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The Posterodorsal Medial Amygdala Regulates the Timing of Puberty Onset in Female Rats.

Li XF, Hu MH, Hanley BP, Lin YS, Poston L, Lightman SL, O'Byrne KT - Endocrinology (2015)

Bottom Line: In both dietary groups, MePD lesions resulted in an increase in socialization and a decrease in play fighting behavior.In conclusion, our results suggest the MePD regulates the timing of puberty via a novel mechanism independent of change in body weight and caloric intake.MePD glutamatergic systems advance the timing of puberty whereas local GABAergic activation results in a delay.

View Article: PubMed Central - PubMed

Affiliation: Division of Women's Health (X.F.L., M.H.L., B.P.H., Y.S.L., L.P., K.T.O.), Faculty of Life Sciences and Medicine, King's College London, Guy's Campus, London SE1 1UL, United Kingdom; and Henry Wellcome Laboratory for Integrative Neuroscience and Endocrinology (S.L.L.), University of Bristol, Bristol BS1 3NY, United Kingdom.

ABSTRACT
Obesity is the major risk factor for early puberty, but emerging evidence indicates other factors including psychosocial stress. One key brain region notable for its role in controlling calorie intake, stress, and behavior is the amygdala. Early studies involving amygdala lesions that included the medial nucleus advanced puberty in rats. More recently it was shown that a critical site for lesion-induced hyperphagia and obesity is the posterodorsal subnucleus of the medial amygdala (MePD), which may explain the advancement of puberty. Glutamatergic activity also increases in the MePD during puberty without a corresponding γ-aminobutyric acid (GABA)ergic change, suggesting an overall activation of this brain region. In the present study, we report that neurotoxic lesioning of the MePD advances puberty and increases weight gain in female rats fed a normal diet. However, MePD lesioned rats fed a 25% nonnutritive bulk diet also showed the dramatic advancement of puberty but without the increase in body weight. In both dietary groups, MePD lesions resulted in an increase in socialization and a decrease in play fighting behavior. Chronic GABAA receptor antagonism in the MePD from postnatal day 21 for 14 days also advanced puberty, increased socialization, and decreased play fighting without altering body weight, whereas glutamate receptor antagonism delayed puberty and decreased socialization without affecting play fighting. In conclusion, our results suggest the MePD regulates the timing of puberty via a novel mechanism independent of change in body weight and caloric intake. MePD glutamatergic systems advance the timing of puberty whereas local GABAergic activation results in a delay.

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Photomicrograph and schematic illustrations of the osmotic minipump microinfusion sites targeted to the MePD. A, Photomicrograph of a coronal brain section in a representative animal implanted with bilateral cannulae in the MePD. Arrows indicate the site corresponding to the tip of the cannulae. B, Schematic illustration showing the target site for bilateral cannulation of the MePD at bregma (AP) of −3.3 mm, ML of ±3.4 mm, and DV of −8.6 mm according to the rat brain atlas of Paxinos and Watson (39). Arrows point to the location of the cannulae tips. C and D, Schematic drawings of the MePD illustrating the individual sites of chronic infusion of the D-AP5 or bicuculline, respectively. E and F, Schematic drawing of the MePD illustrating the individual sites of chronic infusion of aCSF as a control for the D-AP5 or bicuculline group, respectively. Open circles show the injection sites. Numbers in each drawing indicate the distance (millimeters) to bregma in accordance with Paxinos and Watson (39).
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Figure 5: Photomicrograph and schematic illustrations of the osmotic minipump microinfusion sites targeted to the MePD. A, Photomicrograph of a coronal brain section in a representative animal implanted with bilateral cannulae in the MePD. Arrows indicate the site corresponding to the tip of the cannulae. B, Schematic illustration showing the target site for bilateral cannulation of the MePD at bregma (AP) of −3.3 mm, ML of ±3.4 mm, and DV of −8.6 mm according to the rat brain atlas of Paxinos and Watson (39). Arrows point to the location of the cannulae tips. C and D, Schematic drawings of the MePD illustrating the individual sites of chronic infusion of the D-AP5 or bicuculline, respectively. E and F, Schematic drawing of the MePD illustrating the individual sites of chronic infusion of aCSF as a control for the D-AP5 or bicuculline group, respectively. Open circles show the injection sites. Numbers in each drawing indicate the distance (millimeters) to bregma in accordance with Paxinos and Watson (39).

