Publications by authors named "Giovanni Laviola"

159 Publications

Social Interactions of Dat-Het Epi-Genotypes Differing for Maternal Origins: The Development of a New Preclinical Model of Socio-Sexual Apathy.

Biomedicines 2021 Jul 5;9(7). Epub 2021 Jul 5.

Center for Behavioral Sciences and Mental Health, Istituto Superiore di Sanità, 00161 Rome, Italy.

Social interaction is essential for life but is impaired in many psychiatric disorders. We presently focus on rats with a truncated allele for dopamine transporter (DAT). Since heterozygous individuals possess only one non-mutant allele, epigenetic interactions may unmask latent genetic predispositions. Homogeneous "maternal" heterozygous offspring (termed MAT-HET) were born from dopamine-transporter knocked-out (DAT-KO) male rats and wild-type (WT) mothers; "mixed" heterozygous offspring (termed MIX-HET) were born from both DAT-heterozygous parents. Their social behavior was assessed by: partner-preference (PPT), social-preference (SPT) and elicited-preference (EPT) tests. During the PPT, focal MIX-HET and MAT-HET males had a choice between two WT females, one in estrous and the other not. In the SPT, they met as stimulus either a MIX-HET or a WT male. In the EPT, the preference of focal male WT rats towards either a MIX- or a MAT-HET stimulus was tested. MIX-HET focal males showed an abnormal behavior, seeming not interested in socializing either with a female in estrous or with another male if MIX-HET. Focal MAT-HET males, instead, were very attracted by the female in estrous, but totally ignored the MIX-HET male. We assessed the expression of noradrenaline transporter (NET) in prefrontal cortex, hippocampus and hypothalamus, finding differences between the two offspring. MIX-HETs' hypothalamus and hippocampus showed less NET than MAT-HETs, while the latter, in turn, showed higher NET than WTs. These behavioral differences between heterozygous groups may be attributed to different maternal cares received. Results allow preclinical understanding of epigenetic factors involved in social-behavior abnormalities, typical of many psychiatric disorders.
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http://dx.doi.org/10.3390/biomedicines9070778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8301365PMC
July 2021

Treatment with the Bacterial Toxin CNF1 Selectively Rescues Cognitive and Brain Mitochondrial Deficits in a Female Mouse Model of Rett Syndrome Carrying a MeCP2-Null Mutation.

Int J Mol Sci 2021 Jun 23;22(13). Epub 2021 Jun 23.

Center for Behavioral Sciences and Mental Health, Istituto Superiore di Sanità, 00161 Rome, Italy.

Rett syndrome (RTT) is a rare neurological disorder caused by mutations in the X-linked gene and a major cause of intellectual disability in females. No cure exists for RTT. We previously reported that the behavioural phenotype and brain mitochondria dysfunction are widely rescued by a single intracerebroventricular injection of the bacterial toxin CNF1 in a RTT mouse model carrying a truncating mutation of the gene (MeCP2-308 mice). Given the heterogeneity of mutations in RTT patients, we tested the CNF1 therapeutic efficacy in a mouse model carrying a null mutation (MeCP2-Bird mice). CNF1 selectively rescued cognitive defects, without improving other RTT-related behavioural alterations, and restored brain mitochondrial respiratory chain complex activity in MeCP2-Bird mice. To shed light on the molecular mechanisms underlying the differential CNF1 effects on the behavioural phenotype, we compared treatment effects on relevant signalling cascades in the brain of the two RTT models. CNF1 provided a significant boost of the mTOR activation in MeCP2-308 hippocampus, which was not observed in the MeCP2-Bird model, possibly explaining the differential effects of CNF1. These results demonstrate that CNF1 efficacy depends on the mutation beared by MeCP2-mutated mice, stressing the need of testing potential therapeutic approaches across RTT models.
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http://dx.doi.org/10.3390/ijms22136739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8269120PMC
June 2021

Callous unemotional trait-like mice and their stressed dams.

Psychoneuroendocrinology 2021 Sep 9;131:105296. Epub 2021 Jun 9.

Institute of Biochemistry and Cell Biology - IBBC - CNR, Viale del Policlinico 155, 00161 Rome, Italy.

The co-occurrence of excess rates of aggression, general violation of societal norms and callous-unemotional trait confers specific risk for adult psychopathy. With the aim to address experimentally a model of conduct disorder, we investigated the male offspring of individual mouse dams characterized by high basal plasma corticosterone concentration (HC trait). Notably, classification indices correlated selectively in these females with quite poor maternal care devoted to their offspring. Contrary to their HC mothers, adult male offspring exhibited an integrated profile of dampened physiological reactivity to external stressors co-occurring poor sociability/emotional contagion, impaired punishment-induced memory, and exacerbated aggression. A significant reduction of glucocorticoid and opioid mu receptors' expression in frontal cortex of model HC offspring was also evidenced. Moreover, in the absence of changes in oxytocin receptor in behaviorally-relevant neural areas, we showed that intranasal oxytocin administration (0 or 20.0 µg/kg) selectively modulated specific components of the behavioral phenotype. Ultimately, current data support the notion that maternally-inoculated environmental stress early in development may represent a critical risk factor in disturbances characterised by abnormal aggression and excess callousness.
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http://dx.doi.org/10.1016/j.psyneuen.2021.105296DOI Listing
September 2021

Aberrant Early in Life Stimulation of the Stress-Response System Affects Emotional Contagion and Oxytocin Regulation in Adult Male Mice.

Int J Mol Sci 2021 May 10;22(9). Epub 2021 May 10.

Institute of Biochemistry and Cell Biology, IBBC, CNR, Viale del Policlinico 155, 00161 Rome, Italy.

