L-type Voltage-Gated Calcium Channels in Fear Conditioning, Fear Extinction, and Amygdala Neurophysiology.

[摘要] Fear conditioning is a form of learning in which an initially neutral stimulus (e.g., tone or context) comes to be feared after being paired with an aversive stimulus (e.g., shock). After pairing, the neutral stimulus alone can elicit fear responses (e.g., freezing behavior, autonomic arousal, stress hormone release). The initially neutral stimulus is referred to as the ;;conditioned stimulus;; (CS) once it is able to bring about fear responses on its own, the aversive stimulus is the ;;unconditioned stimulus;; (US), and the fear responses elicited by the CS are the ;;conditioned responses;; (CRs).Fear extinction is a process by which the previously conditioned fear responses can be reduced by repeated presentation of the CS alone, in the absence of the aversive US. Fear conditioning and fear extinction are both critically dependent on the amygdala, a medial temporal lobe brain structure. Interestingly, it has been previously demonstrated that L-type voltage-gated calcium channels (L-VGCCs) have a role in fear conditioning, fear extinction, and amygdala neurophysiology. All of the studies implicating L-VGCCs in these phenomena used L-VGCC antagonists to demonstrate the role for L-VGCCs.There are two brain-expressed L-VGCCs, Cav1.2 and Cav1.3, both of which are the targets of currently-available L-VGCC antagonists.In this dissertation, I address the contribution of each of these L-VGCCs to fear conditioning, fear extinction, and amygdala neurophysiology using mouse models in which the genes for either Cav1.2 or Cav1.3 deleted. First, I demonstrate that Cav1.3, but not Cav1.2, mediates consolidation of fear conditioning. Next, I show that neither Cav1.2 nor Cav1.3 alone is necessary for fear extinction.Instead, I find that the L-VGCC antagonist nifedipine used in the previous experiments implicating L-VGCCs in fear extinction impairs locomotion and induces an aversive state. Further, I demonstrate that this aversive state can enter into associations with stimuli present at the time that it is experienced, suggesting that previous studies using nifedipine were likely confounded by drug toxicity. Finally, I show that Cav1.3 mediates long-term potentiation of afferents to the basolateral amygdala (BLA) as well as the afterhyperpolarization in principal neurons of the BLA.

[发布机构] University of Michigan

[效力级别] L-type Voltage-gated Calcium Channels

[关键词] Fear Conditioning;L-type Voltage-gated Calcium Channels;CaV1.2;CaV1.3;Fear Extinction;Fear Consolidation;Neurosciences;Health Sciences;Science;Neuroscience