Modification of GABA-mediated inhibition by various injectable anesthetics.

Increasing doses of the injectable anesthetics etomidate, Saffan, thiopental, ketamine, and xylazine and the vehicles saline and propylene glycol were administered to urethane-anesthetized rats. Their effects in vivo on perforant pathway-evoked field excitatory post-synaptic potentials and population spikes in the hippocampal dentate gyrus were determined. The primary purpose was to ascertain whether these compounds affect hippocampal excitability in a manner consistent with their proposed mechanisms of action. Compared with their respective vehicles, thiopental, etomidate, and xylazine reduced the amplitude of population spikes to single perforant pathway stimulation by 20-30% at the highest doses tested. Xylazine also increased the latency to onset of the population spike. No other effects were observed. Using paired pulse paradigms, it was determined that etomidate produced a dramatic, prolonged reduction in granule cell excitability at interpulse intervals of 10-100 ms. The magnitude of the effect was dose related and was reversible with the discontinuance of administration of the drug. Similar changes occurred with Saffan (althesin) and thiopental. Ketamine produced a small but significant depression in granule cell excitability during intervals of 10-200 ms. Xylazine had no effect. These data corroborate the importance of a prolongation of gamma-aminobutyric acid A-mediated inhibition to the mechanism of actions of etomidate, thiopental, and Saffan at relevant exposure concentrations in vivo.     

Experience-dependent modulation of category-related cortical activity

Naming pictures of objects from different categories (e.g. animals or tools) evokes maximal responses in different brain regions. However, these 'category-specific' regions typically respond to other object categories as well. Here we used stimulus familiarity to further investigate category representation. Naming pictures of animals and tools elicited category-related activity in a number of previously identified regions. This activity was reduced for familiar relative to novel stimuli. Reduced activation occurred in all object responsive areas in the ventral occipito-temporal cortex, regardless of which category initially produced the maximal response. This suggests that object representations in the ventral occipito-temporal cortex are not limited to a discrete area, but rather are widespread and overlapping. In other regions (e.g. the lateral temporal and left premotor cortices), experience-dependent reductions were category specific. Together, these findings suggest that category-related activations reflect the retrieval of information about category-specific features and attributes.     

Dopamine modulation of prefrontal cortical interneurons changes during adolescence

Adolescence is marked by profound psychological and neuroendocrine changes. Cognitive functions that depend on the prefrontal cortex and dopamine (DA), such as decision making, are acquired or refined during adolescence; yet, little is known about how neural circuits mature in the transition to adulthood. Here, we conducted electrophysiological recordings in rat brain slices, unveiling an enhancement of the excitability of interneurons, which are important for cortical network activity, by D(1) and D(2) DA receptors. The D(2) effect was observed in slices from adult (postnatal day [PD] > 50) but not preadolescent (PD < 36) animals suggesting a possible neural substrate for the maturation of DA-dependent prefrontal cortical functions during or after adolescence and identifying a critical neural population that could be involved in the periadolescent onset of neuropsychiatric disorders, such as schizophrenia.     

Bidirectional modulation of goal-directed actions by prefrontal cortical dopamine

Instrumental actions are a vital cognitive asset that endows an organism with sensitivity to the consequences of its behavior. Response-outcome feedback allows responding to be shaped in order to maximize beneficial, and minimize detrimental, outcomes. Lesions of the medial prefrontal cortex (mPFC) result in behavior that is insensitive to changes in outcome value in animals and compulsive behavior in several human psychopathologies. Such insensitivity to changes in outcome value is a defining characteristic of instrumental habits: responses that are controlled by antecedent stimuli rather than goal expectancy. Little is known regarding the neurochemical substrates mediating this sensitivity. The present experiments used sensitivity to posttraining outcome devaluation to index the action-habit status of instrumental responding. Infusions of dopamine into the ventral mPFC (vmPFC), but not dorsal mPFC, restored outcome sensitivity bidirectionally-decreasing responding following outcome devaluation and increasing responding when the outcome was not devalued. This bidirectionality makes the possibility that these infusions nonspecifically dysregulated vmPFC dopamine transmission unlikely. VmPFC dopamine promoted instrumental responding appropriate to outcome value. Reinforcer consumption data indicated that this was not a consequence of altered sensitivity to the reinforcer itself. We suggest that vmPFC dopamine reengages attentional processes underlying goal-directed behavior.     

