Brain Struct Funct (2007) 212:149–179 DOI 10.1007/s00429-007-0150-4

ORIGINAL ARTICLE

Anatomical analysis of afferent projections to the medial in the rat

Walter B. Hoover Æ Robert P. Vertes

Received: 27 February 2007 / Accepted: 4 June 2007 / Published online: 27 July 2007 Springer-Verlag 2007

Abstract The medial prefrontal cortex (mPFC) has been reaches the mPFC via the midline thalamus and basal nu- associated with diverse functions including attentional clei of . As discussed herein, based on patterns of processes, visceromotor activity, decision making, goal afferent (as well as efferent) projections, PL is positioned directed behavior, and . Using retrograde to serve a direct role in cognitive functions homologous to tracing techniques, we examined, compared, and contrasted dorsolateral PFC of primates, whereas IL appears to rep- afferent projections to the four divisions of the mPFC in the resent a visceromotor center homologous to the orbitome- rat: the medial (frontal) agranular (AGm), anterior cingu- dial PFC of primates. late (AC), prelimbic (PL), and infralimbic (IL) cortices. Each division of the mPFC receives a unique set of afferent Keywords Claustrum Á Nucleus reuniens Á Memory Á projections. There is a shift dorsoventrally along the mPFC Mediodorsal nucleus of thalamus Á from predominantly sensorimotor input to the dorsal mPFC (AGm and dorsal AC) to primarily ‘limbic’ input to the Abbreviations ventral mPFC (PL and IL). The AGm and dorsal AC re- AA Anterior area of amygdala ceive afferent projections from widespread areas of the AC Anterior cortex (and associated thalamic nuclei) representing all ACC Nucleus accumbens sensory modalities. This information is presumably inte- AD Anterodorsal nucleus of thalamus grated at, and utilized by, the dorsal mPFC in goal directed AGm Medial agranular (frontal) cortex actions. In contrast with the dorsal mPFC, the ventral AGl Lateral agranular (frontal) cortex mPFC receives significantly less cortical input overall and AH Anterior nucleus of hypothalamus afferents from limbic as opposed to sensorimotor regions of AI,d,p,v Agranular insular cortex, dorsal, posterior, cortex. The main sources of afferent projections to PL/IL ventral divisions are from the orbitomedial prefrontal, agranular insular, AM,d Anteromedial nucleus of thalamus, dorsal perirhinal and entorhinal cortices, the hippocampus, the division claustrum, the medial basal forebrain, the basal nuclei of AON, m,v Anterior olfactory nucleus, medial, ventral amygdala, the midline thalamus and monoaminergic nuclei parts of the brainstem. With a few exceptions, there are few AQ Cerebral aqueduct projections from the hypothalamus to the dorsal or ventral APN Anterior pretectal nucleus mPFC. Accordingly, subcortical limbic information mainly AUD AV Anteroventral nucleus of thalamus BF Basal forebrain W. B. Hoover Á R. P. Vertes (&) BLA Basolateral nucleus of amygdala Center for Complex Systems and Brain Sciences, BMA,p Basomedial nucleus of amygdala, posterior Florida Atlantic University, Boca Raton, FL 33431, USA part e-mail: [email protected] BST Bed nucleus of stria terminalis

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CA1,3 Field CA1 and CA3 of Ammon’s horn mPFC Medial prefrontal cortex CB Cinguum bundle MPO Medial preoptic area CC MR Median raphe nucleus CEA Central nucleus of amygdala MRF Mesencephalic reticular formation CL Central lateral nucleus of the thalamus MS Medial septum CLA Claustrum MT Mammillothalamic tract CLi Central linear nucleus NI Nucleus incertus CM Central medial nucleus of thalamus NLL Nucleus of lateral lemniscus COA Cortical nucleus of amygdala NP Nucleus of pons CP Caudate-putamen OC,1,2 Occipital cortex, primary and secondary CUN Cuneiform nucleus divisions DBh Nucleus of diagonal band, horizontal limb OT Olfactory tubercle DG Dentate of hippocampus PA Posterior nucleus of amygdala DI Dysgranular insular cortex PAG Periaqueductal gray DR Dorsal raphe nucleus PAp Posterior parietal cortex EC,l,m , lateral, medial divisions PARA of HF ECT Ectorhinal cortex PB, l, m Parabrachial nucleus, lateral, medial divisions EN Endopiriform nucleus PC Paracentral nucleus of thalamus FP,l,m Frontal polar cortex, lateral, medial divisions PF Parafascicular nucleus FR Fasciculus retroflexus PH Posterior nucleus of hypothalamus FS Fundus of the striatum PIR GI Granular insular cortex PL Prelimbic cortex GP Globus pallidus PN5 Principal sensory nucleus of trigeminal nerve HF PO Posterior nucleus of thalamus IAM Interanteromedial nucleus of thalamus POST Postsubiculum of HF IC Inferior colliculus PPT Pedunculopontine tegmental nucleus IF Interfascicular nucleus PRC IL PRE Presubiculum of HF IMD Intermediodorsal necleus of thalamus PT Paratenial nucleus of thalamus INC Insular cortex PV Paraventricular nucleus of thalamus IP Interpeduncular nucleus RAM Radial arm maze LA Lateral nucleus of amygdala RE Nucleus reuniens of thalamus LC Locus coeruleus RF Rhinal fissue LD Lateral dorsal nucleus of thalamus RH Rhomboid nucleus of thalamus LDT Laterodorsal tegmental nucleus RLi Rostral linear nucleus LG,d Lateral geniculate nucleus, dorsal division RM Raphe magnus LH Lateral habenula RN Red nucleus LHy Lateral hypothalamus RPC Nucleus pontis caudalis LM Lateral mammillary nucleus RPO Nucleus pontis oralis LO Lateral orbital cortex RSC LP Lateral posterior nucleus of thalamus RR Retrorubral area LPO Lateral preoptic area RT Reticular nucleus of thalamus LS Lateral septum SC Superior colliculus LV Lateral ventricle SF Septofimbrial nucleus MA Magnocellular preoptic nucleus SI Substantia innominata MB Mammillary bodies sm Stria medullaris MD Mediodorsal nucleus of thalamus SM Submedial nucleus of thalamus MEA Medial nucleus of the amygdala SN,c,r Substantia nigra, pars compacta, pars MFB Medial forebrain bundle reticulata MG,v Medial geniculate nucleus, ventral division SSI Primary somatosensory cortex MH Medial habenula SSII Secondary somatosensory cortex MO Medial orbital cortex SUB,d,v Subiculum, dorsal, ventral parts

