2009 — 2011 |
Likhtik, Ekaterina |
F32Activity Code Description: To provide postdoctoral research training to individuals to broaden their scientific background and extend their potential for research in specified health-related areas. |
Network Dynamics of Vhip-Amygdala-Mpfc Circuit in Innate and Learned Anxiety @ Columbia University Health Sciences
DESCRIPTION (provided by applicant): Anxiety disorders include a broad repertoire of behaviors with differing etiologies. For instance, generalized anxiety disorder (GAD) is a state of innate and chronic fear, whereas post-traumatic stress disorder (PTSD) is an anxious response to learned fear that is acquired and cue dependent. The main goal of this proposal is to identify the differing ways in which implicated brain regions process these two types of anxiety. Research has identified the basolateral complex of the amygdala (BLA), the medial prefrontal cortex (mPFC) and the ventral portion of the hippocampus (vHip) as important for various aspects of anxiety processing. The proposed work will dissociate the behavior-driven dynamics of the network formed by these three areas during learned versus innate anxiety. The vHip, BLA and mPFC are directly connected, suggesting that they form a network, the interactions of which could constitute the basis for learned and chronic anxiety phenotypes. Indeed, the vHip and BLA have convergent inputs to the mPFC, which has been suggested as a means of integrating anxiety and context information in the cortex. Separate studies have demonstrated that in innate anxiety paradigms, the vHip and mPFC increase their communication, whereas conditioned fear increases synchrony between the hippocampus and BLA. In contrast, the mPFC and amygdala are thought to act in concert during extinction of learned fear. However, data is lacking on how the mPFC, BLA and vHip integrate or differentiate innate versus learned anxiety. Therefore, we aim to study the network dynamics of this circuit using chronic multisite recordings in vivo in conjunction with behavioral assays probing both types of anxiety. We will test the hypothesis that there are dissociable levels of cooperation between the vHip, BLA and mPFC as a function of the anxiety provoking scenario that is experienced. In addition, behavior and electrophysiological recordings will be used to test the idea that disruption of 5HT1A receptor signaling, an established model of hippocampal dependent anxiety, will enhance innate anxiety via increased vHip-mPFC coupling, while leaving intact amygdala-hippocampal signaling as well as learned anxiety. Given the prevalence of anxiety disorders in the United States and worldwide, as well as their high mortality and high cost to society, the translational nature of this proposal is undoubtedly beneficial to public heath. In particular, by examining the changing ways in which the ventral hippocampus, amygdala and medial prefrontal cortex interact during different anxiogenic scenarios, we aim to provide a network-level approach for differentiating between learned and innate anxiety in humans. The ultimate goal of this work is to create a framework for etiology-tailored therapies of anxiety.
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1 |
2015 — 2017 |
Likhtik, Ekaterina |
K01Activity Code Description: For support of a scientist, committed to research, in need of both advanced research training and additional experience. |
Modulation of Fear and Safety in the Basal Forebrain-Amygdala-Prefrontal Network
? DESCRIPTION (provided by applicant): Anxiety disorders are a cluster of debilitating conditions that affect more than 18% of the adult US population (Kessler et al., 2005). When anxiety is high, whether catalyzed innately (e.g.Generalized Anxiety Disorder (GAD)), or by a traumatic event (e.g. Post-Traumatic Stress Disorder (PTSD)), a patient is severely stressed and in anguish, often becoming isolated and unable to participate in daily life. Anxiety disorders also pose a substantial economic burden on our society, estimated to cost almost $34 billion in US spending in 2013 alone (Shirneshan et al, 2013). A thorough understanding of the neural circuits underlying generalized fear and the ability to differentiate threat from safety is critica to effectively treating anxiety. The goal of the proposed research is to identify how interactions within the prefrontal-basal forebrain-amygdala circuit contribute to processing threat and safety. The basal forebrain has dense inhibitory and cholinergic projections to the amygdala, and both of these neurotransmitters are known to play an important role in shaping amygdala activity during emotional learning. However, we do not yet have a good understanding how different neurochemical inputs from the basal forebrain impact amygdala physiology and affect behavior. To address this, aim 1 of the proposal is to establish the role of inhibitory signaling from the basal forebrain to the amygdala during threat and safety processing. In contrast to the basal forebrain-amygdala, connectivity between the prefrontal cortex and the amygdala has received more attention for its role mediating fear discrimination. However, the prefrontal cortex is known to drive inhibitory cells in the basal forebrain (Guyengési et al, 2008) and inhibitory cells from the basal forebrain have known projections to the amygdala (McDonald et al., 2011). Thus, the basal forebrain may serve as an important interface between the prefrontal cortex and the amygdala during anxiety processing. To test this idea, Aim 2 of the proposal is to isolate the contribution of the indirect prefrontal-basal forebrain-amygdala projection to differentiating threatening and safe stimuli. These studies will employ a combination of clinically relevant behavioral paradigms, large-scale neurophysiological recordings, novel anatomical tracing methods and optogenetic control of circuit function during behavior. The prefrontal-basal forebrain-amygdala network has the potential to be critical for regulating threat-related amygdala activity and affective processing. The proposed research is necessary for a better understanding of how this understudied circuit contributes to adaptive aversive learning. This work will be essential for building a translational model for generalized fear, which can lead to targeted therapies for patients suffering from disorders of learned anxiety, such as PTSD.
