2020 — 2021 |
Kitamura, Takashi |
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. |
Neural Circuit Mechanisms For Temporal Association Learning @ Ut Southwestern Medical Center
PROJECT SUMMARY A critical feature of episodic memory formation is the ability to associate temporally segregated events as an episode, called temporal association learning. Malfunctions of temporal association learning represent well- described findings in human patients suffering from schizophrenia and Alzheimer's disease. There are several critical gaps in our knowledge of current theoretical model and neurobiological evidence about mechanisms of temporal association learning. My long-term goal is to elucidate the neural mechanisms that drive and regulate temporal association learning by understanding neural circuits and their neural processes in entorhinal cortical-hippocampal (EC-HPC) networks, using Pavlovian trace fear conditioning (TFC) as the behavioral paradigm. We previously demonstrated that pOxr1+ excitatory cells in the medial entorhinal cortex layer III (pOxr1+ cells) project to the hippocampal CA1 pyramidal cells and are necessary for TFC. On the other hand, some CalB+ excitatory cells in MECII (CalB+ cells) project to GABAergic neurons in hippocampal CA1, suppress the MECIII input into the CA1 pyramidal cells through the feed-forward inhibition, and inhibit TFC. These findings lead us to propose a disinhibition model to regulate TFC, driving TFC by pOxr1+ cells and regulating TFC by CalB+ cells. The central hypothesis of this model is that successful TFC depends on learning-dependent disinhibition of hippocampal CA1 pyramidal cells through the reduction of feed-forward inhibition mediated by CalB+ cells. Towards this hypothesis, we have identified that pOxr1+ cells show tone-induced sustained neural activity in all trials during TFC, while CalB+ cells show trial-dependent reduction of the tone-induced sustained neural activity. We have also discovered that the CalB+ cells specifically express dopamine D1 receptors (D1R) in MEC and the activation D1R in MEC is essential for the learning-dependent reduction of the c-Fos expression in CalB+ cells and for successful TFC. Guided by strong preliminary data, we propose to pursue three Specific Aims to examine neural circuit mechanism that drive and regulate TFC: (1) To define the roles of pOxr1+ cells and CalB+ cells for TFC. (2) To determine the role of D1R activation in CalB+ cells for TFC. (3) To elucidate the role of dopaminergic inputs into the MEC for TFC. Collectively, our proposed research will broadly impact the field of learning and memory by characterizing novel neural circuits and their neural process that drive and regulate temporal association memory in EC-HPC networks. Our proposed studies will uncover neural substrates for temporal association memory and novel learning-dependent gatekeeper circuits for the regulation of temporal association learning, and potentially, the circuit mechanism can be a pharmaceutical new target for preventing inadequate memory formation.
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0.993 |
2021 |
Kitamura, Takashi |
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. |
Neural Circuit Mechanisms For Experience-Dependent Observational Fear @ Ut Southwestern Medical Center
PROJECT SUMMARY The ability to vicariously experience the other's aversive feelings in a situation, a process called observational fear (OF), is critical to live in society. Malfunctions of OF represent well-described findings in individuals with autism spectrum disorders. In OF, an observer witnesses a demonstrator in an aversive situation and responds with fear behaviors. If the demonstrator's reaction is robust, the observer easily expresses OF without prior similar experience and social familiarity with demonstrator (we refer to as innate OF). However, in nature and our lives, the demonstrator's reaction is often ambiguous and thus difficult for the observer to understand. To fully understand the other's situation, the observer utilizes both prior similar own experience and social familiarity that facilitate OF (we refer to as experience-dependent OF; Exp OF). While innate OF primarily depends on the anterior cingulate cortex (ACC) and basolateral amygdala (BLA), the neural mechanisms of Exp OF remain unexplored. My goal is to elucidate the neural mechanisms of how both prior similar own experience and social familiarity enable the observer to fully understand the other's aversive situation from their ambiguous reaction, by examining hippocampal (HPC)-BLA neural circuits in a mouse OF model that delivers strong electrical shocks to the demonstrator eliciting a robust reaction or weak electrical shocks eliciting an ambiguous reaction. Recently, our preliminary studies showed that ACC is dispensable for Exp OF, while ACC is essential for innate OF. On the other hand, both dorsal HPC (dHPC) and ventral HPC (vHPC) are crucial for Exp OF, but not for innate OF. BLA is required for both Exp and innate OF. These findings lead us to propose distinct neural circuits in Exp and innate OF. The central hypothesis of this model is that the dorsoventral HPC to BLA pathways generate and reactivate a neural ensemble of BLA neurons encoding prior similar own fear Guided by strong preliminary data, first, we propose that the dorsoventral HPC to BLA pathways are crucial for Exp OF, while the ACC to BLA pathway is essential for innate OF. Second, we propose that the reactivation of a neural ensemble of BLA neurons encoding prior similar own fear experience (a fear memory ensemble) mediates Exp OF as the perception-action mechanisms. Third, we propose that the pathway from dHPC to BLA generates the fear memory ensemble in BLA during own fear experience and then vHPC neurons respond to the familiar demonstrator's fearful situation to reactivate the fear memory ensemble in BLA to elicit Exp OF. experience, which facilitates Exp OF, while ACC induces robust BLA activity for innate OF. Collectively, our proposed research will broadly impact the field of learning and memory by characterizing neural circuits and their neural process about how we understand the other's aversive situational experience. Potentially, the neural mechanisms can be generalized for other types of empathy to vicariously experience the other's feeling/situation.
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0.993 |