Kölliker–Fuse GABAergic and glutamatergic neurons project to distinct targets

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The Kölliker–Fuse nucleus (KF), part of the parabrachial complex (PB), is a major component of the “pneumotaxic center” or “pontine respiratory group.” Manipulations in this region perturb breathing rhythm. KF neurons can produce a respiratory pattern with prolonged inspiration known as apneusis, which is likely related to inspiratory off‐switching, that is, the inspiratory‐to‐postinspiratory phase transition (Chamberlin & Saper, 1992; Dutschmann & Herbert, 2006; Bonis et al., 2010; Dutschmann & Dick, 2012; Levitt, Abdala, Paton, Bissonnette, & Williams, 2015). The lateral crescent PB subnucleus (PBlc) shares many features with and is likely functionally related to the KF.
Most PB neurons, including those in the KF and PBlc, are glutamatergic and express the type 2 vesicular glutamate transporter, Vglut2 (Niu, Yokota, Tsumori, Qin, & Yasui, 2010; Kaur et al., 2013). Most PB neurons relay ascending sensory information to the forebrain, but KF and PBlc neurons provide descending projections to respiratory and autonomic sites in the lower brainstem and spinal cord (Herbert, Moga, & Saper, 1990; Yokota, Tsumori, Ono, & Yasui, 2001). Virtually all KF neurons with this projection pattern, and all those responsive to hypercapnia, are glutamatergic (Yokota et al., 2004; Yokota, Oka, Tsumori, Nakamura, & Yasui, 2007; Yokota, Kaur, VanderHorst, Saper, & Chamberlin, 2015).
Although most PB neurons are glutamatergic, putative γ‐aminobutyric acid (GABA)ergic neurons (immunoreactive for glutamate decarboxylase) have been reported in rats, primarily in the caudal KF and PBlc (Ford, Holmes, Mainville, & Jones, 1995; Guthmann, Fritschy, Ottersen, Torp, & Herbert, 1998). However, neither their targets nor their anatomical relationship to glutamatergic KF neurons are known. Recently, the expression of a transcription factor, Forkhead box protein 2 (FoxP2), has been detected in some PB neurons, including KF (Gray, 2008; Geerling et al., 2011; Miller et al., 2012) providing an opportunity to revisit PB anatomy with respect to this marker. Across several PB subnuclei, FoxP2‐expressing neurons are thought to be glutamatergic (Miller et al., 2012). We hypothesized that a caudal subset of FoxP2‐expressing neurons are GABAergic, with distinct axonal projections relative to glutamatergic FoxP2 neurons in this region. As an initial step toward exploring the relationship between inhibitory and excitatory KF neurons, we analyzed the locations and genetic expression patterns of glutamic acid decarboxylase 67 (Gad67 [Gad1], Vgat, and Vglut2 in FoxP2‐immunoreactive (‐ir) neurons throughout the PB complex in rats and mice. We then performed cell‐type–specific axonal tracing from glutamatergic versus GABAergic neurons in and around the KF.
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