Cortical circuit principles predict patterns of trauma induced tauopathy in humans.

Connections in the cortex of diverse mammalian species are predicted reliably by the Structural Model for direction of pathways and signal processing (reviewed in 1,2). The model is rooted in the universal principle of cortical systematic variation in laminar structure and has been supported widely for connection patterns in animals but has not yet been tested for humans. Here, in postmortem brains of individuals neuropathologically diagnosed with chronic traumatic encephalopathy (CTE) we studied whether the hyperphosphorylated tau (p-tau) pathology parallels connection sequence in time by circuit mechanisms. CTE is a progressive p-tau pathology that begins focally in perivascular sites in sulcal depths of the neocortex (stages I-II) and later involves the medial temporal lobe (MTL) in stages III-IV. We provide novel quantitative evidence that the p-tau pathology in MTL A28 and nearby sites in CTE stage III closely follows the graded laminar patterns seen in homologous cortico-cortical connections in non-human primates. The Structural Model successfully predicted the laminar distribution of the p-tau neurofibrillary tangles and neurites and their density, based on the relative laminar (dis)similarity between the cortical origin (seed) and each connection site. The findings were validated for generalizability by a computational progression model. By contrast, the early focal perivascular pathology in the sulcal depths followed local columnar connectivity rules. These findings support the general applicability of a theoretical model to unravel the direction and progression of p-tau pathology in human neurodegeneration via a cortico-cortical mechanism. Cortical pathways converging on medial MTL help explain the progressive spread of p-tau pathology from focal cortical sites in early CTE to widespread lateral MTL areas and beyond in later disease stages.

Pattern of ventral temporal lobe interconnections in rhesus macaques.

The entorhinal cortex (EC, A28) is linked through reciprocal pathways with nearby perirhinal and visual, auditory, and multimodal association cortices in the temporal lobe, in pathways associated with the flow of information for memory processing. The density and laminar organization of these pathways is not well understood in primates. We studied interconnections within the ventral temporal lobe in young adult rhesus monkeys of both sexes with the aid of neural tracers injected in temporal areas (Ts1, Ts2, TE1, area 36, temporal polar area TPro, and area 28) to determine the density and laminar distribution of projection neurons within the temporal lobe. These temporal areas can be categorized into three different cortical types based on their laminar architecture: the sensory association areas Ts1, Ts2, and TE1 have six layers (eulaminate); the perirhinal limbic areas TPro and area 36 have an incipient layer IV (dysgranular); and area 28 lacks layer IV (agranular). We found that (1) temporal areas that are similar in laminar architecture by cortical type are strongly interconnected, and (2) the laminar pattern of connections is dependent on the difference in cortical laminar structure between linked areas. Thus, agranular A28 is more strongly connected with other agranular/dysgranular areas than with eulaminate cortices. Further, A28 predominantly projected via feedback-like pathways that originated in the deep layers, and received feedforward-like projections from areas of greater laminar differentiation, which emanated from the upper layers. Our results are consistent with the Structural Model, which relates the density and laminar distribution of connections to the relationship of the laminar structure between the linked areas. These connections were viewed in the context of the inhibitory microenvironment of A28, which is the key recipient of pathways from the cortex and of the output of hippocampus. Our findings revealed a higher population of calretinin (CR)-expressing neurons in EC, with a significantly higher density in its lateral division. Medial EC had a higher density of CR neurons in the deep layers, particularly in layer Va. In contrast, parvalbumin (PV) neurons were more densely distributed in the deep layers of the lateral subdivisions of rostral EC, especially in layer Va, whereas the densities of calbindin (CB) neurons in the medial and lateral EC were comparable in all layers, except for layer IIIa, in which medial EC had a higher CB population than the lateral. The pattern of connections in the inhibitory microenvironment of EC, which sends and receives input from the hippocampus, may shed light on signal propagation in this network associated with diverse aspects of memory, and disruptions in neurologic and psychiatric diseases that affect this region.

Imbalance of laminar-specific excitatory and inhibitory circuits of the orbitofrontal cortex in autism.

BACKGROUND: The human orbitofrontal cortex (OFC) is involved in assessing the emotional significance of events and stimuli, emotion-based learning, allocation of attentional resources, and social cognition. Little is known about the structure, connectivity and excitatory/inhibitory circuit interactions underlying these diverse functions in human OFC, as well as how the circuit is disrupted in individuals with autism spectrum disorder (ASD). METHODS: We used post-mortem brain tissue from neurotypical adults and individuals with ASD. We examined the morphology and distribution of myelinated axons across cortical layers in OFC, at the single axon level, as a proxy of excitatory pathways. In the same regions, we also examined the laminar distribution of all neurons and neurochemically- and functionally-distinct inhibitory neurons that express the calcium-binding proteins parvalbumin (PV), calbindin (CB), and calretinin (CR). RESULTS: We found that the density of myelinated axons increased consistently towards layer 6, while the average axon diameter did not change significantly across layers in both groups. However, both the density and diameter of myelinated axons were significantly lower in the ASD group compared with the Control group. The distribution pattern and density of the three major types of inhibitory neurons was comparable between groups, but there was a significant reduction in the density of excitatory neurons across OFC layers in ASD. LIMITATIONS: This study is limited by the availability of human post-mortem tissue optimally processed for high-resolution microscopy and immunolabeling, especially from individuals with ASD. CONCLUSIONS: The balance between excitation and inhibition in OFC is at the core of its function, assessing and integrating emotional and social cues with internal states and external inputs. Our preliminary results provide evidence for laminar-specific changes in the ratio of excitation/inhibition in OFC of adults with ASD, with an overall weakening and likely disorganization of excitatory signals and a relative strengthening of local inhibition. These changes likely underlie pathology of major OFC communications with limbic or other cortices and the amygdala in individuals with ASD, and may provide the anatomic basis for disrupted transmission of signals for social interactions and emotions in autism.