Spontaneous Single Unit Activity Research Articles

P279 Distribution of single unit activity patterns in subthalamic nucleus of Parkinsonian patients

Objectives Subthalamic nucleus (STN) is the main target for surgery treatment of Parkinson’s disease (PD) patients. The aim of the study was to characterize spontaneous single unit activity in subthalamic nucleus of PD patients and to search for the possible correlations between characteristics of neuronal activity and clinical phenotype. Methods We have analyzed single unit activity of 493 cells registered in subthalamic nucleus of 9 patients (3 males and 6 females) with PD (56.8 ± 4.8 yrs, UPDRS III score in off-state 52.0 ± 12.2), that were undergoing bilateral DBS surgery at Burdenko Neurosurgery Center in 2015–2017. For each neuron we determined several characteristics: firing rate, coefficient of variation (CV), mean and median interspike interval (ISI), asymmetry index (AI), burst characteristics. We also have performed spectral analysis of oscillations in the spiketrains. Results We have identified three different patterns of neuronal activity: tonic regular activity (AI > 0.7, CV 0.7, CV > 0.85)? in 5–25% of neurons, burst-like activity (AI Significance The unevenness of neuronal activity patterns and oscillations of STN could be used for choosing optimal location of DBS electrodes in PD patients.

Transition from Initial Hypoactivity to Hyperactivity in Cortical Layer V Pyramidal Neurons after Traumatic Brain Injury In Vivo.

Traumatic brain injury (TBI) often results in structural damage and a loss of neurons that is commonly accompanied by early changes in neuronal electrical activity. Loss of neuronal activity has been hypothesized to contribute to post-traumatic epileptogenesis through the regulation of homeostatic plasticity. The existence of activity loss in cortical neurons after TBI and its subsequent transition into hyperactivity over time is not well characterized, however, particularly in models of TBI in vivo. In the current study, changes in neuronal activity in the primary motor cortex after moderate controlled cortical impact (CCI) in mice were studied using a single-unit recording technique in vivo. Recordings were made at different time points after CCI from cortical layer V pyramidal neurons that were within 1-2 mm from the anterior edge of the injured foci. Within 1-4 h after CCI, the frequency of spontaneous single-unit activity depressed significantly, with the mean firing frequency decreasing from 2.59 ± 0.18 Hz in the sham group to 1.05 ± 0.20 Hz of the injured group. The firing frequencies recovered to the normal level at 1 day and 7 days post-CCI, but became significantly higher at 3 days and 14 days post-CCI. The results suggest that TBI caused initial loss of activity in neurons of the perilesional cortical region, which was followed by compensatory recovery and enhancement of activity. These time-dependent changes in neuronal activity may contribute to the development of hyperexcitability through homeostatic activity regulation.

Noradrenergic blockade stabilizes prefrontal activity and enables fear extinction under stress

Stress-induced impairments in extinction learning are believed to sustain posttraumatic stress disorder (PTSD). Noradrenergic signaling may contribute to extinction impairments by modulating medial prefrontal cortex (mPFC) circuits involved in fear regulation. Here we demonstrate that aversive fear conditioning rapidly and persistently alters spontaneous single-unit activity in the prelimbic and infralimbic subdivisions of the mPFC in behaving rats. These conditioning-induced changes in mPFC firing were mitigated by systemic administration of propranolol (10 mg/kg, i.p.), a β-noradrenergic receptor antagonist. Moreover, propranolol administration dampened the stress-induced impairment in extinction observed when extinction training is delivered shortly after fear conditioning. These findings suggest that β-adrenoceptors mediate stress-induced changes in mPFC spike firing that contribute to extinction impairments. Propranolol may be a helpful adjunct to behavioral therapy for PTSD, particularly in patients who have recently experienced trauma.

