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Contextual and Cued Fear Conditioning Test Using a Video Analyzing System in Mice
Published on: March 1, 2014
CB1 cannabinoid receptors modulate kinase and phosphatase activity during extinction of conditioned fear in mice
Astrid Cannich1, Carsten T Wotjak, Kornelia Kamprath
1Groups of Molecular Genetics of Behavior, Max Planck Institute of Psychiatry, 80804 Munich, Germany.
Abstract:
Cannabinoid receptors type 1 (CB1) play a central role in both short-term and long-term extinction of auditory-cued fear memory. The molecular mechanisms underlying this function remain to be clarified. Several studies indicated extracellular signal-regulated kinases (ERKs), the phosphatidylinositol 3-kinase with its downstream effector AKT, and the phosphatase calcineurin as potential molecular substrates of extinction behavior. To test the involvement of these kinase and phosphatase activities in CB1-dependent extinction of conditioned fear behavior, conditioned CB1-deficient mice (CB1(-/-)) and wild-type littermates (CB1(+/+)) were sacrificed 30 min after recall of fear memory, and activation of ERKs, AKT, and calcineurin was examined by Western blot analysis in different brain regions. As compared with CB1(+/+), the nonreinforced tone presentation 24 h after auditory-cued fear conditioning led to lower levels of phosphorylated ERKs and/or calcineurin in the basolateral amygdala complex, ventromedial prefrontal cortex, dorsal hippocampus, and ventral hippocampus of CB1(-/-). In contrast, higher levels of phosphorylated p44 ERK and calcineurin were observed in the central nucleus of the amygdala of CB1(-/-). Phosphorylation of AKT was more pronounced in the basolateral amygdala complex and the dorsal hippocampus of CB1(-/-). We propose that the endogenous cannabinoid system modulates extinction of aversive memories, at least in part via regulation of the activity of kinases and phosphatases in a brain structure-dependent manner.
Insights
The endogenous cannabinoid system, via cannabinoid receptors type 1 (CB1), influences fear memory extinction. CB1 deficiency alters key kinase and phosphatase activity in brain regions critical for memory processing.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- Cannabinoid receptors type 1 (CB1) are crucial for auditory-cued fear memory extinction.
- The precise molecular pathways governing CB1's role in memory extinction are not fully understood.
- Extracellular signal-regulated kinases (ERKs), AKT, and calcineurin are implicated in extinction behavior.
Purpose of the Study:
- To investigate the involvement of ERK, AKT, and calcineurin signaling pathways in CB1-dependent fear memory extinction.
- To compare the activation of these molecular substrates in CB1-deficient and wild-type mice during fear memory recall.
Main Methods:
- Auditory-cued fear conditioning was performed in CB1-deficient (CB1(-/-)) and wild-type (CB1(+/+)) mice.
- Mice were sacrificed 30 minutes after fear memory recall.
- Western blot analysis was used to measure the activation (phosphorylation) of ERKs, AKT, and calcineurin in various brain regions.
Main Results:
- CB1(-/-) mice showed reduced phosphorylated ERKs and/or calcineurin in the basolateral amygdala, ventromedial prefrontal cortex, and hippocampus compared to CB1(+/+).
- Conversely, CB1(-/-) mice exhibited increased phosphorylated p44ERK and calcineurin in the central amygdala.
- Phosphorylated AKT levels were elevated in the basolateral amygdala and dorsal hippocampus of CB1(-/-) mice.
Conclusions:
- The endogenous cannabinoid system modulates aversive memory extinction through CB1 receptors.
- This modulation involves the regulation of kinase and phosphatase activity.
- The effects are dependent on specific brain structures, indicating a regionally specific mechanism.
