Organization Of Intrinsic Connections Research Articles

Principles of Intrinsic Motor Cortex Connectivity in Primates.

The forelimb representation in motor cortex (M1) is an important model system in contemporary neuroscience. Efforts to understand the organization of the M1 forelimb representation in monkeys have focused on inputs and outputs. In contrast, intrinsic M1 connections remain mostly unexplored, which is surprising given that intra-areal connections universally outnumber extrinsic connections. To address this knowledge gap, we first mapped the M1 forelimb representation with intracortical microstimulation (ICMS) in male squirrel monkeys. Next, we determined the connectivity of individual M1 sites with ICMS + intrinsic signal optical imaging (ISOI). Every stimulation site activated a distinctive pattern of patches (∼0.25 to 1.0 mm radius) that we quantified in relation to the motor map. Arm sites activated patches that were mostly in arm zones. Hand sites followed the same principle, but to a lesser extent. The results collectively indicate that preferential connectivity between functionally matched patches is a prominent organizational principle in M1. Connectivity patterns for a given site were conserved across a range of current amplitudes, train durations, pulse frequencies, and microelectrode depths. In addition, we found close correspondence in somatosensory cortex between connectivity that we revealed with ICMS+ISOI and connections known from tracers. ICMS+ISOI is therefore an effective tool for mapping cortical connectivity and is particularly advantageous for sampling large numbers of sites. This feature was instrumental in revealing the spatial specificity of intrinsic M1 connections, which appear to be woven into the somatotopic organization of the forelimb representation. Such a framework invokes the modular organization well-established for sensory cortical areas.SIGNIFICANCE STATEMENT Intrinsic connections are fundamental to the operations of any cortical area. Surprisingly little is known about the organization of intrinsic connections in motor cortex (M1). We addressed this knowledge gap using intracortical microstimulation (ICMS) concurrently with intrinsic signal optical imaging (ISOI). Quantifying the activation patterns from dozens of M1 sites allowed us to uncover a fundamental principle of M1 organization: M1 patches are preferentially connected with functionally matched patches. Relationship between intrinsic connections and neurophysiological map is well-established for sensory cortical areas, but our study is the first to extend this framework to M1. Microstimulation+imaging opened a unique possibility for investigating the connectivity of dozens of tightly spaced M1 sites, which was the linchpin for uncovering organizational principles.

Intrinsic Functional Connectivity is Organized as Three Interdependent Gradients

The intrinsic functional architecture of the brain supports moment-to-moment maintenance of an internal model of the world. We hypothesized and found three interdependent architectural gradients underlying the organization of intrinsic functional connectivity within the human cerebral cortex. We used resting state fMRI data from two samples of healthy young adults (N’s = 280 and 270) to generate functional connectivity maps of 109 seeds culled from published research, estimated their pairwise similarities, and multidimensionally scaled the resulting similarity matrix. We discovered an optimal three-dimensional solution, accounting for 98% of the variance within the similarity matrix. The three dimensions corresponded to three gradients, which spatially correlate with two functional features (external vs. internal sources of information; content representation vs. attentional modulation) and one structural feature (anatomically central vs. peripheral) of the brain. Remapping the three dimensions into coordinate space revealed that the connectivity maps were organized in a circumplex structure, indicating that the organization of intrinsic connectivity is jointly guided by graded changes along all three dimensions. Our findings emphasize coordination between multiple, continuous functional and anatomical gradients, and are consistent with the emerging predictive coding perspective.