The Source of Spontaneous Activity in the Main Olfactory Bulb of the Rat

Introduction In vivo, most neurons in the main olfactory bulb exhibit robust spontaneous activity. This paper tests the hypothesis that spontaneous activity in olfactory receptor neurons drives much of the spontaneous activity in mitral and tufted cells via excitatory synapses.MethodsSingle units were recorded in vivo from the main olfactory bulb of a rat before, during, and after application of lidocaine to the olfactory nerve. The effect of lidocaine on the conduction of action potentials from the olfactory epithelium to the olfactory bulb was assessed by electrically stimulating the olfactory nerve rostral to the application site and monitoring the field potential evoked in the bulb.ResultsLidocaine caused a significant decrease in the amplitude of the olfactory nerve evoked field potential that was recorded in the olfactory bulb. By contrast, the lidocaine block did not significantly alter the spontaneous activity of single units in the bulb, nor did it alter the field potential evoked by electrical stimulation of the lateral olfactory tract. Lidocaine block also did not change the temporal patters of action potential or their synchronization with respiration.ConclusionsSpontaneous activity in neurons of the main olfactory bulb is not driven mainly by activity in olfactory receptor neurons despite the extensive convergence onto mitral and tufted cells. These results suggest that spontaneous activity of mitral and tufted is either an inherent property of these cells or is driven by centrifugal inputs to the bulb.

Detection and localization of multiple rate changes in Poisson spike trains

In statistical spike train analysis, stochastic point process models usually assume stationarity, in particular that the underlying spike train shows a constant firing rate (e.g. [1]). However, such models can lead to misinterpretation of the associated tests if the assumption of rate stationarity is not met (e.g. [2]). Therefore, the analysis of nonstationary data requires that rate changes can be located as precisely as possible. However, present statistical methods focus on rejecting the null hypothesis of stationarity without explicitly locating the change point(s) (e.g. [3]). We propose a test for stationarity of a given spike train that can also be used to estimate the change points in the firing rate. Assuming a Poisson process with piecewise constant firing rate, we propose a Step-Filter-Test (SFT) which can work simultaneously in different time scales, accounting for the high variety of firing patterns in experimental spike trains. Formally, we compare the numbers N1=N1(t,h) and N2=N2(t,h) of spikes in the time intervals (t-h,t] and (h,t+h]. By varying t within a fine time lattice and simultaneously varying the interval length h, we obtain a multivariate statistic D(h,t):=(N1-N2)/√(N1+N2), for which we prove asymptotic multivariate normality under homogeneity. From this a practical, graphical device to spot changes of the firing rate is constructed. Our graphical representation of D(h,t) (Figure ​(Figure1A)1A) visualizes the changes in the firing rate. For the statistical test, a threshold K is chosen such that under homogeneity, |D(h,t)|<K holds for all investigated h and t with probability 0.95. This threshold can indicate potential change points in order to estimate the inhomogeneous rate profile (Figure ​(Figure1B).1B). The SFT is applied to a sample data set of spontaneous single unit activity recorded from the substantia nigra of anesthetized mice. In this data set, multiple rate changes are identified which agree closely with visual inspection. In contrast to approaches choosing one fixed kernel width [4], our method has advantages in the flexibility of h. Figure 1 Graphical representation of the step filter test (SFT) that detects rate changes in Poisson spike trains. A. Curves indicate values of D(h,t) as a function of time t for different window sizes h (in different colors). B. Rate histogram (grey) of the corresponding ...

An ex vivo Multi-Electrode Approach to Evaluate Endogenous Hormones and Receptor Subtype Pharmacology on Evoked and Spontaneous Neuronal Activity within the Ventromedial Hypothalamus; Translation from Female Receptivity

