Distinct regional patterns in noradrenergic innervation of the rat prefrontal cortex
Introduction
Seminal research has produced valuable descriptions of the neuroanatomy and functions of the prefrontal cortex (PFC) of humans, non-human primates and rodents (Carmichael and Price, 1995, 1996; Goldman and Nauta, 1977; Ongur and Price, 2000). In the rat, the PFC can be divided into several areas that include the medial prefrontal cortex (mPFC) and the orbitofrontal cortices (OFC) (Fuster, 2015; Heidbreder and Groenewegen, 2003; Hoover and Vertes, 2011; Laubach et al., 2018; Uylings et al., 2003; Vertes, 2004). These regions are critical actors underlying executive functions, including memory, attention, decision-making and behavioral flexibility (Dalley et al., 2004; Schoenbaum et al., 2009; Uylings et al., 2003). Furthermore, recent studies point to an even greater parcellation, which could depend on the architecture of afferent and efferent patterns of connection along the anteroposterior and mediolateral axes (Bradfield et al., 2018; Izquierdo, 2017; Killcross and Coutureau, 2003; Panayi and Killcross, 2018).
The function of these PFC regions (Arnsten, 2000; Arnsten et al., 1999; Bouret and Sara, 2004; Lammel et al., 2011; Ren et al., 2018; Tronel et al., 2004; Usher et al., 1999) is known to be greatly influenced by the neuromodulatory actions of dopamine, serotonin (5-HT) and noradrenaline (NA) (Beier et al., 2015; Chandler et al., 2013; Hoover and Vertes, 2007; Linley et al., 2013; Murphy and Deutch, 2018). In particular, the PFC receives extensive projections from the locus coeruleus (LC) in the brainstem, which is the major source of NA in the cortex (Berridge and Waterhouse, 2003; but see Robertson et al., 2013). Earlier studies have shown an important and widespread noradrenergic innervation of various cortical regions (Foote et al., 1983; Fuxe et al., 1968; Levitt and Moore, 1978; Lewis and Morrison, 1989; Morrison et al., 1978), which was thought to result from significant branching from single NA axons. This idea has been recently contradicted by data showing that individual LC neurons independently innervate different prefrontal regions (Chandler et al., 2014, 2013; Kebschull et al., 2016; Uematsu et al., 2017). However, the precise organization of NA innervation into the different orbitofrontal and medial regions along their rostro-caudal axis is not well documented.
With this in mind, we performed a detailed analysis of the different prefrontal sub-regions using an automatic quantification method. Our results show that noradrenergic innervation distributes homogeneously into most OFC and mPFC sub-regions. However, we found a specific pattern of innervation along the rostro-caudal axis of the most ventral part of the mPFC and the OFC suggesting a particular route for afferent noradrenergic fibers innervating different prefrontal subregions.
Section snippets
Animals and housing conditions
A total of 11 male Long-Evans rats, aged 2–3 months, were obtained from Centre d’Elevage Janvier (France). Rats were housed in pairs. Environmental enrichment was provided by orange-tinted polycarbonate tubing elements. The facility was maintained at 21 ± 1 °C with lights on from 08:00 to 20:00. The animals of this study previously served as a control group in unpublished study and had received an intra-cerebral injection of an inactive form of saporin. As in our previous papers (see e.g.
Results
Fig. 1 shows the location of the various regions of interest on sections of the PFC at different coordinates (AP + from Bregma). We used these coordinates to examine the distribution of DBH fibers along the rostro-caudal axis for each structure of interest.
Our automated method also provided the distribution of varicosities for each region of interest.
Fig. 2 shows a representative case illustrating both treatments applied to original images (Fig. 2A). The method identifies DBH fibers (Fig. 2B),
Discussion
Using detection of DBH-immunoreactive fibers, the present study shows a distinctive pattern of NA innervation of the rat PFC. DBH fibers volume occupancy was relatively uniform when compared between prefrontal regions at the same level of the rostro-caudal axis. However, when examining each area along the rostro-caudal axis, we found a specific gradient of innervation for both VO and A25 (infralimbic cortex). Moreover, the ratio of varicosities to fibers decreased caudally in both VO and LO
Ethical statement
The experiments were conducted in agreement with French (council directive 2013-118, February 1, 2013) and international (directive 2010-63, September 22, 2010, European Community) legislations and received approval # 5012053-A from the local Ethics Committee.
Funding
This work was supported by the French National Research Agency (grant number ANR-14-CE13-0014 GOAL to E.C); and by the Fondation pour la Recherche Médicale (FRM grant number ECO20160736024 to J-C.C).
Conflict of interest
The authors declare no competing interests.
Acknowledgements
The microscopy was completed at the Bordeaux Imaging Center, a service unit of CNRS-INSERM and Bordeaux University and member of the national infrastructure, France BioImaging. We thank Y. Salafranque for the care provided to the rats during experiments. The authors wish also to thank Drs Shauna Parkes and Mathieu Wolff for their useful comments on an earlier version of this manuscript.
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A.M. and E.C. contributed equally to this work.