Long-term retention of learning-induced receptive-field plasticity in the auditory cortex.

Brief learning experience (classical conditioning) induces frequency-specific receptive-field (RF) plasticity in the auditory cortex, characterized as increased response to the frequency of the conditioned stimulus and decreased responses to most other frequencies, including the pretraining best frequency. This experiment asked (i) whether learning-induced RF plasticity, established in the waking state, can be expressed under general anesthesia and if so (ii) whether it exhibits long-term retention. Pure-tone-frequency RFs were obtained from adult guinea pigs under general anesthesia (sodium pentobarbital or ketamine) before and repeatedly after (1 hr-8 weeks) a 20- to 30-trial session of pairing a non-best-frequency tone with mild footshock. Conditioned-stimulus-specific RF plasticity was expressed under both types of anesthesia and included shifts of the pretraining best frequency toward or even to the frequency of the conditioned stimulus. Moreover, this RF plasticity exhibits long-term retention, being evident 1-8 weeks after training. This satisfies a criterion for the long-term storage of information in the auditory cortex.     

Real-time imaging of human cortical activity evoked by painful esophageal stimulation

BACKGROUND & AIMS: Current models of visceral pain processing derived from metabolic brain imaging techniques fail to differentiate between exogenous (stimulus-dependent) and endogenous (non-stimulus-specific) neural activity. The aim of this study was to determine the spatiotemporal correlates of exogenous neural activity evoked by painful esophageal stimulation. METHODS: In 16 healthy subjects (8 men; mean age, 30.2 +/- 2.2 years), we recorded magnetoencephalographic responses to 2 runs of 50 painful esophageal electrical stimuli originating from 8 brain subregions. Subsequently, 11 subjects (6 men; mean age, 31.2 +/- 1.8 years) had esophageal cortical evoked potentials recorded on a separate occasion by using similar experimental parameters. RESULTS: Earliest cortical activity (P1) was recorded in parallel in the primary/secondary somatosensory cortex and posterior insula (approximately 85 ms). Significantly later activity was seen in the anterior insula (approximately 103 ms) and cingulate cortex (approximately 106 ms; P=.0001). There was no difference between the P1 latency for magnetoencephalography and cortical evoked potential (P=.16); however, neural activity recorded with cortical evoked potential was longer than with magnetoencephalography (P=.001). No sex differences were seen for psychophysical or neurophysiological measures. CONCLUSIONS: This study shows that exogenous cortical neural activity evoked by experimental esophageal pain is processed simultaneously in somatosensory and posterior insula regions. Activity in the anterior insula and cingulate-brain regions that process the affective aspects of esophageal pain-occurs significantly later than in the somatosensory regions, and no sex differences were observed with this experimental paradigm. Cortical evoked potential reflects the summation of cortical activity from these brain regions and has sufficient temporal resolution to separate exogenous and endogenous neural activity.     

Reward-dependent plasticity in the primary auditory cortex of adult monkeys trained to discriminate temporally modulated signals

Adult owl monkeys were trained to detect an increase in the envelope frequency of a sinusoidally modulated 1-kHz tone. Detection was positively correlated with the magnitude of the change in the envelope frequency. Surprisingly, neuronal responses recorded in the primary auditory cortex of trained monkeys were globally suppressed by the modulated tone. However, the contrast in neuronal responsiveness to small increases versus large increases in envelope frequencies was actually enhanced in the trained animals. The results suggest behaviorally contingent inhibitory and excitatory processes that are modulated by the probability that a particular signal predicts a reward.     

