RESUMEN
In April 2023, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), in partnership with the National Institute of Child Health and Human Development, the National Institute on Aging, and the Office of Behavioral and Social Sciences Research, hosted a 2-day online workshop to discuss neural plasticity in energy homeostasis and obesity. The goal was to provide a broad view of current knowledge while identifying research questions and challenges regarding neural systems that control food intake and energy balance. This review includes highlights from the meeting and is intended both to introduce unfamiliar audiences with concepts central to energy homeostasis, feeding, and obesity and to highlight up-and-coming research in these areas that may be of special interest to those with a background in these fields. The overarching theme of this review addresses plasticity within the central and peripheral nervous systems that regulates and influences eating, emphasizing distinctions between healthy and disease states. This is by no means a comprehensive review because this is a broad and rapidly developing area. However, we have pointed out relevant reviews and primary articles throughout, as well as gaps in current understanding and opportunities for developments in the field.
Asunto(s)
Dieta , Metabolismo Energético , Plasticidad Neuronal , Obesidad , Humanos , Metabolismo Energético/fisiología , Plasticidad Neuronal/fisiología , Obesidad/fisiopatología , Obesidad/metabolismo , Homeostasis/fisiología , Ingestión de Alimentos/fisiología , Conducta Alimentaria/fisiología , AnimalesRESUMEN
BACKGROUND: Type 2 alcoholism is characterized by low serotonin system functioning and has a high degree of heritability, with offspring of alcoholics often showing a reduced response to the intoxicating effects of ethanol (EtOH), which is thought to be marker for future alcohol use disorders (AUDs). As such, an important aim of studies investigating the origins of AUDs is to understand the relationship between serotonin system functioning and level of intoxication. A nonhuman primate model was used to evaluate observational ratings of sensitivity to EtOH and to further investigate the relationship between central serotonin activity and behavioral response to EtOH. METHODS: Cerebrospinal fluid (CSF) concentrations of 5-hydroxyindoleacetic acid (5-HIAA) were obtained from 4 cohorts of alcohol-naïve, adolescent rhesus macaques (N = 82, 45 females, 37 males). One to 3 months after the CSF sample, subjects were administered a standardized intravenous EtOH bolus (males: 2.1 g/kg body weight, females: 2.0 g/kg body weight), placed into an open-top, clear plexiglass chamber suspended from the ceiling, and their latency to escape was recorded as a measure of the degree of intoxication. Thereafter, subjects were rated using a Likert scale for the degree of intoxication during a 30-minute observation period. RESULTS: Our results indicate that latency to escape from the chamber was associated with intoxication ratings (p = 0.0009) following the standardized intravenous administration of EtOH. Low CSF 5-HIAA concentrations predicted short escape latency (p = 0.007) and were associated with low intoxication ratings (p = 0.02), indicating that low central nervous system (CNS) serotonin functioning is related to relative insensitivity to the intoxicating effects of alcohol. CONCLUSIONS: Our study shows that, in monkeys exposed to alcohol for the first time, objective measures of intoxication are associated with subjective ratings for intoxication, and both were associated with CSF 5-HIAA concentrations. Our data confirm and extend the finding that low CNS serotonin functioning is predictive of intrinsic low sensitivity to the intoxicating effects of EtOH.
Asunto(s)
Intoxicación Alcohólica/fisiopatología , Conducta Animal/efectos de los fármacos , Depresores del Sistema Nervioso Central/farmacología , Etanol/farmacología , Ácido Hidroxiindolacético/líquido cefalorraquídeo , Intoxicación Alcohólica/líquido cefalorraquídeo , Animales , Femenino , Macaca mulatta , MasculinoRESUMEN
During puberty, attention turns away from same-sex socialization to focus on the opposite sex. How the brain mediates this change in perception and motivation is unknown. Polysialylated neural cell adhesion molecule (PSA-NCAM) virtually disappears from most of the central nervous system after embryogenesis, but it remains elevated in discrete regions of the adult brain. One such brain area is the posterodorsal subnucleus of the medial amygdala (MePD). The MePD has been implicated in male sexual attraction, measured here as the preference to investigate female odors. We hypothesize that PSA-NCAM gates hormone-dependent plasticity necessary for the emergence of males' attraction to females. To evaluate this idea, we first measured PSA-NCAM levels across puberty in several brain regions, and identified when female odor preference normally emerges in male Syrian hamsters. We found that MePD PSA-NCAM staining peaks shortly before the surge of pubertal androgen and the emergence of preference. To test the necessity of PSA-NCAM for female odor preference, we infused endo-neuraminidase-N into the MePD to deplete it of PSAs before female odor preference normally appears. This blocked female odor preference, which suggests that PSA-NCAM facilitates behaviorally relevant, hormone-driven plasticity.
