Anticipatory postural adjustments (APAs) give feedforward postural control of the trunk, but they are delayed with ageing, affecting balance and mobility in older individuals. The reticulospinal tract contributes to postural control of the trunk; however, the extent to which age-related changes affect the reticulospinal contributions to APAs of the trunk remains unknown in humans. Here, we tested the hypothesis that a startling acoustic sound, which activates the reticulospinal tract, improves delayed APAs in older individuals. Twenty-two old (75 ± 6 years) and 20 healthy young adults (21 ± 4 years) performed a self-initiated fast bilateral shoulder flexion or shoulder extension task in response to visual, visual and auditory (80 dB), or visual and startling (115 dB) cues. Electromyography (EMG) was recorded from bilateral anterior deltoid (AD) and erector spinae (ES) during shoulder flexion and from bilateral posterior deltoid (PD) and rectus abdominis (RA) during shoulder extension. EMG onset of all muscles shortened during the startling cue in both age groups, suggesting a non-specific modulation of the reticulospinal tract on prime movers (AD or PD) and non-prime movers (ES or RA). Interestingly, APAs of the ES were accelerated in older participants to a similar degree as in younger participants during the startling cue. Conversely, APAs of the RA were not influenced by the startling cue in older participants. Our results suggest differential effects of ageing on functional contributions of the reticulospinal tract to APAs between back extensors and abdominal muscles.

Corticofugal projections to evolutionarily ancient, subcortical structures are ubiquitous across mammalian sensory systems. These \'descending\' pathways enable the neocortex to control ascending sensory representations in a predictive or feedback manner, but the underlying cellular mechanisms are poorly understood. Here, we combine optogenetic approaches with in vivo and in vitro patch-clamp electrophysiology to study the projection from mouse auditory cortex to the inferior colliculus (IC), a major descending auditory pathway that controls IC neuron feature selectivity, plasticity, and auditory perceptual learning. Although individual auditory cortico-collicular synapses were generally weak, IC neurons often integrated inputs from multiple corticofugal axons that generated reliable, tonic depolarizations even during prolonged presynaptic activity. Latency measurements in vivo showed that descending signals reach the IC within 30 ms of sound onset, which in IC neurons corresponded to the peak of synaptic depolarizations evoked by short sounds. Activating ascending and descending pathways at latencies expected in vivo caused a NMDA receptor-dependent, supralinear excitatory postsynaptic potential summation, indicating that descending signals can nonlinearly amplify IC neurons\' moment-to-moment acoustic responses. Our results shed light upon the synaptic bases of descending sensory control and imply that heterosynaptic cooperativity contributes to the auditory cortico-collicular pathway\'s role in plasticity and perceptual learning.

To understand the neural basis of behavior, it is important to reveal how movements are planned, executed, and refined by networks of neurons distributed throughout the nervous system. Here, we report the neuroanatomical organization and behavioral roles of cerebellospinal (CeS) neurons. Using intersectional genetic techniques, we find that CeS neurons constitute a small minority of excitatory neurons in the fastigial and interpositus deep cerebellar nuclei, target pre-motor circuits in the ventral spinal cord and the brain, and control distinct aspects of movement. CeS neurons that project to the ipsilateral cervical cord are required for skilled forelimb performance, while CeS neurons that project to the contralateral cervical cord are involved in skilled locomotor learning. Together, this work establishes CeS neurons as a critical component of the neural circuitry for skilled movements and provides insights into the organizational logic of motor networks.

Environmental signals act as input and are processed across successive stages in the brain to generate a meaningful behavioral output. However, a ubiquitous observation is that descending feedback projections from more central to more peripheral brain areas vastly outnumber ascending feedforward projections. Such projections generally act to modify how sensory neurons respond to afferent signals. Recent studies in the electrosensory system of weakly electric fish have revealed novel functions for feedback pathways in that their transformation of the afferent input generates neural firing rate responses to sensory signals mediating perception and behavior. In this review, we focus on summarizing these novel and recently uncovered functions and put them into context by describing the more \"classical\" functions of feedback in the electrosensory system. We further highlight the parallels between the electrosensory system and other systems as well as outline interesting future directions.

