Team Koukouli

Cholinergic modulation of cortical inhibitory circuits in health and disease

Team leader :  Fani Koukouli

Team member :  Efigeneia Nikolakopoulou

 

The neocortex plays a crucial role in all cognitive functions. This is accomplished through connections between neuronal networks which emerge from synaptic interactions of many neuron types. Inhibitory interneurons constitute a sparse but crucial neuronal class which coordinate cortical activity. Inhibitory circuits are controlled by different neuromodulators. Among them, the neurotransmitter acetylcholine (ACh) highly controls cortical activity by signaling through two classes of ACh receptors: the ionotropic nicotinic receptors and the metabotropic muscarinic receptors. Cortical ACh signaling shapes neuronal circuit dynamics and underlies specific aspects of cognitive functions and behaviors including attention, learning, memory, perception and motivation. Thus, it is not surprising that ACh receptor gene variants are strongly linked to psychiatric disorders such as schizophrenia and neurodegenerative disorders such as Alzheimer’s disease. Evidence identified that cortical inhibitory circuits and cholinergic neurotransmission are affected in psychiatric disorders, however, the actual interplay between these two systems is unknown.

 

  1. A) Two-photon calcium imaging of neurons in the prefrontal cortex of an awake mouse.
  2. B) Effect of nicotine in neuronal activity.
  3. C) 3D reconstruction of GFP expressing neurons from the brain surface up to 750 μ

5 Main Publications:

Koukouli F, Montmerle M, Aguirre A, De Brito Van Velze M, Peixoto J, Choudhary V, Varilh M, Julio-Kalajzic F, Allene C, Mendéz P, Zerlaut Y, Marsicano G, Schlüter OM, Rebola N, Bacci A, Lourenço J. Visual-area-specific tonic modulation of GABA release by endocannabinoids sets the activity and coordination of neocortical principal neurons. Cell Rep. 2022 Aug 23;40(8):111202. doi: 10.1016/j.celrep.2022.111202.

Zhang CL, Koukouli F, Allegra M, Ortiz C, Kao HL, Maskos U, Changeux JP, Schmidt-Hieber C. Inhibitory control of synaptic signals preceding locomotion in mouse frontal cortex. Cell Reports. 2021 Nov 23;37(8):10035. PMID: 34818555.

Koukouli F and Changeux JP. Do nicotinic receptors modulate high-order cognitive processing? Trends in Neurosciences. 2020 Aug;43(8):550-564. PMID: 32591156.

Koukouli F, Rooy M, Tziotis D, Sailor K.A, O’Neill H, Levenga J, Witte M, Nilges M, Changeux JP, Hoeffer C, Stitzel J.A, Gutkin B, DiGregorio D.A, Maskos U. Nicotine reverses hypofrontality in animal models of addiction and schizophrenia. Nature Medicine. 2017 Mar;23(3):347-354. PMID: 28112735.

Koukouli F#, Rooy M, Changeux JP#, Maskos U#. Nicotinic receptors in mouse prefrontal cortex modulate ultraslow fluctuations related to conscious processing. Proc Natl Acad Sci USA (PNAS). 2016 Dec 20;113(51):14823-14828. # corresponding authors.

Keywords

Prefrontal cortex, Interneurons, Acetylcholine receptors, Psychiatric disorders, Cognition

Main techniques/approaches:

Our team uses multiscale experimental approaches, combining genetics, two-photon calcium imaging in awake mice, behavior, electrophysiology and optogenetics to investigate i) how cholinergic transmission affects specific cortical subnetworks, ii) the cellular, molecular and synaptic logic governing the modulation of inhibitory circuits by cholinergic inputs and iii) how inhibitory interneuron computations are affected by human genetic variants of ACh receptors linked to psychiatric disorders.Our team uses multiscale experimental approaches, combining genetics, two-photon calcium imaging in awake mice, behavior, electrophysiology and optogenetics to investigate i) how cholinergic transmission affects specific cortical subnetworks, ii) the cellular, molecular and synaptic logic governing the modulation of inhibitory circuits by cholinergic inputs and iii) how inhibitory interneuron computations are affected by human genetic variants of ACh receptors linked to psychiatric disorders.

Main Funding: