The BF has been implicated in a variety of brain functions such as arousal, attention, and plasticity (Bakin and Weinberger, 1996; Brown et al., 2012; Everitt and Robbins, 1997; Froemke et al., 2013; Hasselmo and Sarter, 2011; Jones, 2011; Lin et al., 2015; Saper et al., 2010; Sarter et al., 2001). The dysfunction or loss of BF cholinergic neurons is an important feature of Alzheimer’s disease associated with cognitive impairment (Schliebs and Arendt, 2011; Whitehouse et al., 1982). In addition to forming extensive local synapses (Xu et al., 2015; Yang et al., 2014; Zaborszky and Duque, 2000), BF neurons receive inputs (Asanuma, 1989; Freund and Meskenaite, 1992; Grove, 1988a, Henny and Jones, 2006; Manns et al., 2001; Parent et al., 1988; Rye et al., 1984; Semba et al., 1988; Zaborszky and Cullinan, 1992) and send outputs (Cullinan and Zaborszky, 1991; Grove, 1988b; Jones and Cuello, 1989; Mesulam and Mufson, 1984; Paré and Smith, 1994) to many other brain areas (Steriade and McCarley, 2005; Zaborszky et al., 2012). However, how these long-range connections contribute to BF functions remains unclear.

An important challenge in understanding the function of the BF circuit is its neuronal heterogeneity. There are three major cell types spatially intermingled in the BF: cholinergic, glutamatergic, and GABAergic (Semba, 2000; Zaborszky et al., 2012). Selective lesion or pharmacological manipulation of the cholinergic system is well known to affect multiple brain functions (Wenk, 1997). For example, 192-IgG-saporin-mediated lesion of cholinergic neurons impaired the ability of rats to discriminate between signal and non-signal visual events in an attention task (McGaughy et al., 1996) and disrupted training-induced cortical map reorganization associated with motor learning (Conner et al., 2003). Glutamatergic and GABAergic BF neurons are also likely to serve important functions (Lin et al., 2015). For example, in recent studies the activity of non-cholinergic BF neurons was found to correlate with sustained attention (Hangya et al., 2015) or to encode reward and motivational salience information (Avila and Lin, 2014; Lin and Nicolelis, 2008; Nguyen and Lin, 2014), and optogenetic activation of PV+ GABAergic neurons was shown to regulate cortical gamma oscillations (Kim et al., 2015). In a study on sleep-wake control, cholinergic, glutamatergic, and PV+ neuron activity was found to promote wakefulness, while SOM+ neurons promoted sleep; these four cell types form extensive but highly specific local connections with each other for brain-state regulation (Xu et al., 2015). Thus, to understand the BF circuit function, it is crucial to map its inputs and outputs with cell-type specificity.

Most of the previous studies of BF long-range connections focused on specific regions connected to the BF, making it difficult to assess their whole-brain distribution. Recent advances in virus-assisted circuit tracing (Callaway and Luo, 2015; Huang and Zeng, 2013) and high-throughput imaging have greatly facilitated whole-brain mapping of long-range connectivity in a cell-type-specific manner (Oh et al., 2014; Osten and Margrie, 2013). In this study, we traced the long-range inputs and outputs of four genetically defined BF cell types. While the input distributions were similar across cell types, their output patterns showed striking differences. Our quantitative analysis of the whole-brain distributions of inputs and outputs for each BF cell type can serve as an anatomical blueprint for future studies of inter-regional pathways mediating BF functions.

Four Cre mouse lines were used to target different BF subpopulations for virus-mediated circuit tracing: choline acetyltransferase (ChAT)-Cre for cholinergic neurons, vesicular glutamate transporter 2 (VGLUT2)-Cre for glutamatergic neurons, and PV-Cre and SOM-Cre mice for two subtypes of GABAergic neurons. These four Cre lines have been shown to label largely non-overlapping BF neuron populations with high specificity (Xu et al., 2015).

