**3.1 Afferent glutamate-ergic neurotransmision in muscle spindles?**

Bewick and co-workers [44] have demonstrate the occurrence of a complete gutamatergic neurotransmission system in the afferents of muscle spindles associated to the synaptic-like vesicles typical of those terminals. Exogenous glutamate enhances spindle excitability, an effect that can be pharmacologically blocked with specific molecules. On the other hand, synaptic-like vesicles contain glutamate, which is released during membrane cycling and, subsequently, a requirement for a replenishment mechanism.

This observation, however, does not exclude the possibility that other neuroactive substances also occur in these sensory terminals.

### **3.2 Ion channels and mechanorasduction in muscle spindles**

In addition to the possible classical neurotransmission, the primary mechanism of mechanical transduction in muscle spindle sensory endings is the activation of stretch-sensitive ion channels. In mechanotransduction, i.e. the conversion of mechanical stimuli into biological or electrical signal, is triggered by members of the superfamilies of degenerin-epithelial Na+ -channels (Deg-ENa<sup>+</sup> C; including acid-sensing ion channels -ASIC-), transient receptor potential channels (TRP), two-pore domain potassium (K2p), and PIEZO [49, 50]. Some of them have been detected directly in proprioceptors as well as in primary sensory neurons innervating them. However, and similarly as in cutaneous mechanoreceptors, the stretch-sensitive channels responsible for transducing mechanical stimuli in spindle afferents awaits definitive identification (see [51]).

There is mounting evidence for the involvement of members of the Deg/ ENa<sup>+</sup> C superfamily as mechanosensory channel(s) in mammalian primary afferent neurons, and in the sensory endings of muscle spindles [52–54]. All four subunits of the ENaC channel (α, β, γ and δ) are present in in spindle primary-sensory terminals [44, 54].

**ASICs** are members are a family of voltage-insensitive cation channels expressed in the nervous system and many types non-nervous cells. In rodents and humans six ASIC subtypes (ASIC1a, ASIC1b, ASIC2a, ASIC2b, ASIC3, and ASIC4) have been identified and their expression patterns are now rather well known [55, 56]. Regarding muscle spindles, evidence has been obtained in favor of a role of ASIC2 as primary mechanotransducer [53, 54]. Consistently, mice deficient in ASIC2, and also in ASIC3, show deficits in mechanical sensitivity [57–59].

**PIEZO** are Ca2+-permeable mechanosensitive channels characterized by their large size and structure [60–62]. Piezo2 is expressed in proprioceptive dorsal root ganglia (DRG) neurons [63, 64] as well as sensory endings of proprioceptors innervating muscle spindles and Golgi tendon organs in mice [64]. Loss of PIEZO2 in proprioceptive neurons results in ataxia and dysmetria, severely uncoordinated body movements and abnormal limb positions, contracture of multiple joints, and muscle weakness, suggesting that PIEZO2 requirement for the activity of these mechanosensors [64–69]. Recently, an elegant study by the Ana Gomis's group corroborated these findings using mesencephalic nucleus proprioceptive neurons [70].

Regarding TRP channels there is little evidence for a role in low-threshold sensation in spindles.

#### **4. Proprioceptive pathways**

To drive proprioception to the central nervous system two different pathways must be considered: the unconscious proprioception is convoyed primarily via the spinocerebellar tracts to the cerebellum while the conscious proprioception is convoyed by the dorsal column-medial lemniscus pathway and the thalamus to the cerebral cortex.

