Properties of the Caudal Pontine Reticular Nucleus Neurons Determine the Acoustic Startle Response in Cntnap2 KO Rats.

BACKGROUND: Rats with a loss-of-function mutation in the contactin-associated protein-like 2 (Cntnap2) gene have been validated as an animal model of autism spectrum disorder (ASD). Similar to many autistic individuals, Cntnap2 knock-out rats (Cntnap2-⁣/-) are hyperreactive to sound as measured through the acoustic startle response. The brainstem region that mediates the acoustic startle response is the caudal pontine reticular nucleus (PnC), specifically giant neurons in the PnC. We previously reported a sex-dependent genotypic effect in the sound-evoked neuronal activity recorded from the PnC, whereby female Cntnap2-⁣/- rats had a dramatic increase in sound-evoked responses compared with wildtype counterparts, but male Cntnap2-⁣/- rats showed only a modest increase in PnC activity that cannot fully explain the largely increased startle in male Cntnap2-⁣/- rats. The present study therefore investigates activation and histological properties of PnC giant neurons in Cntnap2-⁣/- rats and wildtype littermates. METHODS: The acoustic startle response was elicited by presenting rats with 95 dB startle pulses before rats were euthanized. PnC brain sections were stained and analyzed for the total number of PnC giant neurons and the percentage of giant neurons that expressed phosphorylated cAMP response element binding protein (pCREB) in response to startle stimuli. Additionally, in vitro electrophysiology was conducted to assess the resting state activity and intrinsic properties of PnC giant neurons. RESULTS: Wildtype and Cntnap2-⁣/- rats had similar total numbers of PnC giant neurons and similar levels of baseline pCREB expression, as well as similar numbers of giant neurons that were firing at rest. Increased startle magnitudes in Cntnap2-⁣/- rats were associated with increased percentages of pCREB-expressing PnC giant neurons in response to startle stimuli. Male rats had increased pCREB-expressing PnC giant neurons compared with female rats, and the recruited giant neurons in males were also larger in soma size. CONCLUSIONS: Recruitment and size of PnC giant neurons are important factors for regulating the magnitude of the acoustic startle response in Cntnap2-⁣/- rats, particularly in males. These findings allow for a better understanding of increased reactivity to sound in Cntnap2-⁣/- rats and in CNTNAP2-associated disorders such as ASD.

Functional plasticity of glutamatergic neurons of medullary reticular nuclei after spinal cord injury in mice.

Spinal cord injury disrupts the descending command from the brain and causes a range of motor deficits. Here, we use optogenetic tools to investigate the functional plasticity of the glutamatergic reticulospinal drive of the medullary reticular formation after a lateral thoracic hemisection in female mice. Sites evoking stronger excitatory descending drive in intact conditions are the most impaired after injury, whereas those associated with a weaker drive are potentiated. After lesion, pro- and anti-locomotor activities (that is, initiation/acceleration versus stop/deceleration) are overall preserved. Activating the descending reticulospinal drive improves stepping ability on a flat surface of chronically impaired injured mice, and its priming enhances recovery of skilled locomotion on a horizontal ladder. This study highlights the resilience and capacity for reorganization of the glutamatergic reticulospinal command after injury, along with its suitability as a therapeutical target to promote functional recovery.

Role of autonomic, nociceptive, and limbic brainstem nuclei in core autism features.

Although multiple theories have speculated about the brainstem reticular formation's involvement in autistic behaviors, the in vivo imaging of brainstem nuclei needed to test these theories has proven technologically challenging. Using methods to improve brainstem imaging in children, this study set out to elucidate the role of the autonomic, nociceptive, and limbic brainstem nuclei in the autism features of 145 children (74 autistic children, 6.0-10.9 years). Participants completed an assessment of core autism features and diffusion- and T1-weighted imaging optimized to improve brainstem images. After data reduction via principal component analysis, correlational analyses examined associations among autism features and the microstructural properties of brainstem clusters. Independent replication was performed in 43 adolescents (24 autistic, 13.0-17.9 years). We found specific nuclei, most robustly the parvicellular reticular formation-alpha (PCRtA) and to a lesser degree the lateral parabrachial nucleus (LPB) and ventral tegmental parabrachial pigmented complex (VTA-PBP), to be associated with autism features. The PCRtA and some of the LPB associations were independently found in the replication sample, but the VTA-PBP associations were not. Consistent with theoretical perspectives, the findings suggest that individual differences in pontine reticular formation nuclei contribute to the prominence of autistic features. Specifically, the PCRtA, a nucleus involved in mastication, digestion, and cardio-respiration in animal models, was associated with social communication in children, while the LPB, a pain-network nucleus, was associated with repetitive behaviors. These findings highlight the contributions of key autonomic brainstem nuclei to the expression of core autism features.

