Publications by authors named "Francesco Papaleo"

58 Publications

The Discrete Paired-trial Variable-delay T-maze Task to Assess Working Memory in Mice.

Bio Protoc 2020 Jul 5;10(13):e3664. Epub 2020 Jul 5.

Genetics of Cognition laboratory, Neuroscience area, Istituto Italiano di Tecnologia, Genova, Italy.

Working memory abnormalities involving the prefrontal cortex (PFC) dramatically contribute to poor functional outcomes in patients with schizophrenia and still represent an unmet therapeutic need. Studies in rodents might provide essential tools to understand the mechanisms underlying PFC-dependent working memory dysfunctions, as well as precious tools for genetic and pharmacological testing. However, proper tests assessing working memory and sensitive to PFC-dependent functions must be used. In this regard, the discrete paired-trial variable-delay T-maze task, equivalent to delayed non-match to sample tasks used in humans, has proved to be an effective paradigm to test PFC-dependent working memory dysfunctions with high predictive validity in human studies.
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http://dx.doi.org/10.21769/BioProtoc.3664DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7842707PMC
July 2020

A novel arousal-based individual screening reveals susceptibility and resilience to PTSD-like phenotypes in mice.

Neurobiol Stress 2021 May 24;14:100286. Epub 2020 Dec 24.

Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy.

Translational animal models for studying post-traumatic stress disorder (PTSD) are valuable for elucidating the poorly understood neurobiology of this neuropsychiatric disorder. These models should encompass crucial features, including persistence of PTSD-like phenotypes triggered after exposure to a single traumatic event, trauma susceptibility/resilience and predictive validity. Here we propose a novel arousal-based individual screening (AIS) model that recapitulates all these features. The AIS model was designed by coupling the traumatization (24 h restraint) of C57BL/6 J mice with a novel individual screening. This screening consists of z-normalization of post-trauma changes in startle reactivity, which is a measure of arousal depending on neural circuits conserved across mammals. Through the AIS model, we identified susceptible mice showing long-lasting hyperarousal (up to 56 days post-trauma), and resilient mice showing normal arousal. Susceptible mice further showed persistent PTSD-like phenotypes including exaggerated fear reactivity and avoidance of trauma-related cue (up to 75 days post-trauma), increased avoidance-like behavior and social/cognitive impairment. Conversely, resilient mice adopted active coping strategies, behaving like control mice. We further uncovered novel transcriptional signatures driven by PTSD-related genes as well as dysfunction of hypothalamic-pituitary-adrenal axis, which corroborated the segregation in susceptible/resilient subpopulations obtained through the AIS model and correlated with trauma susceptibility/resilience. Impaired hippocampal synaptic plasticity was also observed in susceptible mice. Finally, chronic treatment with paroxetine ameliorated the PTSD-like phenotypes of susceptible mice. These findings indicate that the AIS model might be a new translational animal model for the study of crucial features of PTSD. It might shed light on the unclear PTSD neurobiology and identify new pharmacological targets for this difficult-to-treat disorder.
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http://dx.doi.org/10.1016/j.ynstr.2020.100286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772817PMC
May 2021

Automated Two-Chamber Operon ID/ED Task for Mice.

Curr Protoc Neurosci 2020 12;94(1):e109

Genetics of Cognition Laboratory, Neuroscience Area, Istituto Italiano di Tecnologia, Genova, Italy.

Attentional set shifting is a measure of cognitive flexibility and executive functions widely assessed in humans by the Wisconsin Card Sorting Test (WCST) and the CANTAB Intra-/Extra-Dimensional set-shifting task (ID/ED). The recently established automated two-chamber "Operon ID/ED" task for mice has proved to be an effective preclinical tool for drug testing and genetic screening, with direct translational valence in healthy human subjects and patients with schizophrenia. Here, we describe an upgraded version of the Operon ID/ED task that is now commercially available. This automated task allows one to study the ability of mice to shift attention through different rules, using two or three different dimensions (i.e., lights, odors, and textures). This unit provides a detailed step-by-step protocol for preparing and testing the mice that includes all procedures required for this upgraded attentional set-shifting paradigm. A short manual for the use of the dedicated ANY-maze software and tools for adapting it to different needs are also provided. Overall, this is a comprehensive guideline for the use of this complex upgraded equipment and paradigm. © 2020 Wiley Periodicals LLC. Basic Protocol: Operon ID/ED testing Support Protocol: Use of ANY-maze software.
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http://dx.doi.org/10.1002/cpns.109DOI Listing
December 2020

Dopamine, Cognitive Impairments and Second-Generation Antipsychotics: From Mechanistic Advances to More Personalized Treatments.

Pharmaceuticals (Basel) 2020 Nov 5;13(11). Epub 2020 Nov 5.

Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy.

The pharmacological treatment of cognitive impairments associated with schizophrenia is still a major unmet clinical need. Indeed, treatments with available antipsychotics generate highly variable cognitive responses among patients with schizophrenia. This has led to the general assumption that antipsychotics are ineffective on cognitive impairment, although personalized medicine and drug repurposing approaches might scale down this clinical issue. In this scenario, evidence suggests that cognitive improvement exerted by old and new atypical antipsychotics depends on dopaminergic mechanisms. Moreover, the newer antipsychotics brexpiprazole and cariprazine, which might have superior clinical efficacy on cognitive deficits over older antipsychotics, mainly target dopamine receptors. It is thus reasonable to assume that despite more than 50 years of elusive efforts to develop novel non-dopaminergic antipsychotics, dopamine receptors remain the most attractive and promising pharmacological targets in this field. In the present review, we discuss preclinical and clinical findings showing dopaminergic mechanisms as key players in the cognitive improvement induced by both atypical antipsychotics and potential antipsychotics. We also emphasize the concept that these mechanistic advances, which help to understand the heterogeneity of cognitive responses to antipsychotics, may properly guide treatment decisions and address the unmet medical need for the management of cognitive impairment associated with schizophrenia.
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http://dx.doi.org/10.3390/ph13110365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7694365PMC
November 2020

Oxytocin Discrepancies in Social Dynamics.

