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. Author manuscript; available in PMC: 2018 May 1.
Published in final edited form as: Brain Struct Funct. 2016 Oct 4;222(4):1971–1988. doi: 10.1007/s00429-016-1321-y

Abundant collateralization of temporal lobe projections to the accumbens, bed nucleus of stria terminalis, central amygdala and lateral septum

Rhett A Reichard 1, Suriya Subramanian 1, Mikiyas T Desta 1, Tej Sura 1, Mary L Becker 1, Comeron W Ghobadi 1, Kenneth P Parsley 1, Daniel S Zahm 1,*
PMCID: PMC5378696  NIHMSID: NIHMS821020  PMID: 27704219

Abstract

Behavioral flexibility is subserved in part by outputs from the cerebral cortex to telencephalic subcortical structures. In our earlier evaluation of the organization of the cortical-subcortical output system (J. Neurosci. 25:11757-67, 2005), retrograde double-labeling was evaluated in the prefrontal cortex following tracer injections into pairs of the following subcortical telencepahlic structures: caudate-putamen, core and shell of the accumbens (Acb), bed nucleus of stria terminalis (BST) and central nucleus of the amygdala (CeA). The present study was done to assess patterns of retrograde labeling in the temporal lobe after similar paired tracer injections into most of the same telencephalic structures plus the lateral septum (LS). In contrast to the modest double-labeling observed in the prefrontal cortex in the previous study, up to 60-80% of neurons in the basal and accessory basal amygdaloid nuclei and amygdalopiriform transition area exhibited double-labeling in the present study. The most abundant double-labeling was generated by paired injections into structures affiliated with the extended amygdala, including the CeA, BST and Acb shell. Injections pairing the Acb core with the BST or CeA produced significantly fewer double-labeled neurons. The ventral subiculum exhibited modest amounts of double-labeling associated with paired injections into the Acb, BST, CeA and LS. The results raise the issue of how an extraordinarily collateralized output from the temporal lobe may contribute to behavioral flexibility.

Keywords: dopamine, motivation, emotion, locomotion, motor, movement

The adaptive success of mammalian foragers and predators, mainly in the primate, carnivore and rodent orders, owes in large part to their deft ability to modify behavior in relation to changing contingencies (Aquili et al., 2014, Hamilton and Brigman, 2015). This capacity, behavioral flexibility, is subserved by the interconnections of the telencephalon with structures in the hypothalamus, brainstem and spinal cord (Ferrier, 1876/1966; Cannon and Britton, 1927; Bard, 1928; Bard and Macht, 1958; Harris, 1958; Woods, 1964; MacLean, 1989; Napier et al., 1991; Kalivas and Barnes, 1993; Holstege et al., 1996; 2004) and important additional intra-telencephalic cortico-subcortical connectional relationships (e.g., Alheid and Heimer, 1988; Holstege, 1991; 1992; Saper, 1996; McGinty, 1999; Swanson, 2000; 2003; Alheid 2003; Heimer, 2003). Heimer and colleagues (Alheid and Heimer, 1988; Heimer and Alheid, 1991; Heimer et al., 1991; Heimer et al., 1997b) emphasized cortical outputs to a collection of basal forebrain functional-anatomical “macrosystems”, including dorsal and ventral striatopallidum (Heimer, 1972; Heimer and Wilson, 1975), extended amygdala (Alheid and Heimer, 1988; Martin et al., 1991; Cassell, 1998; Swanson and Petrovich, 1998; Cassell et al., 1999; McDonald, 2003; Oler et al., 2016) and the lateral septal-preoptic system (Alheid and Heimer, 1988; McDonald, 1991b; Jakab and Leranth, 1995; Risold and Swanson, 1997a;b; Swanson, 2000; Heimer and Van Hoesen, 2006; Zahm, 2006; 2008a). Macrosystems share a common basic cortico-striato-pallidal framework reflected in similar neuronal types and connections, but also distinct chemical neuroanatomical differentiations, kinds of interneurons and patterns of local connectivity (e.g., Alheid and Heimer, 1988; Zahm et al., 2003), such that what one (or a sector of one) macrosystem imparts to the overall cortical-subcortical interaction may in some ways be similar and in others distinct from what is imparted to the interaction by other macrosystems.

Cortical and basal amygdaloid (BA)1 outputs to the subcortical telencephalon have a complex organization, projecting to striatum and other medium spiny neuron-enriched structures (which variously are also regarded as striatum), such as the lateral septum (LS), bed nucleus of stria terminalis (BST) and central nucleus of the amygdala (CeA), both with strict topography and extra-topographically, i.e., to sites outside the predicted topography (Yeterian and Van Hoesen, 1978; McGeorge and Faull, 1989; Berendse et al., 1992; Brog et al., 1993; McIntyre et al., 1996; Reynolds and Zahm, 2005). Of particular interest is a ‘triadic’ organization in which strongly interconnected sites in the cortex and BA project convergently to the same subcortical locus (Yeterian and Van Hoesen, 1978; Groenewegen et al., 1990; 1997; McDonald et al., 1991b). Conversely, cortical and BA sites may also project to more than one macrosystem (McDonald et al., 1991b; 1996; 1999; Shammah-Lagnado and Santiago, 1999; Shi and Cassell, 1998a; McDonald, 1998; Zahm, 1998; 2000; 2006; 2008a;b; Reynolds and Zahm, 2005). The overlap of these different patterns of organization fosters a couple possibilities. Divergent outputs from a particular cortical network representing some aspect of an organism's ongoing circumstances could be subject to subcortical processing executed by more than one macrosystem (Zahm, 2006; 2008a;b). Alternately, different macrosystems might receive outputs from interdigitating but distinct subpopulations of neurons representing functionally or anatomically defined cortical networks (e.g., Mesulam, 1990; Carmichael and Price, 1995; 1996; Öngür and Price, 2000; Jones et al., 2005). In an earlier paper, Reynolds and Zahm (2005) speculated that a “divergence” model of cortico-macrosystem projections predicts greater likelihood that individual cortical output neurons project to more than one macrosystem, and, accordingly, they made ipsilateral pairs of injections using two different retrograde tracers, either into extended amygdala (EA) and dorsal or ventral striatum (heterotypic pairs), or into different parts of the same macrosystem (homotypic pairs). They reported that homotypic injection pairs produced extensive overlap of retrogradely labeled neurons in the medial prefrontal (mPfC) and insular (IC) cortex, and modest double-labeling, suggesting that distinct cortical projections spread broadly within single macrosystems. Heterotypic injection pairs also produced substantially overlapping distributions of retrograde labeling in the mPfC and IC, but little double-labeling, suggesting that different macrosystems get inputs mainly from separate subpopulations of cortical neurons, possibly representing separate networks. The data suggested that the distinct identities of striatopallidum and extended amygdala reflect a corresponding segregation of cortical output networks.

