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• W2063882186 abstract "The primate dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) focus attention on relevant signals and suppress noise in cognitive tasks. However, their synaptic interactions and unique roles in cognitive control are unknown. We report that two distinct pathways to DLPFC area 9, one from the neighboring area 46 and the other from the functionally distinct ACC, similarly innervate excitatory neurons associated with selecting relevant stimuli. However, ACC has more prevalent and larger synapses with inhibitory neurons and preferentially innervates calbindin inhibitory neurons, which reduce noise by inhibiting excitatory neurons. In contrast, area 46 mostly innervates calretinin inhibitory neurons, which disinhibit excitatory neurons. These synaptic specializations suggest that ACC has a greater impact in reducing noise in dorsolateral areas during challenging cognitive tasks involving conflict, error, or reversing decisions, mechanisms that are disrupted in schizophrenia. These observations highlight the unique roles of the DLPFC and ACC in cognitive control. The primate dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) focus attention on relevant signals and suppress noise in cognitive tasks. However, their synaptic interactions and unique roles in cognitive control are unknown. We report that two distinct pathways to DLPFC area 9, one from the neighboring area 46 and the other from the functionally distinct ACC, similarly innervate excitatory neurons associated with selecting relevant stimuli. However, ACC has more prevalent and larger synapses with inhibitory neurons and preferentially innervates calbindin inhibitory neurons, which reduce noise by inhibiting excitatory neurons. In contrast, area 46 mostly innervates calretinin inhibitory neurons, which disinhibit excitatory neurons. These synaptic specializations suggest that ACC has a greater impact in reducing noise in dorsolateral areas during challenging cognitive tasks involving conflict, error, or reversing decisions, mechanisms that are disrupted in schizophrenia. These observations highlight the unique roles of the DLPFC and ACC in cognitive control. The ability to keep track of information and one's actions from moment to moment is necessary to accomplish even the simple tasks of everyday life. Lateral prefrontal cortices in primates, especially dorsolateral areas 46 and 9, have a key role in the process broadly called working memory (Goldman-Rakic, 1995Goldman-Rakic P.S. Cellular basis of working memory.Neuron. 1995; 14: 477-485Abstract Full Text PDF PubMed Scopus (1741) Google Scholar, Tanji and Hoshi, 2008Tanji J. Hoshi E. Role of the lateral prefrontal cortex in executive behavioral control.Physiol. Rev. 2008; 88: 37-57Crossref PubMed Scopus (305) Google Scholar). Lesions of areas 46 and 9 show similar and cumulative deficits in monitoring the sequence of information in working memory tasks (Petrides, 2000Petrides M. The role of the mid-dorsolateral prefrontal cortex in working memory.Exp. Brain Res. 2000; 133: 44-54Crossref PubMed Scopus (325) Google Scholar, Muller and Knight, 2006Muller N.G. Knight R.T. The functional neuroanatomy of working memory: contributions of human brain lesion studies.Neuroscience. 2006; 139: 51-58Crossref PubMed Scopus (260) Google Scholar). The ACC is involved in affective and mnemonic processing, but is also engaged in cognitive operations, especially in tasks with high cognitive demands. However, there is no general agreement on the specific role of dorsolateral areas and the ACC in cognitive control (Devinsky et al., 1995Devinsky O. Morrell M.J. Vogt B.A. Contributions of anterior cingulate cortex to behaviour.Brain. 1995; 118: 279-306Crossref PubMed Scopus (2666) Google Scholar, Carter et al., 1999Carter C.S. Botvinick M.M. Cohen J.D. The contribution of the anterior cingulate cortex to executive processes in cognition.Rev. Neurosci. 