Gianni Laviola - Academia.edu (original) (raw)
Papers by Gianni Laviola
ABSTRACTRett Syndrome (RTT) is a neurodevelopmental disorder mostly caused by mutations in the X-... more ABSTRACTRett Syndrome (RTT) is a neurodevelopmental disorder mostly caused by mutations in the X-linked gene, MeCP2, which encodes for methyl-CpG binding protein 2 (MeCP2). MeCP2 is member of a family of methyl binding proteins that control the expression of several genes according to the genomic context. Emerging evidence suggests that immune dysfunctions would actively contribute to the pathogenesis of RTT. Macrophages are key effector cells that participate in several critical aspects of immune responses. The aim of our work was to assess the response of macrophages in vitro in the context of polarizing stimuli. We used bone marrow-derived macrophages (BMDM) obtained from MeCP2308/y mice, a mouse model that carries a truncated form of MeCP2. Since MeCP2 is expressed as a “partially functional” protein in humans with RTT it becomes crucial to establish how the presence of a mutant form of MeCP2 affects immune responses to support the normal homeostasis of individuals. MeCP2 defici...
Notiziario dell'Istituto Superiore di Sanità, 2010
Current Developmental Disorders Reports, 2014
Alcohol intake by women before planning a pregnancy, during pregnancy, and/or during lactation in... more Alcohol intake by women before planning a pregnancy, during pregnancy, and/or during lactation induces brain, behavioral, and physical abnormalities in the fetus, which are known as fetal alcohol spectrum disorders. Thanks to the availability of animal models, some cellular and biochemical processes affecting offspring exposed to ethanol during early development have been extensively investigated. Ethanol effects may be mitigated or increased if offspring also are exposed to either positive or adverse conditions during early life. These environmental conditions may have an impact on neuronal and behavioral development and may increase the risk of developing neuropsychiatric symptoms. Indeed, brain development largely is modifiable by experiences, and neuroplasticity is particularly evident during early phases of life. Molecular mediators for brain development and synaptic plasticity are neurotrophins, such as nerve growth factor and brain-derived neurotrophic factor. Early ethanol exposure not only affects the fetal brain directly, but it also leads to long-lasting consequences that emerge during adulthood and aging. Although the mechanisms responsible for these abnormalities in the fetus are unclear, it is hypothesized that ethanol might damage the central nervous system through oxidative stress processes by increasing free-radical production and decreasing cellular antioxidant ability. Ethanol's effects on animal models have been investigated in detail; however, only few studies have investigated the consequences of early wine consumption. Wine contains several concentrations of ethanol and is consumed largely by Mediterranean populations. We recently compared the consequences of early exposure to ethanol or red wine (at the same ethanol concentration) administered during different stages of development in animal models. Our studies show a series of behavioral and neurologic abnormalities in juvenile, adult, and aged offspring of mice exposed to ethanol. A much smaller number of changes (if any) were evidenced as a consequence of early exposure to red wine. Antioxidant compounds measurable in red wine may have mitigated the toxicity associated with ethanol in the fetus. These "protective" mechanisms in mice pre-and postnatally exposed to red wine, compared with the ethanol group, remain unknown. As a whole, our data should not be interpreted as encouraging women to consume red wine before or during pregnancy and/or lactation. Indeed, in these cases, alcohol intake absolutely must be avoided.
Journal of Clinical Medicine, 2019
Adverse psychosocial experiences have been shown to modulate individual responses to immune chall... more 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 ...
Neuroscience & Biobehavioral Reviews, 2017
Despite it has not been formally included in DSM-5 as a disorder, 'Internet addic... more Despite it has not been formally included in DSM-5 as a disorder, 'Internet addiction (IA)' has become a worldwide issue. It can be broadly defined as a non-chemical, behavioral addiction, which involves human-machine interaction. We pinpoint it as an "instrumental" form of social interaction (i.e. mediated by machines), a notion that appears useful for the sake of possible preclinical modeling. The features of Internet use reveals as addictive when this comes at the expense of genuine real-life sociability, with an overlap towards the hikikomori phenomenon (i.e., extreme retreat to one's own room). Due to the specific neuro-developmental plasticity in adolescence, IA poses risks to youths' mental health, and may likely produce negative consequences in everyday life. The thwarted development of adolescents' identity, self-image and adaptive social relationships is discussed: the IA adolescents often suffer loss of control, feelings of anger, symptoms of distress, social withdrawal, and familial conflicts. Further, more severe clinical conditions are also associated to IA, such as dysthymic, bipolar, affective, social-anxiety disorders, as well as major depression. This paper overviews the literature on IA, from neuro-biological, psycho-social and clinical standpoints, taking into account recent debates on diagnostic criteria, nosographic label and assessment tools. Neuroimaging data and neurochemical regulations are illustrated with links to pathogenetic hypotheses, which are amenable to validation through innovative preclinical modeling.