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SUM Supramammillary nucleus 1994; Barbas 1995, 2000; Groenewegen and Uylings TE Temporal cortex 2000). TR Amygdalo-piriform transition zone Although efferent projections from the mPFC have been TT,d,v Taenia tecta, dorsal, ventral parts well described in several species (Room et al. 1985; Sesack V3 Third ventricle et al. 1989; Reep et al. 1990, 2003; Chiba et al. 2001; V4 Forth ventricle Hurley et al. 1991; Takagishi and Chiba 1991; Buchanan VAL Ventral anterior-lateral complex of thalamus et al. 1994; Guandalini 1998; Vertes 2002, 2004; Cheat- VB Ventrobasal complex of thalamus wood et al. 2003; Gabbott et al. 2003, 2005), few reports VLO Ventrolateral orbital cortex have examined afferent projections to the mPFC, specifi- VM Ventral medial nucleus of thalamus cally to its various subdivisions. To our knowledge, only a VO Ventral orbital cortex single study (Conde et al. 1995) has compared afferents to VTA Ventral tegmental area the four divisions of the mPFC: IL, PL, AC, and AGm. ZI Zona incerta While Conde et al. (1995) described inputs to subregions of the mPFC in the rat, their injections were relatively large and as they indicated often included more than one mPFC field. By making discrete injections of the retrograde tracer, Fluorogold (FG), into select subfields of the mPFC, we sought to define patterns of (differential) input to the IL, Introduction PL, AC, and AGm cortices in rats. We show that each of the mPFC subfields exhibited a quite unique pattern of The prefrontal cortex (PFC) of the rat has been divided into afferent projections. These distinctive sets of afferents medial, orbital and lateral parts (Ongur and Price 2000). undoubtedly contribute to functional differences among The medial PFC (mPFC) consists of the four main divi- mPFC fields. sions which from dorsal to ventral are the medial agranular (AGm) (or medial precentral), the anterior cingulate (AC), the prelimbic (PL), the infralimbic (IL) cortices (Berendse Materials and methods and Groenewegen 1991; Ray and Price 1992; Ongur and Price 2000; Heidbreder and Groenewegen 2003). Sixty-two male Sprague-Dawley rats (Charles River, Wil- The mPFC has been associated with diverse functions mington, MA) weighing 350–450 g were injected with the including oculomotor control (frontal eye fields), atten- retrograde fluorescent tracer FG (Fluorochrome, Denver, tional processes, visceromotor activity, decision making, CO). These experiments were approved by the Florida goal directed behavior, and working memory (Fuster 1989; Atlantic University Institutional Animal Care and Use Kolb 1990; Neafsey 1990; Goldman-Rakic 1994; Petrides Committee and conform to all federal regulations and 1998; Repovs and Baddeley 2006). Dorsal regions of National Institutes of Health guidelines for the care and use mPFC (AGm and AC) have been implicated in various of laboratory animals. motor behaviors, while ventral regions of mPFC (IL and Fluorogold was dissolved in a 0.1 M sodium acetate PL) have been associated with diverse emotional, cogni- buffer (pH 4.0–5) to yield a 4–5% concentration. Rats were tive, and mnemonic processes (Heidbreder and Groe- anesthetized using a 75 mg/kg dose of sodium pentobarbi- newegen 2003). tal. Single injections of FG were made iontophoretically The IL has been shown to profoundly influence visceral/ using glass micropipettes with outside tip diameters of 25– autonomic activity. IL stimulation produces changes in 50 lm into one of four medial prefrontal cortical areas in respiration, gastrointestinal motility, heart rate, and blood separate rats: AGm, the AC, PL, and IL cortices. Positive pressure (Terreberry and Neafsey 1983; Burns and Wyss direct current (5–10 lA) was applied through a Grass 1985; Hurley-Gius and Neafsey 1986; Verberne et al. stimulator (model 88) coupled with a high-voltage stimu- 1987; Hardy and Holmes 1988). IL is viewed as a vis- lator (FHC, Bowdoinham, ME) at 2 s ‘on’/2 s ‘off’ intervals ceromotor center (Hurley-Gius and Neafsey 1986; Neafsey for 2–10 min. Following a survival time of 7 days, rats were 1990). PL, on the other hand, has been implicated in deeply anesthetized with sodium pentobarbital and perfused cognitive processes. PL lesions have been shown to pro- transcardially with 100 ml of a heparinized saline wash duce pronounced deficits in delayed response tasks (Brito followed by 450 ml of fixative [4% paraformaldehyde in and Brito 1990; Seamans et al. 1995; Delatour and Gisquet- 0.01 M sodium phosphate buffer (PB), pH 7.4]. The brains Verrier 1996, 1999, 2000; Floresco et al. 1997; Ragozzino were then removed and stored for 48 h in a sucrose solution et al. 1998), similar to those seen with lesions of the dor- (30% sucrose in 0.1 M PB) at 4C. Following this, 50 lm solateral PFC of primates (Kolb 1984; Goldman-Rakic coronal sections were taken on a freezing microtome and 123 152 Brain Struct Funct (2007) 212:149–179 collected in 0.1 M PB and stored at 4C. Six series of Afferents to the medial (frontal) agranular cortex sections were taken yielding a representative collection of (AGm) sections that were 300 lm apart. For the reaction, sections of a representative series were incubated in a sodium Figure 1 schematically depicts the pattern of retrogradely borohydride solution (1% sodium borohydride in 0.1 M PB) labeled neurons in the brain following a FG injection in for 30 min, and washed with 0.1 M PB four times at 6 min AGm. At anterior levels of the forebrain (Fig. 1a–d), each (4 · 6 min). The sections were then blocked in a Tris- labeling was pronounced within the medial frontal polar saline solution [0.5% bovine serum albumen (BSA) (Sigma (FPm), orbital, medial prefrontal, and dorsal agranular Chemicals, St. Louis, MO) 0.25% Triton X-100 (Sigma insular (AId) cortices and the CLA, and generally heavier Chemicals) in 0.1 M Tris-saline, pH 7.6] for 1 h. Following ipsilateral than contralateral to the injection. Specifically, the blocking procedure, the sections were incubated for significant numbers of labeled neurons were present within 48 h at room temperature in primary antiserum directed FPm, the medial (MO), ventral (VO), ventrolateral (VLO) against FG (rabbit anti-FG) (Fluorochrome, LLC) at a and lateral (LO) orbital cortices, the AGm, AC, PL and IL concentration of 1:200 in diluent (0.1% BSA and 0.25% of the mPFC and the AId. Labeled cells of FPm, AGm and Triton X-100 in 0.1 M Tris-saline solution). Following AC spread throughout all cortical layers, while those in PL incubation in the primary antiserum, sections were washed and IL were largely concentrated in inner layers 5/6. A (4 · 6 min) in 0.1 M PB, and then incubated in a secondary small to moderate number of labeled neurons were also antiserum (biotinylated goat anti-rabbit IgG) (Vector Labs, present in the anterior olfactory nucleus (AON) (Fig. 1c). Burlingame CA) at a concentration of 1:400 in diluent for Further caudally in the anterior forebrain (Fig. 1e–h), 2 h. Sections were then washed again (4 · 6 min) and labeled cells continued to be present in some of the same incubated in avidin-biotin complex (Vector Labs) at a 1:100 sites, densely within caudal regions of AGm and AC (all concentration in diluent for 1 h. After a final set of layers), the CLA and AId. Labeling was present but thin- 4 · 6 min rinses, the peroxidase reaction product was ned in PL and IL (Fig. 1e, f). Aside from moderate labeling visualized by incubation in a solution containing 0.022% of in the horizontal limb of the diagonal band nucleus (DBh) 3,3¢ diaminobenzidine (DAB, Aldrich, Milwaukee, WI), (Fig. 1h), there was a virtual absence of labeled cells in

0.015% nickel chloride (NiCl), and 0.003% H2O2 in TBS other regions of the rostral forebrain; that is, within the for 6 min. Sections were then rinsed again in PBS lateral (frontal) agranular (AGl), piriform, and anterior (3 · 1 min) and mounted onto chrome-alum gelatin-coated parts of the primary (SSI) and secondary (SSII) somato- slides. An adjacent series of representative sections from sensory cortices, the dorsal and ventral striatum (nucleus each rat was stained with cresyl violet for anatomical ref- accumbens ACC), the olfactory tubercle (OT), and medial erence. Sections were examined using light and darkfield and lateral septum (LS). optics. Injection sites and labeled cells were plotted on At mid-levels of the forebrain (Fig. 1i–l), labeled cells representative schematic coronal sections through the brain were localized to dorsomedial and ventrolateral regions of using sections adapted from the rat atlas of Swanson (1998). the cortex, to CLA, to parts of the basal forebrain (BF), to The brightfield photomicrographs of labeled cells were ta- midline and lateral parts of the thalamus and to the baso- ken with a Nikon DXM1200 camera mounted on a Nikon lateral nucleus of the amygdala (BLA). Cortically, the Eclipse E600 microscope. The photomontages were con- AGm, medial parts of AGl, and the posterior agranular structed using Image-Pro Plus 4.5.1.29 (Media Cybernetics insular cortex (AIp) were densely labeled, whereas AC, the Inc., Silver Spring, MD) and adjusted for brightness and SSI and the granular insular (GI) cortices were lightly to contrast using Adobe PhotoShop 7.0 (Mountain View, CA). moderately labeled. Labeled cells spread throughout the BF, largely confined to the DBh, ventral pallidum (VP), substantia innominata (SI), and the magnocellular preoptic Results nucleus (MA). Of these, DBh and SI were the most heavily labeled. Figure 2a, b shows a discrete group of labeled The pattern of retrogradely labeled cells throughout the neurons spanning SI and VP. The location, size and general brain following injections of the retrograde tracer, FG, into morphological characteristics of these neurons suggest that the four divisions of the mPFC are described. Four repre- they may belong to the cholinergic (ACh) population of sentative cases with injections in the AGm, AC, PL, and IL neurons of the BF (see Discussion). Within the thalamus, cortices are illustrated and discussed in detail. The patterns the nucleus reuniens (RE), paratenial nucleus (PT), and of labeling obtained with the four schematically illustrated ventral anterior-lateral complex (VAL) were densely la- cases are representative of patterns found with non-illus- beled (Fig. 1k, l). A few labeled cells were present within trated cases. the medial nucleus of amygdala (MEA) and the lateral

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PL SSI CP CLA LS IL SSII MS CLA PIR AON AIp EN DBh FS OT

Fig. 1 Series of representative rostro-caudally aligned schematic medial (frontal) agranular cortex (AGm). One dot = one cell. Sections transverse sections (a–x) depicting the location of retrogradely modified from the rat atlas of Swanson (1998). See list for labeled cells in the brain produced by a FG injection (c) in the abbreviations hypothalamus (LHy) (Fig. 1k, l). With few exceptions, retrosplenial (RSC) and motor cortices (AGm and AGl) labeling was predominantly ipsilateral. through primary/secondary somatosensory and auditory More caudally in the forebrain (Fig. 1m–p), prominent (AUD) cortices, to AIp, the ectorhinal (ECT) and perirhinal numbers of labeled neurons were observed over the lateral (PRC) cortices, adjacent to the rhinal fissure. Labeling was convexity of cortex, in CLA, in the midline, intralaminar dense in ECT and PRC, particularly in inner layers and lateral parts of thalamus and in BLA (see Fig. 2c), but (Fig. 1o, p). Several nuclei of the thalamus were strongly with the exception of a few cells in the posterior nucleus of labeled including the paraventricular (PV), mediodorsal the hypothalamus (PH), were noticeably absent in the (MD), interanteromedial (IAM), anteromedial (AM), hypothalamus. As depicted (Fig. 1m–p), a continuous paracentral (PC), central lateral (CL), central medial (CM) stream of labeled neurons extended dorsoventrally from the intermediodorsal (IMD), rhomboid (RH), ventromedial

