Contrasting the functional properties of GABAergic axon terminals with single and multiple synapses in the thalamus

Diverse sources of GABAergic inhibition are a major feature of cortical networks, but distinct inhibitory input systems have not been systematically characterized in the thalamus. Here, we contrasted the properties of two independent GABAergic pathways in the posterior thalamic nucleus of rat, one input from the reticular thalamic nucleus (nRT), and one "extrareticular" input from the anterior pretectal nucleus (APT). The vast majority of nRT-thalamic terminals formed single synapses per postsynaptic target and innervated thin distal dendrites of relay cells. In contrast, single APT-thalamic terminals formed synaptic contacts exclusively via multiple, closely spaced synapses on thick relay cell dendrites. Quantal analysis demonstrated that the two inputs displayed comparable quantal amplitudes, release probabilities, and multiple release sites. The morphological and physiological data together indicated multiple, single-site contacts for nRT and multisite contacts for APT axons. The contrasting synaptic arrangements of the two pathways were paralleled by different short-term plasticities. The multisite APT-thalamic pathway showed larger charge transfer during 50-100 Hz stimulation compared with the nRT pathway and a greater persistent inhibition accruing during stimulation trains. Our results demonstrate that the two inhibitory systems are morpho-functionally distinct and suggest and that multisite GABAergic terminals are tailored for maintained synaptic inhibition even at high presynaptic firing rates. These data explain the efficacy of extrareticular inhibition in timing relay cell activity in sensory and motor thalamic nuclei. Finally, based on the classic nomenclature and the difference between reticular and extrareticular terminals, we define a novel, multisite GABAergic terminal type (F3) in the thalamus.

Patterns of calcium-binding proteins support parallel and hierarchical organization of human auditory areas.

The human primary auditory cortex (AI) is surrounded by several other auditory areas, which can be identified by cyto-, myelo- and chemoarchitectonic criteria. We report here on the pattern of calcium-binding protein immunoreactivity within these areas. The supratemporal regions of four normal human brains (eight hemispheres) were processed histologically, and serial sections were stained for parvalbumin, calretinin or calbindin. Each calcium-binding protein yielded a specific pattern of labelling, which differed between auditory areas. In AI, defined as area TC [see C. von Economo and L. Horn (1930) Z. Ges. Neurol. Psychiatr.,130, 678-757], parvalbumin labelling was dark in layer IV; several parvalbumin-positive multipolar neurons were distributed in layers III and IV. Calbindin yielded dark labelling in layers I-III and V; it revealed numerous multipolar and pyramidal neurons in layers II and III. Calretinin labelling was lighter than that of parvalbumin or calbindin in AI; calretinin-positive bipolar and bitufted neurons were present in supragranular layers. In non-primary auditory areas, the intensity of labelling tended to become progressively lighter while moving away from AI, with qualitative differences between the cytoarchitectonically defined areas. In analogy to non-human primates, our results suggest differences in intrinsic organization between auditory areas that are compatible with parallel and hierarchical processing of auditory information.

Epidermoid cysts of the velum interpositum.

The cistern of the velum interpositum is a space located between the corpus callosum dorsally and the roof of the third ventricle ventrally. Lesions located within the velum interpositum are rare and include meningiomas, pilocytic astrocytomas, atypical teratoid/rhabdoid tumors and arachnoid cysts. Epidermoid cysts in this location have not been reported previously. We report the clinical and radiological features of two patients with epidermoid cysts located in the velum interpositum. The patients presented with gait difficulty and features of raised intracranial pressure and magnetic resonance imaging demonstrated large tumors in the velum interpositum with intensities suggestive of epidermoid cysts. There was ventral displacement of the internal cerebral veins and dorsal displacement of the corpus callosum in keeping with a mass in the velum interpositum. Tumors of the third ventricle displace the internal cerebral veins dorsally. A transcallosal approach was used in both patients to effectively excise the tumors.

Neural control of vascular reactions: impact of emotion and attention.

This study investigated the neural regions involved in blood pressure reactions to negative stimuli and their possible modulation by attention. Twenty-four healthy human subjects (11 females; age = 24.75 ± 2.49 years) participated in an affective perceptual load task that manipulated attention to negative/neutral distractor pictures. fMRI data were collected simultaneously with continuous recording of peripheral arterial blood pressure. A parametric modulation analysis examined the impact of attention and emotion on the relation between neural activation and blood pressure reactivity during the task. When attention was available for processing the distractor pictures, negative pictures resulted in behavioral interference, neural activation in brain regions previously related to emotion, a transient decrease of blood pressure, and a positive correlation between blood pressure response and activation in a network including prefrontal and parietal regions, the amygdala, caudate, and mid-brain. These effects were modulated by attention; behavioral and neural responses to highly negative distractor pictures (compared with neutral pictures) were smaller or diminished, as was the negative blood pressure response when the central task involved high perceptual load. Furthermore, comparing high and low load revealed enhanced activation in frontoparietal regions implicated in attention control. Our results fit theories emphasizing the role of attention in the control of behavioral and neural reactions to irrelevant emotional distracting information. Our findings furthermore extend the function of attention to the control of autonomous reactions associated with negative emotions by showing altered blood pressure reactions to emotional stimuli, the latter being of potential clinical relevance.

