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Behavioral experience induces zif268 expression in mature granule cells but suppresses its expression in immature granule cells.

Huckleberry KA, Kane GA, Mathis RJ, Cook SG, Clutton JE, Drew MR - Front Syst Neurosci (2015)

Bottom Line: The immediate-early gene (IEG) zif268 appears to be an important mediator of these effects, as its expression can be induced by neural activity and knockout of zif268 impairs survival of adult-born neurons (Richardson et al., 1992; Veyrac et al., 2013).In summary, behavioral experience transiently activated expression of zif268 in mature granule cells but caused a more long-lasting suppression of zif268 expression in immature, adult-born granule cells.We hypothesize that zif268 suppression inhibits memory-related synaptic plasticity in immature neurons or mediates learning-induced apoptosis of immature adult-born neurons.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience, Center for Learning and Memory, University of Texas at Austin Austin, TX, USA.

ABSTRACT
Thousands of neurons are born each day in the dentate gyrus (DG), but many of these cells die before reaching maturity. Both death and survival of adult-born neurons are regulated by neuronal activity in the DG. The immediate-early gene (IEG) zif268 appears to be an important mediator of these effects, as its expression can be induced by neural activity and knockout of zif268 impairs survival of adult-born neurons (Richardson et al., 1992; Veyrac et al., 2013). Despite the apparent importance of zif268 for adult neurogenesis, its behavior-induced expression has not been fully characterized in adult-born neurons. Here we characterize behavior-evoked expression of zif268 in mature and newborn dentate granule cells (DGCs). We first quantified zif268 expression in doublecortin-positive (DCX+) immature neurons and in the general granule cell population after brief exposure to a novel environment (NE). In the general granule cell population, zif268 expression peaked 1 h after NE exposure and returned to baseline by 8 h post-exposure. However, in the DCX+ cells, zif268 expression was suppressed relative to home cage for at least 8 h post-exposure. We next asked whether suppression of zif268 in DCX+ immature cells occurs in other behavioral paradigms that recruit the hippocampus. Exposure to Morris water maze (MWM) training, an enriched environment, or a NE caused approximately equal suppression of zif268 expression in DCX+ cells and approximately equal activation of zif268 expression among the general granule cell population. The same behavioral procedures activated zif268 expression in 6-week-old BrdU-labeled adult-born neurons, indicating that zif268 suppression is specific to immature neurons. Finally, we asked whether zif268 suppression varied as a function of age within the DCX+ population, which ranges in age from 0 to approximately 4 weeks. NE exposure had no significant effect on zif268 expression in 2- or 4-week-old BrdU-labeled neurons, but it significantly suppressed zif268 expression in 3-week-old neurons. In summary, behavioral experience transiently activated expression of zif268 in mature granule cells but caused a more long-lasting suppression of zif268 expression in immature, adult-born granule cells. We hypothesize that zif268 suppression inhibits memory-related synaptic plasticity in immature neurons or mediates learning-induced apoptosis of immature adult-born neurons.

No MeSH data available.


Related in: MedlinePlus

Zif268 expression in DCX+ neurons was suppressed by exposure to a novel environment (NE), an enriched environment (EE), and morris water maze (MWM). (A) Mice were injected with BrdU 6 weeks prior to being exposed to a NE for 10 min (n = 4) or 2 h (n = 6), EE for 2 h (n = 6), or MWM training (n = 8). An additional group was euthanized immediately after being removed from the home cage (HC; n = 6). (B,C) Representative images of BrdU and zif268 immunohistochemistry. Scale bars = 27 μm (B) and 9 μm (C). (D) Performance in the MWM improved over the 4 days of training (F(3,21) = 3.555, p = 0.032). (E) During a probe trial on the final day of training, mice displayed a significant preference for the target quadrant (t(7) = 3.382, p = 0.012). (F) The number of DCX+ cells did not differ significantly across experimental conditions (F(4,25) = 2.024, p = 0.122). (G) Total number of zif268+ cells in the GCL. As compared to the HC group, all of the behavioral manipulations caused a significant increase in the total number of DGCs expressing zif268 (F(4,25) = 24.640, p < 0.001; p’s ≤ 0.001). (H) Percentage of DCX+ cells expressing zif268. Compared to the HC group, 2-h NE, EE, and MWM training significantly decreased the percentage of DCX+ cells expressing zif268 (F(4,25) = 2.862; p = 0.044; p’s ≤ 0.048). (I) The number of BrdU+ cells did not differ among experimental conditions (F(4.25) = 1.007, p = 0.422). (J) Percentage of BrdU+ cells expressing zif268. All of the behavioral manipulations significantly increased the percentage of BrdU+ cells expressing zif268 as compared to the HC group (F(4,25) = 26.050, p < 0.0001;  post hocp’s < 0.0001). *p < 0.05.
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Figure 2: Zif268 expression in DCX+ neurons was suppressed by exposure to a novel environment (NE), an enriched environment (EE), and morris water maze (MWM). (A) Mice were injected with BrdU 6 weeks prior to being exposed to a NE for 10 min (n = 4) or 2 h (n = 6), EE for 2 h (n = 6), or MWM training (n = 8). An additional group was euthanized immediately after being removed from the home cage (HC; n = 6). (B,C) Representative images of BrdU and zif268 immunohistochemistry. Scale bars = 27 μm (B) and 9 μm (C). (D) Performance in the MWM improved over the 4 days of training (F(3,21) = 3.555, p = 0.032). (E) During a probe trial on the final day of training, mice displayed a significant preference for the target quadrant (t(7) = 3.382, p = 0.012). (F) The number of DCX+ cells did not differ significantly across experimental conditions (F(4,25) = 2.024, p = 0.122). (G) Total number of zif268+ cells in the GCL. As compared to the HC group, all of the behavioral manipulations caused a significant increase in the total number of DGCs expressing zif268 (F(4,25) = 24.640, p < 0.001; p’s ≤ 0.001). (H) Percentage of DCX+ cells expressing zif268. Compared to the HC group, 2-h NE, EE, and MWM training significantly decreased the percentage of DCX+ cells expressing zif268 (F(4,25) = 2.862; p = 0.044; p’s ≤ 0.048). (I) The number of BrdU+ cells did not differ among experimental conditions (F(4.25) = 1.007, p = 0.422). (J) Percentage of BrdU+ cells expressing zif268. All of the behavioral manipulations significantly increased the percentage of BrdU+ cells expressing zif268 as compared to the HC group (F(4,25) = 26.050, p < 0.0001;  post hocp’s < 0.0001). *p < 0.05.