Frequency preference and attention effects across cortical depths in the human primary auditory cortex

Columnar arrangements of neurons with similar preference have been suggested as the fundamental processing units of the cerebral cortex. Within these columnar arrangements, feed-forward information enters at middle cortical layers whereas feedback information arrives at superficial and deep layers. This interplay of feed-forward and feedback processing is at the core of perception and behavior. Here we provide in vivo evidence consistent with a columnar organization of the processing of sound frequency in the human auditory cortex. We measure submillimeter functional responses to sound frequency sweeps at high magnetic fields (7 tesla) and show that frequency preference is stable through cortical depth in primary auditory cortex. Furthermore, we demonstrate that—in this highly columnar cortex—task demands sharpen the frequency tuning in superficial cortical layers more than in middle or deep layers. These findings are pivotal to understanding mechanisms of neural information processing and flow during the active perception of sounds.Auditory perception starts in our ears, where hair cells at different places in the cochlea respond to different sound frequencies. The spatially ordered arrangement of neural responses to frequencies (tonotopy) that arises from this transduction mechanism is preserved in subcortical (1, 2) and cortical stages of processing, where neuronal populations form multiple tonotopic maps (3, 4). At the cortical level, tonotopic maps describe systematic changes along the surface. In the orthogonal direction (i.e., perpendicular to the cortical surface), aggregates of neurons with parallel axons have been reported (5, 6). These anatomical observations of cortical microcolumns inspired invasive electrophysiological investigations in cats (7), demonstrating that frequency preference is constant across cortical depth (i.e., frequency columns). Since this early study, frequency columns have been observed in a variety of animals (3, 8–10), and a columnar organization has been suggested for other acoustic properties (10, 11). Despite this anatomical and physiological evidence from animal models, the role of cortical columns in auditory perception is not understood (6, 12, 13). To unravel intracolumnar computations, it is of fundamental importance to analyze the transformation of information across cortical depths. Differences in cell types and in patterns of input and output projections suggest a distinct role of cortical layers in neural information processing (5). In particular, behavioral demands and ongoing brain states can modulate the functional properties of layer 2/3 neurons, suggesting that supragranular neuronal populations may be of fundamental relevance for the processing of sensory information in a context-dependent manner (14). Recordings in the primary auditory cortex of animals have shown differences across layers in response latency (15, 16), in frequency selectivity (i.e., tuning width) (8, 16), and in the complexity of neuronal preference to acoustic information (i.e., receptive field) (17). However, the reports are not concordant across species. Moreover, most of the knowledge regarding auditory columnar processing has been obtained in anesthetized animals, making its relation to human behavior unclear.To date, there is no functional evidence for a columnar organization and for the layer-dependent processing of sound frequency in the human auditory cortex from either invasive or noninvasive recordings. In this study, we address this question noninvasively using high magnetic field (7 tesla) functional magnetic resonance imaging (fMRI) at high spatial resolution and specificity (18, 19). We acquired functional images in the primary auditory cortex (PAC) of five healthy volunteers and estimated the best frequency (BF) responses voxel-by-voxel. Then, by analyzing the 3D spatial variations of these responses, we identified the PAC regions with a stable arrangement of BF across cortical depths. The term “column” has been used with multiple meanings in the past (13). Here, we refer to columnar region as the cortical region where the variation of frequency with depth is significantly smaller compared with the frequency variation orthogonal to depth (i.e., across the surface) (SI Text). Further, we examined the functional differences across cortical layers by estimating the cortical depth-dependent changes in frequency tuning during an auditory and a control visual task. We hypothesized that additional top-down processing engaged by the auditory task would modulate the frequency tuning of fMRI responses in the PAC in a cortical depth-dependent manner. Finally, we simulated how the observed changes of frequency tuning across layers and tasks may result in behaviorally relevant changes of neuronal population-based sound representations.     

Spine dynamics of PSD-95-deficient neurons in the visual cortex link silent synapses to structural cortical plasticity

