2014 — 2017 |
Todd, Travis |
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. |
Cortico-Hippocampal Contributions to Context and Extinction Learning.
DESCRIPTION (provided by applicant): Learning processes allow organisms (including humans) to adapt their behavior to changes in the environment, and are thus crucial for survival. However, learning does not take place in a vacuum. Indeed, most learning experiences occur within complex environments composed of visual, auditory, olfactory, and tactile stimuli. To successfully learn about biologically significant events (e.g., the presence of food or prey) that occur within particular environments, animals must first combine individual features of the environment into an integrated memory, or context representation. Contemporary research suggests that this type of learning occurs within cortico-hippocampal networks in the brain. However, the exact pathways and individual functions of particular regions essential for learning about contexts have not been fully resolved. The overarching hypothesis of this proposal is that the restrosplenial cortex (RSP) is essential for forming integrated context representations, and that the postrhinal cortex (POR) is essential for updating these memories. This proposal addresses unanswered questions about the neural substrates of contextual fear learning (Specific Aim 1). It also addresses the functional role of RSP and POR in the recovery of fear to a previously extinguished fear cue. Fear extinction is context specific, and recovery can result either from re-experiencing the aversive event (i.e., reinstatement; Specific Aim 2) or when a significant amount of time has passed since fear extinction occurred (i.e., spontaneous recovery; Specific Aim 3). In all studies, RSP and POR will be temporally inactivated using a new and innovative technique: Designer Receptors Exclusively Activated by Designer Drugs (DREADDs). This temporary inactivation will allow for isolation of the role of these regions during encoding and/or retrieval processes. In sum, this proposal examines the role of RSP and POR in context learning and fear extinction, two processes that are important in the development and subsequent treatment of several mental illnesses in humans (e.g., post-traumatic stress disorder: PTSD; anxiety related disorders, phobias). Further, the RSP is known to be compromised in human disorders such as schizophrenia and Alzheimer's disease. Therefore, investigating the role of RSP and POR, during both fear learning and fear extinction, could prove to be especially informative to clinical practice in humans.
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2019 — 2021 |
Todd, Travis |
K01Activity Code Description: For support of a scientist, committed to research, in need of both advanced research training and additional experience. |
Cortical Ensemble Coding and Circuit Dynamics of Fear Suppression @ University of Vermont & St Agric College
Project Summary Traumatic experiences, such as combat exposure or sexual/physical abuse can lead to the development of post-traumatic stress disorder (PTSD). Patients with PTSD often show generalized fear to non-dangerous or ?safe? stimuli, and have difficulty learning that a previously threatening stimulus is now safe. Although impaired safety learning is a suggested biomarker of PTSD, the precise mechanisms that underlie this impairment are unclear. Notably, human imaging studies have revealed hypoactivity of the ventromedial prefrontal cortex (vmPFC) and retrosplenial cortex (RSC) in patients with PTSD (Hayes et al., 2012; Pissiota et al., 2002) suggesting the possibility that vmPFC ? RSC dysfunction might underlie impairments in safety learning observed in patients with PTSD. Consistent with a role for the RSC in safety learning, a recent study from our lab found that permanent damage of the RSC specifically impairs safety learning (Todd et al., 2016a; see also Gabriel, Sparenborg, & Stolar, 1987). Nevertheless, although the RSC has a putative role in processing safety cues, little is known about how cell populations within the RSC encode safety, or the nature of RSC ? vmPFC interaction during safety learning. In this project, large-scale single unit ensemble recording and analysis, and local field recordings and analysis, will be combined with chemogentics and learning-theory based behavioral analysis to investigate vmPFC ? RSC circuitry in the control of safety learning and behavior. The proposed experiments will therefore establish how cortical ensembles encode safety, and explore interaction between the vmPFC and RSC during two forms of safety learning. Thus, the proposed research is significant in that it will yield a detailed understanding of the mechanisms underlying safety learning, ultimately informing the link between cortical dysfunction and mental illness, including PTSD. In addition to its significance, the current project will provide the trainee with an excellent opportunity to master in vivo electrophysiological recordings and analysis in freely behaving rats. The trainee intends to use this technique, combined with chemogenetic manipulation of neural activity to establish an independent line of research probing the neural circuits underlying learning, memory, and behavior. In addition, the proposed award will ensure the trainee acquires the professional skill necessary to reach his career goals. This training will take place at Dartmouth College, an exceptional research and teaching intuition, under the guidance of an established team of mentors as well as an external advisory committee comprised of luminaries in the fields of behavioral neuroscience and PTSD research. This proposal is well-designed to provide Dr. Todd with the continued career development necessary to establish himself as an independent investigator and leader in the field.
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2020 — 2021 |
Gulledge, Allan T (co-PI) [⬀] Smith, Kyle S (co-PI) [⬀] Todd, Travis Van Der Meer, Matthijs |
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. |
Cortical Circuitry and Mechanisms Underlying Remote Cue-Specific Fear Memory and Extinction @ University of Vermont & St Agric College
Project Summary Individuals with fear disorders such as post-traumatic stress disorder (PTSD) experience excessively strong and intrusive fear memories about stimuli that were encountered during a prior trauma, including individual sounds or visual stimuli (?cue-specific? fear memory) or the combination of stimuli that together define the place in which the event occurred (?contextual? fear memory). The memories may have been formed recently or long ago (?remote? memories), in which case they may plague a person for a substantial portion of his/her life. The development of effective therapies depends on a thorough understanding the neural mechanisms that underlie these different types of fear memories, as well as fear extinction, which is the basis for exposure- based therapy commonly used to reduce fear in humans. To date, a substantial body of research has identified discrete neural systems that support recent versus remote contextual memory, and other studies have identified the substrates of recently-acquired cue-specific memory and extinction, but very little work has focused on the brain mechanisms involved in remote cue- specific memory and extinction. This is important to resolve particularly with respect to PTSD since individuals often do not seek therapy until long after the traumatic event, especially in cases of combat trauma or sexual assault. To address this, the proposed research advances a new theoretical model of the neural circuits that underlie remote cue-specific fear memory and extinction. This model is based on new data from our laboratory and combines state-of-the art chemogenetic and optogentic-anatomical approaches to test the hypotheses that a) communication between the retrosplenial cortex and secondary sensory cortices is necessary for remote cue-specific fear memory, and b) the postrhinal cortex mediates the context-dependency of extinction of remote cue-specific fear.
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