Results over the last decades have provided evidence suggesting that HPA axis dysfunction is a major risk factor predisposing to the development of psychopathological behaviour. This susceptibility can be programmed during developmental windows of marked neuroplasticity, allowing early-life adversity to convey vulnerability to mental illness later in life. Besides genetic predisposition, also environmental factors play a pivotal role in this process, through embodiment of the mother's emotions, or via nutrients and hormones transferred through the placenta and the maternal milk. The aim of the current translational study was to mimic a severe stress condition by exposing female CD-1 mouse dams to abnormal levels of corticosterone (80 µg/mL) in the drinking water either during the last week of pregnancy (PreCORT) or the first one of lactation (PostCORT), compared to an Animal Facility Rearing (AFR) control group. When tested as adults, male mice from PostCORT offspring and somewhat less the PreCORT mice exhibited a markedly increased corticosterone response to acute restraint stress, compared to perinatal AFR controls. Aberrant persistence of adolescence-typical increased interest towards novel social stimuli and somewhat deficient emotional contagion also characterised profiles in both perinatal-CORT groups. Intranasal oxytocin (0 or 20.0 µg/kg) generally managed to reduce the stress response and restore a regular behavioural phenotype. Alterations in density of glucocorticoid and mineralocorticoid receptors, oxytocin and µ- and κ-opioid receptors were found. Changes differed as a function of brain areas and the specific age window of perinatal aberrant stimulation of the HPA axis. Present results provided experimental evidence in a translational mouse model that precocious adversity represents a risk factor predisposing to the development of psychopathological behaviour.
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http://dx.doi.org/10.3390/ijms22095039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8126076PMC
May 2021

"Himalayan Bridge": A New Unstable Suspended Bridge to Investigate Rodents' Venturesome Behavior.

Front Behav Neurosci 2021 28;15:637074. Epub 2021 Apr 28.

Center for Behavioural Sciences and Mental Health, Istituto Superiore di Sanità, Rome, Italy.

While both risk-taking and avoidant behaviors are necessary for survival, their imbalanced expression can lead to impulse-control and anxiety disorders, respectively. In laboratory rodents, the conflict between risk proneness and anxiety can be studied by using their innate fear of heights. To explore this aspect in detail and investigate venturesome behavior, here we used a "Himalayan Bridge," a rat-adapted version of the suspended wire bridge protocol originally developed for mice. The apparatus is composed of two elevated scaffolds connected by bridges of different lengths and stability at 1 m above a foam rubber-covered floor. Rats were allowed to cross the bridge to reach food, and crossings, pawslips, turnabouts, and latencies to cross were measured. Given the link between risky behavior and adolescence, we used this apparatus to investigate the different responses elicited by a homecage mate on the adolescent development of risk-taking behavior. Thus, 24 wild-type (WT) subjects were divided into three different housing groups: WT rats grown up with WT adult rats; control WT adolescent rats (grown up with WT adolescents), which showed a proclivity to risk; and WT rats grown up with an adult rat harboring a truncated mutation for their dopamine transporter (DAT). This latter group exhibited risk-averse responses reminiscent of lower venturesomeness. Our results suggest that the Himalayan Bridge may be useful to investigate risk perception and seeking; thus, it should be included in the behavioral phenotyping of rat models of psychiatric disorders and cognitive dysfunctions.
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http://dx.doi.org/10.3389/fnbeh.2021.637074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113634PMC
April 2021

Stimulation of the Serotonin Receptor 7 Restores Brain Histone H3 Acetylation and MeCP2 Corepressor Protein Levels in a Female Mouse Model of Rett Syndrome.

J Neuropathol Exp Neurol 2021 Feb;80(3):265-273

Center for Behavioral Sciences and Mental Health, Istituto Superiore di Sanità, Roma, Italy.

Rett syndrome (RTT) is a rare neurological disorder caused by mutations in the X-linked MECP2 gene, characterized by severe behavioral and physiological impairments for which no cure is available. The stimulation of serotonin receptor 7 (5-HT7R) with its selective agonist LP-211 (0.25 mg/kg/day for 7 days) was proved to rescue neurobehavioral alterations in a mouse model of RTT. In the present study, we aimed at gaining insight into the mechanisms underpinning the efficacy of 5-HT7R pharmacological stimulation by investigating its epigenetic outcomes in the brain of RTT female mice bearing a truncating MeCP2 mutation. Treatment with LP-211 normalized the reduced histone H3 acetylation and HDAC3/NCoR levels, and increased HDAC1/Sin3a expression in RTT mouse cortex. Repeated 5-HT7R stimulation also appeared to strengthen the association between NCoR and MeCP2 in the same brain region. A different profile was found in RTT hippocampus, where LP-211 rescued H3 hyperacetylation and increased HDAC3 levels. Overall, the present data highlight a new scenario on the relationship between histone acetylation and serotoninergic pathways. 5-HT7R is confirmed as a pivotal therapeutic target for the recovery of neuronal function supporting the translational value of this promising pharmacological approach for RTT.
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http://dx.doi.org/10.1093/jnen/nlaa158DOI Listing
February 2021

Publisher Correction: Mice repeatedly exposed to Group-A β-Haemolytic Streptococcus show perseverative behaviors, impaired sensorimotor gating, and immune activation in rostral diencephalon.

Sci Rep 2020 Aug 3;10(1):13014. Epub 2020 Aug 3.

Sect. Behavioural Neuroscience, Dept. Cell Biology & Neuroscience, Istituto Superiore di Sanità, Viale Regina Elena, 299, I-00161, Roma, Italy.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41598-020-69954-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7398902PMC
August 2020

Striatal dynamics as determinants of reduced gambling vulnerability in the NHE rat model of ADHD.

Prog Neuropsychopharmacol Biol Psychiatry 2020 06 8;100:109886. Epub 2020 Feb 8.

Center for Behavioral Science and Mental Health, Istituto Superiore di Sanità, Rome, Italy; Faculty of Psychology, International Telematic University "Uninettuno", Rome, Italy. Electronic address:

The Naples High-Excitability (NHE) is a validated rat strain to model for a mesocortical variant of Attention Deficit Hyperactivity Disorder (ADHD). NHE rats' brains have a tuned-down cortical and a potentiated limbic loop (Zoratto et al., 2017). ADHD and comorbid pathological gambling (PG) involve similar deficits of prefrontal-striatal dialogue. This work aimed to understand if NHE rats (compared to normal random-bred rats, NRB) can be a useful model for gambling vulnerability in ADHD. Experiment 1 evaluated gambling proneness in NHE rats, namely attraction/avoidance in nose-poking for a "Large & Luck-Linked" (LLL) reward (versus a "Small & Sure" one, SS), when the probability of LLL delivery was progressively reduced. Experiment 2 assessed (by phMRI) differential responsivity of ventral (vStr) versus dorsal (dStr) striatum following a methylphenidate (MPH, 4 mg/kg I.P.) challenge. In NHE rats, reduced attraction by secondary cues (associated with uncertain, rarefying LLL delivery) comes along with little or no activation of dStr and enhanced activation of vStr by MPH. Together, such evidences from NHE rats indicate distinctive roles of ventral (enhanced value given to actual primary reward) and dorsal (lower encoding of repeated stimulus-reward associations into a habit) striatum. In conclusion, the dynamics of reward systems could link an attention deficit with a decreased vulnerability to pathological gambling.
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http://dx.doi.org/10.1016/j.pnpbp.2020.109886DOI Listing
June 2020

Anatomical and behavioral impact of a lentiviral tool tapping onto hippocampal serotonin reuptake in rats.

