Insulin and insulin receptor (IR) kinase are found in abundance in discrete brain regions yet insulin signaling in the CNS is not understood. Because it is known that the highest brain insulin-binding affinities, insulin-receptor density, and IR kinase activity are localized to the olfactory bulb, we sought to explore the downstream substrates for IR kinase in this region of the brain to better elucidate the function of insulin signaling in the CNS. First, we demonstrate that IR is postnatally and developmentally expressed in specific lamina of the highly plastic olfactory bulb (OB). ELISA testing confirms that insulin is present in the developing and adult OB. Plasma insulin levels are elevated above that found in the OB, which perhaps suggests a differential insulin pool. Olfactory bulb insulin levels appear not to be static, however, but are elevated as much as 15-fold after a 72-h fasting period. Bath application of insulin to cultured OB neurons acutely induces outward current suppression as studied by the use of traditional whole-cell and single-channel patchclamp recording techniques. Modulation of OB neurons is restricted to current magnitude; IR kinase activation does not modulate current kinetics of inactivation or deactivation. Transient transfection of human embryonic kidney cells with cloned Kv1.3 ion channel, which carries a large proportion of the outward current in these neurons, revealed that current suppression was the result of multiple tyrosine phosphorylation of Kv1.3 channel. Y to F single-point mutations in the channel or deletion of the kinase domain in IR blocks insulininduced modulation and phosphorylation of Kv1.3. Neuromodulation of Kv1.3 current in OB neurons is activity dependent and is eliminated after 20 days of odor/sensory deprivation induced by unilateral naris occlusion at postnatal day 1. IR kinase but not Kv1.3 expression is downregulated in the OB ipsilateral to the occlusion, as demonstrated in cryosections of right (control) and left (sensory-deprived) OB immunolabeled with antibodies directed against these proteins, respectively. Collectively, these data support the hypothesis that the hormone insulin acts as a multiply functioning molecule in the brain: IR signaling in the CNS could act as a traditional growth factor during development, be altered during energy metabolism, and simultaneously function to modulate electrical activity via phosphorylation of voltage-gated ion channels.
The smooth pursuit eye movement (SPEM) system is much more sensitive to target motion perturbations during pursuit than during fixation. This sensitivity is commonly attributed to a dynamic gain control mechanism. Neither the neural substrate nor the functional architecture for this gain control has been fully revealed. There are at least two cortical areas that crucially contribute to smooth pursuit and are therefore eligible sites for dynamic gain control: the medial superior temporal area (MST) and the pursuit area of the frontal eye fields (FEFs), which both project to brain stem premotor structures via parallel pathways. The aim of this study was to develop a model of smooth pursuit based on behavioral, anatomical, and neurophysiological results to account for nonlinear dynamic gain control. Using a behavioral paradigm in humans consisting of a sinusoidal oscillation (4 Hz, ±8°/s) superimposed on a constant velocity target motion (0–24°/s), we were able to identify relevant gain control parameters in the model. A salient feature of our model is the emergence of two parallel pathways from higher visual cortical to lower motor areas in the brain stem that correspond to the MST and FEF pathways. Detailed analysis of the model revealed that one pathway mainly carries eye velocity related signals, whereas the other is associated mostly with eye acceleration. From comparison with known neurophysiological results we conclude that the dynamic gain control can be attributed to the FEF pathway, whereas the MST pathway serves as the basic circuit for maintaining an ongoing SPEM.
Fast-spiking (FS) interneurons provide the main route of feed-forward inhibition from cortex to spiny projection neurons in the striatum. A steep current-firing frequency curve and a dense local axonal arbor suggests that even small excitatory inputs could translate into powerful feed-forward inhibition, but such an arrangement is also sensitive to amplification of spurious synaptic inputs.
We show that a transient potassium (KA) current allows the FS interneuron to strike a balance between sensitivity to correlated input and robustness to noise, thereby increasing its signal to noise ratio (SNR). First, a compartmental FS neuron model was created to match experimental data from striatal FS interneurons in cortex-striatum-substantia nigra organotypic cultures. Densities of sodium, delayed rectifier and KA channels were optimized to replicate responses to somatic current injection. Spontaneous AMPA and GABA synaptic currents were adjusted to the experimentally measured amplitude, rise time, and inter-event interval histograms. Second, two additional adjustments were required to emulate the remaining experimental observations. GABA channels were localized closer to the soma than AMPA channels to match the synaptic population reversal potential. Correlation among inputs was required to produce the observed firing rate during up-states. In this final model, KA channels were essential for suppressing down-state spikes while allowing reliable spike generation during up-states. This mechanism was particularly important under conditions of high dopamine. Our results suggest that KA channels allow FS interneurons to operate without a decrease in SNR during conditions of increased dopamine, as occurs in response to reward or anticipated reward.
