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Regulation of extinction-related plasticity by opioid receptors in the ventrolateral periaqueductal gray matter.

Parsons RG, Gafford GM, Helmstetter FJ - Front Behav Neurosci (2010)

Bottom Line: The current study examined the effect of drugs that impair the extinction of fear conditioning on the activation of the extracellular-related kinase/mitogen-activated protein kinase (ERK/MAPK) in brain regions that likely participate in the consolidation of extinction learning.Subsequent experiments tested the effect of these drug treatments on the activation of the ERK/MAPK signaling pathway in various brain regions following extinction training.These data support the idea that opiodergic signaling derived from the vlPAG affects plasticity across the brain circuit responsible for the formation of extinction memory.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychology, University of Wisconsin-Milwaukee Milwaukee, WI, USA.

ABSTRACT
Recent work has led to a better understanding of the neural mechanisms underlying the extinction of Pavlovian fear conditioning. Long-term synaptic changes in the medial prefrontal cortex (mPFC) are critical for extinction learning, but very little is currently known about how the mPFC and other brain areas interact during extinction. The current study examined the effect of drugs that impair the extinction of fear conditioning on the activation of the extracellular-related kinase/mitogen-activated protein kinase (ERK/MAPK) in brain regions that likely participate in the consolidation of extinction learning. Inhibitors of opioid and N-methyl-d-aspartic acid (NMDA) receptors were applied to the ventrolateral periaqueductal gray matter (vlPAG) and amygdala shortly before extinction training. Results from these experiments show that blocking opioid receptors in the vlPAG prevented the formation of extinction memory, whereas NMDA receptor blockade had no effect. Conversely, blocking NMDA receptors in the amygdala disrupted the formation of fear extinction memory, but opioid receptor blockade in the same brain area did not. Subsequent experiments tested the effect of these drug treatments on the activation of the ERK/MAPK signaling pathway in various brain regions following extinction training. Only opioid receptor blockade in the vlPAG disrupted ERK phosphorylation in the mPFC and amygdala. These data support the idea that opiodergic signaling derived from the vlPAG affects plasticity across the brain circuit responsible for the formation of extinction memory.

No MeSH data available.


Related in: MedlinePlus

Extracellular-related kinase phosphorylation in the amygdala and mPFC following extinction training. (A) Schematic showing the behavioral procedures in this experiment. (B) Freezing during the CS for animals (N = 16) given extinction training and testing. (C) Freezing during the extinction training session for rats included in the western blot analysis. Expression of phosphorylated ERK in the amygdala (D) and mPFC (E) in rats given no extinction (N = 8, green), 4 trials of extinction (N = 7, blue) or 40 trials of extinction (N = 9, orange) compared to home cage rats (N = 8, gray). Levels of total ERK in the amygdala (F) and mPFC (G) in the same set of rats. The graphs show mean optical density (OD) values (±SEM) for each treatment group (*p < 0.05 relative to HC; **p < 0.01 relative to HC; ^p < 0.05 relative to 4 EXT).
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Figure 3: Extracellular-related kinase phosphorylation in the amygdala and mPFC following extinction training. (A) Schematic showing the behavioral procedures in this experiment. (B) Freezing during the CS for animals (N = 16) given extinction training and testing. (C) Freezing during the extinction training session for rats included in the western blot analysis. Expression of phosphorylated ERK in the amygdala (D) and mPFC (E) in rats given no extinction (N = 8, green), 4 trials of extinction (N = 7, blue) or 40 trials of extinction (N = 9, orange) compared to home cage rats (N = 8, gray). Levels of total ERK in the amygdala (F) and mPFC (G) in the same set of rats. The graphs show mean optical density (OD) values (±SEM) for each treatment group (*p < 0.05 relative to HC; **p < 0.01 relative to HC; ^p < 0.05 relative to 4 EXT).

Mentions: The next experiment characterized the pattern of ERK/MAPK phosphorylation in the amygdala and mPFC following extinction training. The day after acquisition, rats were either exposed to 40 trials of extinction (40 EXT), 4 trials of extinction (4 EXT), or no trials of extinction (NO EXT). Most of the rats were killed 45 min after this session, although some rats were given an extinction memory test the following day (Figure 3A). Freezing during the first 4 extinction trials was compared between the 4 EXT and 40 EXT groups in both sets of rats. No differences were seen between groups on this measure (Figure 3B,C). Data from rats given the full extinction training were also subjected to a repeated measure ANOVA. In both the set of rats tested and those sacrificed after extinction training there was a significant effect of Block [F(1,5) = 11.68, p < 0.05, tested rats; F(1,9) = 10.60, p < 0.05, sacrificed rats] seemingly driven by the decrease in freezing seen over the course of extinction training. A one-way ANOVA on data from the behavioral test session (Figure 3B, right side) yielded a significant group effect [F(2,13) = 7.819, p < 0.01]. Post hoc tests confirmed that rats in the 40 EXT group showed less freezing compared to rats in both the 4 EXT (p < 0.01) and NO EXT (p < 0.01) groups, indicating that only the 40 EXT group showed evidence of extinction learning. These data provide the basis to understand the changes in ERK phosphorylation that occurred following extinction training.


