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. Author manuscript; available in PMC: 2025 Dec 24.
Published in final edited form as: Eur J Neurosci. 2025 Jun;61(12):e70167. doi: 10.1111/ejn.70167

The Cortical Structural Model Extends to Thalamocortical Connections

Helen Barbas 1,2,3,4,*, Basilis Zikopoulos 2,3,4,5
PMCID: PMC12723798  NIHMSID: NIHMS2129441  PMID: 40542691

Summary:

The Structural Model predicts the laminar patterns and strength of corticocortical connections. Here we addressed whether the Structural Model extends to connections between thalamus and prefrontal cortices, which are connected with the mediodorsal (MD) nucleus as well as with other thalamic nuclei. The prefrontal cortex is composed of a series of areas ranging from caudal orbital and medial limbic areas that have the simplest trilaminar architecture through successive areas that show increasing elaboration into six delineated layers. Here we compiled detailed, quantitative tract-tracing data from connectivity studies of the thalamus and cortex in macaques which revealed that the Structural Model extends to thalamocortical connections. The phylogenetically ancient limbic areas were more diffusely connected with thalamic nuclei, projected to thalamus from the canonical layer VI and also substantially from layer V, and were innervated more broadly by thalamic pathways that terminated in the middle and other layers. The pattern of thalamocortical connections became increasingly sharper for prefrontal areas with progressive laminar differentiation, with decreasing contribution of thalamic nuclei besides MD, sharpening of thalamic terminations to the middle cortical layers, gradual decreasing contribution by layer V and increased projection from the canonical layer VI to thalamus. These findings support the hypothesis that the Structural Model can be extended to the broad thalamic connections as well as laminar-specific interactions with the thalamus, tested in a series of prefrontal cortices with gradual increase in laminar complexity.

Keywords: primates, rhesus monkey, thalamus, cortex, bidirectional connection patterns

1.0. Review of the Structural Model and Reach

How is the cortex organized into areas and how are areas connected? The first question occupied scientists for more than a century. Cartographers relied on specific features to map areas of the cortical landscape. In classical and recent studies alike, the most prominent features that differentiate areas include the size and shape of neurons and their density across the depth of the cortex. Along with cellular features, the distribution and density of myelin found in axons is another distinguishing feature among cortical areas (e.g., (Brodmann, 1905; Vogt & Vogt, 1919; Walker, 1940; von Bonin & Bailey, 1947). In the modern era, the introduction of many cellular and molecular features has increased the number of markers used to study cortical architecture (e.g., (Jorstad et al., 2023b), but the central challenge remains: the placement of borders between areas is difficult and is neither absolute nor definitive. The challenge is based on the fact that the differences between adjacent areas are generally subtle. This helps explain why the various maps of cortical architecture differ when regional features are used to place borders between areas.

A different approach to study cortical organization is based on the principle that the architecture of the cortex varies in a systematic way (von Economo, 1927/2009; Sanides, 1972; Pandya & Sanides, 1973). Moreover, the variation pertains to the overall laminar structure of the cortical landscape (Fig 1). Notwithstanding the frequent description of the cortex as having six layers, architectonic studies reveal that not all cortical areas have six layers. Cortical areas have as few as three layers, as seen in areas situated above the corpus callosum on the medial surface, and extending to the baso-medial surface of the brain. These three-layered areas lack a layer IV and have two cellular layers, an upper band and a lower (deep) band, neither of which is easy to subdivide further (reviewed in (Pandya et al., 1988). By classical architectonic terminology these areas are called agranular because they lack a central layer IV. Granular refers to the small neurons found in layer IV that resemble grains of sand, when seen at low magnification of thin sections stained for Nissl to view all neurons and glia. The upper band corresponds to layers II-III and the deep band to layers V-VI. Bordering the swathe of agranular areas, another cortical ribbon is composed of dysgranular areas, which get their moniker for having a sparsely populated granular layer IV. Immediately adjacent to areas with dysgranular architecture, we see, for the first time, areas that have six recognizable layers; collectively, the six-layered areas are called eulaminate. Based on the principle of the systematic variation of the cortex, successive eulaminate areas show further differentiation and elaboration of their six layers.

Figure 1.

Figure 1.