Synapse 2020 04 11;74(4):e22138. Epub 2019 Nov 11.

Core Facilities, Istituto Superiore di Sanità, Rome, Italy.

We aimed at the further characterization of rats in which SERT gene silencing was achieved by hippocampal injection of a lentiviral vector, carrying three si-RNA to block SERT mRNA at 66% of normal levels. Improved self-control and reduced restlessness were already demonstrated in these rats. Present further studies consisted of male adult rats, bilaterally inoculated within the hippocampus; control rats received lentivirus particles inactivated with heat. Both groups were maintained in isolation for 5 months, starting from inoculation. Neurochemical changes were studied by proton magnetic resonance spectroscopy (1H-MRS): we found increased hippocampal viability and bioenergetic potential; however, rats showed a behaviorally depressive pattern, also characterized by enhanced affiliation. Based on the extent of such effects, the whole lenti-SERT group was divided into two subgroups, termed intermediate- and extreme- phenotype profiles. While all rats had a widespread modification within dorsal/ventral striatum, amygdala, and hypothalamus, only the former subgroup showed an involvement of Raphé medialis, while, for the latter subgroup, an increase of SERT within hippocampus was unexpectedly caused. Within the less-affected "intermediate" rats, hippocampal 5-HT7 receptors were down-modulated, and also similarly within substantia nigra, septum, and neocortex. This picture demonstrates that additional rather than fewer neurobiological changes accompany a lower phenotypic expression. Overall, tapping hippocampal SERT affected the balance between habits versus strategies of coping by promoting morphogenetic processes indicative of a serotonergic fiber plasticity. Supplementary studies about serotonergic dynamics and neurogenesis within fronto-striatal circuits are needed.
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http://dx.doi.org/10.1002/syn.22138DOI Listing
April 2020

Brain-Immune Alterations and Mitochondrial Dysfunctions in a Mouse Model of Paediatric Autoimmune Disorder Associated with Streptococcus: Exacerbation by Chronic Psychosocial Stress.

J Clin Med 2019 Sep 20;8(10). Epub 2019 Sep 20.

Centre for Behavioural Sciences and Mental Health, Istituto Superiore di Sanità, Viale Regina Elena, 299, I-00161 Rome, Italy.

Adverse psychosocial experiences have been shown to modulate individual responses to immune challenges and affect mitochondrial functions. The aim of this study was to investigate inflammation and immune responses as well as mitochondrial bioenergetics in an experimental model of Paediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus (PANDAS). Starting in adolescence (postnatal day 28), male SJL/J mice were exposed to five injections (interspaced by two weeks) with Group-A beta-haemolytic streptococcus (GAS) homogenate. Mice were exposed to chronic psychosocial stress, in the form of protracted visual exposure to an aggressive conspecific, for four weeks. Our results indicate that psychosocial stress exacerbated individual response to GAS administrations whereby mice exposed to both treatments exhibited altered cytokine and immune-related enzyme expression in the hippocampus and hypothalamus. Additionally, they showed impaired mitochondrial respiratory chain complexes IV and V, and reduced adenosine triphosphate (ATP) production by mitochondria and ATP content. These brain abnormalities, observed in GAS-Stress mice, were associated with blunted titers of plasma corticosterone. Present data support the hypothesis that challenging environmental conditions, in terms of chronic psychosocial stress, may exacerbate the long-term consequences of exposure to GAS processes through the promotion of central immunomodulatory and oxidative stress.
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http://dx.doi.org/10.3390/jcm8101514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6833026PMC
September 2019

Reduced adolescent risk-assessment and lower nicotinic beta-2 expression in rats exposed to nicotine through lactation by forcedly drinking dams.

Neuroscience 2019 08 19;413:64-76. Epub 2019 Jun 19.

Reference Centre for Behavioural Sciences and Mental Health, Istituto Superiore di Sanità, Rome, Italy. Electronic address:

Few animal studies focus on consequences of nicotine postnatal exposure, particularly through lactation. We have recently shown that forced nicotine drinking elevates maternal care, paradoxically provoking arousal and stress in pups. Present work aimed to evaluate the specific contribution of altered maternal cares, compared to the sequelae merely due to nicotine effects. Two groups were compared to water-drinking control dams: (i) free-choice dams (H2O+NIC group) drinking from two bottles, containing either nicotine or water; (ii) forced dams (NIC+NIC group) drinking from two bottles, both containing nicotine. We previously demonstrated that nicotine was indeed transferred to the lactating offspring. Regarding behavioural consequences at adolescence, both H2O+NIC and NIC+NIC rats were slower than controls in discovering a novel over a familiar compartment, whilst only NIC+NIC rats exhibited reduced risk-related avoidance and assessment behaviour. Brain analyses at adulthood suggest that, in prefrontal cortex, nicotine per se reduced serotonin, while the maternal overcare reduced CHRN-B2 gene-expression. As a whole, unescapable nicotine-enhanced maternal care could have an impact on the offspring arousal by acting on prefrontal CHRN-B2 gene-expression. When present results are translated to consequences of non-voluntary exposure in humans, we propose that children receiving altered attentions by a smoking caregiver might undergo a neuro-behavioural development biased towards emotional shyness.
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http://dx.doi.org/10.1016/j.neuroscience.2019.06.014DOI Listing
August 2019

Rett syndrome before regression: A time window of overlooked opportunities for diagnosis and intervention.

Neurosci Biobehav Rev 2019 12 18;107:115-135. Epub 2019 May 18.

