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The Input-Output Relationship of the Cholinergic Basal Forebrain

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The Input-Output Relationship of the Cholinergic Basal Forebrain Resource The Input-Output Relationship of the Cholinergic Basal Forebrain Graphical Abstract Authors Matthew R. Gielow, Laszlo Zaborszky Correspondence [email protected] In Brief Monosynaptic viral tracing in transgenic rats reveals that patterns of input cells contacting cholinergic neurons are biased according to their cortical or amygdalar output. Mapping inputs across the entire brain, Gielow and Zaborszky provide structural evidence for networks enabling differential acetylcholine release. Highlights d Inputs to cholinergic cells are biased, varying by cortical output target d Proportions of input to a given cortical cholinergic output are reproducible d The most prominent input to many cholinergic cells is the caudate putamen d Medial prefrontal cortex-projecting cholinergic cells receive little caudate input Gielow & Zaborszky, 2017, Cell Reports 18, 1817–1830 February 14, 2017 ª 2017 The Author(s). http://dx.doi.org/10.1016/j.celrep.2017.01.060 Cell Reports Resource The Input-Output Relationship of the Cholinergic Basal Forebrain Matthew R. Gielow1 and Laszlo Zaborszky1,2,* 1Center for Molecular and Behavioral Neuroscience, Rutgers, the State University of New Jersey, Newark, NJ 07102, USA 2Lead Contact *Correspondence: [email protected] http://dx.doi.org/10.1016/j.celrep.2017.01.060 SUMMARY Lesions of the BF in experimental animals or humans cause enhancement of slow oscillations and severe attention and mem- Basal forebrain cholinergic neurons influence cortical ory deficits (Botly and De Rosa, 2012; Buzsa´ ki et al., 1988; Lut- state, plasticity, learning, and attention. They collec- kenhoff et al., 2015), while BF stimulation increases the sponta- tively innervate the entire cerebral cortex, differen- neous and visually driven cortical firing rates, improving neuronal tially controlling acetylcholine efflux across different response reliability (Pinto et al., 2013). Similarly, experiments in cortical areas and timescales. Such control might the somatosensory (Maalouf et al., 1998) or in the auditory cortex be achieved by differential inputs driving separable (Leach et al., 2013; Metherate and Weinberger, 1990)suggest that ACh plays a role in improving sensory perception. Release cholinergic outputs, although no input-output rela- of ACh across different cortical areas covaries between sleep tionship on a brain-wide level has ever been and wake states (Jasper and Tessier, 1971; Phillis, 1968; Sarter demonstrated. Here, we identify input neurons to and Bruno, 2000). BF cells projecting to remote regions of cortex cholinergic cells projecting to specific cortical appear to have overlapping dendritic fields (Woolf, 1991), and regions by infecting cholinergic axon terminals cholinergic cells projecting to different cortical targets often inter- with a monosynaptically restricted viral tracer. This mingle across an extended region of the BF. These data together approach revealed several circuit motifs, such as have been taken as evidence that the cholinergic BF is a diffuse central amygdala neurons synapsing onto basolat- projection system. However, discrete cholinergic efflux occurs eral amygdala-projecting cholinergic neurons or per cortical region at different time points (Fournier et al., 2004; strong somatosensory cortical input to motor cor- Parikh et al., 2007; Rasmusson, 1993), and recent tracing and op- tex-projecting cholinergic neurons. The presence of togenetic activation of cholinergic neurons in the mouse BF sug- gest that cholinergic neurons can modulate sensory cortical areas input cells in the parasympathetic midbrain nuclei in a modality-specific manner (Kim et al., 2016). Part of this contro- contacting frontally projecting cholinergic neurons versy is based upon the complex organization of BF projection suggest that the network regulating the inner eye neurons: cholinergic and non-cholinergic projections to the muscles are additionally regulating cortical state via neocortex are not diffuse but are organized into segregated and acetylcholine efflux. This dataset enables future cir- overlapping pools of neurons that may transmit information from cuit-level experiments to identify drivers of known specific locations in the BF to subsets of cortical areas, themselves cortical cholinergic functions. interconnected (Zaborszky et al., 2015a). Additionally, there are subregional differences in input across the BF (Zaborszky et al., 2015b), although how this affects cortical outputs is unknown. INTRODUCTION The relationship of synaptic inputs to target-identified cell pop- ulations cannot be readily assessed on a whole-brain level with The connectome of the basal forebrain (BF) is