Neuron 2020 08;107(4):591-593

Genetics of Cognition Laboratory, Neuroscience Area, Istituto Italiano di Tecnologia, Genova, Italy. Electronic address:

Social group dynamics are highly complex. In this issue of Neuron, Anpilov et al. use a novel wireless optogenetic device to demonstrate that the repeated stimulation of oxytocin neurons modulates pro-social and agonistic behaviors in a time- and context-dependent manner.
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http://dx.doi.org/10.1016/j.neuron.2020.07.027DOI Listing
August 2020

Immunology of COVID-19: Mechanisms, clinical outcome, diagnostics, and perspectives-A report of the European Academy of Allergy and Clinical Immunology (EAACI).

Allergy 2020 10;75(10):2445-2476

Institute of Pathophysiology and Allergy Research, Center of Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.

With the worldwide spread of the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) resulting in declaration of a pandemic by the World Health Organization (WHO) on March 11, 2020, the SARS-CoV-2-induced coronavirus disease-19 (COVID-19) has become one of the main challenges of our times. The high infection rate and the severe disease course led to major safety and social restriction measures worldwide. There is an urgent need of unbiased expert knowledge guiding the development of efficient treatment and prevention strategies. This report summarizes current immunological data on mechanisms associated with the SARS-CoV-2 infection and COVID-19 development and progression to the most severe forms. We characterize the differences between adequate innate and adaptive immune response in mild disease and the deep immune dysfunction in the severe multiorgan disease. The similarities of the human immune response to SARS-CoV-2 and the SARS-CoV and MERS-CoV are underlined. We also summarize known and potential SARS-CoV-2 receptors on epithelial barriers, immune cells, endothelium and clinically involved organs such as lung, gut, kidney, cardiovascular, and neuronal system. Finally, we discuss the known and potential mechanisms underlying the involvement of comorbidities, gender, and age in development of COVID-19. Consequently, we highlight the knowledge gaps and urgent research requirements to provide a quick roadmap for ongoing and needed COVID-19 studies.
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http://dx.doi.org/10.1111/all.14462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7361752PMC
October 2020

Social Neuroscience: Rats Can Be Considerate to Others.

Curr Biol 2020 03;30(6):R274-R276

Genetics of Cognition Laboratory, Neuroscience Area, Istituto Italiano di Tecnologia, Genova, Italy. Electronic address:

Are rats willing to avoid causing suffering in other rats? A new study shows that rats might change their behaviour if it is harmful to others.
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http://dx.doi.org/10.1016/j.cub.2020.01.093DOI Listing
March 2020

Retinal biomarkers and pharmacological targets for Hermansky-Pudlak syndrome 7.

Sci Rep 2020 03 4;10(1):3972. Epub 2020 Mar 4.

Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania, Italy.

Deletion of dystrobrevin binding protein 1 has been linked to Hermansky-Pudlak syndrome type 7 (HPS-7), a rare disease characterized by oculocutaneous albinism and retinal dysfunction. We studied dysbindin-1 null mutant mice (Dys) to shed light on retinal neurodevelopment defects in HPS-7. We analyzed the expression of a focused set of miRNAs in retina of wild type (WT), Dys and Dys mice. We also investigated the retinal function of these mice through electroretinography (ERG). We found that miR-101-3p, miR-137, miR-186-5p, miR-326, miR-382-5p and miR-876-5p were up-regulated in Dysmice retina. Dys mice showed significant increased b-wave in ERG, compared to WT mice. Bioinformatic analysis highlighted that dysregulated miRNAs target synaptic plasticity and dopaminergic signaling pathways, affecting retinal functions of Dys mice. Overall, the data indicate potential mechanisms in retinal neurodevelopment of Dys mice, which may have translational significance in HSP-7 patients, both in terms of diagnostic/prognostic biomarkers and novel pharmacological targets.
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http://dx.doi.org/10.1038/s41598-020-60931-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7055265PMC
March 2020

Favorable effects of omega-3 polyunsaturated fatty acids in attentional control and conversion rate to psychosis in 22q11.2 deletion syndrome.

Neuropharmacology 2020 05 10;168:107995. Epub 2020 Feb 10.

