Journal of Neurophysiology

Sah, Pankaj

doi: 10.1152/jn.01259.2005pmid: 16551839

Hargreaves, Kenneth M.

doi: 10.1152/jn.00031.2006pmid: 16551840

Finnegan, Thomas F.; Chen, Shao-Rui; Pan, Hui-Lin

doi: 10.1152/jn.01004.2005pmid: 16306173

The basolateral amygdala (BLA) is the major amygdaloid nucleus distributed with µ opioid receptors. The afferent input from the BLA to the central nucleus of the amygdala (CeA) is considered important for opioid analgesia. However, little is known about the effect of µ opioids on synaptic transmission in the BLA. In this study, we examined the effect of µ opioid receptor stimulation on the inhibitory and excitatory synaptic inputs to CeA-projecting BLA neurons. BLA neurons were retrogradely labeled with a fluorescent tracer injected into the CeA of rats. Whole cell voltage-clamp recordings were performed on labeled BLA neurons in brain slices. The specific µ opioid receptor agonist, ( D -Ala 2 , N -Me-Phe 4 ,Gly 5 -ol)-enkephalin (DAMGO, 1 µM), significantly reduced the frequency of miniature inhibitory postsynaptic currents (mIPSCs) in 77% of cells tested. DAMGO also significantly decreased the peak amplitude of evoked IPSCs in 75% of cells examined. However, DAMGO did not significantly alter the frequency of mEPSCs or the peak amplitude of evoked EPSCs in 90% and 75% of labeled cells, respectively. Bath application of the Kv channel blockers, 4-AP (Kv1.1, 1.2, 1.3, 1.5, 1.6, 3.1, 3.2), α-dendrotoxin (Kv1.1, 1.2, 1.6), dendrotoxin-K (Kv1.1), or tityustoxin-Kα (Kv1.2) each blocked the inhibitory effect of DAMGO on mIPSCs. Double immunofluorescence labeling showed that some of the immunoreactivities of Kv1.1 and Kv1.2 were colocalized with synaptophysin in the BLA. This study provides new information that activation of presynaptic µ opioid receptors primarily attenuates GABAergic synaptic inputs to CeA-projecting neurons in the BLA through a signaling mechanism involving Kv1.1 and Kv1.2 channels. Address for reprint requests and other correspondence: Hui-Lin Pan, Department of Anesthesiology and Pain Medicine, University of Texas, M.D. Anderson Cancer Center, 1400 Holcombe Blvd., Unit 409, Houston, TX 77030

Tian, Jun-ru; Mokuno, Eriko; Demer, Joseph L.

doi: 10.1152/jn.00635.2005pmid: 16551841

The linear vestibulo-ocular reflex (LVOR) to surge (fore-aft) translation has complex kinematics varying with target eccentricity and distance. To determine normal responses and aging changes, 9 younger age, 28 ± 2 (SE) yr and 11 older subjects (age, 69 ± 2 yr) underwent 0.5 g whole body surge transients while wearing binocular scleral search coils. Linear chair position and head acceleration were measured with a potentiometer and accelerometer. Subjects viewed centered and 10° horizontally and vertically eccentric targets 50, 25, or 15 cm distant before unpredictable onset of randomly directed surge in darkness (LVOR) and light (V-LVOR). Response directions were kinematically appropriate to eccentricity in all subjects, but there were significantly more measurable LVOR and V-LVOR responses (63–79%) in younger than older subjects (38–44%, P < 0.01). Minimal LVOR latency averaged 48 ± 4 ms for younger and significantly longer at 70 ± 6 ms for older subjects. In the interval 200–300 ms after surge onset, horizontal LVOR gain (relative to ideal velocity) of younger subjects averaged over all target distances was 0.55 ± 0.04 and was significantly reduced in older subjects to 0.33 ± 0.04. Horizontal V-LVOR gain was 0.58 ± 0.04 in younger and significantly lower at 0.35 ± 0.06 in older subjects. Vertical gains did not differ significantly between groups. Target visibility had no effect in either group during the initial 200 ms. The LVOR and V-LVOR were augmented by saccades in younger more than older subjects. Aging thus decreases LVOR velocity gain, response rate, and saccade augmentation, but prolongs latency. Address for reprint requests and other correspondence: J.-R. Tian, Jules Stein Eye Inst., 100 Stein Plaza, UCLA, Los Angeles, CA 90095-7002 (E-mail: [email protected] )