Background: Reelin is a candidate gene for neurodevelopmental disorders such as autism and schizo... more Background: Reelin is a candidate gene for neurodevelopmental disorders such as autism and schizophrenia. Reelin haploinsufficiency in the heterozygous rl/+ mouse causes behavioral abnormalities soon after birth, consisting of decreased ultrasound vocalizations (USV) emitted by pups upon maternal separation, as well as in adult life, producing behavioral rigidity in a task requiring a change in strategy. At the anatomical level, reelin haploinsufficiency causes a loss of GABAergic inhibitory neurons, e.g. parvalbumin-positive neurons in limbic areas and basal ganglia, and Purkinje cells (PC) in the cerebellum. This PC loss is more evident in male than female mice. Objectives: 1) To characterize brain circuit abnormalities of heterozygous reeler (rl/+) mice, and their sex-dependency; 2) To unravel the mechanisms of neuronal loss in brain areas that are relevant for autism, like the cerebellum and limbic system, focusing on interactions between decreased reelin levels and sex steroids...
The Open Neuropsychopharmacology Journal, 2009
Objective: Cortexin is a polypeptide extract, used in clinics for its effects on memory, attentio... more Objective: Cortexin is a polypeptide extract, used in clinics for its effects on memory, attention, and brain cortical processes. A synthetic analog of one Cortexin fraction, Cortagen (i.e. Ala-Glu-Asp-Pro peptide), was developed. Both agents stimulate neural growth in vitro, presumably in association with neurotrophic factors. We assessed the psychoactive effects of Cortexin and cortagen, using elevated plus maze (EPM) and locomotor activity habituation (LAH) paradigms in CD-1 mice. In Exp. I, mice were injected with Cortexin (0, 0.25, 0.50, or 1.00 mg/kg i.p.) and tested in the EPM (acute) and the LAH (sub-chronic response). In Exp. II, separate mice were injected with cortagen (0, 0.01, 0.03, or 0.10 mg/kg i.p.) or a reference dose of Cortexin, and tested in the LAH (acute and sub-chronic) and the EPM (sub-chronic response). Results: Evidence of anxyolitic effects was found in the EPM for acute Cortexin treatment at the 0.25 and 1.00 mg/kg dosages. The Cortexin 0.25 mg/kg was selected as reference dose for Exp. II, since it had no locomotor effects over 4 days, whilst the 1.00 mg/kg dose led to the development of hyperactivity. When comparing to Cortexin reference, the 0.03 mg/kg dose of cortagen enhanced locomotion both upon acute and after sub-chronic treatment, also having few effects on anxiety-related behavior. Conversely, following a sub-chronic regimen (5 days), the Cortexin reference and the other doses of cortagen turned out to produce anxiogenic effects. Conclusion: Cortexin has anxiolytic-like effects when given acutely, and anxiogenic-like arousal emerges following repeated treatment. Conversely, acute and sub-chronic cortagen leads to motor stimulation with no side effects on emotional-affective profiles. Such behavioral stimulation may find beneficial employment in the treatment of affective / depressive symptoms in humans. Peptides are active in very low dosages with no side effects, and deserve deeper investigation for their promising role in therapy.
A Comprehensive Book on Autism Spectrum Disorders, 2011
Frontiers in Pediatrics, 2014
Reviews in the Neurosciences, 2014
The serotonin 7 (5-HT7) receptor was the last serotonin receptor subtype to be discovered in 1993... more The serotonin 7 (5-HT7) receptor was the last serotonin receptor subtype to be discovered in 1993. This receptor system has been implicated in several central nervous system (CNS) functions, including circadian rhythm, rapid eye movement sleep, thermoregulation, nociception, memory and neuropsychiatric symptoms and pathologies, such as anxiety, depression and schizophrenia. In 1999, medicinal chemistry efforts led to the identification of SB-269970, which became the gold standard selective 5-HT7 receptor antagonist, and later of various selective agonists such as AS-19, LP-44, LP-12, LP-211 and E-55888. In this review, we summarize the preclinical pharmacological studies performed using these agonists, highlighting their strengths and weaknesses. The data indicate that 5-HT7 receptor agonists can have neuroprotective effects against N-methyl-d-aspartate-induced toxicity, modulate neuronal plasticity in rats, enhance morphine-induced antinociception and alleviate hyperalgesia consecutive to nerve lesion in neuropathic animals.