Classically, the proprioceptive pathways of the spinal nerves have been described as a 2 neurons chain (**Figure 2**). The primer order neuron is a pseudo-unipolar neuron whose bodies are localized in DRG whose peripheral axonal branches reach proprioceptors (especially muscle spindles and Golgi tendon organs) and the central branch reach the base of the dorsal horn of the spinal cord. The second order neurons are placed in the medial Stilling-Clarke's column (which extends between the medullary segments C8 and L2) and the lateral Bechterew's column, both corresponding to the Rexed's lamina VII of the dorsal horn; in these columns the spinocerebellar tracts (dorsal or Foville-Flechsig fascicle and ventral or Gowers fascicle) originate to ascend and reach the cerebellum. This information is necessary unconscious. The spinocerebellar neurons together provide the major direct sensory projection from the hindlimbs and lower part of the trunk to the cerebellum. A parallel system serving the forelimbs includes the direct cuneocerebellar and rostral spinocerebellar tracts and other indirect pathways via the lateral reticular nucleus and the inferior olive.

Nevertheless, some aspects of the proprioception are conscious, and therefore the information must reach the cerebral cortex. For these components of the proprioceptive sensitivity, the proprioceptive pathways consist of a 3 neurons chain (**Figure 2**). The primary order neurons are placed in DRG and the central branch of their axons ascend throughout the dorsal columns of the spinal cord to reach the gracile and cuneate nuclei in the medulla. In those nuclei are placed the bodies

**7**

**Figure 2.**

*cerebellum and the brain, respectively.*

*Structural and Biological Basis for Proprioception DOI: http://dx.doi.org/10.5772/intechopen.96787*

**4.1 Primary order neurons: the proprioceptive neurons**

markers that define this neuronal population [75].

The proprioceptive neurons represent a small population (about 7–10%) of DRG

primary sensory neurons and correspond with those with the largest cell bodies [72]. They can be classified and distinguished from other dorsal root ganglion neurons as a unique neuronal population using single cell transcriptome analysis [73]. They typically express the neurotrophin receptor TrkC (the preferred ligand for neurotrophin-3) and the Ca2+-binding protein parvalbumin [74], as well as other

*Schematic representation of proprioceptive unconscious (black) and conscious (blue) pathways reaching the* 

nucleus.

of the secondary order neurons whose axons project to the ventral postero-lateral (VPL) nucleus of the thalamus (tertiary order neuron) whose axons end in the somatosensory cortex to provide the conscious perception of proprioception. A particular question arises from cephalic muscles. They are innervated by cranial nerves and most of them (with the exception of jaw muscles and extraocular muscles) lack typical proprioceptors, i.e. muscle spindles. At present is commonly accepted that the proprioception of the cephalic territory depends on the trigeminal nerve [27, 71]. But the Gasser's ganglion of the trigeminal nerve does not contain proprioceptive neurons, while they are localized in the trigeminal mesencephalic

*Structural and Biological Basis for Proprioception DOI: http://dx.doi.org/10.5772/intechopen.96787*

*Proprioception*

terminals [44, 54].

sensation in spindles.

cerebral cortex.

**4. Proprioceptive pathways**

nucleus and the inferior olive.

ENa<sup>+</sup>

There is mounting evidence for the involvement of members of the Deg/

also in ASIC3, show deficits in mechanical sensitivity [57–59].

C superfamily as mechanosensory channel(s) in mammalian primary afferent neurons, and in the sensory endings of muscle spindles [52–54]. All four subunits of the ENaC channel (α, β, γ and δ) are present in in spindle primary-sensory

**ASICs** are members are a family of voltage-insensitive cation channels expressed in the nervous system and many types non-nervous cells. In rodents and humans six ASIC subtypes (ASIC1a, ASIC1b, ASIC2a, ASIC2b, ASIC3, and ASIC4) have been identified and their expression patterns are now rather well known [55, 56]. Regarding muscle spindles, evidence has been obtained in favor of a role of ASIC2 as primary mechanotransducer [53, 54]. Consistently, mice deficient in ASIC2, and

**PIEZO** are Ca2+-permeable mechanosensitive channels characterized by their

To drive proprioception to the central nervous system two different pathways must be considered: the unconscious proprioception is convoyed primarily via the spinocerebellar tracts to the cerebellum while the conscious proprioception is convoyed by the dorsal column-medial lemniscus pathway and the thalamus to the