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0.922 |
2018 — 2019 |
Burghardt, Nesha Star [⬀] Likhtik, Ekaterina |
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.) |
Circuit-Level Regulation of Fear and Safety Learning in Chronically Stressed Mice
Project Summary/Abstract It has long been recognized that chronic exposure to stressful adverse life experiences confers susceptibility to developing post-traumatic stress disorder (PTSD), a stressor and trauma-related disorder characterized by intense fearful memory formation. Many of the long-lasting symptoms associated with PTSD can be attributed to an impaired ability to discriminate between cues associated with threat from those associated with safety. Chronic stress is believed to play a key role in the etiology of PTSD by altering the brain's fear memory system in a way that increases generalization of fear to `safe' cues that are unrelated to the trauma. Recent findings have suggested that memories of fear and safety are encoded and expressed via an elaborate pattern of communication between the medial prefrontal cortex (mPFC) and the basolateral amygdala (BLA), with BLA activity being suppressed by input from the mPFC during periods of recognized safety. Moreover, evidence suggests that basal forebrain (BF) cholinergic inputs to the mPFC play a critical role in facilitating the detection and encoding of certain types of learned cues. It remains unknown, however, whether cholinergic input to the mPFC is involved in the encoding of safety cues, and no studies have conducted a circuit-level analysis to examine how a history of chronic stress regulates dynamic network activity between the BF, mPFC and BLA. In the present proposal, we will first use behavioral and immunocytochemical techniques to characterize the effects of chronic stress on fear and safety discrimination and activity within the basal forebrain cholinergic system in male and female mice (Aim I). Next, we will use multisite neurophysiological recordings in awake-behaving male and female mice to systematically examine how a history of chronic stress regulates dynamic patterns of neural activity between the BF, mPFC and BLA during fear and safety discrimination (Aim II). Finally, we will use optogenetic methods to manipulate activity in the BF-mPFC pathway to determine how cholinergic input contributes to fear discrimination learning and how it might be impacted by a history of chronic stress in both sexes (Aim III). Our findings have the potential to significantly broaden our current understanding of how exposure to chronic stress modulates fear discrimination and the adaptive use of safety cues at the neural circuit level, findings which may have relevance for the treatment of disorders such as PTSD.
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0.922 |
2019 — 2020 |
Likhtik, Ekaterina |
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. |
Emotion Regulation in the Prefrontal - Basal Forebrain-Amygdala Circuit
Abstract Post-traumatic stress disorder (PTSD) is a stress- and trauma- induced condition that affects millions of Americans, with women facing PTSD diagnoses at almost twice the rate of men. PTSD is characterized by persistent anxiety, a dysregulated autonomic nervous system, avoidance behaviors, and is often co-morbid with major depressive disorder and substance abuse. Diminished engagement of the medial prefrontal cortex concomitant with a hyperactive basolateral amygdala (BLA) strongly contribute to the dysregulated emotional responses associated with PTSD. During extinction learning, the medial prefrontal cortex is thought to suppress BLA activity, thereby decreasing defensive responding to non-threatening cues, a process that is disrupted in PTSD. There is much evidence to support the idea that direct prefrontal input affects plasticity in the BLA, and shifts the excitatory-inhibitory balance in the amygdala towards inhibition. However, the mechanisms of this circuit-level interaction are not well understood. Notably, the medial prefrontal cortex is not a monolithic structure, and its contiguous subregions, in rodents designated as the prelimbic (PL) and infralimbic (IL), are associated with increased and decreased defensive responding, respectively. Although some ideas have been proposed, thus far no differences have been found in direct PL vs. IL interactions with the BLA that can account for their functional dichotomy. This gap in knowledge prevents the development of more targeted therapeutic treatments for PTSD. One possibility is that the PL and IL may have differential effects upon amygdala function via indirect pathways. Previous work shows that the PL and IL are differentially connected with the basal forebrain, a critical region for modulating fear and extinction learning in the amygdala. The basal forebrain provides strong cholinergic, glutamatergic, and GABAergic inputs to the amygdala, the cortical mantle, and the hippocampus, making it an intriguing centralized location for prefrontal modulation of extinction learning in downstream structures. The goal of the proposed experiments is to uncover the structure and function of PL and IL -basal forebrain -amygdala communication during extinction. To this end, in Specific Aim I will use viral tracing and immunohistochemistry to uncover the detailed circuitry of PL and IL connectivity with amygdala-projecting cells in the ventral pallidum/substantia innominata, and horizontal limb of the diagonal band of the basal forebrain. Then, in Specific Aims 2 and 3, I will use optogenetics to manipulate IL and PL inputs to the basal forebrain, and multi-site in-vivo recordings to record the neurophysiology across the IL/PL-basal forebrain-BLA circuit during fear conditioning, extinction training and recall. Additional immunohistochemical analyses of neural activity will indicate which cell types the PL and IL drive in the basal forebrain during extinction. All experiments will be performed in both sexes to assess whether this circuit contributes to increased rates of PTSD diagnosis in women. This approach is specifically designed to improve our understanding of the circuitry underlying extinction learning, and is geared toward finding novel therapeutic approaches for improving treatment outcomes in PTSD.
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0.922 |