Noise in Brain Activity Engenders Perception and Influences Discrimination Sensitivity.

Behavioral and brain responses to identical stimuli can vary with experimental and task parameters, including the context of stimulus presentation or attention. More surprisingly, computational models suggest that noise-related random fluctuations in brain responses to stimuli would alone be sufficient to engender perceptual differences between physically identical stimuli. In two experiments combining psychophysics and EEG in healthy humans, we investigated brain mechanisms whereby identical stimuli are (erroneously) perceived as different (higher vs lower in pitch or longer vs shorter in duration) in the absence of any change in the experimental context. Even though, as expected, participants' percepts to identical stimuli varied randomly, a classification algorithm based on a mixture of Gaussians model (GMM) showed that there was sufficient information in single-trial EEG to reliably predict participants' judgments of the stimulus dimension. By contrasting electrical neuroimaging analyses of auditory evoked potentials (AEPs) to the identical stimuli as a function of participants' percepts, we identified the precise timing and neural correlates (strength vs topographic modulations) as well as intracranial sources of these erroneous perceptions. In both experiments, AEP differences first occurred ∼100 ms after stimulus onset and were the result of topographic modulations following from changes in the configuration of active brain networks. Source estimations localized the origin of variations in perceived pitch of identical stimuli within right temporal and left frontal areas and of variations in perceived duration within right temporoparietal areas. We discuss our results in terms of providing neurophysiologic evidence for the contribution of random fluctuations in brain activity to conscious perception.

Role of Go/i subgroup of G proteins in olfactory signaling of Drosophila melanogaster.

Intracellular signaling in insect olfactory receptor neurons remains unclear, with both metabotropic and ionotropic components being discussed. Here, we investigated the role of heterotrimeric Go and Gi proteins using a combined behavioral, in vivo and in vitro approach. Specifically, we show that inhibiting Go in sensory neurons by pertussis toxin leads to behavioral deficits. We heterologously expressed the olfactory receptor dOr22a in human embryonic kidney cells (HEK293T). Stimulation with an odor led to calcium influx, which was amplified via calcium release from intracellular stores. Subsequent experiments indicated that the signaling was mediated by the Gβγ subunits of the heterotrimeric Go/i proteins. Finally, using in vivo calcium imaging, we show that Go and Gi contribute to odor responses both for the fast (phasic) as for the slow (tonic) response component. We propose a transduction cascade model involving several parallel processes, in which the metabotropic component is activated by Go and Gi , and uses Gβγ.

D-serine increases adult hippocampal neurogenesis.

Adult hippocampal neurogenesis results in the continuous formation of new neurons and is a process of brain plasticity involved in learning and memory. The neurogenic niche regulates the stem cell proliferation and the differentiation and survival of new neurons and a major contributor to the neurogenic niche are astrocytes. Among the molecules secreted by astrocytes, D-serine is an important gliotransmitter and is a co-agonist of the glutamate, N-methyl-D-aspartate (NMDA) receptor. D-serine has been shown to enhance the proliferation of neural stem cells in vitro, but its effect on adult neurogenesis in vivo is unknown. Here, we tested the effect of exogenous administration of D-serine on adult neurogenesis in the mouse dentate gyrus. We found that 1 week of treatment with D-serine increased cell proliferation in vivo and in vitro and increased the density of neural stem cells and transit amplifying progenitors. Furthermore, D-serine increased the survival of newborn neurons. Together, these results indicate that D-serine treatment resulted in the improvement of several steps of adult neurogenesis in vivo.

Functional Sub-Types

The paper argues that a functional reduction of ordinary psychology to neuropsychology is possible by means of constructing fine-grained functional, mental sub-types that are coextensive with neuropsychological types. We establish this claim by means of considering as examples the cases of the disconnection syndrome and schizophrenia. We point out that the result is a conservative reduction, vindicating the scientific quality of the mental types of ordinary psychology by systematically linking them with neuroscience. That procedure of conservative reduction by means of functional sub-types is in principle repeatable down to molecular neuroscience.

Treatment and Early Intervention in Psychosis Program (TIPP-Lausanne): implementation of an early intervention programme for psychosis in Switzerland.