A transcriptomic taxonomy of mouse brain-wide spinal projecting neurons.

The brain controls nearly all bodily functions via spinal projecting neurons (SPNs) that carry command signals from the brain to the spinal cord. However, a comprehensive molecular characterization of brain-wide SPNs is still lacking. Here we transcriptionally profiled a total of 65,002 SPNs, identified 76 region-specific SPN types, and mapped these types into a companion atlas of the whole mouse brain1. This taxonomy reveals a three-component organization of SPNs: (1) molecularly homogeneous excitatory SPNs from the cortex, red nucleus and cerebellum with somatotopic spinal terminations suitable for point-to-point communication; (2) heterogeneous populations in the reticular formation with broad spinal termination patterns, suitable for relaying commands related to the activities of the entire spinal cord; and (3) modulatory neurons expressing slow-acting neurotransmitters and/or neuropeptides in the hypothalamus, midbrain and reticular formation for 'gain setting' of brain-spinal signals. In addition, this atlas revealed a LIM homeobox transcription factor code that parcellates the reticulospinal neurons into five molecularly distinct and spatially segregated populations. Finally, we found transcriptional signatures of a subset of SPNs with large soma size and correlated these with fast-firing electrophysiological properties. Together, this study establishes a comprehensive taxonomy of brain-wide SPNs and provides insight into the functional organization of SPNs in mediating brain control of bodily functions.

Effect of Motor Task on Cortex Brainstem Modulation: Preliminary Results.

Reticulospinal Tracts (RSTs) have divergent connections to multiple spinal segments that innervate many upper extremity muscles. Therefore, increased RST engagement can often lead to muscle coactivation across multiple limb joints. The RST originates from the reticular formation (RF) and receives projections from the cortex. This provides the anatomical basis for cortex-brainstem modulation. Currently, we know little about how cortex modulates the RF to control RST engagement during motor preparation for various motor tasks, such as tasks involving proximal and distal upper limb joint coordination vs. a purely distal task. We hypothesize that since a simultaneous arm lifting and hand opening task (LIFTOPEN) requires more selective muscle recruitment than a hand opening task (OPEN), the cortex will suppress the RF to reduce the RST engagement at distal muscles during LIFTOPEN. To test this hypothesis, we investigated the startReact response in thirteen able-bodied participants performing the OPEN and LIFTOPEN tasks in response to a startling and non-startling acoustic stimulation. Our results showed that activation of distal muscles was significantly decreased, and the startle response was delayed in LIFTOPEN compared to OPEN. Both results suggest that the cortex suppressed RF and reduced the RST engagement in LIFTOPEN compared to OPEN.Clinical Relevance- Our results provide foundational knowledge of the task-specific nature of cortex-brainstem modulation. This scientific finding provides a base to compare how a unilateral brain injury may affect this cortex-brainstem modulation.

Involvement of A13 dopaminergic neurons in prehensile movements but not reward in the rat.

Tyrosine hydroxylase (TH)-containing neurons of the dopamine (DA) cell group A13 are well positioned to impact known DA-related functions as their descending projections innervate target regions that regulate vigilance, sensory integration, and motor execution. Despite this connectivity, little is known regarding the functionality of A13-DA circuits. Using TH-specific loss-of-function methodology and techniques to monitor population activity in transgenic rats in vivo, we investigated the contribution of A13-DA neurons in reward and movement-related actions. Our work demonstrates a role for A13-DA neurons in grasping and handling of objects but not reward. A13-DA neurons responded strongly when animals grab and manipulate food items, whereas their inactivation or degeneration prevented animals from successfully doing so-a deficit partially attributed to a reduction in grip strength. By contrast, there was no relation between A13-DA activity and food-seeking behavior when animals were tested on a reward-based task that did not include a reaching/grasping response. Motivation for food was unaffected, as goal-directed behavior for food items was in general intact following A13 neuronal inactivation/degeneration. An anatomical investigation confirmed that A13-DA neurons project to the superior colliculus (SC) and also demonstrated a novel A13-DA projection to the reticular formation (RF). These results establish a functional role for A13-DA neurons in prehensile actions that are uncoupled from the motivational factors that contribute to the initiation of forelimb movements and help position A13-DA circuits into the functional framework regarding centrally located DA populations and their ability to coordinate movement.

