Search

Osmotic transport devices (OTDs) are forward osmosis membrane devices that we recently developed to remove accumulated fluid from swollen tissue, in-vivo, under severe conditions. As such, the relative volume of the fluid required to be removed and the volumetric flowrate may be two orders of magnitude less than the operating volume and tangential flowrate of the device. This makes it challenging to measure the rate of fluid flow from the swollen tissue. Here, we introduce a differential densimetry method for determining ultra-low volumetric flux through tissue samples. This technique uses two vibrating tube density sensors, one placed upstream of the membrane in contact with the tissue sample, and one placed downstream. Any flow of biological fluid withdrawn through the tissue will combine with the OTD operating fluid resulting in an observed density shift in the second density sensor. By measuring the difference in density between the upstream and downstream fluids, one can calculate the amount of fluid flowing across the tissue with a relatively high level of sensitivity. This method is also relatively insensitive to drift from temperature fluctuations and capable of continuously monitoring tissue permeability in real time. As a proof of concept, we used this technique to measure fluid flow across ex-vivo rat spinal tissue for an appropriately scaled OTD. The repeatability error had a maximum of only 12%. This implies that this method can provide highly acceptable flux measurements with reasonable reproducibility in real-time applications of fluid removal in-vivo.

Fragile X Syndrome (FXS) is a leading known genetic cause of intellectual disability with symptoms that include increased anxiety and social and sensory processing deficits. Recent electroencephalographic (EEG) studies in humans with FXS have identified neural oscillation deficits that include increased resting state gamma power, increased amplitude of auditory evoked potentials, and reduced phase locking of sound-evoked gamma oscillations. Similar EEG phenotypes are present in mouse models of FXS, but very little is known about the development of such abnormal responses. In the current study, we employed a 30-channel mouse multielectrode array (MEA) system to record and analyze resting and stimulus-evoked EEG signals in male P21 and P91 WT and Fmr1 KO mice. This led to several novel findings. First, P91, but not P21, Fmr1 KO mice have significantly increased resting EEG power in the low- and high-gamma frequency bands. Second, both P21 and P91 Fmr1 KO mice have markedly attenuated inter-trial phase coherence (ITPC) to spectrotemporally dynamic auditory stimuli as well as to 40 Hz and 80 Hz auditory steady-state response (ASSR) stimuli. This suggests abnormal temporal processing from early development that may lead to abnormal speech and language function in FXS. Third, we found hemispheric asymmetry of fast temporal processing in the mouse auditory cortex in WT but not Fmr1 KO mice. Together, these findings define a set of EEG phenotypes in young and adult mice that can serve as translational targets for genetic and pharmacological manipulation in phenotypic rescue studies., Competing Interests: Declaration of competing interest We report no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Edema formation following traumatic spinal cord injury (SCI) exacerbates secondary injury, and the severity of edema correlates with worse neurological outcome in human patients. To date, there are no effective treatments to directly resolve edema within the spinal cord. The aquaporin-4 (AQP4) water channel is found on plasma membranes of astrocytic endfeet in direct contact with blood vessels, the glia limitans in contact with the cerebrospinal fluid, and ependyma around the central canal. Local expression at these tissue-fluid interfaces allows AQP4 channels to play an important role in the bidirectional regulation of water homeostasis under normal conditions and following trauma. In this review, we consider the available evidence regarding the potential role of AQP4 in edema after SCI. Although more work remains to be carried out, the overall evidence indicates a critical role for AQP4 channels in edema formation and resolution following SCI and the therapeutic potential of AQP4 modulation in edema resolution and functional recovery. Further work to elucidate the expression and subcellular localization of AQP4 during specific phases after SCI will inform the therapeutic modulation of AQP4 for the optimization of histological and neurological outcomes.