Asunto(s)
Complejo Nuclear Corticomedial/metabolismo , Preferencia en el Apareamiento Animal/fisiología , Mesocricetus/fisiología , Molécula L1 de Adhesión de Célula Nerviosa/metabolismo , Odorantes , Maduración Sexual/fisiología , Ácidos Siálicos/metabolismo , Amígdala del Cerebelo/efectos de los fármacos , Amígdala del Cerebelo/fisiología , Animales , Complejo Nuclear Corticomedial/efectos de los fármacos , Cricetinae , Femenino , Masculino , Preferencia en el Apareamiento Animal/efectos de los fármacos , Mesocricetus/psicología , Atractivos Sexuales/metabolismo , Maduración Sexual/efectos de los fármacosRESUMEN
Child abuse is the most potent experiential risk factor for developing a mood disorder later in life. The effects of child abuse are also more severe in girls and women than in men. In this review, we explore the origins of this epidemiological sex difference. We begin by offering the hypothesis that a sex-specific risk factor that influences how social cues are perceived and remembered makes girls more susceptible to the effects of child abuse. We then discuss the neural systems that mediate emotion and stress, and, how child abuse and/or mood disorders like anxiety and depression affect them. Drawing upon human and animal research, several candidates for such a risk factor are discussed. They include glucocorticoid receptor trafficking and corticotropin releasing factor receptor binding and signaling. Our own research shows that the morphometry of the prepubertal amygdala is sexually dimorphic, and could contribute to a sex difference in stimulus appraisal. We have also found that the brain of juvenile female rats is less selective than males' for threatening social stimuli. Thus, one way that women may be more vulnerable to the effects of child abuse is that they are more likely to perceive objectively benign stimuli as threatening. This bias in perception could compound with the genuinely traumatic memories caused by child abuse; the burden of traumatic memories and the increasingly reactive stress response systems could then dispose more women than men to develop depression and/or anxiety.
Asunto(s)
Encéfalo/fisiopatología , Maltrato a los Niños/psicología , Percepción Social , Trastornos de Estrés Traumático/fisiopatología , Animales , Encéfalo/metabolismo , Preescolar , Femenino , Humanos , Masculino , Ratas , Trastornos de Estrés Traumático/metabolismoRESUMEN
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. Because corticotropin-releasing factor (CRF) receptors are implicated, we compared CRF receptor binding in pre- and postpubertal rats. In each brain area, CRF receptor binding was sexually dimorphic, but no two areas were alike in the way the sexes differed. In the nucleus accumbens and olfactory tubercle, CRF1 binding was initially the same in juveniles, but became greater in adult females. In piriform cortex, CRF1 binding increased in females and decreased in males, again becoming sexually dimorphic. CRF1 binding in the anterior cingulate was greater in females than in males at both ages. In CA3, CRF1 binding was greater in males before puberty but decreased during puberty, abolishing the sex difference. CRF2 binding in the posterior bed nucleus of the stria terminalis was greater in males irrespective of age. In contrast, in each of three subdivisions of the lateral septum, females had greater CRF2 binding than males as juveniles, or, as juveniles and as adults. CRF2 binding in the ventromedial hypothalamus was the same in juveniles, but binding levels increased in males, leading to an adult sex difference. Thus, eight CRF receptor-expressing areas displayed eight distinct sex differences. These results show that sex differences pervade the CRF receptor system in juvenile and adult rats, and the mechanisms that control them are likely to be sex-, region-, and subtype-specific.