Critical periods (CPs) are time windows of heightened brain plasticity during which experience refines synaptic connections to achieve mature functionality. At glutamatergic synapses on dendritic spines of principal cortical neurons, the maturation is largely governed by postsynaptic density protein-95 (PSD-95)-dependent synaptic incorporation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors into nascent AMPA-receptor silent synapses. Consequently, in mouse primary visual cortex (V1), impaired silent synapse maturation in PSD-95-deficient neurons prevents the closure of the CP for juvenile ocular dominance plasticity (jODP). A structural hallmark of jODP is increased spine elimination, induced by brief monocular deprivation (MD). However, it is unknown whether impaired silent synapse maturation facilitates spine elimination and also preserves juvenile structural plasticity. Using two-photon microscopy, we assessed spine dynamics in apical dendrites of layer 2/3 pyramidal neurons (PNs) in binocular V1 during ODP in awake adult mice. Under basal conditions, spine formation and elimination ratios were similar between PSD-95 knockout (KO) and wild-type (WT) mice. However, a brief MD affected spine dynamics only in KO mice, where MD doubled spine elimination, primarily affecting newly formed spines, and caused a net reduction in spine density similar to what has been observed during jODP in WT mice. A similar increase in spine elimination after MD occurred if PSD-95 was knocked down in single PNs of layer 2/3. Thus, structural plasticity is dictated cell autonomously by PSD-95 in vivo in awake mice. Loss of PSD-95 preserves hallmark features of spine dynamics in jODP into adulthood, revealing a functional link of PSD-95 for experience-dependent synapse maturation and stabilization during CPs.

Early life of an animal is characterized by time windows of functionally and structurally enhanced brain plasticity known as critical periods (CPs), which have been described initially in the primary visual cortex (V1) of kittens (1). During CPs, experience refines the connectivity of principal excitatory neurons to establish the mature functionality of neural networks. This refinement is governed by the constant generation and elimination of nascent synapses on dendritic spines that sample favorable connections to be consolidated and unfavorable ones to be eliminated (2–5). A fraction of nascent synapses is or becomes α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-receptor silent, expressing N-methyl-D-aspartate (NMDA) receptors only (6–8). At eye opening, silent synapses are abundant in the primary visual cortex (V1) (9, 10) and mature during CPs by stable AMPA receptor incorporation (11–14). The pace of silent synapse maturation is governed by the opposing yet cooperative function of postsynaptic density protein of 95 kDa (PSD-95) and its paralog PSD-93, two signaling scaffolds of the postsynaptic density of excitatory synapses (12, 13). However, whether silent synapses are preferential substrates for spine elimination during CPs remains to be investigated.In juvenile mice (postnatal days [P] 20 to 35), a brief monocular deprivation (MD) of the dominant contralateral eye results in a shift of the ocular dominance (OD) of binocular neurons in V1 toward the open eye, mediated by a reduction of responses to visual stimulation of the deprived eye (15–17). Structurally, MD induces an increase in spine elimination in apical dendrites of layer (L) 2/3 and L5 pyramidal neurons (PNs) which is only observed during the CP and constitutes a hallmark of juvenile OD plasticity (jODP) (18–20). After CP closure, cortical plasticity declines progressively, and in standard cage-raised mice beyond P40, a 4-d MD no longer induces the functional nor anatomical changes associated with jODP (21–24).At least three different mechanisms involved in experience-dependent maturation of cortical neural networks have been described, but the molecular and cellular mechanisms that cause CP closure remain highly debated (18, 25, 26). First, plasticity of local inhibitory neurons, such as increased inhibitory tone or a reduction of release probability by experience-dependent endocannabinoid receptor 1 (CB1R) activation was reported to close the critical period in rodent V1 (27–29). Second, the expression of so-called “plasticity brakes,” such as extracellular matrix (ECM), Nogo receptor 1 (NgR1), paired immunoglobulin-like receptor B (PirB), and Lynx1 were correlated with the end of critical periods (30–33). Experimentally decreasing the inhibitory tone or absence of plasticity brakes enhanced ODP expression in various knockout (KO) mouse models (32, 34, 35), among which only Lynx1 KO mice were shown to exhibit functional hallmarks of jODP, such as selective deprived eye depression after a short MD (36). Structurally, Lynx1 KO mice exhibited elevated spine dynamics at baseline; however, MD induced a reduction in spine elimination in apical dendrites of L5 PNs, whereas in L2/3 PNs there was no change (37). Thus, the effects of removing plasticity brakes on structural plasticity are variable, and it remains unclear to what extend manipulating the plasticity brakes can reinstate cellular signatures of CP plasticity in the adult wild-type (WT) brain (38). Third, the progressive maturation of AMPAR-silent synapses was correlated with the closure of the CP for jODP (12, 13). Consequently, in PSD-95 KO mice, the maturation of silent synapses is impaired; their fraction remains at the eye opening level, and jODP is preserved lifelong (13). Furthermore, visual cortex-specific knockdown (KD) of PSD-95 in the adult brain reinstated jODP. In contrast, in PSD-93 KO mice, silent synapses mature precociously and the CP for jODP closes precociously (12), correlating the presence of silent synapses with functional plasticity during CPs.While these three mechanisms of CP closure are not mutually exclusive in regulating cortical plasticity (26), it remains elusive whether CP-like structural plasticity can be expressed in the adult brain and whether silent synapses might be substrates for it. Here, we performed chronic two-photon imaging of dendrites of L2/3 pyramidal neurons in binocular V1 of PSD-95 KO (and KD) and WT mice, tracking the same dendritic spines longitudinally before, during, and after a 4-d period of MD. As previous studies have reported anesthesia effects on spine dynamics (39–41), we performed our experiments in awake mice, thoroughly trained for head fixation under the two-photon microscope. Our chronic spine imaging experiments revealed that in adult PSD-95 KO and KD mice, a brief MD indeed increased spine elimination about twofold, while adult WT mice did not display experience-dependent changes in spine elimination or spine formation. Thus, the loss of PSD-95 led to a high number of AMPAR-silent synapses which were correlated with jODP after MD, and with juvenile-like structural plasticity even in the adult brain, underscoring the importance of silent synapses for CP-timing and network maturation and stabilization.     

