The spontaneous firing patterns of forebrain neurons. IV. Effects of bilateral and unilateral frontal cortical ablations on firing of caudate, globus pallidus and thalamic neurons

To assess the effects of partial deafferentation of the neostriatum on spontaneous neuronal activity in the basal ganglia and related thalamic nuclei, ablations of frontal cortex were carried out in adult cats. Postoperative measures of interspike intervals of single neurons in the caudate nucleus, globus pallidus and ventral anterior-ventral lateral complex of the thalamus revealed a slowing of neuronal firing in these structures as compared with non-lesioned controls. The fact that deafferentation by cortical damage produces changes in neuronal firing in target neurons of the striatum (globus pallidus) and in thalamic neurons at least two synapses removed from the striatum is noteworthy. The possible extent to which these results might have been influenced by reduction of cortical inputs to or denervation of the thalamus is discussed.     

The spontaneous firing patterns of forebrain neurons. III. Prevention of induced asymmetries in caudate neuronal firing rates by unilateral thalamic lesions.

Unilateral lesions interrupting striatal outputs and inputs (MFB lesions) produce a marked slowing of neuronal firing in the caudate nucleus contralateral to the side of the lesions without affecting neuronal firing in the ipsilateral caudate nucleus. Although the MFB lesion also interrupts the nigrostriatal pathway and depletes the ipsilateral striatum of dipamine and its associated enzymes, the slowing of unit firing rates is apparently due to interruption of striatal outputs rather than inputs. Unilateral thalamic lesions palced ipsilateral to MFB lesions in iether the ventral anterior-ventrolateral nuclei (VA-VL) or in the center median-parafascicular nuclei (CM-PF) prevent the MFB lesion-induced asymmetry in caudate neuronal firing rates. These thalamic lesions do not, however, restore the striatal dopamine content depleted by the MFB lesion. Unilateral CM-PF lesions in otherwise intact cats do not alter caudate unit firing rates nor do they affect striatal dopamine. VA-VL lesions in otherwise intact cats produce a bilateral slowing in the spontaneous firing of neurons in the caudate nuclei, again, whithout altering caudate dopamine concentrations. These results provide further evidence that caudate dopamine concentration per se does not appear to be a potent variable in controlling the spontaneous firing rates of striatal neurons.     

The spontaneous firing pattern of forebrain neurons. I. The effects of dopamine and non-dopamine depleting lesions on caudate unit firing patterns

Unilateral lesions in and around the course of the nigrostriatal pathway (in the substantia nigra, in the supranigral region and more rostrally in the area of the medial forebrain bundle) in cats produced a marked slowing of single unit firing in the caudate nucleus contralateral to the lesion. In addition, the medial forebrain bundle lesion produced a tendency for an increase in unit firing rates in the caudate nucleus ipsilateral to the lesion. Lesions in the supranigral region in monkeys produced indications of a slowing in the firing rate of single units in the contralateral caudate and an increase in the firing rate of units in the caudate ipsilateral to the lesion. These alterations in spontaneous unit firing were independent of lesion-induced changes in concentrations of striatal dopamine or the activities of tyrosine hydroxylase and DOPA decarboxylase.     

The spontaneous firing patterns of forebrain neurons. V. Time course of changes in caudate unit activity following dopamine-depleting lesions

The effects of unilateral medial forebrain bundle (‘MFB’) lesions on the spontaneous firing patterns of caudate neurons on both sides of the brain in cats were studied 3 days, 7 days and more than 2 weeks postlesion. Our results indicate that: (1) the spontaneous firing of neurons in the caudate nucleus ipsilateral to the lesion slows significantly by 3 days postlesion and returns to control values by 7 days postlesion, (2) the spontaneous activity of contralateral caudate neurons slows progressively with postlesion time and (3) these changes in neural activity are not correlated with changes in dopamine concentrations in the caudate nucleus.     

The mechanism of spontaneous firing in histamine neurons.

Histaminergic neurons project to virtually the whole central nervous system and display regular firing related to behavioral state. Electrophysiological studies of histaminergic neurons show that these neurons fire in a beating pacemaker pattern, which is intrinsic to individual neurons. Onset of an action potential occurs as the result of a slow depolarizing potential, which consists of voltage dependent calcium current(s) and non-inactivating sodium current. The calcium component is a voltage-dependent current activated by the return to threshold following the afterhyperpolarization (AHP) while the sodium current appears to be persistent. The action potential is followed by an AHP, which limits firing rate. The AHP is due to two potassium currents, one voltage-, the other calcium-dependent; it determines the amount of voltage-dependent currents available for activation. We show original results indicating that calcium current can be activated during AHP-like ramps and that the amount of calcium current near threshold is strongly dependent on the membrane potential and on the size of the AHP. The amount of calcium entering during the action potential will determine the duration of the AHP and thus, the firing rate.     