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I AGm M SSI RSC

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LP PF CP SSII PT PO AV VAL IMD AM CEM RE ZI ECT SI AIp PERI CEA LHy BLA PH EC PA BLA

Fig. 1 continued

(VM), and RE (Fig. 1m–p). Labeling was particularly As observed rostrally, labeling within the cortex at the pronounced within MD, VM, RH, and RE. Figure 2d caudal diencephalon-rostral midbrain (Fig. 1q–t) was fairly shows a tight cluster of labeled cells ventrally on the widespread, but unlike rostrally was now predominantly midline in RE, others more diffusely distributed dorsolat- confined dorsomedially to RSC, the posterior parietal area erally in RE, and third population dorsally in RH, essen- (PAp) and the secondary (OC2), and ven- tially outlining RH. While the entire rostrocaudal extent of trolaterally to the area bordering the rhinal fissure: ECT, BLA was densely labeled, considerably fewer labeled PRC, and the lateral entorhinal cortex (EC). Labeling was neurons were present in other nuclei of the amygdala, light within temporal (TE) regions of the cortex. Within the namely, in the basomedial (BMA) and posterior (PA) nu- hippocampus, small numbers of reacted neurons were seen clei (Fig. 1m–p). Additional lightly labeled sites at these in the postero-dorsal (Fig. 1q–s) and ventral CA1 (Fig. 1r– levels were the lateral posterior nucleus (LP) of thalamus t). Subcortically, labeling was mainly restricted to ventral and the zona incerta (ZI). regions of the tegmentum; prominent in the substantia ni-

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OC1 U RSCd Q RSC OC1

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SC LP AUD S U PO B PAG v ECT MRF MRF CLi P ZI A PH R ECT RR A VTA PRC ECm EC IP MB SUM TR NP

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MRF TE PPT MR PRC RPO VTA SUBv IF EC

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NI 5 MRF CLi PRC RPC SNc RM EC IP

Fig. 1 continued gra-pars compacta (SNc) and ventral tegmental area median raphe nucleus (MR), and nucleus incertus (NI) (VTA), but considerably less intense in the periaqueductal were lightly to moderately labeled (Fig. 1u–x). A few la- gray (PAG) (Fig. 1q, r), the supramammillary nucleus beled neurons were seen in the pontine gray and pontine (SUM) and the central linear nucleus (CLi). There was a reticular formation—nucleus pontis oralis (RPO) and progressive decline in VTA labeling, proceeding caudally. pontis caudalis (RPC) (Fig. 1w, x). Small numbers of labeled cells were observed in the pos- terior nucleus of thalamus (PO) and the mesencephalic Afferents to the anterior cingulate cortex (AC) reticular formation (MRF) (Fig. 1q). Cortically, at the level of the pons and medulla (Fig. 1u– At the site of injection (Fig. 3d) and rostral to it (Fig. 3a–c) x), labeled cells were mainly localized to ECT and to the labeled cells were found along the medial wall of the mPFC lateral EC (ECl) with scattered labeling throughout RSC within FPm, the anterior PL, and medial orbital cortex (MO), and OC. Subcortically, the dorsal raphe nucleus (DR), the rostrally (Fig. 3a, b), and the AGm, AC, caudal PL, and IL, pedunculopontine tegmental nucleus (PPT), and the locus caudally (Fig. 3c, d). Labeled cells spread to all layers of AC coeruleus (LC) were fairly densely labeled; CLi, the (at and adjacent to the injection), but were mainly localized 123 156 Brain Struct Funct (2007) 212:149–179

Fig. 2 Brightfield photomicrographs depicting retrogradely labeled neurons in the basal forebrain (a, b), the basolateral nucleus (BLA) of the amygdala (c) and the midline thalamus (d) produced by a FG injection in AGm. Note: (a) at low (a) and high (b) levels of magnification, the presence of a loosely distributed group of labeled cells extending dorsoventrally in the lateral basal forebrain localized to the acetylcholine containing cell regions of the substantia innominata and ventral pallidum; (b) the presence of labeled cells densely packed within, and confined to, BLA of amygdala (c); and (c) the presence of labeled cells within the ventral midline thalamus, ventrally in nucleus reuniens (RE) and dorsally in the rhomboid nucleus (RH). Scale bar for a = 1,000 lm; b, c = 250 lm; d = 300 lm. See list for abbreviations

to inner layers of PL and IL. Although labeling was stronger and VM. The entire extent of AM was densely labeled, ipsi- than contralateral to the injection, relatively significant particularly the ventral tier of AM (Fig. 3j, k). This is numbers of labeled neurons were visible contralaterally in depicted in the photomicrograph of Fig. 4a. Interestingly, the mPFC. The VO and CLA were moderately to densely in contrast to heavy AM and IAM labeling, there was a labeled; AId was lightly labeled (Fig. 3a–d). virtual absence of labeled neurons in the anterodorsal (AD) More caudally in the anterior forebrain (Fig. 3e–h), la- and anteroventral (AV) nuclei of the anterior thalamus beled cells were pronounced within the caudal AC, (Fig. 3j–l). dorsomedially, and CLA, ventrolaterally. Light to moder- Further caudally in the forebrain (Fig. 3m–p) labeled ate numbers of labeled neurons were also present in AGm, cells were present in significant numbers in a region dorsal/ dorsal to AC, inner layers of AId, the dorsal taenia tecta dorsolateral to the cingulum bundle (CB); that is, to AGm/ (TTd), and structures of the lateral BF: bed nucleus of stria AGl, rostrally (Fig. 3m, n), and to RSC and the PAp terminalis (BST), lateral preoptic area (LPO), MA, and SI. (Fig. 3o, p), caudally. The SSII, TE, ECT, and PRC were At mid-levels of the forebrain (Fig. 3i–l), labeled cells moderately labeled. Subcortically, labeling was pro- continued to be seen dorsomedially in the cortex, within nounced in the medial and intralaminar nuclei of thalamus AC (Fig. 3i, j), extending caudally to the RSC. A few la- and in the basal nuclei of the amygdala, but was light beled cells were also present in motor cortices (AGm and within the hypothalamus (Fig. 3m–p). Specifically, labeled AGl) lateral to AC (Fig. 3k, l). Ventrolaterally, labeling neurons were fairly densely concentrated within lateral was virtually confined to CLA. As shown (Fig. 3j–l), MD, CL, PC, IMD, RH, and RE of thalamus (Fig. 3m–o) pronounced numbers of labeled neurons were observed and in the basomedial (BMA) and BLA of amygdala within the medial thalamus, mainly localized to PV, PT, (Fig. 3m, n), but loosely (and lightly) dispersed in CM of anteromedial (AM), IAM, lateral parts of MD, RH, CM, thalamus and PH, LHy, SUM, and the lateral mammillary 123 Brain Struct Funct (2007) 212:149–179 157

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Fig. 3 Series of representative rostro-caudally aligned schematic rostral anterior cingulate cortex (AC). One dot = one cell. Sections transverse sections (a–x) depicting the location of retrogradely modified from the rat atlas of Swanson (1998). See list for labeled cells in the brain produced by a FG injection (d) in the abbreviations nucleus (LM) of the hypothalamus. Figure 4c shows a hippocampal formation (HF) (Fig. 3r, s) and fairly densely dense aggregate of labeled neurons in CL and the medially packed within the ventral subiculum (SUBv) (Fig. 3t). This adjacent lateral MD, dorsally, and significant but fewer pattern of labeling is depicted in the photomicrograph of cells ventrally in PC of thalamus. Some labeled neurons Fig. 4b. Subcortically, labeling overall was fairly light; were also present in ZI (Fig. 3n) and PAG (Fig. 3p). strongest in SNc and VTA and less pronounced in PAG, Cortically, at the level of the anterior midbrain (Fig. 3q– interpeduncular nucleus (IP) and CLi (Fig. 3q–t). t), labeled cells were abundant dorsomedially in RSC and Cortically, at the level of the midbrain and pons in the medial OC2 (Fig 3q, r) and ventrolaterally in PRC. (Fig. 3u–x), labeled neurons were essentially restricted to Scattered labeled cells were also found within TE, ECT, ECT and the entorhinal (ECl and ECm) cortices. Labeling lateral EC, and other parts of OC. Although labeling was was densest in ECl (Fig. 3u, v). Labeling thinned subcor- moderate in the ventral hippocampus (Fig. 3q–t), FG-re- tically (Fig. 3u–v), but was nonetheless visible in DR and acted neurons were visible throughout CA1 of the ventral LC and to a much lesser degree in the MR, the laterodorsal