1999; 10: 49-57Crossref PubMed Scopus (474) Google Scholar). To perform a task at hand successfully it is necessary to pay attention to relevant information and ignore irrelevant signals. Damage to dorsolateral areas or the ACC impairs cognitive tasks, especially in the presence of distracters (Posner and DiGirolamo, 1998Posner M.I. DiGirolamo G.J. Executive attention: conflict, target detection, and cognitive control.in: Parasuraman R. The Attentive Brain. The MIT Press, Cambridge1998: 401-423Google Scholar, Knight et al., 1999Knight R.T. Staines W.R. Swick D. Chao L.L. Prefrontal cortex regulates inhibition and excitation in distributed neural networks.Acta Psychol. (Amst.). 1999; 101: 159-178Crossref PubMed Google Scholar, Rushworth et al., 2004Rushworth M.F. Walton M.E. Kennerley S.W. Bannerman D.M. Action sets and decisions in the medial frontal cortex.Trends Cogn. Sci. 2004; 8: 410-417Abstract Full Text Full Text PDF PubMed Scopus (796) Google Scholar, Lee et al., 2007Lee D. Rushworth M.F. Walton M.E. Watanabe M. Sakagami M. Functional specialization of the primate frontal cortex during decision making.J. Neurosci. 2007; 27: 8170-8173Crossref PubMed Scopus (97) Google Scholar). Corticocortical pathways in primates are excitatory and mainly form synapses with other excitatory neurons (White, 1989White E.L. Cortical Circuits. Synaptic Organization of the Cerebral Cortex. Structure, Function and Theory. Birkhäuser, Boston1989Google Scholar, Somogyi et al., 1998Somogyi P. Tamas G. Lujan R. Buhl E.H. Salient features of synaptic organisation in the cerebral cortex.Brain Res. Brain Res. Rev. 1998; 26: 113-135Crossref PubMed Scopus (711) Google Scholar). Theoretical computational studies have proposed that interactions between excitatory neurons underlie selection of relevant signals (Wang, 2001Wang X.J. Synaptic reverberation underlying mnemonic persistent activity.Trends Neurosci. 2001; 24: 455-463Abstract Full Text Full Text PDF PubMed Scopus (703) Google Scholar). A smaller but significant proportion of axons from excitatory neurons form synapses with inhibitory GABAergic neurons, triggering inhibition at the site of termination. Though fewer in number than excitatory neurons, inhibitory neurons are considerably more diverse in morphology and function (Markram et al., 2004Markram H. Toledo-Rodriguez M. Wang Y. Gupta A. Silberberg G. Wu C. Interneurons of the neocortical inhibitory system.Nat. Rev. Neurosci. 2004; 5: 793-807Crossref PubMed Scopus (1945) Google Scholar). In primates, inhibitory neurons can be grouped into three nonoverlapping neurochemical classes identified by their expression of the calcium-binding proteins parvalbumin (PV), calretinin (CR), and calbindin (CB), though each class contains several morphological types (DeFelipe, 1997DeFelipe J. Types of neurons, synaptic connections and chemical characteristics of cells immunoreactive for calbindin-D28K, parvalbumin and calretinin in the neocortex.J. Chem. Neuroanat. 1997; 14: 1-19Crossref PubMed Scopus (445) Google Scholar). PV neurons innervate the proximal dendrites, soma, or axon initial segment of other neurons, eliciting strong inhibition (DeFelipe et al., 1989bDeFelipe J. Hendry S.H. Jones E.G. Visualization of chandelier cell axons by parvalbumin immunoreactivity in monkey cerebral cortex.Proc. Natl. Acad. Sci. USA. 1989; 86: 2093-2097Crossref PubMed Scopus (304) Google Scholar, Thomson and Deuchars, 1997Thomson A.M. Deuchars J. Synaptic interactions in neocortical local circuits: dual intracellular recordings in vitro.Cereb. Cortex. 1997; 7: 510-522Crossref PubMed Scopus (235) Google Scholar). CB neurons innervate mostly distal dendrites of excitatory neurons (DeFelipe et al., 1989aDeFelipe J. Hendry S.H. Jones E.G. Synapses of double bouquet cells in monkey cerebral cortex visualized by calbindin immunoreactivity.Brain Res. 1989; 503: 49-54Crossref PubMed Scopus (198) Google Scholar, Peters and Sethares, 1997Peters A. Sethares C. The organization of double bouquet cells in monkey striate cortex.J. Neurocytol. 1997; 26: 779-797Crossref PubMed Scopus (65) Google Scholar). CR neurons preferentially innervate other inhibitory neurons in the upper cortical layers, and thus have a disinhibitory role (Meskenaite, 1997Meskenaite V. Calretinin-immunoreactive local circuit neurons in area 17 of the cynomolgus monkey, Macaca fascicularis.J. Comp. Neurol. 