Dopamine modulation of hippocampal-prefrontal cortical interaction drives memory-guided behavior

Information gleaned from learning and memory processes is essential in guiding behavior toward a specific goal. However, the neural mechanisms that determine how these processes are effectively utilized to guide goal-directed behavior are unknown. Here, we show that rats utilize retrospective and prospective memory and flexible switching between these 2 memory processes to guide behaviors to obtain rewards. We found that retrospective memory is mainly processed in the hippocampus (HPC) but that this retrospective information must be incorporated within the prefrontal cortex (PFC) to be used to switch to an anticipatory response strategy involving prospective memory. Furthermore, switching between memory processes is regulated by the mesocortical dopamine (DA) system. Thus, DA D1 and D2 receptor activation in the PFC differentially affects retrospective memory processing within the HPC via an indirect feedback pathway. In contrast, D1, but not D2, receptor activation is crucial for incorporation of HPC-based retrospective information into the PFC. However, once this takes place, D2 receptor activation is required for further processing of information to effect preparation of future actions. These results provide a unique perspective on the mechanism of memory-based goal-directed behavior.     

Attentional modulation of cortical neuromagnetic gamma response to biological movement

Processing of biological motion represented solely by a set of lights on the joints of a human body is traditionally viewed as largely independent of attention. Here, by manipulating attention-related task demands, we assess changes in the neuromagnetic cortical response to a point-light walker. Irrespective of task demands, biological motion evokes an increase in oscillatory gamma activity over the left parieto-occipital region at 80 ms post-stimulus. Only an attended walker, however, yielded further peaks over the right parietal (120 ms) and temporal (155 ms) cortices. By contrast, the magnetoencephalographic (MEG) response to an ignored walker is restricted to the left parieto-occipital region. In addition, peaks in oscillatory activity occur in response to both attended (canonical and scrambled) configurations at 180-200 ms from stimulus onset over the right fronto-temporal regions, most likely reflecting maintenance of the target configuration in working memory. For the first time, we demonstrate that the time course and topographic dynamics of oscillatory gamma activity in response to biological movement undergoes top-down influences and can be profoundly modulated by the withdrawal of attention.     

Waking-sleep modulation of paroxysmal activities induced by partial cortical deafferentation

We investigated the dependency of electrical seizures produced by cortical undercut upon behavioral states of vigilance in chronically implanted cats. Experiments were performed 1-12 weeks after white matter transection. Multisite field potentials and intracellular activity were recorded from suprasylvian and marginal gyri. Paroxysmal activity developed within days and consisted of spike-wave complexes at 3-4 Hz occurring during the waking state (correlated with eye movements), being enhanced during slow-wave sleep (SWS) and blocked during rapid eye movement (REM) sleep. Prolonged hyperpolarizing events were seen not only during SWS (which is the case in normal animals) but also during both waking and REM, thus resulting in bimodal distribution of the membrane potential in all 3 natural states of vigilance. The increased synchrony of field potential activity expressed by shorter time of propagation over the cortical surface and the tendency toward generalization are ascribed to changes in intrinsic neuronal properties and potential disinhibition following cortical undercut.     

