2004 — 2005 |
Martinowich, Keri |
F31Activity Code Description: To provide predoctoral individuals with supervised research training in specified health and health-related areas leading toward the research degree (e.g., Ph.D.). |
Novel Factors in Neural Stem Cell Differentiation @ University of California Los Angeles
DESCRIPTION (provided by applicant): The long term objectives of the project intend to characterize presently unknown signalling mechanisms that are used in mediating the neurogenic to gliogenic fate switch of neural stem cells (NSC) within the developing central nervous system (CNS). We have developed an in vitro culture system that recapitulates the events observed in vivo: NSC first enter a neurogenic phase and later switch to an astrogliogenic phase. We have discovered that media collected from cells after several days of culturing has astrogliogenic inducing and neurogenic inhibiting activity. We have hypothesized that as NSC reach the end of their neurogenic potential they secrete some type of factor that is able to promote astrogliogenesis and actively inhibit the neurogenic fate. We have ruled out the possibility that the collected media contains many of the known astrogliogenic inducing factors. Our future goals intend to characterize the biological function of the CM and decipher the exact times and cell ages during which it contains these astroglial inducing and neuronal non-inhibiting activities.
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0.915 |
2015 — 2019 |
Martinowich, Keri |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Regulation of Neural Activity in Fear Circuits by Promoter Iv Derived Bdnf
? DESCRIPTION (provided by applicant): Brain-derived neurotrophic factor (BDNF) is implicated in trauma and stressor-related disorders. These psychiatric conditions include phobias as well as post-traumatic stress disorder, and are characterized by abnormalities in negative valence systems. The biological mechanisms associated with these symptoms are clustered around the constructs of fear and threat, which can be examined in mouse models of fear- conditioning and extinction. Although BDNF is highly associated with impaired fear regulation, how it regulates the underlying circuitry to influence behavior is not well understood. BDNF regulates neural plasticity in the developing and adult brain, and is enriched in regions associated with emotional control including amygdala (AMY), hippocampus (HPC) and prefrontal cortex (PFC). BDNF signaling is complex, including production of multiple transcripts from at least nine different promoters (I through IX). Each of these transcripts contains a 5' non-coding exon spliced to a common coding exon. In response to neuronal activity, the binding of cis-acting calcium-dependent transcription factors and epigenetic chromatin remodeling induces BDNF expression from promoter-IV. Activity-dependent Bdnf transcription plays a role in the homeostatic regulation of neuronal excitability and induction of synaptic plasticity. It has been proposed that aberrant synaptic plasticity in limbic circuits underlies generation of the impaired fear regulation observed in trauma and stressor-related disorders. Our data show that disruption of BDNF from promoter-IV causes resistance to extinction of learned fear, and is accompanied by alterations in HPC and PFC neural activity patterns. These data provide rationale for determining whether this locus can be selectively targeted in disorders associated with impaired fear regulation. Synaptic dysfunction can alter coordination of neuronal oscillations that mediate fear-related behavior, but the molecular and cellular events that control these oscillations have not been fully elucidated. In this proposal we aim to identify network level alterations in fear-related circuits downstream of impaired activity-dependent production of BDNF, and to further reveal the BDNF-dependent cellular and molecular mechanisms that control synchronized network activity in those circuits. These studies then determine whether BDNF-dependent circuits can be directly manipulated to regulate fear expression and extinction. We will assess whether transgenic interventions and novel pharmacological strategies that restore BDNF signaling are able to reverse abnormal fear behavior. The results of these studies are likely to reveal fundamental mechanisms by which activity-dependent BDNF production impacts fear circuit function and behavior. These are critical data because understanding the mechanisms that control the expression and extinction of fear is vital for rational development of improved treatments for anxiety and trauma-related disorders.
