Le rôle des récepteurs nicotiniques dans l'activité neuronale spontanée du cortex préfrontal dans un cerveau normal et malade

The prefrontal cortex (pfc) underlies higher cognitive processes that are modulated by cholinergic inputs largely via nicotinic acetylcholine receptors (nachrs). this brain region exhibits spontaneous “default” activity, which is altered in neuropsychiatric disorders, such as schizophrenia (scz), and neurodegenerative diseases such as alzheimer’s disease (ad). both of these disorders have a strong impact and burden on society. human genetic studies have highlighted the polymorphic nature of specific nachrs genes that increase risk for smoking and scz. several laboratories, including our own, have shown that mice with altered nachr gene function exhibit pfc-dependent behavioral deficits, but how the corresponding human polymorphisms alter the cellular and circuit mechanisms underlying the behaviors is unknown. here, mouse models related to scz, nicotine dependence and ad were developed and studied. using in vivo two-photon imaging in the pfc of both awake and anesthetized mice, different nachr subunits were shown to control spontaneous pfc activity through a hierarchical inhibitory circuit. furthermore, the effect of chronic nicotine administration on brain activity, by delivering concentrations analogous to that observed in smokers, was studied. the impact of nicotine on pfc layer ii/iii microcircuits altered in pathology can be extended to therapeutic strategies with strong candidates being positive allosteric modulators (pams) for defined nachr subunits. we hope that this work sheds light on the role of cholinergic neurotransmission in the orchestration of cognitive functions and will inspire further research in this direction.Le cortex préfrontal (cpf) est à la base des processus cognitifs supérieurs qui sont modulés majoritairement par des entrées cholinergiques via les récepteurs nicotiniques de l'acétylcholine (nachrs). cette région du cerveau présente " par défaut " une activité spontanée, qui est modifiée dans le cas de troubles psychiatriques, tels que la schizophrénie, et de maladies neurodégénératives comme la maladie d'alzheimer. des études de génétique humaine ont mis en évidence la nature polymorphique de gènes spécifiques codant pour les nachr qui augmentent les risques de tabagisme et de schizophrénie. de nombreux laboratoires, dont le notre, ont montré que les souris ayant une altération de la fonction du gène nachr présentent des déficits comportementaux cpf-dépendants. cependant, la manière dont les polymorphismes humains correspondants altèrent les mécanismes cellulaires et circuits sous-jacents aux comportements reste inconnue. de ce fait, nous avons donc développé et étudié des modèles de souris liés à la schizophrénie, à la dépendance à la nicotine et à la maladie d'alzheimer. l'utilisation in vivo de l'imagerie bi-photon au niveau du cpf de souris éveillées et de souris anesthésiées a montré que différentes sous-unités nachr sont impliquées dans le contrôle de l'activité spontanée du cortex préfrontal, via un circuit d'inhibition hiérarchique. de plus, l'effet de l'administration chronique de nicotine sur l'activité cérébrale a été étudié, en fournissant des concentrations analogues à celles observées chez des fumeurs. ce travail met en lumière le rôle de la neurotransmission cholinergique dans l'orchestration des fonctions cognitives

The multiple roles of the α7 nicotinic acetylcholine receptor in modulating glutamatergic systems in the normal and diseased nervous system.

International audienceNeuronal nicotinic acetylcholine receptors (nAChRs) play an important role in a variety of modulatory and regulatory processes including neurotransmitter release and synaptic transmission in various brain regions of the central nervous system (CNS). Glutamate is the principal excitatory neurotransmitter in the brain and the glutamatergic system participates in the pathophysiology of several neuropsychiatric disorders. Underpinning the importance of nAChRs, many studies demonstrated that nAChRs containing the α7 subunit facilitate glutamate release. Here, we review the currently available body of experimental evidence pertaining to α7 subunit containing nAChRs in their contribution to the modulation of glutamatergic neurotransmission, and we highlight the role of α7 in synaptic plasticity, the morphological and functional maturation of the glutamatergic system and therefore its important contribution in the modulation of neural circuits of the CNS

Do nicotinic receptors modulate high-order cognitive processing?