Genetics of Cognition Laboratory, Neuroscience Area, Istituto Italiano di Tecnologia, Via Morego, 30, 16163, Genova, Italy. Electronic address:

Omega-3-polyunsaturated-fatty-acids were suggested against cognitive dysfunctions and conversion to psychosis. However, a recent multicenter trial found no effect in reducing conversion rates in individuals at risk of developing schizophrenia. Patients' genetic heterogeneity and the timing of treatment might influence omega-3 efficacy. Here, we addressed the impact of omega-3 early treatment in both mice and human subjects with a 22q11.2 genetic hemi-deletion (22q11DS), characterized by cognitive dysfunctions and high penetrance of schizophrenia. We first tested the behavioural and cognitive consequences of adolescent exposure to normal or omega-3-enriched diets in wild-type and 22q11DS (LgDel/+) mice. We then contrasted mouse data with those gathered from sixty-two patients with 22q11DS exposed to a normal diet or supplemented with omega-3 during pre-adolescence/adolescence. Adolescent omega-3 exposure had no effects in wild-type mice. However, this treatment ameliorated distractibility deficits revealed in LgDel/+ mice by the Five Choice Serial Reaction Time Task (5CSRTT). The omega-3 improvement in LgDel/+ mice was selective, as no other generalized cognitive and non-cognitive effects were evident. Similarly, omega-3-exposed 22q11DS patients showed long-lasting improvements on distractibility as revealed by the continuous performance test (CPT). Moreover, omega-3-exposed 22q11DS patients showed less risk of developing an Ultra High Risk status and lower conversion rate to psychosis. Our convergent mouse-human findings represent a first analysis on the effects of omega-3 early treatment in 22q11DS. The beneficial effects in attentional control and transition to psychosis could support the early use of omega-3 supplementation in the 22q11DS population.
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http://dx.doi.org/10.1016/j.neuropharm.2020.107995DOI Listing
May 2020

Acute and Repeated Intranasal Oxytocin Differentially Modulate Brain-wide Functional Connectivity.

Neuroscience 2020 10 7;445:83-94. Epub 2020 Jan 7.

Functional Neuroimaging Laboratory, Center for Neuroscience and Cognitive Systems @UniTn, Istituto Italiano di Tecnologia, Corso Bettini 31, 38068 Rovereto (TN), Italy. Electronic address:

Central release of the neuropeptide oxytocin (OXT) modulates neural substrates involved in socio-affective behavior. This property has prompted research into the use of intranasal OXT administration as an adjunctive therapy for brain conditions characterized by social impairment, such as autism spectrum disorders (ASD). However, the neural circuitry and brain-wide functional networks recruited by intranasal OXT administration remain elusive. Moreover, little is known of the neuroadaptive cascade triggered by long-term administration of this peptide at the network level. To address these questions, we applied fMRI-based circuit mapping in adult mice upon acute and repeated (seven-day) intranasal dosing of OXT. We report that acute and chronic OXT administration elicit comparable fMRI activity as assessed with cerebral blood volume mapping, but entail largely different patterns of brain-wide functional connectivity. Specifically, acute OXT administration focally boosted connectivity within key limbic components of the rodent social brain, whereas repeated dosing led to a prominent and widespread increase in functional connectivity, involving a strong coupling between the amygdala and extended cortical territories. Importantly, this connectional reconfiguration was accompanied by a paradoxical reduction in social interaction and communication in wild-type mice. Our results identify the network substrates engaged by exogenous OXT administration, and show that repeated OXT dosing leads to a substantial reconfiguration of brain-wide connectivity, entailing an aberrant functional coupling between cortico-limbic structures involved in socio-communicative and affective functions. Such divergent patterns of network connectivity might contribute to discrepant clinical findings involving acute or long-term OXT dosing in clinical populations.
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http://dx.doi.org/10.1016/j.neuroscience.2019.12.036DOI Listing
October 2020

Somatostatin interneurons in the prefrontal cortex control affective state discrimination in mice.

Nat Neurosci 2020 01 16;23(1):47-60. Epub 2019 Dec 16.

Genetics of Cognition laboratory, Neuroscience area, Istituto Italiano di Tecnologia, Genova, Italy.

The prefrontal cortex (PFC) is implicated in processing of the affective state of others through non-verbal communication. This social cognitive function is thought to rely on an intact cortical neuronal excitatory and inhibitory balance. Here combining in vivo electrophysiology with a behavioral task for affective state discrimination in mice, we show a differential activation of medial PFC (mPFC) neurons during social exploration that depends on the affective state of the conspecific. Optogenetic manipulations revealed a double dissociation between the role of interneurons in social cognition. Specifically, inhibition of mPFC somatostatin (SOM), but not of parvalbumin (PV) interneurons, abolishes affective state discrimination. Accordingly, synchronized activation of mPFC SOM interneurons selectively induces social discrimination. As visualized by in vivo single-cell microendoscopic Ca imaging, an increased synchronous activity of mPFC SOM interneurons, guiding inhibition of pyramidal neurons, is associated with affective state discrimination. Our findings provide new insights into the neurobiological mechanisms of affective state discrimination.
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http://dx.doi.org/10.1038/s41593-019-0551-8DOI Listing
January 2020

SINEUP Non-coding RNA Targeting GDNF Rescues Motor Deficits and Neurodegeneration in a Mouse Model of Parkinson's Disease.

Mol Ther 2020 02 16;28(2):642-652. Epub 2019 Aug 16.

Central RNA Laboratory and Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia (IIT), 16263 Genova, Italy. Electronic address:

Glial cell-derived neurotrophic factor (GDNF) has a potent action in promoting the survival of dopamine (DA) neurons. Several studies indicate that increasing GDNF levels may be beneficial for the treatment of Parkinson's disease (PD) by reducing neurodegeneration of DA neurons. Despite a plethora of preclinical studies showing GDNF efficacy in PD animal models, its application in humans remains questionable for its poor efficacy and side effects due to its uncontrolled, ectopic expression. Here we took advantage of SINEUPs, a new class of antisense long non-coding RNA, that promote translation of partially overlapping sense protein-coding mRNAs with no effects on their mRNA levels. By synthesizing a SINEUP targeting Gdnf mRNA, we were able to increase endogenous GDNF protein levels by about 2-fold. Adeno-associated virus (AAV)9-mediated delivery in the striatum of wild-type (WT) mice led to an increase of endogenous GDNF protein for at least 6 months and the potentiation of the DA system's functions while showing no side effects. Furthermore, SINEUP-GDNF was able to ameliorate motor deficits and neurodegeneration of DA neurons in a PD neurochemical mouse model. Our data indicate that SINEUP-GDNF could represent a new strategy to increase endogenous GDNF protein levels in a more physiological manner for therapeutic treatments of PD.
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http://dx.doi.org/10.1016/j.ymthe.2019.08.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7000958PMC
February 2020

Attenuated palmitoylation of serotonin receptor 5-HT1A affects receptor function and contributes to depression-like behaviors.

