Biology subjects

Smith, P. C.

Publications and source records attributed to Smith, P. C..

6 recordsLinked to original sources

bioRxiv2026

The astrocyte clock controls circadian perineuronal net remodeling, synapse strength and learning behavior

The circadian clock controls a vast array of cellular and organismal functions, from the molecular scale to behavior. While each cell is regimented by a cell-autonomous clock, few studies in the brain have dissected the circuit and behavioral contributions of cell-specific clocks. Relatedly, astrocytes are now known to play key roles in regulating synaptic function, circuit activity and behavior, but whether these functions are guided by astrocyte-autonomous clocks is unknown. Here, we report that post-natal deletion of the critical circadian clock gene Bmal1 in astrocytes, which abrogates core clock function in a cell type specific manner, induced expression of genes related to extracellular matrix (ECM) production, maintenance, and remodeling. Circadian variations have been shown in a specific ECM structure, perineuronal nets (PNNs), which are implicated in synaptic function and plasticity. In astrocyte-specific Bmal1 knockouts, hippocampal PNN abundance was decreased, and the circadian rhythm of these structures was also abolished. In line with evidence implicating PNNs, and the ECM in general, in synaptic function and plasticity, we found that astrocyte-specific Bmal1 KO mice had increased synaptic strength but blunted long term potentiation (LTP), as well as impaired learning and memory performance in a novel object recognition task. Taken together, these findings suggest that the astrocyte circadian clock regulates circadian rhythms in perineuronal net abundance as well as synaptic plasticity and behavioral learning and memory.

neuroscience↗

bioRxiv2025

The Median Preoptic Nucleus is a Key Site for Estradiol Regulation of Sleep-Wake Behaviors in Females Rats

Study ObjectivesWomen experience more sleep disruptions than men, particularly during hormonal transitions such as puberty, pregnancy, and menopause. This study investigated the role of estradiol (E2) in regulating sleep-wake behavior in female rats and identified the brain regions involved. MethodsUsing an exogenous E2 replacement model in ovariectomized rats, we assessed changes in sleep-wake patterns via EEG/EMG telemetry. The effects of E2 and progesterone, selective estrogen receptor agonists, and direct brain infusions of E2 and receptor antagonists were evaluated. ResultsE2 administration increased wakefulness, reduced non-rapid eye movement (NREM) and rapid eye movement (REM) sleep, and decreased NREM slow-wave activity (SWA), predominantly during the dark phase. These effects required both estrogen receptor alpha (ER) and beta (ER{beta}) activation and were mediated by estrogen receptor signaling within the median preoptic nucleus (MnPO). Direct infusion of E2 into the MnPO was sufficient to replicate systemic effects, while local infusion of the pure estrogen receptor antagonist ICI 182,780 (Fulvestrant) attenuated them. Progesterone did not augment E2s actions, and males showed no sleep-wake changes in response to E2, highlighting sex-specific mechanisms. ConclusionsThe MnPO is a critical site where E2 regulates sleep-wake behavior. These findings provide a neurobiological framework for understanding how ovarian hormones contribute to sleep disruptions in women, offering potential therapeutic targets for sleep disorders related to hormonal changes. Statement of significanceSleep disturbances disproportionately affect women, particularly during hormonal transitions such as puberty, pregnancy, and menopause. Despite this, the underlying mechanisms by which estradiol (E2) influences sleep-wake behavior have remained unclear. This study identifies the median preoptic nucleus (MnPO) as a critical site where E2 signaling regulates sleep-wake patterns in female rats. Our findings demonstrate that E2 increases wakefulness and reduces both non-rapid eye movement (NREM) and rapid eye movement (REM) sleep, with effects primarily observed during the dark phase. By showing that local E2 signaling in the MnPO is both necessary and sufficient for these changes, this work offers a novel neurobiological framework for understanding how fluctuations in ovarian hormones contribute to sleep disruptions in women. These insights lay the groundwork for developing targeted therapies to improve sleep health in women, particularly those experiencing hormonal changes.

neuroscience↗

bioRxiv2022

Using Extracellular Vesicles Released by GDNF-transfected Macrophages for Therapy of Parkinson's Disease

Extracellular vesicles (EVs) are cell-derived nanoparticles that facilitate transport of proteins, lipids and genetic material playing important roles in intracellular communication. They have a remarkable potential as non-toxic and non-immunogenic nanocarriers for drug delivery to unreachable organs and tissues, in particular, the central nervous system (CNS). Herein, we developed a novel platform based on macrophage derived EVs to treat Parkinsons disease (PD). Specifically, we evaluated the therapeutic potential of EVs secreted by autologous macrophages that were transfected ex vivo to express glial cell line-derived neurotrophic factor (GDNF). EV-GDNF were collected from conditioned media of GDNF-transfected macrophages and characterized for GDNF content, size, charge, and expression of EV-specific proteins. The data revealed that along with the encoded neurotrophic factor, EVs released by pre-transfected macrophages carry GDNF-encoding DNA. Four months-old transgenic Parkin Q311(X)A mice were treated with EV-GDNF via intranasal administration, and the effect of this therapeutic intervention on locomotor functions was assessed over a year. Significant improvements in mobility, increase in neuronal survival, and decrease in neuroinflammation were found in PD mice treated with EV-GDNF. No offsite toxicity caused by EV-GDNF administrations was detected. Overall, EV-based approach can provide a versatile and potent therapeutic intervention for PD.

