No description available.

No description available.

The monoamine uptake blocking agents, imipramine HC1 (5 mg/kg i.v.) and desipramine HC1 (4.8 mg/kg i.v.), and the monoamine oxidase inhibitor, pargyline HC1 (30 mg/kg i.v.) antagonized bulbospinal inhibition (BSI) of the monosynaptic reflex (MSR) in unanaesthetized cats decerebrated at the mid-collicular level. The effect of imipramine was quantitatively more on BSI of the quadriceps (QUAD)-MSR compared to that on BSI of the posterior biceps-semitendinosus (PBST)-MSR. Imipramine's action on this inhibition was also quantitatively greater compared to that of the equimolar dose of desipramine. Pretreatment of the animals with the tryptophan hydroxylase inhibitor, DL-p-chlorophenylalanine (p-CPA) (300 mg/kg i.p. for 3 consecutive days) completely eliminated the blocking action of imipramine. However, pretreatment of the animals with the tyrosine hydroxylase inhibitor, DL-α-methyl-p-tyrosine methyl ester HC1 (α-MPT) (126 mg/kg i.p. given 16 and 4 hours before the recording ) had no effect on imipramine's action. These findings strongly suggest that a 5-hydroxytryptamine (5-HT, serotonin) system antagonizes BSI of the MSR. They do not support the proposal of Clineschmidt and Anderson (1970) that the bulbospinal inhibitory pathway involves a 5-HT interneurone in the spinal cord. Imipramine HC1 (5 mg/kg i.v.) and pargyline HC1 (30 mg/kg i.v.) blocked recurrent inhibition (RI) of the MSR evoked by stimulation of a dorsal root. Imipramine blocked RI of the QUAD-MSR but had no effect on RI of the PBST-MSR. Pretreatment of the animals with either p-CPA or α-MPT prevented the blocking action of imipramine on RI. Application of a 'cold block' which potentiated RI of the QUAD-MSR also eliminated the blocking action of imipramine on this inhibition. These observations suggest that a supraspinal monoaminergic system which involves 5-HT and noradrenaline links has a tonic inhibitory effect on RI of the QUAD-MSR. / Pharmaceutical Sciences, Faculty of / Graduate

<p>The mouth, throat, and face contain numerous muscles that participate in a large variety of orofacial behaviors. The jaw and tongue can move independently, and thus require a high degree of coordination among the muscles that move them to prevent self-injury. However, different orofacial behaviors require distinct patterns of coordination between these muscles. The method through which motor control circuitry might coordinate this activity has yet to be determined. Electrophysiological, immunohistochemical, and retrograde tracing studies have attempted to identify populations of premotor neurons which directly send information to orofacial motoneurons in an effort to identify sources of coordination. Yet these studies have not provided a complete picture of the population of neurons which monosynaptically connect to jaw and tongue motoneurons. Additionally, while many of these studies have suggested that premotor neurons projecting to multiple motor pools may play a role in coordination of orofacial muscles, no clear functional roles for these neurons in the coordination of natural orofacial movements has been identified.</p><p>In this dissertation, I took advantage of the recently developed monosynaptic rabies virus to trace the premotor circuits for the jaw-closing masseter muscle and tongue-protruding genioglossus muscle in the neonatal mouse, uncovering novel premotor inputs in the brainstem. Furthermore, these studies identified a set of neurons which form boutons onto motor neurons in multiple motor pools, providing a premotor substrate for orofacial coordination. I then combined a retrogradely traveling lentivirus with a split-intein mediated split-Cre recombinase system to isolate and manipulate a population of neurons which project to both left and right jaw-closing motor nuclei. I found that these bilaterally projecting neurons also innervate multiple other orofacial motor nuclei, premotor regions, and midbrain regions implicated in motor control. I anatomically and physiologically characterized these neurons and used optogenetic and chemicogenetic approaches to assess their role in natural jaw-closing behavior, specifically with reference to bilateral masseter muscle electromyogram (EMG) activity. These studies identified a population of bilaterally projecting neurons in the supratrigeminal nucleus as essential for maintenance of an appropriate level of masseter activation during natural chewing behavior in the freely moving mouse. Moreover, these studies uncovered two distinct roles of supratrigeminal bilaterally projecting neurons in bilaterally synchronized activation of masseter muscles, and active balancing of bilateral masseter muscle tone against an excitatory input. Together, these studies identify neurons which project to multiple motor nuclei as a mechanism by which the brain coordinates orofacial muscles during natural behavior.</p> / Dissertation