Center for Behavioral Sciences and Mental Health, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161 Rome, Italy. Electronic address:

Rett syndrome (RTT) is a rare neurological disorder primarily affecting females, causing severe cognitive, social, motor and physiological impairments for which no cure currently exists. RTT clinical diagnosis is based on the peculiar progression of the disease, since patients show an apparently normal initial development with a subsequent sudden regression at around 2 years of age. Accumulating evidences are rising doubts regarding the absence of early impairments, hence questioning the concept of regression. We reviewed the published literature addressing the pre-symptomatic stage of the disease in both patients and animal models with a particular focus on behavioral, physiological and brain abnormalities. The emerging picture delineates subtle, but reliable impairments that precede the onset of overt symptoms whose bases are likely set up already during embryogenesis. Some of the outlined alterations appear transient, suggesting compensatory mechanisms to occur in the course of development. There is urgent need for more systematic developmental analyses able to detect early pathological markers to be used as diagnostic tools and precocious targets of time-specific interventions.
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http://dx.doi.org/10.1016/j.neubiorev.2019.05.013DOI Listing
December 2019

Methylphenidate administration promotes sociability and reduces aggression in a mouse model of callousness.

Psychopharmacology (Berl) 2019 Sep 6;236(9):2593-2611. Epub 2019 Apr 6.

Reference Centre for Behavioural Sciences and Mental Health, Istituto Superiore di Sanità, Viale Regina Elena 299, I-00161, Rome, Italy.

Rationale: Deficits in empathy constitute a distinctive feature of several psychopathologies, including conduct disorder (CD). The co-occurrence of callous-unemotional (CU) traits, excess rates of aggression and violation of societal norms confers specific risk for adult psychopathy. To date, the off-label use of methylphenidate (MPH) constitutes the drug treatment of choice.

Objectives: Herein, we tested the therapeutic potential of MPH in a recently devised mouse model recapitulating the core phenotypic abnormalities of CD.

Methods: Two subgroups of BALB/cJ male mice exhibiting opposite profiles of emotional contagion (i.e. socially transmitted adoption of another's emotional states) were investigated for reactive aggression, sociability, attention control, anxiety-related behaviours and locomotor activity, in response to MPH administration (0.0, 3.0 or 6.0 mg/kg).

Results: Our data indicate that mice selected for excess callousness exhibit phenotypic abnormalities isomorphic to the symptoms of CD: stability of the low emotional contagion trait, increased aggression and reduced sociability. In accordance with our predictions, MPH reduced aggression and increased sociability in callous mice; yet, it failed to restore the low responsiveness to the emotions of a conspecific in pain, isomorphic to CU traits.

Conclusions: Although our data support the notion that MPH may contribute to the management of excess aggression in CD patients, additional studies shall identify specific treatments to target the callousness domain. The latter, unaffected by MPH in our experimental model, demands focused consideration whereby it constitutes a specifier associated with a worse prognosis.
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http://dx.doi.org/10.1007/s00213-019-05229-9DOI Listing
September 2019

Rescue of prepulse inhibition deficit and brain mitochondrial dysfunction by pharmacological stimulation of the central serotonin receptor 7 in a mouse model of CDKL5 Deficiency Disorder.

Neuropharmacology 2019 01 13;144:104-114. Epub 2018 Oct 13.

Center for Behavioral Sciences and Mental Health, Istituto Superiore di Sanità, 00161 Rome, Italy. Electronic address:

Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene cause CDKL5 Deficiency Disorder (CDD), a rare neurodevelopmental syndrome characterized by severe behavioural and physiological symptoms. No cure is available for CDD. CDKL5 is a kinase that is abundantly expressed in the brain and plays a critical role in neurodevelopmental processes, such as neuronal morphogenesis and plasticity. This study provides the first characterization of the neurobehavioural phenotype of 1 year old Cdkl5-null mice and demonstrates that stimulation of the serotonin receptor 7 (5-HTR) with the agonist molecule LP-211 (0.25 mg/kg once/day for 7 days) partially rescues the abnormal phenotype and brain molecular alterations in Cdkl5-null male mice. In particular, LP-211 treatment completely normalizes the prepulse inhibition defects observed in Cdkl5-null mice and, at a molecular level, restores the abnormal cortical phosphorylation of rpS6, a downstream target of mTOR and S6 kinase, which plays a direct role in regulating protein synthesis. Moreover, we demonstrate for the first time that mitochondria show prominent functional abnormalities in Cdkl5-null mouse brains that can be restored by pharmacological stimulation of brain 5-HTR.
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http://dx.doi.org/10.1016/j.neuropharm.2018.10.018DOI Listing
January 2019

Inside the Developing Brain to Understand Teen Behavior From Rat Models: Metabolic, Structural, and Functional-Connectivity Alterations Among Limbic Structures Across Three Pre-adolescent Stages.

Front Behav Neurosci 2018 24;12:208. Epub 2018 Sep 24.

Core Facilities, Istituto Superiore di Sanità, Rome, Italy.

Adolescence is an age of transition when most brain structures undergo drastic modifications, becoming progressively more interconnected and undergoing several changes from a metabolic and structural viewpoint. In the present study, three MR techniques are used in rats to investigate how metabolites, structures and patterns of connectivity do change. We focused in particular on areas belonging to the limbic system, across three post-weaning developmental stages: from "early" (PND 21-25) to "mid" (i.e., a juvenile transition, PND 28-32) and then to "late" (i.e., the adolescent transition, PND 35-39). The rs-fMRI data, with comparison between early and mid (juvenile transition) age-stage rats, highlights patterns of enhanced connectivity from both Striata to both Hippocampi and from there to (left-sided) Nucleus accumbens (NAcc) and Orbitofrontal Cortex (OFC). Also, during this week there is a maturation of pathways from right Striatum to ipsilateral NAcc, from right OFC to ipsilateral NAcc and vice versa, from left Prefrontal Cortex to ipsilateral OFC and eventually from left Striatum, NAcc and Prefrontal Cortex to contralateral OFC. After only 1 week, in late age-stage rats entering into adolescence, the first pathway mentioned above keeps on growing while other patterns appear: both NAcc are reached from contralateral Striatum, right Hippocampus from both Amygdalae, and left NAcc -further- from right Hippocampus. It's interesting to notice the fact that, independently from the age when these connections develop, Striata of both hemispheres send axons to both Hippocampi and both NAcc sides, both Hippocampi reach left NAcc and OFC and finally both NAcc sides reach right OFC. Intriguingly, the Striatum only indirectly reaches the OFC by passing through Hippocampus and NAcc. Data obtained with DTI highlight how adolescents' neurite density may be affected within sub-cortical gray matter, especially for NAcc and OFC at "late" age-stage (adolescence). Finally, levels of metabolites were investigated by 1H-MRS in the anterior part of the hippocampus: we put into evidence an increase in myo-inositol during juvenile transition and a taurine reduction plus a total choline increase during adolescent transition. In this paper, the aforementioned pattern guides the formulation of hypotheses concerning the correlation between the establishment of novel brain connections and the emergence of behavioral traits that are typical of adolescence.
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http://dx.doi.org/10.3389/fnbeh.2018.00208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6165895PMC
September 2018

Proof of nicotine transfer to rat pups through maternal breast feeding to evaluate the neurobehavioral consequences of nicotine exposure.

