Effect of gonadal steroid hormone levels during pubertal development on social behavior of adult mice toward pups and synaptic transmission in the rhomboid nucleus of the bed nucleus of the stria terminalis.

Sexually immature male mice exhibit parenting behavior toward unfamiliar pups; however, the percentage of males that engage in infanticidal behavior gradually increases with age. We previously reported that excitatory synaptic transmission of the rhomboid nucleus of the bed nucleus of the stria terminalis (BSTrh), a brain region implicated in infanticidal behavior, is reinforced during pubertal development. However, it remains unclear how gonadal steroid hormones mediate this behavioral transition and neural plastic change during pubertal development. Here we revealed that administration of either 17ß-estradiol (E2) or 5α-dihydrotestosterone (DHT) to gonadectomized mice during pubertal development induced infanticidal behavior in adulthood (about 7 weeks old). Next, we performed whole-cell patch clamp recording in the BSTrh to study the effect of gonadal steroid hormones on neural synaptic transmission. We found that E2 but not DHT administration during pubertal development considerably enhanced excitatory synaptic transmission in the BSTrh by increasing the probability of excitatory neurotransmitter release from the presynaptic terminalis. These data suggest that reinforcement of excitatory synaptic transmission by estrogen-receptor-dependent signaling in the BSTrh during puberty may contribute to the development of infanticidal behavior.

Functional synergy between cholecystokinin receptors CCKAR and CCKBR in mammalian brain development.

Cholecystokinin (CCK), a peptide hormone and one of the most abundant neuropeptides in vertebrate brain, mediates its actions via two G-protein coupled receptors, CCKAR and CCKBR, respectively active in peripheral organs and the central nervous system. Here, we demonstrate that the CCK receptors have a dynamic and largely reciprocal expression in embryonic and postnatal brain. Using compound homozygous mutant mice lacking the activity of both CCK receptors, we uncover their additive, functionally synergistic effects in brain development and demonstrate that CCK receptor loss leads to abnormalities of cortical development, including defects in the formation of the midline and corpus callosum, and cortical interneuron migration. Using comparative transcriptome analysis of embryonic neocortex, we define the molecular mechanisms underlying these defects. Thus we demonstrate a developmental, hitherto unappreciated, role of the two CCK receptors in mammalian neocortical development.

Dynamic postnatal developmental and sex-specific neuroendocrine effects of prenatal polychlorinated biphenyls in rats.

Gestational exposures to estrogenic compounds, both endogenous hormones and exogenous endocrine-disrupting chemicals (EDCs), have long-term effects on reproductive physiology and behavior. We tested the hypothesis that prenatal treatment of rats with low doses of Aroclor 1221 (A1221), a weakly estrogenic polychlorinated biphenyl mix previously used in industry, or estradiol benzoate (EB), alters development of the hypothalamus in a sexually dimorphic manner and subsequently perturbs reproductive function. Pregnant Sprague-Dawley rats were injected on embryonic days 16 and 18 with vehicle (dimethylsulfoxide), A1221 (1 mg/kg), or EB (50 µg/kg). Developmental milestones were monitored, and on postnatal days 15, 30, 45, and 90, 1 male and 1 female per litter were euthanized. Because of their key roles in the mediation of steroid actions on reproductive function, the anteroventral periventricular nucleus (AVPV) and the arcuate nucleus (ARC) were punched for a low-density quantitative PCR array of 48 neuroendocrine genes and analysis of DNA methylation of a subset of genes. Gestational exposure to A1221 or EB delayed the timing of puberty in males and disrupted estrous cyclicity in females. In the AVPV, 28 genes were affected by treatment in a developmental stage-specific manner, mostly in females, which exhibited a masculinized expression profile. This included 2 clock genes, Per2 and Arntl, implicating circadian circuits as being vulnerable to endocrine disruption. DNA methylation analysis of 2 genes, Per2 and Ar, showed no effect of EDCs and suggested alternative mechanisms for the altered mRNA levels. In the ARC, 12 genes were affected by treatment, mostly in males, again with dynamic developmental changes. Bionetwork analysis of relationships among genes, hormones, and physiological markers showed sexually dimorphic effects of estrogenic EDC exposures, with the female AVPV and the male ARC being most vulnerable, and provided novel relationships among hypothalamic genes and postnatal reproductive maturation.

Assembly of the auditory circuitry by a Hox genetic network in the mouse brainstem.

