Showing papers in "The Journal of Neuroscience in 1995"
TL;DR: The enhanced induction and prolonged expression of BDNF in response to chronic ECS and antidepressant drug treatments could promote neuronal survival, and protect neurons from the damaging effects of stress.
Abstract: The influence of chronic electroconvulsive seizure (ECS) or antidepressant drug treatments on expression of brain-derived neurotrophic factor (BDNF) and its receptor, trkB, was examined by in situ hybridization and Northern blot. In frontal cortex, acute ECS increased BDNF mRNA approximately twofold, an effect significantly augmented by a prior course of chronic ECS treatment (10 d). In the hippocampus, the influence of chronic ECS varied between the major subfields. In the dentate gyrus granule cell layer, chronic ECS decreased the acute induction of BDNF and trkB mRNA by approximately 50%, but prolonged their expression: levels remained elevated two- to threefold 18 hr later after the last chronic ECS treatment, but returned to control 18 hr after acute ECS. In CA3 and CA1 pyramidal cell layers, chronic ECS significantly elevated the acute induction of BDNF, and tended to prolong the expression of BDNF and trkB mRNA. A similar effect was observed in layer 2 of the piriform cortex, where chronic ECS significantly increased the acute induction and prolonged the expression of BDNF and trkB mRNA. Chronic (21 d), but not acute (1 d), administration of several different antidepressant drugs, including tranylcypromine, sertraline, desipramine, or mianserin, significantly increased BDNF mRNA and all but mianserin increased trkB mRNA in hippocampus. In contrast, chronic administration of nonantidepressant psychotropic drugs, including morphine, cocaine, or haloperidol, did not increase levels of BDNF mRNA. Furthermore, chronic administration of ECS or antidepressant drugs completely blocked the down-regulation of BDNF mRNA in the hippocampus in response to restraint stress. The enhanced induction and prolonged expression of BDNF in response to chronic ECS and antidepressant drug treatments could promote neuronal survival, and protect neurons from the damaging effects of stress.
2,077 citations
TL;DR: It is suggested that gamma oscillation emerges from an interaction between intrinsic oscillatory properties of interneurons and the network properties of the dentate gyrus and that Gamma oscillation in the CA3-CA1 circuitry is suppressed by either the hilar region or the entorhinal cortex.
Abstract: The cellular generation and spatial distribution of gamma frequency (40-100 Hz) activity was examined in the hippocampus of the awake rat. Field potentials and unit activity were recorded by multiple site silicon probes (5- and 16-site shanks) and wire electrode arrays. Gamma waves were highly coherent along the long axis of the dentate hilus, but average coherence decreased rapidly in the CA3 and CA1 directions. Analysis of short epochs revealed large fluctuations in coherence values between the dentate and CA1 gamma waves. Current source density analysis revealed large sinks and sources in the dentate gyrus with spatial distribution similar to the dipoles evoked by stimulation of the perforant path. The frequency changes of gamma and theta waves positively correlated (40-100 Hz and 5-10 Hz, respectively). Putative interneurons in the dentate gyrus discharged at gamma frequency and were phase-locked to the ascending part of the gamma waves recorded from the hilus. Following bilateral lesion of the entorhinal cortex the power and frequency of hilar gamma activity significantly decreased or disappeared. Instead, a large amplitude but slower gamma pattern (25-50 Hz) emerged in the CA3-CA1 network. We suggest that gamma oscillation emerges from an interaction between intrinsic oscillatory properties of interneurons and the network properties of the dentate gyrus. We also hypothesize that under physiological conditions the hilar gamma oscillation may be entrained by the entorhinal rhythm and that gamma oscillation in the CA3-CA1 circuitry is suppressed by either the hilar region or the entorhinal cortex.
1,529 citations
TL;DR: It is demonstrated that BDNF and NT-3 are stress-responsive genes and the possibility that alterations in the expression of these or other growth factors might be important in producing some of the physiological and pathophysiological effects of stress in the hippocampus is raised.
Abstract: Chronic stress produces structural changes and neuronal damage especially in the hippocampus. Because neurotrophic factors affect neuron survival, we questioned whether they might be relevant to the heightened vulnerability of hippocampal neurons following stress. To begin investigating this possibility, we examined the effects of immobilization stress (2 hr/d) on the expression of neurotrophic factors in rat brains using in situ hybridization. We found that single or repeated immobilization markedly reduced brain-derived neurotrophic factor (BDNF) mRNA levels in the dentate gyrus and hippocampus. In contrast, NT-3 mRNA levels were increased in the dentate gyrus and hippocampus in response to repeated but not acute stress. Stress did not affect the expression of neurotrophin-4, or tyrosine receptor kinases (trkB or C). Corticosterone negative feedback may have contributed in part to the stress-induced decreases in BDNF mRNA levels, but stress still decreased BDNF in the dentate gyrus in adrenalectomized rats suggesting that additional components of the stress response must also contribute to the observed changes in BDNF. However, corticosterone-mediated increases in NT-3 mRNA expression appeared to be primarily responsible for the effects of stress on NT-3. These findings demonstrate that BDNF and NT-3 are stress-responsive genes and raise the possibility that alterations in the expression of these or other growth factors might be important in producing some of the physiological and pathophysiological effects of stress in the hippocampus.
1,456 citations
TL;DR: FMRI activity in human MT does in fact decrease at and near individually measured equiluminance, and area MT has a much higher contrast sensitivity than that in several other areas, including primary visual cortex (V1).
