Multiple mechanisms for integrating proprioceptive inputs that converge on the same motor pattern-generating network.

Movement-derived sensory feedback adapts centrally generated motor programs to changing behavioral demands. Motor circuit output may also be shaped by distinct proprioceptive systems with different central actions, although little is known about the integrative processes by which such convergent sensorimotor regulation occurs. Here, we explore the combined actions of two previously identified proprioceptors on the gastric mill motor network in the lobster stomatogastric nervous system. Both mechanoreceptors [anterior gastric receptor (AGR) and posterior stomach receptor (PSR)] access the gastric circuit via the same pair of identified projection interneurons that either excite [commissural gastric (CG)] or inhibit [gastric inhibitor (GI)] different subsets of gastric network neurons. Mechanosensory information from the two receptors is integrated upstream to the gastric circuit at two levels: (1) postsynaptically, where both receptors excite the GI neuron while exerting opposing effects on the CG neuron, and (2) presynaptically, where PSR reduces AGR's excitation of the CG projection neuron. Concomitantly PSR selectively enhances AGR's activation of the GI neuron, possibly also via a presynaptic action. PSR's influences also far outlast its transient synaptic effects, indicating the additional involvement of modulatory processes. Consequently, PSR activation causes parallel input from AGR to be conveyed preferentially via the GI interneuron, resulting in a prolonged switch in the pattern of gastric circuit output. Therefore, via a combination of short- and long-lasting, presynaptic and postsynaptic actions, one proprioceptive system is able to promote its impact on a target motor network by biasing the access of a different sensory system to the same circuit.

Disruption of balanced cortical excitation and inhibition by acoustic trauma.

Sensory deafferentation results in rapid shifts in the receptive fields of cortical neurons, but the synaptic mechanisms underlying these changes remain unknown. The rapidity of these shifts has led to the suggestion that subthreshold inputs may be unmasked by a selective loss of inhibition. To study this, we used in vivo whole cell recordings to directly measure tone-evoked excitatory and inhibitory synaptic inputs in auditory cortical neurons before and after acoustic trauma. Here we report that acute acoustic trauma disrupted the balance of excitation and inhibition by selectively increasing and reducing the strength of inhibition at different positions within the receptive field. Inhibition was abolished for frequencies far below the trauma-tone frequency but was markedly enhanced near the edges of the region of elevated peripheral threshold. These changes occurred for relatively high-level tones. These changes in inhibition led to an expansion of receptive fields but not by a simple unmasking process. Rather, membrane potential responses were delayed and prolonged throughout the receptive field by distinct interactions between synaptic excitation and inhibition. Far below the trauma-tone frequency, decreased inhibition combined with prolonged excitation led to increased responses. Near the edges of the region of elevated peripheral threshold, increased inhibition served to delay rather than abolish responses, which were driven by prolonged excitation. These results show that the rapid receptive field shifts caused by acoustic trauma are caused by distinct mechanisms at different positions within the receptive field, which depend on differential disruption of excitation and inhibition.

Effect of motion imagery to counter rest-induced suppression of F-wave as a measure of anterior horn cell excitability.

OBJECTIVE: To test if motor imagery prevents the rest-induced suppression of anterior horn cell excitability. METHODS: Ten healthy subjects underwent two separate experiments, each consisting of stimulating the median nerve 100 times and recording F-waves from abductor pollicis brevis (APB) in three consecutive sessions: (1) after muscle exercise to standardize the baseline, (2) after immobilization of APB for 3h and (3) after muscle exercise to check recovery. We instructed the subject to volitionally relax APB in experiment 1 (relaxation task), and to periodically simulate thumb abduction without actual movement in experiment 2 (imagery task). RESULTS: F-wave persistence and amplitude declined after relaxation task and recovered quickly after exercise, but changed little with imagery task. F-wave latencies showed no change when analyzed individually. The frequency distribution of collective F-waves recorded from all subjects remained the same after relaxation task, but showed a shift toward longer latencies after imagery task. CONCLUSIONS: Mental imagery without overt motor output suffices to counter the effect of sustained volitional muscle relaxation, which would, otherwise, cause a reversible reduction in anterior horn cell excitability. SIGNIFICANCE: This finding documents the importance of central drive for spinal excitability, which affects F-wave studies of a paretic muscle.

