Inhibition of Bone Morphogenetic Protein Signaling Prevents Tau Pathology in iPSC Derived Neurons and PS19 Mice.

Objective: Many neurodegenerative disorders share a common pathologic feature involving the deposition of abnormal tau protein in the brain (tauopathies). This suggests that there may be some shared pathophysiologic mechanism(s). The largest risk factor for the majority of these disorders is aging, suggesting involvement of the aging process in the shared pathophysiology.

Ketamine's rapid and sustained antidepressant effects are driven by distinct mechanisms.

Administration of multiple subanesthetic doses of ketamine increases the duration of antidepressant effects relative to a single ketamine dose, but the mechanisms mediating this sustained effect are unclear. Here, we demonstrate that ketamine's rapid and sustained effects on affective behavior are mediated by separate and temporally distinct mechanisms. The rapid effects of a single dose of ketamine result from increased activity of immature neurons in the hippocampal dentate gyrus without an increase in neurogenesis.

Why Some Mice Are Smarter than Others: The Impact of Bone Morphogenetic Protein Signaling on Cognition.

Inbred mice (C57Bl/6) display wide variability in performance on hippocampal-dependent cognitive tasks. Examination of microdissected dentate gyrus (DG) after cognitive testing showed a highly significant negative correlation between levels of bone morphogenetic protein (BMP) signaling and recognition memory. Cognitive performance decline during the aging process, and the degree of cognitive decline is strongly correlated with aging-related increases in BMP signaling.

Ketamine activates adult-born immature granule neurons to rapidly alleviate depression-like behaviors in mice.

Ketamine treatment decreases depressive symptoms within hours, but the mechanisms mediating these rapid antidepressant effects are unclear. Here, we demonstrate that activity of adult-born immature granule neurons (ABINs) in the mouse hippocampal dentate gyrus is both necessary and sufficient for the rapid antidepressant effects of ketamine. Ketamine treatment activates ABINs in parallel with its behavioral effects in both stressed and unstressed mice.

Hippocampal BMP signaling as a common pathway for antidepressant action.

The benefits of current treatments for depression are limited by low response rates, delayed therapeutic effects, and multiple side effects. Antidepressants affect a variety of neurotransmitter systems in different areas of the brain, and the mechanisms underlying their convergent effects on behavior have been unclear. Here we identify hippocampal bone morphogenetic protein (BMP) signaling as a common downstream pathway that mediates the behavioral effects of five different antidepressant classes (fluoxetine, bupropion, duloxetine, vilazodone, trazodone) and of electroconvulsive therapy.

Activating newborn neurons suppresses depression and anxiety-like behaviors.

The etiology of major depressive disorder (MDD), the leading cause of worldwide disability, is unknown. The neurogenic hypothesis proposes that MDD is linked to impairments of adult neurogenesis in the hippocampal dentate gyrus (DG), while the effects of antidepressants are mediated by increased neurogenesis. However, alterations in neurogenesis and endophenotypes are not always causally linked, and the relationship between increased neurogenesis and altered behavior is controversial.

Premature hippocampus-dependent memory decline in middle-aged females of a genetic rat model of depression.

Aging and major depressive disorder are risk factors for dementia, including Alzheimer's Disease (AD), but the mechanism(s) linking depression and dementia are not known. Both AD and depression show greater prevalence in women. We began to investigate this connection using females of the genetic model of depression, the inbred Wistar Kyoto More Immobile (WMI) rat.

Modeling Fetal Alcohol Spectrum Disorder: Validating an Ex Vivo Primary Hippocampal Cell Culture System.

Background: Fetal alcohol spectrum disorder (FASD) is the leading nongenetic cause of mental retardation. There are no treatments for FASD to date. Preclinical in vivo and in vitro studies could help in identifying novel drug targets as for other diseases.

Thyroxine administration prevents matrilineal intergenerational consequences of in utero ethanol exposure in rats.

The neurodevelopmental fetal alcohol spectrum disorder (FASD) is characterized by cognitive and behavioral deficits in the offspring. Conferring the deficits to the next generation would increase overall FASD disease burden and prevention of this transmission could be highly significant. Prior studies showed the reversal of these behavioral deficits by low dose thyroxine (T4) supplementation to the ethanol-consuming mothers.

Hypothesis: genetic and epigenetic risk factors interact to modulate vulnerability and resilience to FASD.

Fetal alcohol spectrum disorder (FASD) presents a collection of symptoms representing physiological and behavioral phenotypes caused by maternal alcohol consumption. Symptom severity is modified by genetic differences in fetal susceptibility and resistance as well as maternal genetic factors such as maternal alcohol sensitivity. Animal models demonstrate that both maternal and paternal genetics contribute to the variation in the fetus' vulnerability to alcohol exposure.

Intergenerational and parent of origin effects of maternal calorie restriction on Igf2 expression in the adult rat hippocampus.

Insulin-like growth factor 2 (Igf2) regulates development, memory and adult neurogenesis in the hippocampus. Calorie restriction (CR) is known to modulate non-neuronal Igf2 expression intergenerationally, but its effect has not been evaluated on brain Igf2. Here, Sprague-Dawley (S) dams underwent moderate CR between gestational days 8-21.

Intergenerational effects of prenatal ethanol on glucose tolerance and insulin response.

Consequences of prenatal exposure to ethanol (E) include morphological, physiological, and cognitive deficits and are collectively classified as fetal alcohol spectrum disorders. Adult prenatal E exposed offspring show insulin resistance, and given that in utero hyperglycemic environment can cause metabolic disorders in subsequent generations; we investigated the effects of grandmaternal E on functional glucose and insulin responses of the second generation. Sprague-Dawley (S) rat dams, mated with S males, received E-containing liquid diet and two different control diets between gestational days 8 and 20.

Low-dose thyroxine attenuates autism-associated adverse effects of fetal alcohol in male offspring's social behavior and hippocampal gene expression.

Background: Fetal alcohol spectrum disorder (FASD) is characterized by neurodevelopmental anomalies manifesting in cognitive and behavioral deficits in the offspring with diverse severities. Social behavior is affected in FASD, and these deficits overlap with those of autism spectrum disorder (ASD). Identifying some of the molecular characteristics related to ASD in an animal model of FASD could ultimately provide details on the underlying molecular mechanisms of both disorders that could lead to novel treatments.

Nuclear orphan receptor Nor-1 contributes to depressive behavior in the Wistar-Kyoto rat model of depression.

The current study explored the effects of prolonged antidepressant treatment on mRNA levels of two nuclear receptors in specific brain regions of an animal model of depression, the Wistar-Kyoto (WKY) rat. Both nuclear receptors have been implicated in the development or treatment of depression. The expression of nuclear orphan receptor-1 (Nor-1), a member of the NR4A nuclear orphan receptor family, is induced by electroconvulsive shock, an effective treatment for depression.