Changes In Spontaneous Firing Rates Research Articles

Intrinsic plasticity of cerebellar stellate cells is mediated by NMDA receptor regulation of voltage-gated Na+ channels.

We show that NMDA receptors (NMDARs) elicit a long-term increase in the firing rates of inhibitory stellate cells of the cerebellum NMDARs induce intrinsic plasticity through a Ca2+ - and CaMKII-dependent pathway that drives shifts in the activation and inactivation properties of voltage-gated Na+ (Nav ) channels An identical Ca2+ - and CaMKII-dependent signalling pathway is triggered during whole-cell recording which lowers the action potential threshold by causing a hyperpolarizing shift in the gating properties of Nav channels. Our findings open the more general possibility that NMDAR-mediated intrinsic plasticity found in other cerebellar neurons may involve similar shifts in Nav channel gating. Memory storage in the mammalian brain is mediated not only by long-lasting changes in the efficacy of neurotransmitter receptors but also by long-term modifications to the activity of voltage-gated ion channels. Activity-dependent plasticity of voltage-gated ion channels, or intrinsic plasticity, is found throughout the brain in virtually all neuronal types, including principal cells and interneurons. Although intrinsic plasticity has been identified in neurons of the cerebellum, it has yet to be studied in inhibitory cerebellar stellate cells of the molecular layer which regulate activity outflow from the cerebellar cortex by feedforward inhibition onto Purkinje cells. The study of intrinsic plasticity in stellate cells has been particularly challenging as membrane patch breakthrough in electrophysiology experiments unintentionally triggers changes in spontaneous firing rates. Using cell-attached patch recordings to avoid disruption, we show that activation of extrasynaptic N-methyl-d-aspartate receptors (NMDARs) elicits a long-term increase in the firing properties of stellate cells by stimulating a rise in cytosolic Ca2+ and activation of Ca²⁺/calmodulin-dependent protein kinase II (CaMKII). An identical signalling pathway is triggered during whole-cell recording which lowers the action potential threshold by causing a hyperpolarizing shift in the gating properties of voltage-gated sodium (Nav ) channels. Together, our findings identify an unappreciated role of Nav channel-dependent intrinsic plasticity in cerebellar stellate cells which, in concert with non-canonical NMDAR signalling, provides the cerebellum with an unconventional mechanism to fine-tune motor behaviour.

The Neural Bases of Tinnitus: Lessons from Deafness and Cochlear Implants.

Subjective tinnitus is the conscious perception of sound in the absence of any acoustic source. The literature suggests various tinnitus mechanisms, most of which invoke changes in spontaneous firing rates of central auditory neurons resulting from modification of neural gain. Here, we present an alternative model based on evidence that tinnitus is: (1) rare in people who are congenitally deaf, (2) common in people with acquired deafness, and (3) potentially suppressed by active cochlear implants used for hearing restoration. We propose that tinnitus can only develop after fast auditory fiber activity has stimulated the synapse formation between fast-spiking parvalbumin positive (PV+) interneurons and projecting neurons in the ascending auditory path and coactivated frontostriatal networks after hearing onset. Thereafter, fast auditory fiber activity promotes feedforward and feedback inhibition mediated by PV+ interneuron activity in auditory-specific circuits. This inhibitory network enables enhanced stimulus resolution, attention-driven contrast improvement, and augmentation of auditory responses in central auditory pathways (neural gain) after damage of slow auditory fibers. When fast auditory fiber activity is lost, tonic PV+ interneuron activity is diminished, resulting in the prolonged response latencies, sudden hyperexcitability, enhanced cortical synchrony, elevated spontaneous γ oscillations, and impaired attention/stress-control that have been described in previous tinnitus models. Moreover, because fast processing is gained through sensory experience, tinnitus would not exist in congenital deafness. Electrical cochlear stimulation may have the potential to reestablish tonic inhibitory networks and thus suppress tinnitus. The proposed framework unites many ideas of tinnitus pathophysiology and may catalyze cooperative efforts to develop tinnitus therapies.