The ventromedial hypothalamus (VMH) controls female rodent copulatory behavior, which can be modulated by injection of various compounds into the VMH. Aim. The aim was to determine whether evoked excitatory postsynaptic potentials (EPSPs) or single-unit activity within the VMH ex vivo is a better parameter to predict lordosis. VMH slices were placed onto a 64 microelectrode chip and spontaneous single-unit activity was recorded or slices stimulated to evoke EPSPs. The sodium channel blocker, tetrodotoxin and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate antagonist, 6,7-dinitroquinoxaline-2,3-dione (DNQX) inhibited EPSPs, confirming EPSPs were glutamatergic in origin. The GABA(A) antagonist bicuculline potentiated EPSPs implying endogenous GABA tone. Single-unit activity was abolished by tetrodotoxin but unaffected by DNQX or bicuculline. Glutamatergic neurotransmission was greatest during metestrous and following ovariectomization. The number of regions within the VMH eliciting single-unit activity was reduced following ovariectomy without changing spike frequency. Adrenergic agents increasing lordosis via the VMH in vivo, decreased glutamate neurotransmission but increased single-unit activity. Conversely, agents decreasing lordosis via the VMH increased glutamatergic neurotransmission and inhibited single-unit activity (8-OH-DPAT, [D-Ala(2), N-Me-Phe(4), Gly-ol(5)]-enkephalin, corticotropin releasing factor, bicuculline). Melanocortin and pituitary adenylate cyclase-activating polypeptide agonists had no effect. Here we present a novel, robust VMH in vitro technique that (i) is consistent with the hypothesis that glutamate via non-NMDA receptors inhibits lordosis; (ii) glutamate is under the endogenous tone of GABA and steroid hormones; (iii) inhibition of lordosis during metestrous and following ovariectomy potentiates glutamatergic neurotransmission; (iv) activation of G(q)- and G(i)-coupled receptors decreases and increases glutamate neurotransmission, respectively, with an inverse correlation on single-unit activity; (v) activation of G(s)-coupled receptors has no direct effect on glutamate or single-unit activity; and (vi) potency, receptor subtypes and localization can be determined prior to in vivo studies.

Neonatal Cerebral Hypoxia–Ischemia Impairs Plasticity in Rat Visual Cortex

Ocular dominance plasticity (ODP) following monocular deprivation (MD) is a model of activity-dependent neural plasticity that is restricted to an early critical period regulated by maturation of inhibition. Unique developmental plasticity mechanisms may improve outcomes following early brain injury. Our objective was to determine the effects of neonatal cerebral hypoxia-ischemia (HI) on ODP. The rationale extends from observations that neonatal HI results in death of subplate neurons, a transient population known to influence development of inhibition. In rodents subjected to neonatal HI and controls, maps of visual response were derived from optical imaging during the critical period for ODP and changes in the balance of eye-specific response following MD were measured. In controls, MD results in a shift of the ocular dominance index (ODI) from a baseline of 0.15 to -0.10 (p < 0.001). Neonatal HI with moderate cortical injury impairs this shift, ODI = 0.14 (p < 0.01). Plasticity was intact in animals with mild injury and in those exposed to hypoxia alone. Neonatal HI resulted in decreased parvalbumin expression in hemispheres receiving HI compared with hypoxia alone: 23.4 versus 35.0 cells/high-power field (p = 0.01), with no change in other markers of inhibitory or excitatory neurons. Despite abnormal inhibitory neuron phenotype, spontaneous activity of single units and development of orientation selective responses were intact following neonatal HI, while overall visual responses were reduced. Our data suggest that specific plasticity mechanisms are impaired following early brain injury and that the impairment is associated with altered inhibitory neuronal development and cortical activation.

Kindling changes burst firing, neural synchrony and tonotopic organization of cat primary auditory cortex.

The effect of electrical kindling, applied twice daily in primary auditory cortex on the neural response properties and tonotopic organization in the lightly ketamine anesthetized cat is presented. Kindling refers to a highly persistent modification of brain functioning in response to repeated application of initially sub-convulsant electrical stimulation, typically in the limbic system but here in auditory cortex, which results in the development of epileptiform activity. Kindling resulted in approximately two-thirds of the animals reaching a fully generalized state in 40 stimulation sessions. Multi-unit recordings were obtained from primary auditory cortex contralateral to the kindled site. Spontaneous activity of single units in fully kindled animals showed a decrease in the mean firing rate compared to sham controls, and a reduction in the rate of burst firing as well as in the mean interspike interval in a burst as compared with normal and sham controls. A 40% enhancement of spontaneous neural synchrony, as measured by spike cross-correlation, was found. Hearing sensitivity, measured by auditory brainstem response, was not affected by the kindling sessions. A profound alteration of the tonotopic map in AI was observed with a large extent becoming tuned to similar high characteristic frequencies. The percentage of double tuned neurons was significantly increased, nevertheless the frequency-tuning curve bandwidth was on average reduced. Thus, electrical kindling resulted in substantial alterations in unit firing characteristics and reorganization of cat auditory cortex.