Insofar as Reynolds and Zahm (2005) evaluated only mPfC and IC, however, nothing is known regarding collateralization of temporal lobe projections to intra-telencephalic subcortical structures. The possibility of such collateralization was strengthened by the observations of McDonald and others, who showed that the BA, accessory basal amygdaloid nucleus (ABA), amygdalohippocampal transition area (AHip) and amygdalopiriform transition area (APir) all project robustly to the Acb, BST and CeA (McDonald, 1991b; McDonald et al., 1999; Shammah-Lagnado and Santiago, 1999; Santiago and Shammah-Lagnado, 2005). Here, we reveal that outputs to basal forebrain macrosystems from the subiculum, amygdala and some additional temporal lobe cortical areas exhibit exuberant homotypic and modest heterotypic collateralization.

Materials and Methods

Animals

All experiments were carried out in accordance with guidelines published in the National Institutes of Health Guide for the Care and Use of Laboratory Animals and were approved by the animal care committee of Saint Louis University. Male Sprague Dawley rats (Harlan, Indianapolis, IN) were housed under a 12-hour light-dark cycle in groups of 4 – 6 until the tracers were injected, after which they were housed individually. Food and water were provided ad libitum.

Chemicals and reagents

Unless otherwise specified, all were from Sigma Chemical Co., St. Louis, MO.

Injections

Fifty-three male Sprague Dawley rats (Harlan, Indianapolis, IN) weighing between 240 and 320g were deeply anesthetized by intraperitoneal injections of a mixture of ketamine (72 mg/kg) and xylazine (11.2 mg/kg), administered as a cocktail consisting of 45% ketamine (100 mg/ml), 35% xylazine (20 mg/ml) and 20% physiological saline at a dose of 0.16 ml/100g of body weight. The anesthetized rats were subjected to intracranial stereotaxic injections of the retrograde axonal tracers, Fluoro-Gold (FG, Fluorochrome, LLC., Denver, CO) and cholera toxin subunit β (Ctβ, List Biological Laboratories, Inc., Campbell, CA), both dissolved at a concentration of 1%, in 0.067 M cacodylate buffer (FG) and 0.01 M sodium phosphate buffer (SPB), respectively. The tracers were delivered by iontophoresis with positive pulses (7 s on and 7 s off for 15 min) at 1 (FG) and 3 (Ctβ) μA through 1.0 mm pipettes pulled to tip diameters of 15-20 μm. Ipsilateral pairs of basal forebrain structures (Table 1) were injected such that one of the counterparts received FG and the other Ctβ. For each pair, which members of an injection site pair received FG and Ctβ was alternated in successive cases.

Table 1.

List of the cases, injection site pairs and injected tracers evaluated in the present study.

case Inj 1 -Tracer/Site Inj 2 -Tracer/Site
AcbS&BST 09062* Ctβ/AcbS FG/BST
09065* Ctβ/AcbS FG/BST
09066 FG/AcbS Ctβ/BST
15236 Ctβ/AcbS FG/BST
15237 Ctβ/AcbS FG/BST
15238 FG/Acb Ctβ/BST
15239 FG/Acb Ctβ/BST
AcbS&CeA 15240 FG/AcbS Ctβ/CeA
16118 FG/AcbS Ctβ/CeA
16119 FG/AcbS Ctβ/CeA
16120 FG/AcbS Ctβ/CeA
AcbC&BST 15155 FG/AcbC Ctβ/BST
15195 FG/AcbC Ctβ/BST
15196 FG/AcbC Ctβ/BST
15197 Ctβ/AcbC FG/BST
AcbC&CeA 15104 FG/AcbC Ctβ/CeA
15105 FG/AcbC Ctβ/CeA
BST&CEA 15151 FG/BST Ctβ/CeA
15152 FG/BST Ctβ/CeA
16090 Ctβ/BST FG/CeA
16115 FG/BST Ctβ/CeA
LS&Acb 09011* Ctβ/LS FG/AcbS
09019* FG/LS Ctβ/AcbS
09028* FG/LS Ctβ/AcbS
09056* FG/LS Ctβ/AcbS
LS&BST 10021* FG/LS Ctβ/BST
10024* Ctβ/LS FG/BST
10025* FG/LS CtβBST
10027* FG/LS Ctβ/BST
LS&CeA 10008* Ctβ/LS FG/CeA
16015 FG/LS Ctβ/CeA
16016 FG/LS Ctβ/CeA
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*

Ventral subiculum only

Abbreviations: AcbC - accumbens core; AcbS - accumbens shell; BST - bed nucleus of the stria terminalis; CeA - central nucleus of the amygdala; Ctβ - cholera toxin β subunit tracer; FG - Fluorogold tracer; l - lateral division; LS - lateral septum; m - medial division.