Muscle fatigue is ubiquitous in every day life.Muscle fatigue might be considered as an altered state of motor behaviour, which impairs motor performance. By contrast, muscle fatigue could also be considered a positive phenomenon, which protects muscle tissue from damage that might be incurred to it by overuse. The principal aim of the thesis was to explore some of the mechanisms of muscle fatigue at the spinal level in animal models.The activation of multiple motor units of a single calf muscle may influence contractile properties of its neighbouring, otherwise inactive units, providing evidence for spatial spreading of fatigue between different muscle parts. The release of metabolites, their action on inactive muscle units and the effects of local hypoxia are the most likely causes. Fatigue-induced metabolite shift in the interstitium provokes excitation and/or sensitisation of high-threshold afferent fibers, with complex effects on the spinal premotoneuronal network involved in the modulation of motoneuronal output. This was examined by studing the intrasegmental lamellar distribution of the lumbar spinal interneurons following fatiguing contractions of the triceps surae muscle. Furthermore, fatigue of calf muscles enhanced the activity of fusimotor neurons to these muscles irrespective of the regime of muscle activity (isometric vs. lengthening) in conditions that simulate locomotion. Altered fusimotor activity, through increased or maintained muscle spindle afferent responsiveness may be advantageous, providing support to the skeletomotor activity and enhanced information about muscle periphery to higher nervous centres. The particular effects of interneuronal network at motor input (presynaptic inhibition system) and output (recurrent inhibition system) stages were then addressed. Fatigue of triceps surae muscle induced a suppression of the monosynaptic reflex. The intensity of presynaptic inhibition increased, while the intensity of recurrent inhibition decreased. Post fatigue-evoked changes in monosynaptic reflexes and presynaptic inhibition indicate the possibility that high-threshold afferents inhibit group Ia terminals pre-synaptically, which would allow fatigue-induced signals from the muscle to reduce the relevance of proprioceptive feedback. Besides intrasegmental, intersegmental spreading of nociceptive signals was explored. Activation of sensory afferents from dorsal neck muscles by capsaicin induces powerful activation of interneurons located in the cervical spinal cord, as well as a widespread activation of cells in lumbar spinal cord segments. The results confirm the pivotal role of small diameter muscle afferents in the orchestration of segmental responses to fatigue and show complex interactions that may lead to limited accuracy of motor output. They also depict processes that may be related to, and even become precursors of chronic muscle pain.