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Top, The Structural Model for corticocortical connections. Schematic of the primate cerebral cortex shown as two ribbons with association areas arranged by cortical type in a grayscale gradient. Laminar differentiation progresses from the outer (black and dark gray) to the inner rings (lighter shades of gray). The edges of the cortical ribbon (black and dark grey) are thin compared to the greatly expanded eulaminate areas in the center. According to the Structural Model, the laminar pattern and strength of connections are related to the cortical type difference (Δ) of the connected areas. Cortical areas have stronger connections with other areas of the same type (Δ = 0) and display columnar patterns of connections that involve most layers (thick orange lines and arrows): they originate in layers II/III and V/VI and terminate in all layers of the target area. Connections between areas of different types are comparatively less strong and display feedback (Δ < 0, thin blue arrows) and feedforward (Δ > 0, thin green arrows) laminar patterns of connections: feedback connections originate in the deep layers (V/VI) and innervate mainly the superficial layers (I-IIIa); feedforward connections originate in the upper layers (II/III) and innervate mainly the middle layers (deep III-Va). Center, Cortical types (agranular, dysgranular, eulaminate I, II, III and koniocortices) are represented in six sketches based on laminar structure (left, agranular-6 highly differentiated eulaminate) (Barbas, 2015; García-Cabezas et al., 2019; John et al., 2022) for rhesus macaques and (Garcia-Cabezas et al., 2020; 2022) for the human cortex. Bottom, Lateral, medial, and orbital views of the cerebral hemisphere show several prefrontal areas in the rhesus macaque brain. The prefrontal cortex is shaded with a grayscale by structural type (agranular: darkest shade; dysgranular: medium shades; and eulaminate: lightest shades).

The second question, about connections of cortical areas, is more difficult to address, but became feasible in practical ways when tracers were introduced to label pathways. The description of the cortex by morphological features alone does not offer a systematic way to address connectivity. On the other hand, the principle of the systematic variation of the cortex is poised to help study connections broadly.

Early findings from the study of connections, and especially in the sensory systems, revealed consistent patterns. Specifically, it has been observed that pathways directed from primary to secondary sensory cortices originate mostly in layer III and their axons terminate in layer IV; this pattern is called feedforward. In the opposite direction, pathways originate in layers V-VI and their axons terminate mainly in layer I of the target area; this pattern is called feedback (e.g., (Rockland & Pandya, 1979; Maunsell & Van Essen, 1983).

The Structural Model for cortical connections is a generalization of the patterns observed in the sensory systems (Barbas, 1986; Barbas & Rempel-Clower, 1997) and applies to connections of all cortex (e.g., (Hilgetag et al., 2016). It successfully predicts the laminar distribution and strength of corticocortical connections throughout the cortex, according to this general rule: Pathways from areas with simpler laminar structure originate most prominently in neurons found in the deep layers and their axons terminate in the upper layers of areas with comparatively more elaborate laminar structure (reviews in (Barbas, 2015; García-Cabezas et al., 2019). By the rules of the Structural Model, the distribution of connections in cortical layers is relative, not absolute. Accordingly, connections between areas that differ markedly in laminar structure show an extreme laminar pattern: Projection neurons originate in the deep layers of an area with the simplest laminar structure, and their axons terminate mostly in the upper layers, and especially layer I, of an area that has well-differentiated six layers. In the opposite direction, projection neurons from areas with complex laminar structure originate mostly in the upper layers, and especially in layer III, and their axons terminate in the middle layers, defined as deep layer III, IV and upper V, of areas with lower laminar complexity. Because the laminar structure in the cortex is graded, connections are also graded in their distribution in layers. For example, for connections between areas that have comparable lamination the Structural Model predicts participation by most layers: projection neurons are predicted to originate in layers II-III and V-VI, and their axons to innervate all layers at the site of termination (Fig. 1, orange). Layer IV neurons do not participate in corticocortical projections; their short axons do not leave the cortex to enter the white matter to connect with other areas. Instead, layer IV neurons participate in connections above and below them in columns of cortex, or connect with neurons in nearby columns. Layer IV neurons receive projections from other cortices and subcortical structures. The relational nature of the Structural Model predicts that the laminar distribution of connections varies, as connections link pairs of areas that differ markedly, moderately, or not at all, in their laminar structure. The explanatory power of the Structural Model for cortical connections thus is based on its linkage to the universal principle of the systematic variation of the cortex across all cortical systems, be they sensory, or high-order association areas, such as the prefrontal cortex.

The Structural Model predicts the strength of connections as well. Specifically, connections between areas with comparable lamination should be stronger than connections between areas that differ markedly in laminar complexity. Observations abound for stronger connections between neighboring areas. Why are neighboring areas strongly connected? And is neighborhood predictive of strong connections, or the converse, that distant areas should not be strongly connected? By the similarity in features hypothesis, neighboring areas are expected to be somewhat similar, and thereby connections should be stronger. By the laminar structural similarity hypothesis, connections are also expected to be stronger between neighboring areas, and to involve more layers, as noted above. In this case connections are stronger because the linked areas are similar by laminar structure.

But can distant areas be connected as well? For this question, the structural laminar similarity and distance between areas make distinct predictions. Distant areas are more likely to differ in their morphologic features, and thus their connections should be sparse or absent if distance matters most. On the other hand, by the Structural Model, distant connections can be strong if they are between areas with similar overall laminar structure. For example, agranular areas in the anterior cingulate are connected with the distantly situated agranular areas in the occipital region of the medial surface near the splenium of the corpus callosum (Morecraft et al., 2000). This example of strong connections is consistent with the Structural Model. There are many other examples, including the strong connections between latero-posterior prefrontal areas 46 and 8 and caudal lateral intraparietal areas, as well as long range orbitofrontal connections (Pandya et al., 1988; Cavada et al., 2000; Rempel-Clower & Barbas, 2000; Medalla & Barbas, 2006; Joyce & Barbas, 2018; Zikopoulos et al., 2018). In the examples of connections between distant areas, the key predictor is comparable laminar structure, and consistent with the Structural Model, which predicts the distribution of connections in layers and their strength regardless of distance (Barbas, 2015; García-Cabezas et al., 2019; Aparicio-Rodriguez & Garcia-Cabezas, 2023).

The hypothesis that distance is a key factor for connections postulates reduction in strength of connections with increasing distance (e.g., (Ercsey-Ravasz et al., 2013). This hypothesis is not consistent with the strong connections described above. There are multiple other examples of areas that are distant and strongly connected. One might say that all prefrontal connections with temporal, parietal and occipital areas fit the category of strong connections between distant areas (Barbas, 2015).

The Structural Model also makes predictions about the likely direction of signal processing in the cortex. The terms feedforward and feedback were borrowed from signal processing in sensory cortices. In the visual system, for example, feedforward refers to the direction of signals from the peripheral environment to the thalamus and cortex. Thus, a pathway from the retina to the thalamic dorsal lateral geniculate nucleus (dLGN) is feedforward, and so is a pathway from dLGN to layer IV of the primary visual cortex, V1, and from V1 to V2. In the reverse direction, a pathway from V2 to V1 is feedback, and so is the pathway from V1 back to dLGN, as also seen in other pathways that involve the cortex and thalamus (reviewed in (Jones, 1985).

The fact that the above observations extend to corticothalamic connections hints that the Structural Model may apply for these connections as well. The question then arises, what systematic patterns can we identify for corticothalamic connections and how do these patterns change at the level of global areas, layers, or nuclei? At a global level this may mean how many cortical areas innervate one thalamic nucleus, or how many thalamic nuclei innervate one cortical area, and how strong, widespread, or focal these connections are. At the laminar level it refers to how many layers are involved in corticothalamic and thalamocortical pathways, as elaborated below. We will focus on the thalamic connections of prefrontal areas, which are ideal for consideration because they include areas that vary broadly by laminar structure. The prefrontal cortex is thus well-suited for this analysis because it has areas ranging from agranular and dysgranular (limbic) areas to a series of eulaminate areas that have six layers and show a broad range in their laminar definition (Barbas & Pandya, 1989).