Reviews in the Neurosciences, 2014
The serotonin receptor 7 (5-HT7-R) plays important functional roles in learning and memory, in re... more The serotonin receptor 7 (5-HT7-R) plays important functional roles in learning and memory, in regulation of mood and circadian rhythmicity. LP-211 is a new selective agonist, belonging to 1-arylpiperazine category. We report studies aimed to evaluate the modulatory effect of a subchronic regimen on behavioral/molecular parameters. At low dose [0.25 mg/kg intraperitoneally (i.p.)], LP-211 induced a 6-h anticipated wake up in adult mice (with no temporal landmark by constant light), acting as nonphotic stimulus for 'internal clock' resetting. In standard 12:12-h light/dark cycle, a subchronic effect (5-6 days at 0.25 mg/kg, once per day) was observed: delayed wake up, reduced peak of locomotor activity and no evidence for brain cellular proliferation after ex vivo analysis. Other studies in rats were aimed to investigate long-term effects of developmental LP-211 administration into adulthood. Subchronic LP-211 (0.125 mg/kg i.p. once per day during the prepuberal phase) reduced l-glutamate, N-methyl-d-aspartate receptor 1 and dopamine transporter within the ventral striatum. With LP-211 (0.25 mg/kg i.p. once per day during the postpuberal phase), clear reductions were observed in the immunoreactivity of serotonin transporter and dopaminergic D2 receptors in the ventral and dorsal striatum, respectively. Subchronic LP-211 in rats and mice appears to be a suitable tool for studying the role of 5-HT7-R in sleep disorders, emotional/motivational regulations, attentive processes and executive functions.
Pharmacology Biochemistry and Behavior, 1997
The present study evaluated the behavioral repertoire of lactating CD-1 mouse dams when tested in... more The present study evaluated the behavioral repertoire of lactating CD-1 mouse dams when tested in an environment associated with cocaine in the premating period. Virgin females were randomly assigned for conditioning (8-day long schedule with four cocaine or saline injections administered every other day) to three experimental groups: i) Coc-Test females received one injection of cocaine (5 or 20 mg/kg IP) in the testing chamber and saline 24 h later in the home cage, ii) Coc-Home females received one injection of the same doses of cocaine in the home cage and saline 24 h later in the testing chamber, and iii) Sal-Sal control females received one saline injection in both environments. All females underwent a 25-day long wash out period during which they were mated. Their behavior was subsequently scored in the testing chamber on postpartum day 2 (drug-free state) in the presence of 3 pups from their own litter (single 15-min session). As a whole, Coc-Test dams appeared to be more involved in pup-directed activities such as pup-nosing and nest-building when compared with the Coc-Home group. In addition, non-pup directed behaviors, such as crossing, self-grooming, and rearing were higher in Coc-Test group than in other groups. The opposite was true for stereotyped gnawing activity. A measure of females' body weight gain revealed that Coc-Test 20 group was significantly higher than other groups particularly during the postpartum phase. On postpartum day 6, lactating dams were injected with the low cocaine dose (5mg/kg) and their response to a male intruder was assessed in the testing chamber (single 5-min session). A higher number of Coc-Test 5 dams showed the on nest and the upright offensive postures compared to the corresponding Coc-Home 5 group, whereas a significant higher number of Sal-Sal females showed the on top posture with respect to the Coc-Test 20 group. Oxytocin levels measured after the behavioral test showed a tendency, even if not significant, to be higher in the hypothalamus of Coc-Test dams. As a whole, the present results suggest that the alterations in maternal behavior here observed as well as the trend underlined by oxytocin values, cannot be ascribed to carry-over effects of cocaine administration in the pre-mating phase per se; rather, they seem to represent a conditioned response to the distinct environment previously associated with the drug experience.
Psychoneuroendocrinology, 2010
According to the ''extreme-male brain'' theory, elevated fetal testosterone levels may partly exp... more According to the ''extreme-male brain'' theory, elevated fetal testosterone levels may partly explain the skewed sex ratio found in Autism Spectrum Disorders (ASD). Correcting this testosterone imbalance by increasing estrogen levels may mitigate the abnormal phenotype. Accordingly, while control heterozygous reeler (rl/+) male mice-a putative model of neuroanatomical and behavioral endophenotypes in ASD-show a decreased number of Purkinje cells (PC) compared to control wild-type (+/+) littermates, neonatal estradiol administration has been shown to correct this deficit in the short-term (i.e. on postnatal day 15). Here, we further investigated the neuroanatomical and behavioral abnormalities of rl/+ male mice and the potential compensatory effects of neonatal treatment with estradiol. In a longitudinal study, we observed that: i) infant rl/+ mice showed reduced motivation for social stimuli; ii) adult rl/+ male mice showed reduced cognitive flexibility; iii) the number of amygdalar parvalbuminpositive GABAergic interneurons were remarkably reduced in rl/+ mice; iv) neonatal estradiol administration into the cisterna magna reverted the abnormal profile both at the behavioral and at the neuroanatomical level in the amygdala but did not compensate for the cerebellar abnormalities in adulthood. This study supports the view that an increased excitation-toinhibition ratio in the cerebellum and in the amygdala during a critical window of development could be crucial to the social and cognitive phenotype of male rl/+ mice, and that acute estradiol treatment during this critical window may mitigate symptoms' severity.
