(A) Pyramidal tract (PT) neurons (blue) project to ipsilateral striatum, thalamus, subthalamic nucleus (STN), and many brainstem and spinal cord regions. Intratelencephalic (IT) neurons project ipsi- or bilaterally (via corpus callosum, Cal) within the cerebral hemispheres to cortex (IT-CCol, orange), and many of these also to striatum (IT-CStr, red). The ipsilateral striatum (black) is unique in receiving CStr input from both IT and PT neurons. Layer 6 corticothalamic neurons (CT, green) project only to thalamus and its reticular nucleus (RTN). (B) Retrogradely labeled corticospinal (PT-CSpi) and callosally projecting IT-CStr neurons in mouse motor cortex (T. Kiritani). IT (green) and PT (orange) neurons are intermingled in layer 5B, but not double-labeled. (C) A single PT neuron’s axon is multiprojectional, sending branches to many subcortical areas. Modified from .

(A) Excitatory connections across layers differentially target IT and PT neurons. Layer 2 neurons (orange triangles, left) tend to target PT neurons (blue) in upper 5B, and IT neurons (red) in layer 5A but not 5B, whereas layer 3 neurons (orange triangles, right) tend to target PT neurons (blue) in upper 5B, and not IT neurons . This arrangement implies that distinct upstream networks carrying different functional information feed into IT and PT neurons. (B) Excitatory connectivity within layer 5B differs for IT and PT neurons ^-. IT neurons (red) excite each other and PT neurons; PT neurons (blue) excite each other but not IT neurons. This hierarchical arrangement means that PT neurons are hodologically compartmentalized downstream from IT neurons within the local excitatory network. (C) Microcircuits involving inhibitory interneurons converge on both and IT and PT neurons . Fast-spiking (FS) interneurons are preferentially excited by both IT and PT neurons in layer 5A/B. In contrast, low-threshold-spiking (LTS) interneurons are excited by layer 2/3 neurons (orange). Both FS and LTS interneurons inhibit both IT and PT neurons. An implication is that IT and PT neurons share common inhibitory microcircuit mechanisms, which can, however, be differentially accessed by upstream circuits targeting upper versus deeper cortical layers.

(A) Intrinsic properties. Schematics depicting electrophysiological differences. PT neurons have more hyperpolarization-activated current (I_h), appeared as “sag” of the membrane potential during steps of injected current (top row, right). Action potentials are relatively wide (long duration) in IT neurons (middle row, left, arrows), and narrow (fast, short duration) in PT neurons (middle row, right, arrows). Repetitive firing in IT neurons typically follows an adapting (phasic) pattern (bottom row, left), but in PT neurons often follows a more non-adapting (tonic, sustained) pattern ^{, ,} . (B) Neuromodulation. Left, Schematic depicting PT-specific increase in the transfer function relating synaptic input to spiking output, observed or inferred for NE, DA, and ACh (dashed lines) ^-. Right, serotonin (5HT) has an opposite effect on PT neurons, increasing the excitability of IT neurons . These schematics, although greatly oversimplified, are intended to convey a sense of the diverse and either opposing or augmenting actions of neuromodulators on IT and PT neurons. (C) Molecular expression. IT neurons (left) express the transcription factor Satb2, the calcium-binding protein p11, the receptor tyrosine kinase Met, protein kinase A (PKA), types 1B-, 2A-, and 4-5HT receptor, and D1 dopamine receptors. PT neurons (right) express the transcription factors Ctip2 and Fezf2, muscarinic mAChR receptors, 5HT-1A receptors, D2 dopamine receptors, L-type voltage gated calcium channels (L-VGCC), calcium-activated non-selective cation channels (CAN), Kv1 potassium channels, HCN1 and Trip8b channel subunits, type A2 adrenoreceptors, and sonic hedgehog (shh), which interacts with Boc in presynaptic axons from layer 2/3 neurons. Whereas most of the molecules shown here are expressed differentially in IT and PT neurons, others, particularly ion channels such as L-VGCC, may be expressed in both IT and PT neurons, but are likely regulated by distinct signaling mechanisms. This schematic represents a simplified view of current information, with varying degrees of experimental support for the various features, and in some cases not fully capturing the complexity of the available data; for example, Kv1 channel expression is high in PT neurons in motor but not somatosensory cortex . This graphical summary is intended as a starting pointing for further refinement as new information about the types and subcellular distributions of molecules and signaling pathways is gained.