Effects of visceral inputs on the processing of labyrinthine signals by the inferior and caudal medial vestibular nuclei: ramifications for the production of motion sickness

Neurons located in the caudal aspect of the vestibular nucleus complex have been shown to receive visceral inputs and project to brainstem regions that participate in generating emesis, such as nucleus tractus solitarius and the "vomiting region" in the lateral tegmental field (LTF). Consequently, it has been hypothesized that neurons in the caudal vestibular nuclei participate in triggering motion sickness and that visceral inputs to the vestibular nucleus complex can affect motion sickness susceptibility. To obtain supporting evidence for this hypothesis, we determined the effects of intragastric infusion of copper sulfate (CuSO4) on responses of neurons in the inferior and caudal medial vestibular nuclei to rotations in vertical planes. CuSO4 readily elicits nausea and emesis by activating gastrointestinal (GI) afferents. Infusion of CuSO4 produced a >30% change in spontaneous firing rate of approximately one-third of neurons in the caudal aspect of the vestibular nucleus complex. These changes in firing rate developed over several minutes, presumably in tandem with the emetic response. The gains of responses to vertical vestibular stimulation of a larger fraction (approximately two-thirds) of caudal vestibular nucleus neurons were altered over 30% by administration of CuSO4. The response gains of some units went up, and others went down, and there was no significant relationship with concurrent spontaneous firing rate change. These findings support the notion that the effects of visceral inputs on motion sickness susceptibility are mediated in part through the caudal vestibular nuclei. However, our previous studies showed that infusion of CuSO4 produced larger changes in response to vestibular stimulation of LTF neurons, as well as parabrachial nucleus neurons that are believed to participate in generating nausea. Thus, integrative effects of GI inputs on the processing of labyrinthine inputs must occur at brain sites that participate in eliciting motion sickness in addition to the caudal vestibular nuclei. It seems likely that the occurrence of motion sickness requires converging inputs to brain areas that generate nausea and vomiting from a variety of regions that process vestibular signals.

Sodium overload modulates the electrical activity of serotonergic (5HT) neurons of the dorsal raphé nucleus (DRN)

Our previous results indicate that 5HT neuronal activity (as shown by Fos expression) within the DRN is modulated by body sodium status. The effect of body sodium overload on spontaneous firing frequency of the 5HT‐DRN neurons was analyzed.Male Wistar rats were anesthetized, and a catheter was inserted in the yugular vein; subsequently, a micropipette was stereotaxically lowered into the DRN in order to record single cell extracellular action potentials. After recording basal activity for 3 min, a group of rats received a sc injection of 2M NaCl solution (1.7 ml/min), and a second group of animals received an equal volume of 0.15 M NaCl. Fifteen minutes later we determined the neuronal phenotype by iv infusion of fluoxetine. To measure plasma sodium and osmolality other rats were submitted to the same protocol but were decapitated and bled 0, 5, 10 and 15 min after NaCl infusion.Four min after 2M NaCl infusion, neuronal activity increased significantly compared to the 0.15M NaCl group and basal recording activity. 0.15M NaCl infusion produced no change in spontaneous firing rate. Plasma sodium and osmolality significantly increased after 2M NaCl infusion compared to 0.15M NaCl group and baseline levels.We conclude that hypernatremic systemic states increase the firing rate of 5HT‐DRN cells, possibly to modulate sodium and water intake/excretion and avoid an extracellular volume expansion.Supported by ANPCyT CONICET.

Tinnitus-related hyperactivity through homeostatic plasticity in the auditory pathway

Hearing loss through acoustic trauma or administration of ototoxic drugs leads to the development of increased spontaneous firing rates (hyperactivity) in neurons of the auditory pathway. Hyperactivity in the first processing stage, the dorsal cochlear nucleus (DCN), is correlated to behavioral signs of tinnitus, and the distribution of hyperactivity along the tonotopic axis of the DCN corresponds to the patterns of cochlear damage. Recently, we have proposed that the development of hyperactivity after hearing loss is a consequence of activity stabilization through homeostatic plasticity [1]. We now include inhibitory interneurons in our model to reproduce the basic neuronal circuit of the DCN where projection neurons (PNs) are inhibited by type-II and wide-band inhibitory units. By altering the strengths of the inhibitory connections, we can tune the PN responses to resemble the response characteristics of DCN principal cells like type-III and type-IV responses. We then analyze how the activity of the model neurons is changed by hearing loss through different kinds of cochlear damage. After hearing loss, the mean activity of the model neurons depends on the severity of cochlear damage and the strengths of excitation and inhibition. In our model, homeostatic plasticity stabilizes the mean firing rate of the PNs by scaling the strengths of excitatory and inhibitory synapses, which also influences the spontaneous firing rate. After hearing loss and homeostasis, the spontaneous firing rate of PNs depends on the type and severity of cochlear damage and on the ratio of the mean to the spontaneous firing rate before hearing loss. Only those PN types where excitation dominates over inhibition become hyperactive. We observe hyperactivity in type-III and type-IV-T PNs, but not in type-IV PNs whose mean rate is close to the spontaneous rate. Finally, we apply our model to data from tinnitus patients [2] and predict changes in spontaneous firing rates of auditory neurons from the patients' audiograms. Estimates of tinnitus pitch based on the hyperactivity patterns in the model DCN are consistent with observed tinnitus pitch. We conclude that hyperactivity through the action of homeostatic plasticity after hearing loss may be the basis for a tinnitus sensation.