Ann Ist Super Sanita 2018 Jul-Sep;54(3):176-184

Centro Nazionale Sostanze Chimiche, Prodotti Cosmetici e Protezione del Consumatore, Istituto Superiore di Sanità, Rome, Italy.

This study investigates the transfer of nicotine from lactating dams to their offspring through breast milk, in the frame of a research focused to ascertain toxicological and neuro-behavioural effects on pups as consequence of either unavoidable ("yoked & forced") or voluntary ("freely-chosen") maternal nicotine exposure. To this aim, plasmatic concentrations of nicotine and cotinine were determined by LC-MS/MS in Wistar rat pups whose mothers were orally administered with nicotine during lactation. Mothers were divided into a voluntary drinking group, an unavoidable consumption group, and controls. The limits of detection and quantification of the LC-MS/MS method were 0.20 and 0.65 ng/mL, respectively. Within-laboratory reproducibility (CV%) was <12%, with recovery of 86.2-118.8%. Results showed the presence of nicotine in 67% of samples from freely-chosen consumption group (1.30 ± 0.31 ng/mL) and in 60% of samples from yoked-consumption group (1.19 ± 0.62 ng/mL); cotinine was found in all the samples from freely-chosen (1.92 ± 0.77 ng/mL) and yoked-consumption groups (1.43 ± 0.30 ng/mL). Data provide an evidence-based support to maternal/offspring nicotine transfer as function of different ways of oral exposure.
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http://dx.doi.org/10.4415/ANN_18_03_03DOI Listing
February 2019

Intranasal oxytocin administration promotes emotional contagion and reduces aggression in a mouse model of callousness.

Neuropharmacology 2018 12 10;143:250-267. Epub 2018 Sep 10.

Reference Centre for Behavioural Sciences and Mental Health, Istituto Superiore di Sanità (ISS), Viale Regina Elena 299, I-00161, Rome, Italy. Electronic address:

Deficits in empathy, the ability to share an emotion of another individual, constitute a hallmark of several psychopathological conditions, including conduct disorder. The co-occurrence of excess rates of aggression, general violation of societal norms and callous-unemotional traits confers specific risk for adult psychopathy. In the present study, we relied on a recently devised experimental model of conduct disorder in mice to test the potential efficacy of intranasal oxytocin administration. Two subgroups of BALB/cJ male mice exhibiting opposite profiles in emotional contagion (i.e. socially transmitted adoption of another's emotional states) underwent a series of tests mapping onto reactive aggression, information processing, perseverative behaviour, punishment-related emotional memory, physiological arousal and hormonal stress reactivity, with or without intranasal oxytocin administration (5.0 or 20.0 μg/kg). Collectively, our data indicate that a trait of markedly reduced emotional contagion is associated with a behavioural syndrome of sensorimotor gating deficits, impaired emotional memory, increased aggression and stereotyped behaviours, dysregulations in the circadian rhythms of activity and body temperature and dampened physiological reactivity to external stressors. Moreover, in the absence of changes in oxytocin receptor density in the neural network involved in empathy-like behaviour, we showed that oxytocin administration normalised emotional contagion, aggression and behavioural stereotypies, thereby ameliorating the phenotype of mice characterised by deficient empathy-like behaviour. Besides, oxytocin led to a lower, more prolonged neuroendocrine response of the HPA-axis to stress in all mice. Ultimately, current data support the notion that oxytocin may constitute a valid therapeutic approach in disturbances characterised by abnormal aggression and excess callousness.
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http://dx.doi.org/10.1016/j.neuropharm.2018.09.010DOI Listing
December 2018

Chronic treatment with the phytocannabinoid Cannabidivarin (CBDV) rescues behavioural alterations and brain atrophy in a mouse model of Rett syndrome.

Neuropharmacology 2018 09 27;140:121-129. Epub 2018 Jul 27.

Center for Behavioral Sciences and Mental Health, Istituto Superiore di Sanità, Rome, Italy. Electronic address:

Rett syndrome (RTT) is a rare neurodevelopmental disorder, characterized by severe behavioural and physiological symptoms. RTT is caused by mutations in the MECP2 gene in about 95% of cases and to date no cure is available. The endocannabinoid system modulates several physiological processes and behavioural responses that are impaired in RTT and its deregulation has been associated with neuropsychiatric disorders which have symptoms in common with RTT. The present study evaluated the potential therapeutic efficacy for RTT of cannabidivarin (CBDV), a non-psychotropic phytocannabinoid from Cannabis sativa that presents antagonistic properties on the G protein-coupled receptor 55 (GPR55), the most recently identified cannabinoid receptor. Present results demonstrate that systemic treatment with CBDV (2, 20, 100 mg/Kg ip for 14 days) rescues behavioural and brain alterations in MeCP2-308 male mice, a validated RTT model. The CBDV treatment restored the compromised general health status, the sociability and the brain weight in RTT mice. A partial restoration of motor coordination was also observed. Moreover, increased levels of GPR55 were found in RTT mouse hippocampus, suggesting this G protein-coupled receptor as new potential target for the treatment of this disorder. Present findings highlight for the first time for RTT the translational relevance of CBDV, an innovative therapeutic agent that is under active investigation in the clinical setting.
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http://dx.doi.org/10.1016/j.neuropharm.2018.07.029DOI Listing
September 2018

Neonatal corticosterone mitigates autoimmune neuropsychiatric disorders associated with streptococcus in mice.

Sci Rep 2018 07 5;8(1):10188. Epub 2018 Jul 5.

Centre for Behavioural Sciences and Mental Health, Istituto Superiore di Sanità, Roma, Italy.

