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Moreno-Bote R.,University of Barcelona | Moreno-Bote R.,Research Center Biomedica En Red Of Salud Mental Cibersam | Beck J.,University of Rochester | Kanitscheider I.,University of Geneva | And 7 more authors.
Nature Neuroscience | Year: 2014

Computational strategies used by the brain strongly depend on the amount of information that can be stored in population activity, which in turn strongly depends on the pattern of noise correlations. In vivo, noise correlations tend to be positive and proportional to the similarity in tuning properties. Such correlations are thought to limit information, which has led to the suggestion that decorrelation increases information. In contrast, we found, analytically and numerically, that decorrelation does not imply an increase in information. Instead, the only information-limiting correlations are what we refer to as differential correlations: correlations proportional to the product of the derivatives of the tuning curves. Unfortunately, differential correlations are likely to be very small and buried under correlations that do not limit information, making them particularly difficult to detect. We found, however, that the effect of differential correlations on information can be detected with relatively simple decoders. © 2014 Nature America, Inc. All rights reserved.

Sanchez C.,Lundbeck | Artigas F.,Institute Dinvestigacions Biomediques Of Barcelona Iibb | Artigas F.,Research Center Biomedica En Red Of Salud Mental Cibersam | Artigas F.,Institute dinvestigacions Biomediques August Pi i Sunyer IDIBAPS
Pharmacology and Therapeutics | Year: 2015

Vortioxetine, a novel antidepressant for the treatment of major depressive disorder (MDD), is a 5-HT3, 5-HT7 and 5-HT1D receptor antagonist, 5-HT1B receptor partial agonist, 5-HT1A receptor agonist and serotonin (5-HT) transporter (SERT) inhibitor. Here we review its preclinical and clinical properties and discuss translational aspects. Vortioxetine increases serotonergic, noradrenergic, dopaminergic, cholinergic, histaminergic and glutamatergic neurotransmission in brain structures associated with MDD. These multiple effects likely derive from its interaction with 5-HT-receptor-mediated negative feedback mechanisms controlling neuronal activity. In particular, 5-HT3 receptors may play a prominent role, since their blockade i) increases pyramidal neuron activity by removing 5-HT3 receptor-mediated excitation of GABA interneurons, and ii) augments SSRI effects on extracellular 5-HT. However, modulation of the other 5-HT receptor subtypes also likely contributes to vortioxetine's pharmacological effects. Preclinical animal models reveal differences from SSRIs and SNRIs, including antidepressant-like activity, increased synaptic plasticity and improved cognitive function. Vortioxetine had clinical efficacy in patients with MDD: 11 placebo-controlled studies (including one in elderly) with efficacy in 8 (7 positive, 1 supportive), 1 positive active comparator study plus a positive relapse prevention study. In two positive studies, vortioxetine was superior to placebo in pre-defined cognitive outcome measures. The clinically effective dose range (5-20 mg/day) spans ~50 to >80% SERT occupancy. SERT and 5-HT3 receptors are primarily occupied at 5 mg, while at 20 mg, all targets are likely occupied at functionally relevant levels. The side-effect profile is similar to that of SSRIs, with gastrointestinal symptoms being most common, and a low incidence of sexual dysfunction and sleep disruption possibly ascribed to vortioxetine's receptor modulation. © 2014 Elsevier Inc.

Moreno-Bote R.,University of Barcelona | Moreno-Bote R.,Research Center Biomedica En Red Of Salud Mental Cibersam
PLoS Computational Biology | Year: 2014

Neuronal activity in cortex is variable both spontaneously and during stimulation, and it has the remarkable property that it is Poisson-like over broad ranges of firing rates covering from virtually zero to hundreds of spikes per second. The mechanisms underlying cortical-like spiking variability over such a broad continuum of rates are currently unknown. We show that neuronal networks endowed with probabilistic synaptic transmission, a well-documented source of variability in cortex, robustly generate Poisson-like variability over several orders of magnitude in their firing rate without fine-tuning of the network parameters. Other sources of variability, such as random synaptic delays or spike generation jittering, do not lead to Poisson-like variability at high rates because they cannot be sufficiently amplified by recurrent neuronal networks. We also show that probabilistic synapses predict Fano factor constancy of synaptic conductances. Our results suggest that synaptic noise is a robust and sufficient mechanism for the type of variability found in cortex. © 2014 Ruben Moreno-Bote.

Uriguen L.,Research Center Biomedica En Red Of Salud Mental Cibersam
Translational psychiatry | Year: 2013

Overexpression of the mammalian homolog of the unc-18 gene (munc18-1) has been described in the brain of subjects with schizophrenia. Munc18-1 protein is involved in membrane fusion processes, exocytosis and neurotransmitter release. A transgenic mouse strain that overexpresses the protein isoform munc18-1a in the brain was characterized. This animal displays several schizophrenia-related behaviors, supersensitivity to hallucinogenic drugs and deficits in prepulse inhibition that reverse after antipsychotic treatment. Relevant brain areas (that is, cortex and striatum) exhibit reduced expression of dopamine D(1) receptors and dopamine transporters together with enhanced amphetamine-induced in vivo dopamine release. Magnetic resonance imaging demonstrates decreased gray matter volume in the transgenic animal. In conclusion, the mouse overexpressing brain munc18-1a represents a new valid animal model that resembles functional and structural abnormalities in patients with schizophrenia. The animal could provide valuable insights into phenotypic aspects of this psychiatric disorder.

Artigas F.,IIBB CSIC IDIBAPS | Artigas F.,Research Center Biomedica En Red Of Salud Mental Cibersam
Pharmacology and Therapeutics | Year: 2013

The neurotransmitter serotonin (5-hdroxytryptamine; 5-HT) has been implicated in the pathophysiology and treatment of major depression since the serendipitous discovery of antidepressant drugs in the 1950s. However, despite the generalised use of serotonin-enhancing drugs, such as the selective serotonin reuptake inhibitors (SSRIs) and the dual serotonin and norepinephrine reuptake inhibitors (SNRIs), the exact neurobiological mechanisms involved in the therapeutic action of these drugs are poorly understood. Better knowledge of these mechanisms may help to identify new therapeutic targets and to overcome the two main limitations of current treatments: reduced efficacy and slowness of action. Here I review the preclinical and clinical evidence supporting the involvement of different 5-HT receptors in the therapeutic action of antidepressant drugs. Presynaptic 5-HT1A and 5-HT1B autoreceptors play a major detrimental role in antidepressant treatments, as their activation by the excess of the active (extracellular) 5-HT fraction produced by serotonin transporter (SERT) blockade reduces presynaptic serotonergic function. Conversely, stimulation of postsynaptic 5-HT1A receptors in corticolimbic networks appears beneficial for the antidepressant action. The 5-HT2 receptor family is also involved as 5-HT 2A/2C receptor blockade improves the antidepressant action of SSRIs, and recent data suggest that 5-HT2B receptor activation enhances serotonergic activity. Less is known from the rest of postsynaptic 5-HT receptors. However, 5-HT3 receptor blockade augments the 5-HT increase evoked by SERT inhibition, and 5-HT4 receptor activation may have antidepressant effects on its own. Finally, blockade of 5-HT6 and 5-HT7 receptors appears also to augment the antidepressant effects of SERT inhibition. © 2012 Elsevier Inc.

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