Entorhinal cortex of the monkey: VII. Intrinsic connections

The organization of intrinsic connections within the entorhinal cortex was investigated in Macaca fascicularis monkeys. Anterograde tracers ((3)H-amino acids, Phaseolus vulgaris-leucoagglutinin, biotinylated dextran amine, or Fluoro-Ruby) were injected into the deep or superficial layers of the entorhinal cortex in 24 animals. These injections labeled extensive intrinsic projections that terminated throughout all layers of the entorhinal cortex. Labeling was typically continuous i.e., there was no evidence of a patchy or columnar organization. Each injection produced a rostrocaudally oriented band of labeled fibers and terminals that extended for one-third to one-half of the length of the entorhinal cortex. The more extensive distributions of labeled fibers were more typical of caudally placed injection sites. Taken together, the projections identified at least two mediolaterally differentiated bands: a lateral band that encompasses fields Elr, Elc, and the most lateral aspect of fields Ec and Ecl and a wider, medially situated band that encompasses much of fields Er, Ei, Ec, and Ecl. We obtained some evidence that field Eo constitutes a third, very medially placed band. The rostrocaudal organization of labeled fibers and the extent of labeling within the deep and superficial layers were unrelated to the laminar position of the injection. These data suggest that intrinsic associatonal connections in the monkey entorhinal cortex are organized into separate associational networks. Our findings are discussed with reference to the role of interlaminar connections in mediating physiological interactions between the neocortex and the hippocampus.

Entorhinal cortex of the rat: organization of intrinsic connections.

Two sets of experiments were carried out to examine the organization of associational connections within the rat entorhinal cortex. First, a comprehensive analysis of the areal and laminar distribution of intrinsic projections was performed by using the anterograde tracers Phaseolus vulgaris-leuocoagglutinin (PHA-L) and biotinylated dextran amine (BDA). Second, retrograde tracers were injected into the dentate gyrus and PHA-L and BDA were injected into the entorhinal cortex to determine the extent to which entorhinal neurons that project to different septotemporal levels of the dentate gyrus are linked by intrinsic connections. The regional distribution of intrinsic projections within the entorhinal cortex was related to the location of the cells of origin along the mediolateral axis of the entorhinal cortex. Cells located in the lateral regions of the entorhinal cortex gave rise to intrinsic connections that largely remained within the lateral reaches of the entorhinal cortex, i.e., within the rostrocaudally situated entorhinal band of cells that projected to septal levels of the dentate gyrus. Cells located in the medial regions of the entorhinal cortex gave rise to intrinsic projections confined to the medial portion of the entorhinal cortex. Injections made into mid-mediolateral regions of the entorhinal cortex mainly gave rise to projections to mid-mediolateral levels, although some fibers did enter either lateral or medial portions of the entorhinal cortex. These patterns were the same regardless of whether the projections originated from the superficial (II-III) or deep (V-VI) layers of the entorhinal cortex. This organizational scheme indicates, and our combined retrograde/anterograde labeling studies confirmed, that laterally situated entorhinal neurons that project to septal levels of the dentate gyrus are not in direct communication with neurons projecting to the temporal portions of the dentate gyrus. These results suggest that entorhinal intrinsic connections allow for both integration (within a band) and segregation (across bands) of entorhinal cortical information processing.

Organization of intrinsic connections in owl monkey area MT.

Area MT (middle temporal) is a well-defined visual representation common to all primates, which shows a clear selectivity to the analysis of visual motion. In the present study we examined the architecture of the intrinsic connections in area MT in an attempt to reveal its organizing principles and its potential relationship to the functional domains in area MT. Intrinsic connections were studied by placing small injections of the tracer biocytin in area MT of seven adult owl monkeys (Aotus nancymae). The injections were targeted at well-defined orientation domains revealed using optical imaging of intrinsic signals. The distribution of axons labeled by these injections was related both to the cytochrome oxidase histochemistry and to the layout of functional domains in area MT and surrounding tissue. Tracer injections in the superficial layers of area MT produced a complex network of extrinsic and intrinsic axonal connections. Clear instances of extrinsic connections were observed between area MT proper and the MT crescent situated postero-medially to it. The intrinsic connections were laterally spread and organized in patch-like clusters with an average distance from injection center to the furthest patch of 1.8 +/- 0.55 mm (+/-SD, n = 9). The overall axonal distribution tended to be anisotropic, i.e. the patches were distributed within an elongated ellipse [average anisotropy ratio: 1.86 +/- 0.66 (+/-SD)] and were asymmetrically distributed about either side of the injection site [average asymmetry ratio: 2.3 +/- 0.7 (+/-SD)]. Finally, there was a tendency for the intrinsic connections to connect to functional domains of similar orientation preference in area MT. However, this tendency varied substantially between individual cases. The highly specific nature of MT lateral connections puts clear constraints on models of surround influences in the receptive fields of MT neurons.