Neurotoxicity Research, 2013
Important reduction of reelin, a neural development-and plasticity-associated protein, and glutam... more Important reduction of reelin, a neural development-and plasticity-associated protein, and glutamic acid decarboxylase (GAD67) are reported in brains of schizophrenic patients. These individuals are consistently engaged in tobacco smoking and nicotine is thought to alleviate negative behavioral symptoms or cognitive alterations. In mouse brain, nicotine has been shown to reduce GAD67 promoter methylation and increase its transcription. We assessed the effects of administration of nicotine (1 mg/ kg s.c.) for 6 days, in male mice heterozygous for reelin (HRM), a putative model for symptoms related to schizophrenia. Expression of reelin, GAD67 and brain-derived neurotrophic factor (BDNF) was measured in different brain areas. RNA expression analysis evidenced genotype-related changes, with a marked reduction in reelin and GAD67 gene expression in prefrontal cortex, hippocampus, cerebellum, and striatum from HRM. Nicotine treatment selectively reversed the HRM-related phenotype in most brain areas and increased BDNF gene expression in cortex and hippocampus of both genotypes. Locomotor performance in their home cage revealed that HRM subjects were characterized by general hyperactivity; with nicotine administration restoring WT-like levels of locomotion. These findings are interpreted within the hypothesis of pre-existing vulnerability (based on haploinsufficiency of reelin) to brain and behavioral disorders and regulative effects associated with nicotine exposure.
Behavioural Pharmacology, 1996
Psychopharmacology, 2008
Adolescent rodents differ markedly from adults in several neuro-behavioural parameters. Moreover,... more Adolescent rodents differ markedly from adults in several neuro-behavioural parameters. Moreover, 'paradoxical' responses to psychostimulants have been reported at this age. Thus, we investigated the responses of adolescent (post-natal day, PND, 34 to 43) and adult (PND >60) Sprague-Dawley male rats to the psychostimulant drug methylphenidate (MPH). We used pharmacological magnetic resonance imaging (phMRI) performed at 4.7 T under isoflurane anaesthesia. Following anatomical MRI, axial gradient echo images were collected continuously. After baseline recording (32 min), animals received MPH (0 or 4 mg/kg i.p.) and were recorded for further 32 min. Region-specific changes in the blood-oxygenation level dependent (BOLD) signal were evident as a function of age. As expected, among adults MPH induced an increase of BOLD signal in nucleus accumbens (NAcc) and prefrontal cortex (PFC), with no effects in the hippocampus (Hip). Notably, among adolescents, MPH induced a marked and generalised decrease of BOLD signal, which occurred earlier in NAcc and PFC whilst being delayed in the Hip. Any bias in BOLD responses was excluded by the measurement of physiological parameters. The present findings highlight the utility of phMRI in animal models. The peculiar negative BOLD effect found in adolescent rats may be suggestive of a reduced cerebro-vascular feedback and/or an increased MPH-induced neuronal activation. Data are relevant for a better understanding of brain/behavioural regulation during adolescent development. Moreover, a greater understanding of the differences between adult and adolescent drug responses will aid in the development of a more appropriate age-specific treatment strategy.
Testing rodents in their home cages has become i ncreasingly popular. A new low-cost computer-con... more Testing rodents in their home cages has become i ncreasingly popular. A new low-cost computer-controlled operant panel was designed, which can be placed inside the home cage. A pilot study was carried out, using a decisionmaking protocol, which was adapted from the original maze rodent Iowa Gambling Task (r-IGT). Male adult rats were tested in their home cages, containing the operant panel provided with nose-poking holes. Nose-poking was associated with rewards of different value and probability. A tryptophan-free diet was fed to investigate the effect of lowering central serotonin concentration on performance in the r-IGT. The data suggested that control rats behave in a way similar to rats tested in the original r-IGT; that is, they tend to choose the option with the best long-term payoff more often as the test progresses. Tryptophan depleted rats showed a weaker improvement across trials than controls.
