This review summarizes what is presently known about the function, sexual differentiation, and ne... more This review summarizes what is presently known about the function, sexual differentiation, and neural circuitry of juvenile rough-and-tumble play. Juvenile rough-and-tumble play is a unique motivated behavior that is widespread throughout the mammalian order and usually occurs more often in males. Immediate early gene studies indicate that cortical and subcortical circuits, many of which are sensitive to sex steroid hormones, mediate juvenile play. Sex differences in rough-and-tumble play are controlled in part by neonatal exposure to androgens or their estrogenic metabolites. Studies indicate that testicular androgens during play are also necessary to stimulate male-like levels of play initiation. The resemblance of rough-and-tumble play to aggression and sexual behavior has led some to question whether male-typical adult behavior is contingent upon the experience of play. Attempts to control the amount of play through social isolation show that social experience during adolescence is critical for male-typical adult behaviors to be expressed. This wellestablished finding, together with evidence that play induces neural plasticity, supports the hypothesis that juvenile play contributes to male-typical brain development that ultimately enables the expression of adult social and reproductive behavior.
One of the most reliable findings in psychiatry is in the incidence of anxiety and depression. Be... more One of the most reliable findings in psychiatry is in the incidence of anxiety and depression. Beginning at puberty, women develop mood disorders twice as often as men.
Abstract: After experiencing juvenile social subjugation (JSS), adult female rats display more se... more Abstract: After experiencing juvenile social subjugation (JSS), adult female rats display more severe
depression- and anxiety-like behaviours than adult males, suggesting that JSS is encoded in a sexspecific
manner. To test this hypothesis, prepubertal rats (P28 - 33) were subjected to 10 aggressive
acts in ≤ 10 min from an aggressive adult male, a 10 min encounter with a non-aggressive adult male,
or to 10 min in an empty, clean cage (the handled control). We then used unbiased stereology to
estimate the total number and proportion of neurons immunoreactive for the immediate early gene
product Fos bilaterally in the basolateral amygdala (BLA), the anterior and posterior subdivisions of
the bed nucleus of the stria terminalis, and the paraventricular nucleus of the hypothalamus (PVN).
Overall, females' Fos responses were less selective than males'. The BLA in males displayed a selective
Fos response to the non-aggressive male, whereas no such selectivity occurred in the BLA of females.
Additionally, there were more neurons overall in the left BLA than the right and this lateralization was
specific to males. The principal subdivision of the BST (BSTpr) in males responded selectively to JSS,
whereas the BSTpr in females was selective for both the non-aggressive and aggressive males. We also
found that the regional volume and neuron number of the BSTpr is greater in males than in females.
Finally, the PVN in males was, like the BLA, selective for the non-aggressive male, whereas none of the
experiences elicited a selective response in females. The greater selectivity for non-threatening stimuli
in males in three stress-responsive brain regions may be a clue as to why males are less susceptible to
the anxiogenic effects of JSS.
It is well known that the gonadal steroids (estradiol,
progesterone, and testosterone) exert pro... more It is well known that the gonadal steroids (estradiol, progesterone, and testosterone) exert profound effects on the structure and function of the mamma- lian brain. Much progress has been made in identi- fying the cellular and molecular mechanisms that underlie hormone-dependent neural plasticity, and the extent of this progress is summarized in several recent reviews (Mendez et al., 2006; Scharfman and Maclusky, 2005; Woolley, 2007). In the midst of this explosion of new and valuable insights, however, there is risk of losing touch with phenomena that captured early researchers’ imagination: the remark- able effects of natural variation in gonadal hormones on behavior, and on the morphology of the brain. The 4-day estrous cycle of estradiol and progester- one in female rats, and varying levels of testosterone in seasonally breeding male rodents, are but two examples of natural fluctuations in gonadal hor- mones that have powerful effects on both behavior and brain morphology. The parallel effects of hor- mones on the brain and behavior lead to the reason- able expectation that hormone-dependent changes in the brain are in some way responsible for the changes in behavior. The possibility of revealing links between brain infrastructure and behavior is, in our opinion, one of the most compelling reasons to explore hormone-dependent changes in brain morphology.
