Functional organization of the cerebral cortex in columns (cilinders of < 1

mm in diameter) that span across layers: elementary processing modules

Some properties common to cortical circuits:

1. Each cortical layer receives afferent synaptic inputs from a main specific
source and make efferent synapses on specific targets.

2. In each area there are vertical (columnar or radial) connections and

horizontal (or lateral) connections.

3. Neurons with similar function tend to group together and line up radially
across layers and receive afferences that often form radial (columnar)
strias.
Within the neocortex information passes from one synaptic relay to another using
feedforward and feedback long-range connections.

Cortical information processing is organized hierarchically: e.g. within a sensory

system, some areas of the cortex are designated as primary, secondary, tertiary
depending on their functional sequence within the pathway. Each primary sensory
area (the initial site of cortical processing) conveys information to an adjacent
higher-order area (where more complex processing occurs): ascending or
feedforward cortical pathway in which feedforward projections originate mainly
in layer 2-3 and terminate mainly in layer 4.
Long-range connections between different cortical areas are usually reciprocal
(bidirectional); higher order areas send information to lower order areas:
descending or feedback cortical pathway in which feedback projections
originate in layer 5 and 6 and terminate in layers 1, 2 and 6.
The thickness of individual layers and the
details of their functional organization vary
throughout the cortex.

Brodmann, used the relative prominence of the

layers, cell size, and packing characteristics to
distinguish different areas of the neocortex.
Based on such cytoarchitectonic differences,
Brodmann in 1909 divided the cerebral cortex
into 47 regions.

Modern connectional neuroanatomy and

electrophysiology have identified many more
distinct functional regions of the cortex:
for example, Brodmann
identified five regions (areas
17–21) as being concerned
with processing of visual
information in the monkey. In
contrast, modern methods
identified more than 35
functionally distinct cortical
regions within the five regions
studied by Brodmann
The computations taking place in the cerebral cortex depend on highly interconnected
and dynamic microcircuits composed of two broad types of neurons: (1) glutamatergic
excitatory neurons, or principal cells (PCs) (2) GABAergic inhibitory interneurons (INs).

Three main cortical microcircuits core motifs involving inhibitory interneurons

Feedback Feedforward
Disinhibition
inhibition inhibition

˗ ˗

+
Recurrent Lateral

˗
inhibition
˗
inhibition ˗

+
+ + +

Tremblay et al (2016) Neuron

 Feedback inhibition microcircuits
In the local circuits within a given cortical layer and area PCs and INs are
highly connected in a reciprocal manner (individual INs can inhibit >50% of PCs
located within about 100 um and receive excitatory inputs from a large fraction of them).
This connectivity pattern forms the basis for the so called recurrent feedback
inhibition: INs are excited in proportion to the level of local network activity
and directly influence it through their inhibitory feedback.

Recurrent Lateral
inhibition inhibition
˗ ˗

+
+

INs can provide inhibition to neighboring populations of PCs located at a

certain distance that may not have provided excitation to that particular IN
population, a phenomenon more generally referred to as lateral inhibition
 Feedforward inhibition (FFI) microcircuits

Excitatory afferent inputs diverge onto both PCs and interneurons,

which in turn provide disynaptic inhibition to the PCs receiving the
excitatory afferent input, generating FFI microcircuits.

+ +
 Feedback Feedforward
inhibition inhibition

Recurrent Lateral
˗
inhibition
˗
inhibition ˗

+
+ + +

Feedback and feedforward inhibition microcircuits account for the fact that
cortical synaptic excitation and inhibition are inseparable events: through the
recruitment of interneurons via feedforward and/or feedback excitatory projections, inhibition
generated in cortical networks is somehow proportional to local and/or incoming excitation.

The dynamic balance betwen synaptic excitation and inhibition (E/I balance) is
fundamental for proper cortical function. Dynamic, because despite the overall
proportionality of excitation and inhibition, their exact ratio is highly dynamic. Within individuals
neurons the ratio can change on a millisecond basis.

The E/I ratio plays a fundamental role in regulating neuronal output: since changing the E/I ratio
the membrane potential can change between E rev of glutamate receptors and Erev of GABAa
receptors, by changing the ratio, the neuronal membranes can be rapidly brought to threshold for
action-potential generation, just near threshold or far below threshold in a matter of a few
milliseconds
 Disinhibition microcircuits

INs can synapse on other INs and therefore activation of INs may have,
in certain cases, a disinhibitory rather than an inhibitory effect on PCs.
Disinhibition occurs when an IN type inhibits another IN type more
potently than PCs.

˗ ˗
+
 Three main cortical microcircuits core motifs involving inhibitory interneurons

Feedback Feedforward Dishinhibition

inhibition inhibition

˗ ˗

+
Recurrent Lateral

˗
inhibition
˗
inhibition ˗

+
+ + +

--Essential for the correct processing of sensory information

(e.g. gain control and dynamic range modulation, sensory feature selectivity, surround
suppression, synchronization, cell assemblies formation and competition)

--Essential to maintain a dynamic cellular excitatory-inhibitory (E/I) balance

necessary for the transfer of information while preventing runaway excitation
Dysfunctional control of the cortical E/I balance has been associated with the generation of
several types of epilepsy and other diseases, including schizophrenia, anxiety disorders,
autism, migraine.
Inhibitory interneurons are around 20% of cortical neurons (10-15% in rodents).