To identify the long-range inputs to each cell type, we used RV-mediated transsynaptic retrograde tracing, which has been shown to label monosynaptic inputs to selected starter cells with high specificity (Miyamichi et al., 2011; Wall et al., 2013; Watabe-Uchida et al., 2012; Wickersham et al., 2007). First, we expressed avian-specific retroviral receptor (TVA), enhanced green fluorescent protein (eGFP), and rabies glycoprotein (RG) specifically in each cell type by injecting two Cre-inducible AAV vectors (AAV2-EF1α-FLEX-eGFP-2a-TVA and AAV2-EF1α-FLEX-RG) into the BF of ChAT-, VGLUT2-, PV-, or SOM-Cre mice (Figure 1A). The expression of RG was highly cell type specific and not detected in wild-type mice not expressing Cre recombinase (Figure 1—figure supplement 1). Two to three weeks later, we injected a modified RV (rabiesΔG-tdTomato+EnvA) that only infects cells expressing TVA, requires RG to spread retrogradely to presynaptic cells (Figure 1—figure supplement 2), and contains the tdTomato transgene. After histological sectioning and fluorescence imaging, each sample was aligned to a reference atlas (Allen Mouse Brain Atlas, see Materials and methods) to facilitate 3D whole-brain visualization and quantitative comparison across brain samples (Figure 1C). The starter cells (expressing both tdTomato and eGFP) and the transsynaptically labeled presynaptic neurons (expressing tdTomato only) were identified manually, and their locations were registered in the reference atlas (Figure 1—figure supplement 3).

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Brain samples were excluded from the analyses if very few input neurons (<200) were labeled in the whole brain. As noted in previous studies, due to the extremely efficient interaction between TVA and EnvA-pseudotyped rabies virus, the very low-level expression of TVA in non-Cre-expressing cells (not detectable based on fluorescent protein markers) allows the rabies virus to infect and label these cells with tdTomato at the injection site, independent of synaptic connections with starter cells (Beier et al., 2015; Menegas et al., 2015; Miyamichi et al., 2013; Ogawa et al., 2014; Pollak Dorocic et al., 2014; Wall et al., 2013; Watabe-Uchida et al., 2012; Weissbourd et al., 2014). However, this local contamination does not compromise the mapping of long-range inputs because RG (required for transsynaptic spread of RV) is not expressed in any non-Cre-expressing cells at sufficient levels for trans-complementation of rabiesΔG to allow transsynaptic spread of RV (Callaway and Luo, 2015; Miyamichi et al., 2013). To determine the spatial extent of the local contamination, we performed control experiments in the absence of RG and found very few non-specific labeling at >850 μm from the injection center (Figure 1—figure supplement 2D). Thus, presynaptic neurons were counted only in coronal sections outside of this range. While this procedure precludes identification of local inputs, synaptic interactions of the four cell types within the BF have been characterized electrophysiologically in a recent study (Xu et al., 2015). Another technical limitation of the study is that when the brain was removed for histological processing, the olfactory bulb was often damaged, which led to a significant underestimation of labeling (both the input neurons and axon projections) in the olfactory bulb.

We found 900 – 14,631 (median 7002) tdTomato-labeled presynaptic neurons in each brain (n = 17), and the convergence index (ratio between the number of input cells and starter cells) ranged between 4.3 and 77.7 (Figure 1—figure supplement 4). Such variability is comparable to that found in other studies using similar methods (Miyamichi et al., 2011; DeNardo et al., 2015). The presynaptic neurons were predominantly ipsilateral to the starter population (<5% contralateral) but were distributed in a large number of brain areas (Figure 2, Figure 3, Video 1). Since the number of labeled neurons varied across brain samples, and there was no significant difference between the four cell types (P = 0.27, one-way ANOVA), we normalized the data in each area by the total number of labeled neurons in each brain. When the brain was divided into 12 major regions (Figure 3A), the striatum and hypothalamus provided the highest numbers of inputs, while few labeled neurons were found in the medulla or cerebellum (Figure 3A).

Figure 2

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Figure 3

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Figure 3—source data 1

Distribution of input cells in 53 brain areas for ChAT+, VGLUT2+, PV+, and SOM+ BF neurons.

Shown are the mean ± s.e.m. of the percentage of inputs from each area for individual cell types. Note that within each of the 12 brain structures, there are unnamed sub-regions outside of the 53 areas listed in the table; thus the percentages of inputs in the listed areas do not always add up to the total percentage in the given brain region.

https://doi.org/10.7554/eLife.13214.009

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Video 1

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To facilitate data visualization at different levels of detail, we also used an interactive sunburst diagram (adapted from Allen Mouse Brain Atlas, http://www.brain-map.org/api/examples/examples/sunburst/) to represent the whole-brain distribution of inputs to each cell type (http://sleepcircuits.org/bf/). The brain structures are arranged hierarchically from inner to outer circles, and the size of each sector represents the percentage of input from the corresponding structure. The name of each structure and its input percentage can be read out by pointing the cursor, and each region of interest can be expanded with a mouse click.