2.0. Connections between the thalamus and cortex

The Structural Model thus makes specific predictions about the distribution of corticocortical connections that depend on the relationship of the laminar structure of pairs of connected areas, as shown in Figure 1. These patterns have been tested across the cortex (Barbas et al., 1999; Barbas et al., 2005; Grant & Hilgetag, 2005; Medalla & Barbas, 2006; Hilgetag & Grant, 2010; Beul et al., 2015; Hilgetag et al., 2016; García-Cabezas & Barbas, 2017; Goulas et al., 2017; Joyce & Barbas, 2018; Bautista et al., 2023) and can be applied to the human cortex to predict the laminar pattern and strength of connections, with implications for function and dysfunction of cortical networks (Zikopoulos et al., 2018; Charvet, 2020; Hansen et al., 2023; Tucker & Luu, 2023; Barbas et al., 2024). The question now arises: Do connections between the cortex and thalamus also vary, and if so, do they vary in a systematic way as the corticocortical?

2.1. Global differences in thalamocortical connections

At a global level, thalamocortical connections can vary by topography, whereby a specific nucleus or sector of a nucleus may be associated predominantly with one prefrontal area. Or, the number of thalamic nuclei associated with specific prefrontal areas may vary by the target, or a combination of both. Are there differences in thalamic connections based on the laminar complexity of the prefrontal target area?

The mediodorsal (MD) thalamic nucleus is considered to be the principal nucleus for the prefrontal cortex. The organization of interconnections between MD and prefrontal areas varies in a topographic way. The best differentiated prefrontal areas, which include area 46 and area 8, are connected with the parvocellular (MDpc) and lateral, multiform, sector of MD (MDmf) (Giguere & Goldman-Rakic, 1988; Barbas et al., 1991; Siwek & Pandya, 1991; Ray & Price, 1993); reviewed in (Phillips et al., 2021). On the other hand, the posterior orbitofrontal and medial prefrontal areas, especially those that are agranular or dysgranular in architecture, are connected with MDmc (Dermon & Barbas, 1991).

In addition, a sector of MD can be associated with more than one prefrontal area. For example, targeted injections of bidirectional tracers in MDpc, resulted in labeled neurons in several prefrontal areas besides the strong connections with posterior lateral PFC (areas 8 and 46). Additional areas with labeled neurons included areas 9, 12 and 10 (McFarland & Haber, 2002; Erickson & Lewis, 2004; Xiao et al., 2009).

But there is another relationship that distinguishes the thalamic connections of prefrontal areas. While MD is considered to be the main nucleus for the prefrontal cortex, several other thalamic nuclei also project to the prefrontal cortex. The eulaminate areas with the sharpest lamination have restricted connections with other thalamic nuclei, which collectively contribute to fewer than 20% of all projection neurons directed to them ((Barbas et al., 1991); Fig. 2). The converse holds for the thalamic connections of prefrontal areas that are either agranular or dysgranular. For these prefrontal cortices, connections are more broadly distributed among thalamic nuclei (Fig. 2). About 42% of thalamocortical projection neurons originate from MD, while the rest (58%) originate from other thalamic nuclei. Nuclei that include significant numbers of projection neurons directed to limbic prefrontal cortices, in addition to MDmc and MDpc include the midline (ML), intralaminar (IL), anterior (AN), and ventral anterior (VA) nuclei (Dermon & Barbas, 1991; Hsu & Price, 2007). Focal versus distributed connections thus depend on the laminar structure of the target area. Consequently, even though prefrontal cortices are connected with more than one thalamic nucleus, limbic agranular and dysgranular prefrontal cortices have comparatively more distributed thalamic connections by comparison with eulaminate cortices, which have focal connections with one thalamic nucleus and weaker connections with several other thalamic nuclei.

Figure 2.

Figure 2.

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The origin of thalamocortical projections is more distributed and widespread for limbic than eulaminate prefrontal cortex (PFC). Limbic (agranular and dysgranular) PFC areas on the posterior medial and posterior orbital PFC receive a distributed mix of thalamocortical projections from a large pool of thalamic nuclei (left pie chart). By contrast, eulaminate (granular) PFC areas on the dorsal and lateral surface of the brain have more restricted connections with the thalamus, with the vast majority originating from MDpc/mf and a small proportion from other thalamic nuclei. AN, anterior thalamic nuclear group; IL, intralaminar thalamic nuclear group; MDmc, magnocellular portion of the mediodorsal nucleus (medial); MDmf, multiform portion of the mediodorsal nucleus (lateral); MDpc, parvocellular portion of the mediodorsal nucleus (central/lateral); ML, midline thalamic nuclear group; Pm, medial pulvinar nucleus; VA, ventral anterior thalamic nucleus.