The emergence of new and increasingly sophisticated behaviors after birth is accompanied by dramatic increase of newly established synaptic connections in the nervous system. Little is known, however, of how nascent connections are organized to support such new behaviors alongside existing ones. To understand this, in the larval zebrafish we examined the development of spinal pathways from hindbrain V2a neurons and the role of these pathways in the development of locomotion. We found that new projections are continually layered laterally to existing neuropil, and give rise to distinct pathways that function in parallel to existing pathways. Across these chronologically layered pathways, the connectivity patterns and biophysical properties vary systematically to support a behavioral repertoire with a wide range of kinematics and dynamics. Such layering of new parallel circuits equipped with systematically changing properties may be central to the postnatal diversification and increasing sophistication of an animal\'s behavioral repertoire.

The 1967 paper from Hans Kuypers and Don Lawrence provided the first complete description of the projections from every major cortical area to the red nucleus and brainstem in the monkey. The study includes descriptions of some of the major cortical influences on sensory and motor circuits subserving vision, hearing and proprioception, as well as movements of the eyes, head and limbs. It also describes the detailed anatomy of the red nucleus in the monkey, and highlights species differences in this structure. It also postulates that cortical projections to the parvicellular component of the red nucleus provide a recurrent loop returning via the thalamus to the motor cortex. The findings reported in this paper helped to substantiate Kuypers\' new theory on the organisation of the descending motor pathways by showing that the primary motor cortex, as well as providing a direct crossed corticospinal input to spinal circuits controlling movements of the distal extremities (hand and foot), also influenced these same circuits through ipsilateral projections to the cells of origin of the rubrospinal tract. In contrast, projections from more rostral motor, premotor and prefrontal regions terminated bilaterally in the parvicellular red nucleus, and influenced ventromedial descending pathways controlling movements of the head, neck, trunk and proximal limbs. The paper has proved of lasting value to our understanding of sensorimotor control and the contribution of different pathways to it. This article is part of a Special Issue entitled SI:50th Anniversary Issue.

We recently characterized physiologically a pontine reticulospinal (pRS) projection in the neonatal mouse that mediates synaptic effects on spinal motoneurons via parallel uncrossed and crossed pathways (Sivertsen et al. [2014] J Neurophysiol 112:1628-1643). Here we characterize the origins, anatomical organization, and supraspinal axon trajectories of these pathways via retrograde tracing from the high cervical spinal cord. The two pathways derive from segregated populations of ipsilaterally and contralaterally projecting pRS neurons with characteristic locations within the pontine reticular formation (PRF). We obtained estimates of relative neuron numbers by counting from sections, digitally generated neuron position maps, and 3D reconstructions. Ipsilateral pRS neurons outnumber contralateral pRS neurons by threefold and are distributed about equally in rostral and caudal regions of the PRF, whereas contralateral pRS neurons are concentrated in the rostral PRF. Ipsilateral pRS neuron somata are on average larger than contralateral. No pRS neurons are positive in transgenic mice that report the expression of GAD, suggesting that they are predominantly excitatory. Putative GABAergic interneurons are interspersed among the pRS neurons, however. Ipsilateral and contralateral pRS axons have distinctly different trajectories within the brainstem. Their initial spinal funicular trajectories also differ, with ipsilateral and contralateral pRS axons more highly concentrated medially and laterally, respectively. The larger size and greater number of ipsilateral vs. contralateral pRS neurons is compatible with our previous finding that the uncrossed projection transmits more reliably to spinal motoneurons. The information about supraspinal and initial spinal pRS axon trajectories should facilitate future physiological assessment of synaptic connections between pRS neurons and spinal neurons.