When the input distribution was analyzed at a finer spatial scale (e.g., the 6th ring of the sunburst plot), the nucleus accumbens (Mesulam and Mufson, 1984; Zaborszky and Cullinan, 1992), lateral hypothalamus (Cullinan and Zaborszky, 1991; Grove, 1988b; Mesulam and Mufson, 1984), and central nucleus of the amygdala (Grove, 1988b; Pare and Smith, 1994) were among the structures containing the highest numbers of input neurons (Figure 2). Interestingly, many close neighbors of these densely labeled structures (e.g., the basolateral nucleus of the amygdala, immediately adjacent to the central nucleus) showed very sparse or no labeling, indicating high spatial specificity of the long-range inputs. On the other hand, the input distributions were qualitatively similar between cell types, although with quantitative differences. For example, glutamatergic neurons received significantly more inputs from the lateral hypothalamus than the other cell types (P = 0.001, VGLUT2 vs. ChAT; P = 0.001, VGLUT2 vs. PV; P = 0.001, VGLUT2 vs. SOM;, one-way ANOVA and post-hoc Tukey’s test), and PV+ neurons received more inputs from the nucleus accumbens (ACB) (P = 0.004, PV vs. ChAT; P = 0.003, PV vs. VGLUT2; P = 0.001, PV vs. SOM; one-way ANOVA and post-hoc Tukey’s test).

To further verify the inputs revealed by RV-mediated retrograde tracing, we optogenetically tested the synaptic connections from the prefrontal cortex (PFC) and ACB (Figure 4). To verify the innervation from PFC to BF cholinergic neurons, we injected AAV (AAV-DJ-CaMKIIα-hChR2-eYFP) expressing the mammalian codon-optimized channelrhodopsin-2 (hChR2) fused with enhanced yellow fluorescent protein (eYFP) in the orbital and agranular insular areas of the PFC (Figure 4—figure supplement 1) in ChAT-eGFP mice and made whole-cell voltage-clamp recordings from eGFP-labeled cholinergic neurons in acute BF slices (Figure 4A). Activating the ChR2-expressing axon terminals with blue light evoked excitatory responses in all recorded BF cholinergic neurons (n = 9, Figure 4B and C), confirming the input revealed with RV tracing. To confirm the innervation from ACB, we injected Cre-inducible AAV (AAV-DJ-EF1α-FLEX-ChR2-eYFP) expressing ChR2-eYFP in ACB of GAD2-Cre mice, made whole-cell current-clamp recordings from unlabeled postsynaptic BF neurons, and used single cell reverse-transcription PCR (RT-PCR) to identify the cell type. We found that all four BF cell types received inhibitory responses from the ACB (Figure 4D and E; ChAT+: 2 out 5 showed significant responses; VGLUT2+: 2/4; PV+: 3/3; SOM+: 4/8), which is consistent with the finding of an electron microscopic double-immunolabeling study performed in rats (Zaborszky and Cullinan, 1992).

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We next mapped the output of each BF cell type. To label the axonal projections, we injected AAV with Cre-dependent expression of mCherry (Figure 1B) into the BF of ChAT-, VGLUT2-, PV- or SOM-Cre mice. Two to three weeks after injection, the brain tissues were processed, images were registered to the reference atlas, and labeled axons were detected (Figure 1C, see Materials and methods). After the injection site (identified by the existence of labeled cell bodies) and locations with known major fiber tracks were excluded, the projection to each brain area was quantified by the number of pixels occupied by the detected axons (Oh et al., 2014) (see Materials and methods).

Parallel to the broad distribution of inputs (Figure 3), we found that each BF cell type also projected to a large number of brain areas (Figure 5, Figure 6, Video 2, http://sleepcircuits.org/bf/, >95% ipsilateral). Among the 12 major brain subdivisions (Figure 6A), the hypothalamus, pallidum, and striatum received the heaviest BF projections (Grove, 1988a; Henny and Jones, 2006), while very few axons were detected in the medulla or cerebellum (Figure 6A). Analysis at finer scales revealed high spatial specificity of the projections. For example, while several cell types projected strongly to the lateral habenula (Figure 5), few axons were detected in the immediately adjacent but anatomically distinct medial habenula (Hikosaka, 2010). In addition to providing extensive inputs to the BF (Figure 2), the lateral hypothalamus was also a major recipient of BF projections (Figure 5), indicating a strong BF-hypothalamus loop that may be important for brain-state regulation (Brown et al., 2012; Jones, 2011; Saper et al., 2010). Importantly, whereas the input distributions were generally similar across BF cell types (Figure 2, Figure 3), the output patterns showed striking differences. For example, compared to the other cell types, the projection from cholinergic neurons was much stronger in the basolateral amygdala, hippocampus, and visual cortex but much weaker in the lateral hypothalamus, lateral habenula, and the ventral tegmental area (Figure 5). The different projection patterns among cell types are also apparent in the 3D whole-brain view (Figure 6B, Figure 6—source data 1).