The abundance and diversity of interneurons has increased during evolution

Interneuron diversity

-Anatomical (axonal and dendritic morphology)

-Input and output connectivity with different cell types (both PCs and INs)

-Electrophysiological (different firing patterns)

-Efficacy, kinetics, and short-term dynamics of synaptic inputs and outputs

-response to neuromodulators, such as Ach, serotonin, NA and dopamine

Large natomical diversity
of inhibitory interneurons in
the cerebral cortex
Inhibitory interneurons

E,F basket cells

G chandelier cells
D double bouquet cells
I neurogliaform cells
 Cortical GABAergic interneurons

L2-L6 (abundant in L4) L1-L6 (abundant in L5) L1-L6 (abundant

Fast-spiking (FS) in L1 and L2/3)

The somatostatin (SST)-expressing Martinotti cells are the main

interneurons that form inhibitory synapses on apical dendrites of
PV: parvalbumin pyramidal cells. They are localized mainly in layers 5-6 and 2-3
SST: somatostatin (where they are the majority of SsT neurons); their axon ascend
5HT3aR: 5HT3a receptor for and branches mainly in layer 2/3 or layer 1 (depending on subtype).
serotonin

VIP:vasoactive intestinal The somatostatin (SST)-expressing non Martinotti cells are mainly
peptide localized in layer 4 (but present also in L5); their axon is confined to
L4 and they mainly form inhibitory synapses with L4 PV
interneurons
Rudy et al (2011) Developm Neurobiol
 Sst interneurons

Figure 1

L5 Sst interneurons (66% Martinotti; 34% non Martinotti cells)

34% 51% 14%
Red: axon
Blue: dendrites

Neuron 2016 91, 260-292DOI: (10.1016/j.neuron.2016.06.033)

-target mainly L4 -target mainly L2/3

-target mainly L1
-make synapses on L4 -make synapses on apical -make synapses on apical
PCs (not on L5 pyramidal dendrites of L5 pyramidal dendrites of L5 pyramidal
cells) cells within L2/3 cells in L1 (tuft) and in L4
 Cortical GABAergic interneurons

L2-L6 (abundant in L4) L1-L6 (abundant in L5) L1-L6 (abundant

in L1 and L2/3)

The 5HT3aR-expressing interneurons (which also express the nicotinic acetilcholine receptor)
are modulated (depolarized) by the serotoninergic and cholinergic nuclei of the brainstem.
Although very heterogeneous, they can be subdivided in two large groups: VIP-expressing and
non VIP-expressing neurons.
VIP neurons are mainly localized in L2/3 (but present in all layers); their denditic tree extends
through many layers in both directions (in L1 up to the pia) and receives input from many
layers. Their axons also extend vertically and make synapses mainly on SST-expressing
interneurons of all layers.
Non VIP neurons are located mainly in L1 (but present in all layers) and comprise the
neurogliaform cells (which mediate GABA volume transmission)
Tremblay et al (2016) Neuron
Important disinhibitory circuit VIP-SOM-Pyr:
activation of VIP interneurons results in disinhibition of pyramidal cells.

Since L1 dendrites of VIP interneurons in primary sensory areas receive

excitatory input from higher order cortical areas, this disinhibitory circuit is
involved in top-down feedback control of the activity of primary sensory
cortices.
 Three main cortical microcircuits core motifs involving inhibitory interneurons

Feedback Feedforward Dishinhibition

inhibition inhibition

˗ ˗

+
Recurrent Lateral

˗
inhibition
˗
inhibition ˗

+
+ + +

PV, SOM PV VIP----SOM (L2/3, L5)

SOM---PV (L4)

--Essential for the correct processing of sensory information

(e.g. gain control and dynamic range modulation, sensory feature selectivity, surround
suppression, synchronization, cell assemblies formation and competition)

--Essential to maintain a dynamic cellular excitatory-inhibitory (E/I)

balance necessary for the transfer of information while preventing runaway
excitation
Tremblay et al (2016) Neuron
 Thalamocortical disynaptic feedforward inhibition circuit
STIM

Voltage clamp Feedforward dIPSC

Cortex
WT
VB
-60 mV

Stim electrode
EPSC

V-Clamp Erev
IPSC
(-83 mV)
-
EPSC

50 pA
RS FS
+ Layer 4
+ + 10 ms

Cortex
Barrel 2

Feed-forward
disynaptic IPSC
VB
(dIPSC)

TC
Stim -60 mV
thalamus

The thalamocortical FFI sets a very brief time window for temporal integration of thalamic
inputs and generation of spike output in L4 PCs.

As a result of this circuit, thalamo-recipient PCs act as coincidence detectors of near-

synchronous thalamic input.
Asynchronous thalamic activity patterns are suppressed by FFI in the L4 network