Thalamocortical relay fidelity varies across subthalamic nucleus deep brain stimulation protocols in a data-driven computational model.

The therapeutic effectiveness of deep brain stimulation (DBS) of the subthalamic nucleus (STN) may arise through its effects on inhibitory basal ganglia outputs, including those from the internal segment of the globus pallidus (GPi). Changes in GPi activity will impact its thalamic targets, representing a possible pathway for STN-DBS to modulate basal ganglia-thalamocortical processing. To study the effect of STN-DBS on thalamic activity, we examined thalamocortical (TC) relay cell responses to an excitatory input train under a variety of inhibitory signals, using a computational model. The inhibitory signals were obtained from single-unit GPi recordings from normal monkeys and from monkeys rendered parkinsonian through arterial 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine injection. The parkinsonian GPi data were collected in the absence of STN-DBS, under sub-therapeutic STN-DBS, and under therapeutic STN-DBS. Our simulations show that inhibition from parkinsonian GPi activity recorded without DBS-compromised TC relay of excitatory inputs compared with the normal case, whereas TC relay fidelity improved significantly under inhibition from therapeutic, but not sub-therapeutic, STN-DBS GPi activity. In a heterogeneous model TC cell population, response failures to the same input occurred across multiple TC cells significantly more often without DBS than in the therapeutic DBS case and in the normal case. Inhibitory signals preceding successful TC relay were relatively constant, whereas those before failures changed more rapidly. Computationally generated inhibitory inputs yielded similar effects on TC relay. These results support the hypothesis that STN-DBS alters parkinsonian GPi activity in a way that may improve TC relay fidelity.

Modulation of the receptive fields of midbrain neurons elicited by thalamic electrical stimulation through corticofugal feedback.

The ascending and descending projections of the central auditory system form multiple tonotopic loops. This study specifically examines the tonotopic pathway from the auditory thalamus to the auditory cortex and then to the auditory midbrain in mice. We observed the changes of receptive fields in the central nucleus of the inferior colliculus of the midbrain evoked by focal electrical stimulation of the ventral division of the medial geniculate body of the thalamus. The receptive field of an auditory neuron was characterized by five parameters: the best frequency, minimum threshold, bandwidth, size of receptive field, and average spike number. We found that focal thalamic stimulation changed the parametric values characterizing the recorded collicular receptive fields toward those characterizing the stimulated thalamic receptive fields. Cortical inactivation with muscimol prevented the development of the collicular plasticity induced by focal thalamic stimulation. Our data suggest that the intact colliculo-thalamo-cortico-collicular loops are important for the coordination of sound-guided plasticity in the central auditory system.

Effects of GPi stimulation on human thalamic neuronal activity.

OBJECTIVE: Determine the effects of globus pallidus interna (GPi) deep brain stimulation (DBS) on ventral oralis posterior nucleus of the thalamic (Vop) neuronal activity. METHODS: Microelectrode recordings in Vop during high frequency DBS GPi in a patient with dystonia. RESULTS: Twelve (48%) of 25 neurons in five locations neurons decreased their average discharge frequency, 2 (8%) increased and 11(44%) demonstrated no overall change. The patterns of responses were complex with periods of increase and decreased activity. All neurons were inhibited for the time period 3.5-5ms following the DBS pulse. Eighty-eight percent of neurons showed brief but highly consistent increases in the first 1ms following stimulation, 52% showed increased activities from 1.5 to 3ms. Twenty-four percent of neurons increased activity following inhibition. CONCLUSIONS: These findings are consistent with DBS activation of GPi axons to Vop and probable antidromic activation of Vop axons. SIGNIFICANCE: The physiological effects of DBS are far more complicated and will escape any theory that does not address the mechanisms of DBS as stimulation of a complex network of interactions. Further, the findings of post-inhibitory rebound increased raises questions about the role in inhibition in the current concepts of basal ganglia physiology.

The monotonic dependency of prepulse inhibition of the acoustic startle reflex on the intensity of the startle-eliciting stimulus.