computer model; up states; fast spiking interneuron; transient potassium current; dopamine
The neural computations that underlie the processing of auditory-stimulus identity are not well understood, especially how information is transformed across different cortical areas. Here, we compared the capacity of neurons in the superior temporal gyrus (STG) and the ventrolateral prefrontal cortex (vPFC) to code the identity of an auditory stimulus; these two areas are part of a ventral processing stream for auditory-stimulus identity. Whereas the responses of neurons in both areas are reliably modulated by different vocalizations, STG responses code significantly more vocalizations than those in the vPFC. Together, these data indicate that the STG and vPFC differentially code auditory identity, which suggests that substantial information processing takes place between these two areas. These findings are consistent with the hypothesis that the STG and the vPFC are part of a functional circuit for auditory-identity analysis.
We explored cortical fields on the upper bank of the Sylvian fissure using functional magnetic resonance imaging (fMRI) and magnetoencephalography (MEG) to measure responses to two stimulus conditions: a tactile stimulus applied to the right hand and a tactile stimulus with an additional movement component. fMRI data revealed bilateral activation in S2/PV in response to tactile stimulation alone and source localization of MEG data identified a peak latency of 122 ms in a similar location. During the tactile and movement condition, fMRI revealed bilateral activation of S2/PV and an anterior field, while MEG data contained one source at a location identical to the tactile-only condition with a latency of 96 ms and a second rostral source with a longer latency (136 ms). Furthermore, Region-of-interest analysis of fMRI data identified increased bilateral activation in S2/PV and the rostral area in the tactile and movement condition compared with the tactile only condition. An area of cortex immediately rostral to S2/PV in monkeys has been called the parietal rostroventral area (PR). Based on location, latency, and conditions under which this field was active, we have termed the rostral area of human cortex PR as well. These findings indicate that humans, like non-human primates, have a cortical field rostral to PV that processes proprioceptive inputs, both S2/PV and PR play a role in somatomotor integration necessary for manual exploration and object discrimination, and there is a temporal hierarchy of processing with S2/PV active prior to PR.
Anatomical and physiological evidence suggests that common input to motor neurons of hand muscles is an important neural mechanism for hand control. To gain insight into the synaptic input underlying the coordination of hand muscles, significant effort has been devoted to describing the distribution of common input across motor units of extrinsic muscles. Much less is known, however, about the distribution of common input to motor units belonging to different intrinsic muscles and to intrinsic-extrinsic muscle pairs. To address this void in the literature, we quantified the incidence and strength of near-simultaneous discharges of motor units residing in either the same or different intrinsic hand muscles (m. first dorsal, FDI, and m. first palmar interosseus, FPI) during two-digit object hold. To extend the characterization of common input to pairs of extrinsic muscles (previous work) and pairs of intrinsic muscles (present work), we also recorded electromyographic (EMG) activity from an extrinsic thumb muscle (m. flexor pollicis longus, FPL). Motor-unit synchrony across FDI and FPI was weak (common input strength, CIS, mean ± SE: 0.17 ± 0.02). Similarly, motor units from extrinsic-intrinsic muscle pairs were characterized by weak synchrony (FPL-FDI: 0.25 ± 0.02; FPL-FPI: 0.29 ± 0.03) although stronger than FDI-FPI. Last, CIS from within FDI and FPI was more than three times stronger (0.70 ± 0.06 and 0.66 ± 0.06, respectively) than across these muscles. We discuss present and previous findings within the framework of muscle-pair specific distribution of common input to hand muscles based on their functional role in grasping.
The bed nucleus of the stria terminalis (BST) is a cluster of nuclei within the extended amygdala, a forebrain macrostructure with extensive projection to motor nuclei of the hindbrain. The subnuclei of the BST coordinate autonomic, neuroendocrine, and somatomotor functions and receive robust neuromodulatory monoaminergic afferents, including 5-HT-, noradrenaline (NA)-, and dopamine (DA)-containing terminals. In contrast to 5-HT and NA, little is known about how DA modulates neuronal activity or synaptic transmission in the BST. DA-containing afferents to the BST originate in the ventral tegmental area, the periaqueducal gray, and the retrorubral field. They form a fairly diffuse input to the dorsolateral BST with dense terminal fields in the oval (ovBST) and juxtacapsular (jxBST) nuclei. The efferent-afferent connectivity of the BST suggests that it may play a key role in motivated behaviors, consistent with recent evidence that the dorso-lateral BST is a target for drugs of abuse. This study describes the effects of DA on synaptic transmission in the ovBST. Whole cell voltage clamp recordings were performed on ovBST neurons in brain slices from adult rats in the presence or absence of exogenous DA and receptor-targeted agonists and antagonists. The results showed that DA selectively and exclusively reduced inhibitory synaptic transmission in the ovBST in a dose-dependent and D2-like dopamine receptor-dependent manner. DA also modulated excitatory synaptic transmission in a dose-dependent dependent manner. However, this effect was mediated by α2-noradrenergic receptors. Thus these data reveal a double dissociation in catecholaminergic regulation of excitatory and inhibitory synaptic transmission in the ovBST and may shed light on the mechanisms involved in neuropathological behaviors such as stress-induced relapse to consumption of drugs of abuse.
