Proestrous compared to diestrous wildtype, but not estrogen receptor beta knockout, mice have better performance in the spontaneous alternation and object recognition tasks and reduced anxiety-like behavior in the elevated plus and mirror maze

The Centers for Neuroscience, The University at Albany – State University of New York, Albany, NY, USA
Behavioural brain research (Impact Factor: 3.39). 01/2009; 196(2):254-260. DOI: 10.1016/j.bbr.2008.09.016

ABSTRACT 17β-Estradiol (E2) may influence cognitive and/or affective behavior in part via the β isoform of the estrogen receptor (ERβ). Endocrine status and behavior in cognitive (object recognition, T-maze), anxiety (open field, elevated plus maze, mirror maze, emergence), and motor/coordination (rotarod, activity chamber) tasks of proestrous and diestrous wildtype (WT) and ERβ knockout (βERKO) mice was examined. Proestrous (WT or βERKO), versus diestrous, mice had higher E2 and progestin levels in plasma, hippocampus, and cortex. The only effect of genotype on hormone levels was for corticosterone, such that βERKO mice had higher concentrations of corticosterone than did WT mice. Proestrous WT, but not βERKO, mice had improved performance in the object recognition (greater percentage of time with novel object) and T-maze tasks (greater percentage of spontaneous alternations) and less anxiety-like behavior in the plus maze (increased duration on open arms) and mirror chamber task (increased duration in mirror) than did diestrous mice. This pattern was not seen in the rotarod, open field, or activity monitor, suggesting effects may be specific to affective and cognitive behavior, rather than motor behavior/coordination. Thus, enhanced performance in cognitive tasks and anti-anxiety-like behavior of proestrous mice may require actions of ERβ in the hippocampus and/or cortex.

