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Professor Zoltan Molnar has collaborated with colleagues on a new paper in Neuron.

From left to right the collaborative team, Zoltan Molnar, Timothy Zolnik and Matthew Larkham (not pictured, fourth team member Britta Eickholt).

Professor Zoltan Molnar has collaborated with colleagues on a new paper in Neuron. The work was supported by an Einstein Visiting Fellowship for Zoltan, so he could be associated with Charité, Berlin for the last 4 years.

The paper, ‘Layer 6b controls brain state via apical dendrites and the higher-order thalamocortical system’ is about Layer 6b of the cortex. This very thin cortical layer that harbours the deepest cortical neurons, and these cells are special for two reasons.

They are the remnants of the transient subplate cells of the cerebral cortex ( During development they play crucial roles in the thalamocortical axon guidance and cortical circuit assembly. After development, a large portion of them die through preferential cell death, but some cells remain as layer 6b in mouse and interstitial white matter cells in primates, including human.  

These cells are also unique, because they are the only cortical layer responsive to the neuropeptide orexin1 (also known as hypocretin), a vital neuropeptide that is produced in the lateral hypothalamus and regulates the brain’s arousal system, attention, and brain state. 

The paper published by Zolnik and colleagues explains how these layer 6b exert the orexin arousal effect on the cortex. The orexin-sensitive layer 6b subcircuits powerfully excite the cortex and drive circuit loops between L5 pyramidal neurons and higher-order thalamic neurons.

The projections to higher order thalmic nuclei have been described previously but the mechanistic details had to be worked out using optogenetic stimulation experiments. The synaptic output of L6b includes highly plastic facilitating synapses and connections dependent on NMDA-receptor-dependent dendritic spikes.

The paper concludes that orexin/hypocretin-activated cortical neurons form a multifaceted, fine-tuned circuit for the sustained control of the higher-order thalamocortical system. The results support the notion that L6b neurons support both attention and understanding.

These results are also important to the understanding of the pathologies observed in schizophrenia and autism, where more interstitial white matter cells have been observed in humans. The changed distribution and number of these neurons might produce some of the symptoms observed in these conditions.

The results of this paper are relevant to the current research in the Mann, Lak and Molnár laboratories, where the involvement of these circuits in anxiety is being investigated

research slide

[Above] Summary of the input and output relations to the cerebral cortex with special attention to layer 6b neurons. The corticofugal projections from layers 5, 6a, and 6b have distinct relationships to first order (also called relay) nuclei and higher-order (also called association) nuclei of the thalamus. Only the first-order thalamic nuclei receive direct input from the sensory periphery. The higher order thalamic nuclei receive their input from the cortex and relay this back to other cortical areas, providing a route for trans thalamic cortico-cortical communication. The Molnár laboratory previously discovered that a subgroup of layer 6b neurons (Drd1a-Cre line) preferentially target posterior thalamic nucleus, lateral posterior nucleus of thalamus, and other higher-order and midline thalamic nuclei (Hoerder-Suabedissen et al., 2019; and these are the neurons that are selectively sensitive to the neuropeptide orexin/hypocretin that is produced in the lateral hypothalamus.

Right panels are coronal sections in antero-posterior (A-D) order where the tdTom positive cortical layer 6b cells (only in the cortex) develop projections to the overlying cortex and to the higher order thalamic nuclei (such as PO, LP, LD), but not to first order nuclei (VPM, LGd, MG). Left panel is from Horvath et al., 2020 ( right panel is from Hoerder-Suabedissen et al., 2019;

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