Outer Brain Oscillations in Down Syndrome

The present article reviews the relationship between sleep and oscillatory activity in Down Syndrome (DS), as well as the featuring emergent rhythmic activity across different brain states. A comprehensive discussion of the data from electroencephalographic studies in DS humans and transgenic/trisomic mouse models is provided, as well as data from signals collected from local field potentials (LFP) and intracellular recordings in DS mouse models. The first sections focus specially on the alpha phenotype consistently observed in DS subjects, as well as its description in DS childhood and aging. Subsequently, a review of the data reported in DS mouse models is presented with the aim to deepen on the mechanisms underlying altered rhythmic patterns. Further sections situate the state-of-the-art of the field, with a discussion on the possible circuit alterations that may underlie impaired alpha and gamma oscillatory activity. A further aim is to highlight the importance of studying network oscillatory activity in mouse models to infer alterations in the underlying circuits related to cognition, such as in intellectual disability. In this direction, a view of alpha and gamma rhythms generated by the cerebral cortex as a tool for evaluating an unbalance between excitation and inhibition in DS is claimed, which points out toward an over-inhibited network. A final aim is to situate oscillatory activity as a key phenomenon that may be used as a biomarker for monitoring as well the effect of novel therapeutic strategies

Gradual emergence of spontaneous correlated brain activity during fading of general anesthesia in rats: Evidences from fMRI and local field potentials

Intrinsic brain activity is characterized by the presence of highly structured networks of correlated fluctuations between different regions of the brain. Such networks encompass different functions, whose properties are known to be modulated by the ongoing global brain state and are altered in several neurobiological disorders. In the present study, we induced a deep state of anesthesia in rats by means of a ketamine/medetomidine peritoneal injection, and analyzed the time course of the correlation between the brain activity in different areas while anesthesia spontaneously decreased over time. We compared results separately obtained from fMRI and local field potentials (LFPs) under the same anesthesia protocol, finding that while most profound phases of anesthesia can be described by overall sparse connectivity, stereotypical activity and poor functional integration, during lighter states different frequency-specific functional networks emerge, endowing the gradual restoration of structured large-scale activity seen during rest. Noteworthy, our in vivo results show that those areas belonging to the same functional network (the default-mode) exhibited sustained correlated oscillations around 10 Hz throughout the protocol, suggesting the presence of a specific functional backbone that is preserved even during deeper phases of anesthesia. Finally, the overall pattern of results obtained from both imaging and in vivo-recordings suggests that the progressive emergence from deep anesthesia is reflected by a corresponding gradual increase of organized correlated oscillations across the cortex.The research reported herein was supported by the ERC Advanced Grant DYSTRUCTURE (No. 295129), FET Flagship Human Brain Project, Brain Network Recovery Group through the James S. McDonnell Foundation (220020255), FP7-ICT BrainScales (No. 269921), CORONET (No. 269459), Ministerio de Economia y Competitividad (MINECO-PSI2013-42091-P), and Agència Gestió d'Ajuts Universitaris i de Recerca (2009SGR292) to G.D. M.V.S.V. was supported by the Ministerio de Economía y Competitividad (Spain)BFU2011-27094 and EU project CORTICONIC Contract number 600806

Overexpression of Dyrk1A, a down syndrome candidate, decreases excitability and impairs gamma oscillations in the prefrontal cortex

The dual-specificity tyrosine phosphorylation-regulated kinase DYRK1A is a serine/threonine kinase involved in neuronal differentiation and synaptic plasticity and a major candidate of Down syndrome brain alterations and cognitive deficits. DYRK1A is strongly expressed in the cerebral cortex, and its overexpression leads to defective cortical pyramidal cell morphology, synaptic plasticity deficits, and altered excitation/inhibition balance. These previous observations, however, do not allow predicting how the behavior of the prefrontal cortex (PFC) network and the resulting properties of its emergent activity are affected. Here, we integrate functional, anatomical, and computational data describing the prefrontal network alterations in transgenic mice overexpressingDyrk1A(TgDyrk1A). Usingin vivoextracellular recordings, we show decreased firing rate and gamma frequency power in the prefrontal network of anesthetized and awakeTgDyrk1Amice. Immunohistochemical analysis identified a selective reduction of vesicular GABA transporter punctae on parvalbumin positive neurons, without changes in the number of cortical GABAergic neurons in the PFC ofTgDyrk1Amice, which suggests that selective disinhibition of parvalbumin interneurons would result in an overinhibited functional network. Using a conductance-based computational model, we quantitatively demonstrate that this alteration could explain the observed functional deficits including decreased gamma power and firing rate. Our results suggest that dysfunction of cortical fast-spiking interneurons might be central to the pathophysiology of Down syndrome. SIGNIFICANCE STATEMENT:DYRK1Ais a major candidate gene in Down syndrome. Its overexpression results into altered cognitive abilities, explained by defective cortical microarchitecture and excitation/inhibition imbalance. An open question is how these deficits impact the functionality of the prefrontal cortex network. Combining functional, anatomical, and computational approaches, we identified decreased neuronal firing rate and deficits in gamma frequency in the prefrontal cortices of transgenic mice overexpressingDyrk1A We also identified a reduction of vesicular GABA transporter punctae specifically on parvalbumin positive interneurons. Using a conductance-based computational model, we demonstrate that this decreased inhibition on interneurons recapitulates the observed functional deficits, including decreased gamma power and firing rate. Our results suggest that dysfunction of cortical fast-spiking interneurons might be central to the pathophysiology of Down syndrome.This work was supported by Foundation Jerome Lejeune Grant 937-SM2011B, Ministerio de Ciencia e Innovación Grants BFU2011-27094 and BFU2014-52467-R, and the EU PF7 FET CORTICONIC contract 600806 (M.V.S.-V.); Ministerio de Economia y Competitividad Grant FIS2012-37655 and the Institució Catalana de Recerca i Estudis Avançats Academia (J.G.O.); and the FRAXA Foundation, Fondation Jerome Lejeune Grant 937-SM2011B, Ministerio de Economia y Competitividad Grants SAF2013-49129-C2-1-R and “Centro de Excelencia Severo Ochoa 2013–2017” SEV-2012-0208, EU ERA-Net Neuron (FOOD for THOUGHT), Secretaria de Universidades e Investigación del Departamento de Economía y Conocimiento de la Generalidad de Cataluña Grant SGR 2014/1125, and CIBERER (Centro de Investigación Biomédica en Red de Enfermedades Raras) (M.D.)

