TrkB regulates hippocampal neurogenesis and governs sensitivity to antidepressive treatment methods
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(A) Representative images of Nissl stained DG sections from control, TrkB hGFAP and TrkB Syn mice at P15. The decreases in DG size and granular layer thickness were only observed in TrkB hGFAP mice. Red lines and circles highlight the length of the granular layer, and the size of single cell, respectively. Scale bars, 1mm (hippocampus) and 10um (DG).
Ablation of TrkB in early postnatal NPCs impairs DG morphogenesis
The conditional knockout animals, either carrying the hGFAP-Cre (TrkB hGFAP ) or the Syn-Cre (TrkB Syn ) are viable at birth and have normal survival rates (up to 15 months recorded) ( ). The TrkB hGFAP mice displayed a significant reduction in the volume of the DG granular layer ( ) that first became measurable at P10. The volume reduction stabilized at around 30% after the initial postnatal weeks and persisted throughout adulthood. This abnormality was not caused by changes in cell density or cell size (; p>0.2), but rather was a result of decrease in the number of granule neurons, evidenced by a significant reduction in the thickness of DG granular layer (; n=6 for each, F 2,15 =5.477, p=0.0164). The number and morphology of glial cells were not appreciably affected in the TrkB hGFAP mice ( and not shown). The reduction of volume was most prominently observed in the hippocampus a...
Ablation of TrkB impairs proliferation and neurogenesis
We next assessed proliferation by measuring the number of cells that incorporate the DNA synthesis marker 5-bromo-2'-deoxyuridine (BrdU). P15 mice were treated with pulses of BrdU and sacrificed 24 hours after the first injection. Within the area encompassing the inner granular layer and SGZ, the number of BrdU positive cells in the TrkB hGFAP mice displayed a 48% reduction compared to control mice (; n=7-9 for each; F 2,21 =78.39, p<0.0001; p<0.001 for post hoc test of control to TrkB hGFAP comparison). Similarly, the number of cells positive for Ki67, an endogenous marker for actively cycling cells, was decreased by 51% in the SGZ of the TrkB hGFAP mice (; n=7-9 for each; F 2,21 =51.64, p<0.0001; p<0.001 for post hoc test of control to TrkB hGFAP comparison). Again, the numbers of BrdU or Ki67 positive cells were unaffected in the DG of the TrkB Syn mice (; p>0....
Activation of TrkB in response to BDNF facilitates proliferation in vitro
Our finding that the TrkB hGFAP but not the TrkB Syn mice displayed impaired hippocampal neurogenesis suggested a cell autonomous requirement for TrkB in NPCs. To further examine their intrinsic properties, we cultured NPCs from the DG in serum-free conditions. In the presence of epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF), DG NPCs formed neurospheres, which expressed TrkB receptor that could be activated by exogenous BDNF ( ). Although maintaining adult DG-derived primary neurospheres in media containing BDNF (50 ng/ml) for 7-10 days did not increase the frequency of primary neurosphere formation (not shown), there was a significant increase in the size of the neurospheres, suggesting that activation of TrkB facilitates the expansion of neurosphere-forming cells (; n=4 for each group, p<0.05 for post hoc test of with to without BDNF comparison in co...
TrkB is required for induced proliferation and neurogenesis by antidepressants and voluntary exercise
Reduction in hippocampal volume has been observed in animal models of stress (; ), which may be reversed or prevented by chronic AD treatment ( ). Similarly, reduction of hippocampal volume has been reported in some studies of human patients with major depression (; ) and post-traumatic stress disorder (;; ). Although the cellular mechanism is unclear in humans, animal studies have demonstrated that chronic exposure to various types of ADs induces DG proliferation and neurogenesis ( ), thereby potentially contributing to the recovery of volume loss. In this context, we examined whether chronic AD treatment can restore neurogenesis in TrkB hGFAP mice. We thus treated control, TrkB hGFAP and TrkB Syn mice with daily injections of the serotonin reuptake inhibitor fluoxetine (10 µg/g) or the tricyclic imipramine (20 µg/g) for 21 days (n=7-29 for each group, ). As previ...
TrkB is required for induced proliferation and neurogenesis by antidepressants and voluntary exercise
In rodents, voluntary exercise, such as wheel-running behavior has been demonstrated to robustly induce neurogenesis, much in the same fashion as AD treatment ( ). Less is known, however, about the underlying mechanism of this AD-like effect of exercise. To determine whether TrkB is also required for this process, we subjected control and TrkB hGFAP mice to 6 weeks of wheel-running (n=8-16 for each group, ). Both the numbers of Ki67 positive and Doublecortin positive cells increased in control runners, compared to control sedentary animals (: F 1,36 =13.64, p=0.0007 for exercise;: F 1,36 =16.01, p=0.0003; p<0.001 for post hoc test of both comparisons). A significant increase of BDNF protein level was also observed in the hippocampus of runners (66.44 ± 3.65 pg/mg in runners; 45.83 ± 2.99 pg/mg in sedentary controls; n=3 for each; p<0.05). The TrkB hGFAP mice, despite...
