Paola Tognini

Experience-dependent expression of miR-132 regulates ocular dominance plasticity

miR-132 is a CREB-induced microRNA that is involved in dendritic spine plasticity. We found that visual experience regulated histone post-translational modifications at a CRE locus that is important for miR-212 and miR-132 cluster transcription, and regulated miR-132 expression in the visual cortex of juvenile mice. Monocular deprivation reduced miR-132 expression in the cortex contralateral to the deprived eye. Counteracting this miR-132 reduction with an infusion of chemically modified miR-132 mimic oligonucleotides completely blocked ocular dominance plasticity.

Pluronic-coated carbon nanotubes do not induce degeneration of cortical neurons in vivo and in vitro.

Carbon nanotubes (CNTs) are nanodevices with important potential applications in biomedicine such as drug and gene delivery. Brain diseases with no current therapy could be candidates for CNT-based therapies. Little is known about toxicity of CNTs and of their dispersion factors in the brain. Here we show that multiwall CNTs (MWCNTs) coated with Pluronic F127 (PF127) surfactant can be injected in the mouse cerebral cortex without causing degeneration of the neurons surrounding the site of injection. We also show that, contrary to previous reports on lack of PF127 toxicity on cultured cell lines, concentrations of PF127 as low as 0.01% can induce apoptosis of mouse primary cortical neurons in vitro within 24 hours. However, the presence of MWCNTs can avoid PF127-induced apoptosis. These results suggest that PF127-coated MWCNTs do not induce apoptosis of cortical neurons. Moreover, the presence of MWCNTs can reduce PF127 toxicity.

MicroRNA212/132 family: Molecular transducer of neuronal function and plasticity

MicroRNAs (miRNAs) are small non-coding RNAs that mediate post-transcriptional gene silencing. It is increasingly clear that miRNAs are key regulatory factors for a tight gene expression control. MiRNAs are involved in many aspects of organism development and function, in physiological and pathological conditions. MiRNA expression varies with cell type, tissue and developmental stages. The microRNA212/132 family is one of the most studied miRNA family due to the involvement of miR132 and miR212 in important cellular processes, especially in the brain. MiR132 and miR212 have been implicated in tissue development and in the formation and plasticity of neuronal connections. The main aim of this review is to highlight recent discoveries about miR212/132 family functions and its possible involvement in pathological processes.

Gut microbiota directs PPARγ‐driven reprogramming of the liver circadian clock by nutritional challenge

The liver circadian clock is reprogrammed by nutritional challenge through the rewiring of specific transcriptional pathways. As the gut microbiota is tightly connected to host metabolism, whose coordination is governed by the circadian clock, we explored whether gut microbes influence circadian homeostasis and how they distally control the peripheral clock in the liver. Using fecal transplant procedures we reveal that, in response to high‐fat diet, the gut microbiota drives PPARγ‐mediated activation of newly oscillatory transcriptional programs in the liver. Moreover, antibiotics treatment prevents PPARγ‐driven transcription in the liver, underscoring the essential role of gut microbes in clock reprogramming and hepatic circadian homeostasis. Thus, a specific molecular signature characterizes the influence of the gut microbiome in the liver, leading to the transcriptional rewiring of hepatic metabolism.

Experience-dependent DNA methylation regulates plasticity in the developing visual cortex

DNA methylation is an epigenetic repressor mark for transcription dynamically regulated in neurons. We analyzed visual experience regulation of DNA methylation in mice and its involvement in ocular dominance plasticity of the developing visual cortex. Monocular deprivation modulated the expression of factors controlling DNA methylation and exerted opposite effects on DNA methylation and hydroxymethylation in specific plasticity genes. Inhibition of DNA methyltrasferase (DNMT) blocked molecular and functional effects of monocular deprivation, partially reversing the monocular deprivation transcriptional program.

Dynamic DNA methylation in the brain: a new epigenetic mark for experience-dependent plasticity.

Experience-dependent plasticity is the ability of brain circuits to undergo molecular, structural and functional changes as a function of neural activity. Neural activity continuously shapes our brain during all the stages of our life, from infancy through adulthood and beyond. Epigenetic modifications of histone proteins and DNA seem to be a leading molecular mechanism to modulate the transcriptional changes underlying the fine-tuning of synaptic connections and circuitry rewiring during activity-dependent plasticity. The recent discovery that cytosine methylation is an epigenetic mark particularly dynamic in brain cells has strongly increased the interest of neuroscientists in understanding the role of covalent modifications of DNA in activity-induced remodeling of neuronal circuits. Here, we provide an overview of the role of DNA methylation and hydroxylmethylation in brain plasticity both during adulthood, with emphasis on learning and memory related processes, and during postnatal development, focusing specifically on experience-dependent plasticity in the visual cortex.