1997; 379: 113-132Crossref PubMed Scopus (141) Google Scholar, DeFelipe et al., 1999DeFelipe J. Gonzalez-Albo M.C. del Rio M.R. Elston G.N. Distribution and patterns of connectivity of interneurons containing calbindin, calretinin, and parvalbumin in visual areas of the occipital and temporal lobes of the macaque monkey.J. Comp. Neurol. 1999; 412: 515-526Crossref PubMed Scopus (139) Google Scholar, Melchitzky et al., 2005Melchitzky D.S. Eggan S.M. Lewis D.A. Synaptic targets of calretinin-containing axon terminals in macaque monkey prefrontal cortex.Neuroscience. 2005; 130: 185-195Crossref PubMed Scopus (42) Google Scholar). Disinhibition by CR neurons is thought to enhance signals, whereas CB neurons dampen activity at the fringes of active cortical columns to suppress noise, collectively enhancing the signal-to-noise ratio of relevant activity in working memory (Wang et al., 2004Wang X.J. Tegner J. Constantinidis C. Goldman-Rakic P.S. Division of labor among distinct subtypes of inhibitory neurons in a cortical microcircuit of working memory.Proc. Natl. Acad. Sci. USA. 2004; 101: 1368-1373Crossref PubMed Scopus (241) Google Scholar). Prefrontal pathways might interact with these inhibitory neurons to improve response selectivity in behavioral tasks, which is disrupted after blockade of GABAergic activity (Rao et al., 1999Rao S.G. Williams G.V. Goldman-Rakic P.S. Isodirectional tuning of adjacent interneurons and pyramidal cells during working memory: evidence for microcolumnar organization in PFC.J. Neurophysiol. 1999; 81: 1903-1916PubMed Google Scholar, Rao et al., 2000Rao S.G. Williams G.V. Goldman-Rakic P.S. Destruction and creation of spatial tuning by disinhibition: GABA(A) blockade of prefrontal cortical neurons engaged by working memory.J. Neurosci. 2000; 20: 485-494Crossref PubMed Google Scholar). For example, microstimulation of the interareal pathway from prefrontal area 8 improves sensitivity to target stimuli in visual cortex by increasing their gain and decreasing noise from competing signals (Moore et al., 2003Moore T. Armstrong K.M. Fallah M. Visuomotor origins of covert spatial attention.Neuron. 2003; 40: 671-683Abstract Full Text Full Text PDF PubMed Scopus (286) Google Scholar, Reynolds and Chelazzi, 2004Reynolds J.H. Chelazzi L. Attentional modulation of visual processing.Annu. Rev. Neurosci. 2004; 27: 611-647Crossref PubMed Scopus (778) Google Scholar). We reasoned that because ACC and dorsolateral areas differ in their capacity for inhibitory control in cognitive tasks, they might interact differentially with inhibitory neurons. One possibility is that the functionally distinct ACC might help reduce noise by innervating CB neurons in dorsolateral area 9, whereas area 46 might innervate more CR neurons and disinhibit the related area 9, particularly in the upper layers where these interneurons are most prevalent (Condé et al., 1994Condé F. Lund J.S. Jacobowitz D.M. Baimbridge K.G. Lewis D.A. Local circuit neurons immunoreactive for calretinin, calbindin D-28k or parvalbumin in monkey prefrontal cortex: distribution and morphology.J. Comp. Neurol. 1994; 341: 95-116Crossref PubMed Scopus (409) Google Scholar, Gabbott et al., 1997Gabbott P.L. Dickie B.G. Vaid R.R. Headlam A.J. Bacon S.J. Local-circuit neurons in the medial prefrontal cortex (areas 25, 32 and 24b) in the rat: morphology and quantitative distribution.J. Comp. Neurol. 1997; 377: 465-499Crossref PubMed Scopus (215) Google Scholar, Gonchar and Burkhalter, 1997Gonchar Y. Burkhalter A. Three distinct families of GABAergic neurons in rat visual cortex.Cereb. Cortex. 1997; 7: 347-358Crossref PubMed Scopus (392) Google Scholar, Kawaguchi and Kubota, 1997Kawaguchi Y. Kubota Y. GABAergic cell subtypes and their synaptic connections in rat frontal cortex.Cereb. Cortex. 1997; 7: 476-486Crossref PubMed Scopus (1044) Google Scholar, Dombrowski et al., 2001Dombrowski S.M. Hilgetag C.C. Barbas H. Quantitative architecture distinguishes prefrontal cortical systems in the rhesus monkey.Cereb. Cortex. 