Changes in spontaneous neural activity immediately after an acoustic trauma: implications for neural correlates of tinnitus

Changes in spontaneous activity, recorded over 15-min periods before, immediately after and within hours after an acute acoustic trauma, were studied in primary auditory cortex of ketamine-anesthetized cats. We focused on the spontaneous firing rate (SFR), the peak cross-correlation coefficient ( ρ) and burst-firing activity. Multi-units (MUs) were grouped according to characteristic frequency (CF): MUs with a CF below the trauma-tone frequency (TF) were labeled as Be, those with a CF within 1 octave above the TF were labeled as Ab1 and those with a CF more than 1 octave above the TF were labeled as Ab2. Immediately after the trauma, the SFR was not significantly changed. The percentage of time that neurons were bursting, the mean burst duration, the number of spikes per burst and the mean inter-spike interval in a burst were enhanced. ρ was locally increased in the Ab1-Ab2 and Ab2-Ab2 groups. A few hours post trauma, the SFR was increased in the Be and Ab2 groups, whereas burst-firing returned to pre-exposure levels. Moreover, ρ was elevated in the Be-Ab2, Ab1-Ab2 and Ab2-Ab2 groups; this increase was significantly correlated to the changes in SFR. The results are discussed in the context of a neural correlate of tinnitus.

Changes in spontaneous firing rate and neural synchrony in cat primary auditory cortex after localized tone-induced hearing loss

Increase in spontaneous neural activity after noise-induced hearing loss has frequently been associated with the phenomenon of tinnitus. Eighteen juvenile and adult cats were exposed for 2 h to a 6 kHz tone with an intensity of 115 dB SPL at the cat’s head. Seven non-exposed littermates and seven other normal hearing cats were used as age-matched controls. The trauma cats showed localized hearing losses, as assessed by ABR, ranging from less than 20 to 60 dB. The frequency representation in primary auditory cortex was mapped using an eight-electrode array. Single-unit spontaneous activity was recorded for 15 min. Peak cross-correlation coefficients ( R) for unit cluster activity recorded on separate electrodes were calculated. We found elevated spontaneous firing rates in regions with reorganization of the tonotopic map compared to the neurons in the non-reorganized cortical regions in the same animals. A second finding was that in these regions the peak cross-correlation coefficients were also increased relative to the non-reorganized parts. A third finding was that exposed animals showed higher spontaneous activity compared to controls regardless of the presence of cortical reorganization. This may be a correlate of tinnitus in the presence of only minor hearing losses.

Metabolic and neural activity in the song system nucleus robustus archistriatalis: effect of age and gender.

The sexually dimorphic robust archistriatal nucleus (RA) represents the telencephalic output of the bird song system. Here, we document sex-dependent changes in both the metabolic and neuronal activity of RA during the sensory and sensorimotor phases of song learning. From posthatching day (PHD) 20-63 in males but not females, RA and its input nucleus HVc showed sharp increases in cytochrome oxidase (CO) activity relative to surrounding archistriatum and the underlying shelf, respectively. In urethane-anesthetized birds, during the same period, the spontaneous activity of male RA neurons underwent dramatic changes in firing rate, distribution of interspike intervals, and bursting frequency, compared with other archistriatal cells. At PHD 20-21, RA neurons had extremely slow, irregular firing rates in birds of both sexes. In males, from PHD 30-36, RA neurons increased their firing rates and spiking activity became more regular, and at approximately PHD 38, strong bursts followed by inhibition (which in awake animals is associated with singing) began to be observed. Dual recordings from RA and HVc revealed synchronous bursting, with RA spikes lagging approximately 10 msec behind HVc. We conclude that changes in relative CO activity correlate with changes in spontaneous firing rates within RA and that patterns of RA spontaneous activity exhibit gradual change as birds enter early song and then again for plastic song. The emergence of strong burst patterns in RA occurs later in life than does input from HVc as established by tracer studies or based on observed HVc bursting in young animals.

