ETS gene Er81 controls the formation of functional connections between group Ia sensory afferents and motor neurons.

The connections formed between sensory and motor neurons (MNs) play a critical role in the control of motor behavior. During development, the axons of proprioceptive sensory neurons project into the spinal cord and form both direct and indirect connections with MNs. Two ETS transcription factors, ER81 and PEA3, are expressed by developing proprioceptive neurons and MNs, raising the possibility that these genes are involved in the formation of sensory-motor connections. Er81 mutant mice exhibit a severe motor discoordination, yet the specification of MNs and induction of muscle spindles occurs normally. The motor defect in Er81 mutants results from a failure of group Ia proprioceptive afferents to form a discrete termination zone in the ventral spinal cord. As a consequence there is a dramatic reduction in the formation of direct connections between proprioceptive afferents and MNs. ER81 therefore controls a late step in the establishment of functional sensory-motor circuitry in the developing spinal cord.

Effects of testosterone and progesterone on brain 5alpha-reductase and aromatase in Long-Evans males and comparison of aromatase in Long-Evans vs. Sprague-Dawley rats.

We investigated medial basal hypothalamic-preoptic area (MBH-POA) 5alpha-reductase and aromatase enzyme activities in gonadally intact and castrated adult Long-Evans (L-E) male rats treated with testosterone (T), progesterone (P), and a combination of T+P. MBH-POA 5alpha-reductase and aromatase activities did not differ significantly among the groups. The lack of a difference in MBH-POA aromatase between control and castrated L-E animals was unexpected. In two further experiments, MBH-POA aromatase was examined in intact and castrated L-E and Sprague-Dawley (S-D) rats, using direct and indirect assays. The activity in castrated S-D (but again, not in L-E) rats significantly decreased compared to control values. These data suggest that the absence of gonads does not decrease MBH-POA aromatase in adult L-E rats.

Developmental expression of calretinin in the medial basal hypothalamus and amygdala from male and female rats.

Developmental expression of calretinin in the medial basal hypothalamic (MBH) and amygdala region was examined by Western analysis. Males displayed significantly higher calretinin levels compared to females in the MBH (but not the amygdala) on gestational day 19 and 20. These data imply that hormonal factors may regulate developmental MBH calretinin expression. In turn, sexually dimorphic brain structures might be influenced by calretinin levels that can alter sexually dimorphic patterns of steroidogenesis, cellular migration or programmed cell loss mechanism(s) during neuronal development by modulating intracellular calcium concentrations.

Aromatase cytochrome P450 and 5 alpha-reductase in the amygdala and cortex of perinatal rats.

The major androgen metabolizing enzymes, aromatase cytochrome P450 and 5 alpha-reductase play critical role(s) in the development of sexually dimorphic brain structures, the modulation of neuroendocrine function(s) and the regulation of sexual and non-sexual behaviors. Using established assays, we detected 5 alpha-reductase and aromatase enzymatic activities in amygdala and frontal cortical tissue from male and female rats during the perinatal interval (from gestational day (GD) 19 to postnatal day (PND) 6). The present findings indicate that 5 alpha-reductase and aromatase rates in the cortex display different enzyme profiles, while in the amygdala tissue site a similar pattern is seen for both enzymes during perinatal development. In general, there was a lack of sex differences in the enzymatic rates. The importance these enzyme systems play in generating androgen (and progesterone) steroid metabolites which influence neural development and function are discussed.

Calbindin-D28k is regulated by adrenal steroids in hypothalamic tissue during prenatal development.

Regulation of calbindin-D28k (CALB) in the medial basal hypothalamus (MBH) from male and female fetuses was examined by Western analysis. Control fetal males displayed significantly higher MBH CALB levels compared to females at gestational day 20. Whereas, in general, the lowest CALB levels were recorded in male and female fetuses from long-term prenatally stressed or fetuses from adrenalectomized pregnant rats. These data indicate that corticosterone regulates MBH CALB expression during prenatal development and CALB may be implicated in modulating the sexual differentiation of neural structures within the MBH during perinatal development.

Hypothalamic aromatase cytochrome P450 and 5alpha-reductase enzyme activities in pregnant and female rats.

The metabolism of steroid hormones in the medial basal hypothalamus (MBH) is known to play a critical role in neural development, the modulation of neuroendocrine function and regulating sexual behavior. While the important biological functions of the aromatase enzyme are well established, the importance of brain 5alpha-reductase has been revealed and elucidated only in the last few years. The distribution and regulation of brain aromatase and 5alpha-reductase enzyme activities have been investigated for the most part in male rats. Therefore, in the present study, MBH aromatase cytochrome P450 and 5alpha-reductase activities were characterized in pregnant and female rats during postnatal development under various hormonal conditions. MBH aromatase activity was determined in each tissue sample using the 'tritiated water release' assay, whereas, the 5alpha-reductase rates were determined by thin layer chromatography and scintillation counting of the isolated 5alpha-metabolites. Both activities were highest in infantile animals, then declined with increasing postnatal age; whereas, in aged non-cycling or ovariectomized/adrenalectomized (Ovx/Adx) rats high rates of androgen metabolism were seen in MBH tissue. No significant alterations in MBH aromatase were observed when the 5alpha-reductase pathway was blocked in pregnant animals during late gestation with a known 5alpha-reductase inhibitor (Proscar). However, plasma estradiol levels were significantly increased in the Proscar-treated animals. These results indicate that: 1) the decreasing MBH aromatase and 5alpha-reductase profile (in infantile to adult cycling animals) is developmentally regulated, 2) evidently, there is a divergent regulatory mechanism controlling MBH aromatase versus 5alpha-reductase in aged animals where the aromatase activity increased in aged non-cycling and Ovx/Adx rats while 5alpha-reductase rates remained at moderate levels and, 3) apparently, the 5alpha-reductase pathway is not involved in regulating MBH aromatase activity during late pregnancy.

Inhibition of brain 5 alpha-reductase in pregnant rats: effects on enzymatic and behavioral activity.

Medial basal hypothalamic (MBH) 5 alpha-reductase activity was significantly blocked with a known inhibitor, Proscar (Finasteride), in pregnant rats while their open-field behavior was quantified during the last week of pregnancy. In control animals, open-field behavior significantly decreased (in a stair-step fashion) as a function of increasing gestational age. Conversely, in Proscar-treated animals open-field values significantly increased on day 15 and 17 of gestation compared to control values. These data indicate that inhibition of MBH 5 alpha-reductase during pregnancy significantly increased open-field activity levels during late gestation in rats and provides evidence for a link between the production of 5 alpha-reduced metabolites of progesterone in brain and behavioral activity during pregnancy.