Corticotropin-releasing factor receptors type 1 (CRF 1 ) and type 2 (CRF 2 ) have complementary r... more Corticotropin-releasing factor receptors type 1 (CRF 1 ) and type 2 (CRF 2 ) have complementary roles in controlling the hypothalamic-pituitary-adrenal (HPA) axis. Because CRF receptors are expressed in sex steroid-sensitive areas of the forebrain, they may contribute to sex-specific patterns of stress sensitivity and susceptibility to stress-related mood disorders, which are more frequent in women.
The hormone, 17b-estradiol (E2), influences the structure and function of synapses in the CA1 reg... more The hormone, 17b-estradiol (E2), influences the structure and function of synapses in the CA1 region of the hippocampus. E2 increases the density of dendritic spines and excitatory synapses on CA1 pyramidal cells, increases CA1 cells' sensitivity to excitatory synaptic input mediated by the NMDA receptor (NMDAR), enhances NMDAR-dependent long-term potentiation, and improves hippocampusdependent working memory. J Neurosci 26:8517-8522) reported that the larger NMDAR-mediated excitatory postsynaptic currents (EPSCs) recorded after E2 treatment are due primarily to an increased contribution of NR2B-containing NMDARs. We used a combination of electrophysiology, Western blot, and immunofluorescence to investigate two potential mechanisms by which E2 could enhance NR2B-dependent EPSCs: An increase in NMDAR subunit protein levels and/or a change(s) in NR2B phosphorylation. Our studies confirmed the E2-induced increase in NR2B-dependent EPSC amplitude, but we found no evidence that E2 affects protein levels for the NR1, NR2A, or NR2B subunit of the NMDAR, nor that E2 affects phosphorylation of NR2B. Our findings suggest that the effects of E2 on NMDARdependent synaptic physiology in the hippocampus likely result from recruitment of NR2B-containing NMDARs to synapses rather than from increased expression of NMDARs or changes in their phosphorylation state. V V C 2010 Wiley-Liss, Inc.
This review summarizes what is presently known about the function, sexual differentiation, and ne... more This review summarizes what is presently known about the function, sexual differentiation, and neural circuitry of juvenile rough-and-tumble play. Juvenile rough-and-tumble play is a unique motivated behavior that is widespread throughout the mammalian order and usually occurs more often in males. Immediate early gene studies indicate that cortical and subcortical circuits, many of which are sensitive to sex steroid hormones, mediate juvenile play. Sex differences in rough-and-tumble play are controlled in part by neonatal exposure to androgens or their estrogenic metabolites. Studies indicate that testicular androgens during play are also necessary to stimulate male-like levels of play initiation. The resemblance of rough-and-tumble play to aggression and sexual behavior has led some to question whether male-typical adult behavior is contingent upon the experience of play. Attempts to control the amount of play through social isolation show that social experience during adolescence is critical for male-typical adult behaviors to be expressed. This well-established finding, together with evidence that play induces neural plasticity, supports the hypothesis that juvenile play contributes to male-typical brain development that ultimately enables the expression of adult social and reproductive behavior.
There is indirect evidence that heightened exposure to early androgen may increase the probabilit... more There is indirect evidence that heightened exposure to early androgen may increase the probability that a girl will develop a homosexual orientation in adulthood. One such putative marker of early androgen exposure is the ratio of the length of the index finger (2D) to the ring finger (4D), which is smaller in male humans than in females, and is smaller in lesbians than in heterosexual women. Yet there is also evidence that women may have different sexual orientations at different times in their lives, which suggests that other influences on female sexual orientation, presumably social, are at work as well. We surveyed individuals from a gay pride street fair and found that lesbians who identified themselves as “butch” had a significantly smaller 2D:4D than did those who identified themselves as “femme.” We conclude that increased early androgen exposure plays a role in only some cases of female homosexuality, and that the sexual orientation of “femme” lesbians is unlikely to have been influenced by early androgens.