Intrinsic firing patterns of diverse neocortical neurons.

Neurons of the neocortex differ dramatically in the patterns of action potentials they generate in response to current steps. Regular-spiking cells adapt strongly during maintained stimuli, whereas fast-spiking cells can sustain very high firing frequencies with little or no adaptation. Intrinsically bursting cells generate clusters of spikes (bursts), either singly or repetitively. These physiological distinctions have morphological correlates. RS and IB cells can be either pyramidal neurons or spiny stellate cells, and thus constitute the excitatory cells of the cortex. FS cells are smooth or sparsely spiny non-pyramidal cells, and are likely to be GABAergic inhibitory interneurons. The different firing properties of neurons in neocortex contribute significantly to its network behavior.     

Effects of intracerebroventricular L-DOPA on caudate unit firing

Single units were recorded bilaterally from the caudate nuclei of cats before and after 50 μl injections of either Merlis solution or L-DOPA (200 μg) dissolved in Merlis into the left lateral cerebral ventricle. After injection of L-DOPA, but not Merlis solution, there was a period of unit silence in both caudates with an onset of about 10 min and a duration of 30–50 min. This period of caudate silence was coincident with a significant reduction of systolic blood pressure and heart rate. Upon resumption of unit firing in caudate, it was found that the interspike intervals on the contralateral side were markedly increased from 30 min-2 hr postinjection while there was no change on the side of injection. The similarity of this response to that following lesions which interrupt the caudate to thalamus pathway unilaterally was discussed. It is suggested that L-DOPA injection may produce this lesion-like effect by altering the firing of caudate output neurons.     

Fine control of operantly conditioned firing patterns of cortical neurons.

Chronic recording microelectrodes were implanted in the hand-arm area of the precentral gyrus of three Macca mulatta monkeys. The firing patterns of individual and combined units were operantly conditioned with either a four- or an eight-target random tracking task. Neurons were considered “conditioned” only if the performance was significantly different from control runs. Conditioning occurred in 77% (37 of 48) of the single units and 65% (15 of 23) of the combined units. The activity of conditioned neurons was associated with specific hand or limb movements, whereas the activity of unconditioned neurons was either uncorrelated with any movement made by the monkey or correlated with seldom-made movements. Performance was measured in terms of information outflow rate to compare different task parameters. The best performance of 3.85 bits/s was obtained with a four-target, 0.5 s hold-time task. This compared to 4.29 bits/s when the same task was performed with a manipulandum and wrist movement. Monkeys were able to exert fine control of the firing rate of cortical neurons and to change rapidly from one rate to another on visual command.     

Acute application of NGF increases the firing rate of aged rat basal forebrain neurons.

Nerve growth factor (NGF) has been widely used in animal models to ameliorate age-related neurodegeneration, but it cannot cross the blood-brain barrier (BBB). NGF conjugated to an antibody against the transferrin receptor (OX-26) crosses the BBB and affects the biochemistry and morphology of NGF-deprived basal forebrain neurons. The rapid actions of NGF, including electrophysiological effects on these neurons, are not well understood. In the present study, two model systems in which basal forebrain neurons either respond dysfunctionally to NGF (aged rats) or do not have access to target-derived NGF (intraocular transplants of forebrain neurons) were tested. One group of transplanted and one group of aged animals received unconjugated OX-26 and NGF comixture as a control, while other groups received replacement NGF in the form of OX-26-NGF conjugate during the 3 months preceding the electrophysiological recording session. Neurons from animals in both the transplanted and aged control groups showed a significant increase in firing rate in response to acute NGF application, while none of the conjugate-treated groups or young intact rats showed any response. After the recordings, forebrain transplants and aged brains were immunocytochemically stained for the low-affinity NGF receptor. All conjugate treatment groups showed significantly greater staining intensity compared to controls. These data from both transplants and aged rats in situ indicate that NGF-deprived basal forebrain neurons respond to acute NGF with an increased firing rate. This novel finding may have importance even for long-term biological effects of this trophic factor in the basal forebrain.     

