Long Range Circuit Motifs
A population of cells retrogradely labeled by injection of rabies virus
About the Lab
Our research focuses on brain states and multimodal integration across corticothalamic circuits. Information processing in the brain varies between brain states like sleep and wakefulness, and also more subtly between attention and inattention. When we are driving a car for example, and our attention shifts from the scene in front of us to the song on the radio, the processing of auditory and visual information can change dramatically without any anatomical rewiring of circuits in the brain. We study the mechanisms underlying the differential gating and routing of information in multiple sensory areas during these brain state changes. To address this difficult problem we record and manipulate activity in awake mice using cutting-edge techniques like targeted in vivo whole-cell patching, advanced multiphoton calcium imaging, optogenetics, and viral techniques.
Multiphoton Calcium and Voltage Imaging
A 2P-RAM mesoscope allows us to image functional activity with sub-cellular resolution across multiple cortical areas.
Functional Specialization of Cortical Interneurons
Two-photon targeted patching of a somatostatin-positive Martinotti interneuron in an awake animal.
Circuit Mechanisms Underlying Brain State Fluctuations in Mice
Like humans, small fluctuations in the size of the pupil track internal brain state in the mouse.
Large-Scale Functional Connectomics of Visual Cortex (MICrONS)
A 3D reconstruction of a single functionally-imaged L2/3 pyramidal cell in mouse visual cortex. In collaboration with AIBS and Princeton, in the next year we will have access to the full local circuit diagram of more than 70,000 functionally-characterized and EM-reconstructed cells from the mouse visual cortex.
Establishing pupillometry as an indicator of rapid brain state changes in awake mice
We were the first to show that fluctuations in pupil size track brain state changes in the mouse, opening the possibility of using the mouse as a model to study these effects, and emphasizing the importance of monitoring the pupil in order to account for variability in sensory responses. Pupil monitoring of head-fixed mice has since been widely adopted in the field.
Reimer, J., Froudarakis, E., Cadwell, C. R., Yatsenko, D., Denfield, G. H., and Tolias, A. S. (2014). Pupil fluctuations track fast switching of cortical states during quiet wakefulness. Neuron 84(2), 355–362.
Expanding our understanding of the spatial and temporal scale of neuromodulation in the cortex.
We recently performed the first simultaneous imaging of acetylcholine sensors and cholinergic axon activity in vivo, clarifying the temporal relationship between these two signals and highlighting differences in the dynamics of cholinergic release and axonal activity around locomotion and pupil dilation. With high-resolution two-photon imaging, we were able to observe that acetylcholine levels fall off with distance from cholinergic axons and that rapid clearance occurs for small transients, providing insights into the precise spatiotemporal characteristics of cortical acetylcholine signaling in vivo. A complementary manuscript is in preparation on norepinephrine dynamics.
Neyhart, E., Zhou, N., Munn, B. R., Law, R. G., Smith, C., Mridha, Z. H., Blanco, F. A., Li, G., Li, Y., Hu, M., McGinley, M. J., Shine, J. M., & Reimer, J. (2024). Cortical acetylcholine dynamics are predicted by cholinergic axon activity and behavior state. Cell Reports, 43(10). https://doi.org/10.1016/j.celrep.2024.114808. PMID: 39383037.
Dataset: https://dandiarchive.org/dandiset/001176/draft
Funding: R01 NS128901-01 The Spatial and Temporal Scale of Neuromodulation in Mouse Sensory Cortex
Studying changes in neuromodulation across the lifespan and in Alzheimer’s disease.
We are using high-resolution fluorescence imaging in transgenic mice to investigate changes in the dynamics of four key neuromodulators—acetylcholine, norepinephrine, dopamine, and serotonin—during normal aging and Alzheimer's disease progression. The goal of this project is to create a multimodal atlas that links characteristic changes in fast neuromodulator dynamics with anatomical and behavioral markers of aging and disease. A key objective is to explore the translational potential of pupillometry as a non-invasive diagnostic tool for early detection of neuromodulatory dysfunction in Alzheimer's disease. This work is part of a collaborative project with Jeannie Chin (BCM), and Read Montague and Matthew Howe (Virginia Tech).
Neyhart, E., Zhou, N., Chin, J., & Reimer, J. (2024). Arousal-linked levels of norepinephrine and acetylcholine in the cortex change across the lifespan in a mouse model of Alzheimer’s Disease [Poster Presentation]. Neuroscience 2024, Society for Neuroscience, Chicago, IL.
Funding: R56 AG080735 - 01A1 The Dynamic Neuromodulome in Alzheimer's Disease and Aging
Comparing changes in neuromodulators during alertness and attention across species
This project develops the first systematic framework to directly compare the neural mechanisms of global arousal and selective attention across mice and monkeys, bridging a critical gap between traditionally separate research fields. Using innovative cross-species behavioral tasks, advanced neurotransmitter sensors, and optogenetic techniques, we aim to determine whether attention and arousal operate through shared or distinct neural pathways. (This work is a collaboration with Valentin Dragoi at Methodist Hospital)
Funding: R34 NS137454 - 01 Cross-Species comparison of cholinergic neuromodulation in mice and primates
Determining the role of astrocyte calcium on cortical circuits
Astrocytes integrate local changes in neural activity and global neuromodulatory signals, and respond with intracellular calcium increases. We have developed a pipeline to image and analyze astrocytic calcium events in vivo, along with neural calcium activity, neuromodulators (ACh and NE), or glutamate sensors. We can also test the role of astrocyte calcium events on local neural activity by reducing astrocyte calcium with either local expression of CalEx (a constitutively-active calcium pump), or knockout of IP3 receptor subtypes. We have expanded this approach in collaboration with Hyun Kyoung-Lee (BCM) to look at the effects of Slc4a4 knockout in astrocytes. In collaboration with Fabien Sinz (guttenberg) we are also exploring computational (machine learning) methods that may be able to capture a higher resolution picture of the temporal and spatial coordination of astrocyte calcium with local neurons.