Fetal Striatal Transplants Restore Electrophysiological Sensitivity to Dopamine in the Lesioned Striatum of Rats with Experimental Huntington’s Disease

Dopamine (DA), a major neurotransmitter used in the striatum, is involved in movement disorders such as Parkinson’s disease and Huntington’s chorea. With the loss of neurons in the striatum of patients with Huntington’s disease (HD), there is an associated downregulation of DA receptors, which may alter DA-mediated responses. In the present study, DA-mediated electrophysiological depression was studied in animals with quinolinic acid (QA)-induced experimental HD. QA was directly applied to the right striatum of adult female Sprague-Dawley rats. Animals receiving QA developed ipsilateral rotation after the application of apomorphine. Fetal striatal tissue transplants grafted 1 month after lesioning attenuated apomorphine-induced rotation. Six months after lesioning, the animals were anesthetized with urethane for electrophysiological study. DA, applied directly to neurons by pressure microejection, inhibited spontaneous single-unit activity in the striatal neurons of nonlesioned, lesioned and lesioned/grafted rats. QA lesioning reduced responses to DA in the striatal neurons. The dose of DA required to inhibit striatal neuron activity in the lesioned rats was significantly increased compared to that in the nonlesioned rats. Transplantation of fetal striatal tissue restored the electrophysiological sensitivity to DA in the lesioned striatum. The dose of DA used to suppress striatal neuron activity was reduced after grafting. Immunohistostaining showed survival of γ-aminobutyric acid neurons at the graft site. Tyrosine hydroxylase-positive terminals were found innervating the striatal grafts. In conclusion, our data demonstrate that fetal striatal transplants restore electrophysiological sensitivity to DA in the lesioned striatum of animals with experimental HD.

Fetal striatal transplants restore electrophysiological sensitivity to dopamine in the lesioned striatum of rats with experimental Huntington's disease.

Dopamine (DA), a major neurotransmitter used in the striatum, is involved in movement disorders such as Parkinson's disease and Huntington's chorea. With the loss of neurons in the striatum of patients with Huntington's disease (HD), there is an associated downregulation of DA receptors, which may alter DA-mediated responses. In the present study, DA-mediated electrophysiological depression was studied in animals with quinolinic acid (QA)-induced experimental HD. QA was directly applied to the right striatum of adult female Sprague-Dawley rats. Animals receiving QA developed ipsilateral rotation after the application of apomorphine. Fetal striatal tissue transplants grafted 1 month after lesioning attenuated apomorphine-induced rotation. Six months after lesioning, the animals were anesthetized with urethane for electrophysiological study. DA, applied directly to neurons by pressure microejection, inhibited spontaneous single-unit activity in the striatal neurons of nonlesioned, lesioned and lesioned/grafted rats. QA lesioning reduced responses to DA in the striatal neurons. The dose of DA required to inhibit striatal neuron activity in the lesioned rats was significantly increased compared to that in the nonlesioned rats. Transplantation of fetal striatal tissue restored the electrophysiological sensitivity to DA in the lesioned striatum. The dose of DA used to suppress striatal neuron activity was reduced after grafting. Immunohistostaining showed survival of gamma-aminobutyric acid neurons at the graft site. Tyrosine hydroxylase-positive terminals were found innervating the striatal grafts. In conclusion, our data demonstrate that fetal striatal transplants restore electrophysiological sensitivity to DA in the lesioned striatum of animals with experimental HD.

