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The NO-cGMP-PKG signaling pathway coordinately regulates ERK and ERK-driven gene expression at pre- and postsynaptic sites following LTP-inducing stimulation of thalamo-amygdala synapses.

Ping J, Schafe GE - Neural Plast. (2011)

Bottom Line: Here, we show that LTP-inducing stimulation of thalamo-LA inputs regulates the activation of ERK and the expression of ERK-driven immediate early genes (IEGs) in both the LA and MGm/PIN.Further, we show that pharmacological blockade of NMDAR-driven synaptic plasticity, NOS activation, or PKG signaling in the LA significantly impairs high-frequency stimulation-(HFS-) induced ERK activation and IEG expression in both regions, while blockade of extracellular NO signaling in the LA impairs HFS-induced ERK activation and IEG expression exclusively in the MGm/PIN.These findings suggest that NMDAR-driven synaptic plasticity and NO-cGMP-PKG signaling within the LA coordinately regulate ERK-driven gene expression in both the LA and the MGm/PIN following LTP induction at thalamo-LA synapses, and that synaptic plasticity in the LA promotes ERK-driven transcription in MGm/PIN neurons via NO-driven "retrograde signaling".

View Article: PubMed Central - PubMed

Affiliation: Department of Psychology, Yale University, New Haven, CT 06520, USA.

ABSTRACT
Long-term potentiation (LTP) at thalamic input synapses to the lateral nucleus of the amygdala (LA) has been proposed as a cellular mechanism of the formation of auditory fear memories. We have previously shown that signaling via ERK/MAPK in both the LA and the medial division of the medial geniculate nucleus/posterior intralaminar nucleus (MGm/PIN) is critical for LTP at thalamo-LA synapses. Here, we show that LTP-inducing stimulation of thalamo-LA inputs regulates the activation of ERK and the expression of ERK-driven immediate early genes (IEGs) in both the LA and MGm/PIN. Further, we show that pharmacological blockade of NMDAR-driven synaptic plasticity, NOS activation, or PKG signaling in the LA significantly impairs high-frequency stimulation-(HFS-) induced ERK activation and IEG expression in both regions, while blockade of extracellular NO signaling in the LA impairs HFS-induced ERK activation and IEG expression exclusively in the MGm/PIN. These findings suggest that NMDAR-driven synaptic plasticity and NO-cGMP-PKG signaling within the LA coordinately regulate ERK-driven gene expression in both the LA and the MGm/PIN following LTP induction at thalamo-LA synapses, and that synaptic plasticity in the LA promotes ERK-driven transcription in MGm/PIN neurons via NO-driven "retrograde signaling".

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High-frequency stimulation of the MGm/PIN promotes increased immunolabeling of ERK-driven IEGs in the LA (a) Placement of stimulation electrode. (b) Schematic of experimental protocol. Rats were given HFS or LFS and sacrificed 2 hours after stimulation. (c) Schematic of the amygdala at Bregma −3.2. (d) Mean (±SEM) percent Arc/Arg3.1 immunoreactive cells in the LA from rats receiving HFS (n = 6) or LFS (n = 6). (e) Photomicrographs showing Arc/Arg3.1-labeled cells from rats receiving HFS (left) or LFS (right). (f) Mean (±SEM) percent EGR-1 immunoreactive cells in the LA from rats receiving HFS (n = 6) or LFS (n = 6). (g) Photomicrographs showing EGR-1-labeled cells from rats receiving HFS (left) or LFS (right). (h) Mean (±SEM) percent c-Fos immunoreactive cells in the LA from rats receiving HFS (n = 6) or LFS (n = 6). (i) Photomicrographs showing c-Fos-labeled cells from rats receiving HFS (left) or LFS (right). In each experiment, ipsilateral cell counts have been expressed as a percentage of contralateral cell counts for each rat. *P < .05 relative to the ipsilateral side N.S. = not significant.  LAd = dorsal division of the lateral amygdala; LAv l = ventrolateral division of the lateral amygdala; LAvm = ventromedial division of the lateral amygdala; CE = central amygdala; B = basal amygdala; AST = amygdala-striatal transition zone.
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fig3: High-frequency stimulation of the MGm/PIN promotes increased immunolabeling of ERK-driven IEGs in the LA (a) Placement of stimulation electrode. (b) Schematic of experimental protocol. Rats were given HFS or LFS and sacrificed 2 hours after stimulation. (c) Schematic of the amygdala at Bregma −3.2. (d) Mean (±SEM) percent Arc/Arg3.1 immunoreactive cells in the LA from rats receiving HFS (n = 6) or LFS (n = 6). (e) Photomicrographs showing Arc/Arg3.1-labeled cells from rats receiving HFS (left) or LFS (right). (f) Mean (±SEM) percent EGR-1 immunoreactive cells in the LA from rats receiving HFS (n = 6) or LFS (n = 6). (g) Photomicrographs showing EGR-1-labeled cells from rats receiving HFS (left) or LFS (right). (h) Mean (±SEM) percent c-Fos immunoreactive cells in the LA from rats receiving HFS (n = 6) or LFS (n = 6). (i) Photomicrographs showing c-Fos-labeled cells from rats receiving HFS (left) or LFS (right). In each experiment, ipsilateral cell counts have been expressed as a percentage of contralateral cell counts for each rat. *P < .05 relative to the ipsilateral side N.S. = not significant. LAd = dorsal division of the lateral amygdala; LAv l = ventrolateral division of the lateral amygdala; LAvm = ventromedial division of the lateral amygdala; CE = central amygdala; B = basal amygdala; AST = amygdala-striatal transition zone.

