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Cognitive Aging in Zebrafish

Lili Yu, Valter Tucci, Shuji Kishi, Irina V. Zhdanova, Chris Miall
2006 PLoS ONE  
Background. Age-related impairments in cognitive functions represent a growing clinical and social issue. Genetic and behavioral characterization of animal models can provide critical information on the intrinsic and environmental factors that determine the deterioration or preservation of cognitive abilities throughout life. Methodology/Principal Findings. Behavior of wild-type, mutant and gamma-irradiated zebrafish (Danio rerio) was documented using image-analysis technique. Conditioned
more » ... ses to spatial, visual and temporal cues were investigated in young, middle-aged and old animals. The results demonstrate that zebrafish aging is associated with changes in cognitive responses to emotionally positive and negative experiences, reduced generalization of adaptive associations, increased stereotypic and reduced exploratory behavior and altered temporal entrainment. Genetic upregulation of cholinergic transmission attenuates cognitive decline in middle-aged achesb55/+ mutants, compared to wild-type siblings. In contrast, the genotoxic stress of gamma-irradiation accelerates the onset of cognitive impairment in young zebrafish. Conclusions/Significance. These findings would allow the use of powerful molecular biological resources accumulated in the zebrafish field to address the mechanisms of cognitive senescence, and promote the search for therapeutic strategies which may attenuate age-related cognitive decline.
doi:10.1371/journal.pone.0000014 pmid:17183640 pmcid:PMC1762370 fatcat:moprxsfxtnapnatum7wpm4xtzu

Genomic Imprinting: A New Epigenetic Perspective of Sleep Regulation

Valter Tucci, Giovanni Bosco
2016 PLoS Genetics  
Overview A growing corpus of data indicates that epigenetic mechanisms regulate sleep and sleep-wake cycles. Here, I discuss recent evidence showing that genomic imprinting, an epigenetic mechanism that regulates parent-of-origin effects in mammals, is involved in the control of rapid eye movement (REM) sleep. REM sleep is an evolutionarily recent form of sleep that is characterized by important electrophysiological, metabolic, and thermoregulatory changes. The link between imprinting and REM
more » ... eep offers new insights into the epigenetic mechanisms underlying sleep physiology. Sleep is associated with significant changes in the expression of many genes, which suggests that sleep regulates a number of physiological and/or behavioural functions. Approximately 15% of transcripts across the genome oscillate along sleep-wake cycles, more than 40% of protein-coding genes oscillate in at least one tissue [1], and a number of molecular pathways sense epigenetic changes that depend on sleep. For example, sleep loss disrupts the circadian rhythm in 20% of the oscillating genes in the brain [2] and affects the DNA binding of clock genes by acting on the methylation state of their promoters [3] . Moreover, significant methylation changes have recently been reported in mice when their sleep-wake cycles are manipulated starting in the early stages of development after birth [4] . There are various theories for the function of sleep. For example, one theory was proposed that the function of sleep is to decrease energy demands, while another theory suggested that sleep is to restore cellular and subcellular processes [5] . At the moment, a new theory proposes that a positive selective pressure for sleep is associated with the role of sleep in fundamental mechanisms that regulate the communication between neurons [6] and, more generally, in connectivity processes that wire the brain [7] . Neuronal properties are the most frequently investigated functions of sleep, and these studies indicate that sleep has a significant role in cognitive processes (e.g., memory consolidation [8]). Novel insights are now emerging for the epigenetic mechanisms regulating sleep. In particular, the role of genomic imprinting in sleep regulation has been systematically studied in recent years. Genomic imprinting is an epigenetic mechanism that results in the allele-specific expression of approximately 200 genes according to the parental origin and is unique to mammals among vertebrates [9] . Imprinted genes play a crucial role in the placenta and prenatal development and, after birth, have been demonstrated to control important metabolic and physiological functions (e.g., thermogenesis) as well as behavioural and cognitive processes [10, 11] . Imprinted genes have important roles during the perinatal period [11] , which is a crucial time window in development, for the formation and integration of all biological systems, including the homeostatic control of sleep and the formation of the internal (circadian) clock [12, 13] .
doi:10.1371/journal.pgen.1006004 pmid:27228574 pmcid:PMC4881917 fatcat:ltjwsqkoy5fhrdbgqcoj3aejvq

