A direct interareal feedback-to-feedforward circuit in primate visual cortex.

The mammalian sensory neocortex consists of hierarchically organized areas reciprocally connected via feedforward (FF) and feedback (FB) circuits. Several theories of hierarchical computation ascribe the bulk of the computational work of the cortex to looped FF-FB circuits between pairs of cortical areas. However, whether such corticocortical loops exist remains unclear. In higher mammals, individual FF-projection neurons send afferents almost exclusively to a single higher-level area. However, it is unclear whether FB-projection neurons show similar area-specificity, and whether they influence FF-projection neurons directly or indirectly. Using viral-mediated monosynaptic circuit tracing in macaque primary visual cortex (V1), we show that V1 neurons sending FF projections to area V2 receive monosynaptic FB inputs from V2, but not other V1-projecting areas. We also find monosynaptic FB-to-FB neuron contacts as a second motif of FB connectivity. Our results support the existence of FF-FB loops in primate cortex, and suggest that FB can rapidly and selectively influence the activity of incoming FF signals.

VTA Glutamatergic Neurons Mediate Innate Defensive Behaviors.

The ventral tegmental area (VTA) has dopamine, GABA, and glutamate neurons, which have been implicated in reward and aversion. Here, we determined whether VTA-glutamate or -GABA neurons play a role in innate defensive behavior. By VTA cell-type-specific genetic ablation, we found that ablation of glutamate, but not GABA, neurons abolishes escape behavior in response to threatening stimuli. We found that escape behavior is also decreased by chemogenetic inhibition of VTA-glutamate neurons and detected increases in activity in VTA-glutamate neurons in response to the threatening stimuli. By ultrastructural and electrophysiological analysis, we established that VTA-glutamate neurons receive a major monosynaptic glutamatergic input from the lateral hypothalamic area (LHA) and found that photoinhibition of this input decreases escape responses to threatening stimuli. These findings indicate that VTA-glutamate neurons are activated by and required for innate defensive responses and that information on threatening stimuli to VTA-glutamate neurons is relayed by LHA-glutamate neurons.

Synaptic Inputs to the Mouse Dorsal Vagal Complex and Its Resident Preproglucagon Neurons.

Stress responses are coordinated by widespread neural circuits. Homeostatic and psychogenic stressors activate preproglucagon (PPG) neurons in the caudal nucleus of the solitary tract (cNTS) that produce glucagon-like peptide-1; published work in rodents indicates that these neurons play a crucial role in stress responses. While the axonal targets of PPG neurons are well established, their afferent inputs are unknown. Here we use retrograde tracing with cholera toxin subunit b to show that the cNTS in male and female mice receives axonal inputs similar to those reported in rats. Monosynaptic and polysynaptic inputs specific to cNTS PPG neurons were revealed using Cre-conditional pseudorabies and rabies viruses. The most prominent sources of PPG monosynaptic input include the lateral (LH) and paraventricular (PVN) nuclei of the hypothalamus, parasubthalamic nucleus, lateral division of the central amygdala, and Barrington's nucleus (Bar). Additionally, PPG neurons receive monosynaptic vagal sensory input from the nodose ganglia and spinal sensory input from the dorsal horn. Sources of polysynaptic input to cNTS PPG neurons include the hippocampal formation, paraventricular thalamus, and prefrontal cortex. Finally, cNTS-projecting neurons within PVN, LH, and Bar express the activation marker cFOS in mice after restraint stress, identifying them as potential sources of neurogenic stress-induced recruitment of PPG neurons. In summary, cNTS PPG neurons in mice receive widespread monosynaptic and polysynaptic input from brain regions implicated in coordinating behavioral and physiological stress responses, as well as from vagal and spinal sensory neurons. Thus, PPG neurons are optimally positioned to integrate signals of homeostatic and psychogenic stress.SIGNIFICANCE STATEMENT Recent research has indicated a crucial role for glucagon-like peptide-1-producing preproglucagon (PPG) neurons in regulating both appetite and behavioral and autonomic responses to acute stress. Intriguingly, the central glucagon-like peptide-1 system defined in rodents is conserved in humans, highlighting the translational importance of understanding its anatomical organization. Findings reported here indicate that PPG neurons receive significant monosynaptic and polysynaptic input from brain regions implicated in autonomic and behavioral responses to stress, as well as direct input from vagal and spinal sensory neurons. Improved understanding of the neural pathways underlying the recruitment of PPG neurons may facilitate the development of novel therapies for the treatment of stress-related disorders.