Mentions: Correct intra-MePD placement of cannulae connected to the osmotic minipumps filled with GABA or glutamate antagonists was verified with reference to the atlas of Paxinos and Watson (39), and histological analysis is displayed in Figure 5. A representative example is shown in Figure 5A. Schematic diagrams of coronal sections of the rat brain identifying the location of the cannulae tips for all rats that received intra-MePD infusions of D-AP5 (Figure 5C), bicuculline (Figure 5D), or their respective aCSF control (Figure 5, E and F) are illustrated. Chronic infusion of a glutamate antagonist, D-AP5 (90 nmol per 6 μL/d, bilaterally), into the MePD started on pnd 21 for 14 days and did not affect body weight gain (Figure 6A) but resulted in a significant delay of puberty (Figure 6C). The mean age of vaginal opening in the D-AP5 treatment group was significantly later than those controls infused with aCSF (42.7 ± 1.3 vs 38.0 ± 0.9 d, respectively, mean ± SEM; n = 5–7 per group; P < .05). However, bilateral chronic infusion of the GABAA antagonist, bicuculline (13.56 pmol per 6 μL/d, bilaterally), into the MePD from pnd 21 to 35 caused a significant advancement of puberty (Figure 6D) without a change in body weight gain (Figure 6B). The mean age of vaginal opening in the bicuculline treatment group was significantly earlier compared with those animals treated with aCSF (35.9 ± 0.7 vs 38.1 ± 0.8 d, respectively, mean ± SEM; n = 7–8 per group; P < .05; Figure 6D).


The Posterodorsal Medial Amygdala Regulates the Timing of Puberty Onset in Female Rats.

Li XF, Hu MH, Hanley BP, Lin YS, Poston L, Lightman SL, O'Byrne KT - Endocrinology (2015)

Photomicrograph and schematic illustrations of the osmotic minipump microinfusion sites targeted to the MePD. A, Photomicrograph of a coronal brain section in a representative animal implanted with bilateral cannulae in the MePD. Arrows indicate the site corresponding to the tip of the cannulae. B, Schematic illustration showing the target site for bilateral cannulation of the MePD at bregma (AP) of −3.3 mm, ML of ±3.4 mm, and DV of −8.6 mm according to the rat brain atlas of Paxinos and Watson (39). Arrows point to the location of the cannulae tips. C and D, Schematic drawings of the MePD illustrating the individual sites of chronic infusion of the D-AP5 or bicuculline, respectively. E and F, Schematic drawing of the MePD illustrating the individual sites of chronic infusion of aCSF as a control for the D-AP5 or bicuculline group, respectively. Open circles show the injection sites. Numbers in each drawing indicate the distance (millimeters) to bregma in accordance with Paxinos and Watson (39).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4588820&req=5