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PIR

Fig. 3 continued tegmental nucleus (LDT), the lateral parabrachial nucleus injection. Light to moderate numbers of labeled neurons (PBl), and NI. were present in VLO, CLA, AId, and AON (Fig. 5c, d). More caudally in the anterior forebrain (Fig. 5e–h), Afferents to the prelimbic cortex (PL) labeling remained pronounced within the mPFC, strongest in AC, PL and IL, but was also dense in ventrolateral aspects of As depicted (Fig. 5a–d), pronounced numbers of labeled the cortex particularly in the agranular insular cortex (AId neurons were present in the PFC, mainly the medial PFC, and AIv), CLA, and the endopiriform nucleus (EN). Fig- following a FG injection in PL. Labeling was predomi- ure 6c shows heavy concentrations of labeled cells in CLA nantly localized to FPm, MO, VO, AGm, AC, PL (adjacent and AId, ipsilaterally. Additional labeled sites included the to the injection and contralaterally), and IL, spreading TTd, and the LS (Fig. 5f, g). Labeling was considerably fairly evenly throughout all cortical layers of these regions. stronger ipsi- than contralaterally in each of these structures. The photomicrographs of Fig. 6a, b depict heavy labeling At mid-levels of the anterior forebrain (Fig. 5i–l), label- contralaterally in anterior PL and MO, rostral to the ing was restricted to dorsomedial and ventrolateral aspects of

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NI 5

RPC RR RM ECl

Fig. 3 continued cortex, CLA, parts of the lateral BF and the midline thala- At the caudal forebrain, there was a dramatic reduction mus. There was a virtual absence of labeled neurons in other in numbers of labeled neurons in the dorsomedial cortex, regions of cortex (e.g., primary motor, somatosensory, and particularly within RSC (Fig. 5m–p). As observed ros- GI), the dorsal and ventral striatum, the medial BF, and the trally, however, labeled cells remained present on the lat- hypothalamus (Fig. 5i–l). Cortical labeling was essentially eral convexity of cortex, in AIp and CLA, rostrally, and limited dorsomedially to AGm and AC, and ventrolaterally ECT, PRC and anterior EC, caudally (Fig. 5m–p). Sub- to the posterior agranular insular cortex (AIp) (Fig. 5i–l). cortically, labeling was essentially restricted to the midline Labeled cells were present throughout most of the anterior thalamus and the basal nuclei of amygdala. Within the midline thalamus—most heavily concentrated in PV, PT, thalamus, labeling was heavy in PV, MD (medial MD) IAM, and RE (Fig. 5k, l). Within the BF, DBh and the LPO (Fig. 5m–p), RH and RE, but much less pronounced in were moderately labeled, while SI and the anterior LHy were IAM, IMD, and CL of the intralaminar complex. As shown, lightly labeled (Fig. 5i–l). dense aggregates of labeled cells were present throughout

123 160 Brain Struct Funct (2007) 212:149–179

Fig. 4 Brightfield photomicrographs depicting retrogradely labeled neurons at anterior (a) and posterior (c) levels of the thalamus and within the ventral hippocampus (b) produced by a FG injection in AC. Note: (1) the presence of pronounced numbers of labeled cells in the anteromedial nucleus of thalamus (a) and fewer numbers ventrally in nucleus reuniens (a) and dorsally in paratenial nucleus (a) of thalamus; (2) the presence of significant numbers of labeled neurons in the lateral mediodorsal nucleus (MD) and the laterally adjacent central lateral nucleus of thalamus (c) as well as ventromedially in the paracentral nucleus (c) but an absence of labeling in the medial and central MD; and (3) the presence of moderate numbers of labeled cells spread dorsoventrally throughout CA1 of the ventral hippocampus (b). Scale bar for a, b = 500 lm; c = 300 lm. See list for abbreviations

the extent of BLA (Figs. 5m–p, 7b). Light to moderate labeled. Subcortically, the DR was densely labeled; MR numbers were also seen in BMA, the posterior (PA) and and LC were moderately labeled (Fig. 5u–x). anterior cortical nuclei (COA) of amygdala (Fig. 5o, p). Injections in other parts of PL resulted in the same Cortically, at the level of the caudal diencephalon general pattern of labeling, but some differences in relative (Fig. 5q–t), reacted cells were mainly restricted to the densities of labeling. For instance, rostral (present case) parahippocampal cortices and HF; that is, moderate label- compared to caudal PL injections produced stronger cell ing in ECT, PRC and lateral EC, and dense labeling in CA1 labeling in the CA1, BLA of amygdala, medial septum of the ventral hippocampus extending dorso-ventrally (MS) and diagonal band nuclei and DR and MR of the throughout CA1 of the ventral HF (Fig. 5s, t). The prom- brainstem, while caudal injections gave rise to heavier inent CA1 labeling is depicted in the photomicrograph of labeling in several regions of the BF including CLA, MA, Fig. 7a. There was a noticeable absence of labeling in SI, and the VP. remaining regions of the cortex, including RSC, PAp, and OC (Fig. 5q–t). With the exception of fairly dense labeling Afferents to the infralimbic cortex (IL) of BLA/BMA (Fig. 7c) as well as the amygdalo-piriform transition zone (TR), subcortical labeling was confined to Similar to injections in dorsal regions of the mPFC, sig- relatively few structures. Lightly to moderately labeled nificant numbers of labeled cells were observed in anterior sites were PAG, VTA, PH, IP, SUM, and LM (Fig. 5q–t). regions of the forebrain (Fig. 8a–d) with IL injections At the pons-medulla (Fig. 5u–x), labeling was essen- (Fig. 8d, e). Rostrally within mPFC, labeling extended tially confined cortically to the ventral subiculum (Fig. 5u) dorsoventrally throughout the mPFC to FPm, PL, and MO which was densely labeled, and ECl which was moderately (Fig. 8a, b), but caudally was mainly confined to the ven-

123 Brain Struct Funct (2007) 212:149–179 161

A E AGm FPm AC AGl FPl PL AON CLA SSI MO EN AId IL

TTv

AGm B PL FPm F AC

FPl CP LO CLA VO IL ACC

AId EN AIv

C G AGm AC AGl AC SSI

IL CP PL VLO AId CLA MO GI ACC

AId AON EN

D H AGm AGm

AGl AC AC SSI

PL CP CLA SSI LS CLA IL AId ACC AId AIv PIR OT

Fig. 5 Series of representative rostro-caudally aligned schematic prelimbic cortex (PL). One dot = one cell. Sections modified from the transverse sections (a–x) depicting the location of retrogradely rat atlas of Swanson (1998). See list for abbreviations labeled cells in the brain produced by a FG injection (c–e) in the tral mPFC (IL and PL) (Fig. 8c, d). Additional moderately Mid-levels of the forebrain (Fig. 8i–l) were character- to heavily labeled sites were CLA, AId, and parts of AON ized by a marked reduction (from rostral levels) in numbers (Fig. 8b–d). of labeled neurons in the (neo) cortex. A few labeled cells More caudally at the anterior forebrain (Fig. 8e–h), la- were present dorsomedially in AC, extending caudally to beled cells were present in significant numbers in the RSC, but virtually none were seen in motor (AGm and ventral mPFC (IL, PL, and TTd), CLA and AId/AIp. AGl) and somatosensory (SSI and SSII) cortices. Moderate Labeling outside of these areas was restricted to regions of numbers were observed in CLA as well as ventrolaterally the BF; that is, to SI, DBh and the medial and LS. Of these in AIp, rostrally, and PRC, caudally (Fig. 8i–l). In contrast regions, labeling was densest in DBh. Some labeled neu- with the cortex, labeling was pronounced throughout the rons were also seen in the EN (Fig. 8g, h). midline thalamus: heavy within PV, PT, medial MD, RH 123 162 Brain Struct Funct (2007) 212:149–179

I M AGl SSI RSC AC

PV LS CP MD SSII VAL MS CP IAM

RE RH CLA DBh CLA AIp AIp CEA SI EN LHy OT PIR BLA

J AGm N RSC SSI AC

CP SF LD SSII PV VAL MD GP CM CLA SM RH VP AIp LPO AIp RE MA LHy LA MPO PIR BLA

AGl K O RSC AC SSI

AUD

CP PV SSII PT AM PV VB MD GP RT CM GI RE AIp RE SI ZI AH LHy PRC CEA EN LA EC LHy BMA PIR AA BLA

PAp L P RSC RSC SSI CA1

AUD

LP PV PV CL CP SSII AV PO PT IMD RT MD AM TE GP ZI RE ECT CM CLA PRC PH AIp LHy

PA COA BLA BLA BMA

Fig. 5 continued and RE, moderate in IAM and light in CM (Fig. 8i–l). contrast with a general lack of labeling at the rostral Figure 9a shows a dense aggregate of labeled neurons amygdala (Fig. 8i–l), significant numbers of labeled cells outlining the rostral RE. With the exception of a few la- were present in the caudal amygdala, heavily concentrated beled cells in the anterior hypothalamus (AH) and LHy, in BLA and BMA and less so in COA and TR. A few there was notable absence at labeling within the hypo- labeled cells were also found in the lateral nucleus of thalamus at these levels (Fig. 8i–l). amygdala (LA) (Fig. 8m). While some labeled neurons More caudally in the forebrain (Fig. 8m–p), labeled were present rostrally in CA1 of the dorsal hippocampus cells were largely confined to the midline thalamus and (Fig. 8o), numbers greatly increased at successively caudal medial hypothalamus, PRC, and the hippocampus. Similar regions of the dorsal and particularly the ventral hippo- to rostral levels, the PV, medial MD, IMD, RH and RE campus (Fig. 8p). were densely labeled and CM lightly labeled. Labeling was Labeling was generally light within the cortex at the much more pronounced at the caudal than rostral hypo- midbrain (Fig. 8q–t); moderate numbers were observed in thalamus, densest within the SUM (Figs. 8o, p, 9c). In ECT and PRC bordering the rhinal fissure, and far fewer in