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0.984 |
2019 |
Martinowich, Keri |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Epigenomic Contribution to the Antidepressant Response
Project Summary/Abstract Depression is a growing public health problem worldwide. The significance of the problem is compounded by the fact that up to 30% of patients do not adequately respond to currently available pharmacological treatment. As a result, electroconvulsive therapy (ECT), which is the most effective and has the most rapid onset of all FDA- approved therapies available for treatment-resistant depression, is widely used despite limitations, including requirement for repeated anesthesia and cognitive side effects. These drawbacks have stimulated interest in identifying the cellular and molecular mechanisms mediating its antidepressant action to guide development of improved circuit-based brain stimulation therapies for depression. Electroconvulsive seizures (ECS), an animal model of ECT, substantially increase expression of brain-derived neurotrophic factor (BDNF) in the hippocampus, a region that has emerged as a critical locus for mediating the antidepressant effects of ECT. Multiple promoters govern Bdnf expression, yet ECS drives both acute and sustained BDNF production in hippocampus most potently from promoter I. These findings suggest that ECS-responsive, promoter I-expressing BDNF cells are critical components of hippocampal circuits that contribute to the antidepressant response. However, how ECS controls the function of these BDNF-expressing neurons, and how they mediate the antidepressant response is not known. We hypothesize that ECS triggers a cascade of epigenomic changes, which ultimately influence gene expression to control structure and function in neural circuits that facilitate ECT's robust antidepressant response. In this proposal we take a unique approach by using molecular-genetic strategies to selectively isolate BDNF-expressing neurons to profile the transcriptomic and epigenomic response to both acute and chronic ECS. Using these parallel sequencing techniques, this approach allows us to define a genome-wide epigenetic code of the antidepressant response specifically in a population of ECS responsive cells. Importantly, our analysis will assess differences across time to define acute versus chronic changes in gene expression that contribute to the antidepressant response, and will also evaluate changes between males and females, to evaluate how biological sex impacts these effects. This is significant because there have been noted influences of interactions between BDNF and biological sex on the susceptibility to and recovery from depression. In summary, our approach will define the transcriptional programs that are activated by ECS in a population of cells that are functionally linked to the antidepressant response, and are thus are expected to provide significant insight into the ECS-induced chromatin remodeling and gene regulation mechanisms that control behavior.
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0.984 |
2020 — 2021 |
Martinowich, Keri |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Molecular and Cellular Correlates of Plasticity in Hippocampal-Prefrontal Circuitry
The hippocampal-prefrontal circuit is implicated in many neuropsychiatric illnesses. This circuit is critically involved in multiple aspects of cognition and emotional regulation, and is particularly vulnerable to stress, which is a key precipitating factor for many of these disorders. Chronic stress can have deleterious effects on neuronal structure and physiological function in the hippocampus, and impair hippocampal-dependent behavior, including processing of contextual fear memories. The hippocampus and prefrontal cortex communicate during cognitive and emotional tasks by altering the coherence of oscillatory activity between the two regions. However, the cellular and molecular events that drive these changes in hippocampal-prefrontal synchrony, and how they are influenced by stress, are not well understood. Understanding the mechanisms by which exposure to stress leads to disruptions in hippocampal-prefrontal interactions during fear regulation is a high priority given that altered fear-related behavior is prominent in many neuropsychiatric disorders. Our preliminary data support the hypothesis that exposure to stress impacts plasticity in the hippocampal-prefrontal pathway, leading to disrupted connectivity between the two regions and enhanced fear-related behavior. Many of the risk factors for neuropsychiatric disorders, including stress, affect genes that play important roles in the development and plasticity of synapses. Hence, disruptions in synaptic connections of the long-range projections between the hippocampus and prefrontal cortex could contribute to impairments in hippocampal-prefrontal synchrony. However, there is a dearth of research aimed at understanding molecular signaling pathways in these projection cells. The central hypothesis of this proposal is that defined programs of cellular and molecular signaling in hippocampal-prefrontal projection neurons control their structure and function, and that these signaling pathways regulate patterns of neural activity and connectivity between the two structures. The overall goals of this application are to 1) understand how stress drives molecular and cellular signaling in hippocampal-prefrontal projection cells to control their physiological function; and 2) determine how plasticity in hippocampal-prefrontal projections neurons impacts functional connectivity in this circuit to control fear-related behavior. We use a technically sophisticated combination of neuronal morphology analysis with endoscopic imaging and in vivo electrophysiology to understand how stress impacts cellular plasticity in hippocampal-prefrontal projection neurons. We then determine how these cellular correlates of plasticity impact hippocampal-prefrontal synchrony during fear-related behavior. In addition to cellular correlates, we combine molecular profiling techniques with retrograde viral approaches to investigate molecular contributions to plasticity in hippocampal-prefrontal neurons. The research will reveal fundamental information about molecular and cellular signaling programs in hippocampal-prefrontal projection neurons that contribute to functional connectivity, information that will be critical for future strategies targeting this pathway.
