We study Disorders of
Neural Circuit Function
Research Group Leader
Dr. M. McLean Bolton started her research program at the Max Planck Florida Institute for Neuroscience as an independent Research Group Leader focusing on disorders of neural circuitry in January of 2011. Prior to this appointment, she was a Research Assistant Professor in the Department of Pediatrics, Division of Neurology at Duke University Medical Center (2008-2010).
Bolton’s early postgraduate career was in ion channel drug discovery and developing high content screening platforms for neurological disorders (2000-2008). Before returning to basic research in 2008, she worked as a Research Scholar for the Duke Drug Discovery Center, a Senior Scientist at Icagen, Inc., a Scientist II at Amphora Discovery Corporation, and an Investigator at Cogent Neuroscience, Inc.
She received her Ph.D. in Neurobiology at Duke University in 2000 for her work on the regulation of excitatory and inhibitory synaptic transmission in hippocampal cultures by brain-derived neurotrophic factor. Her thesis work was supported by an individual National Research Service Award.
The goal of Bolton’s research is to understand how neural circuits are altered in neuropsychiatric disorders, such as autism and schizophrenia. These complex behavioral disorders are caused by a combination of genetic and environmental factors. Most cases likely result from a combination of mutations in many genes, each with small effects. However, rare mutations in candidate genes with large effects, either de novo or inherited, are major contributors to the etiology of these disorders in a subset of cases.
Studying the impact of these rare mutations on brain function may identify points of intervention to correct the circuit imbalances in these neuropsychiatric disorders. They combine optogenetics, patch-clamp electrophysiology, 2-photon imaging, and behavioral studies to map local circuit and long-range synaptic connectivity in mouse models of these disorders and to relate these circuit changes to behavioral abnormalities and neuronal activity patterns during behavior.
Project 1 – Searching for common circuitry endophenotypes among genetic models of autism
A revolution in psychiatric genetics has led to a growing list of candidate genes conveying susceptibility to autism spectrum disorders (ASD). The implicated molecules have diverse functions, ranging from protein synthesis control to synaptic adhesion, leading to the hypothesis that these disparate genetic changes converge onto a common neuronal circuit pathology in ASD rather than a common molecular pathology. We have developed methods for circuit mapping that enable measurements of functional synaptic connectivity with single-neuron resolution. By expanding a two-photon beam in the imaging plane using the temporal focusing method, and restricting channelrhodopsin to the soma and proximal dendrites, we are able to reliably evoke action potentials in individual neurons, verify spike generation with GCaMP6s, and determine the presence or absence of synaptic connections with patch-clamp electrophysiological recording. We are searching for common circuitry endophenotypes among multiple animal models of ASD using this method.
Project 2 – The role of cannabinoids in susceptibility for developing schizophrenia
Endocannabinoids are powerful neuromodulators that regulate learning, motivation, decision making, and emotion. Whereas endocannabinoids are released with spatial and temporal precision in response to environmental stimuli to control learning and emotional responses, the THC in marijuana hijacks the cannabinoid system. Given that there is evidence that the endocannabinoid system may be off balance in anxiety disorders, PTSD and schizophrenia, it is important to understand how marijuana affects the development and function of brain circuits involved in emotional regulation in models of genetic and environmental susceptibility to these disorders. We combine a constitutive or cell class-specific knock out model of a candidate schizophrenia susceptibility gene with adolescent exposure to cannabinoids and determine how synaptic connectivity, behavior and neural activity during behavior is altered.
Project 3 – Understanding the contribution of amygdala circuitry defects in Autism and Schizophrenia
The amygdala is a critical plasticity site for the acquisition of emotionally charged memories and plays a significant role in emotional behavior. Alterations in amygdala function are consistent with anxiety and social motivation deficits in both disorders, and paranoid ideations in schizophrenia. The lateral amygdala (LA) is the primary site of synaptic plasticity in fear learning. It receives sensory information from both the thalamus and cortex such that it can associate intrinsically aversive stimuli with neutral stimuli that are paired with it. The basal amygdala (BA) is a central integrator of emotional context. The BA is driven by the LA and regulated by inputs from the medial prefrontal cortex (mPFC) to provide executive control over fear behavior. Amygdala processing is regulated by several classes of inhibitory neurons either local circuit interneurons or those located in specialized clusters like the intercalated cells surrounding the basolateral amygdala (BLA). From the BLA information travels to the central amygdala which is the major output nuclei for fear expression. Understanding how individual elements within the amygdala processing stream are altered in models of autism and schizophrenia is the goal of this project.
Research Group Leader