Showing papers in "Nature Neuroscience in 1999"
TL;DR: This large-scale longitudinal pediatric neuroimaging study confirmed linear increases in white matter, but demonstrated nonlinear changes in cortical gray matter, with a preadolescent increase followed by a postadolescent decrease.
Abstract: Pediatric neuroimaging studies1,2,3,4,5, up to now exclusively cross sectional, identify linear decreases in cortical gray matter and increases in white matter across ages 4 to 20. In this large-scale longitudinal pediatric neuroimaging study, we confirmed linear increases in white matter, but demonstrated nonlinear changes in cortical gray matter, with a preadolescent increase followed by a postadolescent decrease. These changes in cortical gray matter were regionally specific, with developmental curves for the frontal and parietal lobe peaking at about age 12 and for the temporal lobe at about age 16, whereas cortical gray matter continued to increase in the occipital lobe through age 20.
5,140 citations
TL;DR: Results suggest that rather than being exclusively feedforward phenomena, nonclassical surround effects in the visual cortex may also result from cortico-cortical feedback as a consequence of the visual system using an efficient hierarchical strategy for encoding natural images.
Abstract: We describe a model of visual processing in which feedback connections from a higher- to a lower- order visual cortical area carry predictions of lower-level neural activities, whereas the feedforward connections carry the residual errors between the predictions and the actual lower-level activities. When exposed to natural images, a hierarchical network of model neurons implementing such a model developed simple-cell-like receptive fields. A subset of neurons responsible for carrying the residual errors showed endstopping and other extra-classical receptive-field effects. These results suggest that rather than being exclusively feedforward phenomena, nonclassical surround effects in the visual cortex may also result from cortico-cortical feedback as a consequence of the visual system using an efficient hierarchical strategy for encoding natural images.
4,149 citations
TL;DR: It is demonstrated that voluntary exercise is sufficient for enhanced neurogenesis in the adult mouse dentate gyrus, in amounts similar to enrichment conditions.
Abstract: Exposure to an enriched environment increases neurogenesis in the dentate gyrus of adult rodents. Environmental enrichment, however, typically consists of many components, such as expanded learning opportunities, increased social interaction, more physical activity and larger housing. We attempted to separate components by assigning adult mice to various conditions: water-maze learning (learner), swim-time-yoked control (swimmer), voluntary wheel running (runner), and enriched (enriched) and standard housing (control) groups. Neither maze training nor yoked swimming had any effect on bromodeoxyuridine (BrdU)-positive cell number. However, running doubled the number of surviving newborn cells, in amounts similar to enrichment conditions. Our findings demonstrate that voluntary exercise is sufficient for enhanced neurogenesis in the adult mouse dentate gyrus.
3,766 citations
TL;DR: A new hierarchical model consistent with physiological data from inferotemporal cortex that accounts for this complex visual task and makes testable predictions is described.
Abstract: Visual processing in cortex is classically modeled as a hierarchy of increasingly sophisticated representations, naturally extending the model of simple to complex cells of Hubel and Wiesel. Surprisingly, little quantitative modeling has been done to explore the biological feasibility of this class of models to explain aspects of higher-level visual processing such as object recognition. We describe a new hierarchical model consistent with physiological data from inferotemporal cortex that accounts for this complex visual task and makes testable predictions. The model is based on a MAX-like operation applied to inputs to certain cortical neurons that may have a general role in cortical function.
3,478 citations
TL;DR: It is reported that the number of adult-generated neurons doubles in the rat dentate gyrus in response to training on associative learning tasks that require the hippocampus, which indicates that adult- generated hippocampal neurons are specifically affected by, and potentially involved in, associative memory formation.
Abstract: Thousands of hippocampal neurons are born in adulthood, suggesting that new cells could be important for hippocampal function. To determine whether hippocampus-dependent learning affects adult-generated neurons, we examined the fate of new cells labeled with the thymidine analog bromodeoxyuridine following specific behavioral tasks. Here we report that the number of adult-generated neurons doubles in the rat dentate gyrus in response to training on associative learning tasks that require the hippocampus. In contrast, training on associative learning tasks that do not require the hippocampus did not alter the number of new cells. These findings indicate that adult-generated hippocampal neurons are specifically affected by, and potentially involved in, associative memory formation.
2,139 citations
TL;DR: Early-onset prefrontal damage resulted in a syndrome resembling psychopathy, suggesting that the acquisition of complex social conventions and moral rules had been impaired.
