Visualizing cholinergic neuromodulation in vivo using optogenetics and fMRI in monkeys
Human Cognitive and Systems Neuroscience
Final Report Abstract
The activity of the brain is constantly varying, wandering between states, and affecting not only our neural responses to sensory inputs but also our ability to process information in or to make decisions and take actions. But what is neuromodulation and why it is so important? Neomodulation provides to neural circuits with the flexibility to adjust their neuronal activity in a variety of temporal and spatial scales. These tasks run on highly variable background of ongoing neuronal activity in the brain, which is usually reflected in the resting state neural response. The present project utilized anatomical tracing using viral vectors, brain-wide fMRI mapping in combination with neurophysiology, and it is on its way of incorporating optegenetics. The use of electrophysiological and imaging experiments in animals have demonstrated that the relationship between multiple brain regions are expressed at multiple spatial and temporal scales and vary with brain state and neuromodulation. The results that we, so far, obtained from this grant, highlights important aspects of neuromodulation and opens new questions to study the role of cholinergic inputs into the high level visual processing. Apart from behavioral context, variations in ongoing activity are also impacted by a wide variety of housekeeping tasks, and some patterns of activity may even simply arise as a bioproduct of the brains anatomical and physiological architecture, which is reflected in our results. Here we focused on the spontaneous activity of single neurons from functionally defined regions of the visual cortex, known to received neuromodulatory inputs, as we showed in the anatomical experiments we conducted. To evaluate the relevance of neuromodulatory inputs in visual cortex, we combined simultaneous fMRI and single-unit recording to assess the intrinsic brain-wide patterns of coupling exhibited by individual neurons, providing an indication of their network affiliations. As we found that cholinergic basal forebrain seems to project to higher order visual areas, we focused our attention in neurons located in brain regions associated to the recognition of faces. As evidenced in our fMRI results, face patch neurons showed substantial correlations with the SN, iDR and the PPT (cholinergic source in the brain stem), which were generally opposite in polarity to the cortical correlations computed from the same neurons. It is possible that this relationship stems from the known projections of brainstem neuromodulatory centers to the temporal cortex including TEO and TE and promotes changes in visual system neurons. However, this explanation does not account for either the inverted correlation profile or the absence of a broader pattern of neuromodulation-based correlations across the cortex. Another important finding emerged from this project is, perhaps the unexpected inverse coupling of face patch neurons with the entire LGN of both hemispheres. While there are some anatomical projections linking the temporal cortex and LGN, current evidence is that they are extremely sparse, particularly in the adult, though this is an active topic of investigation. A more likely explanation relates changes in brain states (neuromodulation), and to the contribution of cholinergic modulation to the thalamus stemming from the PPT. It is possible that, during normal visual behavior, afferents from this brainstem nucleus mediate state-dependent changes in the processing of visual information in the LGN, thus controlling the magnitude of visual input to the cortex. A similar explanation may relate to the dorsal raphe nucleus, which also projects to the LGN, and which also showed inverse correlations. This project has examined important aspects of high-level vision and evaluated the importance of neuromodulation in shaping the relationship of a brain area with the whole brain dynamics. It is worth mentioning, that we are currently working to incorporate optogenetics in our experiments, which a key aspect for my research, and for which this DFG grant help set up the basis.
Publications
- Two distinct profiles of fMRI and neurophysiological activity elicited by acetylcholine in visual cortex. Proc Natl Acad Sci U S A. (2018) Dec 18;115(51):E12073-E12082
Zaldivar D, Rauch A, Logothetis NK & Goense J
(See online at https://doi.org/10.1073/pnas.1808507115) - Local and global correlations of spontaneous electrophysiological activity measured from a single fMRI voxel. IRP Fellow Scientic Training Day, NIMH, NIH. Washington DC, USA
Zaldivar D, Koyano K & Leopold DA
- Whole-brain fMRI mapping of neural activity recorded from a single voxel. FENS forum of Neuroscience, Glasgow, UK
Zaldivar D, Koyano K, Godlove D & Leopold DA
- Using fMRI to map spontaneous activity of single neurons. IRP Fellow Scientic Training Day, NIMH, NIH. Washington DC, USA
Bhik-Ghanie R, Zaldivar D, & Leopold DA
- Brain-wide functional connectivity of face patch neurons during rest Proc Natl Acad Sci U S A. (2022) Sep 6;119(36):e2206559119
Zaldivar D, Koyano KW, Ye FQ, Godlove DC, Park SH, Russ BE, Bhik-Ghanie R & Leopold DA
(See online at https://doi.org/10.1073/pnas.2206559119) - Differential coupling between single-unit fMRI and other seed-based maps. 7th CiNet. Kyoto, Japan
Zaldivar D, Koyano K, Ye F, Park S, Godlove D & Leopold DA
- Neuromodulatory Ascending Systems: Their Influence at the Microscopic and Macroscopic Levels. Frontiers of Neural Circuits (2022)
Giglia G, Gambino G, Puig MV, Ramirez-Villegas J & Zaldivar D (eds.)
(See online at https://doi.org/10.3389/fncir.2022.1028154) - Towards next-generation primate neuroscience: A collaboration-based strategic plan for integrative neuroimaging. Neuron (2022) Jan 5;110(1):16-20
he prime Data and Resource Consortium (PRIME-DRE)
(See online at https://doi.org/10.1016/j.neuron.2021.10.015)