PMID: 21047935 CAMSID: cams4377
Developmental changes in the coordinative organization of masticatory muscles were examined longitudinally in four children over 49 experimental sessions spanning the age range of 12–48 mo. Electromyographic (EMG) records were obtained for right and left masseter muscles, right and left temporalis muscles, and the anterior belly of the digastric. Two independent analytic processes were employed, one that relied on identification of onset and offset of muscle activation and a second that used pairwise cross-correlational techniques. The results of these two analyses, which were found to be consistent with each other, demonstrated that the basic chewing pattern of reciprocally activated antagonistic muscle groups is established by 12 mo of age. Nevertheless, chewing efficiency appears to be improved through a variety of changes in the chewing pattern throughout early development. Coupling of activity among the jaw elevator muscles was shown to strengthen with maturation, and the synchrony of onset and offset of these muscles also increased. Coactivation of antagonistic muscles decreased significantly with development. This decrease in antagonistic coactivation and increase in synchrony among jaw elevators, and a parallel decrease in EMG burst duration, were taken as evidence of increased chewing efficiency. No significant differences in the frequency of chewing were found across the ages studied. Additional considerations include the appropriateness of this coordinative infrastructure for other developing oromotor skills, such as speech production. It is suggested that the relatively fixed coordinative framework for chewing exhibited by these children would not be suitable for adaptation to speech movements, which have been shown to rely on a much more variable and adjustable coordinative organization.
A major contributor to impaired locomotion post-stroke is abnormal phasing of muscle activity. While inappropriate paretic muscle phasing adapts to changing body orientation, load, and speed, it remains unclear whether paretic muscle phasing adapts to reversal of locomotor direction. We examined muscle phasing in backward pedaling, a task that requires shifts in biarticular but not uniarticular muscle phasing relative to forward pedaling. We hypothesized that if paretic and neurologically intact muscle phasing adapt similarly, then paretic biarticular but not paretic uniarticular muscles would shift phasing in backward pedaling. Paretic and neurologically intact individuals pedaled forward and backward while recording electromyograms (EMGs) from vastus medialis (VM), soleus (SOL), rectus femoris (RF), semimembranosus (SM), and biceps femoris (BF). Changes in muscle phasing were assessed by comparing the probability of muscle activity in forward and backward pedaling throughout 18 pedaling cycles. Paretic uniarticular muscles (VM and SOL) showed phase-advanced activity in backward versus forward pedaling, whereas the corresponding neurologically intact muscles showed little to no phasing change. Paretic biarticular muscles were less likely than neurologically intact biarticular muscles to display phasing changes in backward pedaling. Paretic RF displayed no phase change during backward pedaling, and paretic BF displayed no consistent adaptation to backward pedaling. Paretic SM was the only muscle to display backward/forward phase changes that were similar to the neurologically intact group. We conclude that paretic uniarticular muscles are more susceptible and paretic biarticular muscles are less susceptible to direction-dependent phase shifts, consistent with altered sensory integration and impaired cortical control of locomotion.
Mustached bats emit echolocation and communication calls containing both constant frequency (CF) and frequency-modulated (FM) components. Previously we found that 86% of neurons in the ventral division of the external nucleus of the inferior colliculus (ICXv) were directionally selective for linear FM sweeps and that selectivity was dependent on sweep rate. The ICXv projects to the suprageniculate nucleus (Sg) of the medial geniculate body. In this study, we isolated 37 single units in the Sg and measured their responses to best excitatory frequency (BEF) tones and linear 12-kHz upward and downward FM sweeps centered on the BEF. Sweeps were presented at durations of 30, 12, and 4 ms, yielding modulation rates of 400, 1,000, and 3,000 kHz/s. Spike count versus level functions were obtained at each modulation rate and compared with BEF controls. Sg units responded well to both tones and FM sweeps. BEFs clustered at 58 kHz, corresponding to the dominant CF component of the sonar signal. Spike count functions for both tones and sweeps were predominantly non-monotonic. FM directional selectivity was significant in 53–78% of the units, depending on modulation rate and level. Units were classified as up-selective (52%), down-selective (24%), or bi-directional (non-selective, 16%); a few units (8%) showed preferences that were either rate- or level-dependent. Most units showed consistent directional preferences at all SPLs and modulation rates tested, but typically showed stronger selectivity at lower sweep rates. Directional preferences were attributable to suppression of activity by sweeps in the non-preferred direction (~80% of units) and/or facilitation by sweeps in the preferred direction (~20–30%). Latencies for BEF tones ranged from 4.9 to 25.7 ms. Latencies for FM sweeps typically varied linearly with sweep duration. Most FM latency-duration functions had slopes ranging from 0.4 to 0.6, suggesting that the responses were triggered by the BEF. Latencies for BEF tones and FM sweeps were significantly correlated in most Sg units, i.e., the response to FM was temporally related to the occurrence of the BEF in the FM sweep. FM latency declined relative to BEF latency as modulation rate increased, suggesting that at higher rates response is triggered by frequencies in the sweep preceding the BEF. We conclude that Sg and ICXv units have similar, though not identical, response properties. Sg units are predominantly upsweep selective and could respond to either or both the CF and FM components in biosonar signals in a number of echolocation scenarios, as well as to a variety of communication sounds.
