Karlie Intlekofer - Academia.edu (original) (raw)

Papers by Karlie Intlekofer

Bars represent mean ± SEM. (*Significantly different from cells treated with vehicle, &l... more Bars represent mean ± SEM. (*Significantly different from cells treated with vehicle, p<0.05; **significantly different from vehicle-treated, p<0.01; ***significantly different from vehicle-treated, p<0.0001).</p

Heat map of microarray data showing relative expression of genes found to be differentia... more Heat map of microarray data showing relative expression of genes found to be differentially expressed (p<0.05) in all three samples for each treatment (scramble siRNA or Pgrmc1 siRNA).</p

Progesterone membrane receptor component 1 (Pgrmc1) is a cytochrome b5-related protein with wide-... more Progesterone membrane receptor component 1 (Pgrmc1) is a cytochrome b5-related protein with wide-ranging functions studied most extensively in non-neural tissues. We previously demonstrated that Pgrmc1 is widely distributed in the brain with highest expression in the limbic system. To determine Pgrmc1 functions in cells of these regions, we compared transcriptomes of control siRNA-treated and Pgrmc1 siRNA-treated N42 hypothalamic cells using whole genome microarrays. Our bioinformatics analyses suggested that Pgrmc1 plays a role in immune functions and likely regulates proinflammatory cytokine signaling. In follow-up studies, we showed that one of these cytokines, TNFα, increased expression of rtp4, ifit3 and gbp4, genes found on microarrays to be among the most highly upregulated by Pgrmc1 depletion. Moreover, either Pgrmc1 depletion or treatment with the Pgrmc1 antagonist, AG-205, increased both basal and TNFα-induced expression of these genes in N42 cells. TNFα had no effect on levels of Rtp4, Ifit3 or Gbp4 mRNAs in mHippoE-18 hippocampal control cells, but Pgrmc1 knock-down dramatically increased basal and TNFα-stimulated expression of these genes. P 4 had no effect on gbp4, ifit3 or rtp4 expression or on the ability of Pgrmc1 to inhibit TNFα induction of these genes. However, a majority of the top upstream regulators of Pgrmc1 target genes were related to synthesis or activity of steroids, including P 4 , that exert neuroprotective effects. In addition, one of the identified Pgrmc1 targets was Nr4a1, an orphan receptor important for the synthesis of most steroidogenic molecules. Our findings indicate that Pgrmc1 may exert neuroprotective effects by suppressing TNFα-induced neuroinflammation and by regulating neurosteroid synthesis.

Policy Forum Should Participation in Clinical Trials be Mandated? 35

Frontiers in Neuroscience, 2013

I would like to thank Dr. Sandy Petersen, who has served as a supportive mentor and guided me thr... more I would like to thank Dr. Sandy Petersen, who has served as a supportive mentor and guided me through the doctorate and publishing process. Sandy has provided invaluable insight into my work while allowing me to explore many different techniques and approaches. Her ability to provide a challenging and creative work environment have allowed me to grow as a researcher and as an individual. I would like to thank my labmates, past and present, in the Petersen lab: Eser

One method to reduce caloric and sugar intake is non-nutritive sweeteners (NNS) such as acesulfam... more One method to reduce caloric and sugar intake is non-nutritive sweeteners (NNS) such as acesulfame K, aspartame and saccharin. These are additions to food and beverages that replace the sweet taste of sugar, but with negligible calories. Despite the theoretical application, a unified consensus is lacking regarding their use for weight management. On their own, NNS do not reduce weight [3], but an energy reduction can be achieved when used as a sugar substitute. This potential is undermined by an increasingly inflammatory rejection of NNS, complicated by the extrapolation of animal studies and conflation of correlation with causality.