Mentions: The second experiment had three objectives. First, we sought to replicate the zif268 suppression using a behavioral procedure that might produce a more robust effect on zif268 expression. Second, we sought to determine whether zif268 suppression can be induced by behavioral tasks other than NE exposure. Finally, we sought to determine whether the zif268 suppression effect is specific to immature adult-born neurons or is general to all adult-born neurons regardless of age. Mice were injected with BrdU 6 weeks prior to a 10-min NE exposure (n = 4), a 2-h NE exposure (n = 6), a 2-h enriched environment exposure (n = 6), or training in the Morris water maze (MWM; n = 8; Figure 2A). Mice were euthanized 2 h after the start of behavioral testing, except for the home cage condition (n = 6), in which mice were euthanized immediately after removal from the home cage. In the water maze condition, mice were euthanized on the fourth day of training. As shown in Figures 2D,E, maze performance improved over the 4 days of training (F(3, 21) = 3.555, p = 0.032), and in a probe trial on the final day of training, mice displayed a significant preference for the target quadrant (t(7) = 3.382, p = 0.012).


Behavioral experience induces zif268 expression in mature granule cells but suppresses its expression in immature granule cells.

Huckleberry KA, Kane GA, Mathis RJ, Cook SG, Clutton JE, Drew MR - Front Syst Neurosci (2015)

