Effects of antenatal dexamethasone treatment on glucocorticoid receptor and calcyon gene expression in the prefrontal cortex of neonatal and adult common marmoset monkeys

BACKGROUND: Synthetic glucocorticoids such as dexamethasone (DEX) are commonly used to promote fetal lung maturation in at-risk preterm births, but there is emerging evidence of subsequent neurobehavioral abnormalities in these children e.g. problems with inattention/hyperactivity. However, molecular pathways mediating effects of glucocorticoid overexposure on motor and cognitive development are poorly understood. METHODS: In this study with common marmoset monkeys, we investigated for neonatal and adulthood effects of antenatal DEX treatment on the expression of the corticosteroid receptors and also calcyon, a risk gene for attention-deficit/hyperactivity disorder, in the prefrontal cortex (PFC). Pregnant marmosets were exposed to DEX (5 mg/kg body weight) or vehicle during early (days 42-48) or late (days 90-96) stages of the 144-day pregnancy. RESULTS: In neonates, relative to controls, glucocorticoid receptor (GR) mRNA levels were significantly reduced after the late DEX treatment in the medial, orbital and dorsal PFC and after the early DEX treatment in the dorsal PFC. The early DEX exposure, specifically, resulted in significant reduction in calcyon mRNA expression in the medial, orbital, dorsal and lateral PFC relative to controls. Mineralocorticoid receptor (MR) mRNA levels were not significantly affected by DEX treatment. In adults, PFC GR, calcyon, and MR mRNA levels were not significantly affected by early or late prenatal DEX treatment. CONCLUSION: These findings indicate that antenatal DEX treatment could lead to short-term alterations in PFC expression of the GR and calcyon genes, with possible neurodevelopmental functional consequences

Morphology of Pyramidal Neurons in the Rat Prefrontal Cortex: Lateralized Dendritic Remodeling by Chronic Stress

The prefrontal cortex (PFC) plays an important role in the stress response. We filled pyramidal neurons in PFC layer III with neurobiotin and analyzed dendrites in rats submitted to chronic restraint stress and in controls. In the right prelimbic cortex (PL) of controls, apical and distal dendrites were longer than in the left PL. Stress reduced the total length of apical dendrites in right PL and abolished the hemispheric difference. In right infralimbic cortex (IL) of controls, proximal apical dendrites were longer than in left IL, and stress eliminated this hemispheric difference. No hemispheric difference was detected in anterior cingulate cortex (ACx) of controls, but stress reduced apical dendritic length in left ACx. These data demonstrate interhemispheric differences in the morphology of pyramidal neurons in PL and IL of control rats and selective effects of stress on the right hemisphere. In contrast, stress reduced dendritic length in the left ACx

High-voltage-activated Ca2+ currents and the excitability of pyramidal neurons in the hippocampal CA3 subfield in rats depend on corticosterone and time of day

This study tested the time-of-day dependence of the intrinsic postsynaptic properties of hippocampal CA3 pyramidal neurons. High-voltage-activated Ca2+ currents and the Ca2+- and voltage-dependent afterhyperpolarizations were examined in slices of rat brains obtained at four distinct time periods. Just after onset of the dark phase, the steady-state amplitude of the Ca2+ current (-1.24 ± 0.11 nA) was significantly greater (P < 0.03) than that of the light phase (-0.84 ± 0.06 nA). Over the entire time range, the amplitude of the Ca2+ current correlated with plasma corticosterone levels in a U-shaped function. Furthermore, depolarization-induced excitability during the dark phase exhibited an increased spike after depolarization (3.1 ± 0.1 mV) and a slower adaptation of the firing frequency (146 ± 18%). These findings point to a dynamic time-of-day dependence of the CA3 neuronal properties and postsynaptic Ca2+ currents.