Brainstem sources of input to the central mesencephalic reticular formation in the macaque.

Physiological studies indicate that the central mesencephalic reticular formation (cMRF) plays a role in gaze changes, including control of disjunctive saccades. Neuroanatomical studies have demonstrated strong interconnections with the superior colliculus, along with projections to extraocular motor nuclei, the preganglionic nucleus of Edinger-Westphal, the paramedian pontine reticular formation, nucleus raphe interpositus, medullary reticular formation and cervical spinal cord, as might be expected for a structure that is intimately involved in gaze control. However, the sources of input to this midbrain structure have not been described in detail. In the present study, the brainstem cells of origin supplying the cMRF were labeled by retrograde transport of tracer (wheat germ agglutinin conjugated horseradish peroxidase) in macaque monkeys. Within the diencephalon, labeled neurons were noted in the ventromedial nucleus of the hypothalamus, pregeniculate nucleus and habenula. In the midbrain, labeled cells were found in the substantia nigra pars reticulata, medial pretectal nucleus, superior colliculus, tectal longitudinal column, periaqueductal gray, supraoculomotor area, and contralateral cMRF. In the pons they were located in the paralemniscal zone, parabrachial nucleus, locus coeruleus, nucleus prepositus hypoglossi and the paramedian pontine reticular formation. Finally, in the medulla they were observed in the medullary reticular formation. The fact that this list of input sources is very similar to those of the superior colliculus supports the view that the cMRF represents an important gaze control center.

Pairing Transcranial Magnetic Stimulation and Loud Sounds Produces Plastic Changes in Motor Output.

Most current methods for neuromodulation target the cortex. Approaches for inducing plasticity in subcortical motor pathways, such as the reticulospinal tract, could help to boost recovery after damage (e.g., stroke). In this study, we paired loud acoustic stimulation (LAS) with transcranial magnetic stimulation (TMS) over the motor cortex in male and female healthy humans. LAS activates the reticular formation; TMS activates descending systems, including corticoreticular fibers. Two hundred paired stimuli were used, with 50 ms interstimulus interval at which LAS suppresses TMS responses. Before and after stimulus pairing, responses in the contralateral biceps muscle to TMS alone were measured. Ten, 20, and 30 min after stimulus pairing ended, TMS responses were enhanced, indicating the induction of LTP. No long-term changes were seen in control experiments which used 200 unpaired TMS or LAS, indicating the importance of associative stimulation. Following paired stimulation, no changes were seen in responses to direct corticospinal stimulation at the level of the medulla, or in the extent of reaction time shortening by a loud sound (StartReact effect), suggesting that plasticity did not occur in corticospinal or reticulospinal synapses. Direct measurements in female monkeys undergoing a similar paired protocol revealed no enhancement of corticospinal volleys after paired stimulation, suggesting no changes occurred in intracortical connections. The most likely substrate for the plastic changes, consistent with all our measurements, is an increase in the efficacy of corticoreticular connections. This new protocol may find utility, as it seems to target different motor circuits compared with other available paradigms.SIGNIFICANCE STATEMENT Induction of plasticity by neurostimulation protocols may be promising to enhance functional recovery after damage such as following stroke, but current protocols mainly target cortical circuits. In this study, we developed a novel paradigm which may generate long-term changes in connections between cortex and brainstem. This could provide an additional tool to modulate and improve recovery.

Pattern of Driver-Like Input onto Neurons of the Mouse Ventral Lateral Geniculate Nucleus.