Impaired modulation of intracortical inhibition in focal hand dystonia

Previous studies have shown that intracortical inhibition (ICI) plays an important role in shaping the output from primary motor cortex, and that ICI may be impaired in people with Focal Hand Dystonia (FHD). This study explored the muscle-specificity and temporal modulation of ICI during the performance of a phasic index finger flexion task. Eight control subjects and seven with FHD were asked to rest their dominant hand upon a computer mouse, and depress the mouse button using their index finger in time with a 1 Hz auditory metronome, while keeping the rest of their hand as relaxed as possible. Responses to single and paired-pulse transcranial magnetic stimulation were recorded from the first dorsal interosseous (FDI) and abductor pollicis brevis (APB) muscles while subjects were at rest and during 'on' and 'off' phases of the task. For control subjects during the movement (i). FDI motor evoked potential (MEP) amplitude and pretrigger EMG increased, and ICI decreased, as expected, and (ii). there was no significant facilitation of MEP amplitude or pretrigger EMG for APB, which was associated with a significant increase in ICI during the movement. This may have helped prevent the unwanted activation of this muscle. While FHD subjects demonstrated the same patterns of modulation of both MEP amplitude and pretrigger EMG for both FDI and APB, their levels of ICI were not modulated by task performance. This was despite no difference between subject groups in the level of ICI observed at rest. These findings suggest that FHD is associated with impaired modulation of ICI during performance of a precise manual task, which may contribute to a lack of specificity in the output from M1 and the development of dystonic symptoms.     

Cholinergic modulation of sevoflurane potency in cortical and spinal networks in vitro

BACKGROUND: Victims of organophosphate intoxication with cholinergic crisis may have need for sedation and anesthesia, but little is known about how anesthetics work in these patients. Recent studies suggest that cholinergic stimulation impairs gamma-aminobutyric acid type A (GABAA) receptor function. Because GABAA receptors are major targets of general anesthetics, the authors investigated interactions between acetylcholine and sevoflurane in spinal and cortical networks. METHODS: Cultured spinal and cortical tissue slices were obtained from embryonic and newborn mice. Drug effects were assessed by extracellular voltage recordings of spontaneous action potential activity. RESULTS: Sevoflurane caused a concentration-dependent decrease in spontaneous action potential firing in spinal (EC50=0.17+/-0.02 mM) and cortical (EC50=0.29+/-0.01 mM) slices. Acetylcholine elevated neuronal excitation in both preparations and diminished the potency of sevoflurane in reducing action potential firing in cortical but not in spinal slices. This brain region-specific decrease in sevoflurane potency was mimicked by the specific GABAA receptor antagonist bicuculline, suggesting that (1) GABAA receptors are major molecular targets for sevoflurane in the cortex but not in the spinal cord and (2) acetylcholine impairs the efficacy of GABAA receptor-mediated inhibition. The latter hypothesis was supported by the finding that acetylcholine reduced the potency of etomidate in depressing cortical and spinal neurons. CONCLUSIONS: The authors raise the question whether cholinergic overstimulation decreases the efficacy of GABAA receptor function in patients with organophosphate intoxication, thereby compromising anesthetic effects that are mediated predominantly via these receptors such as sedation and hypnosis.     

Pharmacological modulation of cortical plasticity following kainic acid lesion in rat barrel cortex

OBJECT: The brain shows remarkable capacity for plasticity in response to injury. To maximize the benefits of current neurological treatment and to minimize the impact of injury, the authors examined the ability of commonly administered drugs, dextroamphetamine (D-amphetamine) and phenytoin, to positively or negatively affect the functional recovery of the cerebral cortex following excitotoxic injury. METHODS: Previous work from the same laboratory has demonstrated reorganization of whisker functional responses (WFRs) in the rat barrel cortex after excitotoxic lesions were created with kainic acid (KA). In the present study, WFRs were mapped using intrinsic optical signal imaging before and 9 days after creation of the KA lesions. During the post-lesion survival period, animals were either treated with intraperitoneal D-amphetamine, phenytoin, or saline or received no treatment. Following the survival period, WFRs were again measured and compared with prelesion data. RESULTS: The findings suggest that KA lesions cause increases in WFR areas when compared with controls. Treatment with D-amphetamine further increased the WFR area (p < 0.05) while phenytoin-treated rats showed decreases in WFR areas. There was also a statistically significant difference (p < 0.05) between the D-amphetamine and phenytoin groups. CONCLUSIONS: These results show that 2 commonly used drugs, D-amphetamine and phenytoin, have opposite effects in the functional recovery/plasticity of injured cerebral cortex. The authors' findings emphasize the complex nature of the cortical response to injury and have implications for understanding the biology of the effects of different medications on eventual functional brain recovery.     