Operant conditioning of firing patterns in monkey cortical neurons

Intracortical recording microelectrodes were chronically implanted in the precentral gyrus of a monkey to determine the frequency range in which the firing pattern of a single neuron could be operantly conditioned. Single-unit activity attributed to an individual neuron was observed for as long as 28 days. The total range of neuronal firing frequency of a single neuron was divided into eight equal zones, each specified by a separate target and cursor light. The cursor light was controlled by the neuronal firing rate to provide visual feedback. During each trial two different target lights were presented to the animal in succession and both had to be matched to obtain a reward. During a period of 99 days, 280 neuronal conditioning runs were conducted using 28 different neurons. In roughly 79% of these runs, the monkey was able to modulate successfully the firing rate of a cortical neuron between two frequency bands on command and was also able to adjust the rate to several different frequency bands.     

The effect of prefrontal stimulation on the firing of basal forebrain neurons in urethane anesthetized rat

The basal forebrain (BF) contains a heterogeneous population of cholinergic and non-cholinergic corticopetal neurons and interneurons. Neurons firing at a higher rate during fast cortical EEG activity (f>16Hz) were called F cells, while neurons that increase their firing rate during high-amplitude slow-cortical waves (f<4Hz) were categorized as S-cells. The prefrontal cortex (PFC) projects heavily to the BF, although little is known how it affects the firing of BF units. In this study, we investigated the effect of stimulation of the medial PFC on the firing rate of BF neurons (n=57) that were subsequently labeled by biocytin using juxtacellular filling (n=22). BF units were categorized in relation to tail-pinch induced EEG changes. Electrical stimulation of the medial PFC led to responses in 28 out of 41 F cells and in 8 out of 9 S cells. Within the sample of responsive F cells, 57% showed excitation (n=8) or excitation followed by inhibitory period (n=8). The remaining F cells expressed a short (n=6) or long inhibitory (n=6) response. In contrast, 6 out of the 8 responsive S cells reduced their firing after prefrontal stimulation. Among the F cells, we recovered one cholinergic neuron and one parvalbumin-containing (PV) neuron using juxtacellular filling and subsequent immunocytochemistry. While the PV cell displayed short latency facilitation, the cholinergic cell showed significant inhibition with much longer latency in response to the prefrontal stimulus. This is in agreement with previous anatomical data showing that prefrontal projections directly target mostly non-cholinergic cells, including GABAergic neurons.     

Effects of sustained gamma-hydroxybutyrate treatments on spontaneous and evoked firing activity of locus coeruleus norepinephrine neurons

Background

Gamma-hydroxybutyrate is currently used to promote nighttime sleep in the treatment of narcolepsy; however, it is also a drug of abuse (“Liquid Ecstacy”) associated with a withdrawal syndrome with anxiety features. Of interest, the activity of locus coeruleus neurons is a reflective index of these above mentioned behavioral states.

Methods

Using in vivo extracellular unitary recordings, sustained administration of gamma-hydroxybutyrate (40 mg/kg/day via minipump implanted subcutaneously) on the spontaneous and sensory-evoked burst firing of locus coeruleus norepinephrine neurons was assessed in rats.

Results

A 2-day and 10-day gamma-hydroxybutyrate administration decreased the spontaneous firing activity of locus coeruleus neurons by 52% and 54%, respectively, when compared with controls. A similar degree of attenuation on evoked burst firing of norepinephrine neurons also occurred in these rats (2-day gamma-hydroxybutyrate: 47% and 10-day gamma-hydroxybutyrate: 58%), when compared with controls. In contrast, rats treated with gamma-hydroxybutyrate for 10 days followed by removal of the minipump for 36 hours resulted in a 33% augmentation in spontaneous locus coeruleus activity as compared with controls. Furthermore, a robust 79% increase in burst firing in response to paw-pinch was exhibited in theses rats.

Conclusions

Chronic gamma-hydroxybutyrate treatment inhibits the spontaneous and sensory-evoked burst firing of locus coeruleus norepinephrine neurons, whereas these indices are enhanced during drug withdrawal. The alteration in norepinephrine activity during chronic gamma-hydroxybutyrate administration may contribute to the ability of this agent to induce sleep and regulate narcoleptic episodes. Enhanced norepinephrine activity during withdrawal may be related to symptoms of anxiety on rapid termination of this drug in abusers.     

