Owen Lab Research

Research in the Owen lab focuses on three primary questions: How can neuromodulation reveal the function of cell types and circuits? Are these mechanisms conserved between the human brain and animal models? And how can these pathways be engaged for the treatment of neurological disease?

To address these questions, we study modulation of targeted cell types within the cerebral cortex and the basal ganglia. These structures act cooperatively to support motivated behavior and action selection in the healthy brain. Deficits in targeted cell types within the cortex and basal ganglia are central to our understanding and treatment of pervasive and debilitating diseases, including Autism, Obsessive-Compulsive Disorder, and Parkinson’s Disease.

We investigate two complementary means of modulating cell types and circuits: pharmacological modulation of cell-signaling by oxytocin, acetylcholine, and similar agents through G-protein coupled receptors; and physiological modulation of cell types and circuits through deep-brain stimulation. Despite the enormous therapeutic potential of these inter-related approaches, the underlying physiological mechanisms are poorly understood, especially in the human brain. Critically, many drugs or therapeutic interventions that are developed in mouse or other animal models fail to translate to effective treatments in human patients. We therefore integrate study of basic physiological mechanisms in animal models, with direct testing of these mechanisms in human brain tissue.

Modulation of human neuronal cell types

Animal models are essential for understanding healthy brain function and developing new treatments for neurological disease. However, the failure rate of clinical trials in neuroscience is among the highest in biomedical research. Better approaches are required to translate basic discovery in animal models into clinical treatments for the human patient. A major goal of our work is to investigate human-specific features of neuronal physiology and circuit function and to develop methods that reveal translationally relevant mechanisms.

To accomplish this, we use physiological recordings, imaging, and emerging genetic tools in human brain slices prepared from neurosurgically resected tissue. Using an approach called Patch-Seq, in which the contents of a neuron are aspirated into the recording pipette and the RNA is reverse-transcribed and sequenced, we directly connect physiological responses of human cell types to gene expression and transcriptomic cell identity. Key goals of this work are to identify human cell types that are altered in Autism and Obsessive-Compulsive Disorder, and to determine how these neurons may be therapeutically modulated.

Physiological mechanisms of neuromodulation through deep-brain stimulation

Deep-brain stimulation can be a miraculously effective treatment for Parkinson’s Disease, Obsessive-Compulsive Disorder, depression, and other neurological disease in some individuals. However, it is less effective in others. For such a widely used, seemingly simple, and effective intervention, surprisingly little is understood about the underlying physiological mechanisms.

The Owen lab integrates imaging, physiology, operant behavior, and next generation sequencing in mouse models to investigate the basic physiology of deep-brain stimulation in the treatment of Obsessive-Compulsive Disorder and Parkinson’s Disease. Our work defines the cell types, modulatory pathways, and synaptic connections that are altered by deep-brain stimulation, to reveal their function in the healthy and diseased brain. We seek to identify protocols, targets, and interventions to improve cognitive and motor function through deep-brain stimulation.

Mechanisms of flexible learning in dynamic environments

The world is a dynamically changing environment. The brain must efficiently execute everyday tasks, while retaining the flexibility to recognize and adapt to changing circumstances. The basal ganglia are essential for automated execution of common behaviors, and adaptive changes to new environments. An inability to adjust to new and changing circumstances are a common and debilitating deficit in several neurological diseases, including Autism, Obsessive-Compulsive Disorder, Parkinson’s Disease, and addiction.

Research in the Owen lab investigates cellular and synaptic mechanisms that support dynamic learning. How do modulators such as serotonin and acetylcholine shape activity, synaptic connectivity, and interactions between targeted cell types in the cortex and basal ganglia to facilitate changes in behavior? To address these challenging questions, we employ custom-designed and constructed operant behavioral systems that integrate physiology and imaging in mice. Using transcriptomics and human cellular physiology, we examine whether these modulatory responses and cell type-specific physiological features are conserved between the mouse and human brains.