2.2. Systematic differences in the laminar origin of corticothalamic pathways

Corticothalamic connections may also vary by their laminar origin. In the sensory systems, the primary areas, such as V1, issue projections to their respective relay thalamic nuclei almost exclusively from layer VI. But cortical projections directed to the thalamus may also originate from layer V, even though they are fewer in number. Corticothalamic projection neurons from high-order association areas are among those described as contributing to some projections from layer V (Levitt et al., 1995; Guillery & Sherman, 2002; Jones, 2002; Sherman & Guillery, 2002; Rovo et al., 2012; Moore et al., 2019); reviewed in (Phillips et al., 2021).

The question arises as to whether the laminar specificity of the area of origin determines the extent to which layer V contributes to the thalamic projection system. Accordingly, eulaminate areas with the highest laminar definition should project to the thalamus primarily from the canonical layer VI by comparison with areas with less complex laminar structure. We addressed this issue by first focusing on projections from prefrontal areas to the thalamic mediodorsal (MD) nucleus, the principal thalamic nucleus for the prefrontal cortex. The MD nucleus has three parts: a lateral part, called MD multiform (MDmf); a central part, called MD parvocellular (MDpc), and a medial part called MD magnocellular (MDmc). The lateral and adjacent part of MD are connected strongly with areas 8 and 46 (e.g., (Barbas et al., 1991; Erickson & Lewis, 2004), which are eulaminate areas and have the highest laminar complexity within the prefrontal cortex (Dombrowski et al., 2001; John et al., 2022), and to a lesser extent with prefrontal areas that have lower laminar complexity. Accordingly, it has been reported that layer V contributes a significantly higher proportion of projection neurons from limbic area 24 directed to the thalamus by comparison with area 6, a eulaminate premotor area (Erickson & Lewis, 2004). Figure 3 shows the proportion of neurons in layer V ranging from agranular and dysgranular areas to eulaminate areas with the highest laminar definition within the prefrontal cortex. The figure shows a near monotonic decrease from about 40% of projection neurons found in layer V of agranular and dysgranular areas to 20–30% found in the best differentiated eulaminate areas (areas 46 and 8). We saw a similar trend in prefrontal projection neurons directed to the thalamic anterior medial (AM) nucleus, which is most strongly connected with limbic, and to a lesser extent with eulaminate prefrontal cortices (Fig. 3C). These relationships of corticothalamic connections are shown in confocal photomicrographs, which reveal the involvement of layer V in these projections in the agranular area 24, and a comparatively lesser contribution from layer V from eulaminate area dorsal 9 (Fig. 3D, E). Brightfield photomicrographs show similar patterns in the connections of eulaminate area 46 and dysgranular area OPro with MD (Fig. 3H, I). These relationships are also seen in drawings of plotted sections through prefrontal areas after a retrograde tracer injection in the thalamic MD (Fig. 3F) or AM (Fig. 3G).

Figure 3.

Figure 3.

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The laminar origin of corticothalamic projection neurons in prefrontal cortices is associated with cortical type. A-C, The ratio of corticothalamic neurons in layer V that project to different parts of MD (A, B) and AM (C) is higher in limbic (agranular and dysgranular) PFC areas and gradually decreases through eulaminate PFC areas with increasing laminar complexity. D-I, Photomicrographs and plots of coronal PFC sections show examples of the laminar organization of corticothalamic neurons in layers V and VI in limbic and eulaminate prefrontal areas. D, Low power confocal photomicrograph of all layers of agranular area 24 from pia to white matter shows labeled prefrontal corticothalamic neurons in layers V and VI that project to AM (red), and MD (cyan). E, Laminar distribution of corticothalamic projection neurons in eulaminate area dorsal 9 (D9). White dotted lines show the borders between the layers. F-G, Neurolucida plots of tracer-labeled corticothalamic projection neurons in prefrontal coronal sections. Each dot represents one plotted neuron (cyan, neurons project to the central sector of MD (MDpc); G, red, neurons project to AM). Bottom insets in F and G, show maps of the injection sites of retrograde tracers in MDpc (cyan) and AM (red) in two coronal sections through the rhesus macaque thalamus. Insets with orange outline are enlarged to show the laminar distribution of plotted projection neurons in agranular (area 24 in F), dysgranular (area 32 in G), and in a eulaminate (area 46, in F and lateral area 12 in G). Black dotted lines show the top of cortical layer V and green dotted lines show the top of cortical layer VI. H-I, Low power photomicrographs of all layers of eulaminate area 46 (H) and dysgranular orbitofrontal area OPro (I) from pia to white matter show labeled prefrontal corticothalamic neurons in layers V and VI projecting to MD (brown). Scale bar in H also applies to I. A-C were generated using data from (Xiao et al., 2009); D-G are from (Xiao et al., 2009). Cortices used in the analysis included: Agranular areas 24 and 25; Dysgranular areas 32, OPro, posterior 13; Eulaminate I areas 11, anterior 13, M9, D9, O12; Eulaminate II areas L12, 10, D46, V46; Eulaminate III areas D8, V8.