2001; 11: 975-988Crossref PubMed Google Scholar). The synaptic underpinnings of working memory functions for selection and suppression of signals are not known. To address this issue, we investigated the synaptic organization of dorsolateral area 46 and ACC (area 32) with excitatory and inhibitory neurons in dorsolateral area 9. This design allowed us to study the synaptic pathway between two related areas with respect to working memory (dorsolateral area 46 to dorsolateral area 9), and between two distinct areas (ACC to dorsolateral area 9). We provide evidence that the ACC has more prevalent and larger synapses with inhibitory neurons in area 9, in patterns suggesting increased inhibitory control in demanding cognitive tasks. To compare the organization of two pathways, one from dorsolateral area 46 and the other from ACC (area 32), we investigated their synapses within the upper layers (I-IIIa) of area 9. Figure 1 summarizes the essence of our experimental approach. Briefly, injection of distinct neural tracers in areas 32 (Figure 1A, gray and white) and 46 (Figure 1B, gray and black) labeled axon terminals in area 9. We examined at the light and electron microscope (EM) sites in area 9 with labeled terminals among excitatory and inhibitory neurons, which were labeled for PV, CB, or CR (Figure 1B, dotted fill and inset). Labeled terminals from the two pathways were dense in the central anteroposterior extent of area 9. Axon terminals from area 32 were diffuse and widespread, with a strong bias for the upper layers (I–IIIa; Figure 1C), and from area 46 they were more restricted and columnar, including the middle layers (IIIb–Va; Figure 1D). As summarized in Figure 2A, we found three major types of terminals (boutons) from axons originating in area 32 (n = 345 boutons, from three cases) and area 46 (n = 325, from two cases), based on their synapses and postsynaptic targets in area 9. The first and largest group formed single synapses with spines emerging from spiny dendrites of excitatory neurons (from area 32, 69% of labeled boutons; from area 46, 80%; Figures 2A, bouton 1; 2B, 2C, and 2H; see Table S1, available online). The second group of labeled boutons innervated aspiny or sparsely spiny dendritic shafts, characteristic of cortical inhibitory neurons (area 32, 18%; area 46, 13%; Figures 2A, bouton 2; 2D, 2E, and 2I). The third group consisted of multisynaptic boutons that formed synapses with two or more spines (area 32, 6%; area 46, 5%; Figures 2A, bouton 3e; 2F and 2J), or 1 or 2 spines and an aspiny or sparsely spiny dendritic shaft (area 32, 7%; area 46, 3%; Figures 2A, bouton 3m; 2G and 2K). Only a few labeled boutons formed synapses on shafts of spiny dendrites (≤1%). Labeled boutons that appeared to be non-synaptic varicosities were not included in this analysis (4% for area 32; 8% for area 46). We classified boutons with major diameters less than 1.0 μm (2D analysis), or volumes < 0.2 μm3 (3D analysis) as small, and boutons above this size as large, based on cluster analysis (p < 0.01; Figures 3A–3C). Bouton size is correlated with the number of synaptic vesicles (Germuska et al., 2006Germuska M. Saha S. Fiala J. Barbas H. Synaptic distinction of laminar specific prefrontal-temporal pathways in primates.Cereb. Cortex. 2006; 16: 865-875Crossref PubMed Scopus (47) Google Scholar) and synaptic efficacy (Murthy et al., 1997Murthy V.N. Sejnowski T.J. Stevens C.F. Heterogeneous release properties of visualized individual hippocampal synapses.Neuron. 1997; 18: 599-612Abstract Full Text Full Text PDF PubMed Scopus (449) Google Scholar). Small boutons made up the majority in each pathway (Figure 3D, gray bars). A smaller but significant proportion of boutons were large in both pathways (Figure 3D, black bars), but in this respect the two pathways diverged. Boutons from area 32 were larger than boutons from area 46, both at the light microscope (n = 10,920 boutons from 5 cases, measured for major diameter; Figure 3A), and at the synaptic level (n = 197, 2D major diameter, Figure 3B; n = 198, 3D volume, Figure 3C; analysis of variance [ANOVA], Bonferroni's post hoc, p < 0.01). This pathway-specific difference in size was due to a larger overall size of boutons (Figures 3A–3C), as well as a higher frequency of large boutons from area 32 than from area 46 (Figures 3D–3F). Further analysis revealed that the differences in bouton size depended largely