The ventral lateral geniculate nucleus (vLGN) is a retinorecipient region of thalamus that contributes to a number of complex visual behaviors. Retinal axons that target vLGN terminate exclusively in the external subdivision (vLGNe), which is also transcriptionally and cytoarchitectonically distinct from the internal subdivision (vLGNi). While recent studies shed light on the cell types and efferent projections of vLGNe and vLGNi, we have a crude understanding of the source and nature of the excitatory inputs driving postsynaptic activity in these regions. Here, we address this by conducting in vitro whole-cell recordings in acutely prepared thalamic slices and using electrical and optical stimulation techniques to examine the postsynaptic excitatory activity evoked by the activation of retinal or cortical layer V input onto neurons in vLGNe and vLGNi. Activation of retinal afferents by electrical stimulation of optic tract or optical stimulation of retinal terminals resulted in robust driver-like excitatory activity in vLGNe. Optical activation of corticothalamic terminals from layer V resulted in similar driver-like activity in both vLGNe and vLGNi. Using a dual-color optogenetic approach, we found that many vLGNe neurons received convergent input from these two sources. Both individual pathways displayed similar driver-like properties, with corticothalamic stimulation leading to a stronger form of synaptic depression than retinogeniculate stimulation. We found no evidence of convergence in vLGNi, with neurons only responding to corticothalamic stimulation. These data provide insight into the influence of excitatory inputs to vLGN and reveal that only neurons in vLGNe receive convergent input from both sources.

Stimulation of the center of the lateral reticular nucleus suppresses the swallowing reflex in rats.

Morphological studies have demonstrated that the lateral reticular nucleus (LRt) receives fibers projected from sites that are related to control of the swallowing reflex. Although the LRt may therefore be related to control of the swallowing reflex, the functional role of the LRt in the swallowing reflex remains unknown. The present study examined whether the swallowing reflex is modulated by stimulation of the LRt. These experiments were performed on rats anesthetized by urethane. The swallowing reflex was evoked by repetitive electrical stimulation of the superior laryngeal nerve (SLN) and was identified by electromyographic activities from the mylohyoid muscle. Electrical stimulation was applied to the LRt or glutamate was injected into the LRt. The number of swallows was reduced, and the latency of the onset of the first swallow was increased during electrical stimulation near the middle of the rostrocaudal direction of the LRt. The number of swallows was reduced, and the latency of onset of the first swallow increased after microinjection of glutamate near the rostrocaudal center of the LRt. The present study suggests that the LRt is involved in control of the swallowing reflex.

Descending pathways from the superior colliculus mediating autonomic and respiratory effects associated with orienting behaviour.

The ability to discriminate competing external stimuli and initiate contextually appropriate behaviours is a key brain function. Neurons in the deep superior colliculus (dSC) integrate multisensory inputs and activate descending projections to premotor pathways responsible for orienting, attention and defence, behaviours which involve adjustments to respiratory and cardiovascular parameters. However, the neural pathways that subserve the physiological components of orienting are poorly understood. We report that orienting responses to optogenetic dSC stimulation are accompanied by short-latency autonomic, respiratory and electroencephalographic effects in awake rats, closely mimicking those evoked by naturalistic alerting stimuli. Physiological responses were not accompanied by detectable aversion or fear, and persisted under urethane anaesthesia, indicating independence from emotional stress. Anterograde and trans-synaptic viral tracing identified a monosynaptic pathway that links the dSC to spinally projecting neurons in the medullary gigantocellular reticular nucleus (GiA), a key hub for the coordination of orienting and locomotor behaviours. In urethane-anaesthetized animals, sympathoexcitatory and cardiovascular, but not respiratory, responses to dSC stimulation were replicated by optogenetic stimulation of the dSC-GiA terminals, suggesting a likely role for this pathway in mediating the autonomic components of dSC-mediated responses. Similarly, extracellular recordings from putative GiA sympathetic premotor neurons confirmed short-latency excitatory inputs from the dSC. This pathway represents a likely substrate for autonomic components of orienting responses that are mediated by dSC neurons and suggests a mechanism through which physiological and motor components of orienting behaviours may be integrated without the involvement of higher centres that mediate affective components of defensive responses. KEY POINTS: Neurons in the deep superior colliculus (dSC) integrate multimodal sensory signals to elicit context-dependent innate behaviours that are accompanied by stereotypical cardiovascular and respiratory activities. The pathways responsible for mediating the physiological components of colliculus-mediated orienting behaviours are unknown. We show that optogenetic dSC stimulation evokes transient orienting, respiratory and autonomic effects in awake rats which persist under urethane anaesthesia. Anterograde tracing from the dSC identified projections to spinally projecting neurons in the medullary gigantocellular reticular nucleus (GiA). Stimulation of this pathway recapitulated autonomic effects evoked by stimulation of dSC neurons. Electrophysiological recordings from putative GiA sympathetic premotor neurons confirmed short latency excitatory input from dSC neurons. This disynaptic dSC-GiA-spinal sympathoexcitatory pathway may underlie autonomic adjustments to salient environmental cues independent of input from higher centres.