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0.984 |
2020 — 2021 |
Jaffe, Andrew Ellis [⬀] Martinowich, Keri |
U01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Spatial Registration of Gene Expression in the Human Brain
Project Summary/Abstract Extensive effort has been committed to more fully characterize the human brain transcriptome within and across cell types to better understand changes in RNA expression associated with brain development and aging, developmental or psychiatric brain disorders, and local genetic variation. Large consortia, including psychENCODE, have primarily focused on the molecular profiling of RNA extracted from homogenate/bulk tissue from different brain regions across hundreds of individuals, though single nuclei expression approaches are increasingly being utilized in the second phase of projects. While these differences in signatures across brain regions relate to the unique cell types underlying each region, the specific cell types and their corresponding spatial landscapes are largely unknown. Neurons in different cortical and hippocampal layers show distinct expression patterns, morphology, physiology and patterns of connectivity. Converging evidence suggests that impairments in the formation or maintenance of synapses may be involved in schizophrenia, and studies in the postmortem brains of subjects have pointed to specific cell types and revealed differences in neuronal and synaptic structure that are localized to specific layers, suggesting that genetic risk for schizophrenia may manifest with laminar specificity. In this application, we propose to generate detailed spatial transcriptomics maps of the human DLPFC and hippocampus. These spatial expression maps will be combined with complementary single nuclei sequencing data from the same tissue blocks to develop spatial registration approaches that can add spatial information to existing single nuclei datasets in the psychENCODE project. We will combine these spatial and cell type-specific maps to implicate layer- and cell-specific populations in schizophrenia genetic risk and illness state that will be validated using complementary in situ hybridization techniques. These rich spatial transcriptome maps will add another dimension to existing and forthcoming single nuclei RNA-seq datasets in the frontal cortex and hippocampus to further refine the cell types in the human brain and their subsequent dysregulation in debilitating brain disorders.
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0.984 |
2021 |
Martinowich, Keri |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Laminar Dissection of Cortical Human Brain Gene Expression in Neuropsychiatric Disorders
Project Summary/Abstract The DLPFC is a true six layered neocortex, and neurons in different cortical layers show distinct expression patterns, morphology, physiology and patterns of connectivity. Converging evidence suggests that impairments in the formation or maintenance of synapses may be involved in schizophrenia and other neuropsychiatric disorders. Studies in the postmortem brains of subjects have pointed to specific cell types and revealed differences in neuronal and synaptic structure that are localized to specific layers, suggesting that genetic risk for schizophrenia may manifest with laminar specificity. Given the close relationship between brain structure and function, precisely assigning gene expression to the spatial coordinates of individual cell populations within this cortical cytoarchitecture would significantly advance our understanding of how dysregulation in these areas contributes to debilitating neuropsychiatric disorders. In this application, we propose to generate detailed spatial transcriptomics maps of the human DLPFC in patients with schizophrenia (SCZD), bipolar (BPD), major depressive (MDD) and autism spectrum (ASD) disorders, and contrast these laminar expression patterns to those derived from matched neurotypical controls (CONT). We will use the 10x Genomics Visium platform, which combines transcriptome-wide RNA sequencing with detailed high-resolution histology and immunofluorescence imaging, to generate these spatial transcriptomics profiles. We will combine these topographic and cell type-specific maps to implicate layer- and cell type-specific populations in psychiatric disorder genetic risk and illness state that will be validated using complementary quantitative in situ hybridization techniques. These layer-specific and cell type-specific expression profiles can refine the molecular causes and consequences of debilitating neuropsychiatric disorders that can be targeted for prevention and treatment.
