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Luigi Rolando and his pioneering efforts to relate structure to function in the nervous system.

The fissure separating the motor from the sensory cortex and the substantia gelatinosa capping the posterior horn of the spinal cord are still known by the name of the Italian anatomist Rolando, Luigi Rolando was born in Turin, Italy, in 1773 and died in 1831. His life was not easy, the first of his problems being the death of his father when Rolando was still very young. Three people were to be influential in his life and career: Father Maffei, his maternal uncle who raised him; Dr. Cigna, the anatomy professor who discovered his talent; and Dr. Anformi, a general practitioner who introduced him to the practice of medicine and to the best circles of the city. Forced to leave Turin by the Napoleonic invasion of the country, Rolando first stopped in Florence, where he learned about anatomical dissection, drawing, and engraving and studied the appearance of nervous tissue under the microscope. Later he went to Sardinia where, although cut off from European cultural circles, he developed his major theories. Rolando pioneered the idea that brain functions could be differentiated and located in specific areas and discovered the fixed pattern of cerebral convolutions, highlighting motor and sensory gyri. He demonstrated the complexity of the central gray matter of the spinal cord, describing the "substantia gelatinosa," and he deduced that nervous structures are connected in a network of nervous fibers linked by electrical impulses. Rolando had to struggle for recognition, however, as the priority of his discoveries was challenged by the almost contemporaneous work of Gall and Spurzheim on cerebral localization and of Flourens on cerebellar function. Nevertheless, his efforts contributed greatly to the clarification of brain function. His observations on nervous anatomy have been especially accurate, as shown by the nomenclature "fissure of Rolando."

History, 19th Century↗

How antidepressants work: new perspectives on the pathophysiology of depressive disorder.

BACKGROUND: New research in animals is beginning to change radically our understanding of the biology of stress and the effects of antidepressant agents. AIMS: To relate recent findings from the basic neurosciences to the pathophysiology of depressive disorder. METHOD: Drawing together findings from molecular and physiological studies in rats, social studies in primates and neuropsychological studies in humans, we review the neurotrophic and neuroplastic effects of antidepressants and stress. RESULTS: Stress and antidepressants have reciprocal actions on neuronal growth and vulnerability (mediated by the expression of neurotrophins) and synaptic plasticity (mediated by excitatory amino acid neurotransmission) in the hippocampus and other brain structures. Stressors have the capacity to progressively disrupt both the activities of individual cells and the operating characteristics of networks of neurons throughout the life cycle, while antidepressant treatments act to reverse such injurious effects. CONCLUSIONS: We propose a central role for the regulation of synaptic connectivity in the pathophysiology of depressive disorder.

Animals↗

Correlational imaging of thalamocortical coupling in the primary visual pathway of the human brain.

While the anatomy of the human brain is well defined, the functional connectivity of its structures is far less understood. Modern neuroimaging techniques offer the unique opportunity of visualizing physiologic activation in central nervous structures and of identifying the elements underlying distributed networks for information processing. Following improved spatial resolution of deoxyhemoglobin-sensitive magnetic resonance imaging, we were able to detect simultaneous signal changes in the lateral geniculate nucleus and primary visual cortex during periodic photic stimulation. Visualization of coupled activation by cross-correlation analysis resulted in the first demonstration of thalamocortical interaction in the primary visual pathway of the intact human brain.

Adult↗

Afferent and efferent connections of the sexually dimorphic medial preoptic nucleus of the male quail revealed by in vitro transport of DiI.

The medial preoptic nucleus of the Japanese quail is a testosterone-sensitive structure that is involved in the control of male copulatory behavior. The full understanding of the role played by this nucleus in the control of reproduction requires the identification of its afferent and efferent connections. In order to identify neural circuits involved in the control of the medial preoptic nucleus, we used the lipophilic fluorescent tracer DiI implanted in aldheyde-fixed tissue. Different strategies of brain dissection and different implantation sites were used to establish and confirm afferent and efferent connections of the nucleus. Anterograde projections reached the tuberal hypothalamus, the area ventralis of Tsai, and the substantia grisea centralis. Dense networks of fluorescent fibers were also seen in several hypothalamic nuclei, such as the anterior medialis hypothalami, the paraventricularis magnocellularis, and the ventromedialis hypothalami. A major projection in the dorsal direction was also observed from the medial preoptic nucleus toward the nucleus septalis lateralis and medialis. Afferents to the nucleus were seen from all these regions. Implantation of DiI into the substantia grisea centralis also revealed massive bidirectional connections with a large number of more caudal mesencephalic and pontine structures. The substantia grisea centralis therefore appears to be an important center connecting anterior levels of the brain to brain-stem nuclei that may be involved in the control of male copulatory behavior.