Three to five days after surgery, rats were re-anesthetized and killed by vascular perfusion, first with a brief rinse with sodium phosphate (0.01 M) buffered saline containing 0.5% procaine HCl and 2.5% sucrose, followed for 20 minutes with 0.1 M Sorenson's phosphate buffer (SPB, pH 7.4) containing 4% paraformaldehyde and 2.5% sucrose. The brains were immediately removed, stored overnight in fresh fixative, and then transferred to vials containing a solution of 25% sucrose in SPB until they sank to the bottom. Five adjacent series of 50 μm frozen sections were cut in the coronal plane with a sliding microtome and stored at -20°C in 0.1 M SPB containing 30% ethylene glycol and 30% sucrose.

Immunoperoxidase processing

Sections were retrieved from the freezer, rinsed in SPB, immersed for 15 min in an aqueous solution containing 1% sodium borohydride and then rinsed repeatedly in SPB. The sections then were immersed overnight at room temperature with gentle agitation in 0.1 M SPB containing 0.2% triton X-100 (SPB-triton) and a 1:5000 dilution of rabbit anti-FG antibody (Chemicon, Temecula, CA), after which they were rinsed in SPB-triton and immersed for 1 hr in SPB-triton containing a 1:200 dilution of biotinylated donkey anti-rabbit IgG (Jackson ImmunoResearch Labs, Inc., West Grove, PA). Another series of rinses preceded immersion of the sections for 1 hr in SPB-triton containing a 1:200 dilution of avidin-biotin-peroxidase complex (ABC; Vector Laboratories, Burlingame, CA), after which the sections were rinsed in SPB (no triton) and then reacted for 10 min in a solution containing 0.015% diaminonbenzidine (DAB), 0.4% nickel ammonium sulfate, and 0.006% H2O2 in 0.025 M Tris-HCl buffer (pH 8.0). The sections were rinsed and then immersed overnight with agitation in SPB-triton containing a 1:5000 dilution of goat anti-Ctβ antibody (List). Following more rinses, the sections were exposed for 1 hr in SPB-triton with intervening rinses to a 1:100 dilution of donkey anti-goat IgG (Jackson) and a 1:3000 dilution of goat peroxidase-antiperoxidase (Cappel, ICN Biomedicals, Irvine, CA) or a 1:200 dilution of biotinylated donkey anti-goat followed by ABC at 1:200. After rinsing in SPB without triton, the sections then were placed for 30 minutes in 0.05 M SPB (pH 7.4) containing 0.05% DAB, and 0.006% H2O2 in 0.01 M phosphate buffer (pH 7.4) and thereafter rinsed again in SPB. The sections were then mounted in rostrocaudal sequence on glass slides, air dried and coverslipped under Permount (Fisher Chemical Co., St. Louis, MO).

Immunofluorescence processing

Series of sections were immersed in succession at room temperature, with gentle agitation and intervening rinses in SPB-triton containing: [1] a 1:8000 dilution of anti-FG antibody overnight, [2] a 1:200 dilution of biotinylated donkey anti-rabbit IgG for 1 hr, [3] a 1:200 dilution of avidin-Texas Red (Jackson, excitation: 596 nm; emission: 620 nm) or DyLight 594 (Jackson, excitation: 593 nm emission: 618 nm) conjugated to anti-rabbit IGg made in donkey for 1 hr, [4] a 1:5000 dilution of goat anti-Ctβ antibody overnight, and [5] a 1:100 dilution of donkey anti-goat-Cy2 conjugate (Jackson; excitation: 492 nm; emission: 510 nm) or DyLight 488 (Jackson, excitation: 493 nm, emission: 519 nm) conjugated to donkey anti-goat IGg made in donkey for 1 hr. Some series of sections were reacted such that the anti-FG antibody was followed directly by an anti-rabbit IgG-CY2 (or DyLight 488) conjugate used at a dilution of 1:100 and anti-Ctβ was labeled with biotinylated anti-goat from donkey followed by avidin-TR (or DyLight 594) used at a dilution of 1:200. Then the sections were rinsed thoroughly in SPB, mounted on glass slides and coverslipped with DPX (Fluka, Sigma-Aldrich, Steinhem, Germany) or ProLong Gold antifade reagent (Invitrogen).

Microscopy

The sections were visualized with a Nikon Eclipse E600 microscope equipped for bright field and fluorescence microscopy. Immunofluorescence images were generated with a dual-band fluorescence filter set (Chroma Technology Corp, Brattleboro, VT) with excitation bands at 480-505 and 560-590 nm, and emission bands at 505-545 and 600-650 nm, for green (Cy2, DyLight 488) and red (Texas Red, DyLight 594) fluorescence, respectively.

Injection Sites

Tracings of immunoperoxidase-reacted injection sites were referenced against archived sections immunoreacted with antibodies against substance P, glutamate decarboxylase and nitric oxide synthase, as described in several previous papers (e.g., Jhou et al., 2009; Zahm et al., 2014; Yetnikoff et al., 2014a;b; 2015).

Analysis of retrograde labeling

Of 53 cases prepared in the present study, 32 (Table 1) were used to acquire data as follows. Retrogradely labeled neurons exhibiting Cy2 (or DyLight 488), Texas Red (or DyLight 594) and both fluorophores, i.e., double-labeled neurons, were visualized. In order to circumvent the problem of fading of immunofluorescence due to prolonged illumination, digital images were captured using the 20× objective and assembled into montages encompassing the area of each section containing retrogradely labeled neurons. The photomicrographic maps were then superimposed on outlines of sections traced with the aid of Neurolucida software (Microbrightfield, Inc., Williston, VT) and the labeled neurons were plotted. Evaluated sections from each of generally three or four, but at least two, cases for each injection pair were analyzed. Single and double-labeled neurons were tabulated with the aid of NeuroExplorer software (Microbrightfield). A criterion was set that a structure should contain at least 30 retrogradely labeled neurons from each injection in order for double-labeling data to be accepted. For illustratration of red and green fluorescence microscopic images in micrographs, red was converted to magenta with the aid of Photoshop software.