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Figure 6

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Figure 6—source data 1

Distribution of axonal projections to 53 brain areas from ChAT+, VGLUT2+, PV+, and SOM+ BF neurons.

Shown are the mean ± s.e.m. of the percentage of projections to each area for individual cell types.

https://doi.org/10.7554/eLife.13214.015

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To further compare the inputs and outputs between cell types, we averaged the spatial distributions across brain samples of each cell type and computed the correlation coefficient (CC) between cell types. For input distribution, the CCs between all cell types were high (Figure 7A), confirming their overall similarity observed earlier (Figure 2, Figure 3). On the other hand, when we computed the CCs between individual brain samples, we found higher CCs between samples of the same cell type (0.81 ± 0.04, s.e.m.) than of different cell types (0.70 ± 0.02, P = 0.01, t-test; Figure 7—figure supplement 1A). This indicates that despite the overall similarity, there were genuine differences between cell types that were beyond experimental variability.

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Figure 7—source data 1

Distribution of BF input and output from 12 major brain subdivisions across cell-type.

Shown are the mean ± s.e.m. of the inputs (A) and outputs (B) for each color-coded brain region, for individual cell types.

https://doi.org/10.7554/eLife.13214.018

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For output distribution, the CCs between individual samples of the same cell type were also high (0.86 ± 0.05; Figure 7—figure supplement 1B), indicating reproducibility of the mapping. However, most of the CCs between cell types (Figure 7B, computed after averaging across samples of the same cell type) were much lower than those for input distribution. The two lowest CCs (ChAT+ vs. VGLUT2+ and PV+ neurons) reflect the fact that while the cholinergic neurons project strongly to structures within the cerebral cortex (including olfactory areas, isocortex, hippocampus, and cortical subplate) and weakly to the brain stem structures (thalamus, hypothalamus, and midbrain), glutamatergic and PV+ neurons (with output distributions highly similar to each other) showed complementary projection patterns (Figure 6).

Finally, we computed the CC between the input and output distributions of each cell type (Figure 7C). The highest CC was found for SOM+ neurons, reflecting their strong reciprocal connections with a number of brain structures, including the hypothalamus, striatum, pallidum, and olfactory areas (Figure 7D, lower right, Figure 7—source data 1. For glutamatergic neurons, the high CC reflects their strong reciprocal connections with the hypothalamus and striatum (Figure 7D, upper right). For cholinergic and PV+ GABAergic neurons, the CCs between input and output distributions were much lower, reflecting the facts that while both cell types receive strong input from the striatum, cholinergic neurons project strongly to the cerebral cortex, and PV+ neurons to the pallidum and hypothalamus (Figure 7D, upper and lower left).

Using virus-mediated circuit mapping, we have characterized the whole-brain distributions of BF long-range connections, available in an open-access online database (http://sleepcircuits.org/bf/). Our experiments confirmed many previously demonstrated connections, but with cell-type specificity and quantitative analyses at multiple spatial scales. For example, we found that cortical inputs (Mesulam and Mufson, 1984; Steriade and McCarley, 2005) to all four BF cell types originate primarily from the agranular insular and orbital areas of the prefrontal cortex (Figure 2). While a previous ultrastructural study failed to detect convincing synaptic contact between prefrontal axons and BF cholinergic neurons (Zaborszky et al., 1997), our RV-mediated transsynaptic tracing demonstrated extensive monosynaptic innervation, which was also validated by electrophysiological recordings (Figure 4B and C). These findings have important implications on how the prefrontal cortex may exert top-down control of neural processing through its projection to the BF (Sarter et al., 2001). A recent study showed that cholinergic neurons in the BF are strongly activated by reinforcement signals during an auditory detection task (Hangya et al., 2015). Our whole-brain mapping of their inputs provides a list of candidate neurons through which the reinforcement signals are conveyed to the BF cholinergic neurons.

