Maladaptive Fear and L-type Voltage Gated Calcium Channel Subtypes.

fear;calcium channel;L-type;Neurosciences;Health Sciences;Neuroscience

Temme, Stephanie A. J.Seasholtz, Audrey ;

University of Michigan

关键词: fear;    calcium channel;    L-type;    Neurosciences;    Health Sciences;    Neuroscience;   

Others  :  https://deepblue.lib.umich.edu/bitstream/handle/2027.42/111524/stephjz_1.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

Fear learning can be adaptive and maladaptive. Learned fear to a harmful stimulus is adaptive and helps organisms survive in a given environment. However, learned fear can be maladaptive when it is persistent or when it is generalized to a non-threatening stimulus. These types of fears are often diagnosed as trauma or anxiety-related disorders in humans. Despite being the number one most common mental health disorder in the United States, very little is understood about the formation of these disorders and underlying maladaptive fears.Studies have implicated a class of voltage-gated calcium channels (VGCCs), known as L-type VGCCs (LVGCCs), in both the formation and extinction of conditioned fear. Additionally, LVGCCs have been linked to changes in the neuronal plasticity in structures known to be involved in fear learning including the amygdala and the hippocampus. While it is clear that LVGCCs are involved with these forms of fear related learning, it is not clear to what extent LVGCCs and the two LVGCC neuronal subtypes, CaV1.2 and CaV1.3, mediate adaptive and maladaptive fears or the neurophysiology associated with fear. Understanding the contribution of these LVGCCs to maladaptive fear learning could provide insights into the neurobiological mechanism underlying trauma and anxiety-related disorders. The goal of the research presented in this thesis was to investigate adaptive and maladaptive fear phenotypes, as well as explore the individual role of CaV1.2 and CaV1.3 in fear related learning and physiology. Utilizing mice with a conditional knockout of CaV1.2 in neurons in the brain, mice with a global knockout of CaV1.3, and various pure-bred mouse strains and sub-strains, five main points are illustrated: 1) Two forms of maladaptive fear learning, persistent fear and generalized fear exist, 2) CaV1.2 mediates generalized fear, likely through the dentate gyrus and adult neurogenesis, 3) CaV1.2 mediates persistent fear, likely through alterations in the inhibitory/excitatory synaptic activity onto the amygdala. 4) Deletion of CaV1.2 alters neurophysiological correlates of learning in the amygdala, including intrinsic excitability and synaptic plasticity. 5) CaV1.2 appears to alter behavior and neurophysiology in a LVGCC subtype specific manner.