Thèse Modulation Cholinergique et Gabaergique par le Telencéphale Basal du Cortex Piriforme In Vivo H/F - 33

Établissement : Université de Bordeaux
École doctorale : Sciences de la Vie et de la Santé
Laboratoire de recherche : Institut Interdisciplinaire de Neurosciences
Direction de la thèse : Lisa ROUX ORCID 0000000337946468
Début de la thèse : 2026-09-01
Date limite de candidature : 2026-05-20T23:59:59

Les neurones cholinergiques localisés dans les noyaux du télencéphale basal (TB) envoient des projections axonales dans la plupart des régions du cerveau. Ces projections sont connues pour jouer un rôle dans l'éveil, l'attention, le traitement sensoriel, l'apprentissage et la mémoire via l'action neuromodulatrice de l'acetylcholine. Dans les aires sensorielles du néocortex, les entrées cholinergiques produisent une neuromodulation contextuelle qui augmente le rapport signal/bruit lors des réponses sensorielles. Au-delà de ces effets médiés par l'acétylcholine, les noyaux du TB contiennent aussi des neurones de projection GABAergiques qui innervent les mêmes régions corticales que les neurones cholinergiques mais dont la fonction a été beaucoup moins étudiée.

Le cortex piriforme (CP) est considéré comme le principal cortex olfactif et il constitue la plus grande région corticale olfactive où la neuromodulation contextuelle façonne la perception olfactive. Le CP est densément innervé par des projections cholinergiques et GABAergiques en provenance du TB. Cependant, la fonction de ces deux voies neuromodulatrices dans le traitement des odeurs par le CP sont inconnues. Ce projet aura pour but de tester l'impact individuel et combiné de ces afférences du TB sur la réponse aux odeurs des réseaux neuronaux du CP ainsi que sur la détection olfactive.

Nous utiliserons pour cela des enregistrements en silicon probes ou Neuropixels des neurones du CP couplés à des enregistrements de la respiration et à des méthodes d'optogénétique. Ces expériences seront réalisées dans des souris entraînées sur une tâche de détection d'odeurs avec un contrôle précis de la présentation des stimuli en olfactométrie.

1)Piriform cortex and long-range acetylcholine and GABAergic inputs from BF

The PC is a paleocortex composed of three layers located in the ventrolateral forebrain. It receives afferent inputs from the olfactory bulb (OB) via the lateral olfactory tract and is a critical site for odor discrimination, contextualization, and associative memory. The PC also receives cholinergic innervation from the HDB/MCPO nuclei in the BF and expresses muscarinic receptors. Importantly, most of what we know about ACh action in PC relies on exogenous applications of ACh or pharmacological blockade of ACh receptors implying that the specific function of endogenous ACh in PC remains unclear.
Moreover, consistent with recent data, pilot experiments showed that OB-projecting BF-GABA neurons arborize extensively in the PC and provide inhibitory inputs to PC pyramidal cells. However, the functional implications of BF-GABA inputs and whether they are influenced by ACh release have never been studied.

2)Recruitment and temporal dynamics of BF neurons' activity in vivo

BF-ACh neurons: Only few studies have examined how BF neurons are recruited during associative olfactory learning. They report that BF-ACh neurons are transiently activated during exposure to olfactory cues, reward seeking or reward itself. ACh signals are also triggered in the BF by non-olfactory salient or novel sensory cues, aversive or rewarding reinforcers or even neutral sensory cues. Additionally, ACh operates at multiple timescales and broadcasts other types of information: slower tonic fluctuations in cortical areas are associated with changes in internal brain states, arousal level or movement. Degeneration of BF-ACh neurons is linked with early cognitive decline, including olfactory deficits, before the onset of clinical dementia in Alzheimer's disease.

BF-GABA neurons: BF-GABA neurons are five times more abundant than BF-ACh neurons and send dense and widespread projections to many cortical areas as well. Moreover, GABA can be co-released along with ACh from cholinergic terminals on specific targets. Yet, the role of BF GABAergic pathways has received little attention so far. Alike BF-ACh neurons, BF-GABA neurons respond in a phasic manner to behaviorally salient sensory stimuli, including olfactory cues, suggesting a possible role in learning and sensory processing similar to BF-ACh neurons. Consistent with this, inhibition of BF-GABA neurons impairs olfactory discrimination and associative learning. Yet, the impact of BF GABAergic inputs on PC neuronal responses to odorants is unknown.

Given the connections observed between BF and PC, the fact the BF is active during olfactory stimulations, we presume that BF inputs should modulate the way PC neurons respond to odorants. We hypothesize that they facilitate odor detection by increasing the signal to noise ratio of the circuit responses thereby facilitating odor detection.

To understand how long-range inputs from the basal forebrain impact the physiology of the piriform cortex networks, how they respond to odorants and how this modulation impacts the ability of mice to detect incoming olfactory stimuli.

Goals: 1) To characterize changes in odor-evoked responses in the PC when BF-cholinergic inputs are optogenetically suppressed or activated. 2) To characterize changes in odor-evoked responses when BF-GABAergic inputs are optogenetically suppressed or activated. 3) To assess if neuronal responses correlate with BF input activation levels. 4) To link activity to behavior we will use optogenetic silencing of each pathway during an odor-detection task.

Method: We will record neuronal activity in the PC while manipulating BF inputs with optogenetic activation/inactivation during odor stimulation in our olfactometer apparatus (head-fixed preparation for precise stimulus delivery). We will use silicon probes combined with optic fibers to specifically and locally manipulate BF afferents. ChATCre and VgatCre mice expressing cre-dependent opsins in BF-ACh and BF-GABA neurons will be used to control cholinergic and GABAergic inputs, respectively. Instead of passive odor presentations, an odor detection task will be used in order to maintain the attention of the animals towards the stimulus. Control experiments will be conducted with similar light stimuli in mice expressing control viruses in BF (e.g. GFP-expressing). Signal and noise correlations will be assessed in all experiments to evaluate the impact of BF inputs on the signal-to-noise ratio. For goal 3, silicon probe recordings will be combined with fiber photometry with the help of our collaborator to test whether evoked neuronal responses correlate with BF input activation levels before and/or during the stimulus, on the trial-by-trial basis. For the last goal (behavioral impact) we will use cre-dependent opsins in VgatCre and ChATCre mice and perform optogenetic silencing of BF terminals within the PC in the odor detection task.