Figure 5: Photomicrograph and schematic illustrations of the osmotic minipump microinfusion sites targeted to the MePD. A, Photomicrograph of a coronal brain section in a representative animal implanted with bilateral cannulae in the MePD. Arrows indicate the site corresponding to the tip of the cannulae. B, Schematic illustration showing the target site for bilateral cannulation of the MePD at bregma (AP) of −3.3 mm, ML of ±3.4 mm, and DV of −8.6 mm according to the rat brain atlas of Paxinos and Watson (39). Arrows point to the location of the cannulae tips. C and D, Schematic drawings of the MePD illustrating the individual sites of chronic infusion of the D-AP5 or bicuculline, respectively. E and F, Schematic drawing of the MePD illustrating the individual sites of chronic infusion of aCSF as a control for the D-AP5 or bicuculline group, respectively. Open circles show the injection sites. Numbers in each drawing indicate the distance (millimeters) to bregma in accordance with Paxinos and Watson (39).
Mentions: Correct intra-MePD placement of cannulae connected to the osmotic minipumps filled with GABA or glutamate antagonists was verified with reference to the atlas of Paxinos and Watson (39), and histological analysis is displayed in Figure 5. A representative example is shown in Figure 5A. Schematic diagrams of coronal sections of the rat brain identifying the location of the cannulae tips for all rats that received intra-MePD infusions of D-AP5 (Figure 5C), bicuculline (Figure 5D), or their respective aCSF control (Figure 5, E and F) are illustrated. Chronic infusion of a glutamate antagonist, D-AP5 (90 nmol per 6 μL/d, bilaterally), into the MePD started on pnd 21 for 14 days and did not affect body weight gain (Figure 6A) but resulted in a significant delay of puberty (Figure 6C). The mean age of vaginal opening in the D-AP5 treatment group was significantly later than those controls infused with aCSF (42.7 ± 1.3 vs 38.0 ± 0.9 d, respectively, mean ± SEM; n = 5–7 per group; P < .05). However, bilateral chronic infusion of the GABAA antagonist, bicuculline (13.56 pmol per 6 μL/d, bilaterally), into the MePD from pnd 21 to 35 caused a significant advancement of puberty (Figure 6D) without a change in body weight gain (Figure 6B). The mean age of vaginal opening in the bicuculline treatment group was significantly earlier compared with those animals treated with aCSF (35.9 ± 0.7 vs 38.1 ± 0.8 d, respectively, mean ± SEM; n = 7–8 per group; P < .05; Figure 6D).

Bottom Line: In both dietary groups, MePD lesions resulted in an increase in socialization and a decrease in play fighting behavior.In conclusion, our results suggest the MePD regulates the timing of puberty via a novel mechanism independent of change in body weight and caloric intake.MePD glutamatergic systems advance the timing of puberty whereas local GABAergic activation results in a delay.

View Article: PubMed Central - PubMed

Affiliation: Division of Women's Health (X.F.L., M.H.L., B.P.H., Y.S.L., L.P., K.T.O.), Faculty of Life Sciences and Medicine, King's College London, Guy's Campus, London SE1 1UL, United Kingdom; and Henry Wellcome Laboratory for Integrative Neuroscience and Endocrinology (S.L.L.), University of Bristol, Bristol BS1 3NY, United Kingdom.

ABSTRACT
Obesity is the major risk factor for early puberty, but emerging evidence indicates other factors including psychosocial stress. One key brain region notable for its role in controlling calorie intake, stress, and behavior is the amygdala. Early studies involving amygdala lesions that included the medial nucleus advanced puberty in rats. More recently it was shown that a critical site for lesion-induced hyperphagia and obesity is the posterodorsal subnucleus of the medial amygdala (MePD), which may explain the advancement of puberty. Glutamatergic activity also increases in the MePD during puberty without a corresponding γ-aminobutyric acid (GABA)ergic change, suggesting an overall activation of this brain region. In the present study, we report that neurotoxic lesioning of the MePD advances puberty and increases weight gain in female rats fed a normal diet. However, MePD lesioned rats fed a 25% nonnutritive bulk diet also showed the dramatic advancement of puberty but without the increase in body weight. In both dietary groups, MePD lesions resulted in an increase in socialization and a decrease in play fighting behavior. Chronic GABAA receptor antagonism in the MePD from postnatal day 21 for 14 days also advanced puberty, increased socialization, and decreased play fighting without altering body weight, whereas glutamate receptor antagonism delayed puberty and decreased socialization without affecting play fighting. In conclusion, our results suggest the MePD regulates the timing of puberty via a novel mechanism independent of change in body weight and caloric intake. MePD glutamatergic systems advance the timing of puberty whereas local GABAergic activation results in a delay.

Show MeSH
Related in: MedlinePlus