This review summarizes what is presently known about the function, sexual differentiation, and ne... more This review summarizes what is presently known about the function, sexual differentiation, and neural circuitry of juvenile rough-and-tumble play. Juvenile rough-and-tumble play is a unique motivated behavior that is widespread throughout the mammalian order and usually occurs more often in males. Immediate early gene studies indicate that cortical and subcortical circuits, many of which are sensitive to sex steroid hormones, mediate juvenile play. Sex differences in rough-and-tumble play are controlled in part by neonatal exposure to androgens or their estrogenic metabolites. Studies indicate that testicular androgens during play are also necessary to stimulate male-like levels of play initiation. The resemblance of rough-and-tumble play to aggression and sexual behavior has led some to question whether male-typical adult behavior is contingent upon the experience of play. Attempts to control the amount of play through social isolation show that social experience during adolescence is critical for male-typical adult behaviors to be expressed. This wellestablished finding, together with evidence that play induces neural plasticity, supports the hypothesis that juvenile play contributes to male-typical brain development that ultimately enables the expression of adult social and reproductive behavior.
One of the most reliable findings in psychiatry is in the incidence of anxiety and depression. Be... more One of the most reliable findings in psychiatry is in the incidence of anxiety and depression. Beginning at puberty, women develop mood disorders twice as often as men.
Abstract: After experiencing juvenile social subjugation (JSS), adult female rats display more se... more Abstract: After experiencing juvenile social subjugation (JSS), adult female rats display more severe
depression- and anxiety-like behaviours than adult males, suggesting that JSS is encoded in a sexspecific
manner. To test this hypothesis, prepubertal rats (P28 - 33) were subjected to 10 aggressive
acts in ≤ 10 min from an aggressive adult male, a 10 min encounter with a non-aggressive adult male,
or to 10 min in an empty, clean cage (the handled control). We then used unbiased stereology to
estimate the total number and proportion of neurons immunoreactive for the immediate early gene
product Fos bilaterally in the basolateral amygdala (BLA), the anterior and posterior subdivisions of
the bed nucleus of the stria terminalis, and the paraventricular nucleus of the hypothalamus (PVN).
Overall, females' Fos responses were less selective than males'. The BLA in males displayed a selective
Fos response to the non-aggressive male, whereas no such selectivity occurred in the BLA of females.
Additionally, there were more neurons overall in the left BLA than the right and this lateralization was
specific to males. The principal subdivision of the BST (BSTpr) in males responded selectively to JSS,
whereas the BSTpr in females was selective for both the non-aggressive and aggressive males. We also
found that the regional volume and neuron number of the BSTpr is greater in males than in females.
Finally, the PVN in males was, like the BLA, selective for the non-aggressive male, whereas none of the
experiences elicited a selective response in females. The greater selectivity for non-threatening stimuli
in males in three stress-responsive brain regions may be a clue as to why males are less susceptible to
the anxiogenic effects of JSS.
It is well known that the gonadal steroids (estradiol,
progesterone, and testosterone) exert pro... more It is well known that the gonadal steroids (estradiol, progesterone, and testosterone) exert profound effects on the structure and function of the mamma- lian brain. Much progress has been made in identi- fying the cellular and molecular mechanisms that underlie hormone-dependent neural plasticity, and the extent of this progress is summarized in several recent reviews (Mendez et al., 2006; Scharfman and Maclusky, 2005; Woolley, 2007). In the midst of this explosion of new and valuable insights, however, there is risk of losing touch with phenomena that captured early researchers’ imagination: the remark- able effects of natural variation in gonadal hormones on behavior, and on the morphology of the brain. The 4-day estrous cycle of estradiol and progester- one in female rats, and varying levels of testosterone in seasonally breeding male rodents, are but two examples of natural fluctuations in gonadal hor- mones that have powerful effects on both behavior and brain morphology. The parallel effects of hor- mones on the brain and behavior lead to the reason- able expectation that hormone-dependent changes in the brain are in some way responsible for the changes in behavior. The possibility of revealing links between brain infrastructure and behavior is, in our opinion, one of the most compelling reasons to explore hormone-dependent changes in brain morphology.
Corticotropin-releasing factor receptors type 1 (CRF 1 ) and type 2 (CRF 2 ) have complementary r... more Corticotropin-releasing factor receptors type 1 (CRF 1 ) and type 2 (CRF 2 ) have complementary roles in controlling the hypothalamic-pituitary-adrenal (HPA) axis. Because CRF receptors are expressed in sex steroid-sensitive areas of the forebrain, they may contribute to sex-specific patterns of stress sensitivity and susceptibility to stress-related mood disorders, which are more frequent in women.