123 Brain Struct Funct (2007) 212:149–179 163

Q RSC PAp U OC1 RSC

ST O P AUD SC LP S U TE B PAG PAG v MRF MRF ECT ZI VTA ECT RR CLi CA1 m C E ECl MB EC LM SUM IP BLA COA NP TR

R OC2 V OC1 RSC

CA1 P SC R AUD E

LP DR

MRF TE PAG PPT

C A1 PRC PH RPO MR ECl VTA SUM TR

S W OC OC1 RSC IC ECT

SC PAG C E A DR C m 1 NLL MRF SNc RN PRC RPO MR S N SUBv r ECl VTA

T OC2 X RSC

SUBd SC TE C

A

G 1 D V4 LC MRF PRC RR VTA ECl SUBv RPC RM IP

Fig. 5 continued

RSC and ECl. As seen rostrally (Fig. 8p), dorsal and OC (Fig. 8u, v). Subcortically, labeling was prominent in ventral aspects of CA1 were densely labeled and merged to DR (Figs. 8u–w, 9b), in the isthmus region between DR form a continuous band of labeled cells, dorsoventrally in and MR (Fig. 8w), in LDT and in LC (Fig. 9d), moderate CA1 (Fig. 8q–s). This is depicted in Fig. 10a. As with in MR (Fig. 9c) and fairly light in the pontine central gray CA1, labeled cells spread heavily throughout the extent of and NI (Fig. 8x). the ventral subiculum (Figs. 8t, 10b). Subcortically, label- Similar to PL (see above), there were differences in ing was predominantly confined medially to the rostral and relative densities of labeling, but not overall patterns of central linear nuclei and to VTA (Fig. 8q–t). Some labeled labeling with injections in different parts of IL. Specifi- cells were present in the mesencephalic PAG, rostrally cally, denser labeling was observed in rostral parts of BLA (Fig. 8o, p) as well as caudally (Fig. 8t). with rostral compared to caudal (above case) IL injections, Labeling within the cortex at the level of the pons/me- and considerably fewer labeled cells were seen in the dulla (Fig. 8u–x) was essentially confined to ECT and ECl. caudal midline thalamus (caudal PV and IMD) with A few labeled cells were also found scattered throughout superficial (layers 1–3) relative to deep IL injections.

123 164 Brain Struct Funct (2007) 212:149–179

Fig. 6 Brightfield photomicrographs depicting retrogradely labeled neurons in the contralateral prelimbic cortex (a, b) and in the claustrum (CLA) and the dorsal agranular insular cortex (AId) (c) produced by a FG injection in PL. Note: (1) the presence at low (a) and high (b) levels of magnification of dense aggregates of labeled cells in the contralateral PL, spread throughout all layers but most heavily distributed in outer layers 2/3 of PL; and (2) the presence of pronounced numbers of labeled neurons throughout the anterior CLA (3) and equally significant numbers in AId, ventrolateral to CLA. Scale bar for a = 750 lm; b = 200 lm; c = 500 lm. See list for abbreviations

Discussion clei of the amygdala, midline thalamus, VTA, DR, and LC (Figs. 11, 12). We examined afferent projections to the AGm, AC, PL, and IL cortices in the rat. Each subdivision of the mPFC Brief summary and comparisons of main afferents receives a fairly unique set of afferent projections to AGm, AC, PL, and IL (Figs. 11, 12). There were also common projections to the four divisions of the mPFC. These included afferents from The primary sources of afferents projections to the four adjacent regions of the mPFC, the insular and entorhinal divisions of the mPFC are summarized in Figs. 11 and 12. cortices, CLA, CA1/subiculum of hippocampus, basal nu- As depicted, the AGm receives widespread input from 123 Brain Struct Funct (2007) 212:149–179 165

Fig. 7 Brightfield photomicrographs depicting retrogradely labeled neurons in CA1and the dorsal and ventral subiculum of the ventral hippocampus (a) and rostral (b) and caudal (c) levels of the amygdala produced by a FG injection in PL. Note: (1) the presence of pronounced cell labeling throughout the extent of the ventral hippocampus, from the dorsal subiculum through CA1 to the ventral subiculum (a); (2) the presence of labeled neurons, confined to, and distributed throughout the anterior basolateral nucleus of amygdala (BLA); and (3) the presence of labeled cells caudally in the amygdala, mediolaterally spanning the posterior part of the basomedial nucleus (BMAp), posterior BLA and the amygdalo-piriform transition zone (TR). Scale bar for a = 1,100 lm; b = 500 lm; c = 750 lm. See list for abbreviations

non-limbic and limbic regions of the cortex as well as Afferents to the four divisions of the mPFC: from specific (relay) and ‘non-specific’ nuclei of the comparisons with previous studies and functional thalamus. In like manner, AC receives afferents from implications diverse regions of cortex, but less dense from non-limbic cortex and more restricted from limbic cortex than those Medial agranular cortex to AGm (Fig. 11b). There is a considerable overlap in thalamic projections to AGm and AC, with the notable The main sources of input to AGm were from the cortex exception that the anterior medial nucleus of thalamus and thalamus. Extra-thalamic subcortical afferents to AGm distributes densely to AC. There is a dramatic shift in were moderate and less pronounced than to other divisions cortical and thalamic projections to the ventral (PL and of the mPFC. IL) compared to the dorsal (AGm and AC) mPFC, such The AGm of rats is also termed the medial precentral that major inputs to ventral mPFC predominantly origi- area (or Fr2 region of Zilles 1985) and is partially coex- nate from limbic cortices and from the midline thalamus. tensive with the secondary (Zilles and Wree All regions of the mPFC receive complementary (over- 1995; Gabbott et al. 2005). In an early examination of lapping) projections from the BF, amygdala, hypothala- cortical connections of AGm, Reep et al. (1990) described mus and brainstem (Figs. 11, 12), with some important diverse cortical inputs to AGm from the cortex FPm, the differences among divisions. For example, regions of the medial and ventrolateral orbital cortices, AGl (or primary lateral BF primarily target AGm/AC, while the medial BF motor cortex), insular cortex (INC), SSI and SSII, RSC, targets PL/IL, and the amygdala distributes more heavily auditory and occipital cortices. Based on ‘extensive cor- to the ventral than to the dorsal mPFC. Overall hypo- tico-cortical connections,’ Reep et al. (1990) proposed that thalamic projections to the mPFC are light, with the AGm is a multimodal association area with direct actions exception of relatively pronounced projections from the on motor systems, and accordingly serves a central role in SUM to IL. Finally, the VTA and the DR distribute directed spatial attention. Supporting this, lesions of AGm significantly to all divisions of the mPFC. in rats produce contralateral neglect (failure to attend to

123 166 Brain Struct Funct (2007) 212:149–179

A E AGm FPm

PL SSI PL FPl CP IL CLA LO MO ACC AId EN

B F AGm FPm AGl SSI AC AC

CLA CP TTd CLA MO AId LS AON ACC

OT

AGm C G SSI AGm AC AGl PL LS CLA CP MS SSII IL GI AId DBh AIp SI

D H AGl AC AC AGl CP SF SSII CLA IL GP ACC CLA AId MPO VP PIR AIp EN MA DBh LPO

Fig. 8 Series of representative rostro-caudally aligned schematic infralimbic cortex (IL). One dot = one cell. Sections modified from transverse sections (a–x) depicting the location of retrogradely the rat atlas of Swanson (1998). See list for abbreviations labeled cells in the brain produced by a FG injection (d, e) in the meaningful stimuli presented contralaterally), comparable occipital cortex. These differences could involve relative to deficits seen with lesions/damage to Brodmann’s area 8 size and placements of injections across reports. of primates (Crowne and Pathria 1982; Corwin et al. 1986; With respect to the thalamus, it is well established that King and Corwin 1993). MD represents a major input to AGm—as well as to other We described a pattern of cortical projections to AGm subdivisions of the mPFC. In fact, the mPFC of non-pri- largely consistent with that shown by Reep et al. (1984, mates has been described as MD projection cortex (Leon- 1990) as well as others (van Eden et al. 1992; Conde et al. ard 1969; Uylings and van Eden 1990). In accord with 1995; Heidbreder and Groenewegen 2003), with some several previous reports (Krettek and Price 1977; Groe- important differences. Specifically, we demonstrated con- newegen 1988; Conde et al. 1990; Ray and Price 1992; siderably stronger projections from FPm, agranular insular Hicks and Huerta 1991; Reep and Corwin 1999), we found cortex and PRC to AGm than reported previously (Reep that AGm receives pronounced projections from the lateral et al. 1990), but less pronounced projections from RSC and MD. Other prominent sources of thalamic afferents to