Many networks generate distinct rhythms with multiple frequency and amplitude characteristics. The respiratory network in the pre-Bötzinger complex (pre-Böt) generates both the low-frequency, large-amplitude sigh rhythm and a faster, smaller-amplitude eupneic rhythm. Could the same set of pacemakers generate both rhythms? Here we used an in vitro respiratory brainslice preparation. We describe a subset of synaptically isolated pacemakers that spontaneously generate two distinct bursting patterns. These two patterns resemble network activity including sigh-like bursts that occur at low frequencies and have large amplitudes and eupneic-like bursts with higher frequency and smaller amplitudes. Cholinergic neuromodulation altered the network and pacemaker bursting: fictive sigh frequency is increased dramatically, whereas fictive eupneic frequency is drastically lowered. The data suggest that timing and amplitude characteristics of fictive eupneic and sigh rhythms are set by the same set of pacemakers that are tuned by changes in the neuromodulatory state.
A key feature of human recollection is the ability to remember details of the context in which events were experienced, as well as details of the events themselves. Previous studies have implicated a number of regions of prefrontal cortex in contextual recollection, but the role of anterior prefrontal cortex has so far resisted detailed characterization. We used event-related functional MRI (fMRI) to contrast recollection of two forms of contextual information: 1) decisions one had previously made about stimuli (task memory) and 2) which of two temporally distinct lists those stimuli had been presented in (list memory). In addition, a retrieval cue manipulation permitted evaluation of the stage of the retrieval process in which the activated regions might be involved. The results indicated that anterior prefrontal cortex responded significantly more during recollection of task than list context details. Furthermore, activation profiles for lateral and medial aspects of anterior prefrontal cortex suggested differing roles in recollection. Lateral regions seem to be more involved in the early retrieval specification stages of recollection, with medial regions contributing to later stages (e.g., monitoring and verification).
To maintain a stable representation of the visual environment as we move, the brain must update the locations of targets in space using extra-retinal signals. Humans can accurately update after intervening active whole-body translations. But can they also update for passive translations (i.e., without efference copy signals of an outgoing motor command)? We asked six head-fixed subjects to remember the location of a briefly flashed target (five possible targets were located at depths of 23, 33, 43, 63 and 150cm in front of the cyclopean eye) as they moved 10cm left, right, up, down, forward or backward, while fixating a head-fixed target at 53cm. After the movement, the subjects made a saccade to the remembered location of the flash with a combination of version and vergence eye movements. We computed an updating ratio where 0 indicates no updating and 1 indicates perfect updating. For lateral and vertical whole-body motion, where updating performance is judged by the size of the version movement, the updating ratios were similar for leftward and rightward translations, averaging 0.84±0.28 (mean±SD), as compared to 0.51±0.33 for downward and 1.05±0.50 for upward translations. For forward/backward movements, where updating performance is judged by the size of the vergence movement, the average updating ratio was 1.12±0.45. Updating ratios tended to be larger for far targets than near targets, although both intra- and inter-subject variabilities were smallest for near targets. Thus, in addition to self-generated movements, extra-retinal signals involving otolith and proprioceptive cues can also be used for spatial constancy.
We investigated summation of steady excitatory and inhibitory inputs in spinal motoneurons using an in vivo preparation, the decerebrate cat, in which neuromodulatory input from the brain stem facilitated a strong persistent inward current (PIC) in dendritic regions. This dendritic PIC amplified both excitatory and inhibitory synaptic currents two-to threefold, but within different voltage ranges. Amplification of excitatory synaptic current peaked at voltage-clamp holding potentials near spike threshold (about −55 to −50 mV), whereas amplification of inhibitory current peaked at significantly more depolarized levels (about −45 to −40 mV). Thus the linear sum of excitatory and inhibitory currents tended to vary from net excitatory to net inhibitory as holding potential was depolarized. The actual summed currents, however, diverged from the predicted linear currents. At the peak of excitation, summation averaged about 15% sublinear (actual sum was less positive than the linear sum). In contrast, at the peak of inhibition, summation averaged about 18% supralinear (actual more positive than linear). Moreover, these nonlinear effects were substantially larger in cells where the variation from peak excitation to peak inhibition for linear summation was larger. When descending neuromodulatory input was eliminated by acute spinalization, PIC amplification was not observed and summation tended to be either sublinear or approximately linear, depending on input source. Overall, in cells with strong PICs, nonlinear summation of excitation and inhibition does occur, but this nonlinearity results in a more consistent relationship between membrane potential and the summed excitatory and inhibitory current.