Mentions: In our first series of experiments, we observed significant increases in ERK activation in the LA and MGm/PIN following HFS of the thalamo-LA pathway. In the present experiments, we used a combination of Western blotting and immunohistochemistry to examine whether LTP-inducing stimulation of thalamic input synapses to the LA regulate the ERK-driven IEGs Arc/Arg3.1, EGR-1 and c-Fos in the LA and the MGm/PIN. As before, anesthetized rats received either HFS or LFS of thalamic inputs to the LA and were sacrificed by decapitation 2 hours later (Figures 2(a), 3(a), 4(a)), a time point which is sufficient for observing IEG expression in the LA after LTP [27].


The NO-cGMP-PKG signaling pathway coordinately regulates ERK and ERK-driven gene expression at pre- and postsynaptic sites following LTP-inducing stimulation of thalamo-amygdala synapses.

Ping J, Schafe GE - Neural Plast. (2011)

High-frequency stimulation of the MGm/PIN promotes increased immunolabeling of ERK-driven IEGs in the LA (a) Placement of stimulation electrode. (b) Schematic of experimental protocol. Rats were given HFS or LFS and sacrificed 2 hours after stimulation. (c) Schematic of the amygdala at Bregma −3.2. (d) Mean (±SEM) percent Arc/Arg3.1 immunoreactive cells in the LA from rats receiving HFS (n = 6) or LFS (n = 6). (e) Photomicrographs showing Arc/Arg3.1-labeled cells from rats receiving HFS (left) or LFS (right). (f) Mean (±SEM) percent EGR-1 immunoreactive cells in the LA from rats receiving HFS (n = 6) or LFS (n = 6). (g) Photomicrographs showing EGR-1-labeled cells from rats receiving HFS (left) or LFS (right). (h) Mean (±SEM) percent c-Fos immunoreactive cells in the LA from rats receiving HFS (n = 6) or LFS (n = 6). (i) Photomicrographs showing c-Fos-labeled cells from rats receiving HFS (left) or LFS (right). In each experiment, ipsilateral cell counts have been expressed as a percentage of contralateral cell counts for each rat. *P < .05 relative to the ipsilateral side N.S. = not significant.  LAd = dorsal division of the lateral amygdala; LAv l = ventrolateral division of the lateral amygdala; LAvm = ventromedial division of the lateral amygdala; CE = central amygdala; B = basal amygdala; AST = amygdala-striatal transition zone.
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Related In: Results  -  Collection

