Heather M. Jessen

Postmenopausal Increase in KiSS-1, GPR54, and Luteinizing Hormone Releasing Hormone (LHRH-1) mRNA in the Basal Hypothalamus of Female Rhesus Monkeys

The G-protein coupled receptor, GPR54, and its ligand, kisspeptin-54 (a KiSS-1 derived peptide) have been reported to be important players in control of LHRH-1 release. However, the role of the GPR54 signaling in primate reproductive senescence is still unclear. In the present study we investigated whether KiSS-1, GPR54, and LHRH-1 mRNA in the brain change after menopause in female rhesus monkeys using quantitative real-time PCR. Results indicate that KiSS-1, GPR54, and LHRH-1 mRNA levels in the medial basal hypothalamus (MBH) in postmenopausal females (28.3+/-1.1 years of age, n=5) were all significantly higher than that in eugonadal adult females (14.7+/-2.1 years of age, n=9), whereas KiSS-1, GPR54, and LHRH-1 mRNA levels in the preoptic area (POA) did not have any significant changes between the two age groups. To further determine the potential contribution by the absence of ovarian steroids, we compared the changes in KiSS-1, GPR54, and LHRH-1 mRNA levels in young adult ovarian intact vs. young ovariectomized females. Results indicate that KiSS-1 and LHRH-1 mRNA levels in the MBH, not POA, in ovariectomized females were significantly higher than those in ovarian intact females, whereas GPR54 mRNA levels in ovariectomized females had a tendency to be elevated in the MBH, although the values were not quite statistically significant. Collectively, in the primate the reduction in the negative feedback control by ovarian steroids appears to be responsible for the aging changes in kisspeptin-GPR54 signaling and the elevated state of the LHRH-1 neuronal system.

Sex differences in epigenetic mechanisms may underlie risk and resilience for mental health disorders.

Alterations in the epigenetic programming of sex differences in the brain may underlie sexually dimorphic neurodevelopmental disorders. Sex differences have been found in DNA methyltransferases 3a, DNA methylation patterns, MeCP2, and nuclear corepressor within the developing brain. Natural variations in these epigenetic mechanisms have profound consequences on gene expression and brain function. Exogenous or endogenous perturbations during development may impact these epigenetic processes and alter the trajectory of the developing brain and confer sexually dimorphic risk and resilience for developing a neurological or mental health disorder.

Altered gene expression in mice selected for high maternal aggression.

We previously applied selective breeding on outbred mice to increase maternal aggression (maternal defense). In this study, we compared gene expression within a continuous region of the central nervous system (CNS) involved in maternal aggression (hypothalamus and preoptic regions) between lactating selected (S) and nonselected control (C) mice (n= 6 per group). Using microarrays representing over 40 000 genes or expressed sequence tags, two statistical algorithms were used to identify significant differences in gene expression: robust multiarray and the probe logarithmic intensity error method. Approximately 200 genes were identified as significant using an intersection from both techniques. A subset of genes was examined for confirmation by real‐time polymerase chain reaction (PCR). Significant decreases were found in S mice for neurotensin and neuropeptide Y receptor Y2 (both confirmed by PCR). Significant increases were found in S mice for neuronal nitric oxide synthase (confirmed by PCR), the K+ channel subunit, Kcna1 (confirmed by PCR), corticotrophin releasing factor binding protein (just above significance using PCR; P= 0.051) and GABA A receptor subunit 1A (not confirmed by PCR, but similar direction). S mice also exhibited significantly higher levels of the neurotransmitter receptor, adenosine A1 receptor and the transcription factors, c‐Fos, and Egr‐1. Interestingly, for 24 genes related to metabolism, all were significantly elevated in S mice, suggesting altered metabolism in these mice. Together, this study provides a list of candidate genes (some previously implicated in maternal aggression and some novel) that may play an important role in the production of this behavior.

The Nuclear Receptor Corepressor Has Organizational Effects within the Developing Amygdala on Juvenile Social Play and Anxiety-Like Behavior

Nuclear receptor function on DNA is regulated by the balanced recruitment of coregulatory complexes. Recruited proteins that increase gene expression are called coactivators, and those that decrease gene expression are called corepressors. Little is known about the role of corepressors, such as nuclear receptor corepressor (NCoR), on the organization of behavior. We used real-time PCR to show that NCoR mRNA levels are sexually dimorphic, that females express higher levels of NCoR mRNA within the developing amygdala and hypothalamus, and that NCoR mRNA levels are reduced by estradiol treatment. To investigate the functional role of NCoR on juvenile social behavior, we infused small interfering RNA targeted against NCoR within the developing rat amygdala and assessed the enduring impact on juvenile social play behavior, sociability, and anxiety-like behavior. As expected, control males exhibited higher levels of juvenile social play than control females. Reducing NCoR expression during development further increased juvenile play in males only. Interestingly, decreased NCoR expression within the developing amygdala had lasting effects on increasing juvenile anxiety-like behavior in males and females. These data suggest that the corepressor NCoR functions to blunt sex differences in juvenile play behavior, a sexually dimorphic and hormone-dependent behavior, and appears critical for appropriate anxiety-like behavior in juvenile males and females.

