Kafui Dzirasa - US grants

DESCRIPTION (provided by applicant): Multiple studies have identified sensorimotor gating deficits in patients with schizophrenia, their first degree unaffected relatives, and in pharmacological and genetic mouse models of schizophrenia. These deficits in sensorimotor gating may serve as a hallmark endophenotype of the disorder. Here we propose to directly quantify the neurophysiological mechanisms that correspond with sensory gating in mice by implanting arrays of microelectrodes across 7 distinct brain areas comprising mesolimbic, mesocortical, and cortical-striatal-thalamic microcircuits and performing neurophysiological recordings as mice perform a classic sensorimotor gating task. We will then quantify the effect of the psychotomimetic agent PCP and the schizophrenia risk gene DISC1 on these circuit mechanisms. We believe that the insights derived from the current proposal into the distributed circuits that underlie normal sensorimotor gating, and the mechanisms whereby genetic and pharmacological manipulations disrupt these circuits, will provide a detailed network-level understanding of the neurophysiological alterations that may contribute to schizophrenia.

DESCRIPTION (provided by applicant): Though most individuals are capable of maintaining psychological integrity in the face of stress, stress-experiences are well known for instigating th onset and relapse of severe neuropsychiatric disorders including MDD and PTSD. Social stress is common to practically all mammalian species, and chronic subordination stress in rodents is most often followed by the expression of a long-lasting behavioral syndrome that includes social avoidance, anhedonia, impaired coping responses to other environmental stressors, and anxiety-like behaviors. Within the inbred strain of mouse C57BL/6J, the prominently expressed stress-induced syndrome does not occur in all individuals subjected to chronic social defeat stress, thereby allowing for measurements of resiliency. Presumably, these results suggest that individual differences across mice mediate the susceptibility or resistance to the deleterious effects of chronic stress. Nevertheless, unequivocal validation of this hypothesis is lacking since the majority of studies aimed at investigating susceptibility to chronic stress are based on experiments performed in mice that have been previously exposed to chronic stress, or mice that are subjected to molecular manipulations prior to stress exposure (ultimately altering normal brain function).Here were propose to use multi-circuit in vivo recording in conjunction with circuit selective modulation using designer receptors exclusively activated by designer drugs (DREADDs) to characterize the circuit based mechanisms that mediate resistance to stress in C57BL/6J mice. The rationale that underlies the proposed research is that variations in cortical-amygdala circuit function will be associated with stress responses, and that direct modulation of this circuit will alter stress resistance across mice. This strategy will provide an unprecedented circuit level of understanding of how stress exposure ultimately alters activity across neural circuits that regulate fear and reward processing and reveal new circuit based targets for therapeutic intervention for mood and anxiety disorders.

DESCRIPTION (provided by applicant): Though most individuals are capable of maintaining psychological integrity in the face of stress, stress-experiences are well known for instigating th onset and relapse of severe neuropsychiatric disorders including MDD and PTSD. Social stress is common to practically all mammalian species, and chronic subordination stress in rodents is most often followed by the expression of a long-lasting behavioral syndrome that includes social avoidance, anhedonia, impaired coping responses to other environmental stressors, and anxiety-like behaviors. Within the inbred strain of mouse C57BL/6J, the prominently expressed stress-induced syndrome does not occur in all individuals subjected to chronic social defeat stress, thereby allowing for measurements of resiliency. Presumably, these results suggest that individual differences across mice mediate the susceptibility or resistance to the deleterious effects of chronic stress. Nevertheless, unequivocal validation of this hypothesis is lacking since the majority of studies aimed at investigating susceptibility to chronic stress are based on experiments performed in mice that have been previously exposed to chronic stress, or mice that are subjected to molecular manipulations prior to stress exposure (ultimately altering normal brain function).Here were propose to use multi-circuit in vivo recording in conjunction with circuit selective modulation using designer receptors exclusively activated by designer drugs (DREADDs) to characterize the circuit based mechanisms that mediate resistance to stress in C57BL/6J mice. The rationale that underlies the proposed research is that variations in cortical-amygdala circuit function will be associated with stress responses, and that direct modulation of this circuit will alter stress resistance across mice. This strategy will provide an unprecedented circuit level of understanding of how stress exposure ultimately alters activity across neural circuits that regulate fear and reward processing and reveal new circuit based targets for therapeutic intervention for mood and anxiety disorders.