Immunofluorescence controls

In order to confirm the fidelity of yellow fluorescence generated by the dual-band filter as an indicator of double-labeling, samples of images acquired with it were compared with merged digital images generated using single-band filter blocks. This was done both with the Nikon E600 microscope and a Bio-Rad MRC 1024 confocal microscope. Images were merged using Image J software (National Institutes of Health). In illustrations, red was replaced with magenta in the immunofluorescence images with the aid of Adobe Photoshop softaware and in confocal images with the aid of Image J software.

Statistics

Data from the amygdala and adjacent temporal lobe cortex were organized by brain site and injection pairs and tested using a repeated measures ANOVA. A one-way ANOVA was used to distinguish double-labeling produced in the ventral subiculum by different injection pairs. Fisher's LSD post hoc test was used.

Results

Injection sites

FG and Ctβ injected into the Acb, CeA and LS produced injection sites about 0.5 - 0.8 mm in diameter comprising varyingly dense immunoperoxidase reaction product, with a denser core (Figs. 1A and B; 2I, insets; 3A and B; 5A and B), which was typically smaller for Ctβ than FG injections (Figs. 1B, 3B and 5A). Injections into the BST tended to conform to the pyramidal shape that structure typically displays in frontal sections (Fig 1B and 3A). Numerous FG and Ctβ injections involved the Acb core or shell to the relative exclusion of the other (Figs. 1A and 5A). Others that involved both Acb subterritories equivalently or nearly so were not mapped or further included in the analysis. Small injections centered in the medial or lateral divisions of the BST and CEA also were obtained but the spread of tracer from injections of normal size tended more in the BST and CeA than in the Acb to involve more than one subdivision of the structure (Figs. 1B and 3B). Thus, we did not specify whether injections preferentially involved the medial and lateral divisions of the BST and CEA.

Figure 1.

Figure 1

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Photomicrographs of case 15238 showing sections of rat forebrain cut in the frontal plane. A shows an FG injection into the AcbS, which is demarcated by the broken line. B is a Ctβ injection into the BST. C-H are photomicrographs of immunoperoxidase (C and D) and immunofluorescence (E-H) labeling of neurons. C shows the boxed area in its inset, which gives an overview of retrograde labeling produced in the medial temporal lobe by these injections. The box in C is enlarged in D. Black and brown immunoperoxidase labeling can be distinguished but it was generally uncertain with immunoperoxidase whether neurons were double-labeled. E shows immunofluorescence labeling. Ctβ-, FG- and double-labeled neurons are magenta; green and yellow-orange, respectively. F-H show laser scanning confocal images of single and double-labeling (white in H). Abbreviations: ABA - accessory basal nucleus of the amygdala; AcbS - accumbens shell; APir - amygdalopiriform transition area; BA -basal nucleus of the amygdala; BSTl and m – medial and lateral divisions of the bed nucleus of the stria terminalis; CeAm and l - medial and lateral divisions of the central nucleus of the amygdala; Ctβ - cholera toxin β subunit; FG - Fluorogold; ot - optic tract. Scale bar: A and B - 1 mm; C - 100μm; D-H – 50 μm.

Figure 2.

Figure 2

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Further illustration of case 15238. Neurons labeled by injection of FG into the AcbS (green dots) and Ctβ into the BST (magenta dots) and double-labeled neurons (yellow) were mapped in frontal sections of the temporal lobe of ordered in rostrocaudal sequence (A to H). Insets in A-H are provided for orientation. Note densely clustered double-labeled neurons in panels B and D-G. I is a photomicrograph showing green (Acb injection), magenta (BST injection) and yellow (double) labeling of neurons diagrammed in the box in panel F. Insets in I show the immunofluorescence images of the injection site in the Acb (above) and BST. The immunoperoxidse renderings of the injections are shown in Figs. 1A and B, respectively. Abbreviations: ABA - accessory basal nucleus of the amygdala; AHip - amygdalohippocampal transition area; APir -amygdalopiriform transition area; BA - basal nucleus of the amygdala BSTl - bed nucleus of stria terminalis, lateral division; CAa, CApl, CApm - anterior, posterolateral and posteromedial divisions of the cortical nucleus of the amygdala; CeAl - central nucleus of amygdala, lateral division; LA - lateral nucleus of the amygdala; vSub - ventral subiculum. Scale bar: 100 µm

Figure 3.

Figure 3

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Sites of tracer injections of FG into the BST (A) and Ctβ into the CeA (B) and distributions of neurons labeled by BST (green dots) and CeA (magenta dots) injections. Double-labeled neurons are shown in (yellow). The case (16115) is mapped in the temporal lobe in frontal sections ordered in rostrocaudal sequence from C to J. Insets in C-J are provided for orientation. Note densely clustered double-labeled neurons in panels D and E and H-J. Abbreviations: ABA - accessory basal nucleus of the amygdala; AHip - amygdalohippocampal transition area; APir - amygdalopiriform transition area; BA - basal nucleus of the amygdala BSTl - bed nucleus of stria terminalis, lateral division; CAa, CApl, CApm - anterior, posterolateral and posteromedial divisions of the cortical nucleus of the amygdala; CeAl - central nucleus of amygdala, lateral division; LA - lateral nucleus of the amygdala; vSub - ventral subiculum. Scale bar: 1 mm in A and B

Figure 5.

Figure 5

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Photomicrographs showing injection sites in the AcbS (A) and LS (B) and a laser scanning confocal microscopic image of the resulting retrograde labeling in the vSub, shown as green and magenta, respectively. White indicates double-labeling. Abbreviations: ac – anterior commissure; AcbC – accumbens core; AcbS – accumbens shell; CPu – caudate-putamen; LS – lateral septum; MS – medial septum. Scale bar: A and B - I mm; C - 40 μm.