Evidence of functional connectivity between auditory cortical areas revealed by amplitude modulation sound processing

The human auditory cortex includes several interconnected areas. A better understanding of the mechanisms involved in auditory cortical functions requires a detailed knowledge of neuronal connectivity between functional cortical regions. In human, it is difficult to track in vivo neuronal connectivity. We investigated the interarea connection in vivo in the auditory cortex using a method of directed coherence (DCOH) applied to depth auditory evoked potentials (AEPs). This paper presents simultaneous AEPs recordings from insular gyrus (IG), primary and secondary cortices (Heschl's gyrus and planum temporale), and associative areas (Brodmann area [BA] 22) with multilead intracerebral electrodes in response to sinusoidal modulated white noises in 4 epileptic patients who underwent invasive monitoring with depth electrodes for epilepsy surgery. DCOH allowed estimation of the causality between 2 signals recorded from different cortical sites. The results showed 1) a predominant auditory stream within the primary auditory cortex from the most medial region to the most lateral one whatever the modulation frequency, 2) unidirectional functional connection from the primary to secondary auditory cortex, 3) a major auditory propagation from the posterior areas to the anterior ones, particularly at 8, 16, and 32 Hz, and 4) a particular role of Heschl's sulcus dispatching information to the different auditory areas. These findings suggest that cortical processing of auditory information is performed in serial and parallel streams. Our data showed that the auditory propagation could not be associated to a unidirectional traveling wave but to a constant interaction between these areas that could reflect the large adaptive and plastic capacities of auditory cortex. The role of the IG is discussed.     

Task-related modulation of early cortical responses during language production: an event-related synthetic aperture magnetometry study

We used whole-head magnetoencephalography measurements to investigate the spatiotemporal pattern of neural activity related to language production. Eight participants overtly responded by repeating aloud or vocalizing an internally generated verb to auditorily or visually presented nouns. Activity peaked within primary sensory (auditory or visual) cortices between 75 and 130 ms after stimulus onset, association cortices (inferior and superior temporal gyri) between 130 and 170 ms, and inferior frontal and premotor areas between 150 and 240 ms. Common to auditory and visual modalities, peak activity at about 220 ms was significantly larger in bilateral inferior frontal and left precentral regions when participants generated a verb than when they repeated a noun. These early differences in frontal regions may reflect the allocation of resources to the processing of low-level perceptions that are projected to the premotor areas early in the preparation of language production.     

Tuning curve shift by attention modulation in cortical neurons: a computational study of its mechanisms

Physiological studies of visual attention have demonstrated that focusing attention near a visual cortical neuron's receptive field (RF) results in enhanced evoked activity and RF shift. In this work, we explored the mechanisms of attention induced RF shifts in cortical network models that receive an attentional 'spotlight'. Our main results are threefold. First, whereas a 'spotlight' input always produces toward-attention shift of the population activity profile, we found that toward-attention shifts in RFs of single cells requires multiplicative gain modulation. Secondly, in a feedforward two-layer model, focal attentional gain modulation in first-layer neurons induces RF shift in second-layer neurons downstream. In contrast to experimental observations, the feedforward model typically fails to produce RF shifts in second-layer neurons when attention is directed beyond RF boundaries. We then show that an additive spotlight input combined with a recurrent network mechanism can produce the observed RF shift. Inhibitory effects in a surround of the attentional focus accentuate this RF shift and induce RF shrinking. Thirdly, we considered interrelationship between visual selective attention and adaptation. Our analysis predicts that the RF size is enlarged (respectively reduced) by attentional signal directed near a cell's RF center in a recurrent network (resp. in a feedforward network); the opposite is true for visual adaptation. Therefore, a refined estimation of the RF size during attention and after adaptation would provide a probe to differentiate recurrent versus feedforward mechanisms for RF shifts.     