Asunto(s)
Envejecimiento/fisiología , Encéfalo , Receptores de Hormona Liberadora de Corticotropina/metabolismo , Caracteres Sexuales , Factores de Edad , Anciano , Animales , Animales Recién Nacidos , Autorradiografía , Encéfalo/anatomía & histología , Encéfalo/crecimiento & desarrollo , Encéfalo/metabolismo , Femenino , Humanos , Masculino , Unión Proteica , Ratas , Ratas Long-Evans , Receptores de Hormona Liberadora de Corticotropina/genéticaRESUMEN
After experiencing juvenile social subjugation (JSS), adult female rats display more severe depression- and anxiety-like behaviors than adult males, suggesting that JSS is encoded in a sex-specific 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 (handled control) and were sacrificed one hour later. 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 responded to 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.
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Agresión/fisiología , Encéfalo/fisiología , Neuronas/fisiología , Caracteres Sexuales , Predominio Social , Amígdala del Cerebelo/fisiología , Animales , Femenino , Masculino , Proteínas Proto-Oncogénicas c-fos/metabolismo , RatasRESUMEN
Adolescent drug abuse is hypothesized to increase the risk of drug addiction. Yet male rats that self-administer heroin as adolescents show attenuated drug-seeking after abstinence, compared with adults. Here we explore a role for neural activity in the medial prefrontal cortex (mPFC) in age-dependent heroin-seeking. Adolescent (35-day-old at start; adolescent-onset) and adult (86-day-old at start) male rats acquired lever-pressing maintained by heroin using a fixed ratio one reinforcement schedule (0.05 and 0.025 mg/kg per infusion). Following 12 days of forced abstinence, rats were tested for heroin-seeking over 1 h by measuring the number of lever presses on the active lever. Unbiased stereology was then used to estimate the number of Fos-ir(+) and Fos-ir(-) neurons in prelimbic and infralimbic mPFC. As before, adolescents and adults self-administered similar amounts of heroin, but subsequent heroin-seeking was attenuated in the younger rats. Similarly, the adolescent-onset group failed to show significant neural activation in the prelimbic or infralimbic mPFC during the heroin-seeking test, whereas the adult-onset heroin self-administration group showed two to six times more Fos-ir(+) neurons than their saline counterparts in both mPFC subregions. Finally, the overall number of neurons in the infralimbic cortex was greater in rats from the adolescent-onset groups than adults. The mPFC may thus have a key role in some age-dependent effects of heroin self-administration.
Asunto(s)
Conducta Adictiva/metabolismo , Condicionamiento Operante/fisiología , Dependencia de Heroína/metabolismo , Heroína/administración & dosificación , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/fisiología , Factores de Edad , Animales , Conducta Adictiva/psicología , Condicionamiento Operante/efectos de los fármacos , Dependencia de Heroína/psicología , Masculino , Ratas , Ratas Sprague-Dawley , AutoadministraciónRESUMEN
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. To determine whether CRF receptors vary as a function of age and/or sex, we measured receptor binding in the amygdala of male and female, prepubertal and adult rats. Both receptor subtypes demonstrated age- and sex-specific binding patterns. In the basolateral amygdala and posteroventral medial amygdala, CRF(1) binding decreased in males and increased in females after puberty, there, CRF(2) binding increased in males and was unchanged in females. In the posterodorsal medial amygdala, CRF(1) binding was unchanged across puberty, whereas CRF(2) binding increased across puberty far more in males than in females. Binding was lowest overall in the central amygdala; there, CRF(1) was unchanged while CRF(2) binding increased across puberty only in males. Thus, in all four examined areas across prepuberty to adulthood, CRF(2) binding increased far more in males than in females and resulted in significantly more binding in adult males than in adult females. These sex-specific developmental patterns are consistent with sex differences in hypothalamic-pituitary-adrenal responsiveness and may thus contribute to sex differences in mood disorder susceptibility.