Nat Commun 2019 09 2;10(1):3924. Epub 2019 Sep 2.

Cellular Neurophysiology, Hannover Medical School, Carl-Neuberg Str. 1, 30625, Hannover, Germany.

The serotonergic system and in particular serotonin 1A receptor (5-HT1AR) are implicated in major depressive disorder (MDD). Here we demonstrated that 5-HT1AR is palmitoylated in human and rodent brains, and identified ZDHHC21 as a major palmitoyl acyltransferase, whose depletion reduced palmitoylation and consequently signaling functions of 5-HT1AR. Two rodent models for depression-like behavior show reduced brain ZDHHC21 expression and attenuated 5-HT1AR palmitoylation. Moreover, selective knock-down of ZDHHC21 in the murine forebrain induced depression-like behavior. We also identified the microRNA miR-30e as a negative regulator of Zdhhc21 expression. Through analysis of the post-mortem brain samples in individuals with MDD that died by suicide we find that miR-30e expression is increased, while ZDHHC21 expression, as well as palmitoylation of 5-HT1AR, are reduced within the prefrontal cortex. Our study suggests that downregulation of 5-HT1AR palmitoylation is a mechanism involved in depression, making the restoration of 5-HT1AR palmitoylation a promising clinical strategy for the treatment of MDD.
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http://dx.doi.org/10.1038/s41467-019-11876-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6718429PMC
September 2019

Acute Administration of URB597 Fatty Acid Amide Hydrolase Inhibitor Prevents Attentional Impairments by Distractors in Adolescent Mice.

Front Pharmacol 2019 19;10:787. Epub 2019 Jul 19.

Department of Neuroscience and Brain Technologies, Genetics of Cognition Laboratory, Istituto Italiano di Tecnologia, Genova, Italy.

The maturation of attentional control during adolescence might influence later functional outcome or predisposition to psychiatric disorders. During adolescence, the cannabinoid system is particularly sensitive to pharmacological challenges, with potential impact on cognitive functions. Here, we used a recently validated five-choice serial reaction time task protocol to test adolescent C57BL/6J mice. We showed that the pharmacological inhibition (by URB597) of the fatty acid amide hydrolase (FAAH), the major enzyme implicated in anandamide degradation, prevented cognitive disruptions induced by distracting cues in adolescent mice. In particular, these protective effects were indicated by increased accuracy and correct responses and decreased premature responses selectively in the distractor trials. Notably, at the relatively low dose used, we detected no effects in other cognitive, motor, or incentive measures nor long-lasting or rebound effects of FAAH inhibition in cognitive functions. Overall, these data provide initial evidence of selective procognitive effects of FAAH inhibition in measures of attentional control in adolescent mice.
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http://dx.doi.org/10.3389/fphar.2019.00787DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6658611PMC
July 2019

Oxytocin Signaling in the Central Amygdala Modulates Emotion Discrimination in Mice.

Curr Biol 2019 06 6;29(12):1938-1953.e6. Epub 2019 Jun 6.

Department of Neuroscience and Brain Technologies, Genetics of Cognition laboratory, Istituto Italiano di Tecnologia, 16163 Genova, Italy. Electronic address:

Recognition of other's emotions influences the way social animals interact and adapt to the environment. The neuropeptide oxytocin (OXT) has been implicated in different aspects of emotion processing. However, the role of endogenous OXT brain pathways in the social response to different emotional states in conspecifics remains elusive. Here, using a combination of anatomical, genetic, and chemogenetic approaches, we investigated the contribution of endogenous OXT signaling in the ability of mice to discriminate unfamiliar conspecifics based on their emotional states. We found that OXTergic projections from the paraventricular nucleus of the hypothalamus (PVN) to the central amygdala (CeA) are crucial for the discrimination of both positively and negatively valenced emotional states. In contrast, blocking PVN OXT release into the nucleus accumbens, prefrontal cortex, and hippocampal CA2 did not alter this emotion discrimination. Furthermore, silencing each of these PVN OXT pathways did not influence basic social interaction. These findings were further supported by the demonstration that virally mediated enhancement of OXT signaling within the CeA was sufficient to rescue emotion discrimination deficits in a genetic mouse model of cognitive liability. Our results indicate that CeA OXT signaling plays a key role in emotion discrimination both in physiological and pathological conditions.
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http://dx.doi.org/10.1016/j.cub.2019.04.070DOI Listing
June 2019

Dopamine-mediated immunomodulation affects choroid plexus function.

Brain Behav Immun 2019 10 5;81:138-150. Epub 2019 Jun 5.