Tamakawa, Yuichi; Karashima, Akihiro; Koyama, Yoshimasa; Katayama, Norihiro; Nakao, Mitsuyuki

doi: 10.1152/jn.00575.2005pmid: 16282204

Physiological knowledge of the neural mechanisms regulating sleep and wakefulness has been advanced by the recent findings concerning sleep/wakefulness-related preoptic/anterior hypothalamic and perifornical (orexin-containing)/posterior hypothalamic neurons. In this paper, we propose a mathematical model of the mechanisms orchestrating a quartet neural system of sleep and wakefulness composed of the following: 1 ) sleep-active preoptic/anterior hypothalamic neurons (N-R group); 2 ) wake-active hypothalamic and brain stem neurons exhibiting the highest rate of discharge during wakefulness and the lowest rate of discharge during paradoxical or rapid eye movement (REM) sleep (WA group); 3 ) brain stem neurons exhibiting the highest rate of discharge during REM sleep (REM group); and 4 ) basal forebrain, hypothalamic, and brain stem neurons exhibiting a higher rate of discharge during both wakefulness and REM sleep than during nonrapid eye movement (NREM) sleep (W-R group). The WA neurons have mutual inhibitory couplings with the REM and N-R neurons. The W-R neurons have mutual excitatory couplings with the WA and REM neurons. The REM neurons receive unidirectional inhibition from the N-R neurons. In addition, the N-R neurons are activated by two types of sleep-promoting substances (SPS), which play different roles in the homeostatic regulation of sleep and wakefulness. The model well reproduces the actual sleep and wakefulness patterns of rats in addition to the sleep-related neuronal activities across state transitions. In addition, human sleep-wakefulness rhythms can be simulated by manipulating only a few model parameters: inhibitions from the N-R neurons to the REM and WA neurons are enhanced, and circadian regulation of the N-R and WA neurons is exaggerated. Our model could provide a novel framework for the quantitative understanding of the mechanisms regulating sleep and wakefulness. Address for reprint requests and other correspondence: M. Nakao, Graduate School of Information Sciences, Tohoku Univ., Aobayama 6-3-09, Sendai 980-8579, Japan (E-mail: [email protected] )

Viemari, Jean-Charles; Ramirez, Jan-Marino

doi: 10.1152/jn.01308.2005pmid: 16394066

Pacemakers are found throughout the mammalian CNS. Yet, it remains largely unknown how these neurons contribute to network activity. Here we show that for the respiratory network isolated in transverse slices of mice, different functions can be assigned to different types of pacemakers and nonpacemakers. This difference becomes evident in response to norepinephrine (NE). Although NE depolarized 88% of synaptically isolated inspiratory neurons, this neuromodulator had differential effects on different neuron types. NE increased in cadmium-insensitive pacemakers burst frequency, not burst area and duration, and it increased in cadmium-sensitive pacemakers burst duration and area, but not frequency. NE also differentially modulated nonpacemakers. Two types of nonpacemakers were identified: "silent nonpacemakers" stop spiking, whereas "active nonpacemakers" spontaneously spike when isolated from the network. NE selectively induced cadmium-sensitive pacemaker properties in active, but not silent, nonpacemakers. Flufenamic acid (FFA), a blocker of I CAN , blocked the induction as well as modulation of cadmium-sensitive pacemaker activity, and blocked at the network level the NE-induced increase in burst area and duration of inspiratory network activity; the frequency modulation (FM) was unaffected. We therefore propose that modulation of cadmium-sensitive pacemaker activity contributes at the network level to changes in burst shape, not frequency. Riluzole blocked the FM of isolated cadmium-insensitive pacemakers. In the presence of riluzole, NE caused disorganized network activity, suggesting that cadmium-insensitive pacemakers are critical for rhythm generation. We conclude that different types of nonpacemaker and pacemaker neurons differentially control different aspects of the respiratory rhythm. Address for reprint requests and other correspondence: J.-C. Viemari, Department of Organismal Biology and Anatomy, The University of Chicago, 1027 East 57th Street, Chicago, IL 60637 (E-mail: [email protected] )

