Maternal fluoxetine exposure alters cortical hemodynamic and calcium response of offspring to somatosensory stimuli

Epidemiological studies have found an increased incidence of neurodevelopmental disorders in populations prenatally exposed to selective serotonin reuptake inhibitors (SSRIs). Optical imaging provides a minimally invasive way to determine if perinatal SSRI exposure has long-term effects on cortical function. Herein we probed the functional neuroimaging effects of perinatal SSRI exposure in a fluoxetine (FLX)-exposed mouse model. While resting-state homotopic contralateral functional connectivity was unperturbed, the evoked cortical response to forepaw stimulation was altered in FLX mice. The stimulated cortex showed decreased activity for FLX versus controls, by both hemodynamic responses [oxyhemoglobin (Hb

Characterizing Metabolic Alterations in Palbociclib-Resistant ER+ Breast Cancer

Characterizing Metabolic Alterations in Palbociclib-Resistant ER+ Breast Cancer Jessica Shunnarah1, Susan M. Dougherty2, Yoannis Imbert-Fernandez3 1ULBB Program, 2Department of Medicine, University of Louisville Abstract Diverse mechanisms of resistance to inhibitors of cyclin dependent kinases 4 and 6 (CDK4/6) have been described including cell cycle alterations and metabolic changes. Palbociclib was the first CDK4/6inhibitor approved against estrogen receptor positive (ER+) breast cancer however, the development of resistance has limited its success. This study investigates the changes in the expression of key metabolic enzymes using an in vivo model of palbociclib resistance. Palbociclib-resistant patient derive xenografts (PDXs) were generated by treating NSG mice that had ER+ breast cancer was implanted into the mammary fat pat of NSG mice with palbociclib until the tumors grew in the presence of the drug.. At endpoint, the tumors were harvested, flash frozen, and pulverized for western blot analysis. Our analysis shows the up regulation in some of the metabolic enzymes. We have concluded that resistance to palbociclib ER+ breast cancer increases the expression of Glutaminase (GLS1) in the presence and absence of palbociclib. Palbociclib treatment also leads to an increase 6-phosphofructo-2 kinase/fructose-2,6-biphosphotase-3 (PFKFB3) and Glucose-6-phosphate dehydrogenase (G6PDH) and transketolase in both palbociclib-sensitive and palbociclib-resistant PDX models. Keywords: Palbociclib, estrogen receptor positive, patient derive xenograft, glutaminase, 6-phosphofructo-2 kinase/fructo, glucose-6-phosphate dehydrogenas

Examining the reversibility of long-term behavioral disruptions in progeny of maternal SSRI exposure

Serotonergic dysregulation is implicated in numerous psychiatric disorders. Serotonin plays widespread trophic roles during neurodevelopment; thus perturbations to this system during development may increase risk for neurodevelopmental disorders. Epidemiological studies have examined association between selective serotonin reuptake inhibitor (SSRI) treatment during pregnancy and increased autism spectrum disorder (ASD) risk in offspring. It is unclear from these studies whether ASD susceptibility is purely related to maternal psychiatric diagnosis, or if treatment poses additional risk. We sought to determine whether maternal SSRI treatment alone or in combination with genetically vulnerable background was sufficient to induce offspring behavior disruptions relevant to ASD. We exposed C57BL/6J or Celf6(+/-) mouse dams to fluoxetine (FLX) during different periods of gestation and lactation and characterized offspring on tasks assessing social communicative interaction and repetitive behavior patterns including sensory sensitivities. We demonstrate robust reductions in pup ultrasonic vocalizations (USVs) and alterations in social hierarchy behaviors, as well as perseverative behaviors and tactile hypersensitivity. Celf6 mutant mice demonstrate social communicative deficits and perseverative behaviors, without further interaction with FLX. FLX re-exposure in adulthood ameliorates the tactile hypersensitivity yet exacerbates the dominance phenotype. This suggests acute deficiencies in serotonin levels likely underlie the abnormal responses to sensory stimuli, while the social alterations are instead due to altered development of social circuits. These findings indicate maternal FLX treatment, independent of maternal stress, can induce behavioral disruptions in mammalian offspring, thus contributing to our understanding of the developmental role of the serotonin system and the possible risks to offspring of SSRI treatment during pregnancy

Shared developmental gait disruptions across two mouse models of neurodevelopmental disorders

BACKGROUND: Motor deficits such as abnormal gait are an underappreciated yet characteristic phenotype of many neurodevelopmental disorders (NDDs), including Williams Syndrome (WS) and Neurofibromatosis Type 1 (NF1). Compared to cognitive phenotypes, gait phenotypes are readily and comparably assessed in both humans and model organisms and are controlled by well-defined CNS circuits. Discovery of a common gait phenotype between NDDs might suggest shared cellular and molecular deficits and highlight simple outcome variables to potentially quantify longitudinal treatment efficacy in NDDs. METHODS: We characterized gait using the DigiGait assay in two different murine NDD models: the complete deletion (CD) mouse, which models hemizygous loss of the complete WS locus, and the Nf1 RESULTS: Compared to wildtype littermate controls, both models displayed markedly similar spatial, temporal, and postural gait abnormalities during development. Developing CD mice also displayed significant decreases in variability metrics. Multiple gait abnormalities observed across development in the Nf1 CONCLUSIONS: These findings suggest that the subcomponents of gait affected in NDDs show overlap between disorders as well as some disorder-specific features, which may change over the course of development. Our incorporation of spatial, temporal, and postural gait measures also provides a template for gait characterization in other NDD models and a platform to examining circuits or longitudinal therapeutics

Ontogenetic oxycodone exposure affects early life communicative behaviors, sensorimotor reflexes, and weight trajectory in mice

Nationwide, opioid misuse among pregnant women has risen four-fold from 1999 to 2014, with commensurate increase in neonates hospitalized for neonatal abstinence syndrome (NAS). NAS occurs when a fetus exposed to opioid

Activity-dependent translation dynamically alters the proteome of the perisynaptic astrocyte process

Within eukaryotic cells, translation is regulated independent of transcription, enabling nuanced, localized, and rapid responses to stimuli. Neurons respond transcriptionally and translationally to synaptic activity. Although transcriptional responses are documented in astrocytes, here we test whether astrocytes have programmed translational responses. We show that seizure activity rapidly changes the transcripts on astrocyte ribosomes, some predicted to be downstream of BDNF signaling. In acute slices, we quantify the extent to which cues of neuronal activity activate translation in astrocytes and show that this translational response requires the presence of neurons, indicating that the response is non-cell autonomous. We also show that this induction of new translation extends into the periphery of astrocytes. Finally, synaptic proteomics show that new translation is required for changes that occur in perisynaptic astrocyte protein composition after fear conditioning. Regulation of translation in astrocytes by neuronal activity suggests an additional mechanism by which astrocytes may dynamically modulate nervous system functioning