Genetics of Cognition Laboratory, Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genova, Italy. Electronic address:

Immune system alterations have been implicated in various dopamine-related disorders, such as schizophrenia, bipolar disorder, and attention-deficit/hyperactivity disorder (ADHD). How immunity might be influenced by dopaminergic dysfunction and impact on clinically-relevant behaviors is still uncertain. We performed a peripheral and cerebral immunophenotyping in mice bearing dopaminergic alteration produced by genetic liability (hypofunction of the dopamine transporter DAT) and psychostimulant (amphetamine) administration. We found that DAT hypofunction influences immune tolerance by increasing functional Tregs and adrenomedullin levels in the thymus and spleen, while reducing microglia activation and infiltration of brain monocyte-derived macrophages (mo-MΦ). Remarkably, both DAT hypofunction and amphetamine treatment are associated with a weaker activation of the choroid plexus (CP) gateway. Conversely, amphetamine reactivated the CP in the setting of DAT hypofunction, paralleling its paradoxical ADHD-relevant behavioral effects. These findings add new knowledge on dopaminergic immunopharmacology and support the immunomodulation of CP functionality as a promising therapeutic strategy for neurodevelopmental and psychiatric disorders.
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http://dx.doi.org/10.1016/j.bbi.2019.06.006DOI Listing
October 2019

Enhancing cognition through pharmacological and environmental interventions: Examples from preclinical models of neurodevelopmental disorders.

Neurosci Biobehav Rev 2020 03 10;110:28-45. Epub 2019 Apr 10.

Neuroscience and Mental Health Research Institute (NMHRI), Division of Neuroscience, School of Biosciences, Cardiff University, CF24 4HQ, Cardiff, UK. Electronic address:

In this review we discuss the role of environmental and pharmacological treatments to enhance cognition with special regards to neurodevelopmental related disorders and aging. How the environment influences brain structure and function, and the interactions between rearing conditions and gene expression, are fundamental questions that are still poorly understood. We propose a model that can explain some of the discrepancies in findings for effects of environmental enrichment on outcome measures. Evidence of a direct causal correlation of nootropics and treatments that enhanced cognition also will be presented, and possible molecular mechanisms that include neurotrophin signaling and downstream pathways underlying these processes are discussed. Finally we review recent findings achieved with a wide set of behavioral and cognitive tasks that have translational validity to humans, and should be useful for future work on devising appropriate therapies. As will be discussed, the collective findings suggest that a combinational therapeutic approach of environmental enrichment and nootropics could be particularly successful for improving learning and memory in both developmental disorders and normal aging.
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http://dx.doi.org/10.1016/j.neubiorev.2019.02.003DOI Listing
March 2020

Understanding others: Emotion recognition in humans and other animals.

Genes Brain Behav 2019 01;18(1):e12544

Genetics of Cognition Laboratory, Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genoa, Italy.

Emotion recognition represents the ability to encode an ensemble of sensory stimuli providing information about the emotional state of another individual. This ability is not unique to humans. An increasing number of studies suggest that many aspects of higher order social functions, including emotion recognition, might be present in species ranging from primates to rodents, indicating a conserved role in social animals. The aim of this review is to examine and compare how emotions are communicated and perceived in humans and other animals, with the intent to highlight possible new behavioral approaches and research perspectives. We summarize the evidence from human emotion recognition, and latest advances in the development of nonhuman animal behavioral tests, using or implying the use of this cognitive function. The differential implication of sensory modalities used by animals to communicate and decipher emotional states is also discussed. The opportunity to measure emotion recognition abilities in rodents may allow us to better identify the neural mechanisms mediating this complex function, thus promoting the development of new intervention strategies for several neuropsychiatric disorders characterized by social cognitive dysfunctions.
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http://dx.doi.org/10.1111/gbb.12544DOI Listing
January 2019

Publisher Correction: Variations in Dysbindin-1 are associated with cognitive response to antipsychotic drug treatment.

Nat Commun 2018 08 29;9(1):3560. Epub 2018 Aug 29.

Department of Neuroscience and Brain Technologies, Genetics of Cognition laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163, Genova, Italy.

In the original version of this Article, references in the Methods section incorrectly referred to references in the Supplementary References section. The relevant references (now numbered 20, 27, 42, 47, 69-80) have been removed from the Supplementary References section of the Supplementary Information file and added to the References section of the main manuscript, in both the PDF and HTML versions of the Article.
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http://dx.doi.org/10.1038/s41467-018-06062-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6115376PMC
August 2018

NEGR1 and FGFR2 cooperatively regulate cortical development and core behaviours related to autism disorders in mice.

Brain 2018 09;141(9):2772-2794

Local Micro-environment and Brain Development Laboratory, Italian Institute of Technology, Genoa, Italy.

Autism spectrum disorders are neurodevelopmental conditions with diverse aetiologies, all characterized by common core symptoms such as impaired social skills and communication, as well as repetitive behaviour. Cell adhesion molecules, receptor tyrosine kinases and associated downstream signalling have been strongly implicated in both neurodevelopment and autism spectrum disorders. We found that downregulation of the cell adhesion molecule NEGR1 or the receptor tyrosine kinase fibroblast growth factor receptor 2 (FGFR2) similarly affects neuronal migration and spine density during mouse cortical development in vivo and results in impaired core behaviours related to autism spectrum disorders. Mechanistically, NEGR1 physically interacts with FGFR2 and modulates FGFR2-dependent extracellular signal-regulated kinase (ERK) and protein kinase B (AKT) signalling by decreasing FGFR2 degradation from the plasma membrane. Accordingly, FGFR2 overexpression rescues all defects due to Negr1 knockdown in vivo. Negr1 knockout mice present phenotypes similar to Negr1-downregulated animals. These data indicate that NEGR1 and FGFR2 cooperatively regulate cortical development and suggest a role for defective NEGR1-FGFR2 complex and convergent downstream ERK and AKT signalling in autism spectrum disorders.
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http://dx.doi.org/10.1093/brain/awy190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6113639PMC
September 2018

Variations in Dysbindin-1 are associated with cognitive response to antipsychotic drug treatment.