The hormone, 17b-estradiol (E2), influences the structure and function of synapses in the CA1 reg... more The hormone, 17b-estradiol (E2), influences the structure and function of synapses in the CA1 region of the hippocampus. E2 increases the density of dendritic spines and excitatory synapses on CA1 pyramidal cells, increases CA1 cells' sensitivity to excitatory synaptic input mediated by the NMDA receptor (NMDAR), enhances NMDAR-dependent long-term potentiation, and improves hippocampusdependent working memory. J Neurosci 26:8517-8522) reported that the larger NMDAR-mediated excitatory postsynaptic currents (EPSCs) recorded after E2 treatment are due primarily to an increased contribution of NR2B-containing NMDARs. We used a combination of electrophysiology, Western blot, and immunofluorescence to investigate two potential mechanisms by which E2 could enhance NR2B-dependent EPSCs: An increase in NMDAR subunit protein levels and/or a change(s) in NR2B phosphorylation. Our studies confirmed the E2-induced increase in NR2B-dependent EPSC amplitude, but we found no evidence that E2 affects protein levels for the NR1, NR2A, or NR2B subunit of the NMDAR, nor that E2 affects phosphorylation of NR2B. Our findings suggest that the effects of E2 on NMDARdependent synaptic physiology in the hippocampus likely result from recruitment of NR2B-containing NMDARs to synapses rather than from increased expression of NMDARs or changes in their phosphorylation state. V V C 2010 Wiley-Liss, Inc.
This review summarizes what is presently known about the function, sexual differentiation, and ne... more This review summarizes what is presently known about the function, sexual differentiation, and neural circuitry of juvenile rough-and-tumble play. Juvenile rough-and-tumble play is a unique motivated behavior that is widespread throughout the mammalian order and usually occurs more often in males. Immediate early gene studies indicate that cortical and subcortical circuits, many of which are sensitive to sex steroid hormones, mediate juvenile play. Sex differences in rough-and-tumble play are controlled in part by neonatal exposure to androgens or their estrogenic metabolites. Studies indicate that testicular androgens during play are also necessary to stimulate male-like levels of play initiation. The resemblance of rough-and-tumble play to aggression and sexual behavior has led some to question whether male-typical adult behavior is contingent upon the experience of play. Attempts to control the amount of play through social isolation show that social experience during adolescence is critical for male-typical adult behaviors to be expressed. This well-established finding, together with evidence that play induces neural plasticity, supports the hypothesis that juvenile play contributes to male-typical brain development that ultimately enables the expression of adult social and reproductive behavior.
There is indirect evidence that heightened exposure to early androgen may increase the probabilit... more There is indirect evidence that heightened exposure to early androgen may increase the probability that a girl will develop a homosexual orientation in adulthood. One such putative marker of early androgen exposure is the ratio of the length of the index finger (2D) to the ring finger (4D), which is smaller in male humans than in females, and is smaller in lesbians than in heterosexual women. Yet there is also evidence that women may have different sexual orientations at different times in their lives, which suggests that other influences on female sexual orientation, presumably social, are at work as well. We surveyed individuals from a gay pride street fair and found that lesbians who identified themselves as “butch” had a significantly smaller 2D:4D than did those who identified themselves as “femme.” We conclude that increased early androgen exposure plays a role in only some cases of female homosexuality, and that the sexual orientation of “femme” lesbians is unlikely to have been influenced by early androgens.
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Papers by Bradley Cooke
depression- and anxiety-like behaviours than adult males, suggesting that JSS is encoded in a sexspecific
manner. To test this hypothesis, prepubertal rats (P28 - 33) were subjected to 10 aggressive
acts in ≤ 10 min from an aggressive adult male, a 10 min encounter with a non-aggressive adult male,
or to 10 min in an empty, clean cage (the handled control). We then used unbiased stereology to
estimate the total number and proportion of neurons immunoreactive for the immediate early gene
product Fos bilaterally in the basolateral amygdala (BLA), the anterior and posterior subdivisions of
the bed nucleus of the stria terminalis, and the paraventricular nucleus of the hypothalamus (PVN).
Overall, females' Fos responses were less selective than males'. The BLA in males displayed a selective
Fos response to the non-aggressive male, whereas no such selectivity occurred in the BLA of females.