Ethanol Inhibits Spontaneous Activity of Central Nucleus of the Amygdala Neurons but Does Not Impair Retention in the Passive‐Avoidance Task

Behavioral studies using pharmacological manipulations that increase neuronal activity of the central nucleus of the amygdala (CeA) have implicated the CeA in enhancement of memory modulation. To date, however, there has been a dearth of studies investigating the effect of a drug that decreases CeA activity on memory modulation-a drug that inhibits the neuronal activity of the CeA might be expected to impair memory modulation. To determine whether ethanol inhibits CeA activity and, if so, whether decreased CeA activity is associated with impairment of memory modulation, this study investigated the effect of ethanol on spontaneous single-unit activity of CeA neurons and retention in the passive-avoidance task. The effect of ethanol (0.35, 0.75, 1.5, 2.5 g/kg) was determined on spontaneously firing neurons in the CeA in urethane-anesthetized rats by use of standard in vivo single-unit electrophysiological recording techniques. Additionally, the effect of ethanol when administered immediately after training in a standard passive-avoidance task was determined on retention the following day. Ethanol profoundly inhibited spontaneous CeA firing rates in urethane-anesthetized rats at all doses tested. Maximal inhibition was related to dose. Each dose of ethanol significantly inhibited CeA activity within 15 min of administration; within 35 min of administration, 0.75 g/kg of ethanol inhibited CeA activity by 65.2%, and the highest dose (2.5 g/kg) produced nearly complete suppression of CeA activity (81.3%). Although ethanol markedly inhibited CeA activity, these same doses of ethanol failed to impair retention in the passive-avoidance task: 0.35, 0.75, 1.5, and 2.5 g/kg of ethanol, administered immediately after training, failed to alter latency to step-through the following day. These results show that ethanol profoundly inhibits spontaneous CeA activity and suggest that inhibition of the CeA is not sufficient to impair retention in the passive-avoidance task.

Ethanol Inhibits Spontaneous Activity of Central Nucleus of the Amygdala Neurons but Does Not Impair Retention in the Passive-Avoidance Task

Background: Behavioral studies using pharmacological manipulations that increase neuronal activity of the central nucleus of the amygdala (CeA) have implicated the CeA in enhancement of memory modulation. To date, however, there has been a dearth of studies investigating the effect of a drug that decreases CeA activity on memory modulation—a drug that inhibits the neuronal activity of the CeA might be expected to impair memory modulation. To determine whether ethanol inhibits CeA activity and, if so, whether decreased CeA activity is associated with impairment of memory modulation, this study investigated the effect of ethanol on spontaneous single-unit activity of CeA neurons and retention in the passive-avoidance task. Methods: The effect of ethanol (0.35, 0.75, 1.5, 2.5 g/kg) was determined on spontaneously firing neurons in the CeA in urethane-anesthetized rats by use of standard in vivo single-unit electrophysiological recording techniques. Additionally, the effect of ethanol when administered immediately after training in a standard passive-avoidance task was determined on retention the following day. Results: Ethanol profoundly inhibited spontaneous CeA firing rates in urethane-anesthetized rats at all doses tested. Maximal inhibition was related to dose. Each dose of ethanol significantly inhibited CeA activity within 15 min of administration; within 35 min of administration, 0.75 g/kg of ethanol inhibited CeA activity by 65.2%, and the highest dose (2.5 g/kg) produced nearly complete suppression of CeA activity (81.3%). Although ethanol markedly inhibited CeA activity, these same doses of ethanol failed to impair retention in the passive-avoidance task: 0.35, 0.75, 1.5, and 2.5 g/kg of ethanol, administered immediately after training, failed to alter latency to step-through the following day. Conclusions: These results show that ethanol profoundly inhibits spontaneous CeA activity and suggest that inhibition of the CeA is not sufficient to impair retention in the passive-avoidance task.

Cellular responses of nucleus accumbens neurons to opiate-seeking behavior: I. Sustained responding during heroin self-administration.

