The locus coeruleus directs sensory-motor reflex amplitude across environmental contexts

Abstract

Purposeful movement across unpredictable environments requires quick, accurate, and contextually appropriate motor corrections in response to disruptions in balance and posture.^1,2,3 These responses must respect both the current position and limitations of the body, as well as the surrounding environment,^4,5,6 and involve a combination of segmental reflexes in the spinal cord, vestibulospinal and reticulospinal pathways in the brainstem, and forebrain structures such as the motor cortex.^7,8,9,10 These motor plans can be heavily influenced by the animal's surrounding environment, even when that environment has no mechanical influence on the perturbation itself. This environmental influence has been considered as cortical in nature, priming motor responses to a perturbation.^8,11 Similarly, postural responses can be influenced by environments that alter threat levels in humans.^{12,13,14,15,16,17,18} Such studies are generally in agreement with work done in the mouse showing that optogenetic stimulation of the lateral vestibular nucleus (LVN) only results in motor responses when the animal is on a balance beam at height and not when walking on the stable surface of a treadmill.¹⁰ In general, this ability to flexibly modify postural responses across terrains and environmental conditions is a critically important component of the balance system.^19,20 Here we show that LVN-generated motor corrections can be altered by manipulating the surrounding environment. Furthermore, environmental influence on corrections requires noradrenergic signaling from the locus coeruleus, suggesting a potential link between forebrain structures that convey sensory information about the environment and brainstem circuits that generate motor corrections.

Keywords: EMG; balance; lateral vestibular nucleus; locus coeruleus; motor control; muscle.

Figure 1

Environmental context alters response to unexpected perturbation (A) Schematic showing the behavioral apparatus to vary environmental context. (B) Breaths per minute in experimental animals in the high- and low-wall conditions. (C) Traces of the arena displacement (perturbation) in the high- and low-wall conditions. (D) Example images of head position relative to fixed point in the arena prior to perturbation onset (time 0) and 100 ms after perturbation onset. (E) Change in head displacement angle over time from perturbation onset (time 0) in high- and low-wall conditions. (F) Peak head displacement angle after perturbation in high- and low-wall conditions. (G) Diagram showing location of hindlimb muscles implanted with electrodes (see also Figure S1). (H) Example rectified EMG traces from the GS muscle in high- and low-wall conditions after perturbation onset. (I) Peak EMG amplitude of TA and GS muscles during perturbation in high- and low-wall conditions. Each point is the mean of trials from individual experimental animals with the overall mean represented by black lines. ^∗p < 0.05. See also Figures S1 and S2.

Figure 2

Inhibition of the LVN reduces response to perturbation (A) Schematic showing experimental strategy to transiently inhibit neurons in the LVN. (B) Histological image showing virus injection in the LVN and placement of fiber optic cannula. (C) Mean peak EMG amplitude after perturbation without light (control). (D) Mean peak EMG amplitude after perturbation with light on and inhibition of LVN neurons. In (B) and (D), each point is the mean of trials from individual experimental animals with the overall mean represented by black lines. LVN, lateral vestibular nucleus. ^∗p < 0.05.

Figure 3

Disruption of the LC specifically affects strenuous locomotion (A) Experimental plan for disruption of noradrenergic signaling via the injection of the selective noradrenergic neurotoxin DSP-4. (B) Representative path lengths in 10 min open field. (C) Overall path lengths in open field. (D) Locomotor velocity in open field. (E) Ability of control and DSP-4-injected animals to maintain consistent speed on a horizontal treadmill at 0.4, 0.6, and 0.8 m/s. (F) Ability of wild-type and DSP-4-injected animals to maintain consistent speed on an inclined treadmill at 0.4, 0.6, and 0.8 m/s. (G) Step cycle time on incline treadmill at 0.4 m/s. (H) Step cycle time (left) and step length (right) on incline treadmill at 0.8 m/s. (I) Toe position in xy coordinates over the step cycle at 0.8 m/s on horizontal treadmill. (J) Toe position in xy coordinates over the step cycle at 0.8 m/s on inclined treadmill. ^∗p < 0.05. See also Figure S3. Error bars are ± SEM.

Figure 4

The LC is involved in processing information regarding environmental context (A) LVST neurons labeled via CTB-647 injection into the lumbar spinal cord and sections stained with anti-TH. Higher magnification images (middle and right) show apposition of TH-positive enlargements in the vicinity of LVST neurons. (B) Experimental procedure to test effect of noradrenergic neurotoxin DSP-4 on responses to lateral perturbations. (C) Comparison of peak EMG amplitudes in TA after perturbation in control animals in high- and low-wall conditions. (D) Comparison of peak EMG amplitudes in TA muscle after perturbation in animals following DSP-4 injection in high- and low-wall conditions. (E) Experimental procedure for selective labeling of noradrenergic neurons in the LC using the PRSx8 promoter. (F) TH immunostaining at site of injection of AAV described in (E). (G and H) GFP labeling and (H) merge of same site shown in (F). (I) Proportion of TH-positive neurons in the LC that express GFP following AAV injection. (J) Proportion of TH-negative neurons expressing GFP. (K) Experimental strategy for blocking synaptic transmission from neurons in the LC. (L) Bilateral targeting of TeLC-GFP to the LC. (M) Higher magnification of image in (L). (N) Peak EMG responses of TA muscle in response to perturbations in high- or low-wall conditions in animals expressing GFP in the LC. (O) Peak EMG responses of TA muscle in response to perturbations in high- or low-wall conditions in animals expressing GFP-TeLC in the LC. Error bars are ± SEM