Large-Scale Mapping of Vocalization-Related Activity in the Functionally Diverse Nuclei in Rat Posterior Brainstem.

The identity and location of vocalization pattern generating (VPG) circuits in mammals is debated. Based on physiological experiments, investigators suggested anterior brainstem circuits in the reticular formation, and anatomic evidence suggested the nucleus retroambiguus (NRA) in the posterior brainstem, or combinations of these sites as the putative mammalian VPG. Additionally, vocalization loudness is a critical factor in acoustic communication. However, many of the underlying neuronal mechanisms are still unknown. Here, we evoked calls by stimulation of the periaqueductal gray in anesthetized male rats, performed a large-scale mapping of vocalization-related activity using the activity marker c-fos, and high-density recordings of brainstem circuits using Neuropixels probes. Both c-fos expression and recording of vocalization-related activity point to a participation of the NRA in vocalization. More important, among our recorded structures, we found that the NRA is the only brainstem area showing a strong correlation between unit activity and call intensity. In addition, we observed functionally diverse patterns of vocalization-related activity in a set of regions around NRA. Dorsal to NRA, we observed activity specific to the beginning and end of vocalizations in the posterior level of the medullary reticular nucleus, dorsal part, whereas medial and lateral to the NRA, we observed activity related to call initiation. No clear vocalization-related activity was observed at anterior brainstem sites. Our findings suggest a set of functionally heterogeneous regions around the NRA contribute to vocal pattern generation in rats.SIGNIFICANCE STATEMENT Vocalization patterns are shaped in the mammalian brainstem, but the identity and location of the circuits involved is debated. Additionally, the neuronal mechanisms of vocal intensity control are still unknown. This study consisted of a large-scale mapping of brainstem vocalization circuits based on the activity marker c-fos and high-density recordings with Neuropixels probes. The results confirm the role of nucleus retroambiguus in call production and point to a key role of neurons in this nucleus in loudness control. Dorsal to the nucleus retroambiguus and in the posterior medulla, the authors identify neurons with activity specific to the beginning and end of vocalizations. The results point to specific neural dials for various aspects of rat vocalization control in the posterior brainstem.

Noradrenergic substrates sensing light within brainstem reticular formation as targets for light-induced behavioral and cardiovascular plasticity.

The occurrence of pure light exerts a variety of effects in the human body, which span from behavioral alterations, such as light-driven automatic motor activity, cognition and mood to more archaic vegetative functions, which encompass most organs of the body with remarkable effects on the cardiovascular system. Although empirical evidence clearly indicates occurrence of these widespread effects, the anatomical correlates and long-lasting changes within putatively specific neuronal circuitries remain largely unexplored. A specific role is supposed to take place for catecholamine containing neurons in the core of the brainstem reticular formation, which produces a widespread release of noradrenaline in the forebrain while controlling the vegetative nervous system. An indirect as well as a direct (mono-synaptic) retino-brainstem pathway is hypothesized to rise from a subtype of intrinsically photosensitive retinal ganglion cells (iPRGCs), subtype M1, which do stain for Brn3b, and project to the pre-tectal region (including the olivary pre-tectal nucleus). This pathway provides profuse axon collaterals, which spread to the periacqueductal gray and dorsal raphe nuclei. According to this evidence, a retino-reticular monosynaptic system occurs, which powerfully modulate the noradrenergic hub of reticular nuclei in the lateral column of the brainstem reticular formation. These nuclei, which are evidenced in the present study, provide the anatomical basis to induce behavioral and cardiovascular modulation. The occurrence of a highly interconnected network within these nuclei is responsible for light driven plastic effects, which may alter persistently behavior and vegetative functions as the consequence of long-lasting alterations in the environmental light stimulation of the retina. These changes, which occur within the core of an archaic circuitry such as the noradrenaline-containing neurons of the reticular formation, recapitulate, within the CNS, ancestral effects of light-driven changes, which can be detected already within the retina itself at the level of multipotent photic cells.