Abstract: Using noninvasive functional magnetic resonance imaging (fMRI) technique, we analyzed the responses in human area MT with regard to visual motion, color, and luminance contrast sensitivity, and retinotopy. As in previous PET studies, we found that area MT responded selectively to moving (compared to stationary) stimuli. The location of human MT in the present fMRI results is consistent with that of MT in earlier PET and anatomical studies. In addition we found that area MT has a much higher contrast sensitivity than that in several other areas, including primary visual cortex (V1). Functional MRI half-amplitudes in V1 and MT occurred at approximately 15% and 1% luminance contrast, respectively. High sensitivity to contrast and motion in MT have been closely associated with magnocellular stream specialization in nonhuman primates. Human psychophysics indicates that visual motion appears to diminish when moving color-varying stimuli are equated in luminance. Electrophysiological results from macaque MT suggest that the human percept could be due to decreases in firing of area MT cells at equiluminance. We show here that fMRI activity in human MT does in fact decrease at and near individually measured equiluminance. Tests with visuotopically restricted stimuli in each hemifield produced spatial variations in fMRI activity consistent with retinotopy in human homologs of macaque areas V1, V2, V3, and VP. Such activity in area MT appeared much less retinotopic, as in macaque. However, it was possible to measure the interhemispheric spread of fMRI activity in human MT (half amplitude activation across the vertical meridian = approximately 15 degrees).
1,365 citations
TL;DR: A cloned member of a novel class of the rat ionotropic glutamate receptor family, termed chi-1, exhibits an average identity to NMDA subunits and 23% to non-NMDA sub units, which suggests that chi- 1 may specifically interact with NMDA receptor subunits.
Abstract: Ionotropic glutamate receptors are composed of homomeric or heteromeric configurations of glutamate receptor subunits. We have cloned a member of a novel class of the rat ionotropic glutamate receptor family, termed chi-1. This subunit exhibits an average identity of 27% to NMDA subunits and 23% to non-NMDA subunits. Regional transcript levels of chi-1 are elevated just prior to and during the first postnatal week, with the highest levels present in the spinal cord, brainstem, hypothalamus, thalamus, CA1 field of the hippocampus, and amygdala. The spatial distribution of chi-1 expression is similar from postnatal day 1 (P1) to adulthood. However, transcript levels decline sharply between P7 and P14 and remain attenuated into adulthood. Functional expression studies in Xenopus oocytes injected with in vitro transcribed chi-1 RNA did not demonstrate agonist-activated currents. Pairwise expression of chi-1 with members of the AMPA, KA, or delta class of glutamate recepto subunits either failed to generate agonist-activated currents or failed to alter the underlying current generated by the coexpressed subunit. However, coexpression of chi-1 with subunits forming otherwise functional NMDA receptors resulted in an inhibition of current responses. Since chi-1 did not alter the currents generated by non-NMDA subunits, this suggests that chi-1 may specifically interact with NMDA receptor subunits. Further characterization will be required to establish the precise role of this glutamate receptor subunit in neuronal signaling.
1,331 citations
TL;DR: Analyses of the (nonadditive) interaction of the circadian and sleep-dependent components of sleep propensity and sleep structure revealed that the phase relation between the sleep-wake cycle and the circadian pacemaker during entrainment promotes the consolidation of sleep and wakefulness and facilitates the transitions between these vigilance states.
Abstract: The role of the endogenous circadian pacemaker in the timing of the sleep-wake cycle and the regulation of the internal structure of sleep, including REM sleep, EEG slow-wave (0.75-4.5 Hz) and sleep spindle activity (12.75-15.0 Hz) was investigated. Eight men lived in an environment free of time cues for 33-36 d and were scheduled to a 28 hr rest-activity cycle so that sleep episodes (9.33 hr each) occurred at all phases of the endogenous circadian cycle and variations in wakefulness preceding sleep were minimized. The crest of the robust circadian rhythm of REM sleep, which was observed throughout the sleep episode, was positioned shortly after the minimum of the core body temperature rhythm. Furthermore, a sleep-dependent increase of REM sleep was present, which, interacting with the circadian modulation, resulted in highest values of REM sleep when the end of scheduled sleep episodes coincided with habitual wake-time. Slow-wave activity decreased and sleep spindle activity increased in the course of all sleep episodes. Slow-wave activity in non-REM sleep exhibited a low amplitude circadian modulation which did not parallel the circadian rhythm of sleep propensity. Sleep spindle activity showed a marked endogenous circadian rhythm; its crest coincident with the beginning of the habitual sleep episode. Analyses of the (nonadditive) interaction of the circadian and sleep-dependent components of sleep propensity and sleep structure revealed that the phase relation between the sleep-wake cycle and the circadian pacemaker during entrainment promotes the consolidation of sleep and wakefulness and facilitates the transitions between these vigilance states.
1,241 citations
TL;DR: The findings indicate that the intracellularly recorded fast oscillatory rhythm is not solely dependent on membrane currents intrinsic to the CA1 pyramidal cells but it is a network driven phenomenon dependent upon the participation of inhibitory interneurons.
Abstract: Sharp wave bursts, induced by a cooperative discharge of CA3 pyramidal cells, are the most synchronous physiological pattern in the hippocampus. In conjunction with sharp wave bursts, CA1 pyramidal cells display a high-frequency (200 Hz) network oscillation (ripple). In the present study extracellular field and unit activity was recorded simultaneously from 16 closely spaces sites in the awake rat and the intracellular activity of CA1 pyramidal cells during the network oscillation was studied under anesthesia. Current source density analysis of the high-frequency oscillation revealed circumscribed sinks and sources in the vicinity of the pyramidal layer. Single pyramidal cells discharged at a low frequency but were phase locked to the negative peak of the locally derived field oscillation. Approximately 10% of the simultaneously recorded pyramidal cells fired during a given oscillatory event. Putative interneurons increased their discharge rates during the field ripples severalfold and often maintained a 200 Hz frequency during the oscillatory event. Under urethane and ketamine anesthesia the frequency of ripples was slower (100–120 Hz) than in the awake rat (180–200 Hz). Halothane anesthesia prevented the occurrence of high-frequency field oscillations in the CA1 region. Both the amplitude (1–4 mV) and phase of the intracellular ripple, but not its frequency, were voltage dependent. The amplitude of intracellular ripple was smallest between -70 and -80 mV. The phase of intracellular oscillation relative to the extracellular ripple reversed when the membrane was hyperpolarized more than -80 mV. A histologically verified CA1 basket cell increased its firing rate during the network oscillation and discharged at the frequency of the extracellular ripple. These findings indicate that the intracellularly recorded fast oscillatory rhythm is not solely dependent on membrane currents intrinsic to the CA1 pyramidal cells but it is a network driven phenomenon dependent upon the participation of inhibitory interneurons. We hypothesize that fast field oscillation (200 Hz) in the CA1 region reflects summed IPSPs in pyramidal cells as a result of high-frequency barrage of interneurons. The sharp wave associated synchronous discharge of pyramidal cells in the millisecond range can exert a powerful influence on retrohippocampal targets and may facilitate the transfer of transiently stored memory traces from the hippocampus to the entorhinal cortex.