Recent studies provided strong evidence that deficits in cholinergic signaling cause disorders of cognition and affect conscious processing. Technical advances that combine molecular approaches, in vivo recordings in awake behaving animals, human brain imaging, and genetics have strengthened our understanding of the roles of nicotinic acetylcholine receptors (nAChRs) in the modulation of cognitive behavior and network dynamics. Here, we review the emergent role of nAChRs in high-order cognitive processes and discuss recent work implicating cholinergic circuits in cognitive control, including conscious processing

Early and progressive deficit of neuronal activity patterns in a model of local amyloid pathology in mouse prefrontal cortex

International audienceAlzheimer’s Disease (AD) is the most common form of dementia. The condition predominantly affects the cerebral cortex and hippocampus and is characterized by the spread of amyloid plaques and neurofibrillary tangles (NFTs). But soluble amyloid-β (Aβ) oligomers have also been identified to accumulate in the brains of AD patients and correlate with cognitive dysfunction more than the extent of plaque deposition. Here, we developed an adeno-associated viral vector expressing the human mutated amyloid precursor protein (AAV-hAPP). Intracranial injection of the AAV into the prefrontal cortex (PFC) allowed the induction of AD-like deficits in adult mice, thereby modelling human pathology. AAV-hAPP expression caused accumulation of Aβ oligomers, microglial activation, astrocytosis and the gradual formation of amyloid plaques and NFTs. In vivo two-photon imaging revealed an increase in neuronal activity, a dysfunction characteristic of the pathology, already during the accumulation of soluble oligomers. Importantly, we found that Aβ disrupts the synchronous spontaneous activity of neurons in PFC that, as in humans, is characterized by ultraslow fluctuation patterns. Our work allowed us to track brain activity changes during disease progression and provides new insight into the early deficits of synchronous ongoing brain activity, the “default network”, in the presence of Aβ peptide

Nicotinic receptors in mouse prefrontal cortex modulate ultraslow fluctuations related to conscious processing.

International audienceThe prefrontal cortex (PFC) plays an important role in cognitive processes, including access to consciousness. The PFC receives significant cholinergic innervation and nicotinic acetylcholine receptors (nAChRs) contribute greatly to the effects of acetylcholine signaling. Using in vivo two-photon imaging of both awake and anesthetized mice, we recorded spontaneous, ongoing neuronal activity in layer II/III in the PFC of WT mice and mice deleted for different nAChR subunits. As in humans, this activity is characterized by synchronous ultraslow fluctuations and neuronal synchronicity is disrupted by light general anesthesia. Both the α7 and β2 nAChR subunits play an important role in the generation of ultraslow fluctuations that occur to a different extent during quiet wakefulness and light general anesthesia. The β2 subunit is specifically required for synchronized activity patterns. Furthermore, chronic application of mecamylamine, an antagonist of nAChRs, disrupts the generation of ultraslow fluctuations. Our findings provide new insight into the ongoing spontaneous activity in the awake and anesthetized state, and the role of cholinergic neurotransmission in the orchestration of cognitive functions

Cholinergic modulation of hierarchical inhibitory control over cortical resting state dynamics: Local circuit modeling of schizophrenia-related hypofrontality

International audienceNicotinic acetylcholine receptors (nAChRs) modulate the cholinergic drive to a hierarchy of inhibitory neurons in the superficial layers of the PFC, critical to cognitive processes. It has been shown that genetic deletions of the various types of nAChRs impact the properties of ultra-slow transitions between high and low PFC activity states in mice during quiet wakefulness. The impact characteristics depend on specific interneuron populations expressing the manipulated receptor subtype. In addition, recent data indicate that a genetic mutation of the α5 nAChR subunit, located on vasoactive intestinal polypeptide (VIP) inhibitory neurons, the rs16969968 single nucleotide polymorphism (α5 SNP), plays a key role in the hypofrontality observed in schizophrenia patients carrying the SNP. Data also indicate that chronic nicotine application to α5 SNP mice relieves the hypofrontality. We developed a computational model to show that the activity patterns recorded in the genetically modified mice can be explained by changes in the dynamics of the local PFC circuit. Notably, our model shows that these altered PFC circuit dynamics are due to changes in the stability structure of the activity states. We identify how this stability structure is differentially modulated by cholinergic inputs to the parvalbumin (PV), somatostatin (SOM) or the VIP inhibitory populations. Our model uncovers that a change in amplitude, but not duration of the high activity states can account for the lowered pyramidal (PYR) population firing rates recorded in α5 SNP mice. We demonstrate how nicotine-induced desensitization and upregulation of the β2 nAChRs located on SOM interneurons, as opposed to the activation of α5 nAChRs located on VIP interneurons, is sufficient to explain the nicotine-induced activity normalization in α5 SNP mice. The model further implies that subsequent nicotine withdrawal may exacerbate the hypofrontality over and beyond one caused by the SNP mutation