Abstract: The long-term consequences of early prefrontal cortex lesions occurring before 16 months were investigated in two adults. As is the case when such damage occurs in adulthood, the two early-onset patients had severely impaired social behavior despite normal basic cognitive abilities, and showed insensitivity to future consequences of decisions, defective autonomic responses to punishment contingencies and failure to respond to behavioral interventions. Unlike adult-onset patients, however, the two patients had defective social and moral reasoning, suggesting that the acquisition of complex social conventions and moral rules had been impaired. Thus early-onset prefrontal damage resulted in a syndrome resembling psychopathy.
1,426 citations
TL;DR: The pattern of brain maturation during these years was distinct from earlier development, and was localized to large regions of dorsal, medial and orbital frontal cortex and lenticular nuclei, with relatively little change in any other location.
Abstract: We spatially and temporally mapped brain maturation between adolescence and young adulthood using a whole-brain, voxel-by-voxel statistical analysis of high-resolution structural magnetic resonance images (MRI). The pattern of brain maturation during these years was distinct from earlier development, and was localized to large regions of dorsal, medial and orbital frontal cortex and lenticular nuclei, with relatively little change in any other location. This spatial and temporal pattern agrees with convergent findings from post-mortem studies of brain development and the continued development over this age range of cognitive functions attributed to frontal structures.
1,363 citations
TL;DR: Functional magnetic resonance imaging was used to measure changes associated with increasing expertise in brain areas selected for their face preference, and evidence is presented that expertise recruits the fusiform gyrus 'face area'.
Abstract: Part of the ventral temporal lobe is thought to be critical for face perception, but what determines this specialization remains unknown We present evidence that expertise recruits the fusiform gyrus ‘face area’ Functional magnetic resonance imaging (fMRI) was used to measure changes associated with increasing expertise in brain areas selected for their face preference Acquisition of expertise with novel objects (greebles) led to increased activation in the right hemisphere face areas for matching of upright greebles as compared to matching inverted greebles The same areas were also more activated in experts than in novices during passive viewing of greebles Expertise seems to be one factor that leads to specialization in the face area
1,210 citations
TL;DR: These findings suggest that semantic object information is represented in distributed networks that include sites for storing information about specific object attributes such as form and motion in ventral temporal cortex and lateral temporal lobes.
Abstract: The cognitive and neural mechanisms underlying category-specific knowledge remain controversial. Here we report that, across multiple tasks (viewing, delayed match to sample, naming), pictures of animals and tools were associated with highly consistent, category-related patterns of activation in ventral (fusiform gyrus) and lateral (superior and middle temporal gyri) regions of the posterior temporal lobes. In addition, similar patterns of category-related activity occurred when subjects read the names of, and answered questions about, animals and tools. These findings suggest that semantic object information is represented in distributed networks that include sites for storing information about specific object attributes such as form (ventral temporal cortex) and motion (lateral temporal cortex).
1,204 citations
TL;DR: A possible means for movement restoration in paralysis patients is suggested after rats trained to position a robot arm to obtain water by pressing a lever routinely used brain-derived signals to position the robot arm and obtain water.
Abstract: To determine whether simultaneously recorded motor cortex neurons can be used for real-time device control, rats were trained to position a robot arm to obtain water by pressing a lever. Mathematical transformations, including neural networks, converted multineuron signals into ‘neuronal population functions’ that accurately predicted lever trajectory. Next, these functions were electronically converted into real-time signals for robot arm control. After switching to this ‘neurorobotic’ mode, 4 of 6 animals (those with >25 task-related neurons) routinely used these brain-derived signals to position the robot arm and obtain water. With continued training in neurorobotic mode, the animals’ lever movement diminished or stopped. These results suggest a possible means for movement restoration in paralysis patients.
1,133 citations
TL;DR: This approach shows that dynamic stimuli can be encoded efficiently by single neurons and that each spike contributes to information transmission, and argues that the data obtained so far do not suggest a temporal code, in which the placement of spikes relative to each other yields additional information.
