Andrea Hasenstaub, PhD

Genetic, Cellular, Circuit, and Functional Organization of Auditory Cortex

My lab focuses on understanding the genetic, cellular, and network operation of specific cell types in the mouse and human auditory cortex.One line of research focuses on inhibitory microcircuitry in normal and diseased brains. Within the cortex, diverse types of local circuit inhibitory neuron play vital roles in regulating and timing activity, and are key mediators of long-term developmental plasticity. Central auditory processing disorders, such as hyperacusis or tinnitus, may result in part from failure of cortical inhibitory networks to properly control the strength, timing, or plasticity of excitatory activity. These neurons' dysfunction is also implicated in broader neurodevelopmental disorders including schizophrenia, autism, epilepsy, and bipolar disorder. Treatments for these common and devastating diseases will require both a conceptual understanding of cortical interneurons' circuit functions, and a mechanistic understanding of their interactions.

Exciting advances in optical and genetic technology now bring this understanding within reach, by allowing us to systematically measure and manipulate properties of specific cell populations to answer basic questions about their function. Under what conditions are different kind of cortical neuron engaged? What computations do different types of neurons enable? How does each type's activation affect input integration in its targets? How can long-range or neuromodulatory inputs dynamically regulate these interactions, and how does this match moment-to-moment changes in cognitive or behavioral requirements? And what can we infer about design principles common to all neural systems, by studying the biophysical strategies interneurons adopt to fill these circuit roles?

A second line of research focuses on electrophysiological and genetic studies of human cerebral cortex. The majority of our information about cortical microcircuitry has been derived from studies in model systems, particularly mice, rats, ferrets, and cats. These studies have provided fundamental insight into the many aspects of cortical organization which are conserved across species. However, human neocortex differs from that of model systems in numerous ways including the presence of additional neuron types, specializations in conserved neuron types, altered patterns of local and long-range connections, and the presence of additional cytoarchitectonic areas. These evolutionarily recent specializations underlie the differences in cognitive capacity in humans compared to other species. By studying temporal and frontal cortex acutely resected from human surgical patients, we gain direct access to the cellular mechanisms of human brain function and disease, including the numerous human-specific aspects of cortical organization which cannot be directly studied in model systems.

Our overall goal is to identify the conditions under which different kinds of cortical neuron are engaged, understand what computations they enable cortical networks to perform, and establish the biophysical and circuit mechanisms by which they allow these computations to occur. We hope that this will guide us in developing a low-level mechanistic understanding of how their plasticity in aging, hearing loss, and other types of brain injury underlies the functional losses observed in these conditions.

Current Projects

• How do cell types connect to one another in mouse A1? Onto what cell types are long-range and cross-modal connections made, and how are these connections refined during development? (viral and traditional tracing; optogenetics in vitro)
• What are the genetic correlates of electrophysiological variability or cellular identity in single human or mouse neurons? (surgical resection from human patients, followed by single-neuron electrophysiological recording and genetic analysis)
• How can we use large-scale transcriptome measurements to identify the patterns of gene expression underlying cellular identity or disease processes? (development of quantitative genetic analysis techniques)
• How are the changes in auditory processing associated with aging, deafness, or other forms of acoustic trauma mediated by changes in specific cell types' connections or intrinsic properties? (intracellular recordings in vitro)
• How do different neuron types contribute to to auditory processing in anesthetized mice?(multi-electrode recordings + optogenetics)
• How do behavioral or motivational state affect sound processing in different cell types in awake mice? (recording in awake mice during learning and performance of a discrimination task)

Lab Members

Lab Website