Spinal and muscular evoked response following single stimulation of the motor cortex of the rat

The general characteristics of motor evoked potentials recorded from muscle and spinal cord in response to single electrical stimulation of motor cortex were examined in 30 rats. 5 other rats were additionally examined before and after full muscle relaxation, to differentiate the volume-conducted muscle response from spinal cord responses. The first positivity (P1) recorded from the lower thoracic cord following anodal stimulation was 1.1 +/- 0.1 ms and the second positivity (P2) was 2.1 +/- 0.2 ms. P1 was present in 11 animals and P2 in 20. The later components after 2.3 ms latency recorded from the epidural spinal electrode were lost with full muscular relaxation and seem to originate from volume conducted muscular activity. A relatively stable early MEP muscle response (6.1 +/- 0.9 ms) was observed in contralateral lower extremity muscles of all animals. Following this early response, a late MEP muscle response (16.0 +/- 1.9 ms) has been recorded in 43% of all animals. This relatively inconstant and multiphasic late muscle response disappeared during vibration of same extremity tendons and has similar characteristics as Hoffmann's reflex response. Additionally, with increasing stimulus intensities, the amplitude ratio of early to late response was similar to M response/H reflex amplitude ratio. The results suggest that the late MEP muscle response is probably the result of a reflex response caused by the first/early descending volley and traveled back to the spinal cord possibly through the Ia afferents similar to that in the H-reflex.     

Experience-dependent plasticity in the auditory cortex and the inferior colliculus of bats: role of the corticofugal system

In the big brown bat, Eptesicus fuscus, the response properties of neurons and the cochleotopic (frequency) maps in the auditory cortex (AC) and inferior colliculus can be changed by auditory conditioning, weak focal electric stimulation of the AC, or repetitive delivery of weak, short tone bursts. The corticofugal system plays an important role in information processing and plasticity in the auditory system. Our present findings are as follows. In the AC, best frequency (BF) shifts, i.e., reorganization of a frequency map, slowly develop and reach a plateau approximately 180 min after conditioning with tone bursts and electric-leg stimulation. The plateau lasts more than 26 h. In the inferior colliculus, on the other hand, BF shifts rapidly develop and become the largest at the end of a 30-min-long conditioning session. The shifted BFs return (i. e., recover) to normal in approximately 180 min. The collicular BF shifts are not a consequence of the cortical BF shifts. Instead, they lead the cortical BF shifts. The collicular BF shifts evoked by conditioning are very similar to the collicular and cortical BF shifts evoked by cortical electrical stimulation. Therefore, our working hypothesis is that, during conditioning, the corticofugal system evokes subcortical BF shifts, which in turn boost cortical BF shifts. The cortical BF shifts otherwise would be very small. However, whether the cortical BF shifts are consequently boosted depends on nonauditory systems, including nonauditory sensory cortices, amygdala, basal forebrain, etc., which determine the behavioral relevance of acoustic stimuli.     