Is the central mesencephalic reticular formation a purely horizontal gaze center?

Historically, the central mesencephalic reticular formation has been regarded as a purely horizontal gaze center based on the fact that electrical stimulation of this region produces horizontal saccades, it provides monosynaptic input to medial rectus motoneurons, and cells recorded in this region often display a peak in firing when horizontal saccades are made. We tested the proposition that the central mesencephalic reticular formation is purely a horizontal gaze center by examining whether this region also supplies terminals to superior rectus and levator palpebrae superioris motoneurons, both of which fire when making vertical eye movements. The experiments were carried out using dual tracer techniques at the light and electron microscopic level in macaque monkeys. Injections of biotinylated dextran amine or Phaseolus vulgaris leukoagglutinin into the central mesencephalic reticular formation produced anterogradely labeled terminals that were in synaptic contact with superior rectus and levator palpebrae superioris motoneurons that had been retrogradely labeled. These results indicate that this region is not purely connected with horizontal gaze motoneurons. In addition, we found that the number of contacts on vertical gaze motoneurons increased with more rostral injections involving the mesencephalic reticular formation adjacent to the interstitial nucleus of Cajal. This suggests that there is a caudal to rostral gradient for horizontal to vertical saccades, respectively, represented within the midbrain reticular formation. Finally, we utilized post-embedding immunohistochemistry to show that a portion of the labeled terminals were GABAergic, indicating they likely originate from downgaze premotor neurons.

Revisão de anatomia e correlações clínicas do tronco encefálico, parte i: bulbo / Review of brain anatomy and clinical correlations, part i: medulla

O Tronco encefálico (TE) é uma estrutura singular do sistema nervoso central, pois nele passam tratos sensoriais ascendentes da medula espinal, tratos sensoriais da cabeça e do pescoço, os tratos descendentes motores originados no prosencéfalo (divisão mais rostral do encéfalo), e as vias ligadas aos centros de movimento dos olhos. Contém ainda os núcleos dos nervos cranianos e está envolvido na regulação do nível de consciência através de projeções ao prosencéfalo oriundas da formação reticular. Todas essas estruturas coexistem em um espaço muito exíguo, o que faz com que o TE seja um local muito sensível às alterações patológicas, sendo que os pacientes apresentam muitos sinais neurológicos mesmo com lesões muito pequenas nesse local. Compreender a anatomia interna do TE é essencial para o diagnóstico neurológico e a prática da medicina clínica. Outros profissionais da saúde também se beneficiam desse conhecimento para melhor manejo dos seus pacientes neurológicos. Essa revisão apresenta detalhes da anatomia macroscópica e microscópica do bulbo, bem como seus correlatos clínicos frente às lesões mais comuns dessa divisão particular do TE, conhecidas como síndromes bulbares.

The brainstem is a unique structure in the central nervous system, since it gives way to ascending sensory tracts from the spinal cord, sensory tracts from the head and neck, motor descending tracts originating from the forebrain, and the pathways connected to the eye movement centers. It also contains the cranial nerve nuclei and is involved in the regulation of consciousness levels through projections to the forebrain originating in the reticular formation. All these structures coexist in a very small space, which makes the brainstem very sensitive to pathological changes, with patients presenting several neurological symptoms even with very small brainstem lesions. Understanding the internal anatomy of the brainstem is essential for neurological diagnosis and the practice of clinical medicine. Other health professionals also benefit from this knowledge to better manage their neurological patients. This review presents detailed information on the macroscopic and microscopic anatomy of the medulla, as well as its clinical correlates in the face of the most common lesions of this particular division of the brainstem, known as medullary syndromes.

Both Corticospinal and Reticulospinal Tracts Control Force of Contraction.