Wenk, Heather N.; Brederson, Jill-Desiree; Honda, Christopher N.

doi: 10.1152/jn.00394.2005pmid: 16339007

Peripherally delivered opiates attenuate mechanical and thermal hyperalgesia in experimental models of inflammation, suggesting that activation of peripheral opioid receptors decreases the excitability of nociceptors in inflamed tissues. The current study examines the effects of peripheral morphine sulfate on response properties of sensory neurons in healthy and inflamed skin. Afferent units (185) were isolated from tibial nerve of rats using an in vitro glabrous skin-nerve teased-fiber preparation. Of these, 107 units were from normal healthy skin, and 78 were from inflamed skin 18 h after intraplantar injection of complete Freund's adjuvant. As a population, C-fiber units innervating inflamed skin exhibited properties characteristic of sensitization when compared with units innervating healthy control skin. Mechanical thresholds were lowered, responses to noxious mechanical and thermal stimuli were elevated, a greater proportion of units was spontaneously active, and the average rate of spontaneous discharge was higher. Response properties in other conduction velocity groups remained unchanged. Fifty-eight percent of C and C/Aδ nociceptors innervating inflamed skin were opiate-sensitive, and their excitability was attenuated by direct application of morphine to their receptive fields. All morphine-sensitive units were nociceptors from inflamed skin with conduction velocities <1.3 m/s. Morphine effects were concentration-dependent and naloxone-sensitive, indicating that the effects were receptor-mediated. These findings provide direct evidence that morphine acts through peripheral opioid receptors to inhibit the activity of cutaneous nociceptors under conditions of inflammation. Address for reprint requests and other correspondence: C. N. Honda, Neuroscience Department, 6-145 Jackson Hall, 321 Church Street S.E., University of Minnesota, Minneapolis, MN 55455 (E-mail: [email protected] )

Ma, C.; Greenquist, K. W.; LaMotte, R. H.

doi: 10.1152/jn.00748.2005pmid: 16381809

A laterally herniated disk, spinal stenosis, and various degenerative or traumatic diseases of the spine can sometimes lead to a chronic compression and inflammation of the dorsal root ganglion and chronic abnormal sensations including pain. After a chronic compression of the dorsal root ganglion (CCD) in rats, the somata in the dorsal root ganglion (DRG) become hyperexcitable, and some exhibit ectopic, spontaneous activity (SA). Inflammatory mediators have a potential role in modulating the excitability of DRG neurons and therefore may contribute to the neuronal hyperexcitability after CCD. In this study, an inflammatory soup (IS) consisting of bradykinin, serotonin, prostaglandin E 2 , and histamine (each 10 –6 M) was applied topically to the DRG. The responses of DRG neurons were electrophysiologically recorded extracellularly from teased dorsal root fibers or intracellularly from the somata in the intact DRG or from dissociated neurons within 30 h of culture. In all three preparations, IS remarkably increased the discharge rates of SA CCD neurons and evoked discharges in more silent-CCD than control neurons. IS slightly depolarized the resting membrane potential and decreased the current and voltage thresholds of action potential in both intact and dissociated neurons, although the magnitude of depolarization or decrease in action potential threshold was not significantly different between CCD and control. IS-evoked responses were found in a proportion of neurons in each size category including those with and without nociceptive properties. Inflammatory mediators, by increasing the excitability of DRG somata, may contribute to CCD-induced neuronal hyperexcitability and to hyperalgesia and tactile allodynia. Address for reprint requests and other correspondence: *Corresponding author: Robert H. LaMotte, Department of Anesthesiology, Yale University School of Medicine, New Haven, CT 06510; Telephone: 203-737-2720; FAX: 203-737-5220; Email: [email protected]