Receptive field structure in the visual cortex: does selective stimulation induce plasticity?

Sensory areas of adult cerebral cortex can reorganize in response to long-term alterations in patterns of afferent signals. This long-term plasticity is thought to play a crucial role in recovery from injury and in some forms of learning. However, the degree to which sensory representations in primary cortical areas depend on short-term (i.e., minute to minute) stimulus variations remains unclear. A traditional view is that each neuron in the mature cortex has a fixed receptive field structure. An alternative view, with fundamentally different implications for understanding cortical function, is that each cell's receptive field is highly malleable, changing according to the recent history of the sensory environment. Consistent with the latter view, it has been reported that selective stimulation of regions surrounding the receptive field induces a dramatic short-term increase in receptive field size for neurons in the visual cortex [Pettet, M. W. & Gilbert, C. D. (1992) Proc. Natl. Acad. Sci. USA 89, 8366-8370]. In contrast, we report here that there is no change in either the size or the internal structure of the receptive field following several minutes of surround stimulation. However, for some cells, overall responsiveness increases. These results suggest that dynamic alterations of receptive field structure do not underlie short-term plasticity in the mature primary visual cortex. However, some degree of short-term adaptability could be mediated by changes in responsiveness.     

Patches of synchronized activity in the cerebellar cortex evoked by mossy-fiber stimulation: Questioning the role of parallel fibers

The discrepancy between the structural longitudinal organization of the parallel-fiber system in the cerebellar cortex and the functional mosaic-like organization of the cortex has provoked controversial theories about the flow of information in the cerebellum. We address this issue by characterizing the spatiotemporal organization of neuronal activity in the cerebellar cortex by using optical imaging of voltage-sensitive dyes in isolated guinea-pig cerebellum. Parallel-fiber stimulation evoked a narrow beam of activity, which propagated along the parallel fibers. Stimulation of the mossy fibers elicited a circular, nonpropagating patch of synchronized activity. These results strongly support the hypothesis that a beam of parallel fibers, activated by a focal group of granule cells, fails to activate the Purkinje cells along most of its length. It is thus the ascending axon of the granule cell, and not its parallel branches, that activates and defines the basic functional modules of the cerebellar cortex.     

Somatosensory cortical evoked potentials in normal subjects to single and double median nerve stimulation (author's transl)

On the wrist the median nerve of 42 normal subjects was stimulated by single and double stimuli and the contralateral cortical evoked potentials (SRAP) were evaluated with regard to peak-latencies, amplitudes and refractory period. SRAP after single nerve stimulations has 4-6 peaks in the first 100 ms, in 19 of 42 subjects there is an early peak ("peak 14-15") of the brain stem. The peak-latencies of minimum 1, maximum 1 and minimum 2 increase with the age not significantly. There are no right/left differences of the SRAP-amplitudes or -latencies. The duration of the relative refractory period was determined through the lengthening of latency respectively through the loss of minimum 1. The relative refractory time is independent of age, the absolute refractory time increase with advanced age. The refractory times of the first 4 peaks are not different for the right and left hemisphere. A slow alpha-rhythm correlate significantly with a higher absolute refractory time.     

Long-term fenofibrate treatment impairs endothelium-dependent dilation to acetylcholine by altering the cyclooxygenase pathway