The control of contraction strength is a key part of movement control. In primates, both corticospinal and reticulospinal cells provide input to motoneurons. Corticospinal discharge is known to correlate with force, but there are no previous reports of how reticular formation (RF) activity modulates with different contractions. Here we trained two female macaque monkeys (body weight, 5.9-6.9 kg) to pull a handle that could be loaded with 0.5-6 kg weights and recorded from identified pyramidal tract neurons (PTNs) in primary motor cortex and RF cells during task performance. Population-averaged firing rate increased monotonically with higher force for the RF, but showed a complex profile with little net modulation for PTNs. This reflected a more heterogeneous profile of rate modulation across the PTN population, leading to cancellation in the average. Linear discriminant analysis classified the force based on the time course of rate modulation equally well for PTNs and RF cells. Peak firing rate had significant linear correlation with force for 43 of 92 PTNs (46.7%) and 21 of 46 RF cells (43.5%). For almost all RF cells (20 of 21), the correlation coefficient was positive; similar numbers of PTNs (22 vs 21) had positive versus negative coefficients. Considering the timing of force representation, similar fractions (PTNs: 61.2%; RF cells: 55.5%) commenced coding before the onset of muscle activity. We conclude that both corticospinal and reticulospinal tracts contribute to the control of contraction force; the reticulospinal tract seems to specify an overall signal simply related to force, whereas corticospinal cell activity would be better suited for fine-scale adjustments.SIGNIFICANCE STATEMENT For the first time, we compare the coding of force for corticospinal and reticular formation cells in awake behaving monkeys, over a wide range of contraction strengths likely to come close to maximum voluntary contraction. Both cortical and brainstem systems coded similarly well for force, but whereas reticular formation cells carried a simple uniform signal, corticospinal neurons were more heterogeneous. This may reflect a role in the gross specification of a coordinated movement, versus more fine-grained adjustments around individual joints.

Mapping the human corticoreticular pathway with multimodal delineation of the gigantocellular reticular nucleus and high-resolution diffusion tractography.

The corticoreticular pathway (CRP) is a major motor tract that transmits cortical input to the reticular formation motor nuclei and may be an important mediator of motor recovery after central nervous system damage. However, its cortical origins, trajectory and laterality are incompletely understood in humans. This study aimed to map the human CRP and generate an average CRP template in standard MRI space. Following recently established guidelines, we manually delineated the primary reticular formation motor nucleus (gigantocellular reticular nucleus [GRN]) using several group-mean MRI contrasts from the Human Connectome Project (HCP). CRP tractography was then performed with HCP diffusion-weighted MRI data (N = 1065) by selecting diffusion streamlines that reached both the cortex and GRN. Corticospinal tract (CST) tractography was also performed for comparison. Results suggest that the human CRP has widespread origins, which overlap with the CST across most of the motor cortex and include additional exclusive inputs from the medial and anterior prefrontal cortices. The estimated CRP projected through the anterior and posterior limbs of the internal capsule before partially decussating in the midbrain tegmentum and converging bilaterally on the pontomedullary reticular formation. Thus, the CRP trajectory appears to partially overlap the CST, while being more distributed and anteromedial to the CST in the cerebrum before moving posterior to the CST in the brainstem. These findings have important implications for neurophysiologic testing, cortical stimulation and movement recovery after brain lesions. We expect that our GRN and tract maps will also facilitate future CRP research.

Intrinsic properties and synaptic connectivity of Phox2b-expressing neurons in rat rostral parvocellular reticular formation.

The paired-like homeobox 2b gene (Phox2b) is critical for the development of the autonomic nervous system. We have previously demonstrated the distinct characteristics of Phox2b-expressing (Phox2b+) neurons in the reticular formation dorsal to the trigeminal motor nucleus (RdV), which are likely related to jaw movement regulation. In this study, we focused on Phox2b+ neurons in the rostral parvocellular reticular formation (rPCRt), a critical region for controlling orofacial functions, using 2-11-day-old Phox2b-EYFP rats. Most Phox2b+ rPCRt neurons were glutamatergic, but not GABAergic or glycinergic. Approximately 65 % of Phox2b+ rPCRt neurons fired at a low frequency, and approximately 24 % of Phox2b+ rPCRt neurons fired spontaneously, as opposed to Phox2b+ RdV neurons. Stimulation of the RdV evoked inward postsynaptic currents in more than 50 % of Phox2b+ rPCRt neurons, while only one Phox2b+ rPCRt neuron responded to stimulation of the nucleus of the solitary tract. Five of the 10 Phox2b+ neurons sent their axons that ramified within the trigeminal motor nucleus (MoV). Of these, the axons of the two neurons terminated within both the MoV and rPCRt. Our findings suggest that Phox2b+ rPCRt neurons have distinct electrophysiological and synaptic properties that may be involved in the motor control of feeding behavior.