The nucleus accumbens (NAcc) has been hypothesized to be a critical component of the circuit mediating opiate-seeking behaviors. To further explore the electrophysiological correlates of opiate-seeking behavior, we recorded neurons in the NAcc and in the medial prefrontal cortex (mPFC) of rats trained to self-administer heroin for at least 2 weeks. Rats were trained to lever press (FR-1 schedule) for an intravenous (i.v.) infusion of heroin (0.06 mg/kg/injection) in an operant chamber. Spontaneous single unit activity in the NAcc and the mPFC was then recorded while animals were allowed to self-administer heroin. Our data suggest that about 20% (8/42) of the NAcc neurons studied exhibited an inhibitory response immediately after heroin self-administration. However, most of the NAcc neurons studied (76%; 32/42) were not affected during heroin self-administration. In contrast, noncontingent injection of a similar dose of heroin (0.06 mg/kg/injection) had no effect on NAcc spontaneous activity (0/6). On the other hand, passive administration of higher doses of heroin (0.2-0.6/mg/kg/injection) markedly suppressed the firing rate in 46% (6/13) of the neurons studied. These effects of heroin on NAcc activity were antagonized by systemic administration ofnaloxone (4-6 mg/kg, i.v.). Studies characterizing the responses of mPFC neurons during heroin self-administration showed that 40% (2/5) of the neurons tested exhibited an inhibitory effect immediately after heroin self-administration. These data suggest that in animals well-trained to self-administer heroin, only a small number (20%) of the NAcc neurons studied responded to heroin self-administration. Further research is necessary to determine whether these responses are a function of the opiate-seeking state of the animal and the mechanism(s) responsible for these effects of heroin.

Alterations in spontaneous single unit activity of striatal subdivisions during ontogenesis in mutant dystonic hamsters

The pathophysiology of idiopathic dystonia, characterized by sustained twisting movements and postures, is still unknown. Clinically, however, the basal ganglia are thought to be the main causative origin of idiopathic dystonia. In the dt sz hamster, a genetic animal model for idiopathic paroxysmal dystonia, the attacks occur in response to mild stress and the severity of dystonia is age-dependent. Previous autoradiographic studies in the dt sz hamster revealed a decreased dopamine D1 and D2 receptor binding and an increased [ 3 H ]-2-deoxyglucose uptake in the dorsomedial caudate–putamen (CPu), a region supposed to be critically involved in dystonia. Therefore, we were interested whether the spontaneous firing rate of dorsomedial striatal neurons is age-dependently altered in comparison to age-matched non-dystonic control hamsters. Extracellular recordings of spontaneous single unit activity of dorsomedial and ventromedial Type II striatal neurons, i.e., biphasic positive–negative action potentials, from fentanyl anesthetized animals revealed a drastically increased firing rate in the dorsomedial CPu of mutants during age of maximum severity of dystonia. In post-dystonic dt sz hamsters, i.e., after remission of stress-inducible dystonia, no significant differences regarding the dorsomedial CPu could be obtained. We conclude that the dorsomedial subregion of the CPu seems to be critically involved in the dystonic syndrome of dt sz hamsters and that a transiently reduced inhibitory control over excitatory cortico-striatal processes, possibly due to an altered development of GABAergic inhibition, occurs during ontogenesis in dt sz hamsters.

Metabolic correlates of pallidal neuronal activity in Parkinson's disease.

We have used [18F]fluorodeoxyglucose and PET to identify specific metabolic covariance patterns associated with Parkinson's disease and related disorders previously. Nonetheless, the physiological correlates of these abnormal patterns are unknown. In this study we used PET to measure resting state glucose metabolism in 42 awake unmedicated Parkinson's disease patients prior to unilateral stereotaxic pallidotomy for relief of symptoms. Spontaneous single unit activity of the internal segment of the globus pallidus (GPi) was recorded intraoperatively in the same patients under identical conditions. The first 24 patients (Group A) were scanned on an intermediate resolution tomograph (full width at half maximum, 8 mm); the subsequent 18 patients (Group B) were scanned on a higher resolution tomograph (full width half maximum, 4.2 mm). We found significant positive correlations between GPi firing rates and thalamic glucose metabolism in both patient groups (Group A: r = 0.41, P < 0.05; Group B: r = 0.69, P < 0.005). In Group B, pixel-based analysis disclosed a significant focus of physiological-metabolic correlation involving the ventral thalamus and the GPi (statistical parametric map: P < 0.05, corrected). Regional covariance analysis demonstrated that internal pallidal neuronal activity correlated significantly (r = 0.65, P < 0.005) with the expression of a unique network characterized by covarying pallidothalamic and brainstem metabolic activity. Our findings suggest that the variability in pallidal neuronal firing rates in Parkinson's disease patients is associated with individual differences in the metabolic activity of efferent projection systems.