(A) Simplified schematic illustrating that the CStr projection is an integral component in cortico-basal ganglia-thalamocortical loops. IT neurons (red) project only to striatum, but PT neurons (blue) project to striatum and additional parts of the basal ganglia, particularly to excitatory neurons (gray) in the subthalamic nucleus (STN) via the hyperdirect pathway (h), and to dopaminergic (DA) neurons (brown) in the substantia nigra pars compacta (SNc). GABAergic medium spiny neurons (MSNs) in the striatum project either via the direct pathway (d, light green) or indirect pathway (i, dark green) to GABAergic projection neurons (black) further downstream in the basal ganglia, including the external segment of globus pallidus (GPe), and the internal GP and SN pars reticulata (GPi/SNr). The STN also projects back to cortex (not shown) . (B) Direct-pathway MSNs (light green) express D1 DA recptors and indirect-pathway MSNs (dark green) express D2 DA receptors. Both cell types receive both IT and PT inputs, with mixed evidence for cell-type specific biases in the targeting. (C) Striatum is also parceled into matrix (light gray area) and striosome (dark gray zone) compartments. CStr innervation of MSNs in these compartments is biased towards PT→striosome connectivity (right), for CStr projections originating from limbic cortex .

(A) Many changes in ASD are IT-related. Changes (depicted by yellow circles) observed in human ASD include: (1) mildly increased cortical thickness, (2) abnormal interhemispheric and long-range corticocortical synchrony, resulting in a relative disconnection of IT neurons in the contralateral cortex (dashed lines), and (3) thinning of corpus callosum (gray ellipse). Changes observed in mouse models include: (4) increased excitatory synaptic connectivity (small black arrows) from layer 2/3 neurons (orange) to layer 5 IT neurons (red) but not PT neurons (blue), in Met knockout mice; (5) changes at CStr synapses in Shank3 knockout mouse, and changes in striatal neuron dendrites in Met knockout mice. There is (6) relative sparing of pyramidal system functions. (B) Many changes in ALS are PT-related. Changes (depicted by yellow circles) observed include: (1) early cortical hyperexcitability, and hyperactivity during movement; (2) degenerative changes in layer 2/3 neurons; (3) selective degeneration of corticospinal (PT) neurons, with no known pathology of IT-CStr neurons; (4) reduction in PV immunoreactivity in human ALS cortex, but an increase in PV-positive cells in the SOD1 mouse model of ALS; (5) abnormal long-term plasticity at CStr synapses. (C) IT-CStr-related changes in MDD. Changes affecting the CStr projection in MDD include abnormal activity in (1) cortex and (2) striatum in human imaging studies, and (3) IT-CStr-specific upregulation of the calcium-binding protein p11 and 5HT-4 serotonin receptors induced by chronic treatment with the antidepressant fluoxetine (FLX) .

In OCD (blue shading), the circuits primarily affected are CStr circuits involving orbitofrontal (OFC), anterior cingulate (AC), and prefrontal (PFC) cortex. SZ primarily involves dorsolateral PFC circuits. Both disorders involve hyperactivity in these circuits. CStr circuits in other regions appear to be spared. Neuron coloring portrays the differential involvement of the same basic circuits in these disorders. Abnormalities in OCD include: (1) cortical changes, with abnormal frontal activity seen by functional imaging; (2) CStr changes, including increased fronto-striatal connectivity; (3) structural and functional striatal changes, particularly in ventral striatum; (4) changes at CStr synapses, demonstrated in mouse models of OCD; (5) thalamic abnormalities, including increased activity in imaging studies, and thalamocortical dysrhythmia. Abnormalities in SZ include: (6) cortical changes, primarily in dorsolateral PFC, including reduced thickness and functional connectivity with cortex and striatum, and abnormal rhythms; (7) thalamocortical dysrhythmia; (8) striatal changes, including reduced volume associated with SZ risk alleles.

Changes (depicted by yellow circles and line thicknesses) in HD, a hyperkinetic movement disorder, include: (1) neurodegenerative atrophy of striatum, particularly the caudate, preferentially affecting indirect-pathway MSNs (dark green), and (2) of cortex, across several layers, likely involving IT (red) and possibly PT (blue) neurons; (3) dysfunction in CStr projections. Network effects include (4) decrease of indirect pathway (dark green) and (5) increase of direct pathway (light green) activity. The net effect of increasing cortical output via PT neurons is thought to correlate with the hyperkinetic movements typical of HD. Changes in PD, a hypokinetic movement disorder, include: (6) neurodegeneration of SNc neurons (brown; dashed lines); (7) decreased activity in PT (blue) but not IT (red) neurons in the cortex. Network effects include (8) decrease of direct (light green) and (9) increase of indirect (dark green) pathway activity. The net effect of decreasing cortical output via PT neurons is thought to correlate with the hypokinetic movements typical of PD. (10) Abnormalities in the hyperdirect pathway from PT neurons to excitatory neurons (gray) in the STN have been implicated in abnormal rhythms in PD, and deep-brain stimulation in the STN can be an effective therapy. (11) Reduced drive in corticospinal projections is proposed as a downstream consequence of dysfunction in basal ganglia circuits. Modified from ^, . In both HD and PD, the possibility of abnormal IT/PT connectivity to direct/indirect MSNs has not yet been tested (question marks and dashed arrows).