Abstract: Information theory quantifies how much information a neural response carries about the stimulus This can be compared to the information transferred in particular models of the stimulus-response function and to maximum possible information transfer Such comparisons are crucial because they validate assumptions present in any neurophysiological analysis Here we review information-theory basics before demonstrating its use in neural coding We show how to use information theory to validate simple stimulus-response models of neural coding of dynamic stimuli Because these models require specification of spike timing precision, they can reveal which time scales contain information in neural coding This approach shows that dynamic stimuli can be encoded efficiently by single neurons and that each spike contributes to information transmission We argue, however, that the data obtained so far do not suggest a temporal code, in which the placement of spikes relative to each other yields additional information
TL;DR: Injection of multiple tracers into physiologically mapped regions AL, ML and CL of the auditory belt cortex revealed that anterior belt cortex was reciprocally connected with the frontal pole, rostral principal sulcus and ventral prefrontal regions.
Abstract: 'What' and 'where' visual streams define ventrolateral object and dorsolateral spatial processing domains in the prefrontal cortex of nonhuman primates. We looked for similar streams for auditory‐prefrontal connections in rhesus macaques by combining microelectrode recording with anatomical tract-tracing. Injection of multiple tracers into physiologically mapped regions AL, ML and CL of the auditory belt cortex revealed that anterior belt cortex was reciprocally connected with the frontal pole (area 10), rostral principal sulcus (area 46) and ventral prefrontal regions (areas 12 and 45), whereas the caudal belt was mainly connected with the caudal principal sulcus (area 46) and frontal eye fields (area 8a). Thus separate auditory streams originate in caudal and rostral auditory cortex and target spatial and non-spatial domains of the frontal lobe, respectively.
TL;DR: The findings suggest that music may recruit neural mechanisms similar to those previously associated with pleasant/unpleasant emotional states, but different from those underlying other components of music perception, and other emotions such as fear.
Abstract: Neural correlates of the often-powerful emotional responses to music are poorly understood. Here we used positron emission tomography to examine cerebral blood flow (CBF) changes related to affective responses to music. Ten volunteers were scanned while listening to six versions of a novel musical passage varying systematically in degree of dissonance. Reciprocal CBF covariations were observed in several distinct paralimbic and neocortical regions as a function of dissonance and of perceived pleasantness/unpleasantness. The findings suggest that music may recruit neural mechanisms similar to those previously associated with pleasant/unpleasant emotional states, but different from those underlying other components of music perception, and other emotions such as fear. articles
TL;DR: Following sequential exposure of rats to two different environments or to the same environment twice, the proportion of CA1 neurons with cytoplasmic, nuclear or overlapping Arc expression profiles matched predictions derived from ensemble neurophysiological recordings of hippocampal neuronal ensembles.
Abstract: We used fluorescent in-situ hybridization and confocal microscopy to monitor the subcellular distribution of the immediate-early gene Arc. Arc RNA appeared in discrete intranuclear foci within minutes of neuronal activation and subsequently disappeared from the nucleus and accumulated in the cytoplasm by 30 minutes. The time course of nuclear versus cytoplasmic Arc RNA accumulation was distinct, and could therefore be used to infer the activity history of individual neurons at two times. Following sequential exposure of rats to two different environments or to the same environment twice, the proportion of CA1 neurons with cytoplasmic, nuclear or overlapping Arc expression profiles matched predictions derived from ensemble neurophysiological recordings of hippocampal neuronal ensembles. Arc gene induction is thus specifically linked to neural encoding processes.
TL;DR: Event-related potentials (ERPs) and modeling of their neural sources indicated that the initial sensory input to striate cortex at 50–55 milliseconds after the stimulus was not modulated by attention, whereas the earliest facilitation of attended signals was observed in extrastriate visual areas.
Abstract: We investigated the cortical mechanisms of visual-spatial attention while subjects discriminated patterned targets within distractor arrays. Functional magnetic resonance imaging (fMRI) was used to map the boundaries of retinotopic visual areas and to localize attention-related changes in neural activity within several of those areas, including primary visual (striate) cortex. Event-related potentials (ERPs) and modeling of their neural sources, however, indicated that the initial sensory input to striate cortex at 50−55 milliseconds after the stimulus was not modulated by attention. The earliest facilitation of attended signals was observed in extrastriate visual areas, at 70−75 milliseconds. We hypothesize that the striate cortex modulation found with fMRI may represent a delayed, re-entrant feedback from higher visual areas or a sustained biasing of striate cortical neurons during attention. ERP recordings provide critical temporal information for analyzing the functional neuroanatomy of visual attention.
TL;DR: Impairments in functional synaptic plasticity may underlie some of the cognitive deficits in these mice and, possibly, in Alzheimer's patients.