Spatial Impairment and Memory in Genetic Disorders: Insights from Mouse Models

Sang Lee, Valter Tucci, Giorgio Vallortigara
2017 Brain Sciences  
All procedures were conducted under the Italian Policy, license issued to Valter Tucci on 19 June 2009, decreto N • 106/2009-B at the Italian Institute of Technology.  ... 
doi:10.3390/brainsci7020017 pmid:28208764 pmcid:PMC5332960 fatcat:tslqyznyffeuznnyvm2jmf2m3a

Sleep, Circadian Rhythms, and Interval Timing: Evolutionary Strategies to Time Information

Valter Tucci
2012 Frontiers in Integrative Neuroscience  
; Tucci et al., 2014).  ...  From a neurobiological and computational point of view, clock mechanisms can be seen as strategies that involve information processing of internal biological states at different time scales (Tucci, 2011  ...  Tinarelli, F., Nicassio, F., Garcia-Garcia, C., Tucci, V. (2014).  ... 
doi:10.3389/fnint.2011.00092 pmid:22319478 pmcid:PMC3250947 fatcat:nbld6jsn6vb5pdmh2755tc5one

Sleep, Circadian Rhythms and Interval Timing: Evolutionary Strategies to Time Information

Valter Tucci
2014 Procedia - Social and Behavioral Sciences  
; Tucci et al., 2014).  ...  From a neurobiological and computational point of view, clock mechanisms can be seen as strategies that involve information processing of internal biological states at different time scales (Tucci, 2011  ...  Tinarelli, F., Nicassio, F., Garcia-Garcia, C., Tucci, V. (2014).  ... 
doi:10.1016/j.sbspro.2014.02.300 fatcat:y7j4ex7knrgexpidc7jgi2naz4

Sound-Driven Synaptic Inhibition in Primary Visual Cortex

Giuliano Iurilli, Diego Ghezzi, Umberto Olcese, Glenda Lassi, Cristiano Nazzaro, Raffaella Tonini, Valter Tucci, Fabio Benfenati, Paolo Medini
2012 Neuron  
Multimodal objects and events activate many sensory cortical areas simultaneously. This is possibly reflected in reciprocal modulations of neuronal activity, even at the level of primary cortical areas. However, the synaptic character of these interareal interactions, and their impact on synaptic and behavioral sensory responses are unclear. Here, we found that activation of auditory cortex by a noise burst drove local GABAergic inhibition on supragranular pyramids of the mouse primary visual
more » ... rtex, via cortico-cortical connections. This inhibition was generated by sound-driven excitation of a limited number of cells in infragranular visual cortical neurons. Consequently, visually driven synaptic and spike responses were reduced upon bimodal stimulation. Also, acoustic stimulation suppressed conditioned behavioral responses to a dim flash, an effect that was prevented by acute blockade of GABAergic transmission in visual cortex. Thus, auditory cortex activation by salient stimuli degrades potentially distracting sensory processing in visual cortex by recruiting local, translaminar, inhibitory circuits.
doi:10.1016/j.neuron.2011.12.026 pmid:22365553 pmcid:PMC3315003 fatcat:lv2xrojy4fc2dlm7pk357hxjtu

A Simplified In vitro Experimental Model Encompasses the Essential Features of Sleep

Ilaria Colombi, Federico Tinarelli, Valentina Pasquale, Valter Tucci, Michela Chiappalone
2016 Frontiers in Neuroscience  
Copyright © 2016 Colombi, Tinarelli, Pasquale, Tucci and Chiappalone. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY).  ... 
doi:10.3389/fnins.2016.00315 pmid:27458335 pmcid:PMC4935686 fatcat:6x77gty7lbbhrmbsyybfjwsmda

Corrigendum: A Simplified In vitro Experimental Model Encompasses the Essential Features of Sleep

Ilaria Colombi, Federico Tinarelli, Valentina Pasquale, Valter Tucci, Michela Chiappalone
2016 Frontiers in Neuroscience  
., Tucci, V., and Chiappalone, M. (2016). Front. Neurosci. 10:315. doi: 10.3389/fnins.2016.00315 Frontiers in Neuroscience | September 2016 | Volume 10 | Article 409  ...  Copyright © 2016 Colombi, Tinarelli, Pasquale, Tucci and Chiappalone. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY).  ... 
doi:10.3389/fnins.2016.00409 pmid:27610075 pmcid:PMC5013038 fatcat:7ynzyneklnb6vi4nxuclpohtpe