Introduction: Mutations in the Fragile X Messenger Ribonucleoprotein 1 ( FMR1 ) gene cause Fragile X Syndrome, the most common monogenic cause of intellectual disability. Mutations of FMR1 are also associated with reproductive disorders, such as early cessation of reproductive function in females. While progress has been made in understanding the mechanisms of mental impairment, the causes of reproductive disorders are not clear. FMR1-associated reproductive disorders were studied exclusively from the endocrine perspective, while the FMR1 role in neurons that control reproduction was not addressed., Results: Here, we demonstrate that similar to women with FMR1 mutations, female Fmr1 null mice stop reproducing early. However, young null females display larger litters, more corpora lutea in the ovaries, increased inhibin, progesterone, testosterone, and gonadotropin hormones in the circulation. Ovariectomy reveals both hypothalamic and ovarian contribution to elevated gonadotropins. Altered mRNA and protein levels of several synaptic molecules in the hypothalamus are identified, indicating reasons for hypothalamic dysregulation. Increased vascularization of corpora lutea, higher sympathetic innervation of growing follicles in the ovaries of Fmr1 nulls, and higher numbers of synaptic GABA A receptors in GnRH neurons, which are excitatory for GnRH neurons, contribute to increased FSH and LH, respectively. Unmodified and ovariectomized Fmr1 nulls have increased LH pulse frequency, suggesting that Fmr1 nulls exhibit hyperactive GnRH neurons, regardless of the ovarian feedback., Conclusion: These results reveal Fmr1 function in the regulation of GnRH neuron secretion, and point to the role of GnRH neurons, in addition to the ovarian innervation, in the etiology of Fmr1 -mediated reproductive disorders., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Villa, Lainez, Jonak, Berlin, Ethell and Coss.)

Volume-regulated anion channels (VRACs) are a group of ubiquitously expressed outwardly-rectifying anion channels that sense increases in cell volume and act to return cells to baseline volume through an efflux of anions and organic osmolytes, including glutamate. Because cell swelling, increased extracellular glutamate levels, and reduction of the brain extracellular space (ECS) all occur during seizure generation, we set out to determine whether VRACs are dysregulated throughout mesial temporal lobe epilepsy (MTLE), the most common form of adult epilepsy. To accomplish this, we employed the IHKA experimental model of MTLE, and probed for the expression of LRRC8A, the essential pore-forming VRAC subunit, at acute, early-, mid-, and late-epileptogenic time points (1-, 7-, 14-, and 30-days post-IHKA, respectively). Western blot analysis revealed the upregulation of total dorsal hippocampal LRRC8A 14-days post-IHKA in both the ipsilateral and contralateral hippocampus. Immunohistochemical analyses showed an increased LRRC8A signal 7-days post-IHKA in both the ipsilateral and contralateral hippocampus, along with layer-specific changes 1-, 7-, and 30-days post-IHKA bilaterally. LRRC8A upregulation 1 day post-IHKA was observed primarily in astrocytes; however, some upregulation was also observed in neurons. Glutamate-GABA/glutamine cycle enzymes glutamic acid decarboxylase, glutaminase, and glutamine synthetase were also dysregulated at the 7-day timepoint post status epilepticus. The timepoint-dependent upregulation of total hippocampal LRRC8A and the possible subsequent increased efflux of glutamate in the epileptic hippocampus suggest that the dysregulation of astrocytic VRAC may play an important role in the development of epilepsy.

Background: Fragile X syndrome (FXS) is the most common inherited form of neurodevelopmental disability. It is often characterized, especially in males, by intellectual disability, anxiety, repetitive behavior, social communication deficits, delayed language development, and abnormal sensory processing. Recently, we identified electroencephalographic (EEG) biomarkers that are conserved between the mouse model of FXS (Fmr1 KO mice) and humans with FXS., Methods: In this report, we evaluate small molecule target engagement utilizing multielectrode array electrophysiology in the Fmr1 KO mouse and in humans with FXS. Neurophysiologic target engagement was evaluated using single doses of the GABA B selective agonist racemic baclofen (RBAC)., Results: In Fmr1 KO mice and in humans with FXS, baclofen use was associated with suppression of elevated gamma power and increase in low-frequency power at rest. In the Fmr1 KO mice, a baclofen-associated improvement in auditory chirp synchronization was also noted., Conclusions: Overall, we noted synchronized target engagement of RBAC on resting state electrophysiology, in particular the reduction of aberrant high frequency gamma activity, across species in FXS. This finding holds promise for translational medicine approaches to drug development for FXS, synchronizing treatment study across species using well-established EEG biological markers in this field., Trial Registration: The human experiments are registered under NCT02998151., (© 2022. The Author(s).)

