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Function and structure of neuromodulatory inputs to the cerebral cortex

English title Function and structure of neuromodulatory inputs to the cerebral cortex
Applicant Holtmaat Anthony
Number 154453
Funding scheme Sinergia
Research institution Dépt des Neurosciences Fondamentales Faculté de Médecine Université de Genève
Institution of higher education University of Geneva - GE
Main discipline Neurophysiology and Brain Research
Start/End 01.01.2015 - 30.06.2018
Approved amount 1'505'319.00
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Keywords (13)

electron microscopy; primary somatosensory cortex; serotonergic; pyramidal neurons; two photon microscopy; synaptic circuits; barrel cortex; whisker mediated behavior; neocortex; neuromodulation; whole-cell recordings; cholinergic; cortical state

Lay Summary (French)

Lead
La fonction et la structure des projections neuromodulateurs au cortex cérébral
Lay summary

Les fonctions cognitives supérieures, telles que la perception d’influx sensoriels complexes, les comportements complexes et l’apprentissage, sont gouvernées par le cortex cérébral. Les fonctions de ce dernier sont fortement influencées par les états physiologiques et métaboliques. Par exemple, un état de vigilance accru facilite la perception et l’apprentissage, alors que la faim conduit à une plus grande motivation à réagir aux stimuli sensoriels qui sont associés à la nourriture. L’état d’éveil, la motivation, la peur et l’évitement dépendent fortement de neurotransmetteurs tels que la sérotonine et l’acétylcholine, qui sont produits dans des régions subcorticales. Les projections provenant de ces régions atteignent le cortex cérébral où l’on pense que la libération des neurotransmetteurs module les processus cognitifs supérieurs mentionnés ci-dessus, d’où le terme neuromodulateurs. Le dysfonctionnement de neuromodulateurs a été identifié dans divers troubles neurologiques et psychiatriques. Toutefois, la fonction exacte des systèmes neuromodulateurs au niveau du cortex cérébral demeure en grande partie partie inconnue.

Ce projet vise à étudier la fonction des afférences sertoninergiques et cholinergiques dans le cortex cérébral de la souris. Ces études seront conduites dans une aire du cortex qui est impliquée dans le traitement d’information sensorielle provenant des grandes vibrisses situées sur le museau de la souris. Ce système est très bien caractérisé et les chercheurs participant à ce projet en sont des experts. Les outils génétiques et techniques de microscopie les plus récents seront mis à profit afin de suivre spécifiquement l’activité des afférences neuromodulatoires dans le cortex cérébral et d’identifier des liens de causalité entre les états physiologiques, l’activité modulatoire, la perception sensorielle, l’apprentissage et le comportement. 

Direct link to Lay Summary Last update: 27.11.2014

Lay Summary (English)

Lead
Function and structure of neuromodulatory inputs to the cerebral cortex
Lay summary

Higher cognitive functions such as the perception of complex sensory inputs, complex behaviors and learning are governed by the cerebral cortex. Cerebral cortical function in turn is heavily sculpted by metabolic and physiological states. For example wakefulness facilitates perception and behavior. Hunger will lead to a greater motivation to act on sensory stimuli that are associated with food. Wakefulness, motivation, fear and avoidance are strongly dependent on modulatory neurotransmitters such as serotonin and acetylcholine, which are produced in deeper brain regions. Projections from these brain regions reach the cerebral cortex, where the release of the transmitters is thought to modulate the higher cognitive processes mentioned earlier. Hence the name neuromodulators. Dysfunction of neuromodulators have been identified in various neurological and psychiatric disorders. However, the exact function of neuromodulatory inputs to the cerebral cortex remains largely unknown.

This project focuses on studying the function of serotonergic and cholinergic inputs to the cerebral cortex in laboratory mice. The studies will be performed in an area of the cortex that is involved in processing sensory information that is derived from the large whiskers on the mouse's snout. This system is very well characterized and the researchers involved in this project are experts on this particular part of the brain. The latest genetic tools and microscopy techniques will be used to specifically monitor the activity of the modulatory inputs to the cerebral cortex, in order to find causal links between physiological states, modulatory activity, sensory perception, learning and behavior.