Nat Commun 2018 06 11;9(1):2265. Epub 2018 Jun 11.

Department of Neuroscience and Brain Technologies, Genetics of Cognition laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163, Genova, Italy.

Antipsychotics are the most widely used medications for the treatment of schizophrenia spectrum disorders. While such drugs generally ameliorate positive symptoms, clinical responses are highly variable in terms of negative symptoms and cognitive impairments. However, predictors of individual responses have been elusive. Here, we report a pharmacogenetic interaction related to a core cognitive dysfunction in patients with schizophrenia. We show that genetic variations reducing dysbindin-1 expression can identify individuals whose executive functions respond better to antipsychotic drugs, both in humans and in mice. Multilevel ex vivo and in vivo analyses in postmortem human brains and genetically modified mice demonstrate that such interaction between antipsychotics and dysbindin-1 is mediated by an imbalance between the short and long isoforms of dopamine D2 receptors, leading to enhanced presynaptic D2 function within the prefrontal cortex. These findings reveal one of the pharmacodynamic mechanisms underlying individual cognitive response to treatment in patients with schizophrenia, suggesting a potential approach for improving the use of antipsychotic drugs.
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http://dx.doi.org/10.1038/s41467-018-04711-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5995960PMC
June 2018

Internalization of Carbon Nano-onions by Hippocampal Cells Preserves Neuronal Circuit Function and Recognition Memory.

ACS Appl Mater Interfaces 2018 May 9;10(20):16952-16963. Epub 2018 May 9.

Nano Carbon Materials , Istituto Italiano di Tecnologia , via Morego 30 , Genova , Italy.

One area where nanomedicine may offer superior performances and efficacy compared to current strategies is in the diagnosis and treatment of central nervous system (CNS) diseases. However, the application of nanomaterials in such complex arenas is still in its infancy and an optimal vector for the therapy of CNS diseases has not been identified. Graphitic carbon nano-onions (CNOs) represent a class of carbon nanomaterials that shows promising potential for biomedical purposes. To probe the possible applications of graphitic CNOs as a platform for therapeutic and diagnostic interventions on CNS diseases, fluorescently labeled CNOs were stereotaxically injected in vivo in mice hippocampus. Their diffusion within brain tissues and their cellular localization were analyzed ex vivo by confocal microscopy, electron microscopy, and correlative light-electron microscopy techniques. The subsequent fluorescent staining of hippocampal cells populations indicates they efficiently internalize the nanomaterial. Furthermore, the inflammatory potential of the CNOs injection was found comparable to sterile vehicle infusion, and it did not result in manifest neurophysiological and behavioral alterations of hippocampal-mediated functions. These results clearly demonstrate that CNOs can interface effectively with several cell types, which encourages further their development as possible brain disease-targeted diagnostics or therapeutics nanocarriers.
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http://dx.doi.org/10.1021/acsami.7b17827DOI Listing
May 2018

The Dopamine D5 Receptor Is Involved in Working Memory.

Front Pharmacol 2017 6;8:666. Epub 2017 Oct 6.

Clinical Brain Disorders Branch, Genes, Cognition and Psychosis Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, United States.

Pharmacological studies indicate that dopamine D-like receptors (D and D) are critically involved in cognitive function. However, the lack of pharmacological ligands selective for either the D or D receptors has made it difficult to determine the unique contributions of the D-like family members. To circumvent these pharmacological limitations, we used D receptor homozygous (-/-) and heterozygous (+/-) knockout mice, to identify the specific role of this receptor in higher order cognitive functions. We identified a novel role for D receptors in the regulation of spatial working memory and temporal order memory function. The D mutant mice acquired a discrete paired-trial variable-delay T-maze task at normal rates. However, both [Formula: see text] and [Formula: see text] mice exhibited impaired performance compared to [Formula: see text] littermates when a higher burden on working memory faculties was imposed. In a temporal order object recognition task, [Formula: see text] exhibited significant memory deficits. No D-dependent differences in locomotor functions and interest in exploring objects were evident. Molecular biomarkers of dopaminergic functions within the prefrontal cortex (PFC) revealed a selective gene-dose effect on Akt phosphorylation at Ser473 with increased levels in [Formula: see text] knockout mice. A trend toward reduced levels in CaMKKbeta brain-specific band (64 kDa) in [Formula: see text] compared to [Formula: see text] was also evident. These findings highlight a previously unidentified role for D receptors in working memory function and associated molecular signatures within the PFC.
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http://dx.doi.org/10.3389/fphar.2017.00666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5635435PMC
October 2017

Schizophrenia: What's Arc Got to Do with It?

Front Behav Neurosci 2017 20;11:181. Epub 2017 Sep 20.

Department of Neuroscience and Brain Technologies, Istituto Italiano di TecnologiaGenova, Italy.

