Neuronal firing rates can be significantly increased through targeted medication and diet
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CONTESTED
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refutedsupported
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While some studies indicate that specific treatments like carbamazepine can activate certain neurons, other findings show that medications and chemical exposures can also decrease neuronal firing rates, leading to mixed neurophysiological results.
Micro Electrode Arrays were used to simultaneously record spontaneous extracellular action potentials from 10 to 30 dopamine neurons in acute brain slices from the lateral Ventral Tegmental Area (VTA) of the rat. The spike train of an individual neuron was used to characterize the firing pattern: firing rate, firing irregularity and oscillation frequency. Functional connectivity between a pair of neurons was quantified by the Paired Phase Consistency (PPC), taking the oscillation frequency as reference. Under baseline conditions the PPC was significantly different from zero and 42 of the 386 pairs of VTA neurons showed significant coupling. Fifty percent of the recorded dopamine neurons were part of the coupled VTA network. Raising extracellular potassium from 3.5 to 5 mM increased the mean firing rate of the dopamine neurons by 45%. The same increase could be induced by bath application of 300 μm glutamate. High potassium reduced the PPC, but it did not change during the glutamate application. Our findings imply that manipulating excitability has distinct and specific consequences for functional connectivity in the VTA network that cannot be directly predicted from the changes in neuronal firing rates. Functional connectivity reflects the spatial organization and synchronization of the VTA output and thus represents a unique element of the message that is sent to the mesolimbic projection area. It adds a dimension to pharmacological manipulation of the VTA micro circuit that
Fifty percent of the recorded dopamine neurons were part of the coupled VTA network. Raising extracellular potassium from 3.5 to 5 mM increased the mean firing rate of the dopamine neurons by 45%. The same increase could be induced by bath application of 300 μm glutamate. High potassium reduced the PPC, but it did not change during the glutamate application. Our findings imply that manipulating excitability has distinct and specific consequences for functional connectivity in the VTA network that cannot be directly predicted from the changes in neuronal firing rates.
The firing of DA neurons is controlled by an underlying intrinsic rhythm (Drion et al., 2011 ). The dominant oscillation frequency of this rhythm was estimated from the auto-correlation function (with a 50 ms bin size to accommodate the firing rates in the 1–5 Hz range, Figure 2A ). The oscillation frequency was computed from intervals between side-lobes in the auto-correlation function (details are given in Figures 2A,B ).
The oscillation frequency of the neuronal activity was determined from the time intervals between the side-lobes in the auto-correlation (see markers in Figures 2A,B ). The mean oscillation frequency of the recorded neurons was 1.53 (SD 0.47) Hz ( n = 68) and was either equal but often considerable higher than the mean firing rate ( Figure 2C ). The difference between the oscillation frequency and the mean firing rate was more pronounced at low firing rates ( Figure 2C ).
Network Activity Modulation The measured PPC can be considered an emerging property of the VTA network. We investigated the relation between the PPC and increased mean neuronal firing rate, using two different forms of excitability modulation. First, raising [K + ] o from a baseline level of 3.5 to 5 mM, increased the firing rate (4 experiments, 57 neurons under baseline condition). Second, bath application of 300 μM glutamate increases firing rate to about the same level (5 experiments, 55 neurons under baseline condition). The enhanced excitability induced by both procedures was reversible, although some of the newly recruited neurons did not silence at wash-out.
In addition to increasing the neuronal activity, both treatments recruited 22% (high potassium) and 16% (glutamate) additional neurons, shown in Figures 6A,B as neurons with a baseline firing rate set to zero. The neurons recruited by glutamate had an oscillation frequency higher than baseline [ Figure 6D ; ANOVA, p = 0.027, n = (55 baseline, 9 recruited)], whereas those recruited by high potassium had an oscillation frequency similar to baseline [ Figure 6C , n = (57 baseline, 13 recruited)].
The manipulations were chosen so that their effect on mean firing rate and mean oscillation frequency was similar. Interestingly, they had a differential effect on firing irregularity (LV) as well as on functional connectivity as measured with the PPC. The increase in firing rate induced by high potassium correlated with a lower LV, while such correlation was absent in the case of glutamate application. The increased activity of individual neurons propagates through the population level, as high potassium and glutamate both increased the oscillation frequency of the population output.
Glutamate depolarizes the neuron through the activation of post-synaptic AMPA and NMDA receptors (Wang and French, 1993 ). The strongly increased synaptic activity enhances firing irregularity (Drion et al., 2011 ) and could therefore explain the difference between the effect of glutamate- and potassium-induced depolarization. The strengthening of the intrinsic rhythm by larger sodium currents could make the dopamine neurons less sensitive to synchronizing inputs and thus show up as weaker neuronal interactions, based on resonance principles (Hunter et al., 1998 ; Coombes and Bressloff, 1999 ).
Neurons recruited by glutamate had a higher than baseline oscillation frequency and functional connectivity, suggesting that recruitment through increased synaptic input (glutamate) leads to more network participation than recruitment through a direct increase of the membrane potential (high potassium). GABAergic transmission contributed on average very little to the functional connectivity. Our activity modulation demonstrates that physiological relevant stimuli (high potassium and glutamate) can alter the functional connectivity of the local VTA network. This effect seems independent from the modulation of the neuronal firing rate.
