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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

Model for the extinction of fear memories. (A) Diagram showing the activity of the ventrolateral PAG, medial prefrontal cortex, and amygdala during the extinction of fear memory. Activity of opioid receptors in the vlPAG (red circles) causes an increase in activity in the mPFC. Augmented excitability of the mPFC drives NMDA-mediated plasticity (blue circles) in the basolateral nucleus and/or GABAergic intercalated cells (ITC) of the amygdala. Enhancement of BLA/ITC activity results in an inhibition of the central nucleus of the amygdala and a decreased ability to produce fear responses. (B) When opioid receptors are blocked during extinction learning there is no change in excitability of the mPFC or the BLA/ITC, the output of the central nucleus is not affected, and fear responses are sustained.
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Figure 7: Model for the extinction of fear memories. (A) Diagram showing the activity of the ventrolateral PAG, medial prefrontal cortex, and amygdala during the extinction of fear memory. Activity of opioid receptors in the vlPAG (red circles) causes an increase in activity in the mPFC. Augmented excitability of the mPFC drives NMDA-mediated plasticity (blue circles) in the basolateral nucleus and/or GABAergic intercalated cells (ITC) of the amygdala. Enhancement of BLA/ITC activity results in an inhibition of the central nucleus of the amygdala and a decreased ability to produce fear responses. (B) When opioid receptors are blocked during extinction learning there is no change in excitability of the mPFC or the BLA/ITC, the output of the central nucleus is not affected, and fear responses are sustained.

Mentions: Finally, we propose a model (Figure 7) meant to account for the findings of the current study and synthesize them with prior published work. According to our model, opioids are released in the vlPAG when the animals are exhibiting fear to the CS during the early phases of extinction. As the animals keep responding during extinction training the cumulative effect of opioid release is a disinhibition of vlPAG output neurons, including those connected directly or indirectly to the mPFC. The net result of this is in an increase in activity in the mPFC. Other groups have described in detail the effects mPFC can have on the amygdala, in particular the physiology of this circuit as it relates to extinction learning, and our model incorporates these (Royer and Pare, 2002; Quirk et al., 2003; Likthtik et al., 2008). Briefly, excitation of mPFC increases activity of excitatory projection neurons from the mPFC to GABAergic intercalated cells in the amygdala. Accordingly, an increase in these inhibitory neurons dampens the output of the central amygdala, which is responsible for driving the various fear responses. NMDA-dependent processes occur in the amygdala allowing for these changes. When opioid receptors are blocked in the vlPAG, the mPFC does not receive the appropriate signals that allow it to decrease the activity of the amygdala. In addition to accounting for the results of the current and many published studies, a number of predictions are derived from this model. Any number of the other changes in the mPFC and amygdala related to extinction learning or the consolidation of extinction should be blocked by naloxone infusions into the vlPAG. For example, bursting of mPFC neurons associated with consolidation of extinction learning (Burgos-Robles et al., 2007) should be disrupted by NAL in vlPAG. Furthermore, any change in the excitability of the intercalated cells of the amygdala should also be interrupted by vlPAG opioid receptor blockade. Finally, given the effects of opioid receptor antagonists in this study and others, agonists of this receptor applied to the vlPAG should augment extinction learning by enhancing the activity of mPFC inputs into the amygdala. Future experiments should provide answers to these and other important questions.


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

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

Model for the extinction of fear memories. (A) Diagram showing the activity of the ventrolateral PAG, medial prefrontal cortex, and amygdala during the extinction of fear memory. Activity of opioid receptors in the vlPAG (red circles) causes an increase in activity in the mPFC. Augmented excitability of the mPFC drives NMDA-mediated plasticity (blue circles) in the basolateral nucleus and/or GABAergic intercalated cells (ITC) of the amygdala. Enhancement of BLA/ITC activity results in an inhibition of the central nucleus of the amygdala and a decreased ability to produce fear responses. (B) When opioid receptors are blocked during extinction learning there is no change in excitability of the mPFC or the BLA/ITC, the output of the central nucleus is not affected, and fear responses are sustained.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 7: Model for the extinction of fear memories. (A) Diagram showing the activity of the ventrolateral PAG, medial prefrontal cortex, and amygdala during the extinction of fear memory. Activity of opioid receptors in the vlPAG (red circles) causes an increase in activity in the mPFC. Augmented excitability of the mPFC drives NMDA-mediated plasticity (blue circles) in the basolateral nucleus and/or GABAergic intercalated cells (ITC) of the amygdala. Enhancement of BLA/ITC activity results in an inhibition of the central nucleus of the amygdala and a decreased ability to produce fear responses. (B) When opioid receptors are blocked during extinction learning there is no change in excitability of the mPFC or the BLA/ITC, the output of the central nucleus is not affected, and fear responses are sustained.
Mentions: Finally, we propose a model (Figure 7) meant to account for the findings of the current study and synthesize them with prior published work. According to our model, opioids are released in the vlPAG when the animals are exhibiting fear to the CS during the early phases of extinction. As the animals keep responding during extinction training the cumulative effect of opioid release is a disinhibition of vlPAG output neurons, including those connected directly or indirectly to the mPFC. The net result of this is in an increase in activity in the mPFC. Other groups have described in detail the effects mPFC can have on the amygdala, in particular the physiology of this circuit as it relates to extinction learning, and our model incorporates these (Royer and Pare, 2002; Quirk et al., 2003; Likthtik et al., 2008). Briefly, excitation of mPFC increases activity of excitatory projection neurons from the mPFC to GABAergic intercalated cells in the amygdala. Accordingly, an increase in these inhibitory neurons dampens the output of the central amygdala, which is responsible for driving the various fear responses. NMDA-dependent processes occur in the amygdala allowing for these changes. When opioid receptors are blocked in the vlPAG, the mPFC does not receive the appropriate signals that allow it to decrease the activity of the amygdala. In addition to accounting for the results of the current and many published studies, a number of predictions are derived from this model. Any number of the other changes in the mPFC and amygdala related to extinction learning or the consolidation of extinction should be blocked by naloxone infusions into the vlPAG. For example, bursting of mPFC neurons associated with consolidation of extinction learning (Burgos-Robles et al., 2007) should be disrupted by NAL in vlPAG. Furthermore, any change in the excitability of the intercalated cells of the amygdala should also be interrupted by vlPAG opioid receptor blockade. Finally, given the effects of opioid receptor antagonists in this study and others, agonists of this receptor applied to the vlPAG should augment extinction learning by enhancing the activity of mPFC inputs into the amygdala. Future experiments should provide answers to these and other important questions.

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