on the type of postsynaptic target. In the pathway from area 32 to 9, boutons that innervated dendritic shafts of inhibitory neurons were significantly larger (more than two times) than those from area 46 to 9 (two-way ANOVA, Bonferroni's post hoc, p < 0.01; Figures 4A, red dots; 4B, 4H, and 4I). Similarly, multisynaptic boutons from area 32 were larger (more than two times) than multisynaptic boutons from area 46 (p < 0.01; Figures 4A, triangles; 4B, 4F, 4G, 4J, and 4K). In contrast, boutons innervating single spines were comparatively uniform in size across pathways (p = 0.84; Figures 4A, green dots; 4B, 4D, and 4E), consistent for data obtained from 3D and 2D EM analysis (Table S1). Boutons from area 32 that innervated shafts of inhibitory neurons or ensembles of spines and shafts in area 9 were also more prevalent than those from area 46 (p < 0.05, Figure 4C; Table S1). Overall, the pathway from area 32 to 9 formed more synapses with inhibitory neurons (p < 0.01, Figure 5A), through larger boutons than the pathway from area 46 to 9. The two pathways also differed in their synapses in area 9 with specific neurochemical classes of inhibitory neurons labeled for CB, PV, or CR. Boutons from area 32 formed synapses preferentially with aspiny CB+ dendrites (∼49% of labeled inhibitory targets; Figures 5B and 5C), significantly more than in the pathway from area 46 to 9 (∼22% of labeled targets; p < 0.01; Figures 5D1–5D3). Axons from area 32 formed synapses with a lower but significant proportion of CR+ dendrites (∼36% of labeled targets; Figures 5B, 5E, and 5F). The opposite relationship was seen for the pathway from area 46 to area 9, where about half (∼46%) of the labeled inhibitory targets were CR+ (Figures 5B and 5G), and CB constituted a smaller proportion. However, because axons from area 32 innervated inhibitory neurons at a higher frequency (Figure 5A), the extent of synapses with CR+ elements was comparable in the two pathways (∼6% of all targets; Figure 5B). Boutons from area 32 formed fewer synapses with PV+ neurons in area 9 (∼15% of labeled targets; Figures 5B and 5H) than either CB+ or CR+ neurons. In the pathway from area 46 to 9, the proportion of synapses with PV+ neurons was comparable with synapses with CB+ neurons (∼28% of labeled targets; Figures 5B and 5I). The innervation of PV neurons by the two pathways is comparable to prefrontal-temporal pathways in primates (Medalla et al., 2007Medalla M. Lera P. Feinberg M. Barbas H. Specificity in inhibitory systems associated with prefrontal pathways to temporal cortex in primates.Cereb. Cortex. 2007; 17: i136-i150Crossref PubMed Scopus (51) Google Scholar), but lower than in pathways linking visual areas in rats (Gonchar and Burkhalter, 2003Gonchar Y. Burkhalter A. Distinct GABAergic targets of feedforward and feedback connections between lower and higher areas of rat visual cortex.J. Neurosci. 2003; 23: 10904-10912PubMed Google Scholar). These findings might reflect differences in the proportion of PV inhibitory neurons, which is higher in rat visual and frontal cortices than in monkey prefrontal cortex (Condé et al., 1994Condé F. Lund J.S. Jacobowitz D.M. Baimbridge K.G. Lewis D.A. Local circuit neurons immunoreactive for calretinin, calbindin D-28k or parvalbumin in monkey prefrontal cortex: distribution and morphology.J. Comp. Neurol. 1994; 341: 95-116Crossref PubMed Scopus (409) Google Scholar, Gabbott et al., 1997Gabbott P.L. Dickie B.G. Vaid R.R. Headlam A.J. Bacon S.J. Local-circuit neurons in the medial prefrontal cortex (areas 25, 32 and 24b) in the rat: morphology and quantitative distribution.J. Comp. Neurol. 1997; 377: 465-499Crossref PubMed Scopus (215) Google Scholar, Gonchar and Burkhalter, 1997Gonchar Y. Burkhalter A. Three distinct families of GABAergic neurons in rat visual cortex.Cereb. Cortex. 1997; 7: 347-358Crossref PubMed Scopus (392) Google Scholar, Kawaguchi and Kubota, 1997Kawaguchi Y. Kubota Y. GABAergic cell subtypes and their synaptic connections in rat frontal cortex.Cereb. Cortex. 1997; 7: 476-486Crossref PubMed Scopus (1044) Google Scholar, Dombrowski et al., 2001Dombrowski S.M. Hilgetag C.C. Barbas H. Quantitative architecture distinguishes prefrontal cortical systems in the rhesus monkey.Cereb. Cortex. 