Early postnatal behavioral, cellular, and molecular changes in models of Huntington disease are reversible by HDAC inhibition.

Huntington disease (HD) is an autosomal dominant neurodegenerative disorder caused by expanded CAG repeats in the huntingtin gene (HTT). Although mutant HTT is expressed during embryonic development and throughout life, clinical HD usually manifests later in adulthood. A number of studies document neurodevelopmental changes associated with mutant HTT, but whether these are reversible under therapy remains unclear. Here, we identify very early behavioral, molecular, and cellular changes in preweaning transgenic HD rats and mice. Reduced ultrasonic vocalization, loss of prepulse inhibition, and increased risk taking are accompanied by disturbances of dopaminergic regulation in vivo, reduced neuronal differentiation capacity in subventricular zone stem/progenitor cells, and impaired neuronal and oligodendrocyte differentiation of mouse embryo-derived neural stem cells in vitro. Interventional treatment of this early phenotype with the histone deacetylase inhibitor (HDACi) LBH589 led to significant improvement in behavioral changes and markers of dopaminergic neurotransmission and complete reversal of aberrant neuronal differentiation in vitro and in vivo. Our data support the notion that neurodevelopmental changes contribute to the prodromal phase of HD and that early, presymptomatic intervention using HDACi may represent a promising novel treatment approach for HD.

Intermediate filament transcription in astrocytes is repressed by proteasome inhibition.

Increased expression of the astrocytic intermediate filament protein glial fibrillary acidic protein (GFAP) is a characteristic of astrogliosis. This process occurs in the brain during aging and neurodegeneration and coincides with impairment of the ubiquitin proteasome system. Inhibition of the proteasome impairs protein degradation; therefore, we hypothesized that the increase in GFAP may be the result of impaired proteasomal activity in astrocytes. We investigated the effect of proteasome inhibitors on GFAP expression and other intermediate filament proteins in human astrocytoma cells and in a rat brain model for astrogliosis. Extensive quantitative RT-PCR, immunocytochemistry, and Western blot analysis resulted unexpectedly in a strong decrease of GFAP mRNA to <4% of control levels [Control (DMSO) 100+/-19.2%; proteasome inhibitor (epoxomicin) 3.5+/-1.3%, n=8; P < or = 0.001] and a loss of GFAP protein in astrocytes in vitro. We show that the proteasome alters GFAP promoter activity, possibly mediated by transcription factors as demonstrated by a GFAP promoter-luciferase assay and RT(2) Profiler PCR array for human transcription factors. Most important, we demonstrate that proteasome inhibitors also reduce GFAP and vimentin expression in a rat model for induced astrogliosis in vivo. Therefore, proteasome inhibitors could serve as a potential therapy to modulate astrogliosis associated with CNS injuries and disease.

Action information contributes to metacognitive decision-making.

Metacognitive abilities allow us to adjust ongoing behavior and modify future decisions in the absence of external feedback. Although metacognition is critical in many daily life settings, it remains unclear what information is actually being monitored and what kind of information is being used for metacognitive decisions. In the present study, we investigated whether response information connected to perceptual events contribute to metacognitive decision-making. Therefore, we recorded EEG signals during a perceptual color discrimination task while participants were asked to provide an estimate about the quality of their decision on each trial. Critically, the moment participants provided their confidence judgments varied across conditions, thereby changing the amount of action information (e.g., response competition or response fluency) available for metacognitive decisions. Results from three experiments demonstrate that metacognitive performance improved when first-order action information was available at the moment metacognitive decisions about the perceptual task had to be provided. This behavioral effect was accompanied by enhanced functional connectivity (beta phase synchrony) between motor areas and prefrontal regions, exclusively observed during metacognitive decision-making. Our findings demonstrate that action information contributes to metacognitive decision-making, thereby painting a picture of metacognition as a process that integrates sensory evidence and information about our interactions with the world.

Learning to Be Conscious.

Consciousness remains a formidable challenge. Different theories of consciousness have proposed vastly different mechanisms to account for phenomenal experience. Here, appealing to aspects of global workspace theory, higher-order theories, social theories, and predictive processing, we introduce a novel framework: the self-organizing metarerpresentational account (SOMA), in which consciousness is viewed as something that the brain learns to do. By this account, the brain continuously and unconsciously learns to redescribe its own activity to itself, so developing systems of metarepresentations that qualify target first-order representations. Thus, experiences only occur in experiencers that have learned to know they possess certain first-order states and that have learned to care more about certain states than about others. In this sense, consciousness is the brain's (unconscious, embodied, enactive, nonconceptual) theory about itself.