Epigenetic organization of brain sex differences and juvenile social play behavior

The study of epigenetic mechanisms is important for elucidating how gene-by-environment interactions can have lasting outcomes on brain function and behavior. In general, studies of epigenetic processes mainly focus on the methylation status of DNA. While methylation of DNA alone can interfere with gene transcription, it is the binding of methyl-CpG binding proteins to methylated DNA, and subsequent recruitment of nuclear corepressors and histone deacetylases, that results in more efficient gene repression. In this review, we will discuss sex differences in DNA methylation patterns, methyl binding proteins, and corepressor proteins that contribute to lasting differences in brain and juvenile behavior. Specifically, we will discuss new data on sex differences in ERα DNA promoter methylation patterns, and the role of MeCP2 and the nuclear corepressor, NCoR, on the organization of juvenile social play behavior.

Indicators of developmental deviance in individuals at risk for schizophrenia

Schizophrenia is generally conceptualized as a neurodevelopmental disorder. In order to examine psychometrically-identified individuals at risk for schizophrenia in terms of indicators of developmental deviance, we examined digit ratios, nailfold plexus visibility, and dermatoglyphic features in young adults with elevated scores on the Social Anhedonia Scale. These individuals were compared to an age-matched control group. The two groups did not differ in terms of their digit ratios, though across both groups, the males had significantly lower 2D:4D ratios than the females. The socially anhedonic group had a significantly higher prevalence of nailfold plexus visibility. Males reporting excessive social anhedonia exhibited significantly lower a-b ridge counts than controls, though the two groups did not differ in terms of finger ridge counts. Study findings indicate that relationships exist between some indicators of nonspecific developmental injury and negative schizotypy, especially in males.

Corepressors, nuclear receptors, and epigenetic factors on DNA: A tail of repression

The differential exposure to circulating steroid hormones during brain development can have lasting consequences on brain function and behavior; therefore, the tight control of steroid hormone action within the developing brain is necessary for the expression of appropriate sex-typical behavior patterns later in life. The restricted control of steroid hormone action at the level of the DNA can be accomplished through the recruitment of coregulatory complexes. Nuclear receptor action can either be enhanced by the recruitment of coactivator complexes or suppressed by the formation of corepressor complexes. Alternatively, the regulation of nuclear receptor-mediated gene transcription in the developing brain may involve a dynamic process of coactivator and corepressor function on DNA. It is likely that understanding how different combinations of coregulatory matrixes assembly on DNA will lead to further understanding of heterogeneous responses to nuclear receptor activation. We will discuss how coregulators influence gene transcription and repression, the role of chromatin-binding factors in the regulation of gene transcription, and their potential impact on brain development.

Microarray profiling of gene expression patterns in adult male rat brain following acute progesterone treatment

Progesterone can influence various behaviors in adult male rats, however, little is known about which particular genes are regulated by progesterone in the male rat brain. Using focused microarray technology, we where able to define a subset of genes that are responsive to progesterone. Nylon membrane-based cDNA microarrays were used to profile gene expression patterns in the preoptic area/mediobasal hypothalamus (POA/MBH) of male rat brain 7 h following a single injection of progesterone. RNA was isolated from the brains of 6 male rats injected with progesterone and 6 male rats injected with sesame oil. Next, we hybridized the RNA from each animal to individual cDNA microarrays that contained more than 100 target genes, all of which are involved in cAMP and or calcium signaling pathways. Direct side-by-side comparison of all 12 arrays revealed differences in the expression patterns of 12 different genes. We confirmed the data gathered from the arrays on 4 different genes using Real-Time PCR. These data begin to outline the important role played by progesterone in mediating changes in gene expression within the male brain.

Erratum to “Microarray profiling of gene expression patterns in adult male rat brain following acute progesterone treatment” [Brain Res. 1067 (2006) 58–66]

Erratum to “Microarray profiling of gene expression patterns in adult male rat brain following acute progesterone treatment” [Brain Res. 1067 (2006) 58–66] Catherine J. Auger⁎, Heather M. Jessen, Anthony P. Auger Department of Zoology, Birge Hall, 430 Lincoln Drive, University of Wisconsin, Madison, WI 53706, USA Department of Psychology, W.J. Brogden Hall, 1202 West Johnson Street, Madison, WI 53706, USA