123 Brain Struct Funct (2007) 212:149–179 167

I AGl M RSC AC

CP SSII PV SSII AM MD IMD PT VB CM GP GI RE TE CLA RH RE SI PRC AIp AH LA LHy CEA BLA

PIR BLA PIR

PAp J AGm N RSC SSI

AUD FI PV LP AV PV VAL MD IMD AM IAM GI RH RE ZI ECT CM AIp PH LHy CEA LHy

PA BMA PIR BLA

AGl PAp K O RSC SSI RSC CA1

AUD LP MD PV CP VAL PAG IAM MRF RH CLA VM TE ZI ECT RE PH AIp

U S SU PRC M M CEA m m LHy A EC L MB B SUM BLA PIR COA TR

L OC2 1 P RSC RSC PAp CA1

LD 3 SC A AUD MD PV SSII C VB CM GI RH VTA

RE PRC SNc EC A E SUM M BLA SUBv COA TR LHy

Fig. 8 continued

AGm include the CL, PC, CM, posterior (PO), VAL, and In addition to prominent afferents from somatomotor/ VM nuclei of thalamus (Herkenham 1979; Conde et al. visuomotor regions of thalamus to AGm, some reports 1990; Hicks and Huerta 1991; Reep and Corwin 1999, (Conde et al. 1990; Hicks and Huerta 1991; Vertes et al. present results). Reep and Corwin (1999) reported that 2006), but not others (Reep and Corwin 1999), have afferents to successively more caudal regions of AGm demonstrated significant input to AGm from the midline originate from more caudal and lateral parts of the thala- thalamus. We described projections from the PV, PT, IAM, mus. Consistent with this, Hicks and Huerta (1991) de- IMD, CM, rhomboid (RH) and reuniens (RE) nuclei of the scribed projections from the lateral dorsal (LD) and LP midline thalamus to AGm, most heavily from RH and RE. nuclei of thalamus to the caudal but not to the rostral AGm, The latter is consistent with our recent demonstration and we found that injections in the rostral AGm gave rise to (Vertes et al. 2006), using anterograde tracers, of pro- few labeled cells in LD or LP. Hicks and Huerta (1991) nounced RH and RE projections to AGm, mainly to layers proposed that visuomotor thalamic input (LD/LP) to the 1 and 5/6. Other studies have similarly described IAM, caudal AGm supports a role for this area in visuomotor CM, RH, and RE projections to AGm (Conde et al. 1990; functions. Hicks and Huerta 1991). 123 168 Brain Struct Funct (2007) 212:149–179

Q OC1 U RSC RSC

P R E TE SUBd IC AUD

SC ECT R C DR

A A P 1

E MRF RLi NLL C ECT PPT m

MR SNc VTA IF EC SUBv NP

OC2 R V OC1 RSC RSC

IC

AUD ECT SC C A PAG 1 DR E MG C MRF m PRC ECl RN VTA CUN r SN MR RPO EC SUBv IP

OC2 S OC1 W

RSC IC E C T SUBd

m C SC C E DR A

1 PB TE MRF ECT VTA LDT RPO SNc MR SUBv ECl

OC1 T RSC X

P O S SC T

S U B PAG v ECT LDT NI RR E CLi C m RPC

IP

NP

Fig. 8 continued

Other inputs to AGm mPFC. Consistent with this, retrograde injections in the dorsal mPFC were shown to produce dense cell labeling in In addition to thalamus and cortex, other prominent sources CLA (Hur and Zaborszky 2005). CLA appears to represent of afferents to AGm were from CLA, cholinergic cell a hub for intracortical communication (Edelstein and De- groups of the BF, basolateral nucleus of amygdala (BLA), naro 2004). SNc/VTA and monoaminergic nuclei of the brainstem. Similar to CLA, ACh-containing cells of the BF project As well recognized, the CLA is reciprocally linked to widely throughout the cortex (Bigl et al. 1982; Rye et al. virtually all areas of the cortex, including mPFC (Mark- 1984; Saper 1984; Woolf et al. 1984; Luiten et al. 1987; owitsch et al. 1984; Sloniewski et al. 1986; Sherk 1988; Woolf 1991; Gritti et al. 1997), and more densely to limbic Witter et al. 1988; Kowianski et al. 1998; Majak et al. than to non-limbic regions of cortex (Bigl et al. 1982; 2000; Zhang et al. 2001). Using anterograde tracers, Zhang Woolf et al. 1984; Woolf 1991). The present location of et al. (2001) showed that CLA mainly targets AGm of the labeled cells of the BF (SI/VP) corresponds to sites of 123 Brain Struct Funct (2007) 212:149–179 169

Fig. 9 Brightfield photomicrographs depicting retrogradely labeled neurons in the midline thalamus (a), the dorsal (DR) and median raphe (MR) nuclei (b), the supramammillary nucleus (SUM)(c) and the locus coeruleus (LC)(d) produced by a FG injection in IL. Note the presence of a dense aggregate of labeled cells ipsilateral (to the IL injection) within nucleus reuniens of the rostral ventral midline thalamus as well as dense cell labeling in DR, MR, SUM, and LC. Scale bar for a = 130 lm; b, c = 300 lm; d = 350 lm. See list for abbreviations

Fig. 10 Brightfield photomicrographs depicting retrogradely labeled neurons at a rostral (a) and caudal (b) level of the ventral hippocampus produced by a FG injection in IL. Note the presence massive cell labeling throughout the extent of CA1 and the subiculum, rostrally (a) and the ventral subiculum, caudally (b). Scale bar for a, b = 1,000 lm. See list for abbreviations

123 170 Brain Struct Funct (2007) 212:149–179

Fig. 11 Summary of main A sources of afferent projections to AGm (a) and AC (b) from the Non-Limbic Limbic Basal Thalamus cortex (non-limbic and Cortex Cortex Forbrain CL MD MO CLA ‘limbic’), basal forebrain, FPm CM heavy labeling VO AGm DBh PV amygdala, thalamus, VLO SSI SI RH moderate labeling hypothalamus, midbrain, and AC SSII MA RE PL light labeling pons/medulla. Red, green, and OC2 VM AId GP RSC PT blue represents heavy, AIp VP AGl moderate, and light projections, PRC AM GI IAM IL respectively, to AGm and AC. AUD IMD ECT Non-limbic cortex is defined as PAp PC EC motor, somatosensory, special OC1 VAL TE CA1 LP sensory, and associational LO regions of cortex, while ‘limbic’ cortex is defined as remaining AGm regions of cortex including orbital cortices and the hippocampal formation. See list Amygdala Hypothalamus Midbrain Pons/medulla for abbreviations BLA LHy VTA DR BMA PH SNc PPT MEA ZI PAG LC PA SUM SUM MR TR CLi NI MRF RPO IP RPC B Non-Limbic Limbic Basal Thalamus Cortex Cortex Forbrain AM CL AC CLA AGm RE PL PAp SI RH RSC IL TTd IAM OC2 MO BST MD FPm VO DBh PC AUD PRC LPO CL AGl EC MA CM GI CA1 TE IMD AIp SSII PV ECT PC VM PT AC

Amygdala Hypothalamus Midbrain Pons/medulla BLA LHy VTA DR BMA PAG SNc LC PH IP NI SUM CLi LDT LM MR PB anterograde BF injections (Luiten et al. 1987) that gave rise Zaborszky et al. 1986; Gritti et al. 1997, 2003; Zaborszky to significant labeling of mPFC, particularly within AGm 2002). (see their Fig. 6, p. 240). Cholinergic projections to cortex Although earlier reports have described projections from reportedly serve important roles in behavioral/EEG arousal the (BLA) to mPFC (Kita and Kitai 1990; McDonald 1987, and attentional mechanisms (Woolf 1991; Nunez 1996; 1991; Bacon et al. 1996; Gabbott et al. 2006), those to Jimenez-Capdeville et al. 1997; Zaborszky et al. 1999; AGm appear to be considerably less pronounced than Cape et al. 2000; Zaborszky 2002; Jones 2004; Sarter et al. shown here. Evidence suggests that BLA to mPFC pro- 2005). It worth noting, however, that the ACh region of jections (particularly to IL/PL) convey information on the BF, contains other types of neurons, prominently including emotional properties of sensory stimuli (Garcia et al. 1999; GABAergic and glutamatergic cells, that project to most of LeDoux 2000; Pare et al. 2004; Gabbott et al. 2006; Vertes the cortical sites as ACh neurons (Brashear et al. 1986; 2006), involved in executive functions of the mPFC

123 Brain Struct Funct (2007) 212:149–179 171

Fig. 12 Summary of main A sources of afferent projections Non-Limbic Limbic Basal Thalamus to PL (a) and IL (b) from the Cortex Forbrain cortex (non-limbic and Cortex PT PV FPm MO CLA ‘limbic’), basal forebrain, MD heavy labeling VO TTd AGm RE amygdala, thalamus, AC DBh RH moderate labeling hypothalamus, midbrain, and RSC PL LPO IL IMD pons/medulla. Red, green, and EN light labeling AId IAM VP blue represents heavy, AIv CL moderate, and light projections, AIp CA1 respectively, to PL and IL. Non- SUB limbic cortex is defined as PRC motor, somatosensory, special EC sensory, and associational ECT regions of cortex, while ‘limbic’ cortex is defined as remaining PL regions of cortex including orbital cortices and the hippocampal formation. See list Amygdala Hypothalamus Midbrain Pons/medulla for abbreviations BLA SUM VTA DR BMA LM PAG LC TR LHy IP MR PA PH SNc COA B Non-Limbic Limbic Basal Thalamus Cortex Cortex Forbrain RE RH IL DBh FPm PT CA1 CLA RSC PV SUB TTd MD PL EN IAM AIp MS PRC LS IMD EC MPO CM AC SI ECT