2 • The neural mechanisms that underlie the fluctuations in muscle force during isometric contrac... more 2 • The neural mechanisms that underlie the fluctuations in muscle force during isometric contractions are not well characterized. • Specifically, the contribution of afferent feedback from stretch receptors to the fluctuations is not well established. • Muscle spindles can be excited with a vibratory stimulus of the tendon. Afferent projections from muscle spindles exert an excitatory effect on alpha motor neurons to the same muscle. • Tendon vibration may therefore alter the output of a pool of motor neurons acutely and affect the fluctuations in force. • The effect of chronic vibration on motor output variability is different depending on the muscle group (Yoshitake 2004, Shinohara 2004). • The purpose of this project was to examine the effect of acute tendon vibration on fluctuations in force during contractions of the knee extensor muscles in young healthy subjects

Molecular Pharmacology, 2011

Journal of Neuroendocrinology, 2013

Proceedings of the National Academy of Sciences of the United States of America, Sep 1, 2009

Sexually dimorphic brain nuclei underlie gender-specific neural functions and susceptibility to d... more Sexually dimorphic brain nuclei underlie gender-specific neural functions and susceptibility to disease, but the developmental basis of dimorphisms is poorly understood. In these studies, we focused on the anteroventral periventricular nucleus (AVPV), a nucleus that is larger in females and critical for the female-typical cyclic surge pattern of luteinizing hormone (LH) release. Sex differences in the size and function of the AVPV result from apoptosis that occurs preferentially in the developing male. To identify upstream pathways responsible for sexual differentiation of the AVPV, we used targeted apoptosis microarrays and in vivo and in vitro follow-up studies. We found that the tumor necrosis factor ␣ (TNF␣)-TNF receptor 2 (TNFR2)؊NFB cell survival pathway is active in postnatal day 2 (PND2) female AVPV and repressed in male counterparts. Genes encoding key members of this pathway were expressed exclusively in GABAergic neurons. One gene in particular, TNF receptor-associated factor 2 (TRAF2)-inhibiting protein (trip), was higher in males and it inhibited both TNF␣-dependent NFB activation and bcl-2 gene expression. The male AVPV also had higher levels of bax and bad mRNA, but neither of these genes was regulated by either TNF␣ or TRIP. Finally, the trip gene was not expressed in the sexually dimorphic nucleus of the preoptic area (SDN-POA), a nucleus in which apoptosis is higher in females than males. These findings form the basis of a new model of sexual differentiation of the AVPV that may also apply to the development of other sexually dimorphic nuclei.

The virtual mentor : VM, 2012

Proceedings of the National Academy of Sciences, 2009

Neuroscience, 2011

Recent work identified novel progestin signaling molecules, including progesterone receptor membr... more Recent work identified novel progestin signaling molecules, including progesterone receptor membrane component 1 (Pgrmc1), Pgrmc2, serpine mRNA binding protein 1 (Serbp1), progestin and adiponectin receptors 7 (Paqr7) and Paqr8. These molecules mediate rapid progesterone (P 4 ) effects in non-neural tissue and we recently mapped their expression in the brain. Many rapid effects of P 4 require 17β-estradiol (E 2 ) and P 4 priming; therefore, we examined the effects of ovarian hormones on the expression of these non-classical progestin signaling molecules. We focused specifically on the anteroventral periventricular nucleus (AVPV), the sexually dimorphic nucleus of the preoptic area (SDN-POA) and the ventrolateral portion of the ventromedial nucleus (VMNvl). These brain nuclei are important for female reproduction. Ovariectomized adult female rats were implanted with capsules containing sesame oil or E 2 , and injected 48 hours later with sesame oil or P 4 . Brains were collected eight hours later and RNA was isolated from the AVPV, SDN-POA and VMNvl. We assessed the effects of ovarian hormones on mRNA levels using quantitative polymerase chain reaction (QPCR). In the AVPV, Serbp1 mRNA levels were increased by P 4 in the presence of E 2 , and Paqr8 was downregulated by P 4 alone. In the SDN-POA, combined E 2 and P 4 increased Pgrmc1 and Serbp1 mRNA levels, and E 2 alone increased Paqr8 mRNA levels. Finally, in the VMNvl, P 4 increased mRNA levels encoding Pgrmc1, Pgrmc2 and Serbp1, and the combination of E 2 and P 4 increased Pgrmc1 and Serbp1 mRNA levels. Paqr7 was not regulated by E 2 or P 4 in any brain region examined. In summary, we showed that ovarian hormones regulate novel progestin signaling molecules in brain regions important for the neuroendocrine control of reproduction.