Background: Individuals with Fragile X syndrome (FXS) and autism spectrum disorder (ASD) exhibit an array of symptoms, including sociability deficits, increased anxiety, hyperactivity, and sensory hyperexcitability. It is unclear how endocannabinoid (eCB) modulation can be targeted to alleviate neurophysiological abnormalities in FXS as behavioral research reveals benefits to inhibiting cannabinoid (CB) receptor activation and increasing endocannabinoid ligand levels. Here, we hypothesize that enhancement of 2-arachidonoyl-sn-glycerol (2-AG) in Fragile X mental retardation 1 gene knock-out (Fmr1 KO) mice may reduce cortical hyperexcitability and behavioral abnormalities observed in FXS., Methods: To test whether an increase in 2-AG levels normalized cortical responses in a mouse model of FXS, animals were subjected to electroencephalography (EEG) recording and behavioral assessment following treatment with JZL-184, an irreversible inhibitor of monoacylglycerol lipase (MAGL). Assessment of 2-AG was performed using lipidomic analysis in conjunction with various doses and time points post-administration of JZL-184. Baseline electrocortical activity and evoked responses to sound stimuli were measured using a 30-channel multielectrode array (MEA) in adult male mice before, 4 h, and 1 day post-intraperitoneal injection of JZL-184 or vehicle. Behavior assessment was done using the open field and elevated plus maze 4 h post-treatment., Results: Lipidomic analysis showed that 8 mg/kg JZL-184 significantly increased the levels of 2-AG in the auditory cortex of both Fmr1 KO and WT mice 4 h post-treatment compared to vehicle controls. EEG recordings revealed a reduction in the abnormally enhanced baseline gamma-band power in Fmr1 KO mice and significantly improved evoked synchronization to auditory stimuli in the gamma-band range post-JZL-184 treatment. JZL-184 treatment also ameliorated anxiety-like and hyperactivity phenotypes in Fmr1 KO mice., Conclusions: Overall, these results indicate that increasing 2-AG levels may serve as a potential therapeutic approach to normalize cortical responses and improve behavioral outcomes in FXS and possibly other ASDs., (© 2021. The Author(s).)

Fragile X syndrome (FXS) is a genetic neurodevelopmental syndrome characterized by increased anxiety, repetitive behaviors, social communication deficits, delayed language development, and abnormal sensory processing. Recently, we have identified electroencephalographic (EEG) biomarkers that are conserved between the mouse model of FXS (Fmr1 KO mice) and humans with FXS. In this study, we test a specific candidate mechanism for engagement of multielectrode array (MEA) EEG biomarkers in the FXS mouse model. We administered TAK-063, a potent, selective, and orally active phosphodiesterase 10A (PDE10A) inhibitor, to Fmr1 KO mice, and examined its effects on MEA EEG biomarkers. We demonstrate significant dose-related amelioration of inter-trial phase coherence (ITPC) to temporally modulated auditory stimuli by TAK-063 in Fmr1 KO mice. Our data suggest that TAK-063 improves cortical auditory stimulus processing in Fmr1 KO mice, without significantly depressing baseline EEG power or causing any noticeable sedation or behavioral side effects. Thus, the PDE10A inhibitor TAK-063 has salutary effects on normalizing EEG biomarkers in a mouse model of FXS and should be pursued in further translational treatment development., (© 2021. The American Society for Experimental NeuroTherapeutics, Inc.)

Recent findings from the ISCoPe study indicate that, after severe contusion to the spinal cord, edema originating in the spinal cord accumulates and compresses the tissue against the surrounding dura mater, despite decompressive laminectomy. It is hypothesized that this compression results in restricted flow of cerebrospinal fluid (CSF) in the subarachnoid space and central canal and ultimately collapses local vasculature, exacerbating ischemia and secondary injury. Here we developed a surgically mounted osmotic transport device (OTD) that rests on the dura and can osmotically remove excess fluid at the injury site. Tests were performed in 4-h studies immediately following severe (250 kD) contusion at T8 in rats using the OTD. A 3-h treatment with the OTD after 1-h post injury significantly reduced spinal cord edema compared to injured controls. A first approximation mathematical interpretation implies that this modest reduction in edema may be significant enough to relieve compression of local vasculature and restore flow of CSF in the region. In addition, we determined the progression of edema up to 28 days after insult in the rat for the same injury model. Results showed peak edema at 72 h. These preliminary results suggest that incorporating the OTD to operate continuously at the site of injury throughout the critical period of edema progression, the device may significantly improve recovery following contusion spinal cord injury., (Copyright © 2020 Hale, Yonan, Batarseh, Chaar, Jonak, Ge, Binder and Rodgers.)