The paternally imprinted gene Snord116 regulates cortical neuronal activity [article]

Marta Pace, Ilaria Colombi, Matteo Falappa, Andrea Freschi, Mojtaba Bandarabadi, Andrea Armirotti, Blanco Maria Encarnacion, Antoine R. Adamantidis, Amici Roberto, Matteo Cerri, Michela Chiappalone, Valter Tucci
2019 bioRxiv   pre-print
Tucci, & M. Chiappalone, 2016), in mice carrying a paternal deletion of the Snord116 gene (PWScr m+/p-) (Skryabin et al., 2007) and in wild-type mice (PWScr m+/p+ ).  ...  For the sleep analysis, Phenopy was used (Balzani, Falappa, Balci, & Tucci, 2018), while GraphPad Prism6 (GraphPad Prism Software, Inc.) was used for statistical analysis.  ... 
doi:10.1101/809822 fatcat:oyhc55t77ffxlnaypwnhtddbfi

Lithium rescues synaptic plasticity and memory in Down syndrome mice

Andrea Contestabile, Barbara Greco, Diego Ghezzi, Valter Tucci, Fabio Benfenati, Laura Gasparini
2012 Journal of Clinical Investigation  
Down syndrome (DS) patients exhibit abnormalities of hippocampal-dependent explicit memory, a feature that is replicated in relevant mouse models of the disease. Adult hippocampal neurogenesis, which is impaired in DS and other neuropsychiatric diseases, plays a key role in hippocampal circuit plasticity and has been implicated in learning and memory. However, it remains unknown whether increasing adult neurogenesis improves hippocampal plasticity and behavioral performance in the
more » ... context of DS. We report that, in the Ts65Dn mouse model of DS, chronic administration of lithium, a clinically used mood stabilizer, promoted the proliferation of neuronal precursor cells through the pharmacological activation of the Wnt/ β-catenin pathway and restored adult neurogenesis in the hippocampal dentate gyrus (DG) to physiological levels. The restoration of adult neurogenesis completely rescued the synaptic plasticity of newborn neurons in the DG and led to the full recovery of behavioral performance in fear conditioning, object location, and novel object recognition tests. These findings indicate that reestablishing a functional population of hippocampal newborn neurons in adult DS mice rescues hippocampal plasticity and memory and implicate adult neurogenesis as a promising therapeutic target to alleviate cognitive deficits in DS patients. Conflict of interest: The authors have declared that no conflict of interest exists. Citation for this article: J Clin Invest. plasticity and behavioral performance in the multifactorial context of DS. In this study, we used 5-to 6-month-old adult Ts65Dn mice to investigate this critical point. To enhance neurogenesis, the mice were treated with lithium, a mood-stabilizing agent that specifically stimulates the proliferation of NPCs through the Wnt pathway (37, 38) without affecting gliogenesis (39) . The results showed that DG adult neurogenesis could be restored to physiological levels after 4 weeks of lithium administration in the Ts65Dn trisomic mouse, resulting in the full recovery of DG synaptic plasticity and hippocampal-dependent cognitive functions, as determined using contextual fear conditioning (CFC), object location (OL), and novel object recognition (NOR) tasks. We also demonstrated that lithium treatment increased neurogenesis by stimulating NPC proliferation via the Wnt/ β-catenin pathway without affecting fate determination and newborn neuron survival. Results Adult neurogenesis in the DG of Ts65Dn mice is restored to physiological levels using lithium. We initially examined the number of newborn neurons in the Ts65Dn DG and established a protocol for promoting adult neurogenesis through the administration of lithium, a widely used mood stabilizer that stimulates the proliferation of NPCs via Wnt signaling (37, 38). To visualize newborn neurons, we evaluated the early neuronal marker doublecortin (DCX), which is expressed from the late precursor stage until 3 to 4 weeks after newly generated neurons become postmitotic ( Figure 1A and ref. 40) . We observed that the number of maturing newborn neurons expressing DCX was reduced by 60% in the DG of untreated Ts65Dn mice (Figure 1 , B and C). Four weeks of treatment with lithium (Li 2 CO 3 , 2.4 g/kg of chow) fully restored the number of DCX + neurons in the DG of trisomic mice to levels comparable with those of untreated WT littermates (Figure 1, B and C) . The number of DCX + newborn neurons was also augmented in the lithium-treated WT mice. However, the lithium-induced increase was much higher in trisomic mice (174%) than in the WT littermates (50%). Similar results were obtained when neurogenesis was evaluated using the neuronal marker calretinin (CR), which is transiently expressed in adult-born neurons until 1 to 2 weeks after their birth (Figure 1A and ref. 40). The number of CR + neurons was reduced by 45% in the DG of untreated Ts65Dn mice and increased in both WT mice (53%) and trisomic littermates (173%) after lithium treatment (Figure 1, D and E) . Enhancing adult neurogenesis rescues DG synaptic plasticity in Ts65Dn mice. Next, we examined whether the reduced neurogenesis in Ts65Dn mice was associated with impaired DG synaptic plasticity (29) and whether lithium-rescued newborn neurons were physiologically functional. It has been demonstrated that, at 3 to 4 weeks after becoming postmitotic, maturing newborn neurons exhibit unique electrophysiological features, including increased excitability, enhanced synaptic plasticity, insensitivity to GABA inhibition, and a lower threshold for the induction of long-term potentiation (LTP) than mature DGCs (2-4, 6, 8). Neurogenesis-dependent LTP relies on the activation of glutamate receptors containing the NR2B subunit and can be induced in the DG in the presence of intact GABAergic inhibition.
doi:10.1172/jci64650 pmid:23202733 pmcid:PMC3533293 fatcat:kkbk5ihj5bauzd4s37wq7vuexu