2001; 11: 975-988Crossref PubMed Google Scholar). The above findings indicate that the two pathways mainly differed by the higher prevalence of synapses with CB+ inhibitory neurons from the ACC than the area 46 pathway. A majority (74%–80%) of the inhibitory targets of prefrontal pathways were positive for CB, PV, or CR. A smaller proportion of inhibitory targets were morphologically identified as aspiny or sparsely spiny shafts that were immunonegative for CB, PV, or CR, which might be attributed to weak or absent labeling of distal dendrites in the upper cortical layers, suggesting an underestimate of synapses on labeled postsynaptic sites. Alternatively, unlabeled postsynaptic sites might represent the complementary population of inhibitory neurons. For example, in triple-labeled tissue for prefrontal terminals, CB, and CR, unlabeled inhibitory targets could have been PV+. The use of serial sections helped identify and classify postsynaptic elements with a high degree of confidence. Counterbalancing staining methods using gold or tetramethylbenzidine (TMB) yielded consistent results across labeling conditions, suggesting that the pathway specificity found was not due to methodological issues. We also used another approach to classify dendrites as spiny (excitatory) or sparsely spiny (inhibitory), especially because CB and CR also label a minority of pyramidal neurons (DeFelipe et al., 1989aDeFelipe J. Hendry S.H. Jones E.G. Synapses of double bouquet cells in monkey cerebral cortex visualized by calbindin immunoreactivity.Brain Res. 1989; 503: 49-54Crossref PubMed Scopus (198) Google Scholar, del Rio and DeFelipe, 1997del Rio M.R. DeFelipe J. Synaptic connections of calretinin-immunoreactive neurons in the human neocortex.J. Neurosci. 1997; 17: 5143-5154PubMed Google Scholar). In our sample, sparsely spiny dendrites had lower spine densities (<0.5 spines/μm length) than spiny dendrites (>0.5 and up to 4 spines/μm; p < 0.01), consistent with previous studies (Feldman and Peters, 1978Feldman M.L. Peters A. The forms of non-pyramidal neurons in the visual cortex of the rat.J. Comp. Neurol. 1978; 179: 761-793Crossref PubMed Scopus (239) Google Scholar, Larkman, 1991Larkman A.U. Dendritic morphology of pyramidal neurones of the visual cortex of the rat: III. Spine distributions.J. Comp. Neurol. 1991; 306: 332-343Crossref PubMed Scopus (186) Google Scholar, Kawaguchi et al., 2006Kawaguchi Y. Karube F. Kubota Y. Dendritic branch typing and spine expression patterns in cortical nonpyramidal cells.Cereb. Cortex. 2006; 16: 696-711Crossref PubMed Scopus (70) Google Scholar). Further, the average synapse density on shafts of aspiny dendrites (2 synapses/μm), or sparsely spiny dendrites (0.6 synapses/μm) was considerably higher than for spiny dendrites, which virtually had no asymmetric shaft synapses. There was a linear relationship between bouton volume and postsynaptic density (PSD) area across pathways and postsynaptic targets (spine targeting: R2 = 0.51, Figure 6A; shaft targeting: R2 = 0.72, Figure 6D; volume of multisynaptic boutons versus total PSD: R2 = 0.7, not shown; p < 0.01; Table S1). Accordingly, boutons of comparable size that innervated spines had comparable PSD area and spine volume (bouton volume versus spine volume: R2 = 0.49, Figure 6B; spine volume versus PSD: R2 = 0.58, Figure 6C; p < 0.01; Table S1). The same relationships were found for multisynaptic boutons and their postsynaptic targets (spine volume versus PSD: R2 = 0.74–0.81, p < 0.01). However, for boutons innervating dendritic shafts, bouton size was related to synapse size, but not dendritic size (bouton volume versus dendrite diameter: R2 = 0.02, p = 0.53, Figure 6E; dendrite diameter versus PSD: R2 = 0.07, p = 0.21, Figure 6F). To determine whether the two pathways from areas 32 and 46 terminated in similar or distinct compartments of area 9, we used unbiased estimates of populations of unlabeled boutons forming asymmetric synapses in the neuropil around labeled boutons (White, 1989White E.L. Cortical Circuits. Synaptic Organization of the Cerebral Cortex. Structure, Function and Theory. Birkhäuser, Boston1989Google