OBJECTIVE: Experimental studies and opinion articles emphasize that cardiovascular alterations associated with ageing can be improved by the long-term use of fenofibrates. We analyzed the effect of fenofibrate treatment on the acetylcholine-induced relaxation in rat aorta and the participation of nitric oxide (NO) and cyclooxygenase (COX)-derived factors in this effect. METHODS: Acetylcholine relaxation in untreated and 6-week fenofibrate-treated Wistar rats was analyzed in the absence and presence of the NO synthase (NOS) inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME), the specific inducible NO (iNOS) synthase inhibitor 1400W, the nonspecific COX inhibitor indomethacin, the specific COX-2 inhibitor NS-398, the specific thromboxane receptor antagonist SQ-29548, the thromboxane synthesis inhibitor furegrelate, the prostacyclin synthesis inhibitor tranylcypromine, or the 20-HETES synthesis inhibitor formamidine. eNOS, iNOS, COX-1, and COX-2 expression was studied by Western blotting. In addition, production of prostaglandin F(2alpha) (PGF(2alpha)), thromboxane A(2) (TxA(2)), prostaglandin E(2) (PGE(2)), isoprostanes, and prostacyclin (PGI(2)) was also measured. RESULTS: Fenofibrate treatment reduced acetylcholine relaxation. Indomethacin, NS-398, and tranylcypromine decreased acetylcholine relaxation in untreated rats but enhanced relaxation in treated rats. SQ-29548 increased acetylcholine responses in segments from treated rats but not in segments from untreated rats. L-NAME decreased vasodilator response to acetylcholine in both groups while furegrelate, NS-398, 1400W, and formamidine did not affect acetylcholine responses in either group. eNOS and COX-2 expression was higher in aorta from treated rats while COX-1 and iNOS remained unmodified. Basal and acetylcholine-stimulated NO and PGE(2) release were increased, and that of PGI(2) decreased in treated rats. TxA(2) release was similar, but PGF(2alpha) release was undetectable in both groups. CONCLUSIONS: Although it increases NO production through increases in eNOS expression, fenofibrate treatment induces endothelial dysfunction. This effect seems to be mediated by decreased PGI(2) and increased PGE(2) release, and it may help to explain the rise in thromboembolic events observed after long-term fenofibrate treatment in humans.     

Perinatal exposure to a noncoplanar polychlorinated biphenyl alters tonotopy, receptive fields, and plasticity in rat primary auditory cortex

Noncoplanar polychlorinated biphenyls (PCBs) are widely dispersed in human environment and tissues. Here, an exemplar noncoplanar PCB was fed to rat dams during gestation and throughout three subsequent nursing weeks. Although the hearing sensitivity and brainstem auditory responses of pups were normal, exposure resulted in the abnormal development of the primary auditory cortex (A1). A1 was irregularly shaped and marked by internal nonresponsive zones, its topographic organization was grossly abnormal or reversed in about half of the exposed pups, the balance of neuronal inhibition to excitation for A1 neurons was disturbed, and the critical period plasticity that underlies normal postnatal auditory system development was significantly altered. These findings demonstrate that developmental exposure to this class of environmental contaminant alters cortical development. It is proposed that exposure to noncoplanar PCBs may contribute to common developmental disorders, especially in populations with heritable imbalances in neurotransmitter systems that regulate the ratio of inhibition and excitation in the brain. We conclude that the health implications associated with exposure to noncoplanar PCBs in human populations merit a more careful examination.     

Long-term inhibitory plasticity in visual cortical layer 4 switches sign at the opening of the critical period

