A brain-wide functional map of the serotonergic responses to acute stress and fluoxetine

Abstract

Central serotonin (5-HT) orchestrates myriad cognitive processes and lies at the core of many stress-related psychiatric illnesses. However, the basic relationship between its brain-wide axonal projections and functional dynamics is not known. Here we combine optogenetics and fMRI to produce a brain-wide 5-HT evoked functional map. We find that DRN photostimulation leads to an increase in the hemodynamic response in the DRN itself, while projection areas predominately exhibit a reduction of cerebral blood volume mirrored by suppression of cortical delta oscillations. We find that the regional distribution of post-synaptically expressed 5-HT receptors better correlates with DRN 5-HT functional connectivity than anatomical projections. Our work suggests that neuroarchitecture is not the primary determinant of function for the DRN 5-HT. With respect to two 5-HT elevating stimuli, we find that acute stress leads to circuit-wide blunting of the DRN output, while the SSRI fluoxetine noticeably enhances DRN functional connectivity. These data provide fundamental insight into the brain-wide functional dynamics of the 5-HT projection system.

Cortical lesions causing loss of consciousness are anticorrelated with the dorsal brainstem

“…Rat models of TBI have also confirmed diffuse extracellular serotonin increases immediately post injury (Busto, Dietrich, Globus, Alonso, & Ginsberg, ). Furthermore, optogenetic stimulation of the raphe nuclei in mice produced widespread reduction in cerebral blood volume (Grandjean et al, ). Finally, there are both excitatory and inhibitory reciprocal projections back to the raphe nuclei from cerebral cortex in rodents (Celada, Puig, Casanovas, Guillazo, & Artigas, ; Warden et al, ; Weissbourd et al, ), providing a possible anatomical substrate for these functional observations.…”

“…Specifically, there are connections between the dorsal raphe and the claustrum (Pollak Dorocic et al, ), primary motor cortex (Beliveau et al, ; Pollak Dorocic et al, ), and extrastriate visual cortex (Tigges, Walker, & Tigges, ). Motivated by these convergent findings, a testable model of LOC induced by cortical lesions is released inhibition on serotonergic nuclei in the brainstem, which in turn exert diffuse suppressive effects on the cortex, either directly or through effects on adjacent ARAS nuclei (Grandjean et al, ; Tsuiki et al, ).…”

“…An interesting question is exactly which nuclei or cell types in the dorsal brainstem are likely to mediate lesion induced LOC. Answering this question in a definitive way is beyond the spatial resolution of imaging techniques such as fMRI, and is likely to benefit from ongoing work in animal models (Cho et al, 2017;Grandjean et al, 2019). This region of dorsal brainstem is composed of many different nuclei and neuronal subpopulations (Magoun, 1952;Verstegen, Vanderhorst, Gray, Zeidel, & Geerling, 2017;Wang & Morales, 2009).…”

Individual variability in functional connectivity architecture of the mouse brain

“…As a result, it is hard to link individual variation in functional connectomes to brain function and dysfunction. In contrast, tools available in rodents support causal manipulation of brain activity using molecular techniques such as chemogenetics or optogenetics, which can be combined with fMRI 39,[56][57][58][59][60] . However, heretofore such analyses were restricted to the group level.…”

Whole-Brain opto-fMRI Map of Mouse VTA Dopaminergic Activation Reflects Structural Projections with Small but Significant Deviations

“…Following protein expression, stimulation can be delivered via an implanted optic fiber. The combination of this stimulation method with fMRI is commonly referred to as opto-fMRI [24,25].…”