Increased glucocorticoid concentrations have been shown to favor resilience towards autoimmune phenomena. Here, we addressed whether experimentally induced elevations in circulating glucocorticoids mitigate the abnormalities exhibited by an experimental model of Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus (PANDAS). This is a pathogenic hypothesis linking repeated exposures to Group-A-beta-hemolytic streptococcus (GAS), autoantibodies targeting selected brain nuclei and neurobehavioral abnormalities. To persistently elevate glucocorticoid concentrations, we supplemented lactating SJL/J mice with corticosterone (CORT; 80 mg/L) in the drinking water. Starting in adolescence (postnatal day 28), developing offspring were exposed to four injections - at bi-weekly intervals - of a GAS homogenate and tested for behavioral, immunological, neurochemical and molecular alterations. GAS mice showed increased perseverative behavior, impaired sensorimotor gating, reduced reactivity to a serotonergic agonist and inflammatory infiltrates in the anterior diencephalon. Neonatal CORT persistently increased circulating glucocorticoids concentrations and counteracted these alterations. Additionally, neonatal CORT increased peripheral and CNS concentrations of the anti-inflammatory cytokine IL-9. Further, upstream regulator analysis of differentially expressed genes in the striatum showed that the regulatory effect of estradiol is inhibited in GAS-treated mice and activated in GAS-treated mice exposed to CORT. These data support the hypothesis that elevations in glucocorticoids may promote central immunomodulatory processes.
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http://dx.doi.org/10.1038/s41598-018-28372-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6033871PMC
July 2018

Behavioral Phenotyping of Dopamine Transporter Knockout Rats: Compulsive Traits, Motor Stereotypies, and Anhedonia.

Front Psychiatry 2018 22;9:43. Epub 2018 Feb 22.

Center for Behavioral Sciences and Mental Health, Istituto Superiore di Sanità, Rome, Italy.

Alterations in dopamine neurotransmission are generally associated with diseases such as attention-deficit/hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD). Such diseases typically feature poor decision making and lack of control on executive functions and have been studied through the years using many animal models. Dopamine transporter (DAT) knockout (KO) and heterozygous (HET) mice, in particular, have been widely used to study ADHD. Recently, a strain of DAT KO rats has been developed (1). Here, we provide a phenotypic characterization of reward sensitivity and compulsive choice by adult rats born from DAT-HET dams bred with DAT-HET males, in order to further validate DAT KO rats as an animal model for preclinical research. We first tested DAT KO rats' sensitivity to rewarding stimuli, provided by highly appetitive food or sweet water; then, we tested their choice behavior with an Intolerance-to-Delay Task (IDT). During these tests, DAT KO rats appeared less sensitive to rewarding stimuli than wild-type (WT) and HET rats: they also showed a prominent hyperactive behavior with a rigid choice pattern and a wide number of compulsive stereotypies. Moreover, during the IDT, we tested the effects of amphetamine (AMPH) and RO-5203648, a trace amine-associated receptor 1 (TAAR1) partial agonist. AMPH accentuated impulsive behaviors in WT and HET rats, while it had no effect in DAT KO rats. Finally, we measured the levels of tyrosine hydroxylase, dopamine receptor 2 (D2), serotonin transporter, and TAAR1 mRNA transcripts in samples of ventral striatum, finding no significant differences between WT and KO genotypes. Throughout this study, DAT KO rats showed alterations in decision-making processes and in motivational states, as well as prominent motor and oral stereotypies: more studies are warranted to fully characterize and efficiently use them in preclinical research.
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http://dx.doi.org/10.3389/fpsyt.2018.00043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5826953PMC
February 2018

Pronounced Hyperactivity, Cognitive Dysfunctions, and BDNF Dysregulation in Dopamine Transporter Knock-out Rats.

J Neurosci 2018 02 18;38(8):1959-1972. Epub 2018 Jan 18.

St. Petersburg State University, Institute of Translational Biomedicine, Universitetskaya Emb. 7-9, 199034 St. Petersburg, Russia,

Dopamine (DA) controls many vital physiological functions and is critically involved in several neuropsychiatric disorders such as schizophrenia and attention deficit hyperactivity disorder. The major function of the plasma membrane dopamine transporter (DAT) is the rapid uptake of released DA into presynaptic nerve terminals leading to control of both the extracellular levels of DA and the intracellular stores of DA. Here, we present a newly developed strain of rats in which the gene encoding DAT knockout Rats (DAT-KO) has been disrupted by using zinc finger nuclease technology. Male and female DAT-KO rats develop normally but weigh less than heterozygote and wild-type rats and demonstrate pronounced spontaneous locomotor hyperactivity. While striatal extracellular DA lifetime and concentrations are significantly increased, the total tissue content of DA is markedly decreased demonstrating the key role of DAT in the control of DA neurotransmission. Hyperactivity of DAT-KO rats can be counteracted by amphetamine, methylphenidate, the partial Trace Amine-Associated Receptor 1 (TAAR1) agonist RO5203648 ((S)-4-(3,4-Dichloro-phenyl)-4,5-dihydro-oxazol-2-ylamine) and haloperidol. DAT-KO rats also demonstrate a deficit in working memory and sensorimotor gating tests, less propensity to develop obsessive behaviors and show strong dysregulation in frontostriatal BDNF function. DAT-KO rats could provide a novel translational model for human diseases involving aberrant DA function and/or mutations affecting DAT or related regulatory mechanisms. Here, we present a newly developed strain of rats in which the gene encoding the dopamine transporter (DAT) has been disrupted (Dopamine Transporter Knockout rats [DAT-KO rats]). DAT-KO rats display functional hyperdopaminergia accompanied by pronounced spontaneous locomotor hyperactivity. Hyperactivity of DAT-KO rats can be counteracted by amphetamine, methylphenidate, and a few other compounds exerting inhibitory action on dopamine-dependent hyperactivity. DAT-KO rats also demonstrate cognitive deficits in working memory and sensorimotor gating tests, less propensity to develop compulsive behaviors, and strong dysregulation in frontostriatal BDNF function. These observations highlight the key role of DAT in the control of brain dopaminergic transmission. DAT-KO rats could provide a novel translational model for human diseases involving aberrant dopamine functions.
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http://dx.doi.org/10.1523/JNEUROSCI.1931-17.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5824739PMC
February 2018

Low empathy-like behaviour in male mice associates with impaired sociability, emotional memory, physiological stress reactivity and variations in neurobiological regulations.