Repeated non-diffuse optical imaging of the brain is difficult. This is due to the fact that the cranial bone is highly scattering and thus a strong optical barrier. Repeated craniotomies increase the risk of complications and may disrupt the biological systems being imaged. We previously introduced a potential solution in the form of a transparent ceramic cranial implant called the Window to the Brain (WttB) implant. This implant is made of nanocrystalline Yttria-Stabilized Zirconia (nc-YSZ), which possesses the requisite mechanical strength to serve as a permanent optical access window in human patients. In this present study, we demonstrate repeated brain imaging of n = 5 mice using both OCT and LSI across the WttB implant over 4 weeks. The main objectives are to determine if the WttB implant allows for chronic OCT imaging, and to shed further light on the question of whether optical access provided by the WttB implant remains stable over this duration in the body. The Window to the Brain implant allowed for stable repeated imaging of the mouse brain with Optical Coherence Tomography over 28 days, without loss of signal intensity. Repeated Laser Speckle Imaging was also possible over this timeframe, but signal to noise ratio and the sharpness of vessels in the images decreased with time. This can be partially explained by elevated blood flow during the first imaging session in response to trauma from the surgery, which was also detected by OCT flow imaging. These results are promising for long-term optical access through the WttB implant, making feasible chronic in vivo studies in multiple neurological models of brain disease., (Copyright © 2020 Halaney, Jonak, Liu, Davoodzadeh, Cano-Velázquez, Ehtiyatkar, Park, Binder and Aguilar.)

Fragile X Syndrome (FXS) is a leading known genetic cause of intellectual disability with symptoms that include increased anxiety and social and sensory processing deficits. Recent EEG studies in humans with FXS have identified neural oscillation deficits that include increased resting state gamma power, increased amplitude of auditory evoked potentials, and reduced inter-trial phase coherence of sound-evoked gamma oscillations. Identification of comparable EEG biomarkers in mouse models of FXS could facilitate the pre-clinical to clinical therapeutic pipeline. However, while human EEG studies have involved 128-channel scalp EEG acquisition, no mouse studies have been performed with more than three EEG channels. In the current study, we employed a recently developed 30-channel mouse multielectrode array (MEA) system to record and analyze resting and stimulus-evoked EEG signals in WT vs. Fmr1 KO mice. Using this system, we now report robust MEA-derived phenotypes including higher resting EEG power, altered event-related potentials (ERPs) and reduced inter-trial phase coherence to auditory chirp stimuli in Fmr1 KO mice that are remarkably similar to those reported in humans with FXS. We propose that the MEA system can be used for: (i) derivation of higher-level EEG parameters; (ii) EEG biomarkers for drug testing; and (ii) mechanistic studies of FXS pathophysiology., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Objective: Microcirculation plays a critical role in physiologic processes and several disease states. Laser speckle imaging (LSI) is a full-field, real-time imaging technique capable of mapping microvessel networks and providing relative flow velocity within the vessels. In this study, we demonstrate that LSI combine with multispectral reflectance imaging (MSRI), which allows for distinction between veins and arteries in the vascular flow maps produced by LSI. We apply this combined technique to mouse cerebral vascular network in vivo, comparing imaging through the skull, to the dura mater and brain directly through a craniectomy, and through a transparent cranial "Window to the Brain" (WttB) implant., Study Design/materials and Methods: The WttB implant used in this study is made of a nanocrystalline Yttria-Stabilized-Zirconia ceramic. MSRI was conducted using white-light illumination and filtering the reflected light for 560, 570, 580, 590, 600, and 610 nm. LSI was conducted using an 810 nm continuous wave near-infrared laser with incident power of 100 mW, and the reflected speckle pattern was captured by a complementary metal-oxide-semiconductor (CMOS) camera., Results: Seven vessel branches were analyzed and comparison was made between imaging through the skull, craniectomy, and WttB implant. Through the skull, MSRI did not detect any vessels, and LSI could not image microvessels. Imaging through the WttB implant, MSRI was able to identify veins versus arteries, and LSI was able to image microvessels with only slightly higher signal-to-noise ratio and lower sharpness than imaging the brain through a craniectomy., Conclusions: This study demonstrates the ability to perform MSRI-LSI across a transparent cranial implant, to allow for cerebral vascular networks to be mapped, including microvessels. These images contain additional information such as vein-artery separation and relative blood flow velocities, information which is of value scientifically and medically. The WttB implant provides substantial improvements over imaging through the murine cranial bone, where microvessels are not visible and MSRI cannot be performed. Lasers Surg. Med. © 2019 Wiley Periodicals, Inc., (© 2019 Wiley Periodicals, Inc.)