IL

Amygdala Hypothalamus Midbrain Pons/medulla BLA SUM VTA DR BMA CLi LDT LHy TR AH PAG MR COA PAG SNc LC LA NI PA RPO

(Salinas et al. 1993; Balleine et al. 2003; Pare 2003; In an examination of cortical afferents to AGm, Reep Floresco and Ghods-Sharifi 2007). et al. (1990) made control injections in AC. In general accord with present findings, they described afferents to Anterior cingulate cortex AC from AGm, various regions of RSC, and from primary and secondary visual cortices, but failed to Similar to AGm, the main sources of afferents to the identify them from PAp, parahippocampal cortices (PRC anterior AC were from regions of cortex and the thalamus. and EC) and HF. These differences likely involve the As discussed below, however, cortical input to AC differs fact that our injections were mainly rostral, theirs caudal, from that to AGm. The primary sources of cortical affer- in AC. ents to AC were from FPm, other regions of mPFC (mainly In a recent comprehensive examination of intrinsic AC from AC and dorsal PL), PAp, RSC, PRC, entorhinal and connections, Jones et al. (2005) reported that: (1) the rostral secondary visual cortices, as well as CA1/subiculum of HF. one third of AC is primarily connected with IL, PL and Projections were strongest from AC, PAp, and RSC. itself (rostral AC); (2) dorsal and ventral zones of the

123 172 Brain Struct Funct (2007) 212:149–179 caudal two-thirds of AC are extensively interconnected; mid-lateral regions of the thalamus. This involves projec- and (3) the caudal RSC projects to the rostral ACm, while tions from lateral MD, VAL (lightly), VM, CL, PC, and the rostral RSC projects to the caudal AC. The latter anteromedial (AM) nuclei of thalamus. Conde et al. (1990) findings are consistent with present and previous results described similar findings, but also projections (not seen (van Groen and Wyss 1990a, 1992, 2003; Risold et al. here) from PO and LD of thalamus. The conflicting results 1997; Shibata et al. 2004) showing that RSC strongly tar- could involve the (partial) inclusion of AGm in their AC gets AC. Based on extensive RSC connections with AC, injections (Conde et al. 1990, 1995). and additionally with parts of the limbic thalamus, subic- In accord with present findings, van Groen et al. (1999) ulum/postsubiculum, and occipital cortex, van Groen and described massive AM projections to AC, mainly origi- Wyss (2003) proposed that RSC is a focal point for the nating from the ventromedial AM. As has been demon- integration of limbic information. As they noted, RSC is an strated (Sripanidkulchai and Wyss 1986; Shibata and Kato essential component of Papez’s circuit (Papez 1937) and 1993; van Groen et al. 1999), there are marked differ- RSC lesions produce marked deficits in spatial navigation ences in projections from the anterior thalamus to the and memory (Sutherland et al. 1988; Cooper and Mizumori anterior and posterior AC (or RSC), such that AM dis- 2001; Vann and Aggleton 2002). tributes selectively to AC and AV/AD to RSC. While The PAp is a large area, bordered rostrally by the earlier reports described (at best) modest projections from hindlimb sensorimotor cortex, caudally by primary/sec- the midline thalamus to AC (Conde et al. 1990, 1995),we ondary visual cortices, medially by RSC and laterally by showed that several nuclei of the midline thalamus, SSI (Corwin and Reep 1998; Swanson 1998). Reep and including PV, PT, IAM, CM, RH, and RE, distribute colleagues (Reep et al. 1990, 1994, 2003; Corwin and Reep significantly to AC. RE/RH projections to AC have re- 1998; Cheatwood et al. 2005) have described an extended cently been demonstrated using anterograde tracers circuitry involving the medial PAp, AGm, Oc2M, VLO (Vertes et al. 2006). and the dorsocentral striatum that participates in directed spatial attention, and when disrupted, produces spatial ne- Other inputs to AC glect (Corwin et al. 1986; Crowne et al. 1986; King et al. 1989; King and Corwin 1993; Van Vleet et al. 2003). Similar to AGm, AC receives input from several (non- In addition to afferents from orbital, mPFC and visual thalamic) subcortical sites including the CLA, TTd, MA, cortices (and associated thalamic nuclei), PAp receives SI, BST of the BF, the BLA/BMA of amygdala, the pos- input from somatosensory and auditory regions of cortex terior nucleus (PH) of hypothalamus, the mesencephalic (Chandler et al. 1992; Reep et al. 1994). In this respect, PAG, SNc and VTA of the midbrain, and monoaminergic PAp, like RSC, is a mulitmodal integration zone. In accord groups of the brainstem. This is consistent with the findings with earlier reports (Reep et al. 1990; Corwin and Reep of several previous reports of diverse subcortical forebrain 1998), we described strong PAp to AGm projections, but (Bigl et al. 1982; Markowitsch et al. 1984; Rye et al. 1984; also observed equally dense medial PAp projections to AC. Saper 1984; Woolf et al. 1984; Sloniewski et al. 1986; This projection does not seem to have been reported pre- Luiten et al. 1987; McDonald 1987, 1991; Sherk 1988; viously. Witter et al. 1988; Woolf 1991; Vertes et al. 1995; Bacon As indicated, there is a progressive increase in the et al. 1996; Gritti et al. 1997; Kowianski et al. 1998; Majak strength of hippocampal and parahippocampal projections et al. 2000; Zhang et al. 2001; Dong and Swanson 2006a, b; from the dorsal to the ventral mPFC. Similar to AGm, Gabbott et al. 2006) and brainstem inputs to AC (Swanson parahippocampal afferents to AC were shown to primarily 1982; Foote et al. 1983; Waterhouse et al. 1983; Vertes and originate from PRC and lateral EC and to a much lesser Martin 1988; Herrero et al. 1991a; Vertes 1991; Cameron degree from the ectorhinal cortex (ECT). This is consistent et al. 1995; Morin and Meyer-Bernstein 1999; Vertes et al. with the findings of several earlier reports (Swanson and 1999; Carr and Sesack 2000a, b; Berridge and Waterhouse Kohler 1986; Insausti et al. 1997; Delatour and Witter 2003). 2002). While previous studies have demonstrated projec- Regarding VTA and SNc, it is well documented that tions from the hippocampus (CA1/subiculum) to the ven- VTA is a major source of projections to the mPFC (for tral mPFC (IL/PL) (Swanson 1981; Irle and Markowitsch review, Seamans and Yang 2004), but projections from 1982; Ferino et al. 1987; Jay et al. 1989; van Groen and SNc to mPFC are less well established. In support of Wyss 1990b; Jay and Witter 1991; Carr and Sesack 1996), present findings, however, others have demonstrated this is the first report to describe them to the dorsal mPFC: moderate SNc projections to the mPFC (Loughlin and moderate to AC and light to AGm. Fallon 1984; Conde et al. 1995) and, like here, have shown In general accord with previous reports, we showed that that they predominately originate from medial parts of SNc afferents to AC from ‘relay’ nuclei of thalamus arise from and distribute to the dorsal and ventral mPFC. 123 Brain Struct Funct (2007) 212:149–179 173