Asunto(s)
Amígdala del Cerebelo/metabolismo , Regulación del Desarrollo de la Expresión Génica , Receptores de Hormona Liberadora de Corticotropina/metabolismo , Animales , Densitometría/métodos , Femenino , Sistema Hipotálamo-Hipofisario/fisiología , Masculino , Trastornos del Humor , Sistema Hipófiso-Suprarrenal/fisiología , Prosencéfalo/metabolismo , Unión Proteica , Ratas , Ratas Long-Evans , Factores Sexuales , Maduración SexualRESUMEN
To compare the response of the medial amygdala and central amygdala to juvenile social subjugation (JSS), we used unbiased stereology to quantify the immediate early gene product Fos in prepubertal rats after aggressive or benign social encounters or handling. We estimated the overall number of neurons and the proportion of Fos immunoreactive neurons in the posterodorsal (MePD) and posteroventral medial amygdala (MePV) and the central amygdala (CeA). Experience elicited Fos in a sex- and hemisphere-dependent manner in the MePD. The left MePD was selective for JSS in both sexes, but the right MePD showed a specific Fos response to JSS in males only. In the MePV, irrespective of hemisphere or sex, JSS elicited the greatest amount of Fos, benign social experience elicited an intermediate level, and handling the least. None of the experiential conditions elicited significant levels of Fos in the CeA. We found a previously unreported sex difference in the number of CeA neurons (M>F) that was highly significant and a strong trend toward a sex difference (M>F) in the MePD. These data show that the posterior MeA subnuclei are more responsive to JSS than to benign social interaction, that sex interacts with hemispheric laterality to determine the response of the MePD to JSS and that the MePV responds to social experience and JSS. Taken together, these findings support the hypothesis that juvenile rats process JSS in a sex-specific manner.
Asunto(s)
Amígdala del Cerebelo/metabolismo , Conducta Animal/fisiología , Proteínas Proto-Oncogénicas c-fos/metabolismo , Caracteres Sexuales , Conducta Social , Factores de Edad , Amígdala del Cerebelo/anatomía & histología , Amígdala del Cerebelo/ultraestructura , Animales , Femenino , Aprendizaje/fisiología , Masculino , Modelos Biológicos , Neuroanatomía , Ratas , Ratas Long-EvansRESUMEN
Child abuse is the most significant environmental risk factor for the development of mood disorders, which occur twice as frequently in women as in men. To determine whether juvenile social subjugation (JSS) of rats induces mood disorder-like symptoms, we exposed 28 day-old male and female rats to daily aggressive acts from aggressive male residents. Each rat received pins, kicks, and dominance postures from the resident for 10 min per day for 10 days. When the rats were adults, we tested their anxiety- and depression-like behaviors. In addition, we measured circulating basal and stress-evoked corticosterone (CORT) levels, and weighed the adrenal glands. Although the amount of JSS was indistinguishable between males and females, females were nonetheless more severely affected by the experience. Subjugated females became immobile more quickly during forced swim tests, and made fewer investigatory approaches during the social interaction test than control females. Juvenile social subjugation increased closed arm time in the elevated plus maze of males and females, but the effect of social subjugation was greater in females. Finally, stress-evoked CORT levels were significantly higher, and adrenal gland weights were significantly heavier, in subjugated females relative to their controls and to subjugated males. Our results demonstrate that JSS increases depression- and anxiety-like behaviors and sensitizes the stress response system in a sex-specific manner.
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Ansiedad/fisiopatología , Depresión/fisiopatología , Predominio Social , Glándulas Suprarrenales/fisiopatología , Agresión/fisiología , Animales , Ansiedad/psicología , Corticosterona/sangre , Depresión/psicología , Femenino , Masculino , Tamaño de los Órganos , Ratas , Ratas Long-Evans , Factores Sexuales , Estrés Psicológico/fisiopatología , Estrés Psicológico/psicologíaRESUMEN
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.