Among brain structures receiving efferent projections from the histaminergic tuberomammillary nucleus is the pontine locus coeruleus (LC) involved in descending noradrenergic control of pain. Here we studied whether histamine in the LC is involved in descending regulation of neuropathic hypersensitivity. Peripheral neuropathy was induced by unilateral spinal nerve ligation in the rat with a chronic intracerebral and intrathecal catheter for drug administrations. Mechanical hypersensitivity in the injured limb was assessed by monofilaments. Heat nociception was assessed by determining radiant heat-induced paw flick. Histamine in the LC produced a dose-related (1-10μg) mechanical antihypersensitivity effect (maximum effect at 15min and duration of effect 30min), without influence on heat nociception. Pretreatment of LC with zolantidine (histamine H2 receptor antagonist), but not with pyrilamine (histamine H1 receptor antagonist), and spinal administration of atipamezole (an α2-adrenoceptor antagonist), prazosine (an α1-adrenoceptor antagonist) or bicuculline (a GABAA receptor antagonist) attenuated the antihypersensitivity effect of histamine. The histamine-induced antihypersensitivity effect was also reduced by pretreatment of LC with fadolmidine, an α2-adrenoceptor agonist inducing autoinhibition of noradrenergic cell bodies. Zolantidine or pyrilamine alone in the LC failed to influence pain behavior, while A-960656 (histamine H3 receptor antagonist) suppressed hypersensitivity. A plausible explanation for these findings is that histamine, due to excitatory action mediated by the histamine H2 receptor on noradrenergic cell bodies, promotes descending spinal α1/2-adrenoceptor-mediated inhibition of neuropathic hypersensitivity. Blocking the autoinhibitory histamine H3 receptor on histaminergic nerve terminals in the LC facilitates release of histamine and thereby, increases descending noradrenergic pain inhibition.

A sound strategy for improving the clinical efficacy of opioids involves exploiting positive interactions with drugs directed at other targets in pain pathways. The current study investigated the role of dopamine receptor D2 (D2R) in modulation of spinal dorsal horn excitability to noxious input, and interactions therein with μ-opioid receptor (MOR) in an animal model of neuropathic pain induced by spinal nerve ligation (SNL). C-fiber-evoked field potentials in the spinal dorsal horn were depressed concentration dependently by spinal superfusion with the D2R agonist quinpirole both in nerve-injured and sham-operated (control) rats. However, quinpirole-induced depression was significant at 10 μmol/L after SNL but only at 100 μmol/L in control rats. This quinpirole effect was completely abolished by MOR antagonist CTOP at subclinical concentration (1 μmol/L) in nerve-injured rats, but was unaltered in sham-operated rats. Nine days after SNL, D2R was upregulated to both presynaptic and postsynaptic locations in dorsal horn neurons, as revealed by double confocal immunofluorescence stainings for synaptophysin and PSD-95. In addition, D2R/MOR co-localization was increased after SNL. Co-administration of 1 μmol/L quinpirole, insufficient per se to alter evoked potentials, dramatically enhanced inhibition of evoked potentials by MOR agonist DAMGO, reducing the IC50 value of DAMGO by 2 orders of magnitude. The present data provide evidence of profound functional and subcellular changes in D2R-mediated modulation of noxious input after nerve injury, including positive interactions with spinal MOR. These results suggest D2R co-stimulation as a potential avenue to improve MOR analgesia in sustained pain states involving peripheral nerve injury.

Using optical recording of synaptically mediated calcium transients and selective spinal lesions, we investigated the pattern of activation of spinal motoneurons (MNs) by the pontine reticulospinal projection in isolated brain stem-spinal cord preparations from the neonatal mouse. Stimulation sites throughout the region where the pontine reticulospinal neurons reside reliably activated MNs at cervical, thoracic, and lumbar levels. Activation was similar in MNs ipsi- and contralateral to the stimulation site, similar in medial and lateral motor columns that contain trunk and limb MNs, respectively, and similar in the L2 and L5 segments that predominantly contain flexor and extensor MNs, respectively. In nonlesioned preparations, responses in both ipsi- and contralateral MNs followed individual stimuli in stimulus trains nearly one-to-one (with few failures). After unilateral hemisection at C1 on the same side as the stimulation, responses had substantially smaller magnitudes and longer latencies and no longer followed individual stimuli. After unilateral hemisection at C1 on the side opposite to the stimulation, the responses were also smaller, but their latencies were not affected. Thus we distinguish two pontine reticulospinal pathways to spinal MNs, one uncrossed and the other crossed, of which the uncrossed pathway transmits more faithfully and appears to be more direct.