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Abstract The basal ganglia play pivotal roles in motor control and cognitive functioning. These nuclei are embedded in an anatomical loop: cortex to basal ganglia to thalamus back to cortex. We focus here on an essential synapse for descending control, from cortical layer 5 (L5) onto the GABAergic spiny projection neurons (SPNs) of the caudoputamen (CP). We employed genetic labeling to distinguish L5 neurons from somatosensory (S1) and motor (M1) cortices in large volume serial electron microscopy and electrophysiology datasets to better detail these inputs. First, M1 and S1 synapses showed a strong preference to innervate the spines of SPNs and rarely contacted aspiny cells, which are likely to be interneurons. Second, L5 inputs commonly converge from both areas onto single SPNs. Third, compared to unlabeled terminals in CP, those labeled from M1 and S1 show ultrastructural hallmarks of strong driver synapses: They innervate larger spines that were more likely to contain a spine apparatus, more often had embedded mitochondria, and more often contacted multiple targets. Finally, these inputs also demonstrated driver‐like functional properties: SPNs responded to optogenetic activation from S1 and M1 with large EPSP/Cs that depressed and were dependent on ionotropic but not metabotropic receptors. Together, our findings suggest that individual SPNs integrate driver input from multiple cortical areas with implications for how the basal ganglia relay cortical input to provide inhibitory innervation of motor thalamus. 

Abstract The neotenous, or delayed, development of primate neurons, particularly human ones, is thought to underlie primate-specific abilities like cognition. We tested whether synaptic development follows suit—would synapses, in absolute time, develop slower in longer-lived, highly cognitive species like non-human primates than in shorter-lived species with less human-like cognitive abilities, e.g., the mouse? Instead, we find that excitatory and inhibitory synapses in the maleMus musculus(mouse) andRhesus macaque(primate) cortex form at similar rates, at similar times after birth. Primate excitatory and inhibitory synapses and mouse excitatory synapses also prune in such an isochronic fashion. Mouse inhibitory synapses are the lone exception, which are not pruned and instead continuously added throughout life. The monotony of synaptic development clocks across species with disparate lifespans, experiences, and cognitive abilities argues that such programs are likely orchestrated by genetic events rather than experience. 

Neurons in the thalamic reticular nucleus (TRN) are a primary source of inhibition to the dorsal thalamus and, as they are innervated in part by the cortex, are a means of corticothalamic regulation. Previously, cortical inputs to the TRN were thought to originate solely from layer 6 (L6), but we recently reported the presence of putative synaptic terminals from layer 5 (L5) neurons in multiple cortical areas in the TRN [J. A. Prasad, B. J. Carroll, S. M. Sherman, J. Neurosci. 40, 5785–5796 (2020)]. Here, we demonstrate with electron microscopy that L5 terminals from multiple cortical regions make bona fide synapses in the TRN. We further use light microscopy to localize these synapses relative to recently described TRN subdivisions and show that L5 terminals target the edges of the somatosensory TRN, where neurons reciprocally connect to higher-order thalamus, and that L5 terminals are scarce in the core of the TRN, where neurons reciprocally connect to first-order thalamus. In contrast, L6 terminals densely innervate both edge and core subregions and are smaller than those from L5. These data suggest that a sparse but potent input from L5 neurons of multiple cortical regions to the TRN may yield transreticular inhibition targeted to higher-order thalamus. 

Higher order thalamic neurons receive driving inputs from cortical layer 5 and project back to the cortex, reflecting a transthalamic route for corticocortical communication. To determine whether or not individual neurons integrate signals from different cortical populations, we combined electron microscopy “connectomics” in mice with genetic labeling to disambiguate layer 5 synapses from somatosensory and motor cortices to the higher order thalamic posterior medial nucleus. A significant convergence of these inputs was found on 19 of 33 reconstructed thalamic cells, and as a population, the layer 5 synapses were larger and located more proximally on dendrites than were unlabeled synapses. Thus, many or most of these thalamic neurons do not simply relay afferent information but instead integrate signals as disparate in this case as those emanating from sensory and motor cortices. These findings add further depth and complexity to the role of the higher order thalamus in overall cortical functioning. 

Abstract Neural microarchitecture is heterogeneous, varying both across and within brain regions. The consistent identification of regions of interest is one of the most critical aspects in examining neurocircuitry, as these structures serve as the vital landmarks with which to map brain pathways. Access to continuous, three-dimensional volumes that span multiple brain areas not only provides richer context for identifying such landmarks, but also enables a deeper probing of the microstructures within. Here, we describe a three-dimensional X-ray microtomography imaging dataset of a well-known and validated thalamocortical sample, encompassing a range of cortical and subcortical structures from the mouse brain . In doing so, we provide the field with access to a micron-scale anatomical imaging dataset ideal for studying heterogeneity of neural structure.