A functional topography within the cholinergic basal forebrain for encoding sensory cues and behavioral reinforcement outcomes.

Blaise Robert,Yulong Li,Eyal Y Kimchi,Yurika Watanabe,Miao Jing,Tatenda Chakoma,Daniel B Polley

doi:10.7554/elife.69514

Abstract

Basal forebrain cholinergic neurons (BFCNs) project throughout the cortex to regulate arousal, stimulus salience, plasticity, and learning. Although often treated as a monolithic structure, the basal forebrain features distinct connectivity along its rostrocaudal axis that could impart regional differences in BFCN processing. Here, we performed simultaneous bulk calcium imaging from rostral and caudal BFCNs over a 1-month period of variable reinforcement learning in mice. BFCNs in both regions showed equivalently weak responses to unconditioned visual stimuli and anticipated rewards. Rostral BFCNs in the horizontal limb of the diagonal band were more responsive to reward omission, more accurately classified behavioral outcomes, and more closely tracked fluctuations in pupil-indexed global brain state. Caudal tail BFCNs in globus pallidus and substantia innominata were more responsive to unconditioned auditory stimuli, orofacial movements, aversive reinforcement, and showed robust associative plasticity for punishment-predicting cues. These results identify a functional topography that diversifies cholinergic modulatory signals broadcast to downstream brain regions.

Highlights

Basal forebrain projections innervate the neocortex, hippocampus, and amygdala to regulate stimulus salience and global brain state across a wide range of timescales
A transgenic strategy for selective GCaMP expression in HDB and globus pallidus and substantia innominata (GP/SI) Basal forebrain cholinergic neurons (BFCNs) To characterize regional specializations within the cholinergic basal forebrain across a wide range of task-related variables, we performed dual fiber imaging from HDB and GP/SI in the right hemisphere of Chat-Cre mice that were crossed to the GCaMP6f reporter line, Ai148 (Figure 1B-C)
While our transgenic strategy was appropriate for bulk imaging from cholinergic neurons in HDB and GP/SI cholinergic neurons, it would not necessarily be a valid strategy for the study of other brain regions

Summary

Introduction

Basal forebrain projections innervate the neocortex, hippocampus, and amygdala to regulate stimulus salience and global brain state across a wide range of timescales (for recent reviews see Disney and Higley, 2020; Monosov, 2020; Sarter and Lustig, 2020). Rostral and caudal BFCNs are wired into distinct anatomical networks, the suggestion is that they broadcast a relatively unified signal to downstream brain areas The evidence for this conclusion primarily comes from two types of measurements. We observed closely matched responses in rostral and caudal regions, suggesting a common output that would be broadcast to downstream brain regions Both HDB and GP/SI exhibited equivalently weak overall responses to unconditioned visual stimuli and anticipated rewards. Response amplitudes for aversive stimuli were larger in GP/SI, as were responses to orofacial movements, unconditioned auditory stimuli, and learning-related enhancement of punishment-predicting auditory cues These findings identify a coarse functional topography within the cholinergic basal forebrain that can be interpreted in light of the distinct connectivity of each region and will motivate future hypotheses about the causal involvement of each region in brain function and behavior

Results

Discussion

Materials and Methods

Surgical procedure for GCaMP photometry

Surgical procedure for acetylcholine sensor photometry

Figures and Figure Legends