Prepulse inhibition (PPI) of the acoustic startle reflex is a translational behavioural paradigm for the assessment of sensorimotor gating deficit which has been demonstrated in a number of neuropsychiatric conditions. PPI refers to the reduction of the reflexive startle response to a 'pulse' stimulus when its presentation is shortly preceded by a weak 'prepulse' stimulus. We have recently examined the expression of PPI as a function of the startle-eliciting 'pulse' stimulus intensity in mice and in humans. One major discrepancy that emerged was the finding that healthy human subjects, unlike normal mice, did not show a clear monotonic reduction of PPI magnitude (as indexed by % reduction in startle reactivity) with increasingly intense pulse stimulus. This lack of correspondence between species may potentially weaken the translational power of the PPI paradigm. Here, we re-examined this issue in 31 healthy subjects across three levels of pulse stimulus intensity (95, 105 and 115 dB). A clear linear reduction of PPI as a function of pulse intensity was revealed when subjects failing to respond to the lowest pulse stimulus were excluded. Inclusion of such non-responders, on the other hand, resulted in a trend towards an inverted U-shape function as reported previously. The present study thus clarifies an apparent divergence between mouse and man, and provides important qualification to the "First Law of Reflex Modification" proposed by Hoffman and Ison which suggests that the absolute reduction in startle reactivity resulting from a prepulse stimulus preceding the startle-eliciting pulse stimulus is fixed by the prepulse intensity regardless of the pulse stimulus intensity.

Upregulation of striatal dopamine-2 receptors in Brattleboro rats with prepulse inhibition deficits.

BACKGROUND: Brattleboro rats (BRATs) have natural deficits in prepulse inhibition (PPI) of the startle response similar to those exhibited by schizophrenia patients, which are reversed by antipsychotics. We sought to determine whether they also have increases in striatal dopamine-2 (D2) receptors found in some studies examining the brains of schizophrenia patients. METHODS: Several days after startle testing, the brains of BRAT and Long Evans (LE) rats were removed, and D1 and D2 receptor levels were measured by autoradiography. RESULTS: PPI was lower in BRATs consistent with previous reports. D2, but not D1, receptor binding was significantly higher in the nucleus accumbens shell and the dorsomedial caudate of BRAT compared with LE rats, consistent with some findings in schizophrenia patients. Furthermore, individual rat PPI was inversely correlated with D2 binding density. CONCLUSIONS: These findings suggest that the dopamine system in BRATs is dysregulated and these abnormalities may contribute to the PPI deficits observed in these rats.

Interleukin-1beta induces hyperpolarization and modulates synaptic inhibition in preoptic and anterior hypothalamic neurons.

Most of the inflammatory effects of the cytokine interleukin 1beta (IL-1beta) are mediated by induction of cyclooxygenase (COX)2 and the subsequent synthesis and release of prostaglandin E2. This transcription-dependent process takes 45-60 min, but IL-1beta, a well-characterized endogenous pyrogen also exerts faster neuronal actions in the preoptic area/anterior hypothalamus. Here, we have studied the fast (1-3 min) signaling by IL-1beta using whole-cell patch clamp recordings in preoptic area/anterior hypothalamus neurons. Exposure to IL-1beta (0.1-1 nM) hyperpolarized a subset ( approximately 20%) of preoptic area/anterior hypothalamus neurons, decreased their input resistance and reduced their firing rate. These effects were associated with an increased frequency of bicuculline-sensitive spontaneous inhibitory postsynaptic currents and putative miniature inhibitory postsynaptic currents, strongly suggesting a presynaptic mechanism of action. These effects require the type 1 interleukin 1 receptor (IL-1R1), and the adapter protein myeloid differentiation primary response protein (MyD88), since they were not observed in cultures obtained from IL-1R1 (-/-) or from MyD88 (-/-) mice. Ceramide, a second messenger of the IL-1R1-dependent fast signaling cascade, is produced by IL-1R1-MyD88-mediated activation of the neutral sphingomyelinase. C2-ceramide, its cell penetrating analog, also increased the frequency of miniature inhibitory postsynaptic currents in a subset of cells. Both IL-1beta and ceramide reduced the delayed rectifier and the A-type K(+) currents in preoptic area/anterior hypothalamus neurons. The latter effect may account in part for the increased spontaneous inhibitory postsynaptic current frequency as suggested by experiments with the A-type K(+) channel blockers 4-aminopyridine. Taken together our data suggest that IL-1beta inhibits the activity of preoptic area/anterior hypothalamus neurons by increasing the presynaptic release of GABA.