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Conducta del Adolescente/fisiología , Conducta del Adolescente/psicología , Encéfalo/crecimiento & desarrollo , Juego e Implementos de Juego/psicología , Caracteres Sexuales , Adolescente , Animales , Femenino , Humanos , Masculino , Red Nerviosa/crecimiento & desarrollo , Conducta SocialRESUMEN
The hormone, 17ß-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 hippocampus-dependent working memory. Smith and McMahon (2006 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 NMDAR-dependent 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.
Asunto(s)
Región CA1 Hipocampal/metabolismo , Espinas Dendríticas/metabolismo , Estradiol , Plasticidad Neuronal/fisiología , Subunidades de Proteína/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Animales , Estradiol/metabolismo , Estradiol/farmacología , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Potenciales Postsinápticos Excitadores/fisiología , Femenino , Potenciación a Largo Plazo/efectos de los fármacos , Potenciación a Largo Plazo/fisiología , Técnicas de Placa-Clamp , Fosforilación , Ratas , Ratas Sprague-Dawley , Sinapsis/efectos de los fármacos , Sinapsis/metabolismoRESUMEN
About one-third of women with epilepsy have a catamenial seizure pattern, in which seizures fluctuate with the menstrual cycle. Catamenial seizures occur more frequently when the ratio of circulating estradiol to progesterone is high, suggesting that estradiol is proconvulsant. We used adult female rats to test how estradiol-induced suppression of GABAergic inhibition in the hippocampus affects behavioral seizures induced by kainic acid. As expected, estradiol decreased the latency to initiate seizures, indicating increased seizure susceptibility. At the same time, however, estradiol also shortened the duration of late-stage seizures, indicating decreased seizure severity. Additional analyses showed that the decrease in seizure severity was attributable to greater release of the anticonvulsant neuropeptide, neuropeptide Y (NPY). First, blocking hippocampal NPY during seizures eliminated the estradiol-induced decrease in seizure duration. Second, light and electron microscopic studies indicated that estradiol increases the potentially releasable pool of NPY in inhibitory presynaptic boutons and facilitates the release of NPY from inhibitory boutons during seizures. Finally, the presence of estrogen receptor-alpha on large dense-core vesicles (LDCVs) in the hippocampus suggests that estradiol could facilitate neuropeptide release by acting directly on LDCVs themselves. Understanding how estradiol regulates NPY-containing LDCVs could point to molecular targets for novel anticonvulsant therapies.
Asunto(s)
Estradiol/farmacología , Estradiol/uso terapéutico , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Neuropéptido Y/metabolismo , Convulsiones/prevención & control , Animales , Receptor alfa de Estrógeno/metabolismo , Receptor alfa de Estrógeno/fisiología , Femenino , Técnicas In Vitro , Ratas , Ratas Sprague-Dawley , Tiempo de Reacción/efectos de los fármacos , Tiempo de Reacción/fisiología , Vesículas Secretoras/metabolismo , Convulsiones/metabolismoRESUMEN
Mammalian puberty entails the emergence of behaviors such as courtship, coitus, and territorial aggressiveness. In adult rodents, the medial amygdala (MeA) is an important site for gonadal steroid hormone regulation of social behaviors and is sensitive to changes in the level of gonadal steroids. Here we show that prepubertal gonadectomy of male rats reduces the expression of a sexually dimorphic behavior, juvenile rough-and-tumble play, as well as the level of excitatory synaptic transmission assayed in adulthood. Behavioral observations in juveniles showed that gonadectomy reduced the initiation of playful attacks, particularly between postnatal days 31-35. Whole-cell voltage clamp recordings made in slices from adults showed that gonadectomy also reduced the frequency of miniature excitatory postsynaptic currents (mEPSCs) in MeA neurons without affecting paired pulse facilitation, an index of vesicle release probability. As mEPSC frequency can reflect the number of excitatory synapses per neuron, we also compared the dendritic morphology of Lucifer Yellow filled neurons from intact and gonadectomized adults. This showed that gonadectomy significantly reduced the density of dendritic spines without affecting overall dendritic length or branching of MeA neurons, which is consistent with a gonadectomy-induced reduction in the number of excitatory synapses. These findings suggest that peripubertal androgens activate rough-and-tumble play and promote the maintenance and/or development of new excitatory synapses in the MeA.