Overexpression of Dyrk1A, a down syndrome candidate, decreases excitability and impairs gamma oscillations in the prefrontal cortex

The dual-specificity tyrosine phosphorylation-regulated kinase DYRK1A is a serine/threonine kinase involved in neuronal differentiation and synaptic plasticity and a major candidate of Down syndrome brain alterations and cognitive deficits. DYRK1A is strongly expressed in the cerebral cortex, and its overexpression leads to defective cortical pyramidal cell morphology, synaptic plasticity deficits, and altered excitation/inhibition balance. These previous observations, however, do not allow predicting how the behavior of the prefrontal cortex (PFC) network and the resulting properties of its emergent activity are affected. Here, we integrate functional, anatomical, and computational data describing the prefrontal network alterations in transgenic mice overexpressingDyrk1A(TgDyrk1A). Usingin vivoextracellular recordings, we show decreased firing rate and gamma frequency power in the prefrontal network of anesthetized and awakeTgDyrk1Amice. Immunohistochemical analysis identified a selective reduction of vesicular GABA transporter punctae on parvalbumin positive neurons, without changes in the number of cortical GABAergic neurons in the PFC ofTgDyrk1Amice, which suggests that selective disinhibition of parvalbumin interneurons would result in an overinhibited functional network. Using a conductance-based computational model, we quantitatively demonstrate that this alteration could explain the observed functional deficits including decreased gamma power and firing rate. Our results suggest that dysfunction of cortical fast-spiking interneurons might be central to the pathophysiology of Down syndrome. SIGNIFICANCE STATEMENT:DYRK1Ais a major candidate gene in Down syndrome. Its overexpression results into altered cognitive abilities, explained by defective cortical microarchitecture and excitation/inhibition imbalance. An open question is how these deficits impact the functionality of the prefrontal cortex network. Combining functional, anatomical, and computational approaches, we identified decreased neuronal firing rate and deficits in gamma frequency in the prefrontal cortices of transgenic mice overexpressingDyrk1A We also identified a reduction of vesicular GABA transporter punctae specifically on parvalbumin positive interneurons. Using a conductance-based computational model, we demonstrate that this decreased inhibition on interneurons recapitulates the observed functional deficits, including decreased gamma power and firing rate. Our results suggest that dysfunction of cortical fast-spiking interneurons might be central to the pathophysiology of Down syndrome.This work was supported by Foundation Jerome Lejeune Grant 937-SM2011B, Ministerio de Ciencia e Innovación Grants BFU2011-27094 and BFU2014-52467-R, and the EU PF7 FET CORTICONIC contract 600806 (M.V.S.-V.); Ministerio de Economia y Competitividad Grant FIS2012-37655 and the Institució Catalana de Recerca i Estudis Avançats Academia (J.G.O.); and the FRAXA Foundation, Fondation Jerome Lejeune Grant 937-SM2011B, Ministerio de Economia y Competitividad Grants SAF2013-49129-C2-1-R and “Centro de Excelencia Severo Ochoa 2013–2017” SEV-2012-0208, EU ERA-Net Neuron (FOOD for THOUGHT), Secretaria de Universidades e Investigación del Departamento de Economía y Conocimiento de la Generalidad de Cataluña Grant SGR 2014/1125, and CIBERER (Centro de Investigación Biomédica en Red de Enfermedades Raras) (M.D.)