Paired-pulse depression at photoreceptor synapses.

Synaptic depression produced by repetitive stimulation is likely to be particularly important in shaping responses of second-order retinal neurons at the tonically active photoreceptor synapse. We analyzed the time course and mechanisms of synaptic depression at rod and cone synapses using paired-pulse protocols involving two complementary measurements of exocytosis: (1) paired whole-cell recordings of the postsynaptic current (PSC) in second-order retinal neurons and (2) capacitance measurements of vesicular membrane fusion in rods and cones. PSCs in ON bipolar, OFF bipolar, and horizontal cells evoked by stimulation of either rods or cones recovered from paired-pulse depression (PPD) at rates similar to the recovery of exocytotic capacitance changes in rods and cones. Correlation between presynaptic and postsynaptic measures of recovery from PPD suggests that 80-90% of the depression at these synapses is presynaptic in origin. Consistent with a predominantly presynaptic mechanism, inhibiting desensitization of postsynaptic glutamate receptors had little effect on PPD. The depression of exocytotic capacitance changes exceeded depression of the presynaptic calcium current, suggesting that it is primarily caused by a depletion of synaptic vesicles. In support of this idea, limiting Ca2+ influx by using weaker depolarizing stimuli promoted faster recovery from PPD. Although cones exhibit much faster exocytotic kinetics than rods, exocytotic capacitance changes recovered from PPD at similar rates in both cell types. Thus, depression of release is not likely to contribute to differences in the kinetics of transmission from rods and cones.

HZE radiation and dopaminergic modification of startle and prepulse inhibition in mice.

C57BL/6 mice were exposed to 5 Gy (28)Si or (56)Fe particle radiation in order to explore the immediate or short-latency effect of exposure to high energy (HZE) particle radiation on dopaminergic modification of acoustic startle and prepulse inhibition. The radiation is representative of the type which would be encountered as galactic cosmic rays during long-duration space flight. The acoustic startle response was elicited with 120 dB white noise and prepulse inhibition of the startle response was produced with 79 dB and 86 dB stimuli presented with a 125 ms onset asynchrony. Startle reactivity was inhibited by (56)Fe radiation but not by (28)Si particles. Apomorphine (3 mg/kg) produced a general inhibition of startle reactivity while haloperidol (1 mg/kg) facilitated it. Apomorphine disrupted prepulse inhibition, but only in animals which were not exposed to radiation. Both (56)Fe and (28)Si radiation exposure attenuated the disruption of prepulse inhibition induced by apomorphine. In contrast, the facilitation of prepulse inhibition induced by haloperidol was not modified by radiation. These data are consistent with a short-latency disruption of dopaminergic systems by HZE particle radiation. We speculate that this disruption may occur as a restriction in the capacity of the dopaminergic system.

Properties of short-term synaptic depression at larval neuromuscular synapses in wild-type and temperature-sensitive paralytic mutants of Drosophila.

The larval neuromuscular synapse of Drosophila serves as an important model for genetic and molecular analysis of synaptic development and function. Further functional characterization of this synapse, as well as adult neuromuscular synapses, will greatly enhance the impact of this model system on our understanding of synaptic transmission. Here we describe a form of short-term synaptic depression observed at larval, but not adult, neuromuscular synapses and explore the underlying mechanisms. Larval neuromuscular synapses exhibited a form of short-term depression that was strongly dependent on stimulation frequency over a narrow range of low frequencies (0.1-1 Hz). This form of synaptic depression, referred to here as low-frequency short-term depression (LF-STD), results from an activity-dependent reduction in neurotransmitter release. However, in contrast to the predictions of depletion models, the degree of depression was independent of the initial level of neurotransmitter release over a range of extracellular calcium concentrations. This conclusion was confirmed in two temperature-sensitive (TS) paralytic mutants, cacophony and shibire, which exhibit reduced neurotransmitter release resulting from conditional disruption of presynaptic calcium channels and dynamin, respectively. Higher stimulation frequencies (40 or 60 Hz) produced two components of depression that appeared to include LF-STD as well as a more conventional component of short-term depression. These findings reveal novel properties of short-term synaptic depression and suggest that complementary genetic analysis of larval and adult neuromuscular synapses will further define the in vivo mechanisms of neurotransmitter release and short-term synaptic plasticity.