Retrograde labeling

Perikarya, except where occupied by the nucleus, and proximal dendrites were filled with densely packed FG- or Ctβ-immunoreactive granules and diffuse immunoreactivity (Fig. 1C-H). Exposure of FG and Ctβ immunoreacted sections first to DAB in the presence of nickel and then to DAB alone generated, respectively, black and brown reaction product (Fig. 1C and D), of which both are permanent and distinguishable in bright field optics, allowing both the injection sites and retrograde labeling patterns to be evaluated, mapped and archived. However, because double-labeling is shown inadequately in immunoperoxidase material, additional sections were processed for immunofluorescence, which showed single labeled neurons as brilliant red or green and double-labeled neurons in bright yellows and oranges (Fig. 1E). Laser scanning confocal images from the same case (15238) and brain area (BA) confirmed the fidelity of immunofluorescence labeling (Fig. 1F-H).

Double-labeling in the amygdala, AHip and APir

Representative cases illustrating the distribution of labeled neurons in the amygdala, AHip and APir are illustrated in Figures 2 and 3 and quantitation of all of the cases is graphed in Figure 4. Labeling in case 15238, also illustrated in Figure 1, is mapped and further illustrated in Figure 2. Abundant labeling, including double-labeling was observed in the amygdala, AHip and APir following injections of tracers into AcbS&BST (Fig. 2), AcbS&CeA, and CeA&BST (Fig. 3) injection pairs. Very dense double-labeling stretching from rostral parts of the amygdala into caudal APir (e.g., Fig. 2B, 2D-G and 2I and Fig. 3D-E and H-J) was separated by intervals with lesser double-labeling (Figs. 2C and 3F and G). Dense clusters of double-labeled neurons centered in the BA (Fig. 2D), ABA (Figs. 2E and 3F and C) and APir (Figs. 2F-G and 3H-J) spread at their peripheries into adjacent structures such as the LA (Fig. 3F and G) and cortical amygdaloid nuclei (Figs 2F and G and 3A-H). In contrast, AcbC&CeA and AcbC&BST pairs produced only modest double-labeling in all structures (Fig. 4A [blue symbols] and C [blue text]).

Figure 4.

Figure 4

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Scatterplots showing double-labeled neurons expressed as raw numbers (A and C) and percent total of labeled neurons (B and D) and organized by brain structure (A and B) and injection pair (B and D). Symbols reflect averaged data from 2-4 cases as indicated in Table 1. Arrows indicate means of the means. In A and B green and blue symbols indicate homotypic and heterotypic injection pairs, respectively, and magenta symbols indicate pairs that include the caudomedial AcbS. In C and D green and blue text indicates homotypic and heterotypic injection pairs, respectively, and magenta text indicates pairs that include the caudomedial AcbS. Data were tested by repeated measure ANOVA. Brackets indicate differences revealed using the Fishers LSD post hoc test. Missing values reflect trials in which a minimum of 30 retrogradely labeled neurons for each tracer was not reached, which affected mainly the LA. Abbreviations: ABA – accessory basal amygdaloid nucleus; AHip – amygdalohippocampal transition area; APir – amygdalopiriform transition area; BA – basal amygdaloid nucleus; LA – lateral amygdaloid nucleus; vSub – ventral subiculum.

Insofar as the raw numbers of double-labeled neurons correlated strongly with the density of retrograde labeling, the tendency for neurons to be double-labeled was assessed by expressing double-labeling as percent of total retrograde labeling. Markedly less retrograde labeling by FG as compared to Ctβ (Table 2) required that this be calculated using the formula % double-labeling = double-labeled/(FG-labeled + double-labeled) × 100, which exploits the maximal double-labeling of collateralized, FG-labeled neurons by efficacious uptake and transport of Ctβ. Expressed as percent of total, double-labeling was relatively uniform across the APir, ABA, BA, AHip and differed significantly (Fig. 4B; F5,15=6.044, p =0.003) only between APir and LA (p=0.005). Percent double-labeling for injection pairs that included the AcbC was significantly less than for pairs that did not include the AcbC (Fig. 4B [blue symbols] and D [blue text]).

Table 2.

Numbers of retrogradely labeled neurons in evaluated structures following injections of Ctβ and FG into the accumbens shell (AcbS) and core (AcbC), bed nucleus of stria terminalis (BST) and central nucleus of the amygdala (CeA).

Ctβ FG
vSub LA BA ABA AHip APir Sum vSub LA BA ABA AHip APir Sum %
AcbS 1672 40 594 452 310 874 4255 774 11 204 201 71 372 1499 35.2
AcbC 2228 73 399 57 162 540 3459 510 51 310 92 245 88 1296 37.5
BST 800 131 919 751 743 2280 5676 406 40 313 471 272 742 2130 37.5
CeA 364 147 646 1553 270 1753 7394 100 8 304 310 36 863 1621 36.9
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Each value is the mean of the following numbers of cases: AcbS/Ctβ - 7 (vSub), 2 (others); AcbS/FG - 8 (vSub), 6 (others); AcbC/Ctβ - 1; AcbC/FG - 5; BST/Ctβ - 9 (vSub), 6 (others); BST/FG - 8 (vSub), 6 (others); CeA/Ctβ - 12 (vSub), 9 (others); CeA/FG - 1. Sum is the sum of all structures for each Ctβ and FG injection site (AcbS, AcbC, BST, CeA). % = sum (FG)/sum (Ctβ)×100. Additional abbreviations: ABA - accessory basal amygdaloid nucleus; AHip - amygdalohippocampal transition area; APir - amygdalopiriform transition area; BA - basal amygdaloid nucleus, LA - lateral amygdaloid nucleus; vSub - ventral subiculum.