Transient gamma-secretase inhibition accelerates and enhances fracture repair likely via Notch signaling modulation

Approximately 10% of skeletal fractures result in healing complications and non-union, while most fractures repair with appropriate stabilization and without pharmacologic intervention. It is the latter injuries that cannot be underestimated as the expenses associated with their treatment and subsequent lost productivity are predicted to increase to over $74 billion by 2015. During fracture repair, local mesenchymal stem/progenitor cells (MSCs) differentiate to form new cartilage and bone, reminiscent of events during skeletal development. We previously demonstrated that permanent loss of gamma-secretase activity and Notch signaling accelerates bone and cartilage formation from MSC progenitors during skeletal development, leading to pathologic acquisition of bone and depletion of bone marrow derived MSCs. Here, we investigated whether transient and systemic gamma-secretase and Notch inhibition is capable of accelerating and enhancing fracture repair by promoting controlled MSC differentiation near the fracture site. Our radiographic, microCT, histological, cell and molecular analyses reveal that single and intermittent gamma-secretase inhibitor (GSI) treatments significantly enhance cartilage and bone callus formation via the promotion of MSC differentiation, resulting in only a moderate reduction of local MSCs. Biomechanical testing further demonstrates that GSI treated fractures exhibit superior strength earlier in the healing process, with single dose GSI treated fractures exhibiting bone strength approaching that of un-fractured tibiae. These data further establish that transient inhibition of gamma-secretase activity and Notch signaling temporarily increases osteoclastogenesis and accelerates bone remodeling, which coupled with the effects on MSCs likely explains the accelerated and enhanced fracture repair. Therefore, we propose that the Notch pathway serves as an important therapeutic target during skeletal fracture repair.     

Secondary growth of a cortical necrosis: effect of NOS inhibition by aminoguanidine post insult

Summary ¶Background. A cortical tissue necrosis from a focal freezing injury expands to 140% of its initial volume within 24hrs in rats. Previous studies of our laboratory have shown that administration of the NOS inhibitor aminoguanidine (AG) prior to trauma attenuates this process of secondary brain damage. Objective of the present study was to analyse whether this agent is also protective when treatment commences after the insult. Method. A highly standardized freezing lesion was induced in the brain cortex of 30 anaesthetized rats. The animals were divided into three experimental groups. Animals of group I (sham-5min, n=10) were sacrificed 5min after trauma for quantitative histomorphometric assessment of the primary cortical lesion. Animals of group II (sham-24h, n=10) received isotonic saline (16.7ml/kg b.w., i.p.) at 15min and 8hrs after trauma. In the treatment group (group III, AG-24h, n=10), AG was administered (100mg/kg b.w.) also at 15min and 8hrs after trauma. 24hrs later – the time point of maximal lesion spread – the animals of group II and III were sacrificed for quantification of the secondary lesion growth. Findings. The focal freezing injury produced a cortical necrosis volume of 6.07±1.04mm³ immediately after trauma (group I). After sham treatment, the necrosis expanded to 8.39±1.57mm³ within 24hrs (group II) corresponding to a lesion growth of 138% compared to the primary necrosis (p<0.01 vs. group I). In animals treated with AG after the trauma (group III), the volume of necrosis was significantly attenuated at 24hrs to 6.77±0.87mm³ representing an expansion of the lesion to only 112% (p<0.05 vs. group II). Thus, AG was inhibiting the secondary growth of necrosis by no less than 69%. Interpretation. The findings demonstrate that AG retains its neuroprotective potential against secondary brain damage from trauma even when administration begins after trauma.Published online October 20, 2003     