Modeling the effects of transcranial magnetic stimulation on cortical circuits.

Transcranial magnetic stimulation (TMS) is commonly used to activate or inactivate specific cortical areas in a noninvasive manner. Because of technical constraints, the precise effects of TMS on cortical circuits are difficult to assess experimentally. Here, this issue is investigated by constructing a detailed model of a portion of the thalamocortical system and examining the effects of the simulated delivery of a TMS pulse. The model, which incorporates a large number of physiological and anatomical constraints, includes 33,000 spiking neurons arranged in a 3-layered motor cortex and over 5 million intra- and interlayer synaptic connections. The model was validated by reproducing several results from the experimental literature. These include the frequency, timing, dose response, and pharmacological modulation of epidurally recorded responses to TMS (the so-called I-waves), as well as paired-pulse response curves consistent with data from several experimental studies. The modeled responses to simulated TMS pulses in different experimental paradigms provide a detailed, self-consistent account of the neural and synaptic activities evoked by TMS within prototypical cortical circuits.

Inhibition of the central extended amygdala by loud noise and restraint stress.

It is well established that the central nucleus of the amygdala (CEA) is involved in responses to stress, fear and anxiety. Many studies have used c-fos expression to map the brain's response to processive stress, but curiously the CEA generally is not highly activated. We have previously shown that exposure to a novel vs. home environment reduces amphetamine-induced activation of the lateral CEA (CEAl) and the oval nucleus of the bed nucleus of the stria terminalis (BSTov). This is consistent with the idea that processive stress inhibits neurons in these nuclei. We have tested this hypothesis by exposing rats to noise, at a range of intensities from non-stressful to stressful, or to restraint conditions, immediately after a remote injection of amphetamine, 2 mg/kg i.p., or interleukin-1beta (IL-1beta) 0.5 microg/kg i.p. (used to obtain a level of c-fos mRNA against which to measure inhibition). In keeping with our hypothesis, amphetamine- or IL-1beta-induced c-fos and zif-268 mRNA were significantly decreased in the CEAl and BSTov under conditions of loud noise or restraint stress compared with control conditions. This inhibition does not require a stress-induced rise in corticosterone because data were similar in animals that had been adrenalectomized with a low-dose corticosterone replacement. As both the CEAl and BSTov are highly gamma-aminobutyric acid (GABA) -ergic and project to the medial CEA (CEAm), their inhibition potentially causes an increased input to the CEAm. As the CEAm is a major output nucleus of the amygdala, this could have important consequences within the neural circuitry controlling responses to processive stress.

Role of GABAergic inhibition in the coding of interaural time differences of low-frequency sounds in the inferior colliculus.

A major cue for the localization of sound in space is the interaural time difference (ITD). We examined the role of inhibition in the shaping of ITD responses in the inferior colliculus (IC) by iontophoretically ejecting gamma-aminobutyric acid (GABA) antagonists and GABA itself using a multibarrel pipette. The GABA antagonists block inhibition, whereas the applied GABA provides a constant level of inhibition. The effects on ITD responses were evaluated before, during and after the application of the drugs. If GABA-mediated inhibition is involved in shaping ITD tuning in IC neurons, then applying additional amounts of this inhibitory transmitter should alter ITD tuning. Indeed, for almost all neurons tested, applying GABA reduced the firing rate and consequently sharpened ITD tuning. Conversely, blocking GABA-mediated inhibition increased the activity of IC neurons, often reduced the signal-to-noise ratio and often broadened ITD tuning. Blocking GABA could also alter the shape of the ITD function and shift its peak suggesting that the role of inhibition is multifaceted. These effects indicate that GABAergic inhibition at the level of the IC is important for ITD coding.

Acupuncture-mediated inhibition of ethanol-induced dopamine release in the rat nucleus accumbens through the GABAB receptor.