We report on the enhanced optical transmittance in the NIR wavelength range (900 to 2400 nm) offered by a transparent Yttria-stabilized zirconia (YSZ) implant coupled with optical clearing agents (OCAs). The enhancement in optical access to the brain is evaluated upon comparing ex-vivo transmittance measurements of mice native skull and the YSZ cranial implant with scalp and OCAs. An increase in transmittance of up to 50% and attenuation lengths of up to 2.4 mm (i.e., a five-fold increase in light penetration) are obtained with the YSZ implant and the OCAs. The use of this ceramic implant and the biocompatible optical clearing agents offer attractive features for NIR optical techniques for brain theranostics., Competing Interests: The authors declare that there are no conflicts of interest related to this article.

Translational comparison of rodent models of neurological and neuropsychiatric diseases to human electroencephalography (EEG) biomarkers in these conditions will require multisite rodent EEG on the skull surface, rather than local area electrocorticography (ECoG) or multisite local field potential (LFP) recording. We have developed a technique for planar multielectrode array (MEA) implantation on the mouse skull surface, which enables multisite EEG in awake and freely moving mice and reusability of the MEA probes. With this method, we reliably obtain 30-channel low-noise EEG from awake mice. Baseline and stimulus-evoked EEG recordings can be readily obtained and analyzed. For example, we have demonstrated EEG responses to auditory stimuli. Broadband noise elicits reliable 30-channel auditory event-related potentials (ERPs), and chirp stimuli induce phase-locked EEG responses just as in human sound presentation paradigms. This method is unique in achieving chronic implantation of novel MEA technology onto the mouse skull surface for chronic multisite EEG recordings. Furthermore, we demonstrate a reliable method for reusing MEA probes for multiple serial implantations without loss of EEG quality. This skull surface MEA methodology can be used to obtain simultaneous multisite EEG recordings and to test EEG biomarkers in diverse mouse models of human neurological and neuropsychiatric diseases. Reusability of the MEA probes makes it more cost-effective to deploy this system for various studies.

Laser speckle imaging (LSI) of mouse cerebral blood flow was compared through a transparent nanocrystalline yttria-stabilized zirconia (nc-YSZ) cranial implant over time (at days 0, 14, and 28, n = 3 mice), and vs. LSI through native skull (at day 60, n = 1 mouse). The average sharpness of imaged vessels was found to remain stable, with relative change in sharpness under 7.69% ± 1.2% over 28 days. Through-implant images of vessels at day 60 appeared sharper and smaller on average, with microvessels clearly visible, compared to through-skull images where vessels appeared blurred and distorted. These results suggest that long-term imaging through this implant is feasible., Competing Interests: The authors declare that there are no conflicts of interest related to this article.

Increasing prevalence in obesity has become a significant public concern. C57BL/6J mice are prone to diet-induced obesity (DIO) when fed high-fat diet (HFD), and develop chronic inflammation and metabolic syndrome, making them a good model to analyze mechanisms whereby obesity elicits pathologies. DIO mice demonstrated profound sex differences in response to HFD with respect to inflammation and hypothalamic function. First, we determined that males are prone to DIO, while females are resistant. Ovariectomized females, on the other hand, are susceptible to DIO, implying protection by ovarian hormones. Males, but not females, exhibit changes in hypothalamic neuropeptide expression. Surprisingly, ovariectomized females remain resistant to neuroendocrine changes, showing that ovarian hormones are not necessary for protection. Second, obese mice exhibit sex differences in DIO-induced inflammation. Microglial activation and peripheral macrophage infiltration is seen in the hypothalami of males, while females are protected from the increase in inflammatory cytokines and do not exhibit microglia morphology changes nor monocyte-derived macrophage infiltration, regardless of the presence of ovarian hormones. Strikingly, the anti-inflammatory cytokine IL-10 is increased in the hypothalami of females but not males. Third, this study posits a potential mechanism of obesity-induced impairment of hypothalamic function whereby obese males exhibit reduced levels of synaptic proteins in the hypothalamus and fewer spines in GnRH neurons, located in the areas exhibiting macrophage infiltration. Our studies suggest that inflammation-induced synaptic remodeling is potentially responsible for hypothalamic impairment that may contribute to diminished levels of gonadotropin hormones, testosterone, and sperm numbers, which we observe and corresponds to the observations in obese humans. Taken together, our data implicate neuro-immune mechanisms underlying sex-specific differences in obesity-induced impairment of the hypothalamic function with potential consequences for reproduction and fertility.

