Cell types and wiring of the isocortex

Kenneth D. Harris

The isocortex

The isocortex

• Greatly expanded in humans

​

• “Circuit diagram” essentially unchanged

​

• And similar between cortical areas

​

• Suggests cortical areas employ similar “algorithm” to process diverse information

The cortex is a zoo

• Cortical cells are diverse
• Morphology
• Physiology
• Genetics

​

• Laminar architecture
• Largely conserved across areas

​

• Only ~1% of cortical synapses arise from thalamus.
• Recurrent network activity triggered by sensory input.
• Cortex active even without sensory input (imagery, memory recall)

​

• E pluribus unum
• Information processing arises from cooperation of diverse cells

​

Single-cell RNA sequencing

Molecular diversity of cortical cells

MGE-derived V1 interneurons (Tasic et al Nature 2018)

Each symbol = one cell

​

UMAP: nearby cells have similar expression of 150 key genes (chosen automatically from 30,000)

​

Molecular diversity of cortical cells

CGE-derived V1 interneurons (Tasic et al Nature 2018)

Molecular diversity of cortical cells

Excitatory neurons (Tasic et al Nature 2018)

Excitatory cells

Tasic et al 2018

Intratelencephallic (IT) cells.

Found in layers 2-6. Project only within telencephalon (cortex, striatum, amygdala, etc). Project bilaterally

​

Pyramidal Tract (PT) cells.

Found in lower layer 5. Project only to midbrain, brainstem, spinal cortex. Collaterals in higher-order thalamus (e.g. LP/Pulvinar) and basal ganglia. Mainly unilateral projections

​

Corticothalamic (CT) cells.

Found in lower layer 6. Project to first order thalamus (e.g. LGN)

​

Near-projecting (NP) cells.

New cell type identified by transcriptomics, not much know about them.

​

Inhibitory cells: MGE-derived

Tasic et al 2018

Similar between different regions

Inhibitory cells: CGE derived

Tasic et al 2018

Similar between different regions

Main inhibitory cell types

Pvalb basket

Pvalb chandelier

Sst Martinotti

Sncg

Cannabinoid receptor

Sst Chodl

Long-range projection

Vip

Lamp5 neurogliaform

Non-synaptic release

GABA_B GABA_Aδ

Strong inhibition, block firing

Block L1 inputs (top-down?)

Disinhibition

Sleep-active, vasodilation

Layer I

Layer II/III

Layer IV

Layer V

Layer VI

Higher

order cortex

Subcortical structures�(eg tectum/pons/spinal cord)

Excitatory “wiring diagram”

IT

IT

IT

IT

CT

PT

Layer I

Layer II/III

Layer IV

Layer V

Layer VI

Higher

order cortex

Subcortical structures�(eg tectum/pons/spinal cord)

Mysterious new cell types

IT

IT

IT

IT

CT

PT

NP

Car3

L6b

PT Chrna6

???

Juxtacellular & large-scale extracellular recording

Spontaneous and evoked cortical activity

Sakata and Harris, Neuron 2009

Sparseness analysis

Sakata and Harris, Neuron 2009

Evoked and spontaneous events propagate differently across layers

Sakata and Harris, Neuron 2009

Layer I

Layer II/III

Layer IV

Layer V

Layer VI

Higher

order cortex

Subcortical structures

Sensory input

Layer I

Layer II/III

Layer IV

Layer V

Layer VI

Higher

order cortex

Subcortical structures

Spontaneous activity

Cortico-cortical input

In situ transcriptomics

Bugeon et al, Nature 2022

In situ transcriptomics

Bugeon et al, Nature 2022

In situ transcriptomics

Bugeon et al, Nature 2022

2-photon imaging then in situ transcriptomics

Bugeon et al, Nature 2022

​

​

Cell detection in 2D slice

Gad-mCherry (in vivo)

Gad1 mRNA (ex vivo)

​

Spontaneous activity of identified inhibitory Subtypes

Bugeon et al Nature 2022

A single transcriptomic axis predicts many properties of interneurons

Bugeon et al, Nature 2022

​

Summary

• Lots of different cell types, particularly inhibitory
• Inhibitory neurons particularly similar across regions
• Functions of each cell type still being determined
• Activity patterns match connectivity of pyramidal cells