Normal spatial learning and improved spatial working memory in mice (mus musculus) lacking dopamine d4 receptors

Dopamine terminals in the hippocampus and prefrontal cortex modulate cognitive processes such as spatial learning and working memory. Because dopamine D4 receptors are expressed in these brain areas we have analyzed mutant mice lacking this receptor subtype (Drd4-/-). Wild-type and Drd4-/- mice were challenged in two spatial learning paradigms: the Morris water maze and an alternation T-maze. Drd4-/- mice showed normal place learning ability to find a hidden platform based on spatial extra-maze cues. In addition, Drd4-/- mice were able to find a new platform location with the same learning plasticity as wild type-mice. Spatial working memory assessed on a T maze showed that Drd4-/- mice were more efficient than wild-type mice in acquiring the maximum plateau of correct alternation scores. These results provide further evidence that the functional consequence of lacking D4 receptors is more evident in behaviors dependent on the integrity of the prefrontal cortex.Fil: Falzone, Tomas Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Avale, Maria Elena. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Gelman, Diego Matias. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Rubinstein, Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentin

A wide diversity of cortical GABAergic interneurons derives from the embryonic preoptic area

GABA-containing (GABAergic) interneurons comprise a very heterogeneous group of cells that are crucial for cortical function. Different classes of interneurons specialize in targeting specific subcellular domains of excitatory pyramidal cells or other interneurons, which provides cortical circuits with an enormous capability for information processing. As in other regions of the CNS, cortical interneuron diversity is thought to emerge from the genetic specification of different groups of progenitor cells within the subpallium. Most cortical interneurons originate from two main regions, the medial and the caudal ganglionic eminences (MGE and CGE, respectively). In addition, it has been shown that progenitors in the embryonic preoptic area (POA) also produce a small population of cortical GABAergic interneurons. Here, we show that the contribution of the POA to the complement of cortical GABAergic interneurons is larger than previously believed. Using genetic fate mapping and in utero transplantation experiments, we demonstrate that Dbx1-expressing progenitor cells in the POA give rise to a small but highly diverse cohort of cortical interneurons, with some neurochemical and electrophysiological characteristics that were previously attributed to MGE- or CGE-derived interneurons. There are, however, some features that seem to distinguish POA-derived interneurons from MGE- or CGE-derived cells, such as their preferential laminar location. These results indicate that the mechanisms controlling the specification of different classes of cortical interneurons might be more complex than previously expected. Together with earlier findings, our results also suggest that the POA generates nearly 10% of the GABAergic interneurons in the cerebral cortex of the mous

A wide diversity of cortical GABAergic interneurons derives from the embryonic preoptic area

GABA-containing (GABAergic) interneurons comprise a very heterogeneous group of cells that are crucial for cortical function. Different classes of interneurons specialize in targeting specific subcellular domains of excitatory pyramidal cells or other interneurons, which provides cortical circuits with an enormous capability for information processing. As in other regions of the CNS, cortical interneuron diversity is thought to emerge from the genetic specification of different groups of progenitor cells within the subpallium. Most cortical interneurons originate from two main regions, the medial and the caudal ganglionic eminences (MGE and CGE, respectively). In addition, it has been shown that progenitors in the embryonic preoptic area (POA) also produce a small population of cortical GABAergic interneurons. Here, we show that the contribution of the POA to the complement of cortical GABAergic interneurons is larger than previously believed. Using genetic fate mapping and in utero transplantation experiments, we demonstrate that Dbx1-expressing progenitor cells in the POA give rise to a small but highly diverse cohort of cortical interneurons, with some neurochemical and electrophysiological characteristics that were previously attributed to MGE- or CGE-derived interneurons. There are, however, some features that seem to distinguish POA-derived interneurons from MGE- or CGE-derived cells, such as their preferential laminar location. These results indicate that the mechanisms controlling the specification of different classes of cortical interneurons might be more complex than previously expected. Together with earlier findings, our results also suggest that the POA generates nearly 10% of the GABAergic interneurons in the cerebral cortex of the mouse.Fil: Gelman, Diego Matias. Universidad Miguel Hernández; España. Consejo Superior de Investigaciones Cientificas. Instituto de Neurociencia de Alicante; España. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular; ArgentinaFil: Griveau, Amelie. Universite Paris Diderot - Paris 7; FranciaFil: Dehorter, Nathalie. Consejo Superior de Investigaciones Cientificas. Instituto de Neurociencia de Alicante; España. Universidad Miguel Hernández; EspañaFil: Teissier, Anne. Universite Paris Diderot - Paris 7; FranciaFil: Varela, Carolina. Consejo Superior de Investigaciones Cientificas. Instituto de Neurociencia de Alicante; España. Universidad Miguel Hernández; EspañaFil: Pla, Ramon. Consejo Superior de Investigaciones Cientificas. Instituto de Neurociencia de Alicante; España. Universidad Miguel Hernández; EspañaFil: Pierani, Alessandra. Universite Paris Diderot - Paris 7; FranciaFil: Marin, Oscar. Consejo Superior de Investigaciones Cientificas. Instituto de Neurociencia de Alicante; España. Universidad Miguel Hernández; Españ