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0.984 |
2021 |
Carr, Gregory Martinowich, Keri |
R56Activity Code Description: To provide limited interim research support based on the merit of a pending R01 application while applicant gathers additional data to revise a new or competing renewal application. This grant will underwrite highly meritorious applications that if given the opportunity to revise their application could meet IC recommended standards and would be missed opportunities if not funded. Interim funded ends when the applicant succeeds in obtaining an R01 or other competing award built on the R56 grant. These awards are not renewable. |
Neurophysiological Biomarkers in Preclinical Assays of Sustained Attention
Project Summary Sustained attention, the ability to focus on an activity or stimulus over time, is impaired in many brain disorders. Continuous performance tests (CPTs) have been designed to measure sustained attention in multiple species. Similar neural circuits are engaged in both humans and model organisms during CPT performance, supporting their use in translational studies that screen for novel therapeutics. The human dorsal anterior cingulate cortex (dACC), which plays critical roles in attentional processes, shows functional and anatomical similarity to the mouse prelimbic region (PrL). These homologous regions are involved in both conflict detection and allocation of attention to cues before orientation, important components in go/no-go tasks like CPTs. Electroencephalogram (EEG) studies show that neural activity in the dACC is correlated with task engagement and performance in the CPT. The neuromodulator dopamine is hypothesized to play a critical role in regulating attention, a notion supported by the fact that dopamine D1 receptor agonists and antagonists improve and impair CPT performance, respectively. In this application we propose to optimize a mouse touchscreen-based CPT to include measurements of the effects of stimulus degradation and session length (time on task) on accuracy, reaction times, and other task parameters. In this optimized paradigm we will identify electrophysiological correlates of task performance by analyzing spectral measures of power and coupling from the EEG and PrL local field potential. We will evaluate the optimized CPT paradigm by assessing behavioral performance and EEG/LFP correlates in response to pharmacological enhancers that are documented to improve attention. Finally, we will mechanistically test the role of dopaminergic input to the dACC/PrL from the ventral tegmental area on behavioral performance and EEG/LFP correlates in the CPT.
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0.984 |
2021 |
Martinowich, Keri |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Registration of Spatial Gene Expression in Key Nodes of Reward-Related Circuitry in the Human Brain
PROJECT SUMMARY Drug addiction is highly comorbid with psychiatric disorders, particularly post-traumatic stress disorder (PTSD) and major depressive disorder (MDD). These conditions share underlying genetic risk and are exacerbated by similar environmental factors, including exposure to stress and traumatic events. The dorsal anterior cingulate cortex (dACC), nucleus accumbens (NAc) and amygdala constitute key nodes of the brain?s reward circuitry, and perturbations in reward signaling are highly implicated in addiction, MDD and PTSD. The human dACC, NAc and amygdala have unique neuroanatomical features, which correspond to distinct biological functions. Given the close relationship between brain structure and function, precisely assigning gene expression to the spatial coordinates of individual cell populations within the cytoarchitecture can significantly advance our understanding of how dysregulation in these areas contributes to addiction and comorbid neuropsychiatric disorders. Towards this goal, we propose to generate detailed spatial transcriptomic maps, which will be combined with single-nucleus RNA sequencing (snRNA-seq) to register molecularly-defined cell types to their spatial coordinates, facilitating prediction of the anatomical locations of distinct neuronal classes of cells within the dACC, NAc and amygdala. These molecularly- and spatially-defined populations of cells will be associated with gene expression changes linked to substance use and comorbid neuropsychiatric disorders. We hypothesize that these regions have a precise molecular architecture that reveals 1) topographically organized and molecularly-defined cell types within layers of the dACC, and across sub-regions of the NAc and amygdala; 2) spatial-enrichment of genes associated with addiction and comorbid neuropsychiatric disorders. By generating the first transcriptome-scale spatial maps of the human dACC, NAc and amygdala, critical information about the molecular landscape of these regions within the architecture of the human brain will be generated. Our spatial registration approach will facilitate refined annotation of cell types in the human brain, and contribute to understanding addiction and comorbid neuropsychiatric disorders by identifying clinical associations with molecularly- and spatially-defined cell populations that can be targeted for prevention and treatment.
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0.984 |