Self-inhibition alters firing patterns of neurons in aplysia buccal ganglia

The functional consequences of cholinergic self-inhibitory synaptic potentials (SISPs) upon firing patterns were examined in pairs of electronically coupled neurons of Aplysia buccal ganglia. In each neuron, the size of the peak SISP current decrements exponentially with increased number of previous conditioning action potentials (APs).To determine the effect of SISPs on the firing patterns of each cell, AP trains elicited by constant-current steps with the SISP intact were compared to those with the SISP blocked by curare. The SISP prolonged initial interspike intervals, providing an early supplement to accomodation, and produced a 75% increase in the sensitivity of firing frequency vs injected current plots for the first ISI. Firing rates were more regular in the presence of the SISP. However, the efficacy of the SISP, like the size of the underlying current, decrements with repetition.SISP effects were also studied in electronically coupled pairs of self-inhibitory neurons. Although the SISP altered the shape of the hyperpolarizing component of coupling potentials, DC coupling between the neurons was unaffected. Firing synchrony in coupled pairs stimulated with long DC pulses was assessed with cross-correlation histograms. In 60 mM Ca²⁺, the SISP sharpens the central peak of synchrony and deepens the flanking troughs, increasing the probability of synchronous firing within± 4msec by 76%. The major determinants of synchrony were found to be common input, SISP-dependent regularity of firing, and the depolarizing phase of the coupling potential, rather than the SISP-enhanced hyperpolarizing phase.     

正常大鼠丘脑底核神经元放电模式中的随机共振现象

目的 ;验证正常大鼠丘脑底核神经元放电模式中存在随机共振现象。方法运用全细胞膜片钳技术,对大鼠脑片丘脑底核神经元进行阈下正弦电流刺激,通过叠加不同输入频率正弦电流和不同强度噪声,分析峰峰间期(ISIH)和信噪比(SNRISIH),观察神经元放电特点。结果在单细胞水平证明了在中枢神经系统运动神经元中存在随机共振现象。在中等噪声强度时(约在20~25 pA处),丘脑底核神经元对叠加噪声的阈下周期性刺激存在最佳响应,其信噪比达到峰值;在一定频率范围(约为5~10 Hz),噪声和神经元输出反应之间存在最适匹配,神经元对阈下弱信号的检测提取能力最佳。结论正常大鼠丘脑底核神经元放电模式中存在随机共振现象。     

大鼠脑尾状核出血的模型

详细叙述了通过立体定向术向脑内注入自体动脉血而制成的大鼠脑尾状核出血模型。并讨论了几种实验性脑出血模型的优缺点，认为用立体定向术回注自体动脉血制成的大鼠脑出血模型更接近临床脑出血，且操作方便。     

Abnormalities in the spontaneous firing patterns of cultured rat neocortical neurons after chronic exposure to picrotoxin during development in vitro

We have used the GABA-A antagonist picrotoxin (PTX) to investigate whether chronic disinhibition, leading to intensified neuronal firing, would induce a specific pattern of physiological alterations in cultured rat neocortex cells. Overall mean spontaneous discharge rates were little affected by 1 microM PTX but firing occurred mainly as repetitive high-frequency bursts of action potentials. This "phasic" pattern contrasted with the irregular, quasi-random, firing usually seen in control units. Neurons tested in normal growth medium after prolonged exposure to 1 microM PTX showed weaker interspike interval dependencies (Markov value) than in controls, along with reduced regularity in the occurrence of bursts. Since all physiological changes were opposite in direction to those reported earlier after chronic suppression of bioelectric activity, the results support the hypothesis that endogenous synaptic and/or action potentials are important for the maturation of neocortical networks. Since experimental alterations were found only in spike-train parameters which reflect ontogenetic changes in untreated control cultures, GABAergic inhibition (by preventing neuronal discharges from becoming too intense) presumably serves to constrain the rate of development within optimal limits.     

Correlative firing patterns of serotonergic neurons in rat dorsal raphe nucleus

In this study, local neuronal interactions in the midbrain dorsal raphe nucleus (DRN) were analyzed by the use of autocorrelation and cross-correlation histograms. The autocorrelograms of serotonin (5-hydroxytryptamine; 5-HT)-containing cells showed an initial trough and subsequent periodicity which corresponded to their regular rhythmic firing pattern. Cross-correlograms revealed that all adjacent 5-HT neurons recorded from single micropipettes displayed complicated patterns of functional interactions. The interactions could be grouped into the following categories: (1) synchronization (interspike intervals less than 10 msec), (2) synchronization and direct inhibition, (3) synchronization and mutual inhibition. In contrast, cross-correlograms generated from adjacent neuronal pairs consisting of one 5-HT cell and one non-5-HT neuron or from non-adjacent 5-HT neuronal pairs usually failed to show functional interactions. The results of the present study are consistent with previous findings of a powerful auto-and mutual regulatory system for 5-HT neurons in the DRN.