1,069 citations
TL;DR: The results show that bilateral, but not unilateral, damage to the human amygdala impairs the processing of fearful facial expressions, and it is proposed that the amygdala is required to link visual representations of facial expressions with representations that constitute the concept of fear.
Abstract: We have previously reported that bilateral amygdala damage in humans compromises the recognition of fear in facial expressions while leaving intact recognition of face identity (Adolphs et al., 1994). The present study aims at examining questions motivated by this finding. We addressed the possibility that unilateral amygdala damage might be sufficient to impair recognition of emotional expressions. We also obtained further data on our subject with bilateral amygdala damage, in order to elucidate possible mechanisms that could account for the impaired recognition of expressions of fear. The results show that bilateral, but not unilateral, damage to the human amygdala impairs the processing of fearful facial expressions. This impairment appears to result from an insensitivity to the intensity of fear expressed by faces. We also confirmed a double dissociation between the recognition of facial expressions of fear, and the recognition of identity of a face: these two processes can be impaired independently, lending support to the idea that they are subserved in part by anatomically separate neural systems. Based on our data, and on what is known about the amygdala's connectivity, we propose that the amygdala is required to link visual representations of facial expressions, on the one hand, with representations that constitute the concept of fear, on the other. Preliminary data suggest the amygdala's role extends to both recognition and recall of fearful facial expressions.
1,049 citations
TL;DR: It is proposed that hypoxia caused by the onset of neuronal activity is detected by strategically located populations of neuroglia, first astrocytes, then Muller cells, and in response they secrete VEGF, inducing formation of the superficial and deep layers of retinal vessels, respectively.
Abstract: We have studied the role of the hypoxia-inducible angiogenic growth factor vascular endothelial growth factor (VEGF) in the induction and control of vessel growth in the developing retina of rats and cats, using in situ hybridization techniques. VEGF is expressed successively in two layers of neural retina, the innermost (axon) layer and the inner nuclear layer (INL). In the axon layer, VEGF is expressed transiently by astrocytes as they spread across the layer, closely preceding the formation of superficial vessels. In the INL, VEGF is expressed transiently by somas at the middle of the layer (presumably Muller cells), closely preceding the formation of the deep layer of retinal vessels. We propose that hypoxia caused by the onset of neuronal activity is detected by strategically located populations of neuroglia, first astrocytes, then Muller cells. In response they secrete VEGF, inducing formation of the superficial and deep layers of retinal vessels, respectively. As the vessels become patent, they relieve the hypoxic stimulus, so vessel formation is matched to oxygen demand. This hypothesis was tested experimentally in three ways. Expression of the high affinity flk-1 receptor for VEGF was demonstrated in newly formed retinal vessels, confirming that the secreted VEGF acts on the vessels, in a paracrine fashion. Direct hypoxic regulation of VEGF expression by macroglia was demonstrated in primary cultures of astrocytes and in cells of a glioma line. Hypoxic regulation of VEGF expression in the intact developing retina was demonstrated by showing that oxygen-enriched atmospheres that inhibit vessel formation also suppress endogenous VEGF production.
1,005 citations
TL;DR: A 1:4 scale model of a 1700 microns by 200 microms region of layer IV of cat primary visual cortex is presented to demonstrate that local intracortical excitation may provide the dominant source of orientation-selective input and provide a unified account of intracellular and extracellular inhibitory blockade experiments that had previously appeared to conflict over the role of inhibition.
Abstract: It is well known that visual cortical neurons respond vigorously to a limited range of stimulus orientations, while their primary afferent inputs, neurons in the lateral geniculate nucleus (LGN), respond well to all orientations. Mechanisms based on intracortical inhibition and/or converging thalamocortical afferents have previously been suggested to underlie the generation of cortical orientation selectivity; however, these models conflict with experimental data. Here, a 1:4 scale model of a 1700 microns by 200 microms region of layer IV of cat primary visual cortex (area 17) is presented to demonstrate that local intracortical excitation may provide the dominant source of orientation-selective input. In agreement with experiment, model cortical cells exhibit sharp orientation selectivity despite receiving strong iso-orientation inhibition, weak cross-orientation inhibition, no shunting inhibition, and weakly tuned thalamocortical excitation. Sharp tuning is provided by recurrent cortical excitation. As this tuning signal arises from the same pool of neurons that it excites, orientation selectivity in the model is shown to be an emergent property of the cortical feedback circuitry. In the model, as in experiment, sharpness of orientation tuning is independent of stimulus contrast and persists with silencing of ON-type subfields. The model also provides a unified account of intracellular and extracellular inhibitory blockade experiments that had previously appeared to conflict over the role of inhibition. It is suggested that intracortical inhibition acts nonspecifically and indirectly to maintain the selectivity of individual neurons by balancing strong intracortical excitation at the columnar level.
912 citations
TL;DR: The anatomical distribution of CRF2 receptor mRNA indicates a role for this novel receptor in hypothalamic neuroendocrine, autonomic and general behavioral actions of central CRF and suggests distinctive functional roles for each receptor in CRF-related systems.