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Amígdala del Cerebelo/fisiología , Amígdala del Cerebelo/ultraestructura , Conducta Animal/fisiología , Sinapsis/fisiología , Transmisión Sináptica/fisiología , Animales , Animales Recién Nacidos , Dendritas/ultraestructura , Estimulación Eléctrica/métodos , Potenciales Postsinápticos Excitadores/fisiología , Isoquinolinas/metabolismo , Lisina/análogos & derivados , Lisina/metabolismo , Masculino , Orquiectomía , Ratas , Ratas Sprague-Dawley , Conducta Sexual AnimalRESUMEN
We investigated whether puberty influences the morphology of the medial nucleus of the amygdala (MeA) by comparing Siberian hamsters (Phodopus sungorus) that had been raised from birth in either long day (LD; 16:8 h light:dark) or short day (SD; 8:16) photoperiods. Hamsters were sacrificed at 42-49 days of age, at which point all LD hamsters were reproductively mature, as evidenced by adult-like testes weights (mean: 657 mg). In contrast, the testes weights of the SD hamsters were low (mean: 31 mg), indicating that the SD photoperiod had delayed puberty. The regional volume and mean soma size of the four MeA subnuclei was estimated bilaterally by stereological procedures. In the posterior dorsal and ventral MeA subnuclei, regional volume was 22-25% larger, and mean soma size 18% larger, in LD males than SD males. Unbiased cell counts in the posterior dorsal MeA showed that LD and SD hamsters have equivalent neuron numbers. In the anterior MeA subnuclei, regional volumes and soma sizes from LD and SD hamsters were equivalent. Additionally, the regional volume of the posteroventral subnucleus was larger in the right hemisphere than the left, but this laterality did not respond to photoperiod manipulation. These results suggest that the extant neurons within the posterior MeA, a steroid-sensitive nucleus implicated in socio-sexual behavior, grow in response to the elevated levels of circulating androgen accompanying puberty, and that photoperiodic regulation of puberty affects morphological maturation of this nucleus.
Asunto(s)
Amígdala del Cerebelo/crecimiento & desarrollo , Fotoperiodo , Maduración Sexual/fisiología , Testículo/crecimiento & desarrollo , Amígdala del Cerebelo/citología , Amígdala del Cerebelo/efectos de la radiación , Andrógenos/sangre , Animales , Cricetinae , Femenino , Lateralidad Funcional , Luz , Masculino , Neuronas/fisiología , Neuronas/efectos de la radiación , Tamaño de los Órganos , Phodopus , Maduración Sexual/efectos de la radiación , Testículo/efectos de la radiaciónRESUMEN
The medial amygdala (MeA) is crucial in the expression of sex-specific social behaviors. In adult rats the regional volume of the MeA posterodorsal subnucleus (MeApd) is approximately 50% larger in males than in females. The MeApd is also sexually dimorphic in prepubertal rats. We have recently shown that the left MeApd is significantly larger in prepubertal males than females. In contrast with volumetric sex differences elsewhere in the brain, however, we found no sex difference in the number of left MeApd neurons. In the present study we investigated the cellular bases of the sex difference in MeApd regional volume by quantifying the volume occupied by dendrites, axons, synapses, or glia, and by measuring MeApd dendritic morphology in 26-29-day-old male and female rats. We find that the volume occupied by dendritic shafts and glia completely accounts for the sex difference in left MeApd regional volume. Dendritic length measurements in the left hemisphere confirm that males have greater overall dendritic length, which is due to greater branching rather than to longer dendrite segments. In the right hemisphere the pattern of sex differences was different: Males have more MeApd neurons than females, whereas the dendritic morphology of individual neurons is not sexually dimorphic. These results highlight the importance of evaluating laterality in the MeA and suggest that the left and right MeA could play different roles in neuroendocrine regulation and sexually dimorphic social behaviors.
