Neural communication is disrupted in autism by unknown mechanisms. Here, we examined whether in autism there are changes in axons, which are the conduit for neural communication. We investigated single axons and their ultrastructure in the white matter of postmortem human brain tissue below the anterior cingulate cortex (ACC), orbitofrontal cortex (OFC), and lateral prefrontal cortex (LPFC), which are associated with attention, social interactions, and emotions, and have been consistently implicated in the pathology of autism. Area-specific changes below ACC (area 32) included a decrease in the largest axons that communicate over long distances. In addition, below ACC there was overexpression of the growth-associated protein 43 kDa accompanied by excessive number of thin axons that link neighboring areas. In OFC (area 11), axons had decreased myelin thickness. Axon features below LPFC (area 46) appeared to be unaffected, but the altered white matter composition below ACC and OFC changed the relationships among all prefrontal areas examined, and could indirectly affect LPFC function. These findings provide a mechanism for disconnection of long-distance pathways, excessive connections between neighboring areas, and inefficiency in pathways for emotions, and may help explain why individuals with autism do not adequately shift attention, engage in repetitive behavior, and avoid social interactions. These changes below specific prefrontal areas appear to be linked through a cascade of developmental events affecting axon growth and guidance, and suggest targeting the associated signaling pathways for therapeutic interventions in autism.

The classical theory of cortical systematic variation has been independently described in reptiles, monotremes, marsupials and placental mammals, including primates, suggesting a common bauplan in the evolution of the cortex. The Structural Model is based on the systematic variation of the cortex and is a platform for advancing testable hypotheses about cortical organization and function across species, including humans. The Structural Model captures the overall laminar structure of areas by dividing the cortical architectonic continuum into discrete categories (cortical types), which can be used to test hypotheses about cortical organization. By type, the phylogenetically ancient limbic cortices ─ which form a ring at the base of the cerebral hemisphere ─ are agranular if they lack layer IV, or dysgranular if they have an incipient granular layer IV. Beyond the dysgranular areas, eulaminate type cortices have six layers. The number and laminar elaboration of eulaminate areas differs depending on species or cortical system within a species. The construct of cortical type retains the topology of the systematic variation of the cortex and forms the basis for a predictive Structural Model, which has successfully linked cortical variation to the laminar pattern and strength of cortical connections, the continuum of plasticity and stability of areas, the regularities in the distribution of classical and novel markers, and the preferential vulnerability of limbic areas to neurodegenerative and psychiatric diseases. The origin of cortical types has been recently traced to cortical development, and helps explain the variability of diseases with an onset in ontogeny.

The inhibitory thalamic reticular nucleus (TRN) intercepts and modulates all corticothalamic and thalamocortical communications. Previous studies showed that projections from sensory and motor cortices originate in layer VI and terminate as small boutons in central and caudal TRN. Here we show that prefrontal projections to TRN in rhesus monkeys have a different topographic organization and mode of termination. Prefrontal cortices projected mainly to the anterior TRN, at sites connected with the mediodorsal, ventral anterior, and anterior medial thalamic nuclei. However, projections from areas 46, 13, and 9 terminated widely in TRN and colocalized caudally with projections from temporal auditory, visual, and polymodal association cortices. Population analysis and serial EM reconstruction revealed two distinct classes of corticoreticular terminals synapsing with GABA/parvalbumin-positive dendritic shafts of TRN neurons. Most labeled boutons from prefrontal axons were small, but a second class of large boutons was also prominent. This is in contrast to the homogeneous small TRN terminations from sensory cortices noted previously and in the present study, which are thought to arise exclusively from layer VI. The two bouton types were often observed on the same axon, suggesting that both prefrontal layers V and VI could project to TRN. The dual mode of termination suggests a more complex role of prefrontal input in the functional regulation of TRN and gating of thalamic output back to the cortex. The targeting of sensory tiers of TRN by specific prefrontal areas may underlie attentional regulation for the selection of relevant sensory signals and suppression of distractors.

Behavioral state is known to influence interactions between thalamus and cortex, which are important for sensation, action and cognition. The thalamic reticular nucleus (TRN) is hypothesized to regulate thalamo-cortical transmission, but the underlying functional architecture of this process and its state-dependence are unknown. By combining the first TRN ensemble recording with psychophysics and connectivity-based optogenetic tagging, we find that the TRN is composed of distinct sub-networks. While activity of limbic-projecting TRN neurons correlates with arousal, sensory-projecting neurons participate in spindles and show elevated synchrony by slow waves during sleep. Conversely, sensory-projecting neurons are suppressed by attentional states, demonstrating common microcircuit mechanisms of sensory processing in sleep and attention. Bidirectional manipulation of attentional performance was achieved through optogenetic manipulation of these TRN sub-networks. Our findings provide evidence for differential regulation of thalamic inhibition across brain states, suggesting that the TRN separately controls external stimulus processing and internally-generated computations, a basic determinant of cognitive function.