The current study was designed to examine potential interlimb asymmetries in controlling movement extent. Subjects made repetitive single-joint elbow extension movements while the arm was supported on a horizontal, frictionless, air-jet system. Four targets of 10, 20, 35, and 45° excursions were randomly presented over the course of 150 trials. For both arms, peak tangential hand velocity scaled linearly with movement distance. There was no significant difference between either peak velocities or movement accuracies for the two arms. However, the mechanisms responsible for achieving these velocities and extents were quite distinct for each arm. For the dominant arm, peak tangential finger acceleration varied systematically with movement distance. In contrast, nondominant-arm peak tangential acceleration varied little across targets and, as such, was a poor predictor of movement distance. Instead the velocities of the nondominant arm were determined primarily by variation in the duration of the initial acceleration impulse, which corresponds to the time of peak velocity. These different strategies reflect previously identified mechanisms in controlling movement distance: pulse-height control and pulse-width control. The former is characterized by a variation in peak acceleration and has been associated with preplanning mechanisms. The latter occurs after peak acceleration and has been shown to depend on peripheral sensory feedback. Our findings indicate that the dominant-arm system controls movement extent largely through planning mechanisms that specify pulse-height control, whereas the nondominant system does so largely through feedback mediated pulse-width control.
Serotonergic cells are located in a restricted number of brainstem nuclei, send projections to virtually all parts of the central nervous system, and are critical to normal brain function. They discharge tonically at a rate modulated by sleep/wake cycle and, in the case of medullary serotonergic cells in raphe magnus and the adjacent reticular formation (RM), are excited by cold challenge. Yet, beyond behavioral state and cold, endogenous factors that influence serotonergic cell discharge remain largely mysterious. The present study in the anesthetized rat investigated predictors of serotonergic RM cell discharge by testing whether cell discharge correlated to three rhythms observed in blood pressure recordings that averaged >30 minutes in length. A very slow frequency rhythm with a period of minutes, a respiratory rhythm, and a cardiac rhythm were derived from the blood pressure recording. Cross correlations between each of the derived rhythms and cell activity revealed that the discharge of 38 of the 40 serotonergic cells studied was significantly correlated to the very slow and/or respiratory rhythms. Very few serotonergic cells discharged in relation to the cardiac cycle and those that did, did so weakly. The correlations between serotonergic cell discharge and the slow and respiratory rhythms cannot arise from baroreceptive input. Instead we hypothesize that they are by-products of on-going adjustments to homeostatic functions that happen to alter blood pressure. Thus, serotonergic RM cells integrate information about multiple homeostatic activities and challenges and can consequently modulate spinal processes according to the most pressing need of the organism.
In rats, opioids produce analgesia in large part by their effects on two cell populations in the medullary raphe magnus (RM). To extend our mechanistic understanding of opioid analgesia to the genetically tractable mouse, we characterized behavioral reactions and RM neural responses to opioid administration. DAMGO, a mu-opioid receptor agonist, microinjected into the murine RM produced cardiorespiratory depression and reduced slow wave EEG activity as well as increased the noxious heat-evoked withdrawal latencies. As in rat, RM cell types that were excited and inhibited by noxious stimuli, termed on and off cells respectively, were observed in mice. However, in contrast to findings in rat, opioid doses that suppressed withdrawals did not alter the background discharge rate of murine on and off cells, suggesting that the cellular mechanisms by which the murine RM generates opioid analgesia are substantially different from those in rats. Murine on cell discharge did not predict the latency or magnitude of an ensuing withdrawal but did correlate to the magnitude and latency of concurrent withdrawals. Although opioids failed to alter the background discharge of on and off cells, they reduced the responses of RM neurons to noxious stimulation, further evidence that RM modulates on-going withdrawals. In characterizing the role of RM in respiratory modulation, we found that on cells burst and off cells paused during tachypneic events. The effects of opioids in the murine RM on homeostasis and the association of on and off cell discharge with tachypnea corroborate roles for opioid signaling in RM beyond analgesia.
