Modulation of motor behavior by the mesencephalic locomotor region

Abstract

Number of words: Abstract: 147; Main Text: 4669. 22 23 Acknowledgments: 24 This research was supported by an NIH grant NS100824 (J.M.S.), a NJ-DOH grant 25 CSCR20IRG008 (J.M.S.), a NARSAD Young Investigator Award (J.M.S.), the Hungarian 26 National Brain Research Program (B.P.), the OTKA Bridging Fund of the University of 27 Debrecen (B.P.) and Rutgers University. The authors are grateful to Dr. Péter Szücs 28 Abstract 42The mesencephalic locomotor region (MLR) serves as an interface between higher-order 43 motor systems and lower motor neurons. The excitatory module of the MLR is composed 44 of the pedunculopontine nucleus (PPN) and the cuneiform nucleus (CnF), and their 45 activation has been proposed to elicit different modalities of movement, but how the 46 differences in connectivity and physiological properties explain their contributions to motor 47 activity is not known. Here we report that CnF glutamatergic neurons are 48 electrophysiologically homogeneous and have short-range axonal projections, whereas 49 PPN glutamatergic neurons are heterogeneous and maintain long-range connections, 50 most notably with the basal ganglia. Optogenetic activation of CnF neurons produced 51 fast-onset, involuntary motor activity mediated by short-lasting muscle activation. In 52 contrast, activation of PPN neurons produced long-lasting increases in muscle tone that 53 reduced motor activity and disrupted gait. Our results thus reveal a differential contribution 54 to motor behavior by the structures that compose the MLR. 55 56 58 composed of the pedunculopontine nucleus (PPN) and the cuneiform nucleus (CnF) 59 which has been typically described as an output station of forebrain systems reaching 60 lower motor circuits 1-3 . Early experiments defined the MLR by demonstrating that 61 electrical stimulation of this region induced a locomotor response in decorticated cats 4,5 . 62More recently, optogenetic experiments revealed that the motor function of the MLR is 63 dependent on excitatory transmission from glutamatergic neurons 6,7 , which is the most 64 3 prominent cell type in the MLR 8,9 . In the last two decades, a role for these circuits in gait 65 and posture has been proposed 10-13 . Moreover, degeneration of neurons in the MLR may 66 underlie some of the motor impairments in Parkinson's disease [14][15][16][17][18][19] . Deep brain 67 stimulation into the PPN has been shown to produce some improvements in abnormal 68 gait based on the idea that the output from the MLR is excitatory 20-23 . However, it is not 69 fully understood how excitatory MLR neurons contribute to motor behavior and how motor 70 functions are associated with different neuronal types in the MLR. 71 72 The PPN, the largest component of the MLR, is highly heterogeneous. It is composed of 73 three neurotransmitter-defined cell types: cholinergic, GABAergic and glutamatergic 74 neurons. Among PPN glutamatergic neurons, a high degree of variability has been 75 reported in their neurochemical composition 8 , connectivity 24 and firing properties 2...

Dissecting Brainstem Locomotor Circuits: Converging Evidence for Cuneiform Nucleus Stimulation

“…Interestingly, in trials where Josset et al ( 2018 ) used crossed transgenic mice expressing channelrhodopsin in all glutamatergic neurons, the more dorsally located PPN stimulations were able to initiate low-speed locomotion from rest, where they could not with more ventrally located PPN stimulations ( Figure 1C ), nor with the PPN-specific virally-transfected mice. At least one other group supports the view that activation of glutamatergic CnF neurons produces robust locomotion in mice, while activation of glutamatergic PPN neurons reduces locomotor activity, citing important differences between these subpopulations again in terms of their connectivity, but also in their intrinsic membrane properties (Dautan et al, 2020 ). Their finding that glutamatergic CnF neurons are mostly rapidly adapting and accommodating, while glutamatergic PPN neurons are more heterogeneous in their electrophysiologic properties, provides further insight into why experiments regarding the PPN have often provided mixed behavioral results (Dautan et al, 2020 ).…”

“…At least one other group supports the view that activation of glutamatergic CnF neurons produces robust locomotion in mice, while activation of glutamatergic PPN neurons reduces locomotor activity, citing important differences between these subpopulations again in terms of their connectivity, but also in their intrinsic membrane properties (Dautan et al, 2020 ). Their finding that glutamatergic CnF neurons are mostly rapidly adapting and accommodating, while glutamatergic PPN neurons are more heterogeneous in their electrophysiologic properties, provides further insight into why experiments regarding the PPN have often provided mixed behavioral results (Dautan et al, 2020 ).…”

MR Tractography-Based Targeting and Physiological Identification of the Cuneiform Nucleus for Directional DBS in a Parkinson’s Disease Patient With Levodopa-Resistant Freezing of Gait

“…Furthermore, no other groups have used the more recently available directional electrode technology in this region, where the ability to steer current in specific directions could be helpful in minimizing the activation of unrelated fiber tracts passing through the region. Based on many electrical mapping studies (Shik et al, 1966;Eidelberg et al, 1981;Takakusaki et al, 2016;Opris et al, 2019;Chang et al, 2021), as well as more recent optogenetic studies of the MLR (Caggiano et al, 2018;Josset et al, 2018;Dautan et al, 2020), we proposed to target the cuneiform nucleus, rather than the traditionally targeted PPN. We used the subject's regional DTI tractography to refine our pre-determined brainstem normalized coordinates for this target, since this region does not have clear boundaries on T1or T2-weighted MR imaging (Zrinzo et al, 2008;Shimamoto et al, 2010;Cong et al, 2018).…”

“…Recently, several optogenetic studies targeting the MLR in mice have functionally characterized and distinguished neuronal populations within the MLR by neurochemistry and anatomy, suggesting that glutamatergic CnF neurons are the principal group within the MLR involved in initiating and controlling locomotion ( Caggiano et al, 2018 ; Josset et al, 2018 ; Dautan et al, 2020 ). Supported by a recent anatomical-clinical study ( Goetz et al, 2019 ), we hypothesized that targeting the CnF could lead to improved outcomes for PD patients with FOG and devised a pilot feasibility study.…”

Optogenetic stimulation of glutamatergic neurons in the cuneiform nucleus controls locomotor movements in a mouse model of Parkinson’s disease

“…The control of locomotor speed exerted by PPN glutamatergic neurons appears to be less robust than that exerted by CnF ones(Caggiano et al 2018, Josset et al 2018), making their recruitment unlikely here. We did not record any decelerated locomotor rhythms or locomotor stops that were reported to be induced by activation of glutamatergic PPN neurons in certain cases(Josset et al 2018, Dautan et al 2020. At the anatomical level, we carefully verified that the optic fiber tips were located in or above the CnF (Fig.4D)…”