Sensory microcircuits are refined by experience during windows of heightened plasticity termed “critical periods” (CPs). In visual cortex the effects of visual deprivation change dramatically at the transition from the pre-CP to the CP, but the cellular plasticity mechanisms that underlie this change are poorly understood. Here we show that plasticity at unitary connections between GABAergic Fast Spiking (FS) cells and Star Pyramidal (SP) neurons within layer 4 flips sign at the transition between the pre-CP and the CP. During the pre-CP, coupling FS firing with SP depolarization induces long-term depression of inhibition at this synapse, whereas the same protocol induces long-term potentiation of inhibition at the opening of the CP. Despite being of opposite sign, both forms of plasticity share expression characteristics—a change in coefficient of variation with no change in paired-pulse ratio—and depend on GABA_B receptor signaling. Finally, we show that the reciprocal SP→FS synapse also acquires the ability to undergo long-term potentiation at the pre-CP to CP transition. Thus, at the opening of the CP, there are coordinated changes in plasticity that allow specific patterns of activity within layer 4 to potentiate feedback inhibition by boosting the strength of FS↔SP connections.Sensory microcircuits are refined by experience during windows of heightened plasticity termed “critical periods” (CPs). In visual cortex the classical CP was defined based on when visual deprivation (VD) induces ocular dominance (OD) shifts, between approximately postnatal days (P) 20–33 (1–3). However, visual cortex is also plastic during a pre-CP between eye opening (∼P14) and the onset of the classical CP (4–6). Although both developmental windows are characterized by sensitivity to visual experience, the effects of VD change dramatically at the transition between these two developmental stages (7–10).The cellular changes that underlie the transition from pre-CP to CP plasticity remain incompletely understood, but recent work has implicated a specific inhibitory network involving parvalbumin-positive fast-spiking (FS) basket cells in this process (8, 11, 12). FS cells provide strong somatic inhibition onto cortical pyramidal neurons, and this inhibition matures significantly between eye opening and the opening of the classical CP (13–15). Further, reducing or enhancing this inhibition can prevent or prematurely trigger the transition from pre-CP to CP plasticity (11, 16–18). Thus, maturation of FS inhibition is thought to be causally involved in triggering CP plasticity, but exactly what aspect of this maturation drives these changes is unknown. One characteristic of this maturation is a change in the response of FS synapses to VD. Brief monocular VD during the pre-CP decreases inhibitory synaptic strength from FS to star pyramidal (SP) neurons in layer 4 (L4) of the monocular primary visual cortex [V1m (19)] but increases inhibition at the same synapse when performed during the CP (20). There is evidence that long-term potentiation of inhibition (LTPi) is the cellular mechanism behind the VD-driven inhibitory potentiation during the CP (20), but why VD weakens this synapse during the pre-CP has not been determined.To ask whether a change in the cellular plasticity mechanisms present at FS→SP synapses might underlie this developmental shift in the effects of VD, we used paired recordings to analyze transmission and plasticity at unitary connections between FS cells and SP neurons within V1m. We found only subtle changes in the basal properties of this connection between P15–P17 (the pre-CP) and P21–P23 (the opening of the CP). In contrast, plasticity at this synapse changed dramatically. Coupling presynaptic FS firing with postsynaptic SP depolarization induced long-term depression of inhibition (LTDi) during the pre-CP, whereas the same protocol induced LTPi during the CP. Both forms of plasticity were accompanied by changes in the coefficient of variation (CV) of unitary inhibitory postsynaptic current (uIPSC) amplitude without significant changes in paired-pulse ratio (PPR) and were blocked by GABA_B receptor (GABA_BR) antagonists. Finally, we found that during the CP (but not the pre-CP) the same induction protocol at reciprocally connected FS↔SP pairs induced LTP of both connections, suggesting that during the CP both components of this feedback inhibitory loop within L4 can be potentiated as a unit.     

Long-term results in the treatment of atrial tachycardial arrhythmias using temporary electric stimulation procedures

In 12 of 23 patients with atrial flutter, who were cardioversed by means of electric stimulation techniques and underwent a regular after-examination, a sinus rhythm was still existing 24 months after regularization. When these long-term results which in comparison to the late results are more favourable after electroshock cardioversion are interpreted apart from the different selection of patients must be taken into consideration that the rate of immediate success of about 50% was distinctly lower than in the DC-shock cardioversion. It is to be supposed that a stimulation therapy only in those patients leads to regularization, the atrial vulnerability and recidivity of whom is less distinct, whereas in the other cases only the transgression into an atrial fibrillation is successful.     

Pulmonary vasodilator responses to vagal stimulation and acetylcholine in the cat