André, Véronique M.; Cepeda, Carlos; Venegas, Angela; Gomez, Yeranui; Levine, Michael S.

doi: 10.1152/jn.01118.2005pmid: 16381805

Alterations in pyramidal neurons from the sensorimotor cortex may be responsible for some of the cognitive and motor symptoms of Huntington's disease (HD). The present experiments used R6/2 transgenic mice that express exon 1 of the human HD gene with an expanded number of CAG repeats. We characterized α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) currents and their modulation by cyclothiazide (CTZ) as well as N -methyl- D -aspartate (NMDA) currents and their Mg 2+ sensitivity in acutely dissociated cortical pyramidal neurons in R6/2 transgenic and wild-type (WT) mice at 21 days (before overt symptoms), 40 days (when symptoms begin), and 80 days (fully symptomatic). AMPA currents, alone or in the presence of CTZ, were smaller in 21- and 40-day-old R6/2 groups compared with WT mice. In R6/2 mice, more neurons displayed desensitizing AMPA currents in the presence of CTZ, indicating increased expression of "flop" splice variants, whereas the majority of WT cells expressed the "flip" variants of AMPA receptor subunits. NMDA peak currents also were smaller in R6/2 pyramidal neurons at 21 days. At 40 days, NMDA currents were similar in WT and R6/2 mice but Mg 2+ sensitivity was greater in R6/2 mice, resulting in smaller NMDA currents in the presence of Mg 2+ . Differences in AMPA and NMDA currents between WT and R6/2 cells were no longer detected at 80 days. Our findings indicate that currents induced by glutamate receptor agonists are decreased in isolated cortical pyramidal neurons from R6/2 mice and that this decrease occurs early. Altered glutamate receptor function could contribute to changes in cortical output and may underlie some of the cognitive and motor impairments in this animal model of HD. Address for reprint requests and other correspondence: V. M. André, Mental Retardation Research Center, NPI Room 58-258A, 760 Westwood Plaza, University of California, Los Angeles, CA 90095 (E-mail: [email protected] )

Wichmann, Thomas; Soares, Jesus

doi: 10.1152/jn.01013.2005pmid: 16371459

It is known that burst discharges in basal ganglia neurons are more common in parkinsonism than under normal conditions, but changes in the structure of burst or peri-burst epochs have not been reported. In this study, the temporal structure of bursts and the timing of neuronal discharges that precede or follow them were examined in neuronal spike trains recorded in the subthalamic nucleus (STN) and the external and internal pallidal segment (GPe, GPi) in two awake Rhesus monkeys before and after they were rendered hemiparkinsonian by unilateral intracarotid infusion of the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Bursts were detected by the "surprise" method. In the normal state, interspike intervals (ISIs) preceding or following bursts were frequently significantly longer than the average baseline ISI, and their duration was correlated with the burst length (i.e., the number of spikes/burst). Significant correlations were also found in all three structures between the burst length and the duration of interburst intervals. The incidence of burst discharges and the proportion of time spent in bursts increased in GPe, STN, and GPi after MPTP treatment. Burst lengths became more tightly related to preburst ISIs in the STN after MPTP treatment and to postburst ISI duration in all three structures. These results show that bursts in spontaneous GPe, STN, and GPi discharge are often preceded or followed by long ISIs, and that burst length, the length of pre- and postburst ISIs, and the length of interburst intervals are related to one another. Complex changes in these interactions may contribute to abnormal information processing in parkinsonism. Address for reprint requests and other correspondence: T. Wichmann, Dept. of Neurology and Yerkes National Primate Ctr., Emory Univ., School of Medicine, 954 Gatewood Dr., NE, Atlanta, GA 30322 (E-mail: [email protected] )