ABSTRACTRett Syndrome (RTT) is a neurodevelopmental disorder mostly caused by mutations in the X-... more ABSTRACTRett Syndrome (RTT) is a neurodevelopmental disorder mostly caused by mutations in the X-linked gene, MeCP2, which encodes for methyl-CpG binding protein 2 (MeCP2). MeCP2 is member of a family of methyl binding proteins that control the expression of several genes according to the genomic context. Emerging evidence suggests that immune dysfunctions would actively contribute to the pathogenesis of RTT. Macrophages are key effector cells that participate in several critical aspects of immune responses. The aim of our work was to assess the response of macrophages in vitro in the context of polarizing stimuli. We used bone marrow-derived macrophages (BMDM) obtained from MeCP2308/y mice, a mouse model that carries a truncated form of MeCP2. Since MeCP2 is expressed as a “partially functional” protein in humans with RTT it becomes crucial to establish how the presence of a mutant form of MeCP2 affects immune responses to support the normal homeostasis of individuals. MeCP2 defici...
Notiziario dell'Istituto Superiore di Sanità, 2010
Current Developmental Disorders Reports, 2014
Alcohol intake by women before planning a pregnancy, during pregnancy, and/or during lactation in... more Alcohol intake by women before planning a pregnancy, during pregnancy, and/or during lactation induces brain, behavioral, and physical abnormalities in the fetus, which are known as fetal alcohol spectrum disorders. Thanks to the availability of animal models, some cellular and biochemical processes affecting offspring exposed to ethanol during early development have been extensively investigated. Ethanol effects may be mitigated or increased if offspring also are exposed to either positive or adverse conditions during early life. These environmental conditions may have an impact on neuronal and behavioral development and may increase the risk of developing neuropsychiatric symptoms. Indeed, brain development largely is modifiable by experiences, and neuroplasticity is particularly evident during early phases of life. Molecular mediators for brain development and synaptic plasticity are neurotrophins, such as nerve growth factor and brain-derived neurotrophic factor. Early ethanol exposure not only affects the fetal brain directly, but it also leads to long-lasting consequences that emerge during adulthood and aging. Although the mechanisms responsible for these abnormalities in the fetus are unclear, it is hypothesized that ethanol might damage the central nervous system through oxidative stress processes by increasing free-radical production and decreasing cellular antioxidant ability. Ethanol's effects on animal models have been investigated in detail; however, only few studies have investigated the consequences of early wine consumption. Wine contains several concentrations of ethanol and is consumed largely by Mediterranean populations. We recently compared the consequences of early exposure to ethanol or red wine (at the same ethanol concentration) administered during different stages of development in animal models. Our studies show a series of behavioral and neurologic abnormalities in juvenile, adult, and aged offspring of mice exposed to ethanol. A much smaller number of changes (if any) were evidenced as a consequence of early exposure to red wine. Antioxidant compounds measurable in red wine may have mitigated the toxicity associated with ethanol in the fetus. These "protective" mechanisms in mice pre-and postnatally exposed to red wine, compared with the ethanol group, remain unknown. As a whole, our data should not be interpreted as encouraging women to consume red wine before or during pregnancy and/or lactation. Indeed, in these cases, alcohol intake absolutely must be avoided.
Journal of Clinical Medicine, 2019
Adverse psychosocial experiences have been shown to modulate individual responses to immune chall... more 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 ...
Neuroscience & Biobehavioral Reviews, 2017
Despite it has not been formally included in DSM-5 as a disorder, 'Internet addic... more Despite it has not been formally included in DSM-5 as a disorder, 'Internet addiction (IA)' has become a worldwide issue. It can be broadly defined as a non-chemical, behavioral addiction, which involves human-machine interaction. We pinpoint it as an "instrumental" form of social interaction (i.e. mediated by machines), a notion that appears useful for the sake of possible preclinical modeling. The features of Internet use reveals as addictive when this comes at the expense of genuine real-life sociability, with an overlap towards the hikikomori phenomenon (i.e., extreme retreat to one's own room). Due to the specific neuro-developmental plasticity in adolescence, IA poses risks to youths' mental health, and may likely produce negative consequences in everyday life. The thwarted development of adolescents' identity, self-image and adaptive social relationships is discussed: the IA adolescents often suffer loss of control, feelings of anger, symptoms of distress, social withdrawal, and familial conflicts. Further, more severe clinical conditions are also associated to IA, such as dysthymic, bipolar, affective, social-anxiety disorders, as well as major depression. This paper overviews the literature on IA, from neuro-biological, psycho-social and clinical standpoints, taking into account recent debates on diagnostic criteria, nosographic label and assessment tools. Neuroimaging data and neurochemical regulations are illustrated with links to pathogenetic hypotheses, which are amenable to validation through innovative preclinical modeling.