Abstract: We investigated synaptic communication and plasticity in hippocampal slices from mice overexpressing mutated 695-amino-acid human amyloid precursor protein (APP695SWE), which show behavioral and histopathological abnormalities simulating Alzheimer's disease. Although aged APP transgenic mice exhibit normal fast synaptic transmission and short term plasticity, they are severely impaired in in-vitro and in-vivo long-term potentiation (LTP) in both the CA1 and dentate gyrus regions of the hippocampus. The LTP deficit was correlated with impaired performance in a spatial working memory task in aged transgenics. These deficits are accompanied by minimal or no loss of presynaptic or postsynaptic elementary structural elements in the hippocampus, suggesting that impairments in functional synaptic plasticity may underlie some of the cognitive deficits in these mice and, possibly, in Alzheimer's patients.
TL;DR: It is shown that bilateral amygdala activity during memory encoding is correlated with enhanced episodic recognition memory for both pleasant and aversive visual stimuli relative to neutral stimuli, and that this relationship is specific to emotional stimuli.
Abstract: Pleasant or aversive events are better remembered than neutral events. Emotional enhancement of episodic memory has been linked to the amygdala in animal and neuropsychological studies. Using positron emission tomography, we show that bilateral amygdala activity during memory encoding is correlated with enhanced episodic recognition memory for both pleasant and aversive visual stimuli relative to neutral stimuli, and that this relationship is specific to emotional stimuli. Furthermore, data suggest that the amygdala enhances episodic memory in part through modulation of hippocampal activity. The human amygdala seems to modulate the strength of conscious memory for events according to emotional importance, regardless of whether the emotion is pleasant or aversive.
TL;DR: A combination of sensory integration and motor planning could reflect the conversion of visual motion information into a categorical decision about direction and thus give insight into the neural computations behind a simple cognitive act.
Abstract: To make a visual discrimination, the brain must extract relevant information from the retina, represent appropriate variables in the visual cortex and read out this representation to decide which of two or more alternatives is more likely. We recorded from neurons in the dorsolateral prefrontal cortex (areas 8 and 46) of the rhesus monkey while it performed a motion discrimination task. The monkey indicated its judgment of direction by making appropriate eye movements. As the monkey viewed the motion stimulus, the neural response predicted the monkey’s subsequent gaze shift, hence its judgment of direction. The response comprised a mixture of high-level oculomotor signals and weaker visual sensory signals that reflected the strength and direction of motion. This combination of sensory integration and motor planning could reflect the conversion of visual motion information into a categorical decision about direction and thus give insight into the neural computations behind a simple cognitive act.
TL;DR: Paired whole-cell recordings are used to show that inhibitory synaptic potentials generated from single interneurons are sufficiently powerful to delay or entirely block the generation of action potentials in a large number of projection neurons simultaneously.
Abstract: The basal ganglia are a highly interconnected network of nuclei essential for the modulation and execution of voluntary behavior The neostriatum is the principal input and one of the principal controllers of the output of the basal ganglia Neostriatal projection neurons seem to be dynamically and powerfully controlled by GABAergic inputs, but the source(s) and physiological properties of these inputs remain unclear Here we use paired whole-cell recordings to show that this inhibition derives from small populations of GABAergic interneurons that are themselves interconnected through functional electrotonic synapses Inhibitory synaptic potentials generated from single interneurons are sufficiently powerful to delay or entirely block the generation of action potentials in a large number of projection neurons simultaneously
TL;DR: Transcranial magnetic stimulation was applied over the left PPC during target presentation and disrupted path corrections that normally occur in response to target jumps, but had no effect on those directed at stationary targets.
Abstract: The exact role of posterior parietal cortex (PPC) in visually directed reaching is unknown. We propose that, by building an internal representation of instantaneous hand location, PPC computes a dynamic motor error used by motor centers to correct the ongoing trajectory. With unseen right hands, five subjects pointed to visual targets that either remained stationary or moved during saccadic eye movements. Transcranial magnetic stimulation (TMS) was applied over the left PPC during target presentation. Stimulation disrupted path corrections that normally occur in response to target jumps, but had no effect on those directed at stationary targets. Furthermore, left-hand movement corrections were not blocked, ruling out visual or oculomotor effects of stimulation.
TL;DR: It is demonstrated that in response to changes in activity, cultured cortical pyramidal neurons regulate intrinsic excitability to promote stability in firing by selectively regulating voltage-dependent conductances.