2.3. Systematic differences in the laminar termination of thalamocortical pathways

In the direction from thalamus to cortex, studies in primates have shown that the main relay thalamic nuclei project to layer IV (Jones, 2007). This relationship is the sharpest for the primate dLGN to V1, which has a highly specialized layer IV (Rezak & Benevento, 1979). For other primary areas, however, thalamic terminations extend slightly above and below layer IV [e.g., (Hashikawa et al., 1995). In some species, a primary relay nucleus projects not only to the primary cortex but to secondary association areas as well. In these cases the laminar distribution of terminals from the thalamus is more extensive within the cortical layers (see (Jones, 1985; 2007). A similar relationship is seen for projections from the thalamic MD to prefrontal cortex. As shown in Figure 4, terminations of the pathway from the thalamic MD to eulaminate prefrontal areas is concentrated in the middle layers (Fig. 4A–F). By contrast, the same MD pathway to agranular and dysgranular A25 terminates more broadly to include the upper, middle and deep layers (Fig. 4G), as summarized quantitatively in Figure 4J (data are from prior studies (Xiao et al., 2009; Zikopoulos & Barbas, 2012; Timbie et al., 2020)). These findings link a more focal laminar termination from thalamus in eulaminate areas that have the sharpest laminar differentiation and a more diffuse laminar termination from thalamus to agranular and dysgranular areas, which have fewer layers.

Figure 4.

Figure 4.

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Systematic variation of thalamocortical terminations from MD across cortical types in the PFC. Anterogradely labeled axon terminations from MD innervate mostly the upper layers (I-IIIa) of limbic (agranular and dysgranular) PFC cortices, but preferentially innervate the middle/deep layers (IIIb-VI) of eulaminate PFC areas. A-E, Eulaminate PFC areas lateral 12 (L12; A) and 46 (D) show few anterograde thalamocortical terminations in the upper layers and most of the signal is concentrated in the middle layers (IIIb, IV, and top of V). Panels B, C, E, and F are high magnifications of insets in A and D. G-I, Example of a limbic cortical area (agranular/dysgranular subgenual area 25, medial; M25), which exhibits a different pattern of thalamocortical innervation, with most terminations found in the upper cortical layers. Panels H, and I are high magnifications of insets in G. J, The laminar thalamocortical innervation ratio shows the prevalence of MD terminations in the upper layers (I-IIIa) of limbic PFC areas and in middle/deep layers of eulaminate PFC areas. Sections shown are from rhesus macaque cases injected with bidirectional or anterograde neural tracers in MD (material obtained from previous studies (Xiao et al., 2009; Zikopoulos & Barbas, 2012; Timbie & Barbas, 2015; Timbie et al., 2020).

3.0. Summary and Functional Implications

The patterns of corticothalamic and thalamocortical pathways at the level of cortical layers were first described for primary sensory and sensory association cortices (reviewed in (Jones, 1998a; 2001). The same patterns are seen for high-order thalamic nuclei, such as MD and AM, which project to prefrontal cortices (reviewed in (Phillips et al., 2021). These findings suggest that these patterns are general for the pathways that link the cortex with the thalamus, as summarized in Figures 5 and 6. The above analyses suggest that the laminar patterns of corticothalamic and thalamocortical pathways are consistent with the Structural Model. Accordingly, prefrontal projection neurons directed to one thalamic nucleus, be it MD or AM, originate predominantly from layer VI of eulaminate areas, while only a few originate from layer V. By contrast, projection neurons from agranular or dysgranular limbic areas directed to the same thalamic nuclei involve to a larger extent layer V along with the canonical layer VI. The same degree of specificity is also seen in the termination of pathways from one thalamic nucleus to prefrontal cortices, where focal terminations in the middle layers are seen in eulaminate areas, whereas more extensive terminations within layers are seen in limbic areas from the same nuclei.