Abstract: Corticotropin-releasing factor (CRF) is the primary factor involved in controlling the release of ACTH from the anterior pituitary and also acts as a neurotransmitter in a variety of brain systems. The actions of CRF are mediated by G-protein coupled membrane bound receptors and a high affinity CRF receptor, CRF1, has been previously cloned and functionally characterized. We have recently isolated a cDNA encoding a second member of the CRF receptor family, designated CRF2, which displays approximately 70% homology at the nucleotide level to the CRF1 receptor and exhibits a distinctive pharmacological profile. The present study utilized in situ hybridization histochemistry to localize the distribution of CRF2 receptor mRNA in rat brain and pituitary gland and compared this with the distribution of CRF1, receptor expression. While CRF1 receptor expression was very high in neocortical, cerebellar, and sensory relay structures, CRF2 receptor expression was generally confined to subcortical structures. The highest levels of CRF2 receptor mRNA in brain were evident within the lateral septal nucleus, the ventromedial hypothalamic nucleus and the choroid plexus. Moderate levels of CRF2 receptor expression were evident in the olfactory bulb, amygdaloid nuclei, the paraventricular and suraoptic nuclei of the hypothalamus, the inferior colliculus and 5-HT-associated raphe nuclei of the midbrain. CRF2-expressing cells were also evident in the bed nucleus of the stria terminalis, the hippocampal formation and anterior and lateral hypothalmic areas. In addition, CRF2 receptor mRNA was also found in cerebral arterioles throughout the brain. Within the pituitary gland, CRF2 receptor mRNA was detectable only at very low levels in scattered cells while CRF1 receptor mRNA was readily detectable in anterior and intermediate lobes. This heterogeneous distribution of CRF1 and CRF2 receptor mRNA suggests distinctive functional roles for each receptor in CRF-related systems. The CRF1 receptor may be regarded as the primary neuroendocrine pituitary CRF receptor and important in cortical, cerebellar and sensory roles of CRF. The anatomical distribution of CRF2 receptor mRNA indicates a role for this novel receptor in hypothalamic neuroendocrine, autonomic and general behavioral actions of central CRF.
TL;DR: The results show that context modulation within primary visual cortex has a highly sophisticated nature, putting the image features the cells are responding to into their fully evaluated perceptual context.
Abstract: The activity of neurons in the primary visual cortex of the awake macaque monkey was recorded while the animals were viewing full screen arrays of either oriented line segments or moving random dots. A square patch of the screen was made to perceptually pop out as a circumscribed figure by virtue of differences between the orientation or the direction of motion of the texture elements within that patch and the surround. The animals were trained to identify the figure patches by making saccadic eye movements towards their positions. Almost every cell gave a significantly larger response to elements belonging to the figure than to similar elements belonging to the background. The figure-ground response enhancement was present along the entire extent of the patch and was absent as soon as the receptive field was outside the patch. The strength of the effect had no relation with classical receptive field properties like orientation or direction selectivity or receptive field size. The response enhancement had a latency of 30-40 msec relative to the onset of the neuronal response itself. The results show that context modulation within primary visual cortex has a highly sophisticated nature, putting the image features the cells are responding to into their fully evaluated perceptual context.
TL;DR: Preembedding light and electron microscopical immunocytochemistry shows that both GLT-1 and GLAST are restricted to astrocytes, which appear to express both proteins concomitantly, but in different proportions in different parts of the brain.
Abstract: Glutamate, the major excitatory neurotransmitter in brain, is almost exclusively intracellular due to the action of the glutamate transporters in the plasma membranes. To study the localization and properties of these proteins, we have raised antibodies specifically recognizing parts of the sequences of two cloned rat glutamate transporters, GLT-1 (Pines et al., 1992) and GLAST (Storck et al., 1992). On immunoblots the antibodies against GLT-1 label a broad heterogeneous band with maximum density at around 73 kDa, while the antibody against GLAST labels a similarly broad band at around 66 kDa in the cerebellum and a few kilodaltons lower in other brain regions. GLT-1 is expressed at the highest concentrations in the hippocampus, lateral septum, cerebral cortex, and striatum, while GLAST is preferentially expressed in the molecular layer of the cerebellum. However, both transporters are present throughout the brain, and have roughly parallel distributions in the cerebral hemispheres and brainstem. Preembedding light and electron microscopical immunocytochemistry shows that both GLT-1 and GLAST are restricted to astrocytes, which appear to express both proteins concomitantly, but in different proportions in different parts of the brain. Nerve terminal labeling was not observed. Both the amino and carboxyl terminals of GLT-1 and GLAST are located intracellularly, indicating an even number of transmembrane segments. Antibodies against a synthetic peptide corresponding to amino acid residues 2-11 of the proposed sequence of GLT-1 recognize the native rat brain GLT-1 protein, confirming that the translation initiation site is at the first ATG.
TL;DR: Findings suggest that the left inferior prefrontal cortex (LIPC) is part of a semantic executive system that contributes to the on-line retrieval of semantic information.
Abstract: Prefrontal cortical function was examined during semantic encoding and repetition priming using functional magnetic resonance imaging (fMRI), a noninvasive technique for localizing regional changes in blood oxygenation, a correlate of neural activity. Words studied in a semantic (deep) encoding condition were better remembered than words studied in both easier and more difficult nonsemantic (shallow) encoding conditions, with difficulty indexed by response time. The left inferior prefrontal cortex (LIPC) (Brodmann's areas 45, 46, 47) showed increased activation during semantic encoding relative to nonsemantic encoding regardless of the relative difficulty of the nonsemantic encoding task. Therefore, LIPC activation appears to be related to semantic encoding and not task difficulty. Semantic encoding decisions are performed faster the second time words are presented. This represents semantic repetition priming, a facilitation in semantic processing for previously encoded words that is not dependent on intentional recollection. The same LIPC area activated during semantic encoding showed decreased activation during repeated semantic encoding relative to initial semantic encoding of the same words. This decrease in activation during repeated encoding was process specific; it occurred when words were semantically reprocessed but not when words were nonsemantically reprocessed. The results were apparent in both individual and averaged functional maps. These findings suggest that the LIPC is part of a semantic executive system that contributes to the on-line retrieval of semantic information.
TL;DR: Delayed death of the CA1 pyramidal neurons after brief ischemia is not necrotic but apoptotic, suggesting that cathepsin B- immunopositive lysosomes increasing in the neurons after ischemic insult are mostly autolysosomes.