Neuropeptide Y phase advances the in vitro hamster circadian clock during the subjective day with no effect on phase during the subjective night

The mammalian daily (circadian) clock is located in the suprachiasmatic nuclei of the hypothalamus. Clock function can be detected by the measurement of the circadian change in spontaneous firing rate of suprachiasmatic nuclei cells in a brain slice preparation in vitro. We investigated the effects of neuropeptide Y on this rhythm of firing rate in hamster suprachiasmatic nuclei neurons. Slices were prepared using standard techniques. On the 1st day in vitro, neuropeptide Y (200 ng/200 nL; 47 pmol) was applied as a microdrop to the suprachiasmatic nuclei region at various times. Spontaneous single-unit firing was measured for 6-12 h on the 2nd day in vitro. Peak firing rate in treated slices was compared with that of untreated control slices to measure phase shifts induced by the peptide. Neuropeptide Y induced phase advances of circa-3h when applied during the subjective day (ZT 2-10) but did not significantly alter phase when applied during the subjective night. The phase shifts to neuropeptide Y in the hamster tissue in vitro are similar in phase dependency and magnitude to shifts measured in vivo.

The role of neural mechanisms of attention in solving the binding problem.

We thank L. Chelazzi, V. Ferrera, P. Fries, S. Kastner, and A. Rossi for helpful comments on the manuscript.

Transient neurophysiological changes in CA3 neurons and dentate granule cells after severe forebrain ischemia in vivo.

Transient neurophysiological changes in CA3 neurons and dentate granule cells after severe forebrain ischemia in vivo. J. Neurophysiol. 80: 2860-2869, 1998. The spontaneous activities, evoked synaptic responses, and membrane properties of CA3 pyramidal neurons and dentate granule cells in rat hippocampus were compared before ischemia and </=7 days after reperfusion with intracellular recording and staining techniques in vivo. A four-vessel occlusion method was used to induce approximately 14 min of ischemic depolarization. No significant change in spontaneous firing rate was observed in both cell types after reperfusion. The amplitude and slope of excitatory postsynaptic potentials (EPSPs) in CA3 neurons decreased to 50% of control values during the first 12 h reperfusion and returned to preischemic levels 24 h after reperfusion. The amplitude and slope of EPSPs in granule cells slightly decreased 24-36 h after reperfusion. The amplitude of inhibitory postsynaptic potentials in CA3 neurons transiently increased 24 h after reperfusion, whereas that in granule cells showed a transient decrease 24-36 h after reperfusion. The duration of spike width of CA3 and granule cells became longer than that of control values during the first 12 h reperfusion. The spike threshold of both cell types significantly increased 24-36 h after reperfusion, whereas the frequency of repetitive firing evoked by depolarizing current pulse was decreased during this period. No significant change in rheobase and input resistance was observed in CA3 neurons. A transient increase in rheobase and a transient decrease in input resistance were detected in granule cells 24-36 h after reperfusion. The amplitude of fast afterhyperpolarization in both cell types increased for 2 days after ischemia and returned to normal values 7 days after reperfusion. The results from this study indicate that the neuronal excitability and synaptic transmission in CA3 and granule cells are transiently suppressed after severe forebrain ischemia. The depression of synaptic transmission and neuronal excitability may provide protection for neurons after ischemic insult.

Salicylate and quinine selectively increase spontaneous firing rates in secondary auditory cortex

This study presents firing rates for simultaneously recorded spontaneous and stimulus driven multi-unit activity in primary auditory cortex (AI), anterior auditory field (AAF) and secondary auditory cortex (AII) in cats before and after application of salicylate or quinine. From 21 cats, in three cortical areas simultaneously, a total of 1533 multi-unit files were obtained. The data suggest (1) that both salicylate and quinine significantly increase spontaneous firing rates in AII, whereas in AI and AAF both quinine and salicylate reduced the spontaneous rate; (2) the effect of both drugs was to increase spontaneous rates for recording sites with high characteristic frequency (CF) and a tendency to decrease them for low CF sites; (3) the mean stimulus driven firing rates were not affected by either drug except for a decrease produced by quinine in AI; (4) changes in driven firing rate were positively correlated with changes in spontaneous firing rates. This suggests that tinnitus inducing agents selectively increase spontaneous firing rates in the extralemniscal pathway.