Previous neuroimaging studies of language processing in blind individuals described cortical activation of primary (V1) and higher tier visual areas, irrespective of the age of blindness onset. Specifically, participants were given nouns and asked to generate an associated verb. These results confirmed the presence of adaptations in the visual cortex of blind people and suggested that these responses represented linguistic operations. The present functional magnetic resonance imaging study attempted to further characterize these responses as being preferential for semantic or phonological processing. Three groups of participants (sighted, early-onset, and late-onset blind) heard lists of related words and attended to either a common meaning (semantic task) or common rhyme (phonological task) that linked the words. In all three groups, the semantic task elicited stronger activity in the left anterior inferior frontal gyrus and the phonological task evoked stronger activity bilaterally in the inferior parietal cortex and posterior aspects of the left inferior frontal gyrus. Only blind individuals showed activity in occipital, temporal, and parietal components of visual cortex. The spatial extent of visual cortex activity was greatest in early blind, who exhibited activation in all ventral and dorsal visual cortex subdivisions (V1 through MT) for both tasks. Preferential activation appeared for the semantic task. Late blind individuals exhibited responses in ventral and dorsal V1, ventral V2, VP and V8, but only for the semantic task. Our findings support prior evidence of visual cortex activity in blind people engaged in auditory language processing and suggest that this activity may be related to semantic processing.
Literacy for blind people requires learning Braille. Along with others, we have shown that reading Braille activates visual cortex. This includes striate cortex (V1), i.e., banks of calcarine sulcus, and several higher visual areas in lingual, fusiform, cuneus, lateral occipital, inferior temporal, and middle temporal gyri. The spatial extent and magnitude of magnetic resonance (MR) signals in visual cortex is greatest for those who became blind early in life. Individuals who lost sight as adults, and subsequently learned Braille, still exhibited activity in some of the same visual cortex regions, especially V1. These findings suggest these visual cortex regions become adapted to processing tactile information and that this cross-modal neural change might support Braille literacy. Here we tested the alternative hypothesis that these regions directly respond to linguistic aspects of a task. Accordingly, language task performance by blind persons should activate the same visual cortex regions regardless of input modality. Specifically, visual cortex activity in blind people ought to arise during a language task involving heard words. Eight early blind, six late blind, and eight sighted subjects were studied using functional magnetic resonance imaging (fMRI) during covert generation of verbs to heard nouns. The control task was passive listening to indecipherable sounds (reverse words) matched to the nouns in sound intensity, duration, and spectral content. Functional responses were analyzed at the level of individual subjects using methods based on the general linear model and at the group level, using voxel based ANOVA and t-test analyses. Blind and sighted subjects showed comparable activation of language areas in left inferior frontal, dorsolateral prefrontal, and left posterior superior temporal gyri. The main distinction was bilateral, left dominant activation of the same visual cortex regions previously noted with Braille reading in all blind subjects. The spatial extent and magnitude of responses was greatest on the left in early blind individuals. Responses in the late blind group mostly were confined to V1 and nearby portions of the lingual and fusiform gyri. These results confirm the presence of adaptations in visual cortex of blind people but argue against the notion that this activity during Braille reading represents somatosensory (haptic) processing. Rather, we suggest that these responses can be most parsimoniously explained in terms of linguistic operations. It remains possible that these responses represent adaptations which initially are for processing either sound or touch, but which are later generalized to the other modality during acquisition of Braille reading skills.
Brief synaptic inhibition can overwhelm a nearly coincident suprathreshold excitatory input to preclude spike generation. Surprisingly, a brief inhibitory event that occurs in a favorable time window preceding an otherwise subthreshold excitation can facilitate spiking. Such postinhibitory facilitation (PIF) requires that the inhibition has a short (decay) time constant τinh. The timescale ranges of τinh and of the window (width and timing) for PIF depend on the rates of neuronal subthreshold dynamics. The mechanism for PIF is general, involving reduction by hyperpolarization of some excitability-suppressing factor that is partially recruited at rest. Here we illustrate and analyze PIF, experimentally and theoretically, using brain stem auditory neurons and a conductance-based five-variable model. In this auditory case, PIF timescales are in the sub- to few millisecond range and the primary mechanistic factor is a low-threshold potassium conductance gKLT. Competing dynamic influences create the favorable time window: hyperpolarization that moves V away from threshold and hyper-excitability resulting from reduced gKLT. A two-variable reduced model that retains the dynamics only of V and gKLT displays a similar time window. We analyze this model in the phase plane; its geometry has generic features. Further generalizing, we show that PIF behavior may occur even in a very reduced model with linear subthreshold dynamics, by using an integrate-and-fire model with an accommodating voltage-dependent threshold. Our analyses of PIF provide insights for fast inhibition’s facilitatory effects in longer trains. Periodic subthreshold excitatory inputs can lead to firing, even one for one, if brief inhibitory inputs are interleaved within a range of favorable phase lags. The temporal specificity of inhibition’s facilitating effect could play a role in temporal processing, in sensitivity to inhibitory and excitatory temporal patterning, in the auditory and other neural systems.
