Regulation of glycogenolysis by neurotransmitters in the central nervous system

Neurotransmitters are the molecules that neurons use to communicate with each other and with the other cell types of the nervous system, such as glial cells and cells of the vasculature. The best characterized actions of neurotransmitters are the alterations in excitability that they elicit in other neurons. These changes in neuronal firing rate are due to the opening or closing of transmembrane channels selectively permeable to given ionic species. We have however recently demonstrated that certain neurotransmitters can regulate energy metabolism within discrete regions of the central nervous system. In particular we have observed that Vasoactive Intestinal Peptide stimulates glycogenolysis in the cerebral cortex. This action is also exerted by the monoamines noradrenaline, serotonin and histamine. Studies in primary cultures indicate that the glycogenolysis elicited by neurotransmitters may take place in astrocytes, which are glial cells and where glycogen is predominantly stored in the nervous system. These observations suggest that the primary function of certain neuronal circuits may be to regulate the availability of energy substrates within discrete neuronal ensembles.

Optical sensory and motor mapping of mouse dorsal cortex

Matthieu Pierre Auffret

Throughout species, including mice and humans, we all have to make decisions to fulfill our fundamentals needs: eat, drink, explore, communicate, reproduce... To make those decisions, we have to collect informations from the surrounding world and to process them with our nervous system. The neocortex is the most distinctive feature of the brain as it is the substrate of high cognitive functions. One commonly used model to study the brain is the mouse. Mice can be genetically modified to express fluorescent reporters, or optogenetic actuators in their neurons. The questions I ask in this thesis are where and when specific sensory information is processed in the mouse cortex, and where and when these signals are integrated to generate to a motor command. First, I developed a protocol to get reliable sensory maps from wide-field optical intrinsic signal imaging. Mice undergo a surgical procedure to get a relatively transparent view of the left dorsal cortex. Then I sequentially repetitively stimulated different parts of the body of anesthetized mice to map the cortical sensory representation of each stimulated organ. I also successfully imaged optogenetically evoked responses by combining optogenetic experiment with wide-field optical intrinsic signal imaging. Second, I found the coordinates of the tongue/jaw primary sensory cortex tjS1 and of the tongue/jaw primary motor cortex tjM1. While I was mechanically stimulating tongue and jaw in anesthetized Thy1-GCaMP6f mice, I imaged the calcium signals evoked in the left cortical hemisphere with a wide-field fluorescence macroscope. Third, I recorded cortical activity of behaving mice performing a 2-whisker discrimination task with the wide-field calcium imaging technique. There was a large difference between hit and miss trials. The amplitude of the responses in S1, S2, M1 and M2 were decreasing over the days of training. The earliest difference between hit and miss response occurred in S1 and S2 after 100 ms. Then the signals converged toward M2 where the amplitude of the response was amplified to lead to a lick command. Finally, I optogenetically stimulated the cortex of awake mice and I measured the evoked whisker movements to obtain whisker motor maps. I found that almost the entire cortex can evoke whisker movement. The earliest evoked movement occurred when S1 was stimulated, the contralateral whisker had a prolonged retraction. Then the ipsilateral whisker started large rhythmic protractions. When M1 was stimulated, it triggered the most protracted whisker movement of rhythmic protractions. The largest oscillating protraction was observed when the parietal association area (PtA) was stimulated. These data suggest that neuronal information needed to perform even simple tasks requires distributed cortical areas to process sensory inputs, like passive whisker deflection or optogenetic stimulation, and in return generate motor outputs, like licking or whisking. Future experiments must investigate the complex neuronal circuits connecting specific cell- types in various cortical regions using wide-field calcium imaging and combine it with optogenetic manipulations of this network at specific times and brain regions.

EPFL2018

VIP and noradrenaline act synergistically to increase cyclic AMP in cerebral cortex

Pierre Magistretti

There is growing evidence that two, or possibly more, neurotransmitters can coexist within the same neurone. In particular, the presence of a peptide and a biogenic amine has been demonstrated in the same terminals of central and peripheral neurones. These findings have led to the hypothesis that neurotransmitters, coexisting within the same neurones, can interact at pre- or postsynaptic sites in a functionally coordinated manner. However, interactions between neurotransmitters contained in distinct neuronal systems terminating within the same region of the central nervous system (CNS) can be envisaged. We have examined this last possibility in the cerebral cortex, an area of the CNS where the two neurotransmitters vasoactive intestinal polypeptide and noradrenaline are contained in separate neuronal systems and where they both stimulate the formation of cyclic AMP. We report here that vasoactive intestinal polypeptide and noradrenaline act synergistically to stimulate the formation of cyclic AMP and that this synergistic interaction is antagonized by the specific alpha-adrenergic antagonist phentolamine.

1984

Prostaglandins and the synergism between VIP and noradrenaline in the cerebral cortex

Pierre Magistretti

We have previously shown that vasoactive intestinal peptide (VIP) and noradrenaline (NA) interact synergistically to increase cyclic AMP levels in mouse cerebral cortical slices. The pharmacological mechanism of this synergism is the potentiation by NA, through alpha 1 adrenergic receptors, of the stimulatory effect of VIP on cAMP formation. A similar interaction has been confirmed in guinea pig cerebral cortex and in discrete nuclei of the rat hypothalamus. Furthermore VIP and NA interact synergistically to depress the spontaneous activity of identified neurons in rat neocortex. At the cellular level, this synergistic interaction suggests that VIP- and NA-containing neuronal systems may converge, at least in part, on the same target cells to increase cAMP levels in the cerebral cortex. At the molecular level, the interaction may occur at various steps in signal transduction, between receptors, intramembrane transduction processes or intracellular effector mechanisms. Here we report that the alpha 1-adrenergic potentiation of the increases in cAMP elicited by VIP involves the formation of arachidonic acid metabolites and is mimicked by prostglandins F2 alpha and E2.

1987

Optical sensory and motor mapping of mouse dorsal cortex

Matthieu Pierre Auffret

EPFL2018