Morphine modulation of GABA- and glutamate-induced changes of ventral pallidal neuronal activity

Microiontophoresis was used to investigate the influence of morphine on the GABA- and glutamate-evoked responses of ventral pallidal neurons recorded extracellularly from chloral hydrate-anesthetized rats. Of the GABA-sensitive neurons (50 of 69 tested) in the ventral pallidum, all displayed a decreased firing rate when GABA was applied, whereas all of the glutamate-sensitive neurons (29 of 40 tested) increased neuronal activity in the presence of glutamate. The majority of ventral pallidal cells tested (65 of 83) were sensitive to iontophoretically applied morphine, and both increases and decreases in neuronal activity were observed. The ability of morphine to alter the ratio between amino acid-evoked activity (“signal”) and spontaneous firing (“noise”) was used as an indicator of morphine modulation. A morphine subthreshold ejection current, i.e. one that did not change spontaneous firing rate, and a morphine ejection current that produced approximately 50% of the maximum opioid-induced neuronal response were chosen for this evaluation. When morphine was co-iontophoresed with GABA or glutamate, attenuation of the amino acid signal-to-noise ratio was generally seen, though some potentiations were observed. These changes were independent of the direction of morphine-induced changes in spontaneous firing rate. Both sub- and suprathreshold ejection currents were capable of affecting GABA- and glutamate-evoked responses. These data suggest that morphine is a robust ventral pallidal neuromodulator. As ventral pallidal amino acid activity is important in the integration of sensorimotor information, opioid modulation of amino acid transmission in the ventral pallidum may have a profound effect on this integration.

Effects of salicylate and quinine on cat primary auditory cortex--spontaneous firing rate

The effect of salicylate and quinine on the spontaneous firing rate in the cat primary auditory cortex was investigated in 13 healthy cats. Spontaneous firing rates were calculated for each single unit. A dose of 200 mg of sodium salicylate per kg was administered intraperitoneally to six cats, and the findings from the same single unit were recorded prior to application and continuously up to, on average, 6 hours after application. A dose of 100 or 200 mg of quinine hydrochloride per kg was administered intramuscularly to seven cats, and the findings from the same single unit were recorded in the same manner as for the cats treated with sodium salicylate. Twenty one single units in salicylate-treated cats and 29 single units in quinine-treated cats were evaluated. All animals treated with salicylate showed a 20-30 dB threshold shift about 2 hours after application and showed no recovery during the course of the investigation. All animals treated with quinine showed a 10-40 dB threshold shift about 1 hour after application and recovered during the course of the investigation. There was no consistent difference in overall spontaneous firing rate before and after application in either salicylate-treated cats or quinine treated cats. In order to investigate a potential different effect on units with different spontaneous firing rates, we divided the cats into two groups, a high-firing rate group (pre-application firing rate > 1 spike/s) and a low firing rate group (pre-application firing rate < 1 spike/s). A significant decrease in the high-firing rate group (p < 0.05) and a significant increase in the low firing rate (p < 0.01) were observed in salicylate-treated cats. The same tendencies were observed in quinine-treated cats, but only the difference in the low firing rate group was significant (p < 0.05). The difference in the high-firing rate group was close to the significant level (p = 0.055). These changes in spontaneous firing rates in cat primary auditory cortex may be related to the generation of tinnitus.