Background: Reelin is a candidate gene for neurodevelopmental disorders such as autism and schizo... more Background: Reelin is a candidate gene for neurodevelopmental disorders such as autism and schizophrenia. Reelin haploinsufficiency in the heterozygous rl/+ mouse causes behavioral abnormalities soon after birth, consisting of decreased ultrasound vocalizations (USV) emitted by pups upon maternal separation, as well as in adult life, producing behavioral rigidity in a task requiring a change in strategy. At the anatomical level, reelin haploinsufficiency causes a loss of GABAergic inhibitory neurons, e.g. parvalbumin-positive neurons in limbic areas and basal ganglia, and Purkinje cells (PC) in the cerebellum. This PC loss is more evident in male than female mice. Objectives: 1) To characterize brain circuit abnormalities of heterozygous reeler (rl/+) mice, and their sex-dependency; 2) To unravel the mechanisms of neuronal loss in brain areas that are relevant for autism, like the cerebellum and limbic system, focusing on interactions between decreased reelin levels and sex steroids...
The Open Neuropsychopharmacology Journal, 2009
Objective: Cortexin is a polypeptide extract, used in clinics for its effects on memory, attentio... more Objective: Cortexin is a polypeptide extract, used in clinics for its effects on memory, attention, and brain cortical processes. A synthetic analog of one Cortexin fraction, Cortagen (i.e. Ala-Glu-Asp-Pro peptide), was developed. Both agents stimulate neural growth in vitro, presumably in association with neurotrophic factors. We assessed the psychoactive effects of Cortexin and cortagen, using elevated plus maze (EPM) and locomotor activity habituation (LAH) paradigms in CD-1 mice. In Exp. I, mice were injected with Cortexin (0, 0.25, 0.50, or 1.00 mg/kg i.p.) and tested in the EPM (acute) and the LAH (sub-chronic response). In Exp. II, separate mice were injected with cortagen (0, 0.01, 0.03, or 0.10 mg/kg i.p.) or a reference dose of Cortexin, and tested in the LAH (acute and sub-chronic) and the EPM (sub-chronic response). Results: Evidence of anxyolitic effects was found in the EPM for acute Cortexin treatment at the 0.25 and 1.00 mg/kg dosages. The Cortexin 0.25 mg/kg was selected as reference dose for Exp. II, since it had no locomotor effects over 4 days, whilst the 1.00 mg/kg dose led to the development of hyperactivity. When comparing to Cortexin reference, the 0.03 mg/kg dose of cortagen enhanced locomotion both upon acute and after sub-chronic treatment, also having few effects on anxiety-related behavior. Conversely, following a sub-chronic regimen (5 days), the Cortexin reference and the other doses of cortagen turned out to produce anxiogenic effects. Conclusion: Cortexin has anxiolytic-like effects when given acutely, and anxiogenic-like arousal emerges following repeated treatment. Conversely, acute and sub-chronic cortagen leads to motor stimulation with no side effects on emotional-affective profiles. Such behavioral stimulation may find beneficial employment in the treatment of affective / depressive symptoms in humans. Peptides are active in very low dosages with no side effects, and deserve deeper investigation for their promising role in therapy.
A Comprehensive Book on Autism Spectrum Disorders, 2011
Frontiers in Pediatrics, 2014
Reviews in the Neurosciences, 2014
The serotonin 7 (5-HT7) receptor was the last serotonin receptor subtype to be discovered in 1993... more The serotonin 7 (5-HT7) receptor was the last serotonin receptor subtype to be discovered in 1993. This receptor system has been implicated in several central nervous system (CNS) functions, including circadian rhythm, rapid eye movement sleep, thermoregulation, nociception, memory and neuropsychiatric symptoms and pathologies, such as anxiety, depression and schizophrenia. In 1999, medicinal chemistry efforts led to the identification of SB-269970, which became the gold standard selective 5-HT7 receptor antagonist, and later of various selective agonists such as AS-19, LP-44, LP-12, LP-211 and E-55888. In this review, we summarize the preclinical pharmacological studies performed using these agonists, highlighting their strengths and weaknesses. The data indicate that 5-HT7 receptor agonists can have neuroprotective effects against N-methyl-d-aspartate-induced toxicity, modulate neuronal plasticity in rats, enhance morphine-induced antinociception and alleviate hyperalgesia consecutive to nerve lesion in neuropathic animals.