Paternally expressed imprinted Snord116 and Peg3 regulate hypothalamic orexin neurons [article]

Marta Pace, Matteo Falappa, Andrea Freschi, Edoardo Balzani, Chiara Berteotti, Viviana Lo Martire, Fatemeh Kaveh, Eivind Hovig, Giovanna Zoccoli, Matteo Cerri, Roberto Amici, Alfonso Urbanucci (+1 others)
2019 bioRxiv   pre-print
Imprinted genes are highly expressed in the hypothalamus; however, whether specific imprinted genes affect hypothalamic neuromodulators and their functions is unknown. It has been suggested that Prader-Willi syndrome (PWS), a neurodevelopmental disorder caused by lack of paternal expression at chromosome 15q11-q13, is characterised by hypothalamic insufficiency. Here, we investigate the role of the paternally expressed Snord116 gene within the context of sleep and metabolic abnormalities of
more » ... and we report a novel role of this imprinted gene in the function and organisation of the two main neuromodulatory systems of the lateral hypothalamus (LH), namely, the orexin (OX) and melanin concentrating hormone (MCH) systems. We observe that the dynamics between neuronal discharge in the LH and the sleep-wake states of mice with paternal deletion of Snord116 (PWScrm+/p-) are compromised. This abnormal state-dependent neuronal activity is paralleled by a significant reduction in OX neurons in the LH of mutants. Therefore, we propose that an imbalance between OX- and MCH-expressing neurons in the LH of mutants reflects a series of deficits manifested in the PWS, such as dysregulation of rapid eye movement (REM) sleep, food intake and temperature control.
doi:10.1101/820738 fatcat:mvharhbfzrh4lpo3dkbfz3ca3u

Working memory and reference memory tests of spatial navigation in mice (Mus musculus)

Sang Ah Lee, Valter Tucci, Valeria Anna Sovrano, Giorgio Vallortigara
2015 Journal of Comparative Psychology  
Researchers in spatial cognition have debated for decades the specificity of the mechanisms through which spatial information is processed and stored. Interestingly, although rodents are the preferred animal model for studying spatial navigation, the behavioral methods traditionally used to assess spatial memory do not effectively test the predictions of specificity in their representation. To address such issues, the present study tested the ability of mice to use boundary geometry and
more » ... to remember a goal location across 2 types of tasks-a working memory task with a changing goal location, and a reference memory task with 1 rewarded goal location. We show for the first time that mice, like other animals, can successfully encode boundary geometry in a working memory spatial mapping task, just as they do in a reference memory task. Their use of a nongeometric featural cue (striped pattern), in contrast, was more limited in the working memory task, although it quickly improved in the reference memory task. We discuss the implications of these findings for future research on the neural and genetic underpinnings of spatial representations.
doi:10.1037/a0039129 pmid:25984938 fatcat:tdtozjcwofd55gfrjzftvbx3rm