bioengineering↗

bioRxiv2021

Estradiol Influences Adenosinergic Signaling and NREM Sleep Need in Adult Female Rats

Studies report estradiol (E2) suppresses sleep in females; however, the mechanisms of E2 action remain largely undetermined. Our previous findings suggest that the median preoptic nucleus (MnPO) is a key nexus for E2 action on sleep. Here, using behavioral, neurochemical and pharmacological approaches, we investigated whether E2 influenced the sleep homeostat as well as adenosinergic signaling in the MnPO of adult female rats. During the Light Phase, where rats accumulate the majority of sleep, E2 markedly reduced NREM-SWA (a measure of the homeostatic sleep need). Following 6-hours of sleep deprivation, levels of NREM-SWA were significantly increased compared to baseline sleep. However, the NREM-SWA levels were not different between E2 and control treatment despite a significant increase in wake at the expense of NREM sleep. Analysis of NREM-SWA differences between baseline and recovery sleep following sleep deprivation demonstrated that E2 induced a 2-fold increase in delta power compared to controls suggesting that E2 significantly expanded the dynamic range for the sleep homeostat. Correlated with E2-induced changes in physiological markers of homeostatic sleep was a marked increase in extracellular adenosine (a molecular marker of homeostatic sleep need) during unrestricted and recovery sleep following a 6-hour deprivation. Additionally, E2 blocked the ability of an adenosine A2A receptor agonist (CGS-21680) to increase NREM sleep compared to controls. Thus, taken together, the findings that E2 increased extracellular adenosine content, while blocking A2A signaling in the MnPO suggests a potential mechanism for how estrogens impact sleep in the female brain. Statement of SignificanceWhile gonadal steroids and gender are implicated as risk factors for sleep disruptions and insomnia, the relationship between ovarian steroids and sleep is poorly understood. Understanding the mechanisms through which estradiol (E2) is working to influence sleep-wake behavior is a critical first step toward a better understanding of the role of estrogens in sleep pathologies. Using a rodent model, the current study presents novel findings suggesting that estradiol (E2) is influencing adenosinergic actions in the MnPO. The ability of E2 to attenuate the local effects of the A2A receptors in the MnPO suggests that E2 modulation of A2A receptor signaling may underlie estrogenic suppression of sleep behavior as well as changes in homeostatic sleep need.

neuroscience↗

bioRxiv2021

Salted roads lead to edema and reduced locomotor function in wood frogs

Human activities have caused massive losses of natural populations across the globe. Like many groups, amphibians have experienced substantial declines worldwide, driven by environmental changes such as habitat conversion, pollution, and disease emergence. Each of these drivers is often found in close association with the presence of roads. Here we report a novel consequence of roads affecting an amphibian native to much of North America, the wood frog (Rana sylvatica). Across 38 populations distributed from southern to central New England, we found that adult wood frogs living adjacent to roads had higher incidence and severity of edema (bloating caused by fluid accumulation) during the breeding season than frogs living away from the influence of roads. This effect was best explained by increased conductivity of breeding ponds, caused by runoff pollution from road salt used for de-icing. Edema severity was negatively correlated with locomotor performance in more northerly populations. Interestingly, northern populations experience more intense winters, which tends to result in more de-icing salt runoff and increased energetic demands associated with overwintering cryoprotection needs. Thus, this emerging consequence of roads appears to impose potential fitness costs associated with locomotion, and these effects might be most impactful on populations living in regions where de-icing is most intense.

ecology↗

bioRxiv2020

Estradiol Action at the Median Preoptic Nucleus is Necessary and Sufficient for Sleep Suppression in Female Rats

To further our understanding of how gonadal steroids impact sleep biology, we sought to address the mechanism by which proestrus levels of cycling ovarian steroids, particularly estradiol (E2), suppress sleep in female rats. We showed that steroid replacement of proestrus levels of E2 to ovariectomized female rats, suppressed sleep to similar levels as those reported by endogenous ovarian hormones. We further showed that this suppression is due to the high levels of E2 alone, and that progesterone did not have a significant impact on sleep behavior. We found that E2 action within the Median Preoptic Nucleus (MnPO), which contains estrogen receptors (ERs), is necessary for this effect; antagonism of ERs in the MnPO attenuated the E2-mediated suppression of both non-Rapid Eye Movement (NREM) and Rapid Eye Movement (REM) sleep. Finally, we found E2 action at the MnPO is also sufficient for sleep suppression, as direct infusion of E2 into the MnPO suppressed sleep. Based on our findings, we predict proestrus levels of E2 alone, acting at the MnPO, mediate sex-hormone driven suppression of sleep in female rats. Competing Interest StatementMDS is now an employee of Jazz Pharmaceuticals; the views expressed in this manuscript are solely the authors and do not reflect the views, policies or procedures of Jazz Pharmaceuticals.

neuroscience↗