Abstract: The CA1 pyramidal neurons in the hippocampus are selectively vulnerable to transient ischemic damage. In experimental animals, the CA1 pyramidal neurons undergo cell death several days after brief forebrain ischemia. It remains, however, unknown whether this delayed neuronal death is necrosis or apoptosis. To investigate the degenerating processes of the CA1 pyramidal neurons in gerbil hippocampus after brief ischemia, lysosomal and nuclear alterations in the cells were examined using immunocytochemistry, in situ nick-end labeling, and Southern blotting. By light and electron microscopy, immunoreactivity for cathepsins B, H, and L, representative lysosomal cysteine proteinases, increased in the CA1 pyramidal neurons 3 d after ischemic insult, which showed cell shrinkage. By morphometric analysis, the volume density of cathepsin B-positive lysosomes markedly increased 3 d after ischemic insult, while that of autophagic vacuole-like structures also increased at this stage, suggesting that cathepsin B-immunopositive lysosomes increasing in the neurons after ischemic insult are mostly autolysosomes. Nuclei of the CA1 neurons were nick-end labeled by biotinylated dUTP mediated by terminal deoxytransferase 3 and 4 d after ischemic insult, but not in the prior stages. Simultaneously, dense chromatin masses appeared in nuclei of the neurons. By Southern blotting, laddering of DNA occurred only in CA1 hippocampal tissues obtained 4 d after ischemic insult. Confocal laser scanning microscopy demonstrated that the fragmented DNA in the CA1 pyramidal layer was phagocytosed by microglial cells. The results suggest that delayed death of the CA1 pyramidal neurons after brief ischemia is not necrotic but apoptotic.
TL;DR: The Q-type current, the largest of the current components in the granule neurons, resembles currents that can be generated in Xenopus oocytes by expression of cloned alpha 1A subunits.
Abstract: The diversity of Ca2+ channel types in rat cerebellar granule neurons was investigated with whole-cell recordings (5 mM external Ba2+). Contributions of five different high-voltage-activated Ca2+ channel current components were distinguished pharmacologically. Nimodipine-sensitive L-type current and omega-CTx-GVIA-sensitive N-type current contributed 15 and 20% of the total current, respectively. The bulk of the remaining current (46%) was inhibited by omega-Aga-IVA. The current blocked by this toxin was further subdivided into two components, P-type and Q-type, on the basis of differences in their inactivation kinetics and sensitivity to omega-Aga-IVA. P-Type current was noninactivating during 0.1 sec depolarizations, half-blocked at about 1-3 nM omega-Aga-IVA, and contributed approximately 11% of the total current; Q-type current was prominently inactivating, half-blocked at approximately 90 nM omega-Aga-IVA, and comprised 35% of the total current. Both P- and Q-type currents were potently inhibited by the Conus magus toxin omega-CTx-MVIIC. A current component resistant to all of the aforementioned blockers (R-type) displayed more rapid inactivation than the other components and constituted 19% of the total current. The Q-type current, the largest of the current components in the granule neurons, resembles currents that can be generated in Xenopus oocytes by expression of cloned alpha 1A subunits.
TL;DR: Data support the possibility that NMDA receptor-mediated, Ca(2+)-dependent uncoupling of neuronal mitochondrial electron transport may contribute to the oxidative stress initiated by glutamate exposure.
Abstract: Increasing evidence suggests that glutamate neurotoxicity is partly mediated by reactive oxygen species, formed as a consequence of several processes, including arachidonic acid metabolism and nitric oxide production. Here we used an oxidation-sensitive indicator, dihydrorhodamine 123, in combination with confocal microscopy, to examine the hypothesis that electron transport by neuronal mitochondria may be an important source of glutamate-induced reactive oxygen species (ROS). Exposure to NMDA, but not kainate, ionomycin, or elevated potassium stimulated oxygen radical production in cultured murine cortical neurons, demonstrated by oxidation of nonfluorescent dihydrorhodamine 123 to fluorescent rhodamine 123. Electron paramagnetic resonance spectroscopy studies using 5,5-dimethyl-1- pyrroline-N-oxide (DMPO) as a radical-trapping agent, also showed production of ROS by cortical neurons after NMDA but not kainate exposure. NMDA-induced ROS production depended on extracellular Ca2+, and was not affected by inhibitors of nitric oxide synthase or arachidonic acid metabolism. The increased production of ROS was blocked by inhibitors of mitochondrial electron transport, rotenone or antimycin, and mimicked by the electron transport uncoupler, carbonyl cyanide p-trifluoromethoxyphenylhydrazone. These data support the possibility that NMDA receptor-mediated, Ca(2+)-dependent uncoupling of neuronal mitochondrial electron transport may contribute to the oxidative stress initiated by glutamate exposure.
TL;DR: The data suggest that hippocampal input is necessary for accumbens neurons to enter a depolarized, active state, and the hippocampus appears to be capable of gating prefrontal corticoaccumbens throughput.
Abstract: The interactions among excitatory inputs arising from the prefrontal cortex, amygdala, and hippocampus, and innervating nucleus accumbens neurons were studied using in vivo intracellular recording techniques. Neurons recorded in the accumbens displayed one of three activity states: (1) silent, (2) spontaneously firing at low, constant rates, or (3) a bistable membrane potential, characterized by alternating periods of activity and silence occurring in concert with spontaneous transitions between two steady-state membrane potentials (average, -77.3 +/- 7.1 mV base, -63.0 +/- 7.4 mV plateau). These neurons also exhibited a high degree of convergence of responses elicited by stimulation of each of the three excitatory inputs tested. Activation of hippocampal afferents, but not cortical, amygdaloid, or thalamic afferents, induced bistable cells to switch to the depolarized (active) state. In contrast, no bistable cells were encountered in the nucleus accumbens following an acute transection of the fornix. Furthermore, microinjection of lidocaine in the vicinity of the hippocampal afferents at the level of the fornix caused a reversible elimination of the plateau phase in bistable cells. These data suggest that hippocampal input is necessary for accumbens neurons to enter a depolarized, active state. Furthermore, activation of prefrontal cortical inputs fail to evoke spike firing in accumbens neurons unless they are in this active state. Consequently, the hippocampus appears to be capable of gating prefrontal corticoaccumbens throughput.