Gut Microbiota: A Potential Regulator of Neurodevelopment

During childhood, our brain is exposed to a variety of environmental inputs that can sculpt synaptic connections and neuronal circuits, with subsequent influence on behavior and learning processes. Critical periods of neurodevelopment are windows of opportunity in which the neuronal circuits are extremely plastic and can be easily subjected to remodeling in response to experience. However, the brain is also more susceptible to aberrant stimuli that might lead to altered developmental trajectories. Intriguingly, postnatal brain development is paralleled by the maturation of the gut microbiota: the ecosystem of symbionts populating our gastro-intestinal tract. Recent discoveries have started to unveil an unexpected link between the gut microbiome and neurophysiological processes. Indeed, the commensal bacteria seem to be able to influence host behavioral outcome and neurochemistry through mechanisms which remain poorly understood. Remarkably, the efficacy of the gut flora action appears to be dependent on the timing during postnatal life at which the host gut microbes’ signals reaches the brain, suggesting the fascinating possibility of critical periods for this microbiota-driven shaping of host neuronal functions and behavior. Therefore, to understand the importance of the intestinal ecosystem’s impact on neuronal circuits functions and plasticity during development and the discovery of the involved molecular mechanisms, will pave the way to identify new and, hopefully, powerful microbiota-based therapeutic interventions for the treatment of neurodevelopmental and psychiatric diseases.

Distinct Circadian Signatures in Liver and Gut Clocks Revealed by Ketogenic Diet

The circadian clock orchestrates rhythms in physiology and behavior, allowing organismal adaptation to daily environmental changes. While food intake profoundly influences diurnal rhythms in the liver, how nutritional challenges are differentially interpreted by distinct tissue-specific clocks remains poorly explored. Ketogenic diet (KD) is considered to have metabolic and therapeutic value, though its impact on circadian homeostasis is virtually unknown. We show that KD has profound and differential effects on liver and intestine clocks. Specifically, the amplitude of clock-controlled genes and BMAL1 chromatin recruitment are drastically altered by KD in the liver, but not in the intestine. KD induces nuclear accumulation of PPARα in both tissues but with different circadian phase. Also, gut and liver clocks respond differently to carbohydrate supplementation to KD. Importantly, KD induces serum and intestinal β-hydroxyl-butyrate levels to robustly oscillate in a circadian manner, an event coupled to tissue-specific cyclic histone deacetylase (HDAC) activity and histone acetylation.

Mir-132/212 is required for maturation of binocular matching of orientation preference and depth perception

MicroRNAs (miRNAs) are known to mediate post-transcriptional gene regulation, but their role in postnatal brain development is still poorly explored. We show that the expression of many miRNAs is dramatically regulated during functional maturation of the mouse visual cortex with miR-132/212 family being one of the top upregulated miRNAs. Age-downregulated transcripts are significantly enriched in miR-132/miR-212 putative targets and in genes upregulated in miR-132/212 null mice. At a functional level, miR-132/212 deletion affects development of receptive fields of cortical neurons determining a specific impairment of binocular matching of orientation preference, but leaving orientation and direction selectivity unaltered. This deficit is associated with reduced depth perception in the visual cliff test. Deletion of miR-132/212 from forebrain excitatory neurons replicates the binocular matching deficits. Thus, miR-132/212 family shapes the age-dependent transcriptome of the visual cortex during a specific developmental window resulting in maturation of binocular cortical cells and depth perception.

Circadian Coordination of Antimicrobial Responses

Microbial infection poses a threat to organismal homeostasis and therefore must be efficiently counteracted by host defense mechanisms. It has been recently demonstrated that the immune system may anticipate an emerging pathogenic exposure through a heightened inflammatory state. Such anticipatory responses to fluctuating environmental conditions are typically orchestrated by the circadian clock, an intrinsic time-keeping system that adapts tissue physiology to diurnal variations in external influences. Here, we review current knowledge about the interplay between the circadian clock and antimicrobial responses. We summarize the molecular strategies employed by the circadian system against specific pathogens, the core-clock proteins as well as cells in which they are expressed that mediate host defense, and the consequences of circadian variations on immune function. Furthermore, we highlight the possible implications of such circadian gating in immune reactions against pathogenic infections for the chronopharmacology of antibacterial and antiviral therapies.