Double-labeling in vSub

Moderate numbers of double-labeled neurons were observed in vSub following injections of tracers into AcbS&BST, AcbS&CeA, AcbC&BST and AcbC&CeA pairs (Figs. 2F-H; 3H-J, 4A and C and 5). As total numbers of double-labeled neurons (Fig. 4A) these values were exceeded only by those in APir (p=0.026), whereas, expressed as percent of retrograde labeling (Fig. 4B), double-labeling in vSub was significantly less than APir (p<0.001), ABA (p=0.014) and AHip (p=0.035). Injection pairs that included the AcbC produced the least double-labeling in vSub whether measured as raw numbers (Fig. 4C [blue text]) or percent total (Fig. 4D [blue text])

Double-labeling in vSub resulting from injections of tracers into pairs of sites of which one was the LS is reported in Table 3. In this regard it is important that fewer vSub neurons project to BST and CeA than to LS (Table 3B and C) and Acb (Table 3A and C), so even if all vSub projections to the BST or CeA were collaterals of Acb or LS-projecting neurons, they would comprise only a small percentage of Acb- or LS-projecting neurons. Consequently, double-labeling as percent total calculated from numbers of LS-projecting vSub neurons was low (Table 3, 2nd to last column, sections B and C), whereas double-labeling calculated as percent of total from numbers of BST- and CeA-projecting vSub neurons gave values in the 20-25% range (Table 3, last column, sections B and C). LS&AcbS pairs gave slightly greater values of 16-35% for double-labeling calculated as percent of total (Table 3, last column, section A)

Table 3.

Double labeling in the ventral subiculum from paired injections into the lateral septum (LS) and the accumbens shell (AcbS), bed nucleus of stria terminalis (BST) or central nucleus of the amygdala (CeA).

Injection pair case number of sections number of single labeled, Inj 1 (LS) number of single labeled, Inj 2 (AcbS, BST, CeA) number double-labeled double as percent total, Inj 1 double as percent total, Inj 2
A.
LS&AcbS 09011 3 589 581 308 34.3 34.6
LS&AcbS 09019 8 2474 1551 556 18.3 26.4
LS&AcbS 09028 8 1236 2383 491 28.4 17.1
LS&AcbS 09056 6 1480 520 103 6.5 22±6* # † 16.5 24±4**
B.
LS&BST 10021 5 1986 435 141 6.6 24.5
LS&BST 10024 6 3536 678 136 3.7 16.7
LS&BST 10025 5 2047 1266 205 9.1 13.9
LS&BST 10027 7 2796 421 156 5.3 6±1## 27.0 20±3
C.
LS&CeA 10008 6 864 222 39 4.3 14.9
LS&CeA 16015 5 584 353 40 6.4 10.2
LS&CeA 16016 2 380 107 25 6.2 6±1### 18.9 15±3
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Computed values, last 2 columns, are means±SEM

*

(F2,8=5.580, p=0.030), group A vs B - p=0.019, A vs C - p=0.023, group B vs C - NS, one way ANOVA

**

(F2,8=1.481, p=0.284) groups A vs B vs C - NS, one way ANOVA

#

vs last column, group A - NS, t test

##

vs last column, group B - p=0.005, t test

###

vs last column, group C - p=0.026, t test

†

(F3,11=0.664, p=0.591) 2nd last column, group A vs last column, group B vs last column, group C - NS, one way ANOVA

Additional abbreviations: NS - not significant.

Double-labeling in mPfC and IC

We did not repeat with the new cases the entire analysis of PfC and IC done our earlier paper (Reynolds and Zahm, 2005), but we did evaluate the mPfC and IC in several cases (15104, 15105, 15151 and 15152), observing double-labeling expressed as percent of total ranging between 4.9% and 13%, which is consistent with the relatively low values previously reported.

Discussion

Prominent retrograde double-labeling of temporal lobe neurons was observed in the present study following paired injections of different retrograde tracers into combinations of AcbS, AcbC, BST, CeA and LS. Double-labeling of up to 60-80% of retrogradely labeled neurons occupied the BA, ABA and APir following injections into the AcbS, BST and CeA, whereas injections pairing the AcbC with the BST or CeA produced not only significantly fewer double-labeled neurons, but also less double-labeling expressed as percent of total. Alternatively, nominally heterotypic AcbS&CeA and AcbS&BST injection pairs produced very abundant double-labeling in amygdaloid structures and APir. The caudomedial AcbS, which is the part of the Acb injected in this study, has long been regarded as a transitional structure combining features of striatopallidum and extended amygdala (Alheid and Heimer, 1988; Heimer et al., 1997a;b; Koob et al., 1998; Zahm, 1998), so the high proportion of double-labeled amygdaloid and APir neurons produced by injections that paired the AcbS with the CeA or BST is consistent, and, indeed, further supports affiliation of the caudomedial AcbS with extended amygdala. Apropos the high level of double-labeling in the temporal lobe following tracer injections in basal forebrain nuclei, Calderazzo et al. (1996) reported that neurons in the basal amygdaloid nucleus project to both the septum and entorhinal cortex and McDonald (1991a) demonstrated abundant collateralization of basal amygdaloid projections to ventral striatopallidum and prefrontal cortex. Thus, the branching of axonal projections from the basal amygdala is even more widespread than shown here.

Neurons projecting from vSub to distinct output targets were reported by Naber and Witter (1998) to be segregated and relatively uncollateralized, but also, by others, to be overlapping and moderately collateralized. That is, 30% of subicular neurons may project to the ventromedial nucleus of the hypothalamus and entorhinal cortex (Donovan and Wyss, 1983) and 30% (Swanson et al., 1981) or 50% (Calderazzo et al., 1996) of those projecting to the lateral septum may also project to the entorhinal cortex. Our results are consistent with moderate collateralization of vSub outputs and raise an interesting question as to whether vSub or amygdaloid neurons might project via axon collaterals both to macrosystem input structures and medial hypothalamus or entorhinal cortex.