Prelimbic cortex from the mPFC to the hippocampus (Wouterlood et al. 1990; Bokor et al. 2002). For instance, we demonstrated Probably the most significant change in the distribution of that all divisions of the mPFC distribute heavily to RE afferents to PL (and IL) from those to AGm/AC was a (Vertes 2002; McKenna and Vertes 2004), and RE in turn progressive decline in cortical afferents to the ventral is the source of pronounced projections to HF (CA1/su- mPFC. Specifically, there was a marked reduction in biculum) (Vertes et al. 2006, 2007). cortical projections, mainly involving sensory (special Thalamic afferents to PL originate almost entirely from sensory and somatosensory), motor or associational re- the midline thalamus and MD. Of the midline groups, the gions (RSC and PAp) of cortex, to the ventral as com- PT, PV, IAM, CM, rhomboid, and reuniens nuclei dis- pared to the dorsal mPFC. tribute densely to PL. Previous reports using anterograde or With respect to cortical input, however, PL nonetheless retrograde tracers have described similar findings (Her- receives projections from several regions of cortex kenham 1978; Ohtake and Yamada 1989; Berendse and including FPm, anterior PL, medial (MO) and VO, IL, Groenewegen 1991; Conde et al. 1995; Moga et al. 1995; dorsal and (rostral) posterior agranular insular, perirhinal Risold et al. 1997; Van der Werf et al. 2002; Vertes et al. and entorhinal cortices. In addition, the CA1/subiculum 2006). We recently demonstrated that RE and RH distrib- distributes densely to PL—much heavier than to AC or ute throughout the mPFC, terminating heavily in IL/PL, AGm. These findings are consistent with previous dem- mainly within layers 1 and 5/6 of these regions (Vertes onstrations of significant orbital and limbic cortical affer- et al. 2006). It has been suggested that midline thalamic ents to PL (Reep and Winans 1982; Swanson and Kohler input to the mPFC (and other parts of limbic cortex) par- 1986; Jay et al. 1989; Hurley et al. 1991; Jay and Witter ticipate in processes of arousal and attention (Van der Werf 1991; Yasui et al. 1991; Insausti et al. 1997; Shi and et al. 2002) and/or serve to gate the flow of information to Cassell 1998; Delatour and Witter 2002; Gabbott et al. and among limbic forebrain structures (Vertes 2006; Vertes 2003; Jasmin et al. 2004; Vertes 2004). et al. 2006). The insular cortex (INC) interconnects with the ventral mPFC (PL and IL) in a topographically organized manner Other inputs to PL (Allen et al. 1991; Yasui et al. 1991; Shi and Cassell 1998; Gabbott et al. 2003; Jasmin et al. 2004, present results). For We recently reviewed evidence indicating that IL and PL instance, we showed that the rostral INC (mainly AId) pri- of rats serve separate and distinct functions (Vertes 2006). marily targets PL and the caudal INC (mainly AIp) targets IL is primarily involved in affective/visceromotor func- IL. Consistent with this, Gabbott et al. (2003) demonstrated tions, homologous to the orbitomedial PFC of primates, that: (1) AId primarily projects to PL and dysgranular while PL (and ventral AC) participates in cognitive/limbic insular (DI)/AIp mainly to IL; (2) AIv and the GI distribute functions homologous to the lateral/dorsolateral cortex of lightly to IL/PL; and (3) AId fibers to PL mainly terminate primates. Associated with its role in cognition, PL dis- in layers 2/3 and form asymmetric connections with tributes to a relatively small groups of structures that dendritic spines of PL cells. In a complementary manner, subserve cognition and have been designated the ‘PL cir- there are strong (and selective) return projections from PL to cuit’ (Alexander et al. 1990; Groenewegen et al. 1990). AId, and from IL to AIp (Sesack et al. 1989; Hurley et al. They mainly include the insular cortex (AId), the hippo- 1991; Gabbott et al. 2003; Vertes 2004). campus (via RE), CLA, ACC, BLA, MD, RE, and VTA. Supporting present findings, several reports have dem- Lesions of each of these structures, like those of PL, pro- onstrated massive hippocampal projections (CA1/subicu- duce deficits in delayed response tasks and memory (Har- lum) to PL (Swanson 1981; Irle and Markowitsch 1982; rison and Mair 1996; Seamans et al. 1998; Floresco et al. Ferino et al. 1987; Jay et al. 1989; van Groen and Wyss 1999; Romanides et al. 1999; Kalivas et al. 2001; Barros 1990b; Jay and Witter 1991; Carr and Sesack 1996). In et al. 2002;Pare2003; Roozendaal et al. 2004; Seamans contrast, however, with earlier reports (Ferino et al. 1987; and Yang 2004; Cain et al. 2006). Jay et al. 1989), we showed stronger CA1/subicular pro- As demonstrated here, PL receives input from each of its jections to IL than to PL. Interestingly, despite strong HF to major targets including AId, HF, CLA, ACC (via VP and mPFC projections, there are no direct return projections MD), RE, and VTA. Dopaminergic VTA afferents to PL from the mPFC to the hippocampus (Beckstead 1979; (and mPFC) have been extensively examined (Seamans Room et al. 1985; Sesack et al. 1989; Hurley et al. 1991; and Yang 2004) and appear to play a critical role in PL- Takagishi and Chiba 1991; Vertes 2004). In the absence of associated behaviors. Using a disconnection procedure such projections, we have suggested (Vertes 2002, 2004, wherein the VTA and HF were temporarily disrupted on 2006; Vertes et al. 2007) that the RE of the midline thal- opposite sides of the brain, Seamans et al. (1998) showed amus is an important relay in the transfer of information that the simultaneous blockade of hippocampal inputs to 123 174 Brain Struct Funct (2007) 212:149–179

PL and dopamine (D1) receptors at PL disrupted perfor- tively few additional sources of visceral/limbic input to IL mance on delayed, but not on non-delayed, versions of the (or to the mPFC). They include the LS and horizontal the radial arm maze (RAM) task. Regarding the possible nucleus of the diagonal band (DBh) of the BF, the baso- role of dopamine in hippocampal-prefrontal interactions, lateral (BLA) and TR of amygdala, and the SUM of the

Seamans et al. (1998) suggested that: ‘D1 receptors in the hypothalamus. In contrast, the midline thalamus, particu- PFC may modulate the transfer of spatial information from larly the ventral midline thalamus, receives widespread the hippocampus to the PFC at a time when a prospective ‘limbic’ afferents from diverse structures of the BF, series of response must be organized and executed.’ amygdala, hypothalamus and brainstem (Cornwall and Phillipson 1988; Chen and Su 1990; Risold et al. 1997; Infralimbic cortex Krout et al. 2002; Van der Werf et al. 2002; McKenna and Vertes 2004). These findings, coupled with the demon- By comparison with other subdivisions of the mPFC, IL stration that the midline thalamus projects heavily to IL receives considerably fewer inputs from adjacent regions (and to PL), suggest that midline thalamus is a primary of the mPFC. Within the mPFC, PL is the main source of route by which limbic information reaches the mPFC afferents to IL. In a similar manner, cortical inputs to IL are (Vertes 2006). essentially limited to PL, AId, HF, and parahippocampal structures. There is a virtual absence of projections from Other inputs to IL sensorimotor, special sensory or associational regions of cortex to IL. Although IL receives fewer overall inputs than do other Insular cortical projections to IL primarily originate divisions of mPFC, it is nonetheless the target of some from AIp and to a much lesser extent from the dysgranular subcortical limbic structures that do not project elsewhere INC, dorsal to AIp. Consistent with this, using anterograde in the mPFC—or certainly to the same degree as to IL. tracers, Shi and Cassell (1998) demonstrated that AIp These include the LS, DBh, BLA, TR, LHy, SUM, VTA, selectively targets IL of mPFC. AIp receives convergent PAG, DR, MR, NI, and the LDT. This is consistent with visceral and limbic input (Saper 1982; Ruggiero et al. previous demonstrations of relatively substantial projec- 1987; Allen et al. 1991), and reportedly represents a major tions from these sites to IL (Swanson 1982; Rye et al. 1984; source of viscerosensory information to the visceromotor McDonald 1987, 1991; Bacon et al. 1996; Herrero et al. cortex—or IL. 1991a, b; Vertes 1991, 1992; Cameron et al. 1995; Morin Despite limited (neo/allo) cortical input to IL, the hip- and Meyer-Bernstein 1999; Vertes et al. 1999; Carr and pocampus (CA1/subiculum) distributes massively to IL. If, Sesack 2000a, b; Goto et al. 2001; Olucha-Bordonau et al. as indicated, IL represents a visceromotor center, hippo- 2003; Gabbott et al. 2006). Regarding LDT, it is well campal projections to IL may serve to associate past events recognized that LDT is a major source of cholinergic (including their affective quality) to present ones for afferents to the thalamus and parts of the BF (Hallanger impending actions. In this regard, a characteristic feature of and Wainer 1988), but direct LDT projections to the cortex bilateral damage to the ventromedial prefrontal cortex in (or to mPFC) are not well documented. In line, however, humans is a pervasive blunted affect (hypoemotionality) with the present demonstration of moderate LDT projec- coupled with generally inappropriate and often strongly tions (and some PPT projections) to the mPFC, previous negative emotional reactions to relatively minor frustra- reports using various tracers, have similarly identified a tions (Damasio et al. 1990; Barrash et al. 2000; Berlin et al. relatively prominent LDT input to the mPFC (Satoh and 2004; Anderson et al. 2006; Koenigs and Tranel 2007). Fibiger 1986; Cornwall et al. 1990; Herrero et al. 1991b). Related to the foregoing, Mayberg et al. (2005) recently As shown here, they mainly target the ventral mPFC or IL. demonstrated that deep brain stimulation localized to IL These additional afferents undoubtedly supplement those (presumably suppressing IL activity) produced a marked from AIp and the midline thalamus to IL in relaying limbic remission of depression in human subjects. afferent information to IL in visceromotor control. Thalamic afferents to IL largely originate from the same midline thalamic groups that project to PL. They primarily include medial MD, PV, PT, IAM, RH, and RE. Only General summary: an integrative role for the mPFC minor differences were observed in projections to IL and in goal directed behavior PL. Compared with PL, cells projecting to IL were directly aligned along the midline (particularly in MD), and CM Each of the subdivisions of the mPFC receives a fairly distributes much less densely to IL than to PL. unique set of afferent projections. There is a shift dorso- As a putative visceromotor center, IL receives visceral ventrally along the mPFC from predominantly sensorimo- afferent information from the INC (AIp). There are rela- tor (non-limbic) cortical and thalamic input to dorsal 123 Brain Struct Funct (2007) 212:149–179 175 mPFC, to limbic cortical and thalamic (midline thalamus) References input to the ventral mPFC. Each division of mPFC strongly communicates with immediately adjacent regions, and with Alexander GE, Crutcher MD, DeLong MR (1990) Basal ganglia- the possible exception of IL, each division interconnects thalamocortical circuits: parallel substrates for motor, oculomo- tor, ‘‘prefrontal’’ and ‘‘limbic’’ functions. Prog Brain Res with all others. 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