Cochlear basal and apical differences reflected in the effects of cooling on responses of single auditory nerve fibers

Responses of single auditory nerve fibers in the Mongolian gerbil were examined before and during rapid, moderate cooling of the cochlea. Reducing cochlear temperature from 35–39°C to 29–32°C led to stable, reversible changes in spontaneous firing rates (SRs), and responses to tonebursts, as characterized by frequency tuning curves and rate-versus-intensity curves. The nature and extent of effects of cooling were strongly linked to characteristic frequency (CF). Rate thresholds at the CF were increased by 0–15 dB for fibers with CFs below 8 kHz, and by 10–30 dB for higher CFs. Although SRs were generally reduced, the percent reduction in SR was strikingly CF dependent. For fibers with CFs below 4 kHz, the reduction did not exceed 50% of the initial SR. For higher CFs, the reduction was always greater than 50%. The effects of cooling on intensity curve shape differed qualitatively for fibers with CFs below and above 3–4 kHz. The slope of the curve was reduced by an average of 50% for lower CFs, but on average was unchanged for higher CFs. Cooling-related increases in CF threshold probably reflect impairment of active mechanical processes. The CF dependence of these increases suggests either that active mechanical processes are more impaired in the cochlear base relative to the apex, or that they play a more crucial role in determining sensitivity in the base. The CF-dependent changes in SR and in the shape of rate-intensity curves caused by cooling correspond to an enhancement of basal/apical differences seen at normal temperatures. They are best explained by longitudinal gradients in the properties of the inner hair cells and their afferent synapses. Basal and apical differences in the distribution of SRs and in supra-threshold response properties suggest that stimulus coding strategies differ between low and high frequency regions of the cochlea.

Time-dependent changes in the sensitivity of dopamine neurons to low doses of apomorphine following amphetamine infusion

Changes in dopamine autoregulatory mechanisms following a chronic infusion of amphetamine were studied. Rats were infused with D-amphetamine (4.8 mg/day) for 7 days by osmotic minipumps, and were studied at various times after withdrawal. In contrast to no changes in the spontaneous firing rate of single dopamine cells, the potency of apomorphine in the substantia nigra was markedly decreased soon after withdrawal, followed by an increase 7 days later. The ventral tegmental area showed no changes in either spontaneous firing rate or sensitivity to apomorphine following a 7-day withdrawal. Moderate decreases in striatal and tubercle dopamine concentrations were not accompanied by any significant decrease in basal dopamine synthesis. Under intact impulse-flow, the sensitivity of terminal dopamine synthesis to low doses of apomorphine was decreased immediately following withdrawal; by Day 7 supersensitivity was observed. Direct assessment of terminal autoreceptors following a 7-day withdrawal revealed normo- and supersensitivity of these receptors in the striatum and olfactory tubercle, respectively. Possible mediating mechanisms as well as implications of these findings for the development of characteristics behavioral syndromes during and after amphetamine infusion are discussed.

Sex steroid effects on extrahypothalamic CNS. II. Progesterone, alone and in combination with estrogen, modulates cerebellar responses to amino acid neurotransmitters

In a preliminary report we have shown that both intravenous and local application of progesterone (P) are capable of increasing cerebellar Purkinje cell responsiveness to microiontophoretically applied γ-aminobutyric acid (GABA) and decreasing responsiveness to glutamate (GLUT) in the urethane-anesthetized, ovariectomized adult rat. In the present study we have examined the time course of effects of several doses of P and different combinations of both E 2 and P on responses of individual Purkinje cells to GABA and GLUT. Extracellular activity of single Purkinje neurons was recorded using multibarrel glass micropipets. Spontaneous firing rate and responses of neurons to microiontophoretic pulses (10 s pulses every 40 s) of GABA (10–50 nA) and GLUT (3–40 nA) were examined before and after jugular i.v. administration of P or E 2/P combinations to ovariectomized rats. In some cases animals received s.c. injections of E 2 (2 μg) at 24 and 48h before the day of recording. This injection schedule results in maximal reproductive effects of P. Within 5–15 min after P administration (5,50 or 500 μg) to ovariectomized rats, Purkinje cell responses to GLUT were decreased by 87%, and inhibitory responses to GABA were increased by 50%, with no associated change in spontaneous firing rate. In addition, the magnitude of the change in amino acid response was directly proportional to the dose of P. In most cases, complete recovery was observed 20–45 min after P administration. E 2 pretreatment did not alter these P-induced effects. Combinations of E 2 (300 ng/kg) and P (50 or 500 μg) injected simulataneously resulted in effects on GLUT responsiveness which were similar to those seen with P alone, while effects similar to E 2 alone were observed with administration of E 2 plus P at 5 μg. The administration of a protein synthesis inhibitor, anisomycin (30 mg/kg, i.v.), 20 min before the recording session did not prevent any of the above steroid effects. These results indicate that sex steroids can act to alter neuronal responsiveness to putative neurotransmitters in a CNS region not known to contain steroid receptors and that the particular combination of steroids will determine the neuronal response. These findings further suggest that the observed steroid-induced alterations in Purkinje cell responsiveness do not appear to require genomic mechanisms.