Direct link to Lay Summary Last update: 27.11.2014

Responsible applicant and co-applicants

Employees

Publications

Publication
Higher-Order Thalamocortical Inputs Gate Synaptic Long-Term Potentiation via Disinhibition
Williams Leena E., Holtmaat Anthony (2019), Higher-Order Thalamocortical Inputs Gate Synaptic Long-Term Potentiation via Disinhibition, in Neuron, 101(1), 91-102.e4.
Block Face Scanning Electron Microscopy of Fluorescently Labeled Axons Without Using Near Infra-Red Branding
Maclachlan Catherine, Sahlender Daniela A., Hayashi Shuichi, Molnár Zoltán, Knott Graham (2018), Block Face Scanning Electron Microscopy of Fluorescently Labeled Axons Without Using Near Infra-Red Branding, in Frontiers in Neuroanatomy, 12, 88.
NeuroMorph: A Software Toolset for 3D Analysis of Neurite Morphology and Connectivity
Jorstad Anne, Blanc Jérôme, Knott Graham (2018), NeuroMorph: A Software Toolset for 3D Analysis of Neurite Morphology and Connectivity, in Frontiers in Neuroanatomy, 12, 59.
Control of synaptic plasticity in deep cortical networks
Roelfsema Pieter R., Holtmaat Anthony (2018), Control of synaptic plasticity in deep cortical networks, in Nature Reviews Neuroscience, 19(3), 166-180.
Computer assisted detection of axonal bouton structural plasticity in in vivo time-lapse images
Gala Rohan, Lebrecht Daniel, Sahlender Daniela A, Jorstad Anne, Knott Graham, Holtmaat Anthony, Stepanyants Armen (2017), Computer assisted detection of axonal bouton structural plasticity in in vivo time-lapse images, in eLife, 6, e29315.

Collaboration

Group / person Country
Types of collaboration
Christel Genoud Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
Armen Stepanyants United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Neuromodulation of Neural Microcircuits nm2 Talk given at a conference Ultrastructural characterization of neuromodulatory axons in the adult mouse brain 18.09.2017 Lausanne, Switzerland Holtmaat Anthony; Markopoulos Foivos; Blanc Jérôme; Knott Graham; Gasselin Celia; Petersen Carl; Sahlender Daniela;


Associated projects

Number Title Start Funding scheme
139229 Platform for integrated mouse behavior (PIMB) 01.12.2011 R'EQUIP
170795 High resolution fluorescence imaging across large volumes of intact organs 01.12.2016 R'EQUIP
157883 Request for a Serial Block Face Scanning Electron Microscope 01.12.2014 R'EQUIP
170767 High-resolution FIB-SEM Nano-Tomography Tool 01.12.2016 R'EQUIP
170082 Unbiased Analysis of Excitatory Synaptic Connectivity in the Aging Cerebral Cortex 01.09.2017 Project funding (Div. I-III)
135631 Long-term potentiation and the modification of synaptic structures in vivo 01.04.2011 Project funding (Div. I-III)
147486 Barrel Cortex Function (FOR 1341) 01.05.2013 Project funding (Div. I-III)
146252 Synaptic Mechanisms of Sensory Perception and Associative Learning 01.04.2013 Project funding (Div. I-III)
125759 NCCR SYNAPSY: The synaptic bases of mental diseases (phase I) 01.10.2010 National Centres of Competence in Research (NCCRs)
173125 The role of paralemniscal circuits in cortical plasticity and perception 01.10.2017 Project funding (Div. I-III)
153448 Activity-dependent functional and structural plasticity in the somatosensory cortex in vivo 01.04.2014 Project funding (Div. I-III)

Abstract

Neuromodulatory inputs to the cerebral cortex play a significant role in many fundamental brain processes such as: sensory perception, motor function, learning, sensory map plasticity and states of wakefulness. Here, we will focus on the extensive serotonergic and cholinergic innervation of the neocortex. Although a great deal of evidence supports the involvement of these systems, particularly in behaviors such as feeding, reward seeking, alertness and anxiety, little is understood about how they function. This represents a significant and important challenge for neuroscience research today. Dysfunction of these modulatory systems have been identified in various neurological and psychiatric diseases, therefore understanding how these inputs to the cortex are able to influence its function is paramount for opening new perspectives in therapeutic development.This application aims to understand how serotonergic and cholinergic inputs modulate the function of the mouse barrel cortex. Studying the mouse offers significant advantages in the specificity of manipulations offered through the precision of mouse genetics combined with localised viral injections. The barrel cortex offers a well-defined sensory system amenable to quantitative analyses and is thus well-suited to the investigation of neuromodulation. We will express genetically-encoded calcium indicators specifically in serotonergic and cholinergic axons in order to measure their activity during sensory processing and during whisker behaviour. We will also express optogenetic actuators to precisely control the activity of serotonergic and cholinergic neurons, allowing the investigation of their causal contributions to cortical states, psychophysical thresholds for sensory perception and neuronal plasticity. Expression of fluorescent proteins specifically in serotonergic and cholinergic neurons will also be used to reveal the morphology of their axonal projections in the mouse barrel cortex. The fluorescently labelled axons will be studied using 3D volume electron microscopy, allowing quantitative analyses of structure-function relationships, which are critical for being able to provide a mechanistic basis of neuromodulation.This collaborative Swiss National Science Foundation (SNSF) Sinergia grant application brings together three neuroscience laboratories with unique skills ideally suited for this task. Each has a significant standing in the fields of cortical plasticity, processing and structure. Combining their expertise will bring together the very latest technological advances for understanding the mechanistic basis of neuromodulation in a well-defined and functionally important region of the neocortex.
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