Nevertheless, some aspects of the proprioception are conscious, and therefore

the information must reach the cerebral cortex. For these components of the proprioceptive sensitivity, the proprioceptive pathways consist of a 3 neurons chain (**Figure 2**). The primary order neurons are placed in DRG and the central branch of their axons ascend throughout the dorsal columns of the spinal cord to reach the gracile and cuneate nuclei in the medulla. In those nuclei are placed the bodies

Classically, the proprioceptive pathways of the spinal nerves have been described as a 2 neurons chain (**Figure 2**). The primer order neuron is a pseudo-unipolar neuron whose bodies are localized in DRG whose peripheral axonal branches reach proprioceptors (especially muscle spindles and Golgi tendon organs) and the central branch reach the base of the dorsal horn of the spinal cord. The second order neurons are placed in the medial Stilling-Clarke's column (which extends between the medullary segments C8 and L2) and the lateral Bechterew's column, both corresponding to the Rexed's lamina VII of the dorsal horn; in these columns the spinocerebellar tracts (dorsal or Foville-Flechsig fascicle and ventral or Gowers fascicle) originate to ascend and reach the cerebellum. This information is necessary unconscious. The spinocerebellar neurons together provide the major direct sensory projection from the hindlimbs and lower part of the trunk to the cerebellum. A parallel system serving the forelimbs includes the direct cuneocerebellar and rostral spinocerebellar tracts and other indirect pathways via the lateral reticular

large size and structure [60–62]. Piezo2 is expressed in proprioceptive dorsal root ganglia (DRG) neurons [63, 64] as well as sensory endings of proprioceptors innervating muscle spindles and Golgi tendon organs in mice [64]. Loss of PIEZO2 in proprioceptive neurons results in ataxia and dysmetria, severely uncoordinated body movements and abnormal limb positions, contracture of multiple joints, and muscle weakness, suggesting that PIEZO2 requirement for the activity of these mechanosensors [64–69]. Recently, an elegant study by the Ana Gomis's group corroborated these findings using mesencephalic nucleus proprioceptive neurons [70]. Regarding TRP channels there is little evidence for a role in low-threshold

**6**

of the secondary order neurons whose axons project to the ventral postero-lateral (VPL) nucleus of the thalamus (tertiary order neuron) whose axons end in the somatosensory cortex to provide the conscious perception of proprioception.

A particular question arises from cephalic muscles. They are innervated by cranial nerves and most of them (with the exception of jaw muscles and extraocular muscles) lack typical proprioceptors, i.e. muscle spindles. At present is commonly accepted that the proprioception of the cephalic territory depends on the trigeminal nerve [27, 71]. But the Gasser's ganglion of the trigeminal nerve does not contain proprioceptive neurons, while they are localized in the trigeminal mesencephalic nucleus.

**Figure 2.**

*Schematic representation of proprioceptive unconscious (black) and conscious (blue) pathways reaching the cerebellum and the brain, respectively.*

### **4.1 Primary order neurons: the proprioceptive neurons**

The proprioceptive neurons represent a small population (about 7–10%) of DRG primary sensory neurons and correspond with those with the largest cell bodies [72]. They can be classified and distinguished from other dorsal root ganglion neurons as a unique neuronal population using single cell transcriptome analysis [73]. They typically express the neurotrophin receptor TrkC (the preferred ligand for neurotrophin-3) and the Ca2+-binding protein parvalbumin [74], as well as other markers that define this neuronal population [75].

#### *Proprioception*

The peripheral branch of the axons of the proprioceptive pseudo-unipolar neurons forms large-myelinated Aα and Aβ fibers in peripheral nerves, while the central branch stablish synapse in the spinal cord or ascends throughout the dorsal columns of the spinal cord to reach the gracile and cuneate nuclei in the medulla. Some peripheral branches, however, travel through the cuneatus tract and ascend the cervical spinal cord to reach the medulla oblongata to reach the accessory cuneate nucleus.