Clinical trials are currently underway to determine the effectiveness of acupuncture in the treatment of drug abuse. However, there are still many unanswered questions about the basic mechanisms of acupuncture. Studies have shown that the GABA(B) receptor system may play a significant modulatory role in the mesolimbic system in drug abuse, including ethanol. The in vivo microdialysis study was designed to investigate the effect of acupuncture on acute ethanol-induced dopamine release in the nucleus accumbens and the potential role of the GABA(B) receptor system in acupuncture. Male Sprague-Dawley rats were administered with the highly selective GABA(B) antagonist SCH 50911 (3 mg/kg, i.p.) 1h prior to an intraperitoneal injection of ethanol (1 g/kg). Immediately after ethanol treatment, acupuncture was given at bilateral Shenmen (HT7) points for 1min. Acupuncture at the specific acupoint HT7, but not at control points (PC6 or tail) significantly decreased dopamine release in the nucleus accumbens. Inhibition of dopamine release by acupuncture was completely prevented by SCH 50911. These results suggest that stimulation of specific acupoints inhibits ethanol-induced dopamine release by modulating GABA(B) activity and imply that acupuncture may be effective in blocking the reinforcing effects of ethanol.

All talk and no action: a transcranial magnetic stimulation study of motor cortex activation during action word production.

A number of researchers have proposed that the premotor and motor areas are critical for the representation of words that refer to actions, but not objects. Recent evidence against this hypothesis indicates that the left premotor cortex is more sensitive to grammatical differences than to conceptual differences between words. However, it may still be the case that other anterior motor regions are engaged in processing a word's sensorimotor features. In the present study, we used single- and paired-pulse transcranial magnetic stimulation to test the hypothesis that left primary motor cortex is activated during the retrieval of words (nouns and verbs) associated with specific actions. We found that activation in the motor cortex increased for action words compared with non-action words, but was not sensitive to the grammatical category of the word being produced. These results complement previous findings and support the notion that producing a word activates some brain regions relevant to the sensorimotor properties associated with that word regardless of its grammatical category.

Effects of prolonged exposure to an augmented acoustic environment on the auditory system of middle-aged C57BL/6J mice: cochlear and central histology and sex differences.

Genetic progressive sensorineural hearing loss in mice of the C57BL/6J (B6) inbred strain begins at high frequencies during young adulthood and is severe by 12 months (middle age). Nightly treatment with an augmented acoustic environment (AAE)--12-hour periods of exposure to repetitive noise bursts of moderate intensity, begun at age 25 days--resulted in less severe hearing loss compared with control mice. Cochlear histopathological correlates of AAE treatment, assessed at 12-14 months of age, included lessened severity of progressive loss of outer hair cells in both sexes as well as small savings of spiral ganglion cells in females and inner hair cells in males. AAE effects on the number of surviving neurons (age 12-14 months) in the anterior ventral cochlear nucleus (AVCN) depended on sex. Compared with controls, the loss of AVCN neurons that typically accompanies the initial period of hearing loss (between 2 and 7 months of age) was not significantly affected by AAE treatment in females. In contrast, males treated with the AAE exhibited more severe loss of neurons in the dorsal and ventral extremes of the AVCN than male controls of the same age. AAE treatment begun at age 3-5 months resulted in significant but less severe loss of AVCN neurons in 1-year-old male mice.

Slow repetitive transcranial magnetic stimulation increases somatosensory high-frequency oscillations in humans.

Repetitive transcranial magnetic stimulation (rTMS) has been proposed as a possible treatment for psychiatric and neurological disorders characterized by focal brain excitability, such as major depression and action myoclonus. However, the mechanism of modulating excitability by rTMS is unclear. We examined the changes in high frequency oscillations (HFOs) of somatosensory evoked potentials (SEPs) before and after slow rTMS over the right primary somatosensory cortex (0.5 Hz, 50 pulses, 80% motor threshold intensity). The HFOs, which represent a localized activity of intracortical inhibitory interneurons, were significantly increased after slow rTMS, while the SEPs were not changed. Our results suggest that slow rTMS affects cortical excitability by modulating the activity of the intracortical inhibitory interneurons beyond the time of the stimulation and that rTMS may have therapeutic effects on such disorders.