Asunto(s)
Amígdala del Cerebelo/fisiología , Lateralidad Funcional/fisiología , Neuronas/fisiología , Amígdala del Cerebelo/citología , Animales , Recuento de Células , Dendritas/fisiología , Femenino , Masculino , Neuronas/citología , Tamaño de los Órganos , Ratas , Ratas Sprague-Dawley , Caracteres Sexuales , Maduración Sexual/fisiologíaRESUMEN
The medial amygdala is important in social behaviors, many of which differ between males and females. The posterodorsal subnucleus of the medial amygdala (MeApd) is particularly sensitive to gonadal steroid hormones and is a likely site for gonadal hormone regulation of sexually dimorphic social behavior. Here we show that the synaptic organization of the MeApd in the rat is sexually dimorphic and lateralized before puberty. With the use of whole-cell voltage-clamp recording and quantitative electron microscopy, we found that, specifically in the left hemisphere, prepubertal males have approximately 80% more excitatory synapses per MeApd neuron than females. In the left but not the right MeApd, miniature EPSC (mEPSC) frequency was significantly greater in males than in females; mEPSC amplitude was not sexually dimorphic. Paired-pulse facilitation of EPSCs, an index of release probability, also was not sexually dimorphic, suggesting that greater mEPSC frequency is caused by a difference in excitatory synapse number. Electron microscopy confirmed that the asymmetric synapse-to-neuron ratio and the total asymmetric synapse number were significantly greater in the left MeApd of males than of females. In contrast to results for excitatory synapses, we found no evidence of sexual dimorphism or laterality in inhibitory synapses. Neither the frequency nor the amplitude of mIPSCs was sexually dimorphic or lateralized. Likewise, the number of symmetric synapses measured with electron microscopy was not sexually dimorphic. These findings show that the excitatory synaptic organization of the left MeApd is sexually differentiated before puberty, which could provide a sexually dimorphic neural substrate for the effects of hormones on adult social behavior.
Asunto(s)
Amígdala del Cerebelo/crecimiento & desarrollo , Amígdala del Cerebelo/ultraestructura , Caracteres Sexuales , Sinapsis/fisiología , Sinapsis/ultraestructura , Animales , Femenino , Masculino , Ratas , Ratas Sprague-Dawley , Transmisión Sináptica/fisiologíaRESUMEN
Nuclei in the amygdala and bed nuclei of the stria terminalis (BST) form functionally organized units that are linked by topographically organized connections. The posterodorsal part of the medial nucleus of the amygdala (MEApd) and the principal nucleus of the BST (BSTpr) share strong birectional connections that project primarily through the stria terminalis. The presence of structural and neurochemical sexual dimorphisms in both the MEApd and BSTpr suggests that connections between the nuclei may develop during the postnatal critical period for sexual differentiation. In this study, 1,1'dioctadecyl-3,3,3'-tetramethylindocarbocyanine perchlorate (DiI) axonal labeling was used to define the ontogeny of this bidirectional pathway. Placement of DiI crystals into the MEApd of rats perfused on embryonic day (E) 20 resulted in DiI-labeled fibers with axonal morphology in the BSTpr, but similar labeling was not evident in the MEApd until after birth. However, as early as E14, tracer implants into the caudal MEA (the presumptive MEApd) labeled elongated cellular processes in the region of the stria terminalis that extended into the presumptive BSTpr. Based on the correspondence of these DiI-labeled processes with immunostaining for vimentin, these cellular processes are probably derived from glial cells. Implants of DiI into the posterior BST also labeled cellular processes that extended through the medial part of the stria terminalis, but they remained confined to the molecular layer of the MEApd from E14 through P1. Labeled axons derived from the BSTpr were not observed in the MEApd until P5, demonstrating that the bidirectional connections that exist between the MEApd and BSTpr in mature rats do not develop simultaneously. The density of connections between the BSTpr and MEApd increased during the postnatal period and was similar to that of adults by P15. These findings suggest that projections from the MEApd through the stria terminalis to the BSTpr may be specified initially by a glial substrate and that return projections to the amygdala from the BSTpr develop secondary to its innervation by the MEApd.