Abstract: During learning and development, the level of synaptic input received by cortical neurons may change dramatically. Given a limited range of possible firing rates, how do neurons maintain responsiveness to both small and large synaptic inputs? We demonstrate that in response to changes in activity, cultured cortical pyramidal neurons regulate intrinsic excitability to promote stability in firing. Depriving pyramidal neurons of activity for two days increased sensitivity to current injection by selectively regulating voltage-dependent conductances. This suggests that one mechanism by which neurons maintain sensitivity to different levels of synaptic input is by altering the function relating current to firing rate.
TL;DR: Data show that SNS is involved in pain pathways and suggest that blockade of SNS expression or function may produce analgesia without side effects, and show that TTX-resistant sodium channel α subunit is encoded by the sns gene.
Abstract: Many damage-sensing neurons express tetrodotoxin (TTX)-resistant voltage-gated sodium channels. Here we examined the role of the sensory-neuron-specific (SNS) TTX-resistant sodium channel a subunit in nociception and pain by constructing sns-null mutant mice. These mice expressed only TTX-sensitive sodium currents on step depolarizations from normal resting potentials, showing that all slow TTX-resistant currents are encoded by the sns gene. Null mutants were viable, fertile and apparently normal, although lowered thresholds of electrical activation of C-fibers and increased current densities of TTX-sensitive channels demonstrated compensatory upregulation of TTX-sensitive currents in sensory neurons. Behavioral studies demonstrated a pronounced analgesia to noxious mechanical stimuli, small deficits in noxious thermoreception and delayed development of inflammatory hyperalgesia. These data show that SNS is involved in pain pathways and suggest that blockade of SNS expression or function may produce analgesia without side effects.
TL;DR: Separate kinematic and dynamic models were constructed simultaneously based on errors computed in different coordinate frames, and possibly, in different sensory modalities, using separate working-memory systems.
Abstract: Psychophysical studies of reaching movements suggest that hand kinematics are learned from errors in extent and direction in an extrinsic coordinate system, whereas dynamics are learned from proprioceptive errors in an intrinsic coordinate system. We examined consolidation and interference to determine if these two forms of learning were independent. Learning and consolidation of two novel transformations, a rotated spatial reference frame and altered intersegmental dynamics, did not interfere with each other and consolidated in parallel. Thus separate kinematic and dynamic models were constructed simultaneously based on errors computed in different coordinate frames, and possibly, in different sensory modalities, using separate working-memory systems. These results suggest that computational approaches to motor learning should include two separate performance errors rather than one.
TL;DR: Pretreatment with the cannabinoid antagonist SR141716A enhanced the stimulation of motor behavior elicited by systemic administration of quinpirole, suggesting that the endocannabinoid system may act as an inhibitory feedback mechanism countering dopamine-induced facilitation of motor activity.
Abstract: We measured endogenous cannabinoid release in dorsal striatum of freely moving rats by microdialysis and gas chromatography/mass spectrometry Neural activity stimulated the release of anandamide, but not of other endogenous cannabinoids such as 2-arachidonylglycerol Moreover, anandamide release was increased eightfold over baseline after local administration of the D2-like (D2, D3, D4) dopamine receptor agonist quinpirole, a response that was prevented by the D2-like receptor antagonist raclopride Administration of the D1-like (D1, D5) receptor agonist SKF38393 had no such effect These results suggest that functional interactions between endocannabinoid and dopaminergic systems may contribute to striatal signaling In agreement with this hypothesis, pretreatment with the cannabinoid antagonist SR141716A enhanced the stimulation of motor behavior elicited by systemic administration of quinpirole The endocannabinoid system therefore may act as an inhibitory feedback mechanism countering dopamine-induced facilitation of motor activity
TL;DR: Inhibition of ERK phosphorylation by a MEK inhibitor reduced the second phase of formalin-induced pain behavior, a measure of spinal neuron sensitization, and ERK signaling within the spinal cord is therefore involved in generating pain hypersensitivity.
Abstract: We investigated the involvement of extracellular signal-regulated protein kinases (ERK) within spinal neurons in producing pain hypersensitivity. Within a minute of an intense noxious peripheral or C-fiber electrical stimulus, many phosphoERK-positive neurons were observed, most predominantly in lamina I and IIo of the ipsilateral dorsal horn. This staining was intensity and NMDA receptor dependent. Low-intensity stimuli or A-fiber input had no effect. Inhibition of ERK phosphorylation by a MEK inhibitor reduced the second phase of formalin-induced pain behavior, a measure of spinal neuron sensitization. ERK signaling within the spinal cord is therefore involved in generating pain hypersensitivity. Because of its rapid activation, this effect probably involves regulation of neuronal excitability without changes in transcription.