Additionally, there were more neurons overall in the left BLA than the right and this lateralization was
specific to males. The principal subdivision of the BST (BSTpr) in males responded selectively to JSS,
whereas the BSTpr in females was selective for both the non-aggressive and aggressive males. We also
found that the regional volume and neuron number of the BSTpr is greater in males than in females.
Finally, the PVN in males was, like the BLA, selective for the non-aggressive male, whereas none of the
experiences elicited a selective response in females. The greater selectivity for non-threatening stimuli
in males in three stress-responsive brain regions may be a clue as to why males are less susceptible to
the anxiogenic effects of JSS.
progesterone, and testosterone) exert profound
effects on the structure and function of the mamma-
lian brain. Much progress has been made in identi-
fying the cellular and molecular mechanisms that
underlie hormone-dependent neural plasticity, and
the extent of this progress is summarized in several
recent reviews (Mendez et al., 2006; Scharfman and
Maclusky, 2005; Woolley, 2007). In the midst of this
explosion of new and valuable insights, however,
there is risk of losing touch with phenomena that
captured early researchers’ imagination: the remark-
able effects of natural variation in gonadal hormones
on behavior, and on the morphology of the brain.
The 4-day estrous cycle of estradiol and progester-
one in female rats, and varying levels of testosterone
in seasonally breeding male rodents, are but two
examples of natural fluctuations in gonadal hor-
mones that have powerful effects on both behavior
and brain morphology. The parallel effects of hor-
mones on the brain and behavior lead to the reason-
able expectation that hormone-dependent changes
in the brain are in some way responsible for the
changes in behavior. The possibility of revealing
links between brain infrastructure and behavior is,
in our opinion, one of the most compelling reasons
to explore hormone-dependent changes in brain
morphology.
depression- and anxiety-like behaviours than adult males, suggesting that JSS is encoded in a sexspecific
manner. To test this hypothesis, prepubertal rats (P28 - 33) were subjected to 10 aggressive
acts in ≤ 10 min from an aggressive adult male, a 10 min encounter with a non-aggressive adult male,
or to 10 min in an empty, clean cage (the handled control). We then used unbiased stereology to
estimate the total number and proportion of neurons immunoreactive for the immediate early gene
product Fos bilaterally in the basolateral amygdala (BLA), the anterior and posterior subdivisions of
the bed nucleus of the stria terminalis, and the paraventricular nucleus of the hypothalamus (PVN).
Overall, females' Fos responses were less selective than males'. The BLA in males displayed a selective
Fos response to the non-aggressive male, whereas no such selectivity occurred in the BLA of females.
Additionally, there were more neurons overall in the left BLA than the right and this lateralization was
specific to males. The principal subdivision of the BST (BSTpr) in males responded selectively to JSS,
whereas the BSTpr in females was selective for both the non-aggressive and aggressive males. We also
found that the regional volume and neuron number of the BSTpr is greater in males than in females.
Finally, the PVN in males was, like the BLA, selective for the non-aggressive male, whereas none of the
experiences elicited a selective response in females. The greater selectivity for non-threatening stimuli
in males in three stress-responsive brain regions may be a clue as to why males are less susceptible to
the anxiogenic effects of JSS.
progesterone, and testosterone) exert profound
effects on the structure and function of the mamma-
lian brain. Much progress has been made in identi-
fying the cellular and molecular mechanisms that
underlie hormone-dependent neural plasticity, and
the extent of this progress is summarized in several
recent reviews (Mendez et al., 2006; Scharfman and
Maclusky, 2005; Woolley, 2007). In the midst of this
explosion of new and valuable insights, however,
there is risk of losing touch with phenomena that
captured early researchers’ imagination: the remark-
able effects of natural variation in gonadal hormones
on behavior, and on the morphology of the brain.
The 4-day estrous cycle of estradiol and progester-
one in female rats, and varying levels of testosterone
in seasonally breeding male rodents, are but two
examples of natural fluctuations in gonadal hor-
mones that have powerful effects on both behavior
and brain morphology. The parallel effects of hor-
mones on the brain and behavior lead to the reason-
able expectation that hormone-dependent changes
in the brain are in some way responsible for the
changes in behavior. The possibility of revealing
links between brain infrastructure and behavior is,
in our opinion, one of the most compelling reasons
to explore hormone-dependent changes in brain
morphology.