Gradual emergence of spontaneous correlated brain activity during fading of general anesthesia in rats: Evidences from fMRI and local field potentials

Intrinsic brain activity is characterized by the presence of highly structured networks of correlated fluctuations between different regions of the brain. Such networks encompass different functions, whose properties are known to be modulated by the ongoing global brain state and are altered in several neurobiological disorders. In the present study, we induced a deep state of anesthesia in rats by means of a ketamine/medetomidine peritoneal injection, and analyzed the time course of the correlation between the brain activity in different areas while anesthesia spontaneously decreased over time. We compared results separately obtained from fMRI and local field potentials (LFPs) under the same anesthesia protocol, finding that while most profound phases of anesthesia can be described by overall sparse connectivity, stereotypical activity and poor functional integration, during lighter states different frequency-specific functional networks emerge, endowing the gradual restoration of structured large-scale activity seen during rest. Noteworthy, our in vivo results show that those areas belonging to the same functional network (the default-mode) exhibited sustained correlated oscillations around 10 Hz throughout the protocol, suggesting the presence of a specific functional backbone that is preserved even during deeper phases of anesthesia. Finally, the overall pattern of results obtained from both imaging and in vivo-recordings suggests that the progressive emergence from deep anesthesia is reflected by a corresponding gradual increase of organized correlated oscillations across the cortex.The research reported herein was supported by the ERC Advanced Grant DYSTRUCTURE (No. 295129), FET Flagship Human Brain Project, Brain Network Recovery Group through the James S. McDonnell Foundation (220020255), FP7-ICT BrainScales (No. 269921), CORONET (No. 269459), Ministerio de Economia y Competitividad (MINECO-PSI2013-42091-P), and Agència Gestió d'Ajuts Universitaris i de Recerca (2009SGR292) to G.D. M.V.S.V. was supported by the Ministerio de Economía y Competitividad (Spain)BFU2011-27094 and EU project CORTICONIC Contract number 600806

Transverse-momentum and pseudorapidity distributions of charged hadrons in pppp collisions at s\sqrt{s} = 7 TeV

Charged-hadron transverse-momentum and pseudorapidity distributions in proton-proton collisions at $\sqrt{s} = 7$~TeV are measured with the inner tracking system of the CMS detector at the LHC. The charged-hadron yield is obtained by counting the number of reconstructed hits, hit-pairs, and fully reconstructed charged-particle tracks. The combination of the three methods gives a charged-particle multiplicity per unit of pseudorapidity \dnchdeta|_{|\eta| < 0.5} = 5.78\pm 0.01\stat\pm 0.23\syst for non-single-diffractive events, higher than predicted by commonly used models. The relative increase in charged-particle multiplicity from $\sqrt{s} = 0.9$ to 7~TeV is 66.1\%\pm 1.0\%\stat\pm 4.2\%\syst. The mean transverse momentum is measured to be 0.545\pm 0.005\stat\pm 0.015\syst\GeVc. The results are compared with similar measurements at lower energies.Charged-hadron transverse-momentum and pseudorapidity distributions in proton-proton collisions at sqrt(s) = 7 TeV are measured with the inner tracking system of the CMS detector at the LHC. The charged-hadron yield is obtained by counting the number of reconstructed hits, hit-pairs, and fully reconstructed charged-particle tracks. The combination of the three methods gives a charged-particle multiplicity per unit of pseudorapidity, dN(charged)/d(eta), for |eta| < 0.5, of 5.78 +/- 0.01 (stat) +/- 0.23 (syst) for non-single-diffractive events, higher than predicted by commonly used models. The relative increase in charged-particle multiplicity from sqrt(s) = 0.9 to 7 TeV is 66.1% +/- 1.0% (stat) +/- 4.2% (syst). The mean transverse momentum is measured to be 0.545 +/- 0.005 (stat) +/- 0.015 (syst) GeV/c. The results are compared with similar measurements at lower energies

Measurement of the charge ratio of atmospheric muons with the CMS detector

We present a measurement of the ratio of positive to negative muon fluxes from cosmic ray interactions in the atmosphere, using data collected by the CMS detector both at ground level and in the underground experimental cavern at the CERN LHC. Muons were detected in the momentum range from 5 GeV/ c to 1 TeV/ c . The surface flux ratio is measured to be 1.2766±0.0032(stat.)±0.0032(syst.) , independent of the muon momentum, below 100 GeV/ c . This is the most precise measurement to date. At higher momenta the data are consistent with an increase of the charge ratio, in agreement with cosmic ray shower models and compatible with previous measurements by deep-underground experiments.We present a measurement of the ratio of positive to negative muon fluxes from cosmic ray interactions in the atmosphere, using data collected by the CMS detector both at ground level and in the underground experimental cavern at the CERN LHC. Muons were detected in the momentum range from 5 GeV/c to 1 TeV/c. The surface flux ratio is measured to be 1.2766 \pm 0.0032(stat.) \pm 0.0032 (syst.), independent of the muon momentum, below 100 GeV/c. This is the most precise measurement to date. At higher momenta the data are consistent with an increase of the charge ratio, in agreement with cosmic ray shower models and compatible with previous measurements by deep-underground experiments