DESCRIPTION (provided by applicant): Though most individuals are capable of maintaining psychological integrity in the face of stress, stress-experiences are well known for instigating th onset and relapse of severe neuropsychiatric disorders including MDD and PTSD. Social stress is common to practically all mammalian species, and chronic subordination stress in rodents is most often followed by the expression of a long-lasting behavioral syndrome that includes social avoidance, anhedonia, impaired coping responses to other environmental stressors, and anxiety-like behaviors. Within the inbred strain of mouse C57BL/6J, the prominently expressed stress-induced syndrome does not occur in all individuals subjected to chronic social defeat stress, thereby allowing for measurements of resiliency. Presumably, these results suggest that individual differences across mice mediate the susceptibility or resistance to the deleterious effects of chronic stress. Nevertheless, unequivocal validation of this hypothesis is lacking since the majority of studies aimed at investigating susceptibility to chronic stress are based on experiments performed in mice that have been previously exposed to chronic stress, or mice that are subjected to molecular manipulations prior to stress exposure (ultimately altering normal brain function).Here were propose to use multi-circuit in vivo recording in conjunction with circuit selective modulation using designer receptors exclusively activated by designer drugs (DREADDs) to characterize the circuit based mechanisms that mediate resistance to stress in C57BL/6J mice. The rationale that underlies the proposed research is that variations in cortical-amygdala circuit function will be associated with stress responses, and that direct modulation of this circuit will alter stress resistance across mice. This strategy will provide an unprecedented circuit level of understanding of how stress exposure ultimately alters activity across neural circuits that regulate fear and reward processing and reveal new circuit based targets for therapeutic intervention for mood and anxiety disorders.

A fully biological platform for monitoring mesoscale neural activity One of the barriers to understanding the human brain is due to its geometry. Accessing brain tissue at single cell resolution has classically involved implanting electrodes (metallic or optical) directly into the brain. For deep subcortical structures, these approaches result in tissue destruction across the shallow brain areas that must be traversed to access deeper targets. Thus, classic approaches are fundamentally unable to allow concurrent sampling of activity from healthy fully intact tissue at all sites of the brain. While many novel technologies that exploit miniaturized nanoscale recording electrodes will increase number of single cells that can be recorded concurrently in the same brain, these approaches do not address the challenge raised by the geometry of the brain. We intend to develop a new technology to ?functionally? change the geometry of the brain by biologically projecting neural activity onto a flat surface outside of the brain. This ?biological electrode? will allow for the concurrent acquisition of single cell activity from all depths of fully intact brain tissue in awake-behaving animals. Furthermore, this technology will offer several advantages over currently available approaches: 1) Unlike metallic recording electrodes which induce fibrosis at the metal-brain interface and ultimately diminish signal quality, the fully biological electrode will allow investigators to stably monitor brain activity throughout the entire lifespan of model organisms; 2) The biological patch will utilize engineered proteins to form physical connections with target cell types. Thus, this technology will rival gold-standard in vivo intracellular recording approaches such as glass-pipette patching; 3) Since the engineered proteins that form the physical connections between the biological electrode and target cells can be targeted to individual cellular compartments, the biological patch will allow neural activity to be directly acquired from the soma, dendritic spines, and/or axons of single cells in a cell type specific manner; 4) Finally, the biological patch will be readily scalable to allow for recordings from 100,000s of single cells simultaneously. Thus, successful completion of this high-risk project will revolutionize neural recordings across model species and humans.