Development and maintenance of whisker-specific patterns along the rodent trigeminal pathway depends on an intact sensory periphery during the sensitive/critical period in development. Barrelette cells of the brain stem trigeminal nuclei are the first set of neurons to develop whisker-specific patterns. Those in the principal sensory nucleus (PrV) relay these patterns to the ventrobasal thalamus, and consequently, to the somatosensory cortex. Thus PrV barrelette cells are among the first group of central neurons susceptible to the effects of peripheral damage. Previously we showed that membrane properties of barrelette cells are distinct as early as postnatal day 1 (PND 1) and remain unchanged following peripheral denervation in newborn rat pups (Lo and Erzurumlu 2001). In the present study, we investigated the changes in synaptic transmission. In barrelette cells of normal PND 1 rats, weak stimulation of the trigeminal tract (TrV) that was subthreshold for inducing Na+ spikes evoked an excitatory postsynaptic potential–inhibitory postsynaptic potential (EPSP-IPSP) sequence that was similar to the responses seen in older rats (Lo et al. 1999). Infraorbital nerve transection at birth did not alter excitatory and inhibitory synaptic connections of the barrelette cells. These observations suggested that local neuronal circuits are already established in PrV at birth and remain intact after deafferentation. Strong stimulation of the TrV induced a sustained depolarization (plateau potential) in denervated but not in normal barrelette neurons. The plateau potential was distinct from the EPSP-IPSP sequence by 1) a sustained (>80 ms) depolarization above −40 mV; 2) a slow decline slope (<0.1 mV/ms); 3) partially or totally inactivated Na+ spikes on the plateau; and 4) a termination by a steep decay (> 1 mV/ms) to a hyperpolarizing membrane level. The plateau potential was mediated by L-type Ca2+ channels and triggered by a N-methyl-d-aspartate (NMDA) receptor-mediated EPSP. γ-aminobutyric acid-A (GABAA) receptor-mediated IPSP dynamically regulated the latency and duration of the plateau potential. These results indicate that after neonatal peripheral damage, central trigeminal inputs cause a large and longlasting Ca2+ influx through L-type Ca2+ channels in barrelette neurons. Increased Ca2+ entry may play a key role in injury-induced structural remodeling, and/or transsynaptic cell death.
Braille reading depends on remarkable adaptations that connect the somatosensory system to language. We hypothesized that the pattern of cortical activations in blind individuals reading Braille would reflect these adaptations. Activations in visual (occipital-temporal), frontal-language, and somatosensory cortex in blind individuals reading Braille were examined for evidence of differences relative to previously reported studies of sighted subjects reading print or receiving tactile stimulation. Nine congenitally blind and seven late-onset blind subjects were studied with fMRI as they covertly performed verb generation in response to reading Braille embossed nouns. The control task was reading the nonlexical Braille string “######”. This study emphasized image analysis in individual subjects rather than pooled data. Group differences were examined by comparing magnitudes and spatial extent of activated regions first determined to be significant using the general linear model. The major adaptive change was robust activation of visual cortex despite the complete absence of vision in all subjects. This included foci in peri-calcarine, lingual, cuneus and fusiform cortex, and in the lateral and superior occipital gyri encompassing primary (V1), secondary (V2), and higher tier (VP, V4v, LO and possibly V3A) visual areas previously identified in sighted subjects. Subjects who never had vision differed from late blind subjects in showing even greater activity in occipital-temporal cortex, provisionally corresponding to V5/MT and V8. In addition, the early blind had stronger activation of occipital cortex located contralateral to the hand used for reading Braille. Responses in frontal and parietal cortex were nearly identical in both subject groups. There was no evidence of modifications in frontal cortex language areas (inferior frontal gyrus and dorsolateral prefrontal cortex). Surprisingly, there was also no evidence of an adaptive expansion of the somatosensory or primary motor cortex dedicated to the Braille reading finger(s). Lack of evidence for an expected enlargement of the somatosensory representation may have resulted from balanced tactile stimulation and gross motor demands during Braille reading of nouns and the control fields. Extensive engagement of visual cortex without vision is discussed in reference to the special demands of Braille reading. It is argued that these responses may represent critical language processing mechanisms normally present in visual cortex.