Effects of Repeated 20-Hz Electrical Stimulation on Functional Recovery Following Peripheral Nerve Injury.

One hour of 20-Hz continuous electrical stimulation (ES) applied at the time of injury promotes the regeneration of axons in cut peripheral nerves. A more robust enhancement of peripheral axon regeneration is achieved by 2 weeks of daily treadmill exercise. We investigated whether repeated applications of brief ES (mES) would be more effective in promoting regeneration than a single application. Sciatic nerves of C57B6 mice were cut and repaired by end-to-end anastomosis. At that time and every third day for 2 weeks, the repaired nerve was stimulated for 1 hour at 20 Hz. In controls, injured mice were either untreated or treated with ES only once. Direct muscle responses recorded from reinnervated muscles in awake animals were observed earlier both in mice treated with ES and mES than untreated controls. Their amplitudes increased progressively over the post transection study period, but the rate of this progression was increased significantly only in animals treated once with ES. Monosynaptic H reflexes recovered to pretransection levels in both untreated and singly treated mice but in the animals treated repeatedly, they were maintained at more than twice that of the same reflexes recorded prior to injury. In anatomical analyses, both excitatory and inhibitory synaptic contacts with the cell bodies of injured motoneurons, including those expressing the vesicular glutamate transporter 1 (VGLUT1), were sustained in mice treated repeatedly but not in singly treated or untreated mice. Repeated ES does not enhance the rate of restoration of functional muscle reinnervation and results in the retention of exaggerated reflexes.

Hind limb motoneurons activity during fictive locomotion or scratching induced by pinna stimulation, serotonin, or glutamic acid in brain cortex-ablated cats.

In brain cortex-ablated cats (BCAC), hind limb motoneurons activity patterns were studied during fictive locomotion (FL) or fictive scratching (FS) induced by pinna stimulation. In order to study motoneurons excitability: heteronymous monosynaptic reflex (HeMR), intracellular recording, and individual Ia afferent fiber antidromic activity (AA) were analyzed. The intraspinal cord microinjections of serotonin or glutamic acid effects were made to study their influence in FL or FS During FS, HeMR amplitude in extensor and bifunctional motoneurons increased prior to or during the respective electroneurogram (ENG). In soleus (SOL) motoneurons were reduced during the scratch cycle (SC). AA in medial gastrocnemius (MG) Ia afferent individual fibers of L6-L7 dorsal roots did not occur during FS Flexor digitorum longus (FDL) and MG motoneurons fired with doublets during the FS bursting activity, motoneuron membrane potential from some posterior biceps (PB) motoneurons exhibits a depolarization in relation to the PB (ENG). It changed to a locomotor drive potential in relation to one of the double ENG, PB bursts. In FDL and semitendinosus (ST) motoneurons, the membrane potential was depolarized during FS, but it did not change during FL Glutamic acid injected in the L3-L4 spinal cord segment favored the transition from FS to FL During FL, glutamic acid produces a duration increase of extensors ENGs. Serotonin increases the ENG amplitude in extensor motoneurons, as well as the duration of scratching episodes. It did not change the SC duration. Segregation and motoneurons excitability could be regulated by the rhythmic generator and the pattern generator of the central pattern generator.

Conversion of the modulatory actions of dopamine on spinal reflexes from depression to facilitation in D3 receptor knock-out mice.

Descending monoaminergic systems modulate spinal cord function, yet spinal dopaminergic actions are poorly understood. Using the in vitro lumbar cord, we studied the effects of dopamine and D2-like receptor ligands on spinal reflexes in wild-type (WT) and D3-receptor knock-out mice (D3KO). Low dopamine levels (1 microM) decreased the monosynaptic "stretch" reflex (MSR) amplitude in WT animals and increased it in D3KO animals. Higher dopamine concentrations (10-100 microM) decreased MSR amplitudes in both groups, but always more strongly in WT. Like low dopamine, the D3 receptor agonists pergolide and PD 128907 reduced MSR amplitude in WT but not D3KO mice. Conversely, D3 receptor antagonists (GR 103691 and nafadotride) increased the MSR in WT but not in D3KO mice. In comparison, D2-preferring agonists bromocriptine and quinpirole depressed the MSR in both groups. Low dopamine (1-5 microM) also depressed longer-latency (presumably polysynaptic) reflexes in WT but facilitated responses in D3KO mice. Additionally, in some experiments (e.g., during 10 microM dopamine or pergolide in WT), polysynaptic reflexes were facilitated in parallel to MSR depression, demonstrating differential modulatory control of these reflex circuits. Thus, low dopamine activates D3 receptors to limit reflex excitability. Moreover, in D3 ligand-insensitive mice, excitatory actions are unmasked, functionally converting the modulatory action of dopamine from depression to facilitation. Restless legs syndrome (RLS) is a CNS disorder involving abnormal limb sensations. Because RLS symptoms peak at night when dopamine levels are lowest, are relieved by D3 agonists, and likely involve increased reflex excitability, the D3KO mouse putatively explains how impaired D3 activity could contribute to this sleep disorder.