The auditory nerve in congenitally deaf white cats: Correlations between anatomy and electrophysiology

It is well known that cochlear pathology produces alterations in neurons of the cochlear nucleus, but there are few data that directly relate such neuronal changes to the physiology of auditory nerve fibers and structure of auditory nerve endings. These relationships are addressed in a naturally occurring model of deafness, the congenitally deaf white cat. Cats with no intact organ of Corti exhibited no measurable hearing thresholds and had severely reduced spontaneous activity in single auditory nerve fibers. Furthermore, there was structural atrophy of endbulbs of Held in the anteroventral cochlear nucleus, and hypertrophied synapses. These hypertrophied synapses were characterized by large postsynaptic densities with highly thickened membrane specializations and markedly diminished numbers of synaptic vesicles. Cats with elevated but measurable hearing thresholds had normal-appearing organs of Corti with abundant spontaneous single unit activity but infrequent sound-evoked activity. These partially deaf cats displayed modest atrophy of their endbulbs and exhibited more normal appearing synapses. The data reveal that early onset partial or total deafness that is uncorrected for 6 months or more produces unambiguous alterations in synaptic structure. These observations are relevant to selection strategies for human cochlear implant candidates. [Work supported by NIH/NIDCD.]

Nucleus ambiguus inhibits activity of cardiovascular units in RVLM

To investigate interactions between sites in the medulla which control the sympathetic (SNS) and the parasympathetic (PNS) nervous system, the activity of cardiovascular neurons in the rostral ventrolateral medulla (RVLM) was recorded during chemical stimulation of cardioinhibitory neurons in the nucleus ambiguus (NA). Cardioinhibitory sites in the NA were identified in urethane anesthetized rats. The spontaneous activity of single units in the RVLM was recorded and cardiovascular units were identified as units which displayed a cardiac cycle-related rhythmicity (CR) and decreased activity after i.v. phenylephrine. Of 55 units studied, 36 units were identified as cardiovascular and of these, 24 decreased activity after glutamate (GLU) microinjection in the NA, two units were excited and ten did not respond. Decreases in RVLM unit activity were positively correlated with the magnitude and duration of heart rate decreases elicited by GLU. Seven of the 24 units were tested for their response to microinjection of glycine (GLY) in the NA. GLY did not change firing frequency but did accentuate CR. These results demonstrate an inhibitory connection between the NA and RVLM which influences the rhythmicity of RVLM unit activity and provide clear evidence for functional interactions between the SNS and PNS within the central nervous system.

Reduction in firing rate of substantia nigra pars reticulata neurons by valproate: influence of different types of anesthesia in rats