Increased neuronal spontaneous firing rates have been observed throughout the central auditory system after trauma to the cochlea and this hyperactivity is believed to be associated with the phantom perception of tinnitus. Previously we have shown in an animal model of hearing loss, that an acute injection with furosemide can significantly decrease hyperactivity after cochlear trauma and eliminate behavioural evidence of tinnitus of early onset. However, furosemide also has the potential to affect cochlear thresholds. In this paper we measured the effects of a chronic (daily injections for 7 days) furosemide treatment on the spontaneous firing rate of inferior colliculus neurons and on cochlear thresholds in order to establish whether a beneficial effect on hyperactivity can be obtained without causing additional hearing loss. Guinea pigs were exposed to a 10 kHz, 124dB, 2 hour acoustic trauma, and after 5 days of recovery, were given daily i.p. injections of 80mg/kg furosemide or an equivalent amount of saline. The activity of single IC neurons was recorded 24 hours following the last injection. The furosemide treatment had no effect on cochlear thresholds compared to saline injections but did result in significant reductions in spontaneous firing rates recorded in inferior colliculus. These results that suggest a long term beneficial effect of furosemide on hyperactivity after cochlear trauma may be achievable without detrimental effects on hearing, which is important when
The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Increased neuronal spontaneous firing rates have been observed throughout the central auditory system after trauma to the cochlea and this hyperactivity is believed to be associated with the phantom perception of tinnitus.
Previously, we have shown in an animal model of hearing loss, that an acute injection with furosemide can significantly decrease hyperactivity after cochlear trauma and eliminate behavioral evidence of tinnitus of early onset. However, furosemide also has the potential to affect cochlear thresholds. In this paper, we measured the effects of a chronic (daily injections for 7 days) furosemide treatment on the spontaneous firing rate of inferior colliculus neurons and on cochlear thresholds in order to establish whether a beneficial effect on hyperactivity can be obtained without causing additional hearing loss.
The electrocardiogram was continuously monitored and heart rate never increased over pre-paralysis levels at any stage of the experiments. After the animals were mounted in hollow ear bars, the left and right cochleae were exposed and CAP audiograms were recorded on both sides with a silver wire placed on the round window as described for the recovery procedures. Paralysis was then induced with 0.1 ml pancuronium bromide (2 mg/ml intramuscularly).
(B) Histogram showing median spontaneous firing rate in CNIC in saline (362 neurons from four animals, white bar) and furosemide treated groups (398 neurons from five animals, black bar) 12 days after acoustic trauma. Median shown with 25 and 75% percentile. (C) Histogram showing median spontaneous firing rate of CNIC neurons in high and low frequency regions in saline treated animals (white bars) and furosemide treated animals (black bars) on day 12 after acoustic trauma. Bars show median with 25 and 75% percentile
Effects of chronic furosemide on central neural activity In total, data were obtained from 362 neurons in the CNIC of saline treated animals and 398 neurons from the CNIC of furosemide treated animals. Spontaneous firing rates in saline treated animals varied between 0 and 77.6 spikes/s with a mean spontaneous firing rate of 6.5 ± 0.65 (median 1.5) spikes/s and in furosemide treated animals between 0 and 52.5 spikes/s with an average rate of 3.45 ± 0.36 spikes/s (median 0.4) (Figure 1 B). The spontaneous firing rate in furosemide treated animals was significantly reduced compared to saline treated animals ( p < 0.0001).
In order to investigate whether furosemide was equally affecting the spontaneous firing rate of all neurons throughout the tonotopic map of the IC, neurons were also sorted according to CF. The spontaneous firing rates in saline and furosemide treated animals were compared for neurons with a CF < 12 kHz (non-hearing loss region) and a CF > 12 kHz (hearing loss region). Results from this analysis are shown in Figure 1 C.
In agreement with previously published data that showed a strong correlation between the frequency regions in the CNIC showing increased spontaneous firing and the peripheral frequency regions of hearing loss ( 16 ), Figure 1 C shows statistically elevated levels of spontaneous firing rate in the CF region >12 kHz compared to the CF region <12 kHz in saline treated animals ( p < 0.0001). Statistical analysis showed a significant decrease after furosemide in both CF groups ( p < 0.01 for CFs <12 kHz and p < 0.0001 for CFs >12 kHz). The largest effect of furosemide was seen in the frequency region that showed the most prominent hyperactivity.
This is also in agreement with our previous study showing initial increases in neuronal thresholds in IC after intracochlear perfusion of furosemide, which recovered fully after 1 h ( 9 ). The dose of furosemide used in this study may therefore have decreased the sound-evoked activity for a brief period after the injection, but there was no long-lasting effect on peripheral thresholds as the CAP audiogram data indicate. Overall spontaneous firing rates were significantly reduced after the chronic treatment with furosemide as compared to saline. This is the same effect as observed after acute administration of furosemide at the same dosage ( 9 ).
The action of anticonvulsant drugs on the firing of locus coeruleus neurons: selective, activating effect of carbamazepine.
The action of various doses of intraperitoneally administered carbamazepine, ethosuximide, Na-valproate, phenobarbital and diphenylhydantoin on the neuronal firing rate of presumed noradrenergic neurons of the locus coeruleus was investigated in the anaesthetized rat. Carbamazepine was the only compound which produced a statistically significant, dose-dependent activation of these neurons. The other anticonvulsant drugs caused a small but non significant reduction in locus coeruleus cell firing. It is concluded that this brain nucleus is not a main target of anticonvulsant drugs.
Published in European journal of pharmacology (1983)
For instance, the firing rate of 28 of 42 neurons was reduced during the initial amphetamine-induced locomotion as compared with the rate during predrug locomotion. Moreover, with the higher doses of amphetamine, there was a further reduction in firing rate corresponding to the transition from locomotion to stereotypies. In contrast to previous studies, which suggest that amphetamine generally increases neostriatal firing rate in behaving animals, these results suggest that amphetamine inhibits the numerous slowly firing neostriatal neurons, many of which were identified as projection neurons. Thus amphetamine alters the magnitude and pattern of neostriatal control of its neural targets. Published in Behavioral neuroscience (1989)
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