TL;DR: It is shown that reducing corticosteroid levels in aged rats restored the rate of cell proliferation, resulting in increased numbers of new granule neurons, indicating that the neuronal precursor population in the dentate gyrus remains stable into old age, but that neurogenesis is normally slowed by high levels of Corticosteroids.
Abstract: The production of hippocampal granule neurons continues throughout adulthood but dramatically decreases in old age Here we show that reducing corticosteroid levels in aged rats restored the rate of cell proliferation, resulting in increased numbers of new granule neurons This result indicates that the neuronal precursor population in the dentate gyrus remains stable into old age, but that neurogenesis is normally slowed by high levels of corticosteroids The findings further suggest that decreased neurogenesis may contribute to age-related memory deficits associated with high corticosteroids, and that these deficits may be reversible
TL;DR: A physiological basis for the effects of spatially directed visual attention is identified and retinotopic mapping of attention-related activation was found in primary visual cortex, as well as in dorsomedial and ventral occipital visual areas previously implicated in processing the attended target features.
Abstract: Here we identify a neural correlate of the ability to precisely direct visual attention to locations other than the center of gaze. Human subjects performed a task requiring shifts of visual attention (but not of gaze) from one location to the next within a dense array of targets and distracters while functional MRI was used to map corresponding displacements of neural activation within visual cortex. The cortical topography of the purely attention-driven activity precisely matched the topography of activity evoked by the cued targets when presented in isolation. Such retinotopic mapping of attention-related activation was found in primary visual cortex, as well as in dorsomedial and ventral occipital visual areas previously implicated in processing the attended target features. These results identify a physiological basis for the effects of spatially directed visual attention.
TL;DR: Grafted neurons can continue for a decade to store and release dopamine and give rise to substantial symptomatic relief in a patient with Parkinson's disease.
Abstract: Synaptic dopamine release from embryonic nigral transplants has been monitored in the striatum of a patient with Parkinson's disease using [11C]-raclopride positron emission tomography to measure dopamine D2 receptor occupancy by the endogenous transmitter. In this patient, who had received a transplant in the right putamen 10 years earlier, grafts had restored both basal and drug-induced dopamine release to normal levels. This was associated with sustained, marked clinical benefit and normalized levels of dopamine storage in the grafted putamen. Despite an ongoing disease process, grafted neurons can thus continue for a decade to store and release dopamine and give rise to substantial symptomatic relief.
TL;DR: Findings indicate that 'silent' SCC synapses are smaller than the majority of S CC synapses at which AMPA and NMDA receptors are colocalized, and synapse size may determine important properties of SCCsynapses.
Abstract: Postembedding immunogold labeling was used to determine the relationship between AMPA and NMDA receptor density and size of Schaffer collateral–commissural (SCC) synapses of the adult rat. All SCC synapses expressed NMDA receptors. AMPA and NMDA receptors were colocalized in at least 75% of SCC synapses; the ratio of AMPA to NMDA receptors was a linear function of postsynaptic density (PSD) diameter, with AMPA receptor number dropping to zero at a PSD diameter of ~180 nm. These findings indicate that 'silent' SCC synapses are smaller than the majority of SCC synapses at which AMPA and NMDA receptors are colocalized. Thus synapse size may determine important properties of SCC synapses.
TL;DR: It is shown that TASK and TREK-1, two recently cloned mammalian two-P-domain K+ channels similar to IKAn in biophysical properties, are activated by volatile general anesthetics.
Abstract: Volatile anesthetics produce safe, reversible unconsciousness, amnesia and analgesia via hyperpolarization of mammalian neurons. In molluscan pacemaker neurons, they activate an inhibitory synaptic K+ current (IKAn), proposed to be important in general anesthesia. Here we show that TASK and TREK-1, two recently cloned mammalian two-P-domain K+ channels similar to IKAn in biophysical properties, are activated by volatile general anesthetics. Chloroform, diethyl ether, halothane and isoflurane activated TREK-1, whereas only halothane and isoflurane activated TASK. Carboxy (C)-terminal regions were critical for anesthetic activation in both channels. Thus both TREK-1 and TASK are possibly important target sites for these agents.