Impaired brain glucose metabolism and presynaptic dopaminergic functioning in a mouse model of schizophrenia

Background: Schizophrenia is a disease diagnosed by visible signs and symptoms from late adolescence to early adulthood. The etiology of this disease remains unknown. An objective diagnostic approach is required. Here, we used a mouse model that shows schizophrenia-like phenotypes to study brain glucose metabolism and presynaptic dopaminergic functioning by positron emission tomography (PET) and immunohistochemistry. PET scannings were performed on mice after the administration of [18F]-FDG or [18F]-F-DOPA. Glucose metabolism was evaluated in basal conditions and after the induction of a hyperdopaminergic state.Results: Mutant animals show reduced glucose metabolism in prefrontal cortex, amygdala, and nucleus reuniens under the hyperdopaminergic state. They also show reduced [18F]-F-DOPA uptake in prefrontal cortex, substantia nigra reticulata, raphe nucleus, and ventral striatum but increased [18F]-F-DOPA uptake in dorsal striatum. Mutant animals also show reduced tyrosine hydroxylase expression on midbrain neurons.Conclusions: Dopamine D2 mutant animals show reduced glucose metabolism and impaired presynaptic dopaminergic functioning, in line with reports from human studies. This mouse line may be a valuable model of schizophrenia, useful to test novel tracers for PET scanning diagnostic.Fil: Tomasella, María Eugenia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Falasco, Germán Alfredo. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; ArgentinaFil: Urrutia, Leandro. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; ArgentinaFil: Bechelli, Maria Lucila. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Padilla Franzotti, Carla Luciana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Gelman, Diego Matias. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentin

Psychological essentialism and cultural variation: children's beliefs about aggression in the United States and South Africa

The present study compared indigenous South African versus African-American schoolchildren's beliefs about aggression. Eighty 7–9 year olds (40 from each country) participated in interviews in which they were asked to make inferences about the stability, malleability, and causal origins of aggressive behaviour. Although a minority of participants from both countries endorsed essentialist beliefs about aggression, South African children were more likely than American children to do so. Results also revealed some degree of coherence in children's patterns of beliefs about aggression, such that children responded across superficially different measures in ways that appear theoretically consistent. The authors consider these findings in light of debates concerning the role of cultural forces in shaping person perception. Copyright © 2007 John Wiley & Sons, Ltd.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/58579/1/537_ftp.pd

Central Dopamine D2 Receptors Regulate Growth-HormoneDependent Body Growth and Pheromone Signaling to Conspecific Males

Competition between adult males for limited resources such as food and receptive females is shaped by the male pattern of pituitary growth hormone (GH) secretion that determines body size and the production of urinary pheromones involved in male-to-male aggression. In the brain, dopamine (DA) provides incentive salience to stimuli that predict the availability of food and sexual partners. Although the importance of the GH axis and central DA neurotransmission in social dominance and fitness is clearly appreciated, the two systems have always been studied unconnectedly. Here we conducted a cell-specific genetic dissection study in conditional mutant mice that selectively lack DA D2 receptors (D2R) from pituitary lactotropes (lacDrd2KO) or neurons (neuroDrd2KO). Whereas lacDrd2KO mice developed a normal GH axis, neuroDrd2KO mice displayed fewer somatotropes; reduced hypothalamic Ghrh expression, pituitary GH content, and serum IGF-I levels; and exhibited reduced body size and weight. As a consequence of a GH axis deficit, neuroDrd2KO adult males excreted low levels of major urinary proteins and their urine failed to promote aggression and territorial behavior in control male challengers, in contrast to the urine taken from control adult males. These findings reveal that central D2Rs mediate a euroendocrineexocrine cascade that controls the maturation of the GH axis and downstream signals that are critical for fitness, social dominance, and competition between adult males.Fil: Noain, Daniela Maria Clara. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones En Ingeniería Genética y Biología Molecular; ArgentinaFil: Pérez Millán, María Inés. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Bello Gay, Estefania Pilar. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones En Ingeniería Genética y Biología Molecular; ArgentinaFil: Luque, Guillermina Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Casas Cordero, Rodrigo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones En Ingeniería Genética y Biología Molecular; ArgentinaFil: Gelman, Diego Matias. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones En Ingeniería Genética y Biología Molecular; ArgentinaFil: Peper, Marcela. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones En Ingeniería Genética y Biología Molecular; ArgentinaFil: Isabel Garcia-tornadu. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Malcolm J Low. Michigan State University; Estados Unidos;Fil: Becu, Damasia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Rubinstein, Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones En Ingeniería Genética y Biología Molecular; Argentin

Kinesin-1-mediated axonal transport of CB1 receptors is required for cannabinoid-dependent axonal growth and guidance