Methodological considerations

Whereas standard measures taken in the present study to minimize uptake of tracers by fibers of passage - injecting by iontophoresis with small tip diameters and low ejection currents (Brog et al., 1993) – do not entirely exclude the possibility of fiber-of-passage artifact, it is unlikely that fibers-of-passage caused the abundant double-labeling we observed. The present injections into the BST may have inadvertently involved some stria terminalis or ventral amygdalofugal fibers enroute to the Acb, but it is difficult to conceive that the abundant double-labeling associated with CeA&BST and CeA&Acb injection pairs is attributable to fibers-of-passage, inasmuch as these structures lie at opposite ends of these pathways. Furthermore, all of the injection pairs, except ones that included the AcbC, produced abundant double-labeling and it is unlikely that a fibers-of-passage artifact involved all equivalently. It also seems inappropriate for two reasons to attribute the more efficacious labeling by Ctβ observed in the present study to greater uptake of Ctβ by fibers of passage (Chen and Aston-Jones, 1995). [1] FG has a similar fiber-of-passage liability (Dado et al., 1990). [2] All analyzed structures exhibited many more Ctβ-labeled as compared to FG-labeled neurons (Table 2) and, again, it is unlikely that fibers-of-passage would similarly affect all.

We were confronted in this study with the complication that FG injections produced on average just over one-third as many labeled neurons as Ctβ injections (Table 2). To offset this source of error, we calculated percent of total labeling exclusively as a function of numbers of neurons labeled by the less efficacious tracer (i.e., % double-labeled = double-labeled/[FG-labeled + double-labeled] × 100), which excludes the possibility of misidentifying branched Ctβ-labeled neurons that could have been double-labeled, but, due to suboptimal FG transport, were not. Having been compelled to calculate double-labeling in this way in the present material, we came to realize that there is likely no better way to do it. Data calculated in this way were consistently more orderly than data derived with Ctβ-labeling in the denominator, by the averaging method used by Reynolds and Zahm (2005) or with total labeled neurons (both tracers) in the denominator (Naber and Witter, 1998), which both artificially about halves percent double-labeled and magnifies errors related to deficient labeling by one of the tracers. While calculations of proportions of collateralized neurons provide an important dimension to the study, the main conclusion of the study, that temporal lobe outputs collateralize abundantly among basal forebrain macrosystem input structures, excepting the AcbC, is adequately supported just by the raw counts of double-labeled neurons.

Functional implications

It is well known that the amygdaloid and cortical projections evaluated in this study are dense, glutamatergic outputs that terminate in relation to medium densely spiny neurons occupying input structures of basal forebrain macrosystems (Krettek and Price, 1978a; Groenewegen et al., 1987; Brog et al., 1993; Sun and Cassell, 1994; McDonald et al., 1999; Shammah-Lagnado and Santiago, 1999; Canteras and Swanson, 1992; Jolkkonen et al., 2001; deCampo and Fudge, 2013). As noted in the Introduction, highly differentiated patterns of organization characterize some of these projections, not the least being the ‘triadic’ organization in which strongly interconnected cortical loci tend to have convergent corticostriatal projections (Yeterian and Van Hoesen, 1978; Groenewegen et al., 1990; 1997; McDonald et al., 1991b). The specificity of such highly differentiated connectional relationships, if not degraded, is certainly complicated, by abundant collateralization of cortical ouputs. That is, the functional impact of convergence of cortico-subcortical outputs (e.g., McDonald, 1991b) must in some way be modulated if neurons that give rise to it also project via collaterals to other intra-telencephalic sites, perhaps in other macrosystems. Collateralized outputs may reflect a more primitive, less specific pattern of cortical-subcortical connectivity that diminishes with cortical evolution, resulting in a greater proportional representation of the more specific ‘triadic’ organization in areas with greater connectional specificity, such as the mPfC and IC.