Neurophysiology of the saccadic system: The reticular formation.

This chapter discusses the neurophysiology and function of subcortical circuits and cortical areas involved in saccade generation. While cells within the different nuclei of the brainstem reticular formation shape the temporal details of ipsiversive horizontal and vertical/cyclotorsional saccade components, the cerebellar flocculus, vermis and fastigial nucleus are thought to modulate these saccadic waveforms. Burst neurons in the deep layers of the superior colliculus encode the saccade vector in the contralateral field by a localized population in a motor-error map. The complexity of the saccadic system is evident in the different subclasses of SC cells, ranging from purely visual, to visual-motor, purely motor, and quasi-visual cells. Movement-related activity in all SC cells is dissociated from the retinotopic visual activity. The chapter further discusses neurophysiological findings obtained from the substantia nigra (pars reticulata), the medial thalamus, the frontal eye fields, the supplementary motor area and the parietal lobes, discussing the ever more complex response patterns of their neurons in relation to saccades.

Topological Analysis of the Brainstem of the Australian Lungfish Neoceratodus forsteri.

This paper presents a survey of the cell masses in the brainstem of the Australian lungfish Neoceratodus forsteri, based ontransversely cut Bodian-stained serial sections, supplemented by immunohistochemical data from the recent literature. This study is intended to serve a double purpose. First it concludes and completes a series of publications on the structure of the brainstem in representative species of all groups of anamniote vertebrates. Within the framework of this comparative program the cell masses in the brainstem and their positional relations are analyzed in the light of the Herrick-Johnston concept, according to which the brainstem nuclei are arranged in four longitudinal, functional zones or columns, the boundaries of which are marked by ventricular sulci. The procedure employed in this analysis essentially involves two steps: first, the cell masses and large individual cells are projected upon the ventricular surface, and next, the ventricular surface is flattened out, that is, subjected to a one-to-one continuous topological transformation [J Comp Neurol. 1974;156:255-267]. The second purpose of the present paper is to complement our mapping of the longitudinal zonal arrangement of the cell masses in the brainstem of Neoceratoduswith a subdivision in transversely oriented neural segments. Five longitudinal rhombencephalic sulci - the sulcus medianus inferior, the sulcus intermedius ventralis, the sulcus limitans, the sulcus intermedius dorsalis and the sulcus medianus superior - and four longitudinal mesencephalic sulci - the sulcus tegmentalis medialis, the sulcus tegmentalis lateralis, the sulcus subtectalis and the sulcus lateralis mesencephali - could be distinguished. Two obliquely oriented grooves, present in the isthmic region - the sulcus isthmi dorsalis and ventralis - deviate from the overall longitudinal pattern of the other sulci. Although in Neoceratodus most neuronal perikarya are situated within a diffuse periventricular gray, 45 cell masses could be delineated. Ten of these are primary efferent or motor nuclei, eight are primary afferent or sensory centers, six are considered to be components of the reticular formation and the remaining 21 may be interpreted as "relay" nuclei. The topological analysis showed that in most of the rhombencephalon the gray matter is arranged in four longitudinal zones or areas, termed area ventralis, area intermedioventralis, area intermediodorsalis and area dorsalis. The sulcus intermedius ventralis, the sulcus limitans, and the sulcus intermedius dorsalis mark the boundaries between these morphological entities. These longitudinal zones coincide largely, but not entirely, with the functional columns of Herrick and Johnston. The most obvious incongruity is that the area intermediodorsalis contains, in addition to the viscerosensory nucleus of the solitary tract, several general somatosensory and special somatosensory centers. The isthmus region does not exhibit a clear morphological zonal pattern. The mesencephalon is divisible into a ventral, primarily motor zone and a dorsal somatosensory zone. The boundary between these zones is marked by the sulcus tegmentalis lateralis, which may be considered as an isolated rostral extremity of the sulcus limitans. The results of this study are summarized in a "classical" topological map, as well as in a "modernized" version of this map, in which neuromere borders are indicated.