Asunto(s)
Amígdala del Cerebelo/crecimiento & desarrollo , Vías Nerviosas/crecimiento & desarrollo , Núcleos Septales/crecimiento & desarrollo , Amígdala del Cerebelo/citología , Animales , Animales Recién Nacidos , Biomarcadores , Colorantes , Femenino , Proteína Ácida Fibrilar de la Glía/metabolismo , Inmunohistoquímica , Masculino , Vías Nerviosas/citología , Proteínas de Neurofilamentos/metabolismo , Embarazo , Ratas , Ratas Sprague-Dawley , Núcleos Septales/citología , Caracteres Sexuales , Vimentina/metabolismoRESUMEN
This review focuses on the effect of gonadal steroid hormones, androgen and estrogen, on dendrites in the adult rat central nervous system (CNS). Four hormone-responsive nuclei are considered: The spinal nucleus of the bulbocavernosus (SNB), the medial nucleus of the amygdala (MeA), the ventromedial nucleus of the hypothalamus (VMN), and the CA1 region of the dorsal hippocampus. Particular emphasis is placed on the mode of hormone action in each nucleus. In the SNB, VMN, and hippocampus, hormones appear to mediate their effects indirectly, via cells other than those that display morphological plasticity. In the MeA, estrogen and/or androgen appears to act primarily on those cells whose dendrites are modulated by the hormone. Importantly, increasing levels of gonadal hormones do not simply result in increases in dendritic parameters. In the VMN, high levels of estrogen associated with proestrus increase dendritic spine density in one subset of cells and reduce spine density in another subset. The pyramidal cells of dorsal CA1 also undergo phasic changes in dendritic spine and synapse density across the estrous cycle. The estrogen-induced excitatory synapses connect with preexisting axonal boutons that also form synapses with other CA1 cells, thereby increasing the divergence of excitatory afferents to dorsal CA1. These findings indicate that gonadal steroids have a profound impact on the morphology of dendrites and patterns of synaptic connectivity. Consequently, the experimental manipulation of hormone levels is a powerful tool to study structure-function relationships in the mammalian brain.
Asunto(s)
Sistema Nervioso Central/citología , Dendritas/fisiología , Hormonas Gonadales/fisiología , Neuronas/citología , Animales , Aprendizaje por Laberinto/fisiología , Modelos Biológicos , Plasticidad Neuronal/fisiología , Neuronas/fisiología , Caracteres Sexuales , Factores de TiempoRESUMEN
In male rats, a steroid-sensitive circuit in the forebrain regulates mating behavior. The masculine phenotype in one component of the circuit, the posterodorsal nucleus of the medial amygdala (MePD), depends on the level of circulating androgens in the adult. To investigate which gonadal steroid receptor(s) mediate sexual arousal and MePD plasticity, adult male rats were castrated and given Silastic capsules containing the nonaromatizable androgen 5alpha-dihydrotestosterone (DHT), 17beta-estradiol (E2), both steroids, or nothing. A fifth group was sham-castrated and treated with blank capsules. DHT treatment was necessary and sufficient to maintain the expression of noncontact penile erections and ultrasonic vocalizations in castrates. E2 had no significant effect on these measures. Both DHT and E2 increased olfactory investigation ("nosepokes") during the noncontact penile erection test. E2, but not DHT, maintained intromission patterns, while either steroid, alone or in combination, maintained ejaculatory behavior. Regional volume and cell soma size of the MePD both decreased following castration. Additionally, MePD cell size was lateralized, with left hemisphere neurons larger than those on the right, an effect that appeared independent of steroid manipulations. DHT and E2 each maintained neuronal soma size. E2 maintained MePD regional volume more effectively in the left MePD than in the right, which may have been due to a greater sensitivity of the left to both castration and hormone treatment. Thus, both androgen receptors and estrogen receptors appear to participate in sexual behaviors that may be mediated by the MePD in adult rats, and both receptors contribute to the steroid-regulated structural plasticity in this brain region.