Sex steroid effects on extrahypothalamic CNS. I. Estrogen augments neuronal responsiveness to iontophoretically applied glutamate in the cerebellum

The purpose of this study was to test whether 17β-estradiol (E 2) could alter neuronal activity or responsiveness to iontophoretically applied amino acid neurotransmitters in an area not reported to contain classical E 2 receptors. Such a region is the cerebellum, which was selected as a model system for these studies because it has been well characterized electrophysiologically. Extracellular activity of cerebellar Purkinje neurons was recorded from urethane-anesthetized, adult, ovariectomized rats using multibarrel glass micropipets. Spontaneous firing rate and responses of single units to microiontophoretic pulses (10 s pulses every 40 s) of GABA (10–50 nA) or glutamate (GLUT, 3–40 nA) were examined before, during and after iontophoretic (0.25 mM 17β-estradiol hemisuccinate) or jugular i.v. (100, 300 or 1000 ng/kg 17β-estradiol) administration of E 2. Both modes of E 2 administration resulted in a significant increase in Purkinje cell excitatory responses to GLUT, independent of the direction of change in spontaneous firing rate. This effect was seen as early as one minute after iontophoretic application of E 2 and 10–40 min following i.v. E 2. In all cases, recovery to the control level of response was not observed by 2 h following E 2 administration.17α-E 2 (300ng/kg) resulted in a less pronounced, transient increase in GLUT response, while a lower dose (100 ng/kg) did not have any effect. Prior administration of the anti-estrogen tamoxifen did not prevent any of the observed E 2 effects. In addition, estrogen-priming did not alter E 2-induced potentiation of GLUT responses. In contrast to the effect of E 2 on GLUT responsiveness, GABA-mediated inhibition of Purkinje cells was either increased, antagonized or unchanged following E 2 application. In summary, this study suggests the hypothesis that circulating levels of E 2 may alter neuronal sensitivity to specific neurotransmitter substances within the cerebellar circuitry.

Polygraphic study of anterior hypothalamic-preoptic neuron thermosensitivity during sleep

Thermal responsiveness of anterior hypothalamic-preoptic (AH-PO) neurons was studied in unanesthetized sleeping cats carrying chronically implanted electrodes and thermistors for recording EEG, EMG and AH-PO temperature. Activity of AH-PO neurons was recorded using tungsten microelectrodes during atraumatic stereotaxic head restraint in a sound-attenuated chamber at 22–25°C. Direct cooling or warming of the AH-PO region was accomplished with bilaterally positioned water-perfused thermodes. 110 thermosensitive neurons (77% cold-sensitive and 23% warm-sensitive) were sampled during wakefulness and synchronized sleep. In contrast, the changes in spontaneous firing rate shown by AH-PO neurons during desynchronized sleep were often associated with a strong depression or outright suppression of their responsiveness to AH-PO thermal stimulation.

Effects of caudate nuclear or frontal cortical ablation in neonatal kittens or adult cats on the spontaneous firing of forebrain neurons

In this paper we have determined the long-lasting consequences of caudate and frontal cortical lesions on spontaneous neuronal firing. Lesions were made both in neonatal and adult cats. All recordings were made in adults. Qualitatively, the effects of the caudate ablations were similar whether they had been carried out in kittens or in adult cats. Caudate lesions produced long-lasting (≥ 1 year) decreases in the spontaneous firing of cortical neurons. These changes were more pronounced when made in neonates than in adults. The distributions of mean interspike intervals were also altered by these caudate lesions in the pallidum and in the ventral lateral nucleus of the thalamus. Again these effects were more marked if the animals were lesioned as neonates than as adults. Frontal cortical lesions inflicted upon adult cats produced more widespread changes in spontaneous firing rates than similar lesions made in neonates. In both groups frontal lesions slowed spontaneous firing and changed the distributions of mean interspike intervals of caudate neurons. These effects were long-lasting (≥ 1 year in neonatally-ablated animals). Cortical lesions made in adult cats markedly altered thalamic and pallidal spontaneous activity. Similar lesions made in neonates produced relatively small changes in thalamic and pallidal activity.