Neuroscience, 2011

Several lines of evidence suggest the existence of multiple progestin receptors that may account ... more Several lines of evidence suggest the existence of multiple progestin receptors that may account for rapid and delayed effects of progesterone in the CNS. The delayed effects have been long attributed to activation of the classical progestin receptor (Pgr). Recent studies have discovered novel progestin signaling molecules that may be responsible for rapid effects. These include progesterone receptor membrane component 1 (Pgrmc1), Pgrmc2, progestin and adipoQ receptor 7 (Paqr7) and Paqr8. The functions of these molecules have been investigated extensively in non-neural, but not in neural tissues, partly because it is unclear which are expressed in the brain and where they are expressed. To address these issues, we compared the distributions of mRNAs encoding Pgr, Pgrmc1, Pgrmc2, Paqr7 and Paqr8 using in situ hybridization with radiolabeled oligodeoxynucleotidyl probes in forebrain tissues of estradiol-treated female rats. We also examined the distribution of serpine mRNA binding protein 1 (Serbp1), a putative binding partner of Pgrmc1. Analyses of adjacent brain sections showed that the highest expression of mRNAs encoding Pgr, Pgrmc1, Pgrmc2 and Serbp1 was detected in several hypothalamic nuclei important for female reproduction. In contrast, expression patterns of Paqr7 and Paqr8 were low and homogeneous in the hypothalamus, and more abundant in thalamic nuclei. The neuroanatomical distributions of these putative progestin signaling molecules suggest that Pgrmc1 and Pgrmc2 may play roles in neuroendocrine functions while Paqr7 and Paqr8 are more likely to regulate sensory and cognitive functions.

Neuropsychopharmacology, 2013

We demonstrate that exercise enables hippocampal-dependent learning in conditions that are normal... more We demonstrate that exercise enables hippocampal-dependent learning in conditions that are normally subthreshold for encoding and memory formation, and depends on hippocampal induction of brain-derived neurotrophic factor (BDNF) as a key mechanism. Using a weak training paradigm in an object location memory (OLM) task, we show that sedentary mice are unable to discriminate 24 h later between familiar and novel object locations. In contrast, 3 weeks of prior voluntary exercise enables strong discrimination in the spatial memory task. Cognitive benefits of exercise match those attained with post-training sodium butyrate (NaB), a histone deacetylase (HDAC) inhibitor previously shown to enable subthreshold learning. We demonstrate that the enabling effects of exercise and NaB on subthreshold OLM learning are dependent on hippocampal BDNF upregulation, and are blocked by hippocampal infusion of BDNF short-interfering RNA. Exercise and NaB increased bdnf transcripts I and IV, and the increases were associated with BDNF promoter acetylation on H4K8 but not H4K12. These data provide support for the concept that exercise engages epigenetic control mechanisms and serves as a natural stimulus that operates in part like NaB and potentially other HDAC inhibitors, placing the brain into a state of readiness for plasticity.

Policy Forum Should Participation in Clinical Trials be Mandated? 35

Frontiers in Neuroscience, 2013

Molecular Pharmacology, 2011

Journal of Neuroendocrinology, 2013

Proceedings of the National Academy of Sciences of the United States of America, Sep 1, 2009

The virtual mentor : VM, 2012

Proceedings of the National Academy of Sciences, 2009

Neuroscience, 2011

Neuropsychopharmacology, 2013