Figure 5.

Figure 5.

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Predicted systematic variation of corticothalamic projections and thalamocortical terminations within the framework of the Structural Model for connections. The proposed model relates reciprocal thalamocortical connectivity based on the following hypotheses: Corticothalamic pathways (blue) originate almost exclusively from layer VI of koniocortical areas, such as V1; the contribution of layer V corticothalamic projection neurons increases gradually in cortices with less elaborate laminar structure (Ag, Dys). Thalamocortical terminations (red) in the middle/deep layers predominate in eulaminate areas with high laminar complexity (e.g., EuI, II, III, K), but are more broadly distributed in the cortical layers of limbic (agranular, Ag and dysgranular, Dys) cortices, with expected variation for areas that lie between the extremes.

Figure 6.

Figure 6.

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Structural Model predictions of the pattern of connections between thalamus and cortex. Top, Corticothalamic neurons (blue triangles) from limbic cortices (agranular or dysgranular, left) originate from both layers V and VI, while projection neurons from eulaminate areas with progressive laminar differentiation through eulaminate III areas originate progressively from layer VI. Thalamic terminations in limbic areas innervate robustly the upper layers (orange) and also the middle layers (red), but more focally innervate the middle layers of areas with increasing definition of their laminar structure. Bottom, left, Quantitative findings from tracing studies show the broad distribution of projection neurons in the thalamus directed to limbic cortices in contrast to the more focal origin of thalamic projections directed to cortices with high laminar differentiation (right).

Thalamocortical terminations in the upper layers were previously considered to be ‘nonspecific’, whereas those terminating in the middle layers were considered to be ‘specific’. Jones changed the way we view these pathways through a series of seminal studies on what are now known as ‘core’ and ‘matrix’ projection neurons in the thalamus (Jones, 1998a; 2001). In primates, core circuits originate in thalamic excitatory projection neurons that are positive for parvalbumin and project focally to the middle layers of cortex. On the other hand, excitatory thalamic neurons that label for calbindin project widely to the upper layers, including a strong projection to layer I.

Recent transcriptomic, anatomical, and single cell axon tracing studies in rodents have not shown a clear core/matrix distinction, like the one broadly supported in the literature for primates (Jones, 1998b; Briggs & Callaway, 2001; Jones, 2003; Briggs & Callaway, 2005; Jones, 2009; Xiao et al., 2009). Rodent studies instead showed a large variety of molecular profiles of thalamocortical projection neurons and axons that project to both middle and superficial layers (Clasca et al., 2012; Phillips et al., 2019; Winnubst et al., 2019; Mukherjee et al., 2020), obviating a distinction into core/matrix. However, despite the large variability of molecular profiles of thalamocortical projection neurons in rodents, studies have reduced the dimensionality of the transcriptomic complexity of thalamocortical systems in mice (Phillips et al., 2019; Winnubst et al., 2019) by grouping them into three major circuits that generally correspond to core, matrix, and mixed circuits (Phillips et al., 2019; Rodriguez-Moreno et al., 2020).

The key difference between rodents and primates may be due to the significant expansion and specialization of the primate thalamus and cortical areas that have no homologues in rodents (García-Cabezas et al., 2009; Saalmann et al., 2012; Arcaro et al., 2015; Timbie et al., 2020; Garcia-Cabezas et al., 2022; Joyce et al., 2022; Chartrand et al., 2023; Jorstad et al., 2023b; Kim et al., 2023; Mengxing et al., 2023; Perez-Santos et al., 2023). The primate specialization shows a clearer separation of core and matrix thalamocortical circuits, which differ by laminar distribution of cortical and thalamic projection neurons, and their termination patterns, and neurochemical profiles in thalamus (Jones, 2007; Murray et al., 2007; Zikopoulos & Barbas, 2007; Xiao et al., 2009; Phillips et al., 2021; Yazdanbakhsh et al., 2023). The distinction into core and matrix neurons can be made in spite of the even larger diversity of cell types in primates compared to rodents (Jorstad et al., 2023a; Kim et al., 2023; Siletti et al., 2023). Integrating and mixing of these circuits likely takes place through extensive connections within cortical columns and across areas, as suggested by connectivity studies in primates (Callaway, 1998; Zikopoulos & Barbas, 2007; Piantoni et al., 2016; Krishnan et al., 2018; Buckner & DiNicola, 2019; Barbas et al., 2022; Dickey et al., 2022; Gonzalez et al., 2022; Adusei et al., 2024) and our recent computational work (Yazdanbakhsh et al., 2023). The evidence from studies in rodents and especially in primates strongly suggests that the large diversity of thalamocortical projection neuron profiles is not in conflict with a general core/matrix dichotomy of thalamocortical circuits.