Human studies of schizophrenia are now reporting a previously unidentified genetic convergence on postsynaptic signaling complexes such as the activity-regulated cytoskeletal-associated (Arc) gene. However, because this evidence is still very recent, the neurobiological implication of Arc in schizophrenia is still scattered and unrecognized. Here, we first review current and developing findings connecting Arc in schizophrenia. We then highlight recent and previous findings from preclinical mouse models that elucidate how Arc genetic modifications might recapitulate schizophrenia-relevant behavioral phenotypes following the novel Research Domain Criteria (RDoC) framework. Building on this, we finally compare and evaluate several lines of evidence demonstrating that Arc genetics can alter both glutamatergic and dopaminergic systems in a very selective way, again consistent with molecular alterations characteristic of schizophrenia. Despite being only initial, accumulating and compelling data are showing that Arc might be one of the primary biological players in schizophrenia. Synaptic plasticity alterations in the genetic architecture of psychiatric disorders might be a rule, not an exception. Thus, we anticipate that additional evidence will soon emerge to clarify the Arc-dependent mechanisms involved in the psychiatric-related dysfunctional behavior.
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http://dx.doi.org/10.3389/fnbeh.2017.00181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5611489PMC
September 2017

Dopamine, the antipsychotic molecule: A perspective on mechanisms underlying antipsychotic response variability.

Neurosci Biobehav Rev 2018 02 29;85:146-159. Epub 2017 Sep 29.

Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, via Morego 30, 16163 Genova, Italy.

All antipsychotics bind to the dopamine D2 receptor. An "optimal" level of D2 receptor blockade with antipsychotics is thought to ameliorate the positive symptoms of schizophrenia. However, persistent D2 receptor blockade is associated with a deteriorating clinical response in a subset of patients. Interestingly, antipsychotics with a weaker D2 receptor binding profile appear somewhat superior in this respect. This evidence challenges the hypothesis that D2 receptor blockade is the sole mechanism of antipsychotic efficacy and points to consistent inter-individual responses to antipsychotic treatment. Here, we hypothesize that clinically effective doses of antipsychotics would lead to the formation of a D2 receptor "reserve" that is likely composed of presynaptic dopamine D2 autoreceptors. The majority of the remaining postsynaptic dopamine receptors are instead occupied by antipsychotics. Endogenous dopamine would then mainly interact with this D2 autoreceptor reserve, thereby reducing the presynaptic synthesis and release of dopamine and resulting in an indirect antipsychotic effect. This new proposal reconciles conceptual and empirical gaps encountered when clinical outcomes are compared to the pharmacology of antipsychotics.
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http://dx.doi.org/10.1016/j.neubiorev.2017.09.027DOI Listing
February 2018

Attentional Control in Adolescent Mice Assessed with a Modified Five Choice Serial Reaction Time Task.

Sci Rep 2017 08 30;7(1):9936. Epub 2017 Aug 30.

Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, via Morego, 30, 16163, Genova, Italy.

Adolescence is a critical period for the development of higher-order cognitive functions. Unlike in humans, very limited tools are available to assess such cognitive abilities in adolescent rodents. We implemented a modified 5-Choice Serial Reaction Time Task (5CSRTT) to selectively measure attentiveness, impulsivity, broad monitoring, processing speed and distractibility in adolescent mice. 21-day old C57BL/6J mice reliably acquired this task with no sex-dependent differences in 10-12 days. A protocol previously used in adults was less effective to assess impulsiveness in adolescents, but revealed increased vulnerability in females. Next, we distinctively assessed selective, divided and broad monitoring attention modeling the human Spatial Attentional Resource Allocation Task (SARAT). Finally, we measured susceptibility to distractions using non-predictive cues that selectively disrupted attention. These paradigms were also applied to two genetically modified lines: the dopamine transporter (DAT) and catechol-O-methyltransferase (COMT) heterozygous. Adolescent DAT hypo-functioning mice showed attentional deficits and higher impulsivity as found in adults. In contrast to adults, adolescent COMT hypo-functioning mice showed decreased impulsivity and attentional resilience to distractors. These paradigms open new avenues to study the establishment of higher-order cognitive functions in mice, as well as an effective tool for drug-testing and genetic screenings focused on adolescence.
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http://dx.doi.org/10.1038/s41598-017-10112-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5577211PMC
August 2017

A schizophrenia relevant 5-Choice Serial Reaction Time Task for mice assessing broad monitoring, distractibility and impulsivity.

Psychopharmacology (Berl) 2017 Jul 5;234(13):2047-2062. Epub 2017 Apr 5.

Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, via Morego, 30, 16163, Genova, Italy.

The 5-Choice Serial Reaction Time Task (5-CSRTT) is an automated test for rodents allowing the assessment of multiple cognitive measures. Originally designed to assess cognitive deficits relevant to attention deficit hyperactivity disorder, it has been widely used in the investigation of neural systems of attention. In the current study, we have set up a modified version, which reduced the training phase to only 8-9 days with minimal food deprivation and without single-housing. Furthermore, based on evidence that patients with schizophrenia are more impaired in broad monitoring abilities than in sustained attention, we successfully developed a protocol replicating the Spatial Attentional Resource Allocation Task (SARAT), used in humans to assess broad monitoring. During this task, when the target appeared at a single pre-cued location, mice selectively responded faster. Instead, increasing the number of validly cued locations proportionately decreased accuracy. We then validated a protocol which is relevant for neuropsychiatric disorders in which additional irrelevant pre-cue lights selectively disrupted attention (distractibility). Finally, we improved previously used protocols changing inter-trial intervals from 5 to 7 s by randomly presenting this shift only in 20% of the trials. This resulted in a selective effect on premature responses (impulsivity), with important implications for schizophrenia as well as for other mental disorders. Therefore, this revised 5-CSRTT reduced training and stress on the animals while selectively measuring different cognitive functions with translational validity to schizophrenia and other psychiatric disorders.
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http://dx.doi.org/10.1007/s00213-017-4611-zDOI Listing
July 2017

CRF receptor-deficiency increases cocaine reward.