not well under- classic anatomical techniques that rely on the combination of con- stood due to the anatomical complexity of the region. Patients ventional anterograde and retrograde tracing (Zaborszky et al., with Alzheimer’s disease and related dementias have a signifi- 2006). Here, we employed output-specific monosynaptic viral cant decrease of acetylcholine (ACh) in the cortex and show tracing in cells expressing choline acetyltransferase (ChAT) to pathological changes in cholinergic neurons in the BF (Za- sample the input-output relationship of the cholinergic BF, and borszky et al., 2008). Thus, a complete understanding of its func- thereby identify on a whole-brain scale the neuronal populations tional organization is warranted. ACh is released in the cortex by likely to drive differential ACh efflux in particular output structures. neurons whose cell bodies are located in the BF. Each of these Genetic access to BF ChAT cells was achieved by injecting Cre- cholinergic neurons supplies a small portion of cortex (Price dependent helper viruses (AAV-EF1a-FLEX-TVAmCherry and and Stern, 1983), and ACh release is controlled precisely across AAV-CA-FLEX-RG) (Watabe-Uchida et al., 2012) at five points different cortical regions and timescales, thought to be respon- across the BF in ChAT::Cre rats (Witten et al., 2011)(Figures 1A sible for the variety of its cognitive effects (for review, see Gritton and 1B). When these same helper viruses were used in the BF et al., 2016; Mun˜ oz and Rudy, 2014). However, the mechanism of the same line of rats, expression of helper viral product only oc- behind this control is unknown. cured in cells immunopositive for ChAT (Chavez and Zaborszky, Cell Reports 18, 1817–1830, February 14, 2017 ª 2017 The Author(s). 1817 This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Figure 1. Monosynaptic Viral Tracing (A) Cre-dependent helper viruses limit starter cells to the cholinergic cell type. Virus placed at cortical terminals retrogradely labels a subset of cholinergic cells that project to the cortical injection site (figure based on Wall et al., 2010). (B and C) 12 subjects (B) received helper virus across five basal forebrain sites and (C) received retrograde virus in a single BF projection target, whether in motor cortex (red), medial prefrontal cortex (green), orbitofrontal cortex (blue), or amygdala (yellow) (figure based on Paxinos and Watson, 2007). (D) Cells are visualized by the presence of mCherry (helper virus in cholinergic cells), GFP (afferent cells, monosynaptic inputs to starter cells), or both fluorophores (cholinergic starter cells). 2016). Tracing restricted to ChAT terminals was achieved by sub- sively, resulting in many examples of ChAT populations that proj- sequently injecting a pseudotyped, helper-dependent, replica- ect to different targets yet partially overlap in the BFc space (for tion-defective rabies vector (EnvA-DG-rabies-eGFP) (Wall et al., ref see Zaborszky et al., 2015a). The BF topography of starter 2010; Wickersham et al., 2007) into a single target area (prefrontal, cells in the current study confirms this rule of partial overlap (Fig- orbitofrontal, motor cortex, or amygdala) in each subject (n = 12; ure 2; Table S1; Movie S1). When the monosynaptic inputs to the three subjects per group; Figures 1A and 1C). Complementation starter cells are considered across the three cortical target of the deficient rabies with the rabies glycoprotein occurred in groups and the basolateral amygdala (a cortex-like structure), BF ChAT cells (starter cells) projecting to the cortical area of rabies we find specific sets of inputs differ significantly between the injection. This allowed for retrograde monosynaptic spread of four groups depending on the viral-injected cholinergic projec- GFP-tagged rabies from these starter cells back to the cell bodies tion target (Wilks’ Lambda one-way multivariate analysis of vari- of their synaptic inputs (Figures 1A and 1D), whereas in the control ance [MANOVA]; F = 21.21, p = 0.008) (Figure S1). To make condition, ChAT::Cre with rabies injection but no helper viruses, sense of this result, we took a detailed look at differential distri- no GFP was detected. Therefore, we could map the inputs to spe- butions of afferents in each input region. cific output populations, regardless of how output somata are distributed across the BF itself. Dorsal Striatal and Accumbens Input Disparity Dorsal striatum is on average the largest input source for RESULTS cholinergic BF cells. The proportion of these inputs is far less in the case of medial prefrontal cortex (mPFC) injection The topography of basal forebrain cholinergic (BFc) cell bodies (Figure 3), with an average of 5% of inputs for mPFC cases projecting to particular cortical targets has been studied exten- versus 47% for the motor cortex
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