Responses to vagal stimulation and acetylcholine were investigated in the feline pulmonary vascular bed under conditions of controlled pulmonary blood flow and constant left atrial pressure. Under baseline conditions, electrical stimulation of vagal efferent fibers increases lobar arterial pressure. However, when vasoconstrictor tone was increased, a depressor response was unmasked. The pressor response under baseline conditions and the depressor response under enhanced tone conditions were blocked by phenoxybenzamine and atropine. These data suggest that, in the cat, the vagus is composed of efferent fibers from both the sympathetic and parasympathetic systems. After treatment with 6-hydroxydopamine to destroy the integrity of the sympathetic system, vagal stimulation caused significant frequency-dependent decreases in lobar arterial pressure when lobar vascular tone was increased by infusion of a stable prostaglandin endoperoxide analog or ventilatory hypoxia. Injections of acetylcholine also caused significant dose-related decreases in lobar arterial pressure when lobar vascular resistance was elevated. Depressor responses to vagal stimulation and acetylcholine in 6-hydroxydopamine-treated animals were blocked by atropine and enhanced by physostigmine. Decreases in lobar arterial pressure in response to vagal stimulation in 6-hydroxydopamine-treated animals with enhanced tone were blocked by hexamethonium, whereas responses to injected acetylcholine were not altered by the ganglionic blocking agent. Decreases in lobar arterial pressure in response to vagal stimulation and acetylcholine were similar when the lung was ventilated and when the left lower lobe bronchus was obstructed. In addition, responses to vagal stimulation were similar when systemic arterial pressure was decreased to the level of pressure in the perfused lobar artery. Responses to acetylcholine were not altered after treatment with 5,8,11,14-eicosatetraynoic acid, a lipoxygenase inhibitor. The present data suggest that the feline pulmonary vascular bed is functionally innervated by cholinergic nerves and that vagal stimulation dilates the pulmonary vascular bed by releasing acetylcholine which acts on muscarinic receptors in pulmonary vessels.     

Induction of the rectoanal reflex by electric stimulation

We induced the rectoanal reflex electrically in three groups of children, following rectal dilatation with a balloon. In normal children, and in children with constipation or ileus due to causes other than Hirschsprung's disease, the rectoanal reflex was induced by electric stimulation as well as by dilatation of the rectum with a balloon. In children with Hirschsprung's disease, however, no typical reflex was obtained by either of these stimuli. Since electric stimulation does not dilate the rectum, passive dilatation of the anus or shift of the probe along with balloon expansion does not take place, so no false-positive reflex is elicited. Electric current, moreover, is capable of providing a constant quantifiable stimulus. We have demonstrated the induction of the rectoanal reflex by electric stimulation alone; distention of the circular muscle of the rectum does not appear necessary for the induction of this reflex.     

Cerebral potentials evoked by electrical stimulation of the anal canal

We describe the procedure with which cortical potential responses are evoked by a stimulation of the anal canal to assess the integrity of its sensory pathways. These potentials were recorded in 66 patients. In 44 patients, a cortical evoked response was obtained with a succession of positive and negative peaks, W shaped (35 cases) or V shaped (nine cases). In seven cases, cortical responses were interpreted differently by two independent observers. In these seven patients, such differences could be explained by an insufficient amplification of the recorded electrical waves recorded on paper (<10 mm). Fifteen patients gave no cortical response. Eight had a neurologic disease that could explain the lack of response. In the seven others, the absence of response was considered as false negative, but six of these stimulations had been carried out during the first part of the study. There is some evidence that cortical evoked potentials may be obtained after an electrical stimulation of the anal canal, but a training period seems necessary to master the technique and obtain reproducible and recognizable responses.Supported by a grant from the INSERM, 101 rue de Tolbiac 75654 Paris Cedex 13.     

Nucleus basalis-enabled stimulus-specific plasticity in the visual cortex is mediated by astrocytes

Although cholinergic innervation of the cortex by the nucleus basalis (NB) is known to modulate cortical neuronal responses and instruct cortical plasticity, little is known about the underlying cellular mechanisms. Using cell-attached recordings in vivo, we demonstrate that electrical stimulation of the NB, paired with visual stimulation, can induce significant potentiation of visual responses in excitatory neurons of the primary visual cortex in mice. We further show with in vivo two-photon calcium imaging, ex vivo calcium imaging, and whole-cell recordings that this pairing-induced potentiation is mediated by direct cholinergic activation of primary visual cortex astrocytes via muscarinic AChRs. The potentiation is absent in conditional inositol 1,4,5 trisphosphate receptor type 2 KO mice, which lack astrocyte calcium activation, and is stimulus-specific, because pairing NB stimulation with a specific visual orientation reveals a highly selective potentiation of responses to the paired orientation compared with unpaired orientations. Collectively, these findings reveal a unique and surprising role for astrocytes in NB-induced stimulus-specific plasticity in the cerebral cortex.