Modulation of motor behavior by the mesencephalic locomotor region.

Dautan, D., Kovacs, A., Bayasgalan, T., Diaz-Acevedo, M.A., Pal, B. and Mena-Segovia, J.

Cell Reports (2021); 36(8):109594.

https://doi.org/10.1101/2020.06.25.172296.

In this paper we show that differences in connectivity and physiological properties of MLR neurons uncover fundamental differences in the modulation of muscle activity and reveal their differential roles in motor behavior. We show that activation of PPN neurons produces a long-lasting increase in the amplitude of the ipsilateral muscles consistent with an increased muscle resistance to passive movement, whereas the bilateral nature of the short-lasting muscle activation observed after unilateral CnF stimulation is consistent with the frequency-dependent bouts of locomotor activity. We propose that the lasting increase in muscle tone observed following PPN stimulation may act as a readiness signal that precedes locomotion, suggesting that both MLR structures act in coordination to modulate the motor output.

Cholinergic midbrain afferents modulate striatal circuits and shape encoding of action strategies.

Dautan D., Huerta-Ocampo I., Gut N.K., Valencia M., Kondabolu K., Kim Y., Gerdjikov T.V. and Mena-Segovia J.

Nature Communications (2020); 11(1):1739.

In this paper we show that PPN and LDT cholinergic axons make direct monosynaptic connections with striatal cholinergic interneurons and activate them through a putative nicotinic mechanism. These midbrain inputs are able to modulate striatal behavior suggesting the existence of two hierarchically-organized modes of cholinergic transmission in the striatum where cholinergic interneurons are modulated by cholinergic neurons of the midbrain. We propose that the activation of cholinergic interneurons may thus underlie the mechanism by which PPN is able to shape striatal output and block ongoing motor programs at the level of SPNs in order to update the behavioral state and reinforce novel actions.

Distribution of Midbrain Cholinergic Axons in the Thalamus.

Huerta-Ocampo I., Hacioglu-Bay H., Dautan D. and Mena-Segovia J.

eNeuro (2020). 7(1). pii: ENEURO.0454-19.2019.

In this paper we traced the axons of two midbrain cholinergic structures that provide extensive innervation of the thalamus, the PPN and the LDT. We found that they provide cholinergic innervation to virtually every single thalamic nucleus. In addition, we observe that PPN preferentially innervates thalamic structures involved in motor circuits while LDT targets mainly thalamic structures involved in limbic circuits.

Pedunculopontine glutamatergic neurons provide a novel source of feedforward inhibition in the striatum by selectively targeting interneurons.

Assous M., Dautan D., Tepper, J.M. and Mena-Segovia J.

Journal of Neuroscience (2019). pii: 2913-18.

In this study we demonstrate the existence of an excitatory glutamatergic projection that originates in the PPN and modulates striatal neuronal activity. Using ex vivo recordings, we show that this projection selectively targets multiple subtypes of striatal interneurons and generates feedforward inhibition in spiny projection neurons. Using in vivo extracellular recordings, we demonstrate that striatal interneurons are activated following the stimulation of PPN glutamatergic axons and SPNs show a long-latency decrease in firing rate. Our results reveal a unique mechanism by which midbrain glutamatergic projections selectively recruit striatal interneurons resulting in suppression of striatal output.

Rethinking the Pedunculopontine Nucleus: From Cellular Organization to Function.

Mena-Segovia J. and Bolam J.P.

Neuron (2017) 94 (1): 7-18.

In this review we put together classical concepts and new evidence that dissects the influence of its different neuronal subtypes on their various targets, and we propose that the cholinergic neurons of the PPN have a central role in updating the behavioral state as a result of changes in environmental contingencies. Such a function is accomplished by a combined mechanism that simultaneously restrains ongoing obsolete actions while it facilitates new contextual associations.

Segregated cholinergic transmission modulates dopamine neurons integrated in distinct functional circuits.

Dautan D., Souza A.S., Huerta-Ocampo I., Valencia M., Assous M., Witten I.B., Deisseroth K., Tepper J.M., Bolam J.P., Gerdjikov T.V. and Mena-Segovia J.

Nature Neuroscience (2016) 19 (8):1025-33.

We show how dopamine neurons operate in the context of cholinergic transmission and find that the afferents originating from two functionally distinct (motor and limbic) cholinergic nuclei of the brainstem selectively modulate subsets of neurons in the ventral tegmental area.

[Link]

Extrinsic Sources of of Cholinergic Innervation of the Striatal Complex: A Whole-Brain Mapping Analysis.

Dautan D, Hacioğlu Bay H, Bolam JP, Gerdjikov TV and Mena-Segovia J.

Frontiers in Neuroanatomy (2016) 10:1.

After our publication in 2014 of the existence of an extrinsic source of acetylcholine to the striatum originated in the brainstem, it raised questions on whether other sources of acetylcholine may have passed unrecognized in the same way. In order to provide a solid and definite answer to these questions, we used conditional tracing in all brain cholinergic cell groups in ChAT::Cre rats and mapped cholinergic axons across the brain. Our results show that brainstem cholinergic axons (PPN and LDT) provide the only extrinsic cholinergic innervation to the striatal complex.

[Download]

Decoding brain state transitions in the pedunculopontine nucleus: cooperative phasic and tonic mechanisms.

Petzold A., Valencia M., Pal B. and Mena-Segovia J.

Frontiers in Neural Circuits (2015) 9:68. 

In this paper we demonstrate that cholinergic neurons of the PPN discharge phasically during brain state transitions, in contrast to putative glutamatergic neurons that discharge tonically and are likely to show a sustained high firing rate during the waking state. 

[Download]