The first part of my thesis involves an investigation into mechanisms underlying the presynaptic regulation of transmitter release from myelinated hindlimb sensory afferents in rodents. The central hypothesis is that in addition to chemical transmission in spinal neuronal networks, electrical synapses formed by connexins are critically involved in presynaptic inhibition of large diameter sensory afferents. Subsequent sections of the thesis present a detailed examination of the distribution of connexins in the rodent spinal cord with a particular emphasis on the neuronal connexin, Cx36. Connexin36 (Cx36) is widely believed to be the protein forming the neuronal gap junctions that create electrical synapses between mammalian neurons in many areas of the central nervous system (Condorelli et al 1998). The first part of thesis concerns a previously unknown role of neuronal connexins in interneurone pathways involved in presynaptic control of synaptic transmission in the lumbar spinal cord of rodents. As far as we are aware, the idea that electrical contacts between spinal neurons contribute to spinal presynaptic inhibition is a novel hypothesis. Evidence will be presented: 1) that Cx36 is present in regions of the spinal cord containing interneurons involved in presynaptic inhibition, 2) that the lack of Cx36 in Cx36-/- knockouts mice results in a severe impairment of presynaptic inhibition, and 3) that blocking gap junctions pharmacologically in wild type mice impairs presynaptic inhibition. The exploration of this hypothesis will involve a combination of electrophysiological and immunohistochemical approaches in juvenile wild-type and knockout mice lacking Cx36, as well as immunohistochemical observations in adult rodents. This first section of the thesis begins with the development of a preparation in which several measures of presynaptic inhibition described in the in vivo adult cat preparation can be examined in vitro in young mice. The following sections of the thesis describe the distribution and features of Cx36 on neurons in mice and rats of different ages in four parts. The first will show that Cx36 is the only connexin associated with spinal neurons and refutes claims in the literature about the existence of a variety of connexions on spinal neurons. The second part will show that while gap junctions between some spinal neurons are only a transient developmental phenomenon, they persist in abundance in adult animals. The third part will present evidence of a previously unsuspected III association of Cx36 gap junctions at the chemical synapse between muscle afferent fibres and motoneurons. Specifically, an association between Cx36 and the glutamate transporter used in primary afferents, Vglut1 will be described. To our knowledge these results are the first to suggest the existence of mixed (electrical and chemical) synapses between primary afferents and motoneurons in the mature mammalian spinal cord. The final part of the thesis will describe the presence of Cx36 gap junctions on adult sacral motoneurons involved in control of sexual, urinary and defecation functions in the rodent.

The first part of my thesis involves an investigation into mechanisms underlying the presynaptic regulation of transmitter release from myelinated hindlimb sensory afferents in rodents. The central hypothesis is that in addition to chemical transmission in spinal neuronal networks, electrical synapses formed by connexins are critically involved in presynaptic inhibition of large diameter sensory afferents. Subsequent sections of the thesis present a detailed examination of the distribution of connexins in the rodent spinal cord with a particular emphasis on the neuronal connexin, Cx36. Connexin36 (Cx36) is widely believed to be the protein forming the neuronal gap junctions that create electrical synapses between mammalian neurons in many areas of the central nervous system (Condorelli et al 1998). The first part of thesis concerns a previously unknown role of neuronal connexins in interneurone pathways involved in presynaptic control of synaptic transmission in the lumbar spinal cord of rodents. As far as we are aware, the idea that electrical contacts between spinal neurones contribute to spinal presynaptic inhibition is a novel hypothesis. Evidence will be presented: 1) that Cx36 is present in regions of the spinal cord containing interneurones involved in presynaptic inhibition, 2) that the lack of Cx36 in Cx36-/- knockouts mice results in a severe impairment of presynaptic inhibition, and 3) that blocking gap junctions pharmacologically in wild type mice impairs presynaptic inhibition. The exploration of this hypothesis will involve a combination of electrophysiological and immunohistochemical approaches in juvenile wild-type and knockout mice lacking Cx36, as well as immunohistochemical observations in adult rodents. This first section of the thesis begins with the development of a preparation in which several measures of presynaptic inhibition described in the in vivo adult cat preparation can be examined in vitro in young mice. The following sections of the thesis describe the distribution and features of Cx36 on neurones in mice and rats of different ages in four parts. The first will show that Cx36 is the only connexin associated with spinal neurons and refutes claims in the literature about the existence of a variety of connexions on spinal neurons. The second part will show that while gap junctions between some spinal neurons are only a transient developmental phenomenon, they persist in abundance in adult animals. The third part will present evidence of a previously unsuspected III association of Cx36 gap junctions at the chemical synapse between muscle afferent fibres and motoneurones. Specifically, an association between Cx36 and the glutamate transporter used in primary afferents, Vglut1 will be described. To our knowledge these results are the first to suggest the existence of mixed (electrical and chemical) synapses between primary afferents and motoneurones in the mature mammalian spinal cord. The final part of the thesis will describe the presence of Cx36 gap junctions on adult sacral motoneurones involved in control of sexual, urinary and defecation functions in the rodent.

No description available.