Satellite-Dominated Sulfur L2,3_{2,3} X-ray Emission of Alkaline Earth Metal Sulfides

The sulfur L2,3 X-ray emission spectra of the alkaline earth metal sulfides BeS, MgS, CaS, SrS, and BaS are investigated and compared with spectra calculations based on density functional theory. Very distinct spectral shapes are found for the different compounds. With decreasing electronegativity of the cation, that is, increasing ionic bonding character, the upper valence band width and its relative spectral intensity decrease. These general trends are qualitatively reproduced by the spectra calculations, which give quite an accurate description of the spectral shapes in the upper valence band region. On the low energy side of the sulfur 3s → 2p transition dominating the spectra, we find strong satellites caused by “semi-Auger” decays involving configuration interaction. These satellites, previously believed to be energetically forbidden for sulfur L2,3 emission and only observed for the L2,3 emission of Cl to Cr, increase in intensity as the bonding character becomes more ionic and dominate the spectra for SrS and BaS. The intensities, energies, and widths of the satellites vary strongly between the investigated compounds, giving a very specific spectral fingerprint that can be used for speciation analysis

Novel Drug Developmental Strategies for Treatment-Resistant Depression

Major depressive disorder is a leading cause of disability worldwide. Because conventional therapies are ineffective in many patients, novel strategies are needed to overcome treatment‐resistant depression (TRD). Limiting factors of successful drug development in the last decades were the lack of (1) knowledge of pathophysiology, (2) translational animal models and (3) objective diagnostic biomarkers. Here, we review novel drug targets and drug candidates currently investigated in Phase I–III clinical trials. The most promising approaches are inhibition of glutamatergic neurotransmission by NMDA and mGlu(5) receptor antagonists, modulation of the opioidergic system by κ receptor antagonists, and hallucinogenic tryptamine derivates. The only registered drug for TRD is the NMDA receptor antagonist, S‐ketamine, but add‐on therapies with second‐generation antipsychotics, certain nutritive, anti‐inflammatory and neuroprotective agents seem to be effective. Currently, there is an intense research focus on large‐scale, high‐throughput omics and neuroimaging studies. These results might provide new insights into molecular mechanisms and potential novel therapeutic strategies

Gender agreement attraction in Greek comprehension

This work explores gender agreement attraction in comprehension. Attraction occurs when an agreement error (such as, “the key to the cabinets are rusty”) goes unnoticed, leading to the illusion of grammaticality due to a mismatch between the value of the head and the value of a local intervening phase (attractor). According to retrieval accounts, these errors occur during cue retrieval from memory and predict illusions of grammaticality. Alternatively, representational accounts predict that the errors occur due to the faulty representation of certain features, thus, illusions of ungrammaticality are also expected. In four experiments we explore: (a) whether gender agreement attraction occurs in Greek and the strategy/-ies employed, (b) the role of the agreement target, (c) the timing of gender agreement attraction, (d) the role of phonological matching between the nominal inflectional morphemes of the attractor and the agreement target, and (e) participants’ sensitivity to agreement when there is no conflict from the attractor. In all four experiments, the grammaticality of the sentence and the attractor value (match or mismatch with the head) and also the phonological matching between the attractor and the agreement target in ungrammatical sentences were manipulated. The agreement target was either an adjectival predicate or an object-clitic and the gender value of the head was feminine or neuter. Attraction was found in all measures during the time-course of adjectival predicates (Experiment 1) and object-clitics (Experiment 2), and in timed (Experiment 3), and untimed (Experiment 4) judgments. Even more, both gender values showed attraction and the results mainly suggest that participants experience illusions of grammaticality, confirming retrieval accounts. Phonological matching did not modulate attraction in any of the experiments, suggesting that the similarity in the morphophonological realization between the agreement target and the attractor does not increase attraction. Furthermore, participants were sensitive to gender agreement violations in the absence of gender mismatch between the head and the attractor, suggesting that they respect agreement rules and have both neuter and feminine available in their feature content repertoire, although with some tendency in favor of neuter in feminine agreement contexts. The impact of these findings is discussed within the concept of attraction and sensitivity to agreement violations