How do thalamocortical circuits fit within the systematic variation of the cortical connectome and the associated plasticity-stability continuum (Garcia-Cabezas et al., 2017)? Little is known about the primate thalamocortical connectome, and principles that underlie its organization are yet to be established. However, by analogy with corticocortical connections, termination patterns of core and matrix thalamocortical pathways can be likened to feedforward and feedback patterns. Thus, core thalamocortical pathways have a focal, short vertical termination in the middle cortical layers, akin to feedforward corticocortical pathways. Matrix thalamocortical pathways, have broad terminations in the upper cortical layers (I-IIIa), resembling feedback connections (Zikopoulos & Barbas, 2007; Barbas et al., 2022). Moreover, based on the graded pattern of corticocortical connections, we expect a similar variation in the relative prevalence of thalamocortical core/matrix connections, related to the laminar definition of the target area, as discussed above.

These patterns provide support for our overarching hypothesis that the Structural Model, which predicts the laminar pattern and strength of corticocortical connections, can be applied to thalamocortical circuit motifs. Importantly, many cortical areas in primates, and especially humans, are on the eulaminate spectrum in contrast to rodents (Garcia-Cabezas et al., 2022; John et al., 2022). The primate thalamus has also expanded to include more specialized nuclei that are strongly connected with eulaminate cortices (Jones, 2007). Consequently, we expect that the balance of core/matrix thalamocortical circuits is different in primates, compared to rodent animal models. The specificity and broad range of thalamocortical interactions in primate animal models have functional implications for recruitment of areas for complex behavior, and point to the potential for disruption in disease.

Acknowledgments

Supported by grants R01 MH117785 (HB); R01 MH136013 (BZ and HB); R01 MH118500 (BZ).

Abbreviations

AD

anterior dorsal nucleus

Ag

agranular cortices

AM

anterior medial nucleus

AN

anterior nuclei

AV

anterior ventral nucleus

Cg

cingulate sulcus

CM

centromedian nucleus

D8

dorsal area 8

D9

dorsal area 9

D46

dorsolateral prefrontal area 46

Dys

dysgranular cortices

Δ

Cortical type difference

Eu I-III

eulaminate cortices 1–3

IL

intralaminar nuclei

K

koniocortices (the primary sensory cortices which have the highest laminar definition) eulaminate cortices)

L12

lateral area 12

LD

laterodorsal nucleus

LO

lateral orbital sulcus

M9

medial area 9

M25

medial subgenual area 25

MD

mediodorsal nucleus

MDmc

mediodorsal nucleus, magnocellular part

MDmf

mediodorsal nucleus, multiform part

MDpc

mediodorsal nucleus, parvocellular part

ML

midline nuclei

MO

medial orbital sulcus

O12

orbital area 12

OPro

orbital proisocortex (dysgranular cortex

P

principal sulcus

PFC

prefrontal cortices

Pm

medial pulvinar

Ro

rostral sulcus

TRN

thalamic reticular nucleus

V1

primary visual cortex (area 17)

V2

secondary visual cortex (area 18)

V8

ventral area 8

V46

ventrolateral prefrontal area 46

VA

ventral anterior thalamic nucleus

VPL

ventral posterolateral thalamic nucleus

WM

white matter

Footnotes

Conflict of Interest Statement: The authors have nothing to declare.

Data availability:

All data presented in this review are available in published research articles.

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Data Availability Statement

All data presented in this review are available in published research articles.

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