Reviews in the Neurosciences, 2014
The serotonin receptor 7 (5-HT7-R) plays important functional roles in learning and memory, in re... more The serotonin receptor 7 (5-HT7-R) plays important functional roles in learning and memory, in regulation of mood and circadian rhythmicity. LP-211 is a new selective agonist, belonging to 1-arylpiperazine category. We report studies aimed to evaluate the modulatory effect of a subchronic regimen on behavioral/molecular parameters. At low dose [0.25 mg/kg intraperitoneally (i.p.)], LP-211 induced a 6-h anticipated wake up in adult mice (with no temporal landmark by constant light), acting as nonphotic stimulus for 'internal clock' resetting. In standard 12:12-h light/dark cycle, a subchronic effect (5-6 days at 0.25 mg/kg, once per day) was observed: delayed wake up, reduced peak of locomotor activity and no evidence for brain cellular proliferation after ex vivo analysis. Other studies in rats were aimed to investigate long-term effects of developmental LP-211 administration into adulthood. Subchronic LP-211 (0.125 mg/kg i.p. once per day during the prepuberal phase) reduced l-glutamate, N-methyl-d-aspartate receptor 1 and dopamine transporter within the ventral striatum. With LP-211 (0.25 mg/kg i.p. once per day during the postpuberal phase), clear reductions were observed in the immunoreactivity of serotonin transporter and dopaminergic D2 receptors in the ventral and dorsal striatum, respectively. Subchronic LP-211 in rats and mice appears to be a suitable tool for studying the role of 5-HT7-R in sleep disorders, emotional/motivational regulations, attentive processes and executive functions.
Pharmacology Biochemistry and Behavior, 1997
The present study evaluated the behavioral repertoire of lactating CD-1 mouse dams when tested in... more The present study evaluated the behavioral repertoire of lactating CD-1 mouse dams when tested in an environment associated with cocaine in the premating period. Virgin females were randomly assigned for conditioning (8-day long schedule with four cocaine or saline injections administered every other day) to three experimental groups: i) Coc-Test females received one injection of cocaine (5 or 20 mg/kg IP) in the testing chamber and saline 24 h later in the home cage, ii) Coc-Home females received one injection of the same doses of cocaine in the home cage and saline 24 h later in the testing chamber, and iii) Sal-Sal control females received one saline injection in both environments. All females underwent a 25-day long wash out period during which they were mated. Their behavior was subsequently scored in the testing chamber on postpartum day 2 (drug-free state) in the presence of 3 pups from their own litter (single 15-min session). As a whole, Coc-Test dams appeared to be more involved in pup-directed activities such as pup-nosing and nest-building when compared with the Coc-Home group. In addition, non-pup directed behaviors, such as crossing, self-grooming, and rearing were higher in Coc-Test group than in other groups. The opposite was true for stereotyped gnawing activity. A measure of females' body weight gain revealed that Coc-Test 20 group was significantly higher than other groups particularly during the postpartum phase. On postpartum day 6, lactating dams were injected with the low cocaine dose (5mg/kg) and their response to a male intruder was assessed in the testing chamber (single 5-min session). A higher number of Coc-Test 5 dams showed the on nest and the upright offensive postures compared to the corresponding Coc-Home 5 group, whereas a significant higher number of Sal-Sal females showed the on top posture with respect to the Coc-Test 20 group. Oxytocin levels measured after the behavioral test showed a tendency, even if not significant, to be higher in the hypothalamus of Coc-Test dams. As a whole, the present results suggest that the alterations in maternal behavior here observed as well as the trend underlined by oxytocin values, cannot be ascribed to carry-over effects of cocaine administration in the pre-mating phase per se; rather, they seem to represent a conditioned response to the distinct environment previously associated with the drug experience.
Psychoneuroendocrinology, 2010
According to the ''extreme-male brain'' theory, elevated fetal testosterone levels may partly exp... more According to the ''extreme-male brain'' theory, elevated fetal testosterone levels may partly explain the skewed sex ratio found in Autism Spectrum Disorders (ASD). Correcting this testosterone imbalance by increasing estrogen levels may mitigate the abnormal phenotype. Accordingly, while control heterozygous reeler (rl/+) male mice-a putative model of neuroanatomical and behavioral endophenotypes in ASD-show a decreased number of Purkinje cells (PC) compared to control wild-type (+/+) littermates, neonatal estradiol administration has been shown to correct this deficit in the short-term (i.e. on postnatal day 15). Here, we further investigated the neuroanatomical and behavioral abnormalities of rl/+ male mice and the potential compensatory effects of neonatal treatment with estradiol. In a longitudinal study, we observed that: i) infant rl/+ mice showed reduced motivation for social stimuli; ii) adult rl/+ male mice showed reduced cognitive flexibility; iii) the number of amygdalar parvalbuminpositive GABAergic interneurons were remarkably reduced in rl/+ mice; iv) neonatal estradiol administration into the cisterna magna reverted the abnormal profile both at the behavioral and at the neuroanatomical level in the amygdala but did not compensate for the cerebellar abnormalities in adulthood. This study supports the view that an increased excitation-toinhibition ratio in the cerebellum and in the amygdala during a critical window of development could be crucial to the social and cognitive phenotype of male rl/+ mice, and that acute estradiol treatment during this critical window may mitigate symptoms' severity.