Endocannabinoids (eCB) modulate growth cone dynamics and axonal pathfinding through the stimulation of cannabinoid type-1 receptors (CB1R), the function of which depends on their delivery and precise presentation at the growth cone surface. However, the mechanism involved in the axonal transport of CB1R and its transport role in eCB signaling remains elusive. As mutations in the kinesin-1 molecular motor have been identified in patients with abnormal cortical development and impaired white matter integrity, we studied the defects in axonal pathfinding and fasciculation in mice lacking the kinesin light chain 1 (Klc1^-/-^) subunit of kinesin-1. Reduced levels of CB1R were found in corticofugal projections and axonal growth cones in Klc1^-/-^ mice. By live-cell imaging of CB1R-eGFP we characterized the axonal transport of CB1R vesicles and described the defects in transport that arise after KLC1 deletion. Cofilin activation, which is necessary for actin dynamics during growth cone remodeling, is impaired in the Klc1^-/-^ cerebral cortex. In addition, Klc1^-/-^ neurons showed expanded growth cones that were unresponsive to CB1R-induced axonal elongation. Together, our data reveal the relevance of kinesin-1 in CB1R axonal transport and in eCB signaling during brain wiring.Fil: Saez, Trinidad María de Los Milagros. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; ArgentinaFil: Fernandez Bessone, Iván. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; ArgentinaFil: Rodriguez, María S.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; ArgentinaFil: Alloatti, Matías. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; ArgentinaFil: Otero, María G.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; ArgentinaFil: Cromberg, Lucas Eneas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; ArgentinaFil: Pozo Devoto, Victorio Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; ArgentinaFil: Oubiña, Gonzalo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Sosa, Lucas Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Buffone, Mariano Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Gelman, Diego Matias. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Falzone, Tomas Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; Argentin

Cardiovascular and renal outcomes of renin-angiotensin system blockade in adult patients with diabetes mellitus: a systematic review with network meta-analyses

Medications aimed at inhibiting the renin-angiotensin system (RAS) have been used extensively for preventing cardiovascular and renal complications in patients with diabetes, but data that compare their clinical effectiveness are limited. We aimed to compare the effects of classes of RAS blockers on cardiovascular and renal outcomes in adults with diabetes

The pharmacological and non-pharmacological treatment of attention deficit hyperactivity disorder in children and adolescents: A systematic review with network meta-analyses of randomised trials

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is one of the most commonly diagnosed psychiatric disorders in childhood. A wide variety of treatments have been used for the management of ADHD. We aimed to compare the efficacy and safety of pharmacological, psychological and complementary and alternative medicine interventions for the treatment of ADHD in children and adolescents. METHODS AND FINDINGS: We performed a systematic review with network meta-analyses. Randomised controlled trials (≥ 3 weeks follow-up) were identified from published and unpublished sources through searches in PubMed and the Cochrane Library (up to April 7, 2016). Interventions of interest were pharmacological (stimulants, non-stimulants, antidepressants, antipsychotics, and other unlicensed drugs), psychological (behavioural, cognitive training and neurofeedback) and complementary and alternative medicine (dietary therapy, fatty acids, amino acids, minerals, herbal therapy, homeopathy, and physical activity). The primary outcomes were efficacy (treatment response) and acceptability (all-cause discontinuation). Secondary outcomes included discontinuation due to adverse events (tolerability), as well as serious adverse events and specific adverse events. Random-effects Bayesian network meta-analyses were conducted to obtain estimates as odds ratios (ORs) with 95% credibility intervals. We analysed interventions by class and individually. 190 randomised trials (52 different interventions grouped in 32 therapeutic classes) that enrolled 26114 participants with ADHD were included in complex networks. At the class level, behavioural therapy (alone or in combination with stimulants), stimulants, and non-stimulant seemed significantly more efficacious than placebo. Behavioural therapy in combination with stimulants seemed superior to stimulants or non-stimulants. Stimulants seemed superior to behavioural therapy, cognitive training and non-stimulants. Behavioural therapy, stimulants and their combination showed the best profile of acceptability. Stimulants and non-stimulants seemed well tolerated. Among medications, methylphenidate, amphetamine, atomoxetine, guanfacine and clonidine seemed significantly more efficacious than placebo. Methylphenidate and amphetamine seemed more efficacious than atomoxetine and guanfacine. Methylphenidate and clonidine seemed better accepted than placebo and atomoxetine. Most of the efficacious pharmacological treatments were associated with harms (anorexia, weight loss and insomnia), but an increased risk of serious adverse events was not observed. There is lack of evidence for cognitive training, neurofeedback, antidepressants, antipsychotics, dietary therapy, fatty acids, and other complementary and alternative medicine. Overall findings were limited by the clinical and methodological heterogeneity, small sample sizes of trials, short-term follow-up, and the absence of high-quality evidence; consequently, results should be interpreted with caution. CONCLUSIONS: Clinical differences may exist between the pharmacological and non-pharmacological treatment used for the management of ADHD. Uncertainties about therapies and the balance between benefits, costs and potential harms should be considered before starting treatment. There is an urgent need for high-quality randomised trials of the multiple treatments for ADHD in children and adolescents. PROSPERO, number CRD42014015008