Thalamic Microinfusion of Antibody to a Voltage-gated Potassium Channel Restores Consciousness during Anesthesia
ABSTRACT The Drosophila Shaker mutant fruit-fly, with its malfunctioning voltage-gated potassium channel, exhibits anesthetic requirements that are more than twice normal. Shaker mutants with an abnormal Kv1.2 channel also demonstrate significantly reduced sleep. Given the important role the thalamus plays in both sleep and arousal, the authors investigated whether localized central medial thalamic (CMT) microinfusion of an antibody designed to block the pore of the Kv1.2 channel might awaken anesthetized rats.
Male Sprague-Dawley rats were implanted with a cannula aimed at the CMT or lateral thalamus. One week later, unconsciousness was induced with either desflurane (3.6 +/- 0.2%; n = 55) or sevoflurane (1.2 +/- 0.1%; n = 51). Arousal effects of a single 0.5-microl infusion of Kv1.2 potassium channel blocking antibody (0.1- 0.2 mg/ml) or a control infusion of Arc-protein antibody (0.2 mg/ml) were then determined.
The Kv1.2 antibody, but not the control antibody, temporarily restored consciousness in 17% of all animals and in 75% of those animals where infusions occurred within the CMT (P < 0.01 for each anesthetic). Lateral thalamic infusions showed no effects. Consciousness returned on average (+/- SD) 170 +/- 99 s after infusion and lasted a median time of 398 s (interquartile range: 279-510 s). Temporary seizures, without apparent consciousness, predominated in 33% of all animals.
These findings support the idea that the CMT plays a role in modulating levels of arousal during anesthesia and further suggest that voltage-gated potassium channels in the CMT may contribute to regulating arousal or may even be relevant targets of anesthetic action.
- SourceAvailable from: Jacqueline R Hembrook-Short
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- "By contrast, central thalamic activity is diminished when subjects are rendered unconscious by general anesthesia (Fiset et al., 1999; White and Alkire, 2003). This relationship has been confirmed by evidence that the effects of anesthesia are reversed in animal models when central thalamus is activated by microinjection of nicotine or an antibody to a voltage-gated potassium channel directly into central thalamus (Alkire et al., 2007, 2009). Central thalamic neurons show phasic as well as tonic patterns of activation . "
ABSTRACT: Central thalamus regulates forebrain arousal, influencing activity in distributed neural networks that give rise to organized actions during alert, wakeful states. Central thalamus has been implicated in working memory by the effects of lesions and microinjected drugs in this part of the brain. Lesions and drugs that inhibit neural activity have been found to impair working memory. Drugs that increase activity have been found to enhance and impair memory depending on the dose tested. Electrical deep brain stimulation (DBS) similarly enhances working memory at low stimulating currents and impairs it at higher currents. These effects are time dependent. They were observed when DBS was applied during the memory delay (retention) or choice response (retrieval) but not earlier in trials during the sample (acquisition) phase. The effects of microinjected drugs and DBS are consistent with the Yerkes-Dodson law, which describes an inverted-U relationship between arousal and behavioral performance. Alternatively these results may reflect desensitization associated with higher levels of stimulation, spread of drugs or current to adjacent structures, or activation of less sensitive neurons or receptors at higher DBS currents or drug doses.Dose-Response 07/2011; 9(3):313-31. DOI:10.2203/dose-response.10-017.Mair · 1.22 Impact Factor
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- "However, the Kcna2 short sleeping phenotype is far from being as dramatic as in Shaker flies, perhaps because of redundancy -there is one Shaker gene in Drosophila, but at least 16 genes code for alpha subunits of voltage-dependent potassium channels in mammals (Misonou and Trimmer 2004, Yuan and Chen 2006). Finally in mice, the injection of an antibody against the kv1.2 potassium channel into the central medial thalamus induces arousal from anesthesia (Alkire et al. 2009). "
ABSTRACT: Sleep consists of quiescent periods with reduced responsiveness to external stimuli. Despite being maladaptive in that when asleep, animals are less able to respond to dangerous stimuli; sleep behavior is conserved in all animal species studied to date. Thus, sleep must be performing at least one fundamental, conserved function that is necessary, and/or whose benefits outweigh its maladaptive consequences. Currently, there is no consensus on what that function might be. Over the last 10 years, multiple groups have started to characterize the molecular mechanisms and brain structures necessary for normal sleep in Drosophila melanogaster. These researchers are exploiting genetic tools developed in Drosophila over the past century to identify and manipulate gene expression. Forward genetic screens can identify molecular components in complex biological systems and once identified, these genes can be manipulated within specific brain areas to determine which neuronal groups are important to initiate and maintain sleep. Screening for mutations and brain regions necessary for normal sleep has revealed that several genes that affect sleep are involved in synaptic plasticity and have preferential expression in the mushroom bodies (MBs). Moreover, altering MB neuronal activity alters sleep. Previous genetic screens found that the same genes enriched in MB are necessary for learning and memory. Increasing evidence in mammals, including humans, points to a beneficial role for sleep in synaptic plasticity, learning and memory. Thus, results from both flies and mammals suggest a strong link between sleep need and wake plasticity.International Review of Neurobiology 01/2011; 99:213-44. DOI:10.1016/B978-0-12-387003-2.00009-4 · 1.92 Impact Factor
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- "Conversely neural inertia can be narrowed by genetic manipulation as demonstrated by the effects of the mutant allele Shmns in Drosophila. This result is consistent with work done in rats, which demonstrated that microinjection of an antibody against the Shaker potassium channel (Kv1.2) into the central medial thalamus also reverses deep states of anesthetic-induced hypnosis by abruptly triggering emergence, with signs of return to consciousness, despite ongoing delivery of volatile anesthetics . Near-total collapse of neural inertia in Shaker mutant flies raises concerns of additional anesthetic morbidity. "
ABSTRACT: One major unanswered question in neuroscience is how the brain transitions between conscious and unconscious states. General anesthetics offer a controllable means to study these transitions. Induction of anesthesia is commonly attributed to drug-induced global modulation of neuronal function, while emergence from anesthesia has been thought to occur passively, paralleling elimination of the anesthetic from its sites in the central nervous system (CNS). If this were true, then CNS anesthetic concentrations on induction and emergence would be indistinguishable. By generating anesthetic dose-response data in both insects and mammals, we demonstrate that the forward and reverse paths through which anesthetic-induced unconsciousness arises and dissipates are not identical. Instead they exhibit hysteresis that is not fully explained by pharmacokinetics as previously thought. Single gene mutations that affect sleep-wake states are shown to collapse or widen anesthetic hysteresis without obvious confounding effects on volatile anesthetic uptake, distribution, or metabolism. We propose a fundamental and biologically conserved concept of neural inertia, a tendency of the CNS to resist behavioral state transitions between conscious and unconscious states. We demonstrate that such a barrier separates wakeful and anesthetized states for multiple anesthetics in both flies and mice, and argue that it contributes to the hysteresis observed when the brain transitions between conscious and unconscious states.PLoS ONE 07/2010; 5(7):e11903. DOI:10.1371/journal.pone.0011903 · 3.23 Impact Factor