Jordan P. Hamm, Ph.D. - US grants

? DESCRIPTION (provided by applicant): Research into the biological substrate of schizophrenia (SZ) over the past several decades has focused on identifying empirical markers of the disorder which are more proximal to etiological processes than the phenomenological symptomology on which the diagnosis is based. Such biomarkers suggest fundamental disruptions in sensory cortical processing, carry the potential to explain phenomenological and higher order cognitive aspects of the disorder, and provide a critical translational strategy for targeted clinical intervention. Despite some encouraging leads, we still do not understand the pathophysiology behind most biomarkers, or how the measures themselves relate to the essential computations of the cerebral cortical circuit, limiting their utility as translational tols and theoretical benchmarks. Recent advances in transgenic and optical imaging in mice provide exciting new tools with which these specific questions can be answered. The proposed project will use cutting-edge two-photon optical imaging and photostimulation methods to identify the microcircuit level substrate of two established oscillatory biomarkers of SZ: alpha and gamma-band synchronization in visual cortex. Specifically, we will use chronic ketamine exposure in mice to generate a model of disordered sensoricortical processing and measure spontaneous and visually evoked oscillatory dynamics in V1 with dense microelectrode recordings. We will then (AIM1) employ state-of-the-art fast 3D 2- photon Ca2+ imaging to measure the multicellular activity of cortical microcircuits in vivo, describing how oscillatory biomarkers relate to the patterned activity of local cell assemblies and to the function of specific inhibitory interneuron subpopulations with demonstrated disease relevance. Based on these findings, we will then (AIM2) employ optogenetic manipulation of cortical cells in the same imaging/stimulation context to assess casual links between oscillatory biomarkers of SZ, circuit dynamics, and the function of local inhibitory interneuron populations. These studies will yield i) key biomechanistic information for interpreting measures in humans, helping to mature them from biomarkers to clinical assays, and ii) potentially novel insights into how these measures and the psychotic states they mark (e.g. SZ) relate to the emergent patterns of neural activity and their associated network-level dynamics. Moreover, the proposed work will build directly on my graduate work on sensory biomarkers of psychotic disturbance by identifying the cortical substrate of these measures and expanding my expertise into the visual domain, animal research, two-photon optical imaging and photostimutlation with optogenetics. This training will position me to pursue follow-up studies in genetic mouse models of SZ and which further explore the behavioral/perceptual consequences of disrupted microcircuit dynamics, sensory modalities other than vision, and intervention strategies based on these bioassays.

PROJECT SUMMARY Sensory stimuli are naturally perceived within a spatiotemporal and behavioral context, wherein novel events are processed and repetitive elements ignored. Novelty detection is thus cognitive as well as perceptual and is critical for daily function and survival. Studies using ?oddball? stimuli demonstrate that psychiatric disorders, including schizophrenia (SZ), involve abnormal sensorineuronal processing of novelty which predicts deficits in cognition and everyday functioning. In his PhD, the candidate characterized the multivariate complexity and heritability of oddball EEG responses to show how they could help build a biological taxonomy of psychosis. Yet a mechanistic understanding of how brain circuits process context, and the pathophysiology underlying patient deficits, is unattainable with human studies alone. As a postdoc, the candidate mastered two-photon calcium imaging (2P-Ca++) and chemicogenetics to develop a mouse model of novelty detection in visual cortical circuits (V1), showing a key role for somatostatin interneurons, a pathophysiologically relevant cell type in SZ. While context processing involves ongoing adaptations within sensory cortex, it also requires information about the past and behavioral goals, which may implicate larger brain networks involving prefrontal cortex (PFC). AIM1 expands the candidates work in V1 to study the mechanisms and nature of PFC?s top-down influence. Experiments will test how direct axonal inputs from PFC actively modify the multicellular circuit dynamics in V1 during in oddball paradigms. To this end, the candidate must learn a state of the art holographic technique using spatial light modulators (SLM) developed in the host lab (NIkolenko et al, 2008; Yang et al 2016) to enable the i) simultaneous observation of layer I (PFC axons) and underlying layer 2-5 (V1 neurons) with fast 3D 2P-Ca++, and ii) holographic optogenetic manipulation of specific circuit elements (e.g. PFC inputs to interneurons) to uncover the causal interactions among three critical neurobiological scales: cells, ensembles, and networks. Patient oddball studies highlight deficits in both passive (automatic) and active (attentional) aspects of novelty processing, which may involve non-overlapping neural pathophysiology. In AIM2, the candidate will uncover the behavioral relevance of this PFC-V1 circuit. Working closely with consultants Drs. Churchland and Gogos, the candidate will learn to design behavioral training protocols in head-fixed mice, eliciting responses to novelty in a dynamic oddball paradigm. Building on findings from in AIM1, the candidate will differentiate attentive from pre-attentive circuit functions and establish when and how context is encoded and used to guide behavior. These studies will yield i) biomechanistic information for interpreting novelty processing deficits in humans and ii) key insights into how emergent activity of the cerebral cortex arises from cellular diversity and interregional connectivity. This work will position the candidate to pursue his career goal of a research program which translates empirical biomarkers of sensory and cognitive deficits to model systems, wherein basic research with cutting edge neuroscience tools can provide promising insights and strategies for novel treatments.