The Zfhx3-Mediated Axis Regulates Sleep and Interval Timing in Mice

Edoardo Balzani, Glenda Lassi, Silvia Maggi, Siddharth Sethi, Michael J. Parsons, Michelle Simon, Patrick M. Nolan, Valter Tucci
2016 Cell Reports  
Highlights d The Zfhx3 Sci/+ mutation leads to a defect in sleep homeostasis d This mutation accelerates biological timers across timescales d The Zfhx3 Sci/+ -dependent gene network contains a significant number of sleep targets d Sleep and the circadian clock are predictors of behavioral performance in mice
doi:10.1016/j.celrep.2016.06.017 pmid:27373158 pmcid:PMC5991551 fatcat:cnb4tbzb6bhonh6ozrkqgtw5wm

The development of synaptic transmission is time-locked to early social behaviors in rats

Shovan Naskar, Roberto Narducci, Edoardo Balzani, Andrzej W. Cwetsch, Valter Tucci, Laura Cancedda
2019 Nature Communications  
The development of functional synapses is a sequential process preserved across many brain areas. Here, we show that glutamatergic postsynaptic currents anticipated GABAergic currents in Layer II/III of the rat neocortex, in contrast to the pattern described for other brain areas. The frequencies of both glutamatergic and GABAergic currents increased abruptly at the beginning of the second postnatal week, supported by a serotonin upsurge. Integrative behaviors arose on postnatal day (P)9, while
more » ... most motor and sensory behaviors, which are fundamental for pup survival, were already in place at approximately P7. A reduction in serotonin reuptake accelerated the development of functional synapses and integrative huddling behavior, while sparing motor and sensory function development. A decrease in synaptic transmission in Layer II/III induced by a chemogenetic approach only inhibited huddling. Thus, precise developmental sequences mediate early, socially directed behaviors for which neurotransmission and its modulation in supragranular cortical layers play key roles.
doi:10.1038/s41467-019-09156-3 pmid:30867422 pmcid:PMC6416358 fatcat:giwf3qhntbgenm4hr4k5aefnkq

Metformin promotes tau aggregation and exacerbates abnormal behavior in a mouse model of tauopathy

Erica Barini, Odetta Antico, Yingjun Zhao, Francesco Asta, Valter Tucci, Tiziano Catelani, Roberto Marotta, Huaxi Xu, Laura Gasparini
2016 Molecular Neurodegeneration  
Alzheimer disease (AD) and other tauopathies develop cerebral intracellular inclusions of hyperphosphorylated tau. Epidemiological and experimental evidence suggests a clear link between type 2 diabetes mellitus and AD. In AD animal models, tau pathology is exacerbated by metabolic comorbidities, such as insulin resistance and diabetes. Within this context, anitidiabetic drugs, including the widely-prescribed insulin-sensitizing drug metformin, are currently being investigated for AD therapy.
more » ... wever, their efficacy for tauopathy in vivo has not been tested. Results: Here, we report that in the P301S mutant human tau (P301S) transgenic mouse model of tauopathy, chronic administration of metformin exerts paradoxical effects on tau pathology. Despite reducing tau phosphorylation in the cortex and hippocampus via AMPK/mTOR and PP2A, metformin increases insoluble tau species (including tau oligomers) and the number of inclusions with β-sheet aggregates in the brain of P301S mice. In addition, metformin exacerbates hindlimb atrophy, increases P301S hyperactive behavior, induces tau cleavage by caspase 3 and disrupts synaptic structures. Conclusions: These findings indicate that metformin pro-aggregation effects mitigate the potential benefits arising from its dephosphorylating action, possibly leading to an overall increase of the risk of tauopathy in elderly diabetic patients.
doi:10.1186/s13024-016-0082-7 pmid:26858121 pmcid:PMC4746897 fatcat:ysnos4dxwre43pzfgmcu43lvee
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