To the extent that collateralization may degrade the specificity of inputs to macrosystems, it should be noted that the functions of the different macrosystems may be less specific than once had been entertained. Despite abundant evidence that the EA is most concerned with detection and response to threat (Pascoe and Kapp, 1985; Campeau and Davis, 1995; LeDoux, 1995; 2000; Rogan and LeDoux, 1996; Killcross et al., 1997; Nader and LeDoux, 1997; Davis and Shi, 1999; Fendt and Faneslow, 1999; Guarraci et al., 1999a; 1999b; 2000; Amorapanth et al., 2000; Jolkkonen et al., 2001; Walker et al., 2003; 2009; Paré et al., 2004; Maren, 2005a; b; Phelps and LeDoux, 2005; Santiago and Shammah-Lagnado, 2005; Wilensky et al., 2006; Miller and Urcelay, 2007; Walker and Davis, 2008; Duvarci et al., 2009; Skorzewska et al., 2009; Ciocchi et al., 2010; Davis et al., 2010; Haubensak et al., 2010; McDannald, 2010; Poulos et al., 2010; Crestani et al., 2013; Davis and Walker, 2013; Elharrar et al., 2013; Haufler et al., 2013; Ide et al., 2013; Li et al., 2013; Nagai et al., 2013; Silberman and Winder, 2013; Shackman and Fox, 2016; Gungor and Paré, 2016) and ventral striatum with approach (Kelly et al., 1975; Yokel and Wise, 1975; 1976; Roberts et al., 1980; Wise, 1985; 2004; 2008; Petit et al., 1984; Taylor and Robbins, 1984; 1986; Wickens and Kötter, 1995; Berridge and Robinson, 1998; Cannon and Palmiter, 2003; Hnasko et al., 2005; Robinson et al., 2005; Berridge, 2007; Berridge et al., 2009; Schultz et al., 1997), much additional evidence indicates that the EA and ventral striatum are in many ways functionally redundant. Thus, the CeA is reported to modulate responses to appetitive stimuli (Gallagher et al., 1990; Gallagher and Holland, 1994; Will et al., 2004; Lee et al., 2005; 2010; Difeliceantonio and Berridge, 2012; Mahler and Berridge, 2012; Knapska et al., 2013), just as the Acb modulates responses to threatening ones (Riedel et al., 1997; Parkinson et al., 1999; Haralambous and Westbrook, 1999; Reynolds and Berridge, 2001; 2008; Levita et al., 2002; Richard and Berridge, 2011a;b; McCutcheon et al., 2012; Richard et al., 2013). The expression of cyclic AMP response element binding protein (CREB) in Acb medium spiny neurons is regulated bidirectionally in relation to anxiety and reward (Carlezon et al., 1998; Barrot et al., 2002; 2005; Carlezon et al., 2005; Nestler and Carlezon, 2006; Dong et al., 2006; Wallace et al., 2009). EA and ventral striatum both respond vigorously to novelty (Garris et al., 1997; Rebec et al., 1997; Lee et al., 2006; 2008; Horvitz, 2000) and both also modulate reactions to stress, pain and depression (Altier and Stewart, 1998; 1999; Neugebauer et al., 2004; Leknes and Tracey, 2008; Rouwette et al., 2012; Chen et al., 2012; Kim et al., 2016). An integrated response to reward, threat and novelty thus reflects considerable overlap among the functions of the EA and ventral striatum, and it shouldn't be neglected that the LS also contributes to numerous and diverse associative and affective functions shared by the EA and ventral striatum (Jakab and Leranth, 1995; Risold and Swanson, 1997a; b; Sheehan et al., 2003).

Substantial functional differences do appear to characterize parts of the macrosystem complex that receive exuberantly versus sparely collateralized inputs. Earlier results reported by Reynolds and Zahm (2005) and counts from 4 cases in the present study support a generally low level of collateralization of prefrontocortical projections to basal forebrain macrosystems, consistent with the finely discriminative control that the frontal lobe is thought to exert on behavioral flexibility (e.g., de Bruin et al., 1994; Seamans et al., 1995; Ragozzino et al., 1999; Dias et al., 2000; Lanser et al., 2001; Ragozzino, 2002; 2007; Floresco et al., 2006; 2009; Block et al., 2007; Boulougouris et al., 2007; Ragozzino and Rozman, 2007; Stainaker et al., 2007; Tait and Brown, 2007; Churchwell et al., 2009; Clarke et al., 2008; Kosaki and Watanabe, 2012; Cholvin et al., 2013; Mala et al. 2015). Our present observation of relatively few collateralized temporal lobe projections to the AcbC is consonant with strong AcbC connections to the dorsal prelimbic and dorsal aganular insular cortices (Brog et al., 1993; Zahm, 2000; 2008a;b) and the key AcbC role in the acquisition and execution of conditioned responses (Kelley et al., 1997; Smith-Roe and Kelley, 2000), critical elements in behavioral flexibility. Alternatively, the abundance of collateralized temporal lobe projections from the amygdala and APir, and, to a lesser extent, vSub, to the AcbS fits with the reported role of that ventral striatal subterritory in modulating the vigor of conditioned responding (Taylor and Robbins, 1984; 1986; Parkinson et al., 1999), which, while not contributing specifically to decision-making, can nonetheless also be conceived as an important aspect of behavioral flexibility.

In summary, generously collateralized temporal lobe cortical and amygdaloid projections to the macrosystems could act in a variety of ways. They may serve to activate functionally similar circuitries in multiple input structures, possibly to facilitate more coherent subcortical responses to particular kinds of stimuli. Responding of parts of the input structure complex that are pertinent to specific sensory modalities could be enhanced by such an arrangement. For example, the afference of APir, a highly collateralized input to EA and AcbS, and, to a lesser extent, LS, is more or less dominated by converging inputs from the olfactory system (Santiago and Shammah-Lagnado, 2005). Alternatively, the impact of axon collaterals may truly generalize so as to decrease response threshold in parts of the macrosystem complex that receive highly collateralized inputs, rendering those parts of the complex more sensitive to inputs from the prefrontal cortex, which, as referenced, likely exerts granular, discriminative effects within the subcortical forebrain. The tremendous associative capacity of forebrain macrosystems might thus be more sensitively brought to bear in the service of behavioral flexibility. Yet another possibility is that the target relationships of the collaterals are flexible and change with an organism's sensory-motor experiences. These speculations aside, figuring out a mechanistic basis underlying any benefits conferred by abundant collateralization of inputs to the LS, Acb, BST and CeA is a tantalizing goal.

Acknowledgments

Grant support: USPHS NIH NS-23805

List of Abbreviations

ABA

accessory basal nucleus of the amygdala

ABC

avidin-biotin-peroxidase complex

Acb

nucleus accumbens

AcbC

Acb core

AcbS

Acb shell

AHip

amygdalohippocampal transition area

APir

amygdalopiriform transition area

BA

basal nucleus of the amygdala

BST

bed nucleus of the stria terminalis

CeA

central nucleus of the amygdala

CPu

caudate-putamen

Ctβ

cholera toxin, β subunit

DAB

diaminobenzidine

FG

FluoroGold

IC

insular cortex

LS

lateral septum

mPfC

medial prefrontal cortex

SPB

Sorenson's phosphate buffer

vSub

ventral subiculum

Footnotes

1

Consistent with ample considerations described elsewhere (Alheid and Heimer, 1988; Carlssen and Heimer, 1988), basal amygdala will be treated in this paper as a cortical-like structure.

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