Nondopaminergic, presumably GABAergic neurons in the substantia nigra pars reticulata (SNR) are thought to function as a gating mechanism for seizure propagation. Systemic administration of anticonvulsant doses of the antiepileptic drug valproate (VPA) has previously been reported to inhibit the firing of nondopaminergic SNR neurons in anesthetized but not in awake, paralyzed and locally anesthetized rats, suggesting that the findings in anesthetized rats were due to an interaction between VPA and the general anesthetic used. In the present study, we determined the influence of different anesthetic measures on the effect of an anticonvulsant dose of VPA (100 mg/kg) on extracellularly recorded spontaneous single unit activity of nondopaminergic SNR neurons in rats. Rats were anesthetized by continuous infusion of the general anesthetic chloral hydrate, the dissociative anesthetic ketamine or the narcotic opioid fentanyl, or were only locally anesthetized and paralyzed. VPA significantly reduced SNR firing in all groups with a time course that matched its anticonvulsant time course in rodents. However, VPA's inhibitory effect on SNR firing was significantly less marked under anesthesia with chloral hydrate than in any of the other groups, indicating that this anesthetic suppresses the action of VPA, which may be related to an interaction with GABA-related processes in the SNR. The closest approximation to the effect of VPA in awake rats was obtained under anesthesia with ketamine, while VPA's inhibitory action on SNR neuronal firing seemed to be enhanced in the fentanyl group, which exhibited the highest baseline firing rates of all groups. Determination of VPA in the SN showed that the difference in VPA's inhibitory effect on SNR neurons was not secondary to differences in local drug concentrations. The data demonstrate that VPA is capable of significantly slowing the spontaneous activity of nondopaminergic SNR neurons, but that the magnitude of this effect depends on the anesthetic measures used. In view of the presumed role of SNR neurons in seizure propagation and the finding that VPA consistently inhibits these neurons at an anticonvulsant dose, the present data suggest that suppression of spontaneous SNR neuronal firing may be an important mechanism through which VPA exerts its anticonvulsant properties.

Site-selective acute desensitization following local administration of opioid in the hippocampus.

Electrophoretic administration of the mu selective opioid agonist [D-Ala2, NMe-Phe4, Gly-ol]-Enkephalin (DAMGO) in the dentate gyrus of the hippocampus acutely produces a marked increase in the responsiveness of dentate granule cells to perforant path stimulation. This can be measured by an increase in the primary population spike (PS) amplitude and by disinhibition in the paired-pulse (PP) paradigm. Concomitantly, the spontaneous single unit activity of interneurons is usually inhibited. We have observed that after prolonged (usually 10-20 min) local (electrophoretic) administration of DAMGO, a second, late effect is noted, suggesting acute desensitization. There is a loss of the disinhibition seen in the PP paradigm while the primary PS shows only some increased variability in response to stimulation. Furthermore, in a time course parallel to the loss of disinhibition, single cell activity initially inhibited by DAMGO appears to lose its responsiveness. Pretreatment with kappa or delta opioid agonists, or with GABA agonists and antagonists, does not affect the development of this desensitization suggesting selective involvement of the mu receptor. We further propose a regional specificity within the hippocampus since we are unable to detect evidence of desensitization to opioid in CA1 using the same techniques.

Effects of excitotoxic striatal lesions on single unit activity in globus pallidus and entopeduncular nucleus of the cat

Striatal projections to the globus pallidus and entopeduncular nucleus are thought to be GABAergic and inhibitory. Thus, striatal lesions might be expected to increase the spontaneous discharge rate of neurons in these nuclei. To test this prediction, we recorded spontaneous single unit activity from awake cats sitting quietly before and 7–160 days after striatal lesions. Striatal lesions were produced by injecting ibotenic acid into the caudate nucleus and putamen. Median, standard deviation, mean, and coefficient of variation of the interspike intervals were calculated for each unit. In globus pallidus the striatal lesion resulted in a significant decrease in median interval length, i.e. an increase in the discharge rate. The prelesion median of 36 ms (S.E.M.= 2.3) decreased 11% to a postlesion value of 32 ms (S.E.M.= 2.1.). The lesion also resulted in a significant decrease in the variability of interspike intervals. The coefficient of variation, 1.31 (S.E.M.= 0.08) before the lesion, decreased 25% to 0.97 (S.E.M.= 0.06) after the lesion. In entopeduncular nucleus, the lesion had no statistically significant effect on the rate of activity, but a significant decrease in the variability of activity occurred. The median interval was 33 ms (S.E.M.= 3.3) before the lesion and decreased 2% to 32 ms (S.E.M.= 2.4). The coefficient of variation decreased 48% from 1.44 (S.E.M.= 0.1) to 0.73 (S.E.M.= 0.03). These observations support the hypothesis that loss of GABAergic inputs to the globus pallidus results in disinhibition. The discharge rate in entopeduncular nucleus was not affected by the striatal lesion, suggesting that striatal substance P or subthalamic excitatory inputs may have a role in regulating discharge rate in the entopeduncular nucleus.