TL;DR: The results suggest that adult neurogenesis in the dentate gyrus of the rat is altered by afferent input, via NMDA receptors, and may be regulated naturally by endogenous excitatory amino acids.
Abstract: The effects of afferent input and N-methyl-D-aspartate (NMDA) receptor activation on neurogenesis were examined in an intact system, the rat dentate gyrus, where neurons are naturally born in the adult. In the adult dentate gyrus, activation of NMDA receptors rapidly decreased the number of cells synthesizing DNA, whereas blockade of NMDA receptors rapidly increased the number of cells in the S phase identified with 3H-thymidine. Acute treatment with NMDA receptor antagonists increased the birth of neurons and increased the overall density of neurons in the granule cell layer. Lesion of the entorhinal cortex, the main excitatory afferent population to the granule neurons, also increased the birth of cells in the dentate gyrus. These results suggest that adult neurogenesis in the dentate gyrus of the rat is altered by afferent input, via NMDA receptors, and may be regulated naturally by endogenous excitatory amino acids.
TL;DR: A critical role for mitochondria in the production of ROS in association with glutamate excitotoxicity is suggested, and the feasibility of measuring theProduction of ROS at the level of the single cell is demonstrated.
Abstract: Using the fluorescent dye 2′,7′-dichlorodihydrofluorescein (DCF-H2) we investigated the role of glutamate in the production of reactive oxygen species (ROS) in cultured neurons from fetal rat forebrain. The addition of an excitotoxic concentration of glutamate (100 microM) produced a generalized decrease in cellular DCF fluorescence accompanied by local areas of increased fluorescence around the margins of the cell body that could be observed within 2–4 min of glutamate exposure. Increases in fluorescence were dependent on NMDA receptor activation and Ca2+ entry and were blocked by the mitochondrial proton ionophore carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP). Additional studies suggested that the generalized decrease in fluorescence was due to intracellular acidification. These studies suggest a critical role for mitochondria in the production of ROS in association with glutamate excitotoxicity, and additionally demonstrate the feasibility of measuring the production of ROS at the level of the single cell.
TL;DR: Fast spiking interneurons in the CA1 area of the dorsal hippocampus were recorded from and filled with biocytin in anesthetized rats to indicate that interneURons with distinct axonal targets have differential functions in shaping the physiological patterns of theCA1 network.
Abstract: Fast spiking interneurons in the CA1 area of the dorsal hippocampus were recorded from and filled with biocytin in anesthetized rats. The full extent of their dendrites and axonal arborizations as well as their calcium binding protein content were examined. Based on the spatial extent of axon collaterals, local circuit cells (basket and O-LM neurons) and long-range cells (bistratified, trilaminar, and backprojection neurons) could be distinguished. Basket cells were immunoreactive for parvalbumin and their axon collaterals were confined to the pyramidal layer. A single basket cell contacted more than 1500 pyramidal neurons and 60 other parvalbumin-positive interneurons. Commissural stimulation directly discharged basket cells, followed by an early and late IPSPs, indicating interneuronal inhibition of basket cells. The dendrites of another local circuit neuron (O-LM) were confined to stratum oriens and it had a small but high-density axonal terminal field in stratum lacunosum-moleculare. The fastest firing cell of all interneurons was a calbindin-immunoreactive bistratified neuron with axonal targets in stratum oriens and radiatum. Two neurons with their cell bodies in the alveus innervated the CA3 region (backprojection cells), in addition to rich axon collaterals in the CA1 region. The trilaminar interneuron had axon collaterals in strata radiatum, oriens and pyramidale with its dendrites confined to stratum oriens. Commissural stimulation evoked an early EPSP-IPSP-late depolarizing potential sequence in this cell. All interneurons formed symmetric synapses with their targets at the electron microscopic level. These findings indicate that interneurons with distinct axonal targets have differential functions in shaping the physiological patterns of the CA1 network.
TL;DR: These experiments indicate that amphetamine acts at the vesicular level where it redistributes dopamine to the cytosol, promoting reverse transport, and dopamine release.
Abstract: Whether amphetamine acts principally at the plasma membrane or at synaptic vesicles is controversial. We find that d-amphetamine injection into the Planorbis giant dopamine neuron causes robust dopamine release, demonstrating that specific amphetamine uptake is not required. Arguing for action at vesicles, whole-cell capillary electrophoresis of single Planorbis dopamine neurons shows that amphetamine reduces vesicular dopamine, while amphetamine reduces quantal dopamine release from PC12 cells by > 50% per vesicle. Intracellular injection of dopamine into the Planorbis dopamine neuron produces rapid nomifensine-sensitive release, showing that an increased substrate concentration gradient is sufficient to induce release. These experiments indicate that amphetamine acts at the vesicular level where it redistributes dopamine to the cytosol, promoting reverse transport, and dopamine release.
TL;DR: The results corroborate recent findings that mGluRs are required for the induction of LTP in CA1 and CA3 in vitro and in vivo and find the process of STP is found to be independent of mGLUR activation.