Rhombomeres (r) contribute to brainstem auditory nuclei during development. Hox genes are determinants of rhombomere-derived fate and neuronal connectivity. Little is known about the contribution of individual rhombomeres and their associated Hox codes to auditory sensorimotor circuitry. Here, we show that r4 contributes to functionally linked sensory and motor components, including the ventral nucleus of lateral lemniscus, posterior ventral cochlear nuclei (VCN), and motor olivocochlear neurons. Assembly of the r4-derived auditory components is involved in sound perception and depends on regulatory interactions between Hoxb1 and Hoxb2. Indeed, in Hoxb1 and Hoxb2 mutant mice the transmission of low-level auditory stimuli is lost, resulting in hearing impairments. On the other hand, Hoxa2 regulates the Rig1 axon guidance receptor and controls contralateral projections from the anterior VCN to the medial nucleus of the trapezoid body, a circuit involved in sound localization. Thus, individual rhombomeres and their associated Hox codes control the assembly of distinct functionally segregated sub-circuits in the developing auditory brainstem.

Accelerated postnatal growth increases lipogenic gene expression and adipocyte size in low-birth weight mice.

OBJECTIVE: To characterize the hormonal milieu and adipose gene expression in response to catch-up growth (CUG), a growth pattern associated with obesity and diabetes risk, in a mouse model of low birth weight (LBW). RESEARCH DESIGN AND METHODS: ICR mice were food restricted by 50% from gestational days 12.5-18.5, reducing offspring birth weight by 25%. During the suckling period, dams were either fed ad libitum, permitting CUG in offspring, or food restricted, preventing CUG. Offspring were killed at age 3 weeks, and gonadal fat was removed for RNA extraction, array analysis, RT-PCR, and evaluation of cell size and number. Serum insulin, thyroxine (T4), corticosterone, and adipokines were measured. RESULTS: At age 3 weeks, LBW mice with CUG (designated U-C) had body weight comparable with controls (designated C-C); weight was reduced by 49% in LBW mice without CUG (designated U-U). Adiposity was altered by postnatal nutrition, with gonadal fat increased by 50% in U-C and decreased by 58% in U-U mice (P < 0.05 vs. C-C mice). Adipose expression of the lipogenic genes Fasn, AccI, Lpin1, and Srebf1 was significantly increased in U-C compared with both C-C and U-U mice (P < 0.05). Mitochondrial DNA copy number was reduced by >50% in U-C versus U-U mice (P = 0.014). Although cell numbers did not differ, mean adipocyte diameter was increased in U-C and reduced in U-U mice (P < 0.01). CONCLUSIONS: CUG results in increased adipose tissue lipogenic gene expression and adipocyte diameter but not increased cellularity, suggesting that catch-up fat is primarily associated with lipogenesis rather than adipogenesis in this murine model.

Neonatal stimulation of 5-HT(2) receptors reduces androgen receptor expression in the rat anteroventral periventricular nucleus and sexually dimorphic preoptic area.

Masculinization of the brain is dependent upon a perinatal surge in testosterone. It also requires a transient decrease in hypothalamic 5-HT concentration and turnover and an increase in androgen receptor (AR) expression during the second postnatal week. We have previously shown that increasing 5-HT activity over this period in male or androgenized female rats feminizes their adult behaviour and also feminizes the size of their anteroventral periventricular nucleus (AVPV) and sexually dimorphic nucleus of the preoptic area (SDN-POA). To investigate the role of 5-HT in sexual differentiation of the brain, 5-HT activity was raised over postnatal days 8-16 in male, female and androgenized female rats by daily administration of the 5-HT(2) receptor agonist (-)[2,5 dimethoxy-4-iodophenyl]-2-amino propane hydrochloride [(-)DOI]. By postnatal day 18, the size of the AVPV and SDN-POA was sexually dimorphic; their sizes were feminized by (-)DOI treatment. In the absence of (-)DOI treatment, there were significantly more AR-immunoreactive cells in the AVPV of males, and in the SDN-POA of males and androgenized females, than in those of females on postnatal day 18. (-)DOI treatment reduced the number of AR-immunoreactive cells in the AVPV and SDN-POA of males and androgenized females, but not of females, by postnatal day 18. These results suggest that 5-HT(2) receptor activation can influence sexual differentiation of the brain by controlling AR expression.

Characteristic of hypothalamic kisspeptin expression in the pubertal development of precocious female rats.

To investigate the potential role of kisspeptin in the advance onset of puberty in precocious puberty, model rats induced by danazol were used to study the developmental expression of hypothalamic kisspeptin. Kisspeptin immunoreactive cells were observed in the arcuate nucleus (ARC), periventricular nucleus (PeN) and preoptic area (POA) in model rats on the day of onset-puberty. On the day of post-puberty, however, the number of kisspeptin immunoreactive cells in ARC and PeN decreased while the number of those cells in POA increased. Kisspeptin immunoreactive cells were not detected in hypothalamus in both normal and model rats at their pre-puberty stages. Furthermore, the expression of hypothalamic Kiss-1 mRNA reached top on the day of onset-puberty in both of the normal and model rats, and the expression of Kiss-1 mRNA increased significantly in the model rats compared with those in the normal ones. Our results indicated that kisspeptin might involve in the advance onset of puberty in danazol induced female precocious model rats.