Neuropharmacology 2017 05 27;117:41-48. Epub 2017 Jan 27.

INSERM U1215, NeuroCentre Magendie, 33077 Bordeaux, France; Univ. Bordeaux, 33000 Bordeaux, France.

Stimulant drugs produce reward but also activate stress-responsive systems. The corticotropin-releasing factor (CRF) and the related hypothalamus-pituitary-adrenal (HPA) axis stress-responsive systems are activated by stimulant drugs. However, their role in stimulant drug-induced reward remains poorly understood. Herein, we report that CRF receptor-deficient (CRF-/-), but not wild-type, mice show conditioned place preference (CPP) responses to a relatively low cocaine dose (5 mg/kg, i.p.). Conversely, wild-type, but not CRF-/-, mice display CPP responses to a relatively high cocaine dose (20 mg/kg, i.p.), indicating that CRF receptor-deficiency alters the rewarding effects of cocaine. Acute pharmacological antagonism of the CRF receptor by antalarmin also eliminates cocaine reward. Nevertheless, CRF-/- mice display higher stereotypy responses to cocaine than wild-type mice. Despite the very low plasma corticosterone concentration, CRF-/- mice show higher nuclear glucocorticoid receptor (GR) levels in the brain region of the hippocampus than wild-type mice. Full rescue of wild-type-like corticosterone and GR circadian rhythm and level in CRF-/- mice by exogenous corticosterone does not affect CRF receptor-dependent cocaine reward but induces stereotypy responses to cocaine. These results indicate a critical role for the CRF receptor in cocaine reward, independently of the closely related HPA axis activity.
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http://dx.doi.org/10.1016/j.neuropharm.2017.01.024DOI Listing
May 2017

Intranasal Oxytocin and Vasopressin Modulate Divergent Brainwide Functional Substrates.

Neuropsychopharmacology 2017 Jun 20;42(7):1420-1434. Epub 2016 Dec 20.

Functional Neuroimaging Laboratory, Center for Neuroscience and Cognitive Systems @UniTn, Istituto Italiano di Tecnologia, Rovereto (TN), Italy.

The neuropeptides oxytocin (OXT) and vasopressin (AVP) have been identified as modulators of emotional social behaviors and associated with neuropsychiatric disorders characterized by social dysfunction. Experimental and therapeutic use of OXT and AVP via the intranasal route is the subject of extensive clinical research. However, the large-scale functional substrates directly engaged by these peptides and their functional dynamics remain elusive. By using cerebral blood volume (CBV) weighted fMRI in the mouse, we show that intranasal administration of OXT rapidly elicits the transient activation of cortical regions and a sustained activation of hippocampal and forebrain areas characterized by high oxytocin receptor density. By contrast, intranasal administration of AVP produced a robust and sustained deactivation in cortico-parietal, thalamic and mesolimbic regions. Importantly, intravenous administration of OXT and AVP did not recapitulate the patterns of modulation produced by intranasal dosing, supporting a central origin of the observed functional changes. In keeping with this notion, hippocampal local field potential recordings revealed multi-band power increases upon intranasal OXT administration. We also show that the selective OXT-derivative TGOT reproduced the pattern of activation elicited by OXT and that the deletion of OXT receptors does not affect AVP-mediated deactivation. Collectively, our data document divergent modulation of brainwide neural systems by intranasal administration of OXT and AVP, an effect that involves key substrates of social and emotional behavior. The observed divergence calls for a deeper investigation of the systems-level mechanisms by which exogenous OXT and AVP modulate brain function and exert their putative therapeutic effects.
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http://dx.doi.org/10.1038/npp.2016.283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5436116PMC
June 2017

KCNH2-3.1 expression impairs cognition and alters neuronal function in a model of molecular pathology associated with schizophrenia.

Mol Psychiatry 2016 11 9;21(11):1517-1526. Epub 2016 Feb 9.

Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, Baltimore, MD, 21205, USA.

Overexpression in humans of KCNH2-3.1, which encodes a primate-specific and brain-selective isoform of the human ether-a-go-go-related potassium channel, is associated with impaired cognition, inefficient neural processing and schizophrenia. Here, we describe a new mouse model that incorporates the KCNH2-3.1 molecular phenotype. KCNH2-3.1 transgenic mice are viable and display normal sensorimotor behaviors. However, they show alterations in neuronal structure and microcircuit function in the hippocampus and prefrontal cortex, areas affected in schizophrenia. Specifically, in slice preparations from the CA1 region of the hippocampus, KCNH2-3.1 transgenic mice have fewer mature dendrites and impaired theta burst stimulation long-term potentiation. Abnormal neuronal firing patterns characteristic of the fast deactivation kinetics of the KCNH2-3.1 isoform were also observed in prefrontal cortex. Transgenic mice showed significant deficits in a hippocampal-dependent object location task and a prefrontal cortex-dependent T-maze working memory task. Interestingly, the hippocampal-dependent alterations were not present in juvenile transgenic mice, suggesting a developmental trajectory to the phenotype. Suppressing KCNH2-3.1 expression in adult mice rescues both the behavioral and physiological phenotypes. These data provide insight into the mechanism of association of KCNH2-3.1 with variation in human cognition and neuronal physiology and may explain its role in schizophrenia.
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http://dx.doi.org/10.1038/mp.2015.219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4980295PMC
November 2016