Abstract: Metabotropic glutamate receptors (mGluRs) are critically involved in the maintenance of long-term potentiation (LTP) (Reymann and Matthies, 1989; Behnisch et al., 1991; Izumi et al., 1991; Bashir et al., 1993). In order to assess further the physiological role of MGluRs in LTP, we injected freely moving rats with the recently available, competitive mGluR antagonist (R,S)-alpha-methyl-4-carboxyphenylglycine (MCPG) intraventricularly and recorded extracellularly the population spike (PS) as well as the field excitatory postsynaptic potential (fEPSP) of the granule cells of the dentate gyrus in response to stimulation of fibers of the perforant path. MCPG was administered in two concentrations (A = 20 mM/5 microliters; B = 200 mM/5 microliters) either 30 min prior to or 5 min after LTP induction. Sodium chloride infusion served as a control. Normal synaptic transmission was not altered by MCPG. However, the mGluR antagonist inhibited LTP in a concentration-dependent manner. Concentration A did not influence the potentiation shortly after the tetanus. In the PS, short-term potentiation (STP), which is decremental in its time course, occurred normally, but in contrast to controls the potentiation declined back to baseline values after 2–3 hr. This dose also reduced the posttetanic increase in the slope function of the fEPSP, and led to a time course of potentiation similar to that for the PS. Concentration B completely abolished the tetanus-induced potentiation. This block was similar to that obtained for the NMDA antagonist 2-amino-5-phosphonopentanoate (AP5). Both MCPG concentrations had no influence on the time course of preestablished LTP. These effects seem to be due to the action of the (+)-isomer of MCPG, since intracerebroventricular application of the (- )-isomer was without effect on the duration and magnitude of LTP. In addition, we were interested in the mGluR subtypes involved in the blocking mechanism of MCPG. 1S,3R-aminocyclopentane-1,3-dicarboxic acid (ACPD)-activated PPI hydrolysis in hippocampal slices was competitively inhibited by MCPG at a concentration of 1 mM or higher. In contrast, this concentration of MCPG did not affect the reduction of forskolin- stimulated cAMP formation by ACPD. These results corroborate recent findings that mGluRs are required for the induction of LTP in CA1 and CA3 in vitro (Bashir et al., 1993; Sergueeva et al., 1993) and in vivo (Riedel and Reymann, 1993). The process of STP is found to be independent of mGluR activation.(ABSTRACT TRUNCATED AT 400 WORDS)
TL;DR: The G1 phase is most likely to be the phase of the cell cycle which is modulated by extrinsically and intrinsically acting mechanisms involved in the regulation of neuronal cytogenesis.
Abstract: Neurons destined for the cerebral neocortex are formed in the pseudostratified ventricular epithelium (PVE) lining the ventricular cavity of the developing cerebral wall. The present study, based upon cumulative S-phase labeling with bromodeoxyuridine, is an analysis of cell cycle parameters of the PVE. It is undertaken in the dorsomedial cerebral wall of mouse embryos from the eleventh to the seventeenth gestational day (E11-E17, day of conception = E0) corresponding to the complete period of neuronogenesis. The growth fraction (fraction of cells in the population which is proliferating) is virtually 1.0 from E11 through E16. The length of the cell cycle increases from 8.1 to 18.4 hr, which corresponds to a sequence of 11 integer cell cycles over the course of neuronal cytogenesis in mice. The increase in the length of the cell cycle is due essentially to a fourfold increase in the length of G1 phase which is the only phase of the cell cycle which varies systematically. Thus, the G1 phase is most likely to be the phase of the cell cycle which is modulated by extrinsically and intrinsically acting mechanisms involved in the regulation of neuronal cytogenesis.
TL;DR: In order to screen for brain region specific mRNAs which are transcriptionally regulated by acute cocaine and amphetamine, PCR differential display was employed and identified a previously uncharacterized mRNA whose relative levels in the striatum are induced four- to fivefold by acute psychomotor stimulant administration.
Abstract: involves alterations in specific patterns of gene expression. In order to screen for brain region specific mRNAs which are transcriptionally regulated by acute cocaine and amphetamine, PCR differential display was employed. This approach identified a previously uncharacterized mRNA whose relative levels in the striatum are induced four- to fivefold by acute psychomotor stimulant administration. Isolation and characterization of corresponding cDNA clones resulted in complete nucleotide sequence analysis, including prediction of the encoded protein product. Alternate polyA site utilization in the predicted 3′ noncoding region results in the appearance of an RNA doublet, approximately 700 and 900 bases in length, following Northern analysis. A presumed alternate splicing event further generates diversity within the transcripts, and results in the presence or absence of an in-frame 39 base insert within the putative protein coding region. As a result, the predicted translation products are either 129 or 116 amino acids in length. A common hydrophobic leader sequence at the amino terminus is present within each predicted polypeptide, suggesting that the protein product is targeted for entry into the secretory pathway. Basal expression of the RNA doublet is limited to neuroendocrine tissues, further implying that the protein product plays a functional role in both neuronal and endocrine tissues.
TL;DR: Since associative learning, especially of the classical type, is well described at the phenomenological and operational level (Rescorla, 1988), it provides a favorable approach in the search for the neural substrate underlying learning and memory.
Abstract: The understanding of the physiology of learning is dominated by two basically different hypotheses. The deterministic view, following Hebb’s (1949) concept of the memory engram, presupposes a memory groove which is built during memory formation by the adaptive change of a relatively small number of reacting sites or switch points. These so-called ’switchpoint theories’ or ‘place theories’ assume that memory involves a discrete set of cells reserved for the special function of information storage (Young 1964; Eccles 1964; Ungar 1970). The non-deterministic or statistical theory is based on Lashley’s (1950) findings which suggest that all, or nearly all, stored information is distributed throughout the whole association cortex rather than by distinct association paths or centres. The individual neuronal switch points may then be involved in the storage of many different memory traces (John 1967, 1972). The two views are similar in that they take the adaptivity of single synapses between neurones as the basic modifiable component of the nervous system (Eccles and McIntyre 1953; Eccles 1964; Ungar 1970; John 1972). They differ, however, in their conception of the gross structure of the memory system. The crucial problem, then, is to locate the stored information. The spatio-temporal pattern of activity during memory formation produces a localised change in the excitability of specific neurones. It should be possible to find such neurones using the same techniques as have been employed for the location of units in the sensory integration centres.
TL;DR: During low-frequency oscillatory states, characteristic of slow-wave sleep, neocortical and thalamic neurons display phase relations that are restricted to narrow time windows, and that synchronization results from a generalized inhibitory phenomenon.