TrkB is required for behavioral improvement induced by ADs and exercise
To determine whether the lack of neurogenic response in the TrkB hGFAP mice was coupled with general insensitivity to chronic ADs and exercise, we compared the depression and anxiety-like behaviors in control and TrkB hGFAP mice. First, mice treated with fluoxetine, imipramine, or saline for 21 days were examined in the novelty-suppressed feeding test (NSFT), a conflict paradigm in which the latency to feed in a novel environment is used as an indicator of anxiety level ( ). In agreement with the general capacity of chronic ADs to ease anxiety, 24 hours after the last dose, control mice receiving fluoxetine or imipramine displayed significantly shorter latency to feed compared to saline-treated control mice (; F 2,100 =8.022, p=0.0006 for treatment; p<0.001 for post hoc test both AD-to-saline comparisons). The TrkB hGFAP mice, on the contrary, were insensitive to the effects of eithe...
TrkB is required for behavioral improvement induced by ADs and exercise
Next we examined depression-like behavior in the control and TrkB hGFAP mice by using the tail-suspension test (TST), a paradigm of inescapable stress ( ). All mice were tested 48 hours after the last dose of AD or saline to exclude the acute effects on behaviors that do not correlate with prior duration of drug treatment, or clinical responses. Control runners and AD treated control mice showed decreased immobility (a state of "behavioral despair"), compared to sedentary or saline treated control mice, respectively (: F 1,41 =9.082, p=0.0044 for exercise, post hoc p<0.01;: F 2,100 =20.03, p<0.0001 for AD, post hoc p<0.01 for fluoxetine, p<0.001 for imipramine). The TrkB hGFAP mice again failed to display any appreciable response to either treatment (: F 2,100 =4.233, p=0.0172 for genotype;: F 1,41 =9.082, p=0.0044 for genotype).
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(A) Representative images of Nissl stained DG sections from control, TrkB hGFAP and TrkB Syn mice at P15. The decreases in DG size and granular layer thickness were only observed in TrkB hGFAP mice. Red lines and circles highlight the length of the granular layer, and the size of single cell, respectively. Scale bars, 1mm (hippocampus) and 10um (DG).
The conditional knockout animals, either carrying the hGFAP-Cre (TrkB hGFAP ) or the Syn-Cre (TrkB Syn ) are viable at birth and have normal survival rates (up to 15 months recorded) ( ). The TrkB hGFAP mice displayed a significant reduction in the volume of the DG granular layer ( ) that first became measurable at P10. The volume reduction stabilized at around 30% after the initial postnatal weeks and persisted throughout adulthood. This abnormality was not caused by changes in cell density or cell size (; p>0.2), but rather was a result of decrease in the number of granule neurons, evidenced by a significant reduction in the thickness of DG granular layer (; n=6 for each, F 2,15 =5.477, p=0.0164). The number and morphology of glial cells were not appreciably affected in the TrkB hGFAP mice ( and not shown). The reduction of volume was most prominently observed in the hippocampus and DG, and did not appear to be a secondary result of broader developmental defect, as the TrkB hGFAP mice had normal body and brain size at all ages examined ( ). We also measured the volumes of other anatomical regions, such as the striatum, in 2-month old TrkB hGFAP mice and found normal volume (...
We next assessed proliferation by measuring the number of cells that incorporate the DNA synthesis marker 5-bromo-2'-deoxyuridine (BrdU). P15 mice were treated with pulses of BrdU and sacrificed 24 hours after the first injection. Within the area encompassing the inner granular layer and SGZ, the number of BrdU positive cells in the TrkB hGFAP mice displayed a 48% reduction compared to control mice (; n=7-9 for each; F 2,21 =78.39, p<0.0001; p<0.001 for post hoc test of control to TrkB hGFAP comparison). Similarly, the number of cells positive for Ki67, an endogenous marker for actively cycling cells, was decreased by 51% in the SGZ of the TrkB hGFAP mice (; n=7-9 for each; F 2,21 =51.64, p<0.0001; p<0.001 for post hoc test of control to TrkB hGFAP comparison). Again, the numbers of BrdU or Ki67 positive cells were unaffected in the DG of the TrkB Syn mice (; p>0.2 for control to TrkB Syn comparisons).