Regarding the outputs, we found striking differences across cell types (Figure 6). A recent study has shown that cholinergic, glutamatergic, and PV+ neurons all promote wakefulness, while SOM+ neurons promote sleep (Xu et al., 2015). The distinct projection patterns between cholinergic and glutamatergic/PV+ neurons (Figure 6) suggest that they preferentially regulate different brain functions during wakeful states. In a recent study, optogenetic activation of BF PV+ neurons was shown to enhance cortical gamma band oscillations (Kim et al., 2015). In addition to direct projections to the cortex, our study showed extensive subcortical projections of PV neurons, which may also contribute to the regulation of cortical gamma oscillations. The output distribution of SOM+ neurons, on the other hand, was highly correlated with the input distributions of all BF cell types (Figure 7C, bottom row); the broad GABAergic inhibition of these input areas by SOM+ neurons may be important for the sleep-promoting effect. Thus, while the highly convergent inputs from multiple brain areas allow a variety of sensory, motor, cognitive, and emotional signals to be integrated within the BF, the distinct projections by different cell types may enhance the versatility of the BF in coordinating diverse functions of multiple brain networks.

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Author details

1. Johnny Phong Do

   Division of Neurobiology, Department of Molecular and Cell Biology, Helen Wills Neuroscience Institute, Howard Hughes Medical Institute, University of California, Berkeley, United States

   Contribution

   JPD, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Contributed equally with

   Min Xu and Seung-Hee Lee

   Competing interests

   No competing interests declared.

2. Min Xu

   Division of Neurobiology, Department of Molecular and Cell Biology, Helen Wills Neuroscience Institute, Howard Hughes Medical Institute, University of California, Berkeley, United States

   Contribution

   MX, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Contributed equally with

   Johnny Phong Do and Seung-Hee Lee

   Competing interests

   No competing interests declared.

3. Seung-Hee Lee

   Division of Neurobiology, Department of Molecular and Cell Biology, Helen Wills Neuroscience Institute, Howard Hughes Medical Institute, University of California, Berkeley, United States

   Present address

   Korea Advanced Institute of Science and Technology, Republic of Korea

   Contribution

   S-HL, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Contributed equally with

   Johnny Phong Do and Min Xu

   Competing interests

   No competing interests declared.

   "This ORCID iD identifies the author of this article:" 0000-0002-9486-5771

4. Wei-Cheng Chang

   Division of Neurobiology, Department of Molecular and Cell Biology, Helen Wills Neuroscience Institute, Howard Hughes Medical Institute, University of California, Berkeley, United States

   Contribution

   W-CC, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   No competing interests declared.

5. Siyu Zhang

   Division of Neurobiology, Department of Molecular and Cell Biology, Helen Wills Neuroscience Institute, Howard Hughes Medical Institute, University of California, Berkeley, United States

   Contribution

   SZ, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   No competing interests declared.

6. Shinjae Chung

   Division of Neurobiology, Department of Molecular and Cell Biology, Helen Wills Neuroscience Institute, Howard Hughes Medical Institute, University of California, Berkeley, United States

   Contribution

   SC, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   No competing interests declared.

7. Tyler J Yung

   Division of Neurobiology, Department of Molecular and Cell Biology, Helen Wills Neuroscience Institute, Howard Hughes Medical Institute, University of California, Berkeley, United States

   Contribution

   TJY, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   No competing interests declared.

   "This ORCID iD identifies the author of this article:" 0000-0002-8361-837X

8. Jiang Lan Fan

   Division of Neurobiology, Department of Molecular and Cell Biology, Helen Wills Neuroscience Institute, Howard Hughes Medical Institute, University of California, Berkeley, United States

   Contribution

   JLF, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   No competing interests declared.

9. Kazunari Miyamichi

   Department of Biology, Howard Hughes Medical Institute, Stanford University, Stanford, United States

   Present address

   Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan

   Contribution

   KM, Analysis and interpretation of data, Drafting or revising the article, Contributed unpublished essential data or reagents

   Competing interests

   No competing interests declared.

10. Liqun Luo

    Department of Biology, Howard Hughes Medical Institute, Stanford University, Stanford, United States

    Contribution

    LL, Analysis and interpretation of data, Drafting or revising the article, Contributed unpublished essential data or reagents

    Competing interests

    LL: Reviewing editor, eLife

11. Yang Dan

    Division of Neurobiology, Department of Molecular and Cell Biology, Helen Wills Neuroscience Institute, Howard Hughes Medical Institute, University of California, Berkeley, United States

    Contribution

    YD, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

    For correspondence

    ydan@berkeley.edu

    Competing interests

    No competing interests declared.

    "This ORCID iD identifies the author of this article:" 0000-0002-3818-877X

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