Abstract: A slow oscillation (< 1 Hz) has recently been described in intracellular recordings from the neocortex and thalamus (Steriade et al., 1993c-e). The aim of the present study was to determine the phase relations between cortical and thalamic neuronal activities during the slow EEG oscillation. Intracellular recordings were performed in anesthetized cats from neurons in motor and somatosensory cortical areas, the rostrolateral sector of the reticular (RE) thalamic nucleus, and thalamocortical (TC) cells from ventrolateral (VL) nucleus. The EEG was used as time reference for alignment of activities in different, simultaneously recorded neurons, including dual impalements of cortical cells as well as cortical and TC cells. The spontaneous EEG oscillation was characterized by slowly recurring (0.3–0.9 Hz) sequences of surface- positive (depth-negative) sharp deflections, often followed by oscillatory activity within the frequency range of sleep spindles (7–14 Hz) or at faster frequencies. Cortical and RE cells were similarly hyperpolarized during the depth-positive EEG waves and were depolarized during the depth-negative EEG deflections. In many instances, the cell depolarization was associated with oscillations at the spindle frequency or with tonic firing at rates related to the level of depolarization. TC neurons were hyperpolarized during the depth- positive EEG waves and displayed a series of IPSPs, at the spindle frequencies, during the depth-negative EEG waves. Depending on the membrane potential (Vm), TC cells could fire spike bursts at the onset of the EEG depth-negativity, or their firing could be delayed by subsequent IPSPs. The sequence of spontaneous EEG and cellular events described above also characterized the responses to cortical and thalamic stimulation. Simultaneous intracellular recordings of pairs of cortical cells or cortical and TC cells showed that spontaneous transitions from less synchronized to more synchronized EEG states were marked by a simultaneous hyperpolarization, coincident with an overt depth-positive EEG wave. We conclude that during low-frequency oscillatory states, characteristic of slow-wave sleep, neocortical and thalamic neurons display phase relations that are restricted to narrow time windows, and that synchronization results from a generalized inhibitory phenomenon. Moreover, EEG synchronization is reflected as active inhibition in TC neurons. That this pattern is also present in states of hypersynchronization, such as seizure activity, is shown in the following paper (Steriade and Contreras, 1994).
TL;DR: These experiments suggest that areas of frontal cortex play a role in explicit recall and that an effect of priming may be to require less activation of perceptual regions for the processing of recently presented information.
Abstract: Across three experiments, PET scans were obtained while subjects performed different word-stem completion and FIXATION control tasks designed to study the functional anatomy of memory retrieval. During each of three different word-stem completion scans, word-stem cues were visually presented in uppercase letters. The RECALL task required explicit retrieval of study words presented prior to the PET scan. The PRIMING task addressed the implicit effects of the prior study words without requiring intentional recall. The BASELINE task encouraged retrieval of information from a general knowledge store. Across experiments, the similarity between study words and word stems was manipulated by presenting prescan study words in either uppercase letters identical to the stems, in lowercase letters, or auditorily. The PRIMING task was not studied with auditory presentation. Many activations were consistent across experiments. The BASELINE task activated several regions in response to the reading and verbal- response demands of the task (visual, motor, and premotor cortices, cerebellum), as well as a left prefrontal region. The RECALL task additionally activated regions in anterior right prefrontal cortex. Bilateral occipitotemporal regions showed blood flow reductions during the PRIMING task as compared to the BASELINE task. Activation in the right hippocampal/parahippocampal region was observed only in one experiment, and no experiment showed activation in the left medial temporal lobe. These experiments suggest that areas of frontal cortex play a role in explicit recall and that an effect of priming may be to require less activation of perceptual regions for the processing of recently presented information.
TL;DR: The distribution and targeting of another opioid receptor, the mu-opioid receptor (MOR1), is studied by raising anti-peptide antisera to the C-terminal peptide of MOR1 by providing a morphological basis for understanding pre- and postsynaptic functions mediated by MOR1.
Abstract: Opioid receptors regulate neuronal activity by both pre- and postsynaptic mechanisms We recently reported that the cloned delta- opioid receptor (DOR1) is primarily targeted to axons, suggesting a presynaptic role In the present study we have studied the distribution and targeting of another opioid receptor, the mu-opioid receptor (MOR1), by raising anti-peptide antisera to the C-terminal peptide of MOR1 The specificity of the antisera was determined by analysis of transfected cells, Western blots, and immunoisolation studies Immunohistochemistry showed that MOR1 immunoreactivity was enriched in many brain areas including cerebral cortex, striatum, hippocampus, locus coeruleus, and the superficial laminae of the dorsal horn Moreover, MOR1-expressing neurons seem to target this receptor preferentially to their somatodendritic domain as determined by double- labeling experiments with MAP2 However, discrete populations of neurons target MOR1 to their axons, including some primary afferent neurons that express DOR1 In many regions enkephalin-containing axons were complementary to MOR1, suggesting by their proximity that enkephalins may be physiologically relevant ligands for this receptor Thus, these results provide a morphological basis for understanding pre- and postsynaptic functions mediated by MOR1
TL;DR: This work investigated the topographic organization of visual cortex connections with frontal eye field (FEF), the final stage of cortical processing for saccadic eye movements in individual macaque monkeys.
Abstract: The primate visual system consists of at least two processing streams, one passing ventrally into temporal cortex that is responsible for object vision, and the other running dorsally into parietal cortex that is responsible for spatial vision How information from these two streams is combined for perception and action is not understood Visually guided eye movements require information about both feature identity and location, so we investigated the topographic organization of visual cortex connections with frontal eye field (FEF), the final stage of cortical processing for saccadic eye movements Multiple anatomical tracers were placed either in parietal and temporal cortex or in different parts of FEF in individual macaque monkeys Convergence from the dorsal and ventral processing streams occurred in lateral FEF but not in medial FEF Certain extrastriate areas with retinotopic visual field organizations projected topographically onto FEF The dorsal bank of the superior temporal sulcus projected to medial FEF; the ventral bank, to lateral FEF, and the fundus, throughout FEF Thus, lateral FEF, which is responsible for generating short saccades, receives visual afferents from the foveal representation in retinotopically organized areas, from areas that represent central vision in inferotemporal cortex and from other areas having no retinotopic order In contrast, medial FEF, which is responsible for generating longer saccades, is innervated by the peripheral representation of retinotopically organized areas, from areas that emphasize peripheral vision or are multimodal and from other areas that have no retinotopic order or are auditory