Zif268 expression in DCX+ neurons was suppressed by exposure to a novel environment (NE), an enriched environment (EE), and morris water maze (MWM). (A) Mice were injected with BrdU 6 weeks prior to being exposed to a NE for 10 min (n = 4) or 2 h (n = 6), EE for 2 h (n = 6), or MWM training (n = 8). An additional group was euthanized immediately after being removed from the home cage (HC; n = 6). (B,C) Representative images of BrdU and zif268 immunohistochemistry. Scale bars = 27 μm (B) and 9 μm (C). (D) Performance in the MWM improved over the 4 days of training (F(3,21) = 3.555, p = 0.032). (E) During a probe trial on the final day of training, mice displayed a significant preference for the target quadrant (t(7) = 3.382, p = 0.012). (F) The number of DCX+ cells did not differ significantly across experimental conditions (F(4,25) = 2.024, p = 0.122). (G) Total number of zif268+ cells in the GCL. As compared to the HC group, all of the behavioral manipulations caused a significant increase in the total number of DGCs expressing zif268 (F(4,25) = 24.640, p < 0.001; p’s ≤ 0.001). (H) Percentage of DCX+ cells expressing zif268. Compared to the HC group, 2-h NE, EE, and MWM training significantly decreased the percentage of DCX+ cells expressing zif268 (F(4,25) = 2.862; p = 0.044; p’s ≤ 0.048). (I) The number of BrdU+ cells did not differ among experimental conditions (F(4.25) = 1.007, p = 0.422). (J) Percentage of BrdU+ cells expressing zif268. All of the behavioral manipulations significantly increased the percentage of BrdU+ cells expressing zif268 as compared to the HC group (F(4,25) = 26.050, p < 0.0001;  post hocp’s < 0.0001). *p < 0.05.
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Figure 2: Zif268 expression in DCX+ neurons was suppressed by exposure to a novel environment (NE), an enriched environment (EE), and morris water maze (MWM). (A) Mice were injected with BrdU 6 weeks prior to being exposed to a NE for 10 min (n = 4) or 2 h (n = 6), EE for 2 h (n = 6), or MWM training (n = 8). An additional group was euthanized immediately after being removed from the home cage (HC; n = 6). (B,C) Representative images of BrdU and zif268 immunohistochemistry. Scale bars = 27 μm (B) and 9 μm (C). (D) Performance in the MWM improved over the 4 days of training (F(3,21) = 3.555, p = 0.032). (E) During a probe trial on the final day of training, mice displayed a significant preference for the target quadrant (t(7) = 3.382, p = 0.012). (F) The number of DCX+ cells did not differ significantly across experimental conditions (F(4,25) = 2.024, p = 0.122). (G) Total number of zif268+ cells in the GCL. As compared to the HC group, all of the behavioral manipulations caused a significant increase in the total number of DGCs expressing zif268 (F(4,25) = 24.640, p < 0.001; p’s ≤ 0.001). (H) Percentage of DCX+ cells expressing zif268. Compared to the HC group, 2-h NE, EE, and MWM training significantly decreased the percentage of DCX+ cells expressing zif268 (F(4,25) = 2.862; p = 0.044; p’s ≤ 0.048). (I) The number of BrdU+ cells did not differ among experimental conditions (F(4.25) = 1.007, p = 0.422). (J) Percentage of BrdU+ cells expressing zif268. All of the behavioral manipulations significantly increased the percentage of BrdU+ cells expressing zif268 as compared to the HC group (F(4,25) = 26.050, p < 0.0001;  post hocp’s < 0.0001). *p < 0.05.
Mentions: The second experiment had three objectives. First, we sought to replicate the zif268 suppression using a behavioral procedure that might produce a more robust effect on zif268 expression. Second, we sought to determine whether zif268 suppression can be induced by behavioral tasks other than NE exposure. Finally, we sought to determine whether the zif268 suppression effect is specific to immature adult-born neurons or is general to all adult-born neurons regardless of age. Mice were injected with BrdU 6 weeks prior to a 10-min NE exposure (n = 4), a 2-h NE exposure (n = 6), a 2-h enriched environment exposure (n = 6), or training in the Morris water maze (MWM; n = 8; Figure 2A). Mice were euthanized 2 h after the start of behavioral testing, except for the home cage condition (n = 6), in which mice were euthanized immediately after removal from the home cage. In the water maze condition, mice were euthanized on the fourth day of training. As shown in Figures 2D,E, maze performance improved over the 4 days of training (F(3, 21) = 3.555, p = 0.032), and in a probe trial on the final day of training, mice displayed a significant preference for the target quadrant (t(7) = 3.382, p = 0.012).

Bottom Line: The immediate-early gene (IEG) zif268 appears to be an important mediator of these effects, as its expression can be induced by neural activity and knockout of zif268 impairs survival of adult-born neurons (Richardson et al., 1992; Veyrac et al., 2013).In summary, behavioral experience transiently activated expression of zif268 in mature granule cells but caused a more long-lasting suppression of zif268 expression in immature, adult-born granule cells.We hypothesize that zif268 suppression inhibits memory-related synaptic plasticity in immature neurons or mediates learning-induced apoptosis of immature adult-born neurons.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience, Center for Learning and Memory, University of Texas at Austin Austin, TX, USA.

ABSTRACT
Thousands of neurons are born each day in the dentate gyrus (DG), but many of these cells die before reaching maturity. Both death and survival of adult-born neurons are regulated by neuronal activity in the DG. The immediate-early gene (IEG) zif268 appears to be an important mediator of these effects, as its expression can be induced by neural activity and knockout of zif268 impairs survival of adult-born neurons (Richardson et al., 1992; Veyrac et al., 2013). Despite the apparent importance of zif268 for adult neurogenesis, its behavior-induced expression has not been fully characterized in adult-born neurons. Here we characterize behavior-evoked expression of zif268 in mature and newborn dentate granule cells (DGCs). We first quantified zif268 expression in doublecortin-positive (DCX+) immature neurons and in the general granule cell population after brief exposure to a novel environment (NE). In the general granule cell population, zif268 expression peaked 1 h after NE exposure and returned to baseline by 8 h post-exposure. However, in the DCX+ cells, zif268 expression was suppressed relative to home cage for at least 8 h post-exposure. We next asked whether suppression of zif268 in DCX+ immature cells occurs in other behavioral paradigms that recruit the hippocampus. Exposure to Morris water maze (MWM) training, an enriched environment, or a NE caused approximately equal suppression of zif268 expression in DCX+ cells and approximately equal activation of zif268 expression among the general granule cell population. The same behavioral procedures activated zif268 expression in 6-week-old BrdU-labeled adult-born neurons, indicating that zif268 suppression is specific to immature neurons. Finally, we asked whether zif268 suppression varied as a function of age within the DCX+ population, which ranges in age from 0 to approximately 4 weeks. NE exposure had no significant effect on zif268 expression in 2- or 4-week-old BrdU-labeled neurons, but it significantly suppressed zif268 expression in 3-week-old neurons. In summary, behavioral experience transiently activated expression of zif268 in mature granule cells but caused a more long-lasting suppression of zif268 expression in immature, adult-born granule cells. We hypothesize that zif268 suppression inhibits memory-related synaptic plasticity in immature neurons or mediates learning-induced apoptosis of immature adult-born neurons.

No MeSH data available.


Related in: MedlinePlus