Neurotoxicity Research, 2013
Important reduction of reelin, a neural development-and plasticity-associated protein, and glutam... more Important reduction of reelin, a neural development-and plasticity-associated protein, and glutamic acid decarboxylase (GAD67) are reported in brains of schizophrenic patients. These individuals are consistently engaged in tobacco smoking and nicotine is thought to alleviate negative behavioral symptoms or cognitive alterations. In mouse brain, nicotine has been shown to reduce GAD67 promoter methylation and increase its transcription. We assessed the effects of administration of nicotine (1 mg/ kg s.c.) for 6 days, in male mice heterozygous for reelin (HRM), a putative model for symptoms related to schizophrenia. Expression of reelin, GAD67 and brain-derived neurotrophic factor (BDNF) was measured in different brain areas. RNA expression analysis evidenced genotype-related changes, with a marked reduction in reelin and GAD67 gene expression in prefrontal cortex, hippocampus, cerebellum, and striatum from HRM. Nicotine treatment selectively reversed the HRM-related phenotype in most brain areas and increased BDNF gene expression in cortex and hippocampus of both genotypes. Locomotor performance in their home cage revealed that HRM subjects were characterized by general hyperactivity; with nicotine administration restoring WT-like levels of locomotion. These findings are interpreted within the hypothesis of pre-existing vulnerability (based on haploinsufficiency of reelin) to brain and behavioral disorders and regulative effects associated with nicotine exposure.
Behavioural Pharmacology, 1996
Psychopharmacology, 2008
Adolescent rodents differ markedly from adults in several neuro-behavioural parameters. Moreover,... more Adolescent rodents differ markedly from adults in several neuro-behavioural parameters. Moreover, 'paradoxical' responses to psychostimulants have been reported at this age. Thus, we investigated the responses of adolescent (post-natal day, PND, 34 to 43) and adult (PND >60) Sprague-Dawley male rats to the psychostimulant drug methylphenidate (MPH). We used pharmacological magnetic resonance imaging (phMRI) performed at 4.7 T under isoflurane anaesthesia. Following anatomical MRI, axial gradient echo images were collected continuously. After baseline recording (32 min), animals received MPH (0 or 4 mg/kg i.p.) and were recorded for further 32 min. Region-specific changes in the blood-oxygenation level dependent (BOLD) signal were evident as a function of age. As expected, among adults MPH induced an increase of BOLD signal in nucleus accumbens (NAcc) and prefrontal cortex (PFC), with no effects in the hippocampus (Hip). Notably, among adolescents, MPH induced a marked and generalised decrease of BOLD signal, which occurred earlier in NAcc and PFC whilst being delayed in the Hip. Any bias in BOLD responses was excluded by the measurement of physiological parameters. The present findings highlight the utility of phMRI in animal models. The peculiar negative BOLD effect found in adolescent rats may be suggestive of a reduced cerebro-vascular feedback and/or an increased MPH-induced neuronal activation. Data are relevant for a better understanding of brain/behavioural regulation during adolescent development. Moreover, a greater understanding of the differences between adult and adolescent drug responses will aid in the development of a more appropriate age-specific treatment strategy.
Testing rodents in their home cages has become i ncreasingly popular. A new low-cost computer-con... more Testing rodents in their home cages has become i ncreasingly popular. A new low-cost computer-controlled operant panel was designed, which can be placed inside the home cage. A pilot study was carried out, using a decisionmaking protocol, which was adapted from the original maze rodent Iowa Gambling Task (r-IGT). Male adult rats were tested in their home cages, containing the operant panel provided with nose-poking holes. Nose-poking was associated with rewards of different value and probability. A tryptophan-free diet was fed to investigate the effect of lowering central serotonin concentration on performance in the r-IGT. The data suggested that control rats behave in a way similar to rats tested in the original r-IGT; that is, they tend to choose the option with the best long-term payoff more often as the test progresses. Tryptophan depleted rats showed a weaker improvement across trials than controls.