PLoS One 2017 4;12(12):e0188907. Epub 2017 Dec 4.

Reference Centre for Behavioural Sciences and Mental Health, Istituto Superiore di Sanità (ISS), Rome, Italy.

Deficits in empathy have been proposed to constitute a hallmark of several psychiatric disturbances like conduct disorder, antisocial and narcissistic personality disorders. Limited sensitivity to punishment, shallow or deficient affect and reduced physiological reactivity to environmental stressors have been often reported to co-occur with limited empathy and contribute to the onset of antisocial phenotypes. Empathy in its simplest form (i.e. emotional contagion) is addressed in preclinical models through the evaluation of the social transmission of emotional states: mice exposed to a painful stimulus display a higher response if in the presence of a familiar individual experiencing a higher degree of discomfort, than in isolation. In the present study, we investigated whether a reduction of emotional contagion can be considered a predictor of reduced sociality, sensitivity to punishment and physiological stress reactivity. To this aim, we first evaluated emotional contagion in a group of Balb/cJ mice and then discretised their values in four quartiles. The upper (i.e. Emotional Contagion Prone, ECP) and the lower (i.e. Emotional Contagion Resistant, ECR) quartiles constituted the experimental groups. Our results indicate that mice in the lower quartile are characterized by reduced sociability, impaired memory of negative events and dampened hypothalamic-pituitary-adrenocortical reactivity to external stressors. Furthermore, in the absence of changes in oxytocin receptor density, we show that these mice exhibit elevated concentrations of oxytocin and vasopressin and reduced density of BDNF receptors in behaviourally-relevant brain areas. Thus, not only do present results translate to the preclinical investigation of psychiatric disturbances, but also they can contribute to the study of emotional contagion in terms of its adaptive significance.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0188907PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5714342PMC
December 2017

Potential for diagnosis versus therapy monitoring of attention deficit hyperactivity disorder: a new epigenetic biomarker interacting with both genotype and auto-immunity.

Eur Child Adolesc Psychiatry 2018 Feb 18;27(2):241-252. Epub 2017 Aug 18.

Faculty of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, Teramo, Italy.

In view of the need for easily accessible biomarkers, we evaluated in ADHD children the epigenetic status of the 5'-untranslated region (UTR) in the SLC6A3 gene, coding for human dopamine transporter (DAT). We analysed buccal swabs and sera from 30 children who met DSM-IV-TR criteria for ADHD, assigned to treatment according to severity. Methylation levels at six-selected CpG sites (among which, a CGGCGGCGG and a CGCG motif), alone or in combination with serum titers in auto-antibodies against dopamine transporter (DAT aAbs), were analysed for correlation with CGAS scores (by clinicians) and Conners' scales (by parents), collected at recruitment and after 6 weeks. In addition, we characterized the DAT genotype, i.e., the variable number tandem repeat (VNTR) polymorphisms at the 3'-UTR of the gene. DAT methylation levels were greatly reduced in ADHD patients compared to control, healthy children. Within patients carrying at least one DAT 9 allele (DAT 9/x), methylation at positions CpG2 and/or CpG6 correlated with recovery, as evident from delta-CGAS scores as well as delta Conners' scales ('inattentive' and 'hyperactive' subscales). Moreover, hypermethylation at CpG1 position denoted severity, specifically for those patients carrying a DAT 10/10 genotype. Intriguingly, high serum DAT-aAbs titers appeared to corroborate indications from high CpG1 versus high CpG2/CpG6 levels, likewise denoting severity versus recovery in DAT 10/10 versus 9/x patients, respectively. These profiles suggest that DAT 5'UTR epigenetics plus serum aAbs can serve as suitable biomarkers, to confirm ADHD diagnosis and/or to predict the efficacy of treatment.
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http://dx.doi.org/10.1007/s00787-017-1040-9DOI Listing
February 2018

Persistent Unresolved Inflammation in the -308 Female Mutated Mouse Model of Rett Syndrome.

Mediators Inflamm 2017 16;2017:9467819. Epub 2017 May 16.

Child Neuropsychiatry Unit, University Hospital Azienda Ospedaliera Universitaria Senese (AOUS), Viale M. Bracci 16, 53100 Siena, Italy.

Rett syndrome (RTT) is a rare neurodevelopmental disorder usually caused by mutations in the X-linked gene (). Several mutant mouse lines have been developed recapitulating part of the clinical features. In particular, -308 female heterozygous mice, bearing a truncating mutation, are a validated model of the disease. While recent data suggest a role for inflammation in RTT, little information on the inflammatory status in murine models of the disease is available. Here, we investigated the inflammatory status by proteomic 2-DE/MALDI-ToF/ToF analyses in symptomatic -308 female mice. Ten differentially expressed proteins were evidenced in the -308 mutated plasma proteome. In particular, 5 positive acute-phase response (APR) proteins increased (i.e., kininogen-1, alpha-fetoprotein, mannose-binding protein C, alpha-1-antitrypsin, and alpha-2-macroglobulin), and 3 negative APR reactants were decreased (i.e., serotransferrin, albumin, and apolipoprotein A1). CD5 antigen-like and vitamin D-binding protein, two proteins strictly related to inflammation, were also changed. These results indicate for the first time a persistent unresolved inflammation of unknown origin in the -308 mouse model.
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http://dx.doi.org/10.1155/2017/9467819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5448068PMC
March 2018

Stimulation of the brain serotonin receptor 7 rescues mitochondrial dysfunction in female mice from two models of Rett syndrome.

Neuropharmacology 2017 Jul 15;121:79-88. Epub 2017 Apr 15.