Abstract Impulsive sensation seeking (ISS), the tendency and willingness to seek, and take risks for, novel and intense sensations and experiences is a characteristic feature of bipolar disorder (BD), particularly during manic episodes. High ISS often leads to risky decision-making and behaviors with deleterious consequences, including poor social and occupational function, injury, and even death. Identifying objective, neural markers of ISS would facilitate novel treatments for BD, perhaps through modulation of specific neuronal circuits. Work from our collaborators indicate a significant positive relationship between ISS and activity in the brain, especially in the left ventrolateral prefrontal cortex (vlPFC) to uncertain reward expectancy across unaffected and BD individuals, and a positive relationships among these measures and risky decision-making. Furthermore, pilot EEG data indicate a positive relationship between greater trait ISS and greater beta power (20-30Hz) within, and phase synchrony among, left vlPFC and other reward cortical regions during uncertain reward expectancy, using the same reward task as in the fMRI studies. While human fMRI and EEG studies can elucidate neurophysiological correlates of ISS and BD, only rodent studies can use invasive local field potential recordings (LFPs) to identify the precise neurophysiological mechanisms by which rodent homologs of high ISS and BD (Clock?19 mice, an experimental model with high ISS) predispose to risky decision making. Working closely with our collaborators, we have developed a novel reward/punishment expectancy task for mice, which mirrors the new task that we have been employing in the human studies described above. The development of this task will allow us to directly correlate reward expectancy with novelty seeking and risk taking behavior both in normal mice and Clock?19 mice, and determine the electrophysiological signatures across the brain in these animals during precise phases of this task. These studies will help inform the human work to determine the important circuits and frequencies of activity that should be targeted for future treatment of BD.

Title: Dissecting and modifying temporal dynamics underlying major depressive disorder Multiple human imaging studies have described aberrant spatiotemporal dynamics in specific brain networks across subjects with major depressive disorder. Furthermore, rodent studies have identified dysfunctional synchrony across cortical limbic circuits in genetic and stress- induced models of major depressive disorder. Nevertheless, it remains to be clarified whether these observed changes in neural dynamics play a causal role or simply reflect (i.e., correlate with) the behavioral-state observed in major depressive disorder. Several major challenges to addressing this question exist. 1) The brain synchronizes dynamics across multiple timescales. Rodent studies classically monitor dynamics at the millisecond time scale (reflecting circuits), and human studies typically monitor brain dynamics at the seconds time scale (reflect circuit and network level activity). 2) Rodent studies are generally limited in their ability to monitor large-scale activity from many brain regions concurrently, while human imaging studies observe activity across the whole brain. 3) To our knowledge, few approaches/models integrate changes in cell-type specific gene expression implicated in depression to changes in circuit and network- specific brain dynamics. 4) Techniques which directly manipulate brain dynamics (neural synchrony and cross-frequency coupling) have yet to be largely implemented throughout the rodent research community. To address these challenges, we propose to perform multi-circuit in vivo neural recordings in the two widely used rodent models of depression. We will then utilize machine learning to determine the spatiotemporal dynamic alterations that are shared between the two models. Next, we will test whether cellular molecular manipulations implicated in major depressive disorder are sufficient to induce the same spatiotemporal dynamic alterations. Finally, we will verify that these spatiotemporal dynamics are causal by directly inducing and suppressing them and measuring their impact on behavior. This strategy will yield an unprecedented understanding of how altered dynamics within specific brain circuits contribute to depression.

MULTIREGIONAL ELECTRICAL ENCODING OF SOCIAL AGGRESSION Critical developments in neuroscience have included technologies for sequencing individual brain cells, progress towards completing a full mesoscale brain cell atlas in mice, new tools for monitoring and manipulating the activity of brain cells, refined imaging techniques for developing structural and functional connectome atlases in humans, and new objective measures for characterizing behavior across species. Nevertheless, a critical gap that has yet to be addressed is the development of a model that would allow this emerging catalog of cellular information to be linked to the broad functional networks that encode emotional behavior in mammals. This gap exists in part because 1) technologies that measure, monitor, and decode mesoscale activity throughout the depth of the brain during free behavior in mammalian model species have yet to be implemented in conjunction with cellular activity can be monitored and manipulated, and 2) theoretical frameworks that link cellular activity to mesoscale network activity and that generalize across subjects on a mouse-by-mouse basis have yet to be developed. Our multi-disciplinary team has built a suite of tools for studying how brain dynamics encode complex brain states. These include advanced techniques to measure and monitor brain dynamics in vivo concurrently for months across many regions located throughout the depth of the brain at high spatiotemporal resolution in freely-behaving mice, machine-learning analytic approaches that build individual circuit activity measures into composite networks, behavioral manipulations that can be used to induce brain states related to emotions, viral methods that probe the relationship between cellular changes and the expression of brain-wide neural dynamics, and closed-loop stimulation tools that can potentially test the causality of brain network-states in mediating emotion. By integrating this suite of tools in a single framework, we intend to create a model that will catalogue how the brain generates aggression. Critically, we believe that this model framework will be broadly applicable to other emotional brain states as well.