Balancing central control and sensory feedback produces adaptable and robust locomotor patterns in a spiking, neuromechanical model of the salamander spinal cord.

This study introduces a novel neuromechanical model employing a detailed spiking neural network to explore the role of axial proprioceptive sensory feedback, namely stretch feedback, in salamander locomotion. Unlike previous studies that often oversimplified the dynamics of the locomotor networks, our model includes detailed simulations of the classes of neurons that are considered responsible for generating movement patterns. The locomotor circuits, modeled as a spiking neural network of adaptive leaky integrate-and-fire neurons, are coupled to a three-dimensional mechanical model of a salamander with realistic physical parameters and simulated muscles.

Dopamine-sensitive neurons in the mesencephalic locomotor region control locomotion initiation, stop, and turns.

The locomotor role of dopaminergic neurons is traditionally attributed to their ascending projections to the basal ganglia, which project to the mesencephalic locomotor region (MLR). In addition, descending dopaminergic projections to the MLR are present from basal vertebrates to mammals. However, the neurons targeted in the MLR and their behavioral role are unknown in mammals.

Dopamine control of downstream motor centers.

The role of dopamine in the control of movement is traditionally associated with ascending projections to the basal ganglia. However, more recently descending dopaminergic pathways projecting to downstream brainstem motor circuits were discovered. In lampreys, salamanders, and rodents, these include projections to the downstream Mesencephalic Locomotor Region (MLR), a brainstem region controlling locomotion.

Locomotor pattern generation and descending control: a historical perspective.

The ability to generate and control locomotor movements depends on complex interactions between many areas of the nervous system, the musculoskeletal system, and the environment. How the nervous system manages to accomplish this task has been the subject of investigation for more than a century. In vertebrates, locomotion is generated by neural networks located in the spinal cord referred to as central pattern generators.

The Mesencephalic Locomotor Region: Multiple Cell Types, Multiple Behavioral Roles, and Multiple Implications for Disease.

The mesencephalic locomotor region (MLR) controls locomotion in vertebrates. In humans with Parkinson disease, locomotor deficits are increasingly associated with decreased activity in the MLR. This brainstem region, commonly considered to include the cuneiform and pedunculopontine nuclei, has been explored as a target for deep brain stimulation to improve locomotor function, but the results are variable, from modest to promising.

From retina to motoneurons: A substrate for visuomotor transformation in salamanders.

The transformation of visual input into motor output is essential to approach a target or avoid a predator. In salamanders, visually guided orientation behaviors have been extensively studied during prey capture. However, the neural circuitry involved is not resolved.

Optogenetic stimulation of glutamatergic neurons in the cuneiform nucleus controls locomotion in a mouse model of Parkinson's disease.

In Parkinson's disease (PD), the loss of midbrain dopaminergic cells results in severe locomotor deficits, such as gait freezing and akinesia. Growing evidence indicates that these deficits can be attributed to the decreased activity in the mesencephalic locomotor region (MLR), a brainstem region controlling locomotion. Clinicians are exploring the deep brain stimulation of the MLR as a treatment option to improve locomotor function.

Emergence of robust self-organized undulatory swimming based on local hydrodynamic force sensing.

Undulatory swimming represents an ideal behavior to investigate locomotion control and the role of the underlying central and peripheral components in the spinal cord. Many vertebrate swimmers have central pattern generators and local pressure-sensitive receptors that provide information about the surrounding fluid. However, it remains difficult to study experimentally how these sensors influence motor commands in these animals.

Freely Behaving Mice Can Brake and Turn During Optogenetic Stimulation of the Mesencephalic Locomotor Region.

A key function of the mesencephalic locomotor region (MLR) is to control the speed of forward symmetrical locomotor movements. However, the ability of freely moving mammals to integrate environmental cues to brake and turn during MLR stimulation is poorly documented. Here, we investigated whether freely behaving mice could brake or turn, based on environmental cues during MLR stimulation.

Reproducing Five Motor Behaviors in a Salamander Robot With Virtual Muscles and a Distributed CPG Controller Regulated by Drive Signals and Proprioceptive Feedback.

Diverse locomotor behaviors emerge from the interactions between the spinal central pattern generator (CPG), descending brain signals and sensory feedback. Salamander motor behaviors include swimming, struggling, forward underwater stepping, and forward and backward terrestrial stepping. Electromyographic and kinematic recordings of the trunk show that each of these five behaviors is characterized by specific patterns of muscle activation and body curvature.

S100β-mediated astroglial control of firing and input processing in layer 5 pyramidal neurons of the mouse visual cortex.

Key Points: Inputs impinging on layer 5 pyramidal neurons perform essential operations as these cells represent one of the most important output carriers of the cerebral cortex. However, the contribution of astrocytes, a type of glial cell, to these operations is poorly documented. Here we found that optogenetic activation of astrocytes in the vicinity of layer 5 in the mouse primary visual cortex induces spiking in local pyramidal neurons through Nav1.

Serotonergic Modulation of Locomotor Activity From Basal Vertebrates to Mammals.