Scholar). In addition to the types of synapses seen for labeled pathways, unlabeled boutons also innervated somata (<1%), or multiple dendrites (<1%). We found a comparable proportion of unlabeled synapses with spines and dendrites as for labeled synapses in each pathway (p > 0.05; Table S1). However, as shown above, the two pathways differed from each other, suggesting that boutons from areas 32 and 46 terminate in distinct compartments of area 9. Unlabeled boutons in the surrounding neuropil (mean volume ± SEM, 0.13 ± 0.02 μm3) were comparable in size with labeled boutons from area 46 (p = 0.42), but were significantly smaller (0.12 ± 0.01 μm3) than boutons from area 32 (p < 0.01), especially those innervating dendritic shafts or multiple postsynaptic sites (Table S1). There was a higher prevalence of large multisynaptic boutons labeled from area 32 than in the surrounding neuropil (∼6% of unlabeled boutons; p < 0.01; Table S1). Further, within the same dendritic segment, synapses from area 32 (PSD area, 0.14 ± 0.02 μm2) were larger than unlabeled synapses (0.07 ± 0.005 μm2; p < 0.05), whereas synapses from area 46 (0.1 ± 0.02 μm2) were comparable in size with unlabeled synapses (0.1 ± 0.03 μm2; p = 0.63) on the same dendrite. We provide evidence that two pathways from ACC and dorsolateral area 46 differ specifically in their synapses with inhibitory neurons in dorsolateral area 9. The pathway from the functionally distinct ACC formed more and larger synapses with inhibitory neurons, and targeted preferentially the neurochemical class of calbindin inhibitory neurons, than the pathway linking the functionally related areas 46 and 9. This evidence suggests that ACC has strong influence on an inhibitory control system of dorsolateral prefrontal cortex. Both pathways innervated mostly spines of excitatory neurons in area 9, as in other corticocortical pathways (White, 1989White E.L. Cortical Circuits. Synaptic Organization of the Cerebral Cortex. Structure, Function and Theory. Birkhäuser, Boston1989Google Scholar, Callaway, 1998Callaway E.M. Local circuits in primary visual cortex of the macaque monkey.Annu. Rev. Neurosci. 1998; 21: 47-74Crossref PubMed Scopus (436) Google Scholar), and these terminals did not differ in size. The significance of the large terminals from ACC that targeted inhibitory neurons is based on evidence that bouton size is correlated with the number of synaptic vesicles (Germuska et al., 2006Germuska M. Saha S. Fiala J. Barbas H. Synaptic distinction of laminar specific prefrontal-temporal pathways in primates.Cereb. Cortex. 2006; 16: 865-875Crossref PubMed Scopus (47) Google Scholar, Zikopoulos and Barbas, 2007Zikopoulos B. Barbas H. Parallel driving and modulatory pathways link the prefrontal cortex and thalamus.PLoS ONE. 2007; 2: e848Crossref PubMed Scopus (83) Google Scholar) and with multivesicular release upon stimulation (Tong and Jahr, 1994Tong G. 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Neurocytol. 1997; 26: 779-797Crossref PubMed Scopus (65) Google Scholar), and are thought to decrease activity at the fringes of active cortical columns (Wang et al., 2004Wang X.J. Tegner J. Constantinidis C. Goldman-Rakic P.S. Division of labor among distinct subtypes of inhibitory neurons in a cortical microcircuit of working memory.Proc. Natl. Acad. Sci. USA. 2004; 101: 1368-1373Crossref PubMed Scopus (241) Google Scholar, Zaitsev et al., 2005Zaitsev A.V. Gonzalez-Burgos G. Povysheva N.V. Kroner S. Lewis D.A. Krimer L.S. Localization of calcium-binding proteins in physiologically and morphologically characterized interneurons of monkey dorsolateral prefrontal cortex.Cereb. Cortex. 2005; 15: 1178-1186Crossref PubMed Scopus (135) Google Scholar). In co" @default.
• W2063882186 created "2016-06-24" @default.
• W2063882186 creator A5014167212 @default.
• W2063882186 creator A5027043416 @default.
• W2063882186 date "2009-02-01" @default.
• W2063882186 modified "2023-10-16" @default.
• W2063882186 title "Synapses with Inhibitory Neurons Differentiate Anterior Cingulate from Dorsolateral Prefrontal Pathways Associated with Cognitive Control" @default.
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