AIM: In a survey conducted in the Lausanne catchment area in 2000, we could estimate on the basis of file assessment that first-episode psychosis (FEP) patients had psychotic symptoms for more than 2 years before treatment and that 50% did not attend any outpatient appointment after discharge from hospital. In this paper, we describe the implementation of a specialized programme aimed at improving engagement and quality of treatment for early psychosis patients in the Lausanne catchment area in Switzerland. METHOD: The Treatment and Early Intervention in Psychosis Program-Lausanne is a comprehensive 3-year programme composed of (i) an outpatient clinic based on assertive case management; (ii) a specialized inpatient unit; and (iii) an intensive mobile team, connected for research to the Center for Psychiatric Neuroscience. RESULTS: Eight years after implementation, the programme has included 350 patients with a disengagement rate of 9% over 3 years of treatment. All patients have been assessed prospectively and 90 participated in neurobiological research. Based on this experience, the Health Department funded the implementation of similar programmes in other parts of the state, covering a total population of 540 000 people. CONCLUSION: Programmes for early intervention in psychosis have a major impact on patients' engagement into treatment. While development of mobile teams and assertive case management with specific training are crucial, they do not necessitate massive financial support to be started. Inclusion of a research component is important as well, in terms of service planning and improvement of both quality of care and impact of early intervention strategies.

Thyroid hormone enhances transected axonal regeneration and muscle reinnervation following rat sciatic nerve injury.

Improvement of nerve regeneration and functional recovery following nerve injury is a challenging problem in clinical research. We have already shown that following rat sciatic nerve transection, the local administration of triiodothyronine (T3) significantly increased the number and the myelination of regenerated axons. Functional recovery is a sum of the number of regenerated axons and reinnervation of denervated peripheral targets. In the present study, we investigated whether the increased number of regenerated axons by T3-treatment is linked to improved reinnervation of hind limb muscles. After transection of rat sciatic nerves, silicone or biodegradable nerve guides were implanted and filled with either T3 or phosphate buffer solution (PBS). Neuromuscular junctions (NMJs) were analyzed on gastrocnemius and plantar muscle sections stained with rhodamine alpha-bungarotoxin and neurofilament antibody. Four weeks after surgery, most end-plates (EPs) of operated limbs were still denervated and no effect of T3 on muscle reinnervation was detected at this stage of nerve repair. In contrast, after 14 weeks of nerve regeneration, T3 clearly enhanced the reinnervation of gastrocnemius and plantar EPs, demonstrated by significantly higher recovery of size and shape complexity of reinnervated EPs and also by increased acetylcholine receptor (AChRs) density on post synaptic membranes compared to PBS-treated EPs. The stimulating effect of T3 on EP reinnervation is confirmed by a higher index of compound muscle action potentials recorded in gastrocnemius muscles. In conclusion, our results provide for the first time strong evidence that T3 enhances the restoration of NMJ structure and improves synaptic transmission.

Pial and arachnoid welding for restoration of normal cord anatomy after excision of intramedullary spinal cord tumors.

A significant postoperative problem in patients undergoing excision of intramedullary tumors is painful dysesthesiae, attributed to various causes, including edema, arachnoid scarring and cord tethering. The authors describe a technique of welding the pia and arachnoid after the excision of intramedullary spinal cord tumors used in seven cases. Using a fine bipolar forcep and a low current, the pial edges of the myelotomy were brought together and welded under saline irrigation. A similar method was used for closing the arachnoid while the dura was closed with a running 5-0 vicryl suture. Closing the pia and arachnoid restores normal cord anatomy after tumor excision and may reduce the incidence of postoperative painful dysesthesiae.

Lhermitte-Duclos disease.

Lhermitte-Duclos disease (dysplastic gangliocytoma of the cerebellum) is a rare pseudo-neoplastic disorder of the cerebellum with typical MRI findings. A 25-year-old man presenting with progressive neck pain, dizziness, and impaired vision is reported. CT and MRI revealed a left cerebellar haemispheric mass and obstructive hydrocephalus. Lhermitte-Duclos disease was histologically confirmed after surgical removal of the lesion. The typical MRI appearance of a nonenhancing haemispheric cerebellar mass with preservation and exaggeration of the normal gyral pattern allows pre-operative diagnosis of this condition. The literature is reviewed and clinical presentation, radiology and histopathology are discussed.

Identification of optimal structural connectivity using functional connectivity and neural modeling.

The complex network dynamics that arise from the interaction of the brain's structural and functional architectures give rise to mental function. Theoretical models demonstrate that the structure-function relation is maximal when the global network dynamics operate at a critical point of state transition. In the present work, we used a dynamic mean-field neural model to fit empirical structural connectivity (SC) and functional connectivity (FC) data acquired in humans and macaques and developed a new iterative-fitting algorithm to optimize the SC matrix based on the FC matrix. A dramatic improvement of the fitting of the matrices was obtained with the addition of a small number of anatomical links, particularly cross-hemispheric connections, and reweighting of existing connections. We suggest that the notion of a critical working point, where the structure-function interplay is maximal, may provide a new way to link behavior and cognition, and a new perspective to understand recovery of function in clinical conditions.