Center for Behavioral Sciences and Mental Health, Istituto Superiore di Sanità, Rome, Italy. Electronic address:

Rett syndrome (RTT) is a rare neurodevelopmental disorder, characterized by severe behavioral and physiological symptoms. Mutations in the methyl CpG binding protein 2 gene (MECP2) cause more than 95% of classic cases, and currently there is no cure for this devastating disorder. Recently we have demonstrated that neurobehavioral and brain molecular alterations can be rescued in a RTT mouse model, by pharmacological stimulation of the brain serotonin receptor 7 (5-HT7R). This member of the serotonin receptor family, crucially involved in the regulation of brain structural plasticity and cognitive processes, can be stimulated by systemic repeated treatment with LP-211, a brain-penetrant selective agonist. The present study extends previous findings by demonstrating that LP-211 treatment (0.25 mg/kg, once per day for 7 days) rescues mitochondrial respiratory chain impairment, oxidative phosphorylation deficiency and the reduced energy status in the brain of heterozygous female mice from two highly validated mouse models of RTT (MeCP2-308 and MeCP2-Bird mice). Moreover, LP-211 treatment completely restored the radical species overproduction by brain mitochondria in the MeCP2-308 model and partially recovered the oxidative imbalance in the more severely affected MeCP2-Bird model. These results provide the first evidence that RTT brain mitochondrial dysfunction can be rescued targeting the brain 5-HT7R and add compelling preclinical evidence of the potential therapeutic value of LP-211 as a pharmacological approach for this devastating neurodevelopmental disorder.
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http://dx.doi.org/10.1016/j.neuropharm.2017.04.024DOI Listing
July 2017

Can laboratory animals violate behavioural norms? Towards a preclinical model of conduct disorder.

Neurosci Biobehav Rev 2018 08 3;91:102-111. Epub 2017 Feb 3.

Centre for Behavioural Sciences and Mental Health, Viale Regina Elena, 299, I-00161 Roma, Italy.

Conduct disorder (CD), a disturbance characterised by excess rates of aggression - often associated with callousness, lack of empathy and shallow/deficient affect - is extremely prevalent (2-10%) in the juvenile population. CD symptoms are quantitative rather than qualitative in nature whereby, rather than exhibiting abnormal behaviours, CD patients indulge in normal behaviours at abnormal rates. Although genetic and environmental factors contribute to CD aetiology, their precise contribution is yet to be determined. Experimental animal models may aid discriminating genetic vs. environmental effects and designing innovative therapeutic approaches. Here we discuss a theoretical framework potentially favouring the design of experimental models of CD. We suggest that the latter shall recapitulate the "norm violation" typical of the human disorder across the core domains involved in CD: aggression, callousness, empathy and emotionality. We first review how these domains have been operationalised in preclinical models; we then suggest that these experimental paradigms shall be combined with appropriate statistical tools to identify a subset of individuals consistently characterised by abnormal values in CD-relevant phenotypes.
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http://dx.doi.org/10.1016/j.neubiorev.2017.01.047DOI Listing
August 2018

Down-regulation of serotonin and dopamine transporter genes in individual rats expressing a gambling-prone profile: A possible role for epigenetic mechanisms.

Neuroscience 2017 01 24;340:101-116. Epub 2016 Oct 24.

Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy. Electronic address:

Gambling Disorder (GD) is characterized by excessive gambling despite adverse consequences on individual functioning. In spite of some positive findings, it is difficult to draw any conclusion on the genetics of GD. Indeed, beyond DNA sequence variation, other regulatory mechanisms (like those that engage epigenetics) may explain gene alterations in this addictive disease. Wistar male rats underwent an operant task for the evaluation of individual propensity to gamble. Few rats, after having learnt to prefer nose-poking for a large over a small food reward, were sacrificed to obtain a baseline profile of gene expression at both central and peripheral levels. In the remaining rats, probability of occurrence of large-reward delivery decreased progressively to very low levels. Thus, rats were faced with temptation to "gamble", i.e. to nose-poke for a binge reward, whose delivery was omitted the majority of times. After 3weeks of testing, rats showing a clear-cut profile of either gambling proneness or aversion were selected and sacrificed after the last session. A selective down-regulation of i) serotonin transporter in prefrontal cortex, ii) tyrosine hydroxylase in ventral striatum, iii) dopamine transporter in lymphocytes was evidenced in "gambler" vs "non-gambler" rats. The exposure to such operant task (compared to home-cage alone) modulated ventrostriatal but not prefrontal genes. A consistent increase of DNA methylation, in one specific CpG site at serotonin transporter gene, was evident in prefrontal cortex of "gambler" rats. Elucidation of epigenetic changes occurring during GD progression may pave the way to the development of new therapeutic strategies through specific modulation of epigenetic factors.
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http://dx.doi.org/10.1016/j.neuroscience.2016.10.041DOI Listing
January 2017

Commentary on the special issue "The Adolescent Brain": How can we run operant paradigms in a preclinical adolescent model? Technical tips and future perspectives.

Neurosci Biobehav Rev 2016 11 30;70:323-328. Epub 2016 Jul 30.

Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy.

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http://dx.doi.org/10.1016/j.neubiorev.2016.07.028DOI Listing
November 2016

Polymorphism of the 3'-UTR of the dopamine transporter gene (DAT) in New World monkeys.

Primates 2017 Jan 8;58(1):169-178. Epub 2016 Aug 8.

Department of Medical-Surgical Sciences and Biotechnologies, University of Rome "La Sapienza", Corso della Repubblica 79, 04100, Latina, Italy.

Genetic polymorphism in the 3'-untranslated region (3'-UTR) of the dopamine transporter (DAT) gene has been reported in both human and nonhuman primates, and the variable number of tandem repeats (VNTR) polymorphism has been related to several neurological and psychiatric disorders. As New World primates have been employed as models in biomedical research in these fields, in the present study we assessed genetic variation in the DAT gene in 25 robust capuchin monkeys (Sapajus spp.) and 39 common marmosets (Callithrix jacchus). Using enzymatic amplification followed by sequencing of amplified fragments, a VNTR polymorphism in the 3'-UTR region of the DAT gene was identified in both robust capuchins and common marmosets. The polymorphic tandem repeat of 40-bp basic units is similar to the human VNTR consensus sequence, with size variants composed of 9, 10, and 11 units in marmosets and 8, 9, 13, and 17 basic units in capuchins. We found behavioral evidence that carrying the 10-repeat DAT allele promotes flexible choice and maximization of foraging in marmosets tested in an operant choice paradigm. Moreover, in an intertemporal choice task, capuchins with longer repeat variants show less self-controlled choices than capuchins with at least one short repeat variant. Future research should focus on the relationship between these DAT polymorphisms, dopamine reuptake via the dopamine transporter, and behavioral and cognitive variation across New World monkey individuals.
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http://dx.doi.org/10.1007/s10329-016-0560-0DOI Listing
January 2017
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