[Anatomical basis of motricity for the study of spasticity]. / Bases anatomiques de la motricité appliquées à l'étude de la spasticité.

The spinal motoneurone is under the permanent influence of peripheral afferent fibers, interneurons, and numerous descending projections from supraspinal structures. Motoneuronal activity summarizes these different and convergent modulations at one moment. Spasticity corresponds to exageration of monosynpatic reflex, from IA fiber to motoneuron alpha, associated with spinal hyperexitability. Various lesions of central nervous system give rise to spasticity, specially if they affect supra spinal descending controls, mainly reticulo-spinal tracts. The role of neuronal plasticity to explain the progressive time course of spasticity is also discussed.

Frequency of occurrence of the F wave in distal flexor muscles as a function of hypnotic susceptibility and hypnosis.

The aim of the experiment was to assess whether the membrane excitability of flexor cervical and/or lumbar motoneurons is related to hypnotic susceptibility (measured with the Stanford Hypnotic Susceptibility Scale, Form A) and hypnosis. During the experimental sessions, hypnotized subjects were given only suggestions of relaxation (neutral hypnosis) while awake subjects were given instructions to be quiet and relaxed (simple relaxation). F waves were recorded from the abductor digiti minimi and abductor hallucis of both sides after electrical stimulation of the ulnar or tibial nerve, respectively, and were used as an index of motoneuron membrane excitability in three groups of subjects: highly susceptible under neutral hypnosis, highly susceptible and non-susceptible during simple relaxation sessions. In lower limbs, there was no difference among the groups in the frequency of occurrence of F waves. In upper limbs, hypnosis selectively reduced F frequency of occurrence in flexor motoneurons on the right side. This reduction persisted after the end of hypnosis and also occurred during the last period of relaxation in highly susceptible non-hypnotized subjects. Results support the idea that hypnotic phenomena develop along a continuum in which some trait differences can be more easily revealed by the induction of hypnosis.

[Generators of walking movements in humans: spinal mechanisms of their activation]. / Generatory shagatel'nykh dvizhenii cheloveka: spinal'nye mekhanizmy ikh aktivatsii.

The paper is focused on spinal generation of walking movements in patients afflicted with loss of supraspinal control consequent to back trauma. The author cites literature on methods of initiation of walking movements with pharmacological and proprioceptive stimulation. On his own experimental investigations with epidural electrical stimulation of the spinal marrow dorsal surface he proves existence of walking generators in the human. There is evidence that the walking pattern in extensors is formed through amplitude modulation of monosynaptic reflexes, whereas in flexors it is established through switching of the reflex paths from the monosynaptic reflex to the polysynaptic neuron network. Investigations of the functional deafferentation of lower extremities showed that walking movements as a result of epidural stimulation are intraspinal by origin and adjusted by way of peripheral feedback. A hypothetical sequence of activation of walking generators through the propriospinal system of dorsolateral and ventrilateral funiculi has been put forward.

Post-tetanic modification of the efficiency of excitatory transmission in neural networks including interhemispheric connections.

This is the first report of modifiable reciprocal transcallosal monosynaptic excitatory connections, detected in in vivo experiments in the rat motor cortex by recording of multineuron activity and cross-correlation analysis. High-frequency microstimulation of a small group of cortical neurons in one hemisphere was shown to alter the efficiency of transcallosal excitatory connections, and also altered the efficiency of ipsilateral connections in both hemispheres. Post-tetanic changes consisted of long-term potentiation and depression. Neurons producing spike trains were found to have better conditions (compared with other neurons) for long-term potentiation of inputs converging on them. Synapses formed by axon collaterals of a given callosal cell on several neurons could simultaneously induce both long-term potentiation and long-term depression, while a given callosal neuron could simultaneously show long-term potentiation in some synapses and long-term depression in others. After microstimulation there were increases in the number of background-active callosal neurons, along with increases in the number and efficiency of transcallosal connections, while the number and efficiency of ipsilateral connections decreased. These data lead to the conclusion that ipsilateral inhibition is more effective than transcallosal inhibition. Microstimulation modified the pattern of initially existing connections between the many elements of ensembles including callosal cells in both hemispheres.