Intrinsic inhibitory pathways in mouse barrel cortex.

The organization of intrinsic connections in the mouse somatosensory cortex was studied by combining tract-tracing and immunocytochemical techniques. Injections of HRP or fluorescent beads were made into the supragranular or infragranular layers of the posteriomedial barrel subfield. Numerous cells were retrogradely labeled within a vertical column centered on each injection site. Retrogradely labeled cells were also found > 3 mm horizontal to the injection. Dual-label immunocytochemistry identified the population of inhibitory, GABAergic cells forming intrinsic horizontal connections. Double-labeled cells were found predominantly within a 200 microns radius horizontal to an injection site. These findings indicate that intrinsic inhibitory pathways in the barrel cortex do not provide a substrate for direct GABAergic interactions among barrel columns, and that inter-columnar interactions are primarily excitatory.

Specific patterns of intrinsic connections between representation zones in the rat motor cortex.

The organization of intrinsic connections in rat motor cortex was studied by combining microstimulation and tract-tracing techniques. Maps of forelimb and vibrissal movements were constructed from the distribution of cortical sites from which movements were evoked in response to intracortical microstimulation. Then, a single injection of a fluorescent dextran was placed into either a vibrissal or a wrist representation zone, or into a region bordering these zones, resulting in anterograde labeling of long intrinsic, horizontal axons. Following injection into the vibrissal area, axons were largely restricted to the whisker representation zone and to the border region with the forelimb representation. Injections into a wrist zone labeled projections largely restricted to the forelimb area and to the border with the vibrissal area. Injections into a border region labeled dense projections throughout most of the forelimb and vibrissal areas. These findings indicate that intrinsic axon collaterals in the motor cortex form specific and extensive connections among representation zones related to movements of the same body part. These connections may be involved in the coordination of activity in different representation zones for the execution of complex movement patterns. The projection of axon collaterals into border regions may be the anatomical substrate for the rapid reorganization of motor cortical maps that occurs following various experimental manipulations.

Cortical hierarchy reflected in the organization of intrinsic connections in macaque monkey visual cortex.

Neuronal response properties vary markedly at increasing levels of the cortical hierarchy. At present it is unclear how these variations are reflected in the organization of the intrinsic cortical circuitry. Here we analyze patterns of intrinsic horizontal connections at different hierarchical levels in the visual cortex of the macaque monkey. The connections were studied in tangential sections of flattened cortices, which were injected with the anterograde tracer biocytin. We directly compared the organization of connections in four cortical areas representing four different levels in the cortical hierarchy. The areas were visual areas 1, 2, 4 and Brodman's area 7a (V1, V2, V4 and 7a, respectively). In all areas studied, injections labeled numerous horizontally coursing axons that formed dense halos around the injection sites. Further away, the fibers tended to form separate clusters. Many fibers could be traced along the way from the injection sites to the target clusters. At progressively higher order areas, there was a striking increase in the spread of intrinsic connections: from a measured distance of 2.1 mm in area V1 to 9.0 mm in area 7a. Average interpatch distance also increased from 0.61 mm in area V1 to 1.56 mm in area 7a. In contrast, patch size changed far less at higher order areas, from an average width of 230 micron(s) in area V1 to 310 micron(s) in area 7a. Analysis of synaptic bouton distribution along axons revealed that average interbouton distance remained constant at 6.4 micron(s) (median) in and out of the clusters and in the different cortical areas. Larger injections resulted in a marked increase in the number of labeled patches but only a minor increase in the spread of connections or in patch size. Thus, in line with the more global computational roles proposed for the higher order visual areas, the spread of intrinsic connections is increased with the hierarchy level. On the other hand, the clustered organization of the connections is preserved at higher order areas. These clusters may reflect the existence of cortical modules having blob-like dimensions throughout macaque monkey visual cortex.