During the last 50 years, the serotonergic (5-HT) system was reported to exert a complex modulation of locomotor activity. Here, we focus on two key factors that likely contribute to such complexity. First, locomotion is modulated directly and indirectly by 5-HT neurons.

Walking with Salamanders: From Molecules to Biorobotics.

How do four-legged animals adapt their locomotion to the environment? How do central and peripheral mechanisms interact within the spinal cord to produce adaptive locomotion and how is locomotion recovered when spinal circuits are perturbed? Salamanders are the only tetrapods that regenerate voluntary locomotion after full spinal transection. Given their evolutionary position, they provide a unique opportunity to bridge discoveries made in fish and mammalian models. Genetic dissection of salamander neural circuits is becoming feasible with new methods for precise manipulation, elimination, and visualisation of cells.

Descending Dopaminergic Inputs to Reticulospinal Neurons Promote Locomotor Movements.

Meso-diencephalic dopaminergic neurons are known to modulate locomotor behaviors through their ascending projections to the basal ganglia, which in turn project to the mesencephalic locomotor region, known to control locomotion in vertebrates. In addition to their ascending projections, dopaminergic neurons were found to increase locomotor movements through direct descending projections to the mesencephalic locomotor region and spinal cord. Intriguingly, fibers expressing tyrosine hydroxylase (TH), the rate-limiting enzyme of dopamine synthesis, were also observed around reticulospinal neurons of lampreys.

Heterogeneous expression of dopaminergic markers and Vglut2 in mouse mesodiencephalic dopaminergic nuclei A8-A13.

Co-transmission of glutamate by brain dopaminergic (DA) neurons was recently proposed as a potential factor influencing cell survival in models of Parkinson's disease. Intriguingly, brain DA nuclei are differentially affected in Parkinson's disease. Whether this is associated with different patterns of co-expression of the glutamatergic phenotype along the rostrocaudal brain axis is unknown in mammals.

The serotonin reuptake blocker citalopram destabilizes fictive locomotor activity in salamander axial circuits through 5-HT receptors.

Serotoninergic (5-HT) neurons are powerful modulators of spinal locomotor circuits. Most studies on 5-HT modulation focused on the effect of exogenous 5-HT and these studies provided key information about the cellular mechanisms involved. Less is known about the effects of increased release of endogenous 5-HT with selective serotonin reuptake inhibitors.

Motor Control: Swim Harder, Faster, Stronger.

A new study provides evidence in zebrafish that dopamine increases the activity of motor neurons in the spinal cord, and this translates into faster swimming bouts in response to visual stimulation.

Nigral Glutamatergic Neurons Control the Speed of Locomotion.

The mesencephalic locomotor region (MLR) plays a crucial role in locomotor control. In vertebrates, stimulation of the MLR at increasing intensities elicits locomotion of growing speed. This effect has been presumed to result from higher brain inputs activating the MLR like a dimmer switch.

Dopamine and the Brainstem Locomotor Networks: From Lamprey to Human.

In vertebrates, dopamine neurons are classically known to modulate locomotion via their ascending projections to the basal ganglia that project to brainstem locomotor networks. An increased dopaminergic tone is associated with increase in locomotor activity. In pathological conditions where dopamine cells are lost, such as in Parkinson's disease, locomotor deficits are traditionally associated with the reduced ascending dopaminergic input to the basal ganglia.

A descending dopamine pathway conserved from basal vertebrates to mammals.

Dopamine neurons are classically known to modulate locomotion indirectly through ascending projections to the basal ganglia that project down to brainstem locomotor networks. Their loss in Parkinson's disease is devastating. In lampreys, we recently showed that brainstem networks also receive direct descending dopaminergic inputs that potentiate locomotor output.

The mesencephalic locomotor region sends a bilateral glutamatergic drive to hindbrain reticulospinal neurons in a tetrapod.

In vertebrates, stimulation of the mesencephalic locomotor region (MLR) on one side evokes symmetrical locomotor movements on both sides. How this occurs was previously examined in detail in a swimmer using body undulations (lamprey), but in tetrapods the downstream projections from the MLR to brainstem neurons are not fully understood. Here we examined the brainstem circuits from the MLR to identified reticulospinal neurons in the salamander Notophthalmus viridescens.

Flexibility of the axial central pattern generator network for locomotion in the salamander.

In tetrapods, limb and axial movements are coordinated during locomotion. It is well established that inter- and intralimb coordination show considerable variations during ongoing locomotion. Much less is known about the flexibility of the axial musculoskeletal system during locomotion and the neural mechanisms involved.

Forebrain dopamine neurons project down to a brainstem region controlling locomotion.

The contribution of dopamine (DA) to locomotor control is traditionally attributed to ascending dopaminergic projections from the substantia nigra pars compacta and the ventral tegmental area to the basal ganglia, which in turn project down to the mesencephalic locomotor region (MLR), a brainstem region controlling locomotion in vertebrates. However, a dopaminergic innervation of the pedunculopontine nucleus, considered part of the MLR, was recently identified in the monkey. The origin and role of this dopaminergic input are unknown.