Regulation of extinction-related plasticity by opioid receptors in the ventrolateral periaqueductal gray matter.

Parsons RG, Gafford GM, Helmstetter FJ - Front Behav Neurosci (2010)

Extracellular-related kinase phosphorylation in the amygdala and mPFC following extinction training. (A) Schematic showing the behavioral procedures in this experiment. (B) Freezing during the CS for animals (N = 16) given extinction training and testing. (C) Freezing during the extinction training session for rats included in the western blot analysis. Expression of phosphorylated ERK in the amygdala (D) and mPFC (E) in rats given no extinction (N = 8, green), 4 trials of extinction (N = 7, blue) or 40 trials of extinction (N = 9, orange) compared to home cage rats (N = 8, gray). Levels of total ERK in the amygdala (F) and mPFC (G) in the same set of rats. The graphs show mean optical density (OD) values (±SEM) for each treatment group (*p < 0.05 relative to HC; **p < 0.01 relative to HC; ^p < 0.05 relative to 4 EXT).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2927240&req=5

Figure 3: Extracellular-related kinase phosphorylation in the amygdala and mPFC following extinction training. (A) Schematic showing the behavioral procedures in this experiment. (B) Freezing during the CS for animals (N = 16) given extinction training and testing. (C) Freezing during the extinction training session for rats included in the western blot analysis. Expression of phosphorylated ERK in the amygdala (D) and mPFC (E) in rats given no extinction (N = 8, green), 4 trials of extinction (N = 7, blue) or 40 trials of extinction (N = 9, orange) compared to home cage rats (N = 8, gray). Levels of total ERK in the amygdala (F) and mPFC (G) in the same set of rats. The graphs show mean optical density (OD) values (±SEM) for each treatment group (*p < 0.05 relative to HC; **p < 0.01 relative to HC; ^p < 0.05 relative to 4 EXT).
Mentions: The next experiment characterized the pattern of ERK/MAPK phosphorylation in the amygdala and mPFC following extinction training. The day after acquisition, rats were either exposed to 40 trials of extinction (40 EXT), 4 trials of extinction (4 EXT), or no trials of extinction (NO EXT). Most of the rats were killed 45 min after this session, although some rats were given an extinction memory test the following day (Figure 3A). Freezing during the first 4 extinction trials was compared between the 4 EXT and 40 EXT groups in both sets of rats. No differences were seen between groups on this measure (Figure 3B,C). Data from rats given the full extinction training were also subjected to a repeated measure ANOVA. In both the set of rats tested and those sacrificed after extinction training there was a significant effect of Block [F(1,5) = 11.68, p < 0.05, tested rats; F(1,9) = 10.60, p < 0.05, sacrificed rats] seemingly driven by the decrease in freezing seen over the course of extinction training. A one-way ANOVA on data from the behavioral test session (Figure 3B, right side) yielded a significant group effect [F(2,13) = 7.819, p < 0.01]. Post hoc tests confirmed that rats in the 40 EXT group showed less freezing compared to rats in both the 4 EXT (p < 0.01) and NO EXT (p < 0.01) groups, indicating that only the 40 EXT group showed evidence of extinction learning. These data provide the basis to understand the changes in ERK phosphorylation that occurred following extinction training.

Bottom Line: The current study examined the effect of drugs that impair the extinction of fear conditioning on the activation of the extracellular-related kinase/mitogen-activated protein kinase (ERK/MAPK) in brain regions that likely participate in the consolidation of extinction learning.Subsequent experiments tested the effect of these drug treatments on the activation of the ERK/MAPK signaling pathway in various brain regions following extinction training.These data support the idea that opiodergic signaling derived from the vlPAG affects plasticity across the brain circuit responsible for the formation of extinction memory.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychology, University of Wisconsin-Milwaukee Milwaukee, WI, USA.

ABSTRACT
Recent work has led to a better understanding of the neural mechanisms underlying the extinction of Pavlovian fear conditioning. Long-term synaptic changes in the medial prefrontal cortex (mPFC) are critical for extinction learning, but very little is currently known about how the mPFC and other brain areas interact during extinction. The current study examined the effect of drugs that impair the extinction of fear conditioning on the activation of the extracellular-related kinase/mitogen-activated protein kinase (ERK/MAPK) in brain regions that likely participate in the consolidation of extinction learning. Inhibitors of opioid and N-methyl-d-aspartic acid (NMDA) receptors were applied to the ventrolateral periaqueductal gray matter (vlPAG) and amygdala shortly before extinction training. Results from these experiments show that blocking opioid receptors in the vlPAG prevented the formation of extinction memory, whereas NMDA receptor blockade had no effect. Conversely, blocking NMDA receptors in the amygdala disrupted the formation of fear extinction memory, but opioid receptor blockade in the same brain area did not. Subsequent experiments tested the effect of these drug treatments on the activation of the ERK/MAPK signaling pathway in various brain regions following extinction training. Only opioid receptor blockade in the vlPAG disrupted ERK phosphorylation in the mPFC and amygdala. These data support the idea that opiodergic signaling derived from the vlPAG affects plasticity across the brain circuit responsible for the formation of extinction memory.

No MeSH data available.


Related in: MedlinePlus