From circuits to behaviour: motor networks in vertebrates

Abstract

Neural networks in the hindbrain and spinal cord generate the simple patterns of motor activity that are necessary for breathing and locomotion. These networks function autonomously, producing simple yet flexible rhythmic motor behaviours that are highly responsive to sensory inputs and central control. This review outlines recent advances in our understanding of the genetic programmes controlling the assembly and functioning of circuits in the hindbrain and spinal cord that are responsible for respiration and locomotion. In addition, we highlight the influence that target-derived retrograde signaling and experience-dependent mechanisms have on establishing connectivity, particularly with respect to sensory afferent innervation of the spinal cord.

Figure 1

Respiratory centres in the medulla that are responsible for the breathing rhythm and chemosensitivity. (a) Schematic of the neonate hindbrain showing the location of the major excitatory regions involved in respiratory rhythm generation, the e-pF/pFRG/RTN (embryonic parafacial nucleus/parafacial respiratory group/retrotrapezoid nucleus; orange), the PBC (preBötzinger complex; red, green/yellow), as well as the VRG (ventral respiratory group). (b) Structure of the e-pF and preBötzC. Neurons in the e-pF (orange) express a combination of VGlut2, Lbx1, Atoh1 and Phox2b [22•-24•] and they exhibit uniform pacemaker properties [21••]. Neurons in the preBötzC express different combinations of NKR1 and Sst [17-19], and exhibit various constellations of cellular currents [6,7,11-13]. Serotonergic neurons in the Raphe are indicated in blue with projections (arrows) to multiple structures including the pFRG/RTN and preBötC. The e-PF and later pFRG/RTN are connected by excitatory (red) and inhibitory (black) connections, although the neural nature of these connections connections is not clear. Dashed lines indicate putative reciprocal excitatory and inhibitory connections between both rhythmic centres. e-pF/pFRG/RTN and preBötzC neurons on either side of the medulla are also mutually connected and excited (red).

Figure 2

Organization and function of the locomotor central pattern generator (CPG) (a) Schematic of the mouse neonatal spinal cord illustrating lumbar segments 2 (L2) and 5 (L5) involved in flexor and extensor motor control, respectively. In the ventral spinal cord, CPG networks that contribute to generate rhythmic motor activity and control left-right alternation are located in laminae VI-IX [36] (pink; left). Summary of flexor-related activity recorded in vitro from left and right L2 ventral roots. The pattern of left-right alternation in wild-type, Chox10-DTA [39••] and Sim1-Cre; R26-TeNT [50••] mice during induced fictive locomotion is shown schematically (right). (b) Table summarizing the expression of transcription factors that define ventral (V0-V3) interneuron classes and their subclasses, neurotransmitter markers, axonal projections, known connections and function [37,38,39••,40••,50]. Adapted from [82]. IaIN, Ia inhibitory interneuron; Calb, Calbindin; GABA, GABAergic; Glu, glutamatergic; Gly, glycinergic; Parv, Parvalbumin; RC, Renshaw cell.

Figure 3

Motor pool organization and sensorimotor connectivity in the spinal cord. (a) Schematic representation depicting a longitudinal view of forelimb motor pools in the mouse spinal cord (left). The cell bodies of motor neurons (MNs) that send axons to specific limb muscles are contained within the lateral motor column (LMC). Motor pools are generated at specific rostrocaudal positions within the brachial LMC. At C7-T1 levels, motor pools projecting to the cutaneous maximus (Cm, green) and triceps (Tri, red) muscles can be molecularly defined by the expression of ETS transcription factors. At the intrasegmental level, the Cm motor pool can be distinguished by the expression of Pea3 [63]. GDNF from the intrafusal muscle spindle induces the expression of Pea3 in Cm MNs [64], which in turn activates Sema3E gene expression [63]. Note that Cm MNs receive polysynaptic input from Ia propioceptive afferents (open line) whereas Tri Ia propioceptive afferents make direct monosynaptic contacts to Tri MNs [65] (right). (b) Summary of the connectivity patterns in Cm and Tri reflex pathways in wildtype, Pea3 mutants and mice with altered Sema3E expression. In wildtype, Tri afferents contact homonymous MNs. In Pea3 mutants, Cm MNs receive contacts from Tri afferents [65]. In Sema3E mutants, Cm MNs receive monosynaptic contacts from Cm afferents [66•]. Ectopic expression of Sema3E prevents monosynaptic connections between Tri afferents and Tri MNs [66•]. Role of Pea3 in the genetic program controlling Cm sensorimotor connectivity, cell body position and dendrite arborization [63,65,66•] (bottom). For details see text.