Rogier Poorthuis en Bernard Bloem provide Cerebral Cortex Cover

07 January 2013

Function of nicotinic receptors uncovered: Rogier Poorthuis and Bernard Bloem, PhD students at the department of Integrative Neurophysiology, published on the mechanisms by which nicotinic acetylcholine receptors regulate synaptic circuits and neuronal excitability in the prefrontal cortex. They show that these processes markedly differ across cortical layers. A 3D illustration of the layered prefrontal cortical network is now selected to be on the cover of Cerebral Cortex

Cholinergic signaling in the Prefrontal Cortex (PFC) plays a key role in attention processes. Different types of receptors process acetylcholine signals. Nicotinic receptors are an important target of acetylcholine in regulating attention. A recent CNCR paper in Science showed that the β2-containing nicotinic receptor controls attention in the PFC. How nicotinic receptors modulate activity in the underlying neuronal network was not yet known and is investigated in the Cerebral Cortex paper.

The PFC is, like all cortical areas, a layered structure. The layers comprise a network of highly interconnected pyramidal and interneurons. Pyramidal neurons are the output neurons of these circuits. Across layers, pyramidal neurons are known to preferentially target different (sub)cortical areas. Hence, nicotinic receptor modulation of these different layers potentially alters different streams of information in the brain. We hypothesized that activation of the PFC by nicotinic receptors would differ across layers.

Using whole cell recordings from mouse brain slices showed that pyramidal neuron modulation markedly differs across layers. Layer II/III pyramidal neurons, as well as glutamatergic inputs to these neurons, do not express nicotinic receptors. Pyramidal neurons in layer V are modulated by presynaptic β2-containing nicotinic receptors and by postsynaptic α7 receptors. Showing that nicotinic receptors can have diverse effects on the same neuron, depending on the receptor type and location of the receptor in the circuit. Layer VI pyramidal neurons are stimulated through postsynaptic β2-containing nicotinic receptors. Interneurons in all layers are regulated by nicotinic receptors, uncovering that this is an ubiquitous mechanism in cholinergic modulation of the cortex. Fast-spiking interneurons are regulated by α7 receptors whereas non-fast-spiking interneurons are regulated by both α7 and β2-containing nicotinic receptors. Finally, using two-photon imaging we investigated how nicotinic receptor activation in these different circuits balances out to activate the PFC. We show that output neuron activity is dominated in PFC layer VI, moderate in layer V and absent in layer II-III.

Together, this comprehensive study shows that the fundamental mechanisms by which nicotinic receptors regulate neuronal circuits are layer-dependent in the PFC. The results indicate that these receptors serve a specific role to modulate sensory representations in the PFC by stimulating thalamocortical circuits in layer V and VI. In addition, nicotinic receptors recruit inhibition. Nicotinic receptors are thereby able to increase the signal-to-noise ratio in across the whole PFC network, which might be important for regulating attention processes. 

The cover illustration represents the different layers of the PFC and shows typical pyramidal neurons of all layers, reconstructed by the team of Christiaan de Kock. They are embedded in a network of neurons loaded with a calcium indicator to study neuronal activity using two-photon imaging. Below the nicotinic receptor currents of these neurons are displayed.

Layer-Specific Modulation of the Prefrontal Cortex by Nicotinic Acetylcholine Receptors.
Poorthuis RB*, Bloem B*, Schak B, Wester J, de Kock CP, Mansvelder HD.
Cerebral Cortex. Published Online 2012 Jan 30.

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