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    • "involved in allopregnanolone metabolism and biosynthesis, as well as these neurotransmitter targets, but also revealed a novel target of interest, the pregnane xenobiotic receptor (PXR; Frye and Walf, 2008; Frye, 2009). The findings to date about this novel target in the midbrain are described as follows. "
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    ABSTRACT: Neurosteroids are cholesterol-based hormones that can be produced in the brain, independent of secretion from peripheral endocrine glands, such as the gonads and adrenals. A focus in our laboratory for over 25 years has been how production of the pregnane neurosteroid, allopregnanolone, is regulated and the novel (i.e., non steroid receptor) targets for steroid action for behavior. One endpoint of interest has been lordosis, the mating posture of female rodents. Allopregnanolone is necessary and sufficient for lordosis, and the brain circuitry underlying it, such as actions in the midbrain ventral tegmental area (VTA), has been well-characterized. Published and recent findings supporting a dynamic role of allopregnanolone are included in this review. First, contributions of ovarian and adrenal sources of precursors of allopregnanolone, and the requisite enzymatic actions for de novo production in the central nervous system will be discussed. Second, how allopregnanolone produced in the brain has actions on behavioral processes that are independent of binding to steroid receptors, but instead involve rapid modulatory actions via neurotransmitter targets (e.g., γ-amino butyric acid-GABA, N-methyl-D-aspartate- NMDA) will be reviewed. Third, a recent focus on characterizing the role of a promiscuous nuclear receptor, pregnane xenobiotic receptor (PXR), involved in cholesterol metabolism and expressed in the VTA, as a target for allopregnanolone and how this relates to both actions and production of allopregnanolone will be addressed. For example, allopregnanolone can bind PXR and knocking down expression of PXR in the midbrain VTA attenuates actions of allopregnanolone via NMDA and/or GABAA for lordosis. Our understanding of allopregnanolone's actions in the VTA for lordosis has been extended to reveal the role of allopregnanolone for broader, clinically-relevant questions, such as neurodevelopmental processes, neuropsychiatric disorders, epilepsy, and aging.
    Frontiers in Cellular Neuroscience 04/2014; 8:106. DOI:10.3389/fncel.2014.00106 · 4.18 Impact Factor
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    • "However, administration of agonists that selectively activate either estrogen receptor ␣ or ␤ have been show to enhance performance on object placement tasks, which also rely on detection of spatial novelty [8] [18] [23]. Furthermore, when levels of estradiol are elevated, expression of estrogen receptor ␤ was necessary for enhancements in spatial cognition to occur on an object location task [23] and a spontaneous spatial alternation task [35]. Therefore, in addition to GPR30, both the estrogen receptor ␣ and ␤ isoforms impact learning and memory on tasks that rely upon the detection of spatial novelty. "
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    ABSTRACT: In ovariectomized rats, administration of estradiol, or selective estrogen receptor agonists that activate either the α or β isoforms, have been shown to enhance spatial cognition on a variety of learning and memory tasks, including those that capitalize on the preference of rats to seek out novelty. Although the effects of the putative estrogen G-protein-coupled receptor 30 (GPR30) on hippocampus-based tasks have been reported using food-motivated tasks, the effects of activation of GPR30 receptors on tasks that depend on the preference of rats to seek out spatial novelty remain to be determined. Therefore, the aim of the current study was to determine if short-term treatment of ovariectomized rats with G-1, an agonist for GPR30, would mimic the effects on spatial recognition memory observed following short-term estradiol treatment. In Experiment 1, ovariectomized rats treated with a low dose (1μg) of estradiol 48h and 24h prior to the information trial of the Y-maze task exhibited a preference for the arm associated with the novel environment on the retention trial conducted 48h later. In Experiment 2, treatment of ovariectomized rats with G-1 (25μg) 48h and 24h prior to the information trial of the Y-maze task resulted in a greater preference for the arm associated with the novel environment on the retention trial. Collectively, the results indicated that short-term treatment of ovariectomized rats with a GPR30 agonist was sufficient to enhance spatial recognition memory, an effect that also occurred following short-term treatment with a low dose of estradiol.
    Behavioural brain research 01/2014; DOI:10.1016/j.bbr.2014.01.006 · 3.39 Impact Factor
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    • "e l s e v i e r . c o m / l o c a t e / y h b e h during proestrous, female rodents spend more time in the open arms of the EPM than when E levels are low during diestrous (Marcondes et al., 2001; Walf et al., 2009; Zuloaga et al., 2011a). Likewise, E-treated females enter the center area of an OF more often and spend more time in the open arms of an EPM than do untreated females (Walf et al., 2008), while females given inhibitors of estrogen biosynthesis show more anxiety-related behavior in the OF and EPM (Meng et al., 2011; however, Morgan and Pfaff, 2002). "
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    ABSTRACT: Men are less likely than women to suffer from anxiety disorders. Because gonadal hormones play a crucial role in many behavioral sex differences, they may underlie sex differences in human anxiety. In rodents, testosterone (T) exerts anxiolytic effects via the androgen receptor (AR): we found that male mice with a naturally-occurring mutation rendering the AR dysfunctional, referred to as spontaneous testicular feminization mutation (sTfm), showed more anxiety-like behaviors than wildtype (WT) males. Here, we used CreLox recombination technology to create another dysfunctional allele for AR. These induced Tfm (iTfm) animals also displayed more anxiety-like behaviors than WTs. We further found that AR-modulation of these behaviors interacts with circadian phase. When tested in the resting phase, iTfms appeared more anxious than WTs in the open field, novel object and elevated plus maze tests, but not the light/dark box. However, when tested during the active phase (lights off), iTfms showed more anxiety-related behavior than WTs in all four tests. Finally, we confirmed a role of T acting via AR in regulating HPA axis activity, as WT males with T showed a lower baseline and overall corticosterone response, and a faster return to baseline following mild stress than did WT males without T or iTfms. These findings demonstrate that this recombined AR allele is a valuable model for studying androgenic modulation of anxiety, that the anxiolytic effects of AR in mice are more prominent in the active phase, and that HPA axis modulation by T is AR dependent.
    Hormones and Behavior 01/2014; DOI:10.1016/j.yhbeh.2014.01.001 · 4.51 Impact Factor
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