Inhibitory control of synaptic signals preceding locomotion in mouse frontal cortex

International audienceThe frontal cortex is essential for organizing voluntary movement. The secondary motor cortex (MOs) is a frontal subregion thought to integrate internal and external inputs before motor action. However, how excitatory and inhibitory synaptic inputs to MOs neurons are integrated preceding movement remains unclear. Here, we address this question by performing in vivo whole-cell recordings from MOs neurons of head-fixed mice moving on a treadmill. We find that principal neurons produce slowly increasing membrane potential and spike ramps preceding spontaneous running. After goal-directed training, ramps show larger amplitudes and accelerated kinetics. Chemogenetic suppression of interneurons combined with modeling suggests that the interplay between parvalbumin-positive (PV+) and somatostatin-positive (SOM+) interneurons, along with principal neuron recurrent connectivity, shape ramping signals. Plasticity of excitatory synapses on SOM+ interneurons can explain the ramp acceleration after training. Altogether, our data reveal that local interneurons differentially control task-dependent ramping signals when MOs neurons integrate inputs preceding movement

Towards an Algorithm for Near Real Time Profiling of Aerosol Species, Trace Gases, and Clouds Based on the Synergy of Remote Sensing Instruments

In this manuscript we present the concept of a novel algorithmic chain that aims to a dataset of unprecedented detail in the vertical distribution of multiple atmospheric components in near real time conditions. The analysis will be based on the following remote sensing instruments: a depolarization Raman lidar, a visible and a thermal all-sky camera, a Brewer spectrophotometer, and up to three mini DOAS/MAX-DOAS systems. Based on both individual and synergistic processing of the data collected, novel products will be made available in near real time conditions to the end users. Columnar aerosol information from the spectrophotometers will be combined with lidar data to retrieve vertical profiles of individual aerosol species. Cloud layers will be detected and classified based mainly on the synergy of the lidar and the sky cameras and a realistic 3D representation of cloud conditions around the measurement site will be produced. Lidar profiles will be implemented as a priori information for radiative transfer purposes, that are necessary in order to obtain high quality trace gases profiles from the DOAS/MAX-DOAS spectrophotometer. Fast synergistic data processing will ensure that the algorithm can be applied for near real time public data dissemination in the future

Towards an Algorithm for Near Real Time Profiling of Aerosol Species, Trace Gases, and Clouds Based on the Synergy of Remote Sensing Instruments

In this manuscript we present the concept of a novel algorithmic chain that aims to a dataset of unprecedented detail in the vertical distribution of multiple atmospheric components in near real time conditions. The analysis will be based on the following remote sensing instruments: a depolarization Raman lidar, a visible and a thermal all-sky camera, a Brewer spectrophotometer, and up to three mini DOAS/MAX-DOAS systems. Based on both individual and synergistic processing of the data collected, novel products will be made available in near real time conditions to the end users. Columnar aerosol information from the spectrophotometers will be combined with lidar data to retrieve vertical profiles of individual aerosol species. Cloud layers will be detected and classified based mainly on the synergy of the lidar and the sky cameras and a realistic 3D representation of cloud conditions around the measurement site will be produced. Lidar profiles will be implemented as a priori information for radiative transfer purposes, that are necessary in order to obtain high quality trace gases profiles from the DOAS/MAX-DOAS spectrophotometer. Fast synergistic data processing will ensure that the algorithm can be applied for near real time public data dissemination in the future