Modulation of spinal cord excitability by subthreshold repetitive transcranial magnetic stimulation of the primary motor cortex in humans.

Repetitive transcranial magnetic stimulation (rTMS) allows the modulation of intra-cortical excitability and may therefore affect the descending control of spinal excitability. We applied rTMS at subthreshold intensity and 1 Hz frequency for 10 min to the left primary motor cortex representation of the flexor carpi radialis muscle (FCR) in 10 subjects and assessed the H and M responses to median nerve stimulation before and after the rTMS. Following rTMS, H wave thresholds significantly reduced by approximately 20%. Maximal H but not M wave amplitude significantly increased over the baseline, so that H/M amplitude ratio was increased by 41%. Sham stimulation did not induce any noticeable change in M or H waves. Slow rTMS might facilitate monosynaptic spinal cord reflexes by inhibiting the cortico-spinal projections modulating spinal excitability.

Mental simulation of an action modulates the excitability of spinal reflex pathways in man.

The question of whether mental simulation of an action has an effect on the spinal reflex circuits was examined in normal humans. Subjects were instructed either to exert or to mentally simulate a strong or a weak pressure on a pedal with the left or the right foot. Changes in the H- and T-reflexes activated by electrical and mechanical stimuli were measured on both legs during motor performance as well as during mental simulation of the same task. Asynchronous EMG activity of the soleus muscles was simultaneously recorded. Reflex excitability increased during performance of the pressure. It was larger when the H-reflex was triggered in the muscle involved in the task as compared to the contralateral side. Because actual performance modified the tension of the tendon and the location of the stimulus, ipsilateral changes of T-reflex amplitude could not be evaluated. Mental simulation of foot pressure in this condition resulted in a large increase of spinal reflex excitability, which was only slightly weaker than the reflex facilitation associated with the actual performance. Changes in T-reflex amplitude, but not in H-reflex amplitude, depended upon the lateralization and force of the simulated pressure, being larger in the leg involved in the simulation than in the contralateral leg, and larger for a strong than for a weak simulated movement. EMG activity was found to be weakly increased during mental imagery. This increase was significantly, although slightly, modulated by the lateralization and intensity of the imagined movement. However, no correlation was found across subjects between reflex amplitude and the amplitude of EMG activity.

Diisopropylfluorophosphate-induced depression of segmental monosynaptic transmission in neonatal rat spinal cord is also mediated by increased axonal activity.

Involvement of dorsal and ventral root activity for the depressant action of diisopropylfluorophosphate (DFP) on synaptic transmission was examined using in vitro spinal cord/root preparations. Superfusion of DFP produced a dose-dependent depression of monosynaptic reflex (MSR) and maximal depression of about 80% occurred at 1000 microM. The concentration to produce 50% of the maximal inhibition was about 100 microM of DFP. The DFP (100 microM)-induced depression of MSR was reversed by atropine (0.5 microM) but not by mecamylamine (0.5 microM). Contrary to the action on MSR, DFP potentiated the ventral root potential and 1st peak of dorsal root potential. The maximal potentiation was about 25% of control in both the root potentials at 100 microM of DFP. However, the second peak of dorsal root potential was slightly depressed (10-20% of control) by DFP (1-1000 microM). Further, the cords treated with DFP (100 microM) showed significant decrease in the cholinesterase (ChE) activity (27% of control). Results suggest that the DFP-induced depression was mediated at least by two different mechanisms, one through the inhibition of ChE activity and the other through the activation axonal activity having inhibitory inputs to the segmental synaptic transmission. These inputs mediate their action through muscarinic receptors.

The role of GABA and glycine in the physostigmine-induced alterations of spinal cord reflexes.