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fig3: High-frequency stimulation of the MGm/PIN promotes increased immunolabeling of ERK-driven IEGs in the LA (a) Placement of stimulation electrode. (b) Schematic of experimental protocol. Rats were given HFS or LFS and sacrificed 2 hours after stimulation. (c) Schematic of the amygdala at Bregma −3.2. (d) Mean (±SEM) percent Arc/Arg3.1 immunoreactive cells in the LA from rats receiving HFS (n = 6) or LFS (n = 6). (e) Photomicrographs showing Arc/Arg3.1-labeled cells from rats receiving HFS (left) or LFS (right). (f) Mean (±SEM) percent EGR-1 immunoreactive cells in the LA from rats receiving HFS (n = 6) or LFS (n = 6). (g) Photomicrographs showing EGR-1-labeled cells from rats receiving HFS (left) or LFS (right). (h) Mean (±SEM) percent c-Fos immunoreactive cells in the LA from rats receiving HFS (n = 6) or LFS (n = 6). (i) Photomicrographs showing c-Fos-labeled cells from rats receiving HFS (left) or LFS (right). In each experiment, ipsilateral cell counts have been expressed as a percentage of contralateral cell counts for each rat. *P < .05 relative to the ipsilateral side N.S. = not significant. LAd = dorsal division of the lateral amygdala; LAv l = ventrolateral division of the lateral amygdala; LAvm = ventromedial division of the lateral amygdala; CE = central amygdala; B = basal amygdala; AST = amygdala-striatal transition zone.
Mentions: In our first series of experiments, we observed significant increases in ERK activation in the LA and MGm/PIN following HFS of the thalamo-LA pathway. In the present experiments, we used a combination of Western blotting and immunohistochemistry to examine whether LTP-inducing stimulation of thalamic input synapses to the LA regulate the ERK-driven IEGs Arc/Arg3.1, EGR-1 and c-Fos in the LA and the MGm/PIN. As before, anesthetized rats received either HFS or LFS of thalamic inputs to the LA and were sacrificed by decapitation 2 hours later (Figures 2(a), 3(a), 4(a)), a time point which is sufficient for observing IEG expression in the LA after LTP [27].

Bottom Line: Here, we show that LTP-inducing stimulation of thalamo-LA inputs regulates the activation of ERK and the expression of ERK-driven immediate early genes (IEGs) in both the LA and MGm/PIN.Further, we show that pharmacological blockade of NMDAR-driven synaptic plasticity, NOS activation, or PKG signaling in the LA significantly impairs high-frequency stimulation-(HFS-) induced ERK activation and IEG expression in both regions, while blockade of extracellular NO signaling in the LA impairs HFS-induced ERK activation and IEG expression exclusively in the MGm/PIN.These findings suggest that NMDAR-driven synaptic plasticity and NO-cGMP-PKG signaling within the LA coordinately regulate ERK-driven gene expression in both the LA and the MGm/PIN following LTP induction at thalamo-LA synapses, and that synaptic plasticity in the LA promotes ERK-driven transcription in MGm/PIN neurons via NO-driven "retrograde signaling".

View Article: PubMed Central - PubMed

Affiliation: Department of Psychology, Yale University, New Haven, CT 06520, USA.

ABSTRACT
Long-term potentiation (LTP) at thalamic input synapses to the lateral nucleus of the amygdala (LA) has been proposed as a cellular mechanism of the formation of auditory fear memories. We have previously shown that signaling via ERK/MAPK in both the LA and the medial division of the medial geniculate nucleus/posterior intralaminar nucleus (MGm/PIN) is critical for LTP at thalamo-LA synapses. Here, we show that LTP-inducing stimulation of thalamo-LA inputs regulates the activation of ERK and the expression of ERK-driven immediate early genes (IEGs) in both the LA and MGm/PIN. Further, we show that pharmacological blockade of NMDAR-driven synaptic plasticity, NOS activation, or PKG signaling in the LA significantly impairs high-frequency stimulation-(HFS-) induced ERK activation and IEG expression in both regions, while blockade of extracellular NO signaling in the LA impairs HFS-induced ERK activation and IEG expression exclusively in the MGm/PIN. These findings suggest that NMDAR-driven synaptic plasticity and NO-cGMP-PKG signaling within the LA coordinately regulate ERK-driven gene expression in both the LA and the MGm/PIN following LTP induction at thalamo-LA synapses, and that synaptic plasticity in the LA promotes ERK-driven transcription in MGm/PIN neurons via NO-driven "retrograde signaling".

Show MeSH
Related in: MedlinePlus