanisms to result in alcohol cravings.

Project Summary: Heavy alcohol consumption is associated with a decline in cognitive ability with age and may contribute to neurodegenerative disease such as Alzheimer's disease (AD). However, the causal mechanisms underlying this association are essentially unknown. One of the major readouts of AD is a buildup of neurotoxic amyloid beta-peptide (A?) in the brain. The integral membrane enzyme ?-secretase cleaves amyloid precursor protein (APP), which in some conditions is converted to A? after proteolysis. ?-secretase also cleaves Notch, a highly conserved cell-signaling receptor. Several recent studies suggest that enhanced Notch signaling is instrumental in AD-associated neurodegeneration. Data derived from the parent R01 for this supplement suggests that alcohol directly activates Notch signaling in memory circuits in the Drosophila brain. Using a Drosophila model of AD, we will determine whether alcohol causally exacerbates AD pathology through the highly-conserved Notch signaling pathway. We hypothesize that alcohol increases Notch activity, which leads to enhanced AD pathology. Thus, genetically decreasing Notch activity will nullify the effects of alcohol on AD pathology. Together, this data may provide new pharmacological targets for developing more effective treatments for AD.

PROJECT SUMMARY: Opioid abuse is a serious public health issue. Opiates have lasting physiological effects on reward memory circuitry, which contributes to cravings for the drug and changes the brain's response to other drugs of abuse. However, little is known of the molecular mechanisms underlying these opioid-induced changes. The sheer number and heterogeneity of neurons within reward circuits, combined with their elaborate connectivity, has prevented a deeper understanding of the identity of these lasting molecular alterations. A small but sophisticated brain and impressive array of neurogenetic tools for in vivo analysis have shown the fruit fly, Drosophila melanogaster to be an ideal model for discovery of novel mechanisms underlying the effects of drugs of abuse on the brain. Remarkably, no work has successfully shown that Drosophila are behaviorally responsive to opiates, despite several invertebrate species showing robust responses to opiate treatment. Our data suggest that Drosophila show acute behavioral responses to the synthetic opiate fentanyl, and will self-administer volatilized fentanyl after injury. Here we propose to establish Drosophila as an effective model to understand the neural and molecular mechanisms underlying the motivation to seek fentanyl. Our goal is to use an innovative neurogenetic approach to map Drosophila opioid receptor circuits responsive to acute nociception and to self- administration, and their post-synaptic connections. This work will provide a brain-wide map of expression of opioid receptors at a single cell level, define which of these neurons are involved in reward and aversion, and determine how these circuits are integrated.