Our finding that the TrkB hGFAP but not the TrkB Syn mice displayed impaired hippocampal neurogenesis suggested a cell autonomous requirement for TrkB in NPCs. To further examine their intrinsic properties, we cultured NPCs from the DG in serum-free conditions. In the presence of epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF), DG NPCs formed neurospheres, which expressed TrkB receptor that could be activated by exogenous BDNF ( ). Although maintaining adult DG-derived primary neurospheres in media containing BDNF (50 ng/ml) for 7-10 days did not increase the frequency of primary neurosphere formation (not shown), there was a significant increase in the size of the neurospheres, suggesting that activation of TrkB facilitates the expansion of neurosphere-forming cells (; n=4 for each group, p<0.05 for post hoc test of with to without BDNF comparison in control cells). Primary neurospheres derived from the DG of adult TrkB hGFAP mice, when plated at equal density, displayed reduction in both the number (; n=4 for each group, p<0.005) and size (; p<0.005 for post hoc test of control to TrkB hGFAP comparison without BDNF; F 1,12 =102.2, p<0.0001 for...
Reduction in hippocampal volume has been observed in animal models of stress (; ), which may be reversed or prevented by chronic AD treatment ( ). Similarly, reduction of hippocampal volume has been reported in some studies of human patients with major depression (; ) and post-traumatic stress disorder (;; ). Although the cellular mechanism is unclear in humans, animal studies have demonstrated that chronic exposure to various types of ADs induces DG proliferation and neurogenesis ( ), thereby potentially contributing to the recovery of volume loss. In this context, we examined whether chronic AD treatment can restore neurogenesis in TrkB hGFAP mice. We thus treated control, TrkB hGFAP and TrkB Syn mice with daily injections of the serotonin reuptake inhibitor fluoxetine (10 µg/g) or the tricyclic imipramine (20 µg/g) for 21 days (n=7-29 for each group, ). As previously established, compared with mice receiving daily saline injections, both drugs induced substantial Ki67 immuno-reactivity in the DG of control mice (; F 2,98 =40.48, p<0.0001 for treatment; p<0.001 for post hoc test of both AD-to-saline comparisons). The induction of proliferation was echoed b...
In rodents, voluntary exercise, such as wheel-running behavior has been demonstrated to robustly induce neurogenesis, much in the same fashion as AD treatment ( ). Less is known, however, about the underlying mechanism of this AD-like effect of exercise. To determine whether TrkB is also required for this process, we subjected control and TrkB hGFAP mice to 6 weeks of wheel-running (n=8-16 for each group, ). Both the numbers of Ki67 positive and Doublecortin positive cells increased in control runners, compared to control sedentary animals (: F 1,36 =13.64, p=0.0007 for exercise;: F 1,36 =16.01, p=0.0003; p<0.001 for post hoc test of both comparisons). A significant increase of BDNF protein level was also observed in the hippocampus of runners (66.44 ± 3.65 pg/mg in runners; 45.83 ± 2.99 pg/mg in sedentary controls; n=3 for each; p<0.05). The TrkB hGFAP mice, despite normal running distance (5.96 ± 0.41 km/day in controls, 5.48 ± 0.34 km/day in TrkB hGFAP, p>0.2) as well as elevation of BDNF level in runners (60.33 ± 4.43 pg/mg in runners; 40.94 ± 1.37 pg/ml in sedentary controls; n=3 for each; p<0.05), did not show any increase in prolifer...
To determine whether the lack of neurogenic response in the TrkB hGFAP mice was coupled with general insensitivity to chronic ADs and exercise, we compared the depression and anxiety-like behaviors in control and TrkB hGFAP mice. First, mice treated with fluoxetine, imipramine, or saline for 21 days were examined in the novelty-suppressed feeding test (NSFT), a conflict paradigm in which the latency to feed in a novel environment is used as an indicator of anxiety level ( ). In agreement with the general capacity of chronic ADs to ease anxiety, 24 hours after the last dose, control mice receiving fluoxetine or imipramine displayed significantly shorter latency to feed compared to saline-treated control mice (; F 2,100 =8.022, p=0.0006 for treatment; p<0.001 for post hoc test both AD-to-saline comparisons). The TrkB hGFAP mice, on the contrary, were insensitive to the effects of either AD (; F 2,100 =10.49, p<0.0001 for genotype). Similarly, TrkB hGFAP mice exposed to 6 weeks of running showed no improvement in the NSFT, whereas the control runners displayed clear decrease in latency compared to sedentary animals (; F 1,41 =15.09, p=0.0004 for genotype; p<0.05 for post hoc tes...
Next we examined depression-like behavior in the control and TrkB hGFAP mice by using the tail-suspension test (TST), a paradigm of inescapable stress ( ). All mice were tested 48 hours after the last dose of AD or saline to exclude the acute effects on behaviors that do not correlate with prior duration of drug treatment, or clinical responses. Control runners and AD treated control mice showed decreased immobility (a state of "behavioral despair"), compared to sedentary or saline treated control mice, respectively (: F 1,41 =9.082, p=0.0044 for exercise, post hoc p<0.01;: F 2,100 =20.03, p<0.0001 for AD, post hoc p<0.01 for fluoxetine, p<0.001 for imipramine). The TrkB hGFAP mice again failed to display any appreciable response to either treatment (: F 2,100 =4.233, p=0.0172 for genotype;: F 1,41 =9.082, p=0.0044 for genotype).
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