The purpose of this study was to determine which inhibitory pathway(s) mediate the alterations in the monosynaptic (MSR) and polysynaptic (PSR) reflexes after two different doses of physostigmine. It was found previously that 0.8 mg/kg physostigmine facilitated the MSR and 2.0 mg/kg initially depressed and then facilitated the MSR. Both doses facilitated the PSR. In this study, the animals were pretreated with either strychnine (0.1 mg/kg) or bicuculline (0.5 mg/kg), prior to the administration of either dose of physostigmine. It was found that both strychnine and bicuculline blocked the facilitation produced by the small dose of physostigmine, while bicuculline alone blocked the depression of the MSR produced by the large dose of physostigmine. Strychnine partially blocked the effects of both doses of physostigmine on the PSR, while bicuculline only partially blocked the effects of the small dose of physostigmine. These data suggest that the depression of the MSR was the result of a GABA-mediated pathway, while the facilitation of MSR involved both glycine and GABA.

[Status of the spinal inhibitory reactions in humans subjected to hyperbaric oxygenation]. / Sostoianie spinal'nykh tormoziashchikh reaktsii v usloviiakh giperbaricheskogo vozdeistviia na cheloveka.

The state of human spinal inhibition responses under normo- and hyperbaric pressure (6.5 ata) was comparatively studied. The paired stimulation method has been used to estimate resetting of tested monosynaptic reflex in the 20-900 ms interval of paired stimulation at rest or against the background of supraspinal modulation of spinal reflective processes (Jendrassik manoeuvre, voluntary plantar flexion) were studied. The depression of inhibition reactions under hyperbaric pressure identical to that during the supraspinal modulation under normobaric conditions is shown. It is supposed that these influences on spinal reflection processes are caused by the same neuronal mechanism.

Further evidence for Renshaw inhibition in man. A combined electrophysiological and pharmacological approach.

Experiments involving the acute administration of a central cholinergic substance (L-acetylcarnitine) were performed on 6 healthy subjects to obtain additional evidence that the electrophysiological method developed by Bussel and Pierrot-Deseilligny in 1977 does actually assess recurrent inhibition in man. In all the subjects, the drug further decreased the amplitude of a test H reflex (H') following a conditioning H reflex (H1). The amount of this supplementary inhibition was found to be related to the size of H1 reflex. Experimental evidence is also presented that H' reflex supplementary depression is not contaminated by homonymous Ib effects. It is concluded that the method effectively tests the excitability of Renshaw cells in man.

Modification of human spinal stretch reflexes: preliminary studies.

Modulation of the human spinal stretch reflex (SSR) may be important in treating hyperactive reflexes or may be a tool to enhance normal performance. Eight of 9 subjects given feedback of biceps brachii SSR amplitude and instructed to increase (uptrain) or decrease (downtrain) this response were able to do so in the appropriate direction. These results imply that, as in non-human primates, SSR amplitude can be modified.

[Effect of electric stimulation of auricular acupuncture points on H-reflex]. / Vliianie élektrostimuliatsii aurikuliarnykh akupunkturnykh tochek na H-refleks.

The non-nociceptive H-reflex in the musculus soleus were recorded before and after auricular electroacupuncture (AEAP) in patients with vertebrogenic pain syndrome. Changes of the H-reflex on the side of the pain syndrome were observed after ipsi- and contralateral AEAP, the latter producing effect more often. Changes of H-reflex are mainly of facilitating character (71.4%) and, rarely, of inhibitory character (14.3%). In the part of patients AEAP produced distinct facilitation of M-response.

Changes in electromyographically recorded human monosynaptic reflex in relation to hypnotic susceptibility and hypnosis.

The aim of the present experiment was to study how hypnotic susceptibility and hypnosis affect motoneuron excitability. In a first trial, human subjects were selected according to their hypnotic susceptibility. In a second trial, the Hoffmann (H) reflex amplitude of the soleus muscle was studied in 3 groups: (1) highly susceptible subjects during hypnosis with standardized suggestions of simple relaxation, anesthesia, analgesia and paralysis (group I), (2) highly susceptible subjects (group II), and (3) non-susceptible subjects (group III) during long-lasting control conditions. Surface Ag/AgCl electrodes were used to stimulate the posterior tibial nerve using a constant current stimulator and to record the soleus EMG. Analysis of variance was performed on the data. The linear correlation coefficient within groups was evaluated. The H reflex amplitude decreased significantly during the recording session in groups I and II and there was no change in group III. In group I the effect of different suggestions could not be distinguished from the effect of hypnotic relaxation. The decrements in H amplitude did not differ between groups I and II, suggesting that the effect was related to personality traits rather than hypnotic induction.