STAR

Alterations in the hippocampus - the brain’s memory center - can lead to cognitive impairment and circuit malfunctions in pathologies such as Alzheimer’s and epilepsy.

Studies suggesting that astrocytes are integrated into the hippocampal circuit, and contribute to memory consolidation and performance, have resulted in growing interest in the role of astrocytes in memory.

Unlike the electrical signals of neurons, astrocytes use chemical signals - changes in their intracellular calcium (Ca2+) concentration - to communicate among themselves and with other nearby cells, including neurons.

Abnormal signaling of astrocytes in the hippocampus is thought to cause, or contribute to, cognitive impairment.

Using mini endoscopes to measure astrocyte Ca2+ signals in the brains of mice with Alzheimer’s disease, and normal mice, during learning and memory tasks, the team aims to identify how astrocytes help encode memory and how they are involved in memory alteration in Alzheimer’s disease.

Listing image: a mini endoscope used to measure astrocyte signaling.

To probe how astrocytes contribute to hippocampal memory processing, the team is using live cell imaging to decode the exact mode of astrocyte communication. Some features of astrocyte Ca2+ signaling lead to the release of gliotransmitters - neuroactive molecules that are important potential targets for future therapies. Using dynamic two-photon imaging - a technique that uses femtosecond pulsed lasers to image activity in living cells with high resolution - the team aims to identify the trigger signals coming from neuronal circuits, and the cellular mechanisms in astrocytes that lead to the release of gliotransmitters.

Listing image: 3D Ca2+ dynamics (golden) in a single astrocyte (azur, SR-101-labelled) via 3D two-photon microscopy. Volterra lab, related to Bindocci et al., Science, 2017.

To further investigate the role of astrocytes in the hippocampal circuit, the team will determine if the circuit comprises connections between neurons only, as generally accepted, or also connections between astrocytes and neurons. Using neural tracing approaches to label connections, the approach will show if astrocytes form unusual paths in the hippocampal circuit that could carry an additional layer of information. Integrated maps will reveal the position and structure of astrocyte connections as well as the associated functional and molecular information.

Listing image: Two-photon image showing the axon fibers (white) connecting the entorhinal cortex with the dentate gyrus of the hippocampus and the local astrocytes (red). From Bindocci et al., Science, 2017.

Inflammation of the brain is a hallmark of several neurological and psychiatric conditions. Recent studies in mice and humans show that hippocampal astrocytes undergo alterations in certain genes at early disease stages, resulting in an increase in inflammatory and neurotoxic astrocytes. Cytokines - molecules involved in the immune response - are among the mediators of normal astrocyte signaling. In pathological brain conditions with inflammation, cytokine levels rise, causing dramatic changes in astrocyte-neuron interactions that contribute to cognitive alterations. To tease apart the connection between astrocyte inflammation and information processing in the brain during disease the team will assess how deletion of an astrocyte cytokine signaling pathway affects the molecular, functional and behavioral alterations that develop during Alzheimer’s disease progression and epilepsy in mice with the aim of uncovering innovative therapeutic targets.

Listing image: Confocal picture showing astrocytes (white, GFAP labelling), β-amyloid plaques (red) and nuclei of all cells (labeled in blue with DAPI). A single granule cell neuron patched with a green dye is also visible. Volterra lab, unpublished.