Gonadotropin-releasing hormone (GnRH) from the hypothalamus regulates synthesis and secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the anterior pituitary gonadotropes. LH and FSH are heterodimers composed of a common α-subunit and unique β-subunits, which provide biological specificity and are limiting components of mature hormone synthesis. Gonadotrope cells respond to GnRH via specific expression of the GnRH receptor (Gnrhr). GnRH induces the expression of gonadotropin genes and of the Gnrhr by activation of specific transcription factors. The JUN (c-Jun) transcription factor binds to AP-1 sites in the promoters of target genes and mediates induction of the FSHβ gene and of the Gnrhr in gonadotrope-derived cell lines. To analyze the role of JUN in reproductive function in vivo, we generated a mouse model that lacks JUN specifically in GnRH receptor‒expressing cells (conditional JUN knockout; JUN-cKO). JUN-cKO mice displayed profound reproductive anomalies such as reduced LH levels resulting in lower gonadal steroid levels, longer estrous cycles in females, and diminished sperm numbers in males. Unexpectedly, FSH levels were unchanged in these animals, whereas Gnrhr expression in the pituitary was reduced. Steroidogenic enzyme expression was reduced in the gonads of JUN-cKO mice, likely as a consequence of reduced LH levels. GnRH receptor‒driven Cre activity was detected in the hypothalamus but not in the GnRH neuron. Female, but not male, JUN-cKO mice exhibited reduced GnRH expression. Taken together, our results demonstrate that GnRH receptor‒expression levels depend on JUN and are critical for reproductive function.

Follicle-stimulating hormone (FSH) regulates follicular growth and stimulates estrogen synthesis in the ovaries. FSH is a heterodimer consisting of an α subunit, also present in luteinizing hormone, and a unique β subunit, which is transcriptionally regulated by gonadotropin-releasing hormone 1 (GNRH). Because most FSH is constitutively secreted, tight transcriptional regulation is critical for maintaining FSH levels within a narrow physiological range. Previously, we reported that GNRH induces FSHβ ( Fshb ) transcription via induction of the AP-1 transcription factor, a heterodimer of c-FOS and c-JUN. Herein, we identify c-JUN-dimerization protein 2 (JDP2) as a novel repressor of GNRH-mediated Fshb induction. JDP2 exhibited high basal expression and bound the Fshb promoter at an AP-1-binding site in a complex with c-JUN. GNRH treatment induced c-FOS to replace JDP2 as a c-JUN binding partner, forming transcriptionally active AP-1. Subsequently, rapid c-FOS degradation enabled reformation of the JDP2 complex. In vivo studies revealed that JDP2 null male mice have normal reproductive function, as expected from a negative regulator of the FSH hormone. Female JDP2 null mice, however, exhibited early puberty, observed as early vaginal opening, larger litters, and early reproductive senescence. JDP2 null females had increased levels of circulating FSH and higher expression of the Fshb subunit in the pituitary, resulting in elevated serum estrogen and higher numbers of large ovarian follicles. Disruption of JDP2 function therefore appears to cause early cessation of reproductive function, a condition that has been associated with elevated FSH in women., (© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.)

cFOS is a pleiotropic transcription factor, which binds to the AP1 site in the promoter of target genes. In the pituitary gonadotropes, cFOS mediates induction of FSHβ and GnRH receptor genes. Herein, we analyzed reproductive function in the cFOS-deficient mice to determine its role in vivo. In the pituitary cFOS is necessary for gonadotropin subunit expression, while TSHβ is unaffected. Additionally, cFOS null animals have the same sex-steroid levels, although gametogenesis is impeded. In the brain, cFOS is not necessary for GnRH neuronal migration, axon targeting, cell number, or mRNA levels. Conversely, cFOS nulls, particularly females, have decreased Kiss1 neuron numbers and lower Kiss1 mRNA levels. Collectively, our novel findings suggest that cFOS plays a cell-specific role at multiple levels of the hypothalamic-pituitary-gonadal axis, affecting gonadotropes but not thyrotropes in the pituitary, and kisspeptin neurons but not GnRH neurons in the hypothalamus, thereby contributing to the overall control of reproduction., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)