Voltage-dependent membrane conductances support specific neurophysiological properties. To investigate the mechanisms of coincidence detection, we activated gerbil medial superior olivary (MSO) neurons with dynamic current-clamp stimuli in vitro. Spike-triggered reverse-correlation analysis for injected current was used to evaluate the integration of subthreshold noisy signals. Consistent with previous reports, the partial blockade of low-threshold potassium channels (IKLT) reduced coincidence detection by slowing the rise of current needed on average to evoke a spike. However, two factors point toward the involvement of a second mechanism. First, the reverse correlation currents revealed that spike generation was associated with a preceding hyperpolarization. Second, rebound action potentials are 45% larger compared to depolarization-evoked spikes in the presence of an IKLT antagonist. These observations suggest that the sodium current (INa) was substantially inactivated at rest. To test this idea, INa was enhanced by increasing extracellular sodium concentration. This manipulation reduced coincidence detection, as reflected by slower spike-triggering current, and diminished the hyperpolarization phase in the reverse-correlation currents. As expected, a small outward bias current decreased the pre-spike hyperpolarization phase, and TTX blockade of INa nearly eliminated the hyperpolarization phase in the reverse correlation current. A computer model including Hodgkin-Huxley type conductances for spike generation and for IKLT showed reduction in coincidence detection when IKLT was reduced or when INa was increased. We hypothesize that desirable synaptic signals first remove some inactivation of INa and reduce activation of IKLT to create a brief temporal window for coincidence detection of subthreshold noisy signals.
Neurons of the hypothalamic paraventricular nucleus (PVN) are key controllers of sympathetic nerve activity and receive input from angiotensin II (ANG II)–containing neurons in the forebrain. This study determined the effect of ANG II on PVN neurons that innervate in the rostral ventrolateral medulla (RVLM)—a brain stem site critical for maintaining sympathetic outflow and arterial pressure. Using an in vitro brain slice preparation, whole cell patch-clamp recordings were made from PVN neurons retrogradely labeled from the ipsilateral RVLM of rats. Of 71 neurons tested, 62 (87%) responded to ANG II. In current-clamp mode, bath-applied ANG II (2 μM) significantly (P < 0.05) depolarized membrane potential from −58.5 ± 2.5 to −54.5 ± 2.0 mV and increased the frequency of action potential discharge from 0.7 ± 0.3 to 2.8 ± 0.8 Hz (n = 4). Local application of ANG II by low-pressure ejection from a glass pipette (2 pmol, 0.4 nl, 5 s) also elicited rapid and reproducible excitation in 17 of 20 cells. In this group, membrane potential depolarization averaged 21.5 ± 4.1 mV, and spike activity increased from 0.7 ± 0.4 to 21.3 ± 3.3 Hz. In voltage-clamp mode, 41 of 47 neurons responded to pressure-ejected ANG II with a dose-dependent inward current that averaged −54.7 ± 3.9 pA at a maximally effective dose of 2.0 pmol. Blockade of ANG II AT1 receptors significantly reduced discharge (P < 0.001, n = 5), depolarization (P < 0.05, n = 3), and inward current (P < 0.01, n = 11) responses to locally applied ANG II. In six of six cells tested, membrane input conductance increased (P < 0.001) during local application of ANG II (2 pmol), suggesting influx of cations. The ANG II current reversed polarity at +2.2 ± 2.2 mV (n = 9) and was blocked (P < 0.01) by bath perfusion with gadolinium (Gd3+, 100 μM, n = 8), suggesting that ANG II activates membrane channels that are nonselectively permeable to cations. These findings indicate that ANG II excites PVN neurons that innervate the ipsilateral RVLM by a mechanism that depends on activation of AT1 receptors and gating of one or more classes of ion channels that result in a mixed cation current.
Capsaicin, the vanilloid that selectively activates vanilloid receptors (VRs) on sensory neurons for noxious perception, has been reported to increase cochlear blood flow (CBF). VR-related receptors have also been found in the inner ear. This study aims to address the question as to whether VRs exist in the organ of Corti and play a role in cochlear physiology. Capsaicin or the more potent VR agonist, resiniferatoxin (RTX), was infused into the scala tympani of guinea pig cochlea, and their effects on cochlear sensitivity were investigated. Capsaicin (20 µM) elevated the threshold of auditory nerve compound action potential and reduced the magnitude of cochlear microphonic and electrically evoked otoacoustic emissions. These effects were reversible and could be blocked by a competitive antagonist, capsazepine. Application of 2 µM RTX resulted in cochlear sensitivity alterations similar to that by capsaicin, which could also be blocked by capsazepine. A desensitization phenomenon was observed in the case of prolonged perfusion with either capsaicin or RTX. Brief increase of CBF by capsaicin was confirmed, and the endocochlear potential was not decreased. Basilar membrane velocity (BM) growth functions near the best frequency and BM tuning were altered by capsaicin. Immunohistochemistry study revealed the presence of vanilloid receptor type 1 of the transient receptor potential channel family in the hair cells and supporting cells of the organ of Corti and the spiral ganglion cells of the cochlea. The results indicate that the main action of capsaicin is on outer hair cells and suggest that VRs in the cochlea play a role in cochlear homeostasis.