Synaptic plasticity in local cortical network in vivo and its modulation by the level of neuronal activity

Neocortical neurons maintain high firing rates across all behavioral states of vigilance but the discharge patterns vary during different types of brain oscillations, which are assumed to play an important role in information processing and memory consolidation. In the present study, we report that trains of stimuli applied to local neocortical networks of cats, at frequencies that mimic endogenous brain rhythms, produced depression or potentiation of postsynaptic potentials, which lasted for several minutes. This form of synaptic plasticity was not mediated through NMDA receptors since it persisted after blockade of these receptors, but was strongly modulated by the level of background neuronal activity. Using different preparations in vivo, we found that increased background neuronal activity decreased the probability of plastic changes but enhanced the probability of potentiation over depression. Conversely, when the level of background neuronal activity was low, plasticity was observed in all neurons, but mainly depression was induced. Our results demonstrate that high levels of neuronal activity in the cortical network promote potentiation and insure the stability of synaptic connections.     

Neuronal correlates of local, lateral, and translaminar inhibition with reference to cortical columns

In the neocortex, inhibition by gamma-aminobutyric acidergic (GABAergic) interneurons is essential for shaping cortical maps, which represent sensory signals. For a detailed understanding of the stream of excitation evoked, for example, by a sensory stimulus, interneurons must be identified with reference to their impact on excitatory neurons located in different laminae of the same (home) and surround columns. We analyzed the axonal projection of layer 2/3 (L2/3) interneurons with reference to geometric landmarks of cortical columns by staining neurons in acute slices of rat barrel cortex (P20-P29) and a subsequent cluster analysis using morphological parameters that described the spatial distribution of axons. The cluster analysis defined 4 main axonal projection "types" referred to as 1) "local inhibitors" (including "chandelier neurons"), 2) "lateral inhibitors," 3) "translaminar L2/3-to-L4/5 inhibitors," and 4) "translaminar L2/3-to-L1 inhibitors." The putative innervation domains established by axonal projections of the 4 types of interneurons and the dendritic domains of their target excitatory neurons were 1) L2/3 of the home column, 2) L2/3 of both the home and neighboring columns, 3) L4 and L5A of the home column, and 4) L1 and L2/3 of the home column. The quantitative analysis of the axonal projection patterns of an unselected sample of 51 interneurons located in L2/3 thus defined anatomical correlates for local, lateral, and translaminar inhibition within and between cortical columns.     

Regulation of persistent activity by background inhibition in an in vitro model of a cortical microcircuit

We combined in vitro intracellular recording from prefrontal cortical neurons with simulated synaptic activity of a layer 5 prefrontal microcircuit using a dynamic clamp. During simulated in vivo background conditions, the cell responded to a brief depolarization with a sequence of spikes that outlasted the depolarization, mimicking the activity of a cell recorded during the delay period of a working memory task in the behaving monkey. The onset of sustained activity depended on the number of action potentials elicited by the cue-like depolarization. Too few spikes failed to provide enough NMDA drive to elicit sustained reverberations; too many spikes activated a slow intrinsic hyperpolarization current that prevented spiking; an intermediate number of spikes produced sustained activity. When high dopamine levels were simulated by depolarizing the cell and by increasing the amount of NMDA current, the cell exhibited spontaneous 'up-states' that terminated by the activation of a slow intrinsic hyperpolarizing current. The firing rate during the delay period could be effectively modulated by the standard deviation of the inhibitory background synaptic noise without significant changes in the background firing rate before cue onset. These results suggest that the balance between fast feedback inhibition and slower AMPA and NMDA feedback excitation is critical in initiating persistent activity and that the maintenance of persistent activity may be regulated by the amount of correlated background inhibition.