Afferent Pathways↗

Beta-galactosidase-labelled relay neurons of homotopic olfactory bulb transplants establish proper afferent and efferent synaptic connections with host neurons.

The vertebrate olfactory system has long been an attractive model for studying neuronal regeneration and adaptive plasticity due to the continuous neurogenesis and synaptic remodelling throughout adult life in primary and secondary olfactory centres, its precisely ordered synaptic network and accessibility for manipulation. After homotopic transplantation of fetal olfactory bulbs in bulbectomized neonatal rodents, newly regenerated olfactory neurons form glomeruli within the graft, and the efferent mitral/tufted cells of the transplant innervate the host brain, terminating in higher olfactory centres. However, the synaptic connections of the transplanted relay neurons within the graft and/or host's olfactory centres could not be characterized mainly because of lack of suitable cell-specific markers for these neurons. In this study, we have used olfactory bulbs from transgenic fetuses, in which the majority of the mitral/tufted cells express the bacterial enzyme beta-galactosidase, for homotopic olfactory bulb transplantation following complete unilateral bulbectomy. In the transplants, the cell bodies and terminals of the donor mitral/tufted cells were identified by beta-galactosidase histochemistry and immunocytochemistry at both light and electron microscope levels. We demonstrate that transplanted relay neurons re-establish specific synaptic connections with host neurons of the periphery, source of the primary signal and central nervous system, thereby providing the basis for a functional recovery in the lesioned olfactory system.

Afferent Pathways↗

fMRI models of dendritic and astrocytic networks.

In order to elucidate the relationships between hierarchical structures within the neocortical neuropil and the information carried by an ensemble of neurons encompassing a single voxel, it is essential to predict through volume conductor modeling LFPs representing average extracellular potentials, which are expressed in terms of interstitial potentials of individual cells in networks of gap-junctionally connected astrocytes and synaptically connected neurons. These relationships have been provided and can then be used to investigate how the underlying neuronal population activity can be inferred from the measurement of the BOLD signal through electrovascular coupling mechanisms across the blood-brain barrier. The importance of both synaptic and extrasynaptic transmission as the basis of electrophysiological indices triggering vascular responses between dendritic and astrocytic networks, and sequential configurations of firing patterns in composite neural networks is emphasized. The purpose of this review is to show how fMRI data may be used to draw conclusions about the information transmitted by individual neurons in populations generating the BOLD signal.

Animals↗

Telencephalin: a neuronal area code molecule?

Cell adhesion molecules (CAMs) with expression restricted to specific developmental and structural units of the brain and/or selective neuronal types would play critical roles in the formation of functional neuronal networks. In this article, we summarize recent progress in knowledge on a brain segment-specific CAM, telencephalin (TLN). TLN has the following characteristic properties. (1) TLN is a neuronal glycoprotein whose expression is restricted within telencephalon, the most rostal segment of the brain. (2) TLN is localized to the soma-dendritic membrane of subsets of telencephalic neurons, but not to the axonal membrane. (3) Abrupt appearance of TLN around birth parallels the timing of dendritic development and synapse formation in the telencephalon. (4) TLN belongs to the immunoglobulin superfamily and its structure is most closely related to intercellular adhesion molecules (ICAMs)-1 and -3. These findings suggest that TLN is the first example of dendrite-associated cell adhesion molecules (DenCAMs) and that TLN may be involved in the brain segmental organization, cell-cell interactions during dendritic development, and maintenance of functional neuronal networks. We discuss the possibility that TLN is an area code-like address signal that is displayed selectively by telencephalic neurons and is decoded by specific subsets of growing axons to make proper synaptic connections.

Animals↗

Steroid hormones and excitability in the mammalian brain.

Adrenocortical and gonadal steroid hormones can pass the blood-brain barrier and bind to intracellular receptors in the brain. In addition to steroid hormones binding to intracellular steroid receptors, metabolites of these steroids and steroid hormones produced in the brain (neurosteroids) are thought to bind to membrane recognition sites. Actions mediated by the intracellular receptors are generally delayed in onset and are of prolonged duration, whereas the hormones binding to membrane recognition sites induce fast effects. Both fast and delayed actions by steroid hormones potentially alter the electrical properties of neuronal membranes and thus the firing patterns of neurons carrying receptors for the hormones. We here review the fast and delayed actions by steroid hormones on single cell electrical properties in the mammalian nervous system. In general, fast effects by corticosteroids-presumably mediated by membrane receptors-induce inhibitory effects on cellular firing, although regional differences seem to exist. Delayed effects by corticosteroid hormones via mineralocorticoid receptors serve to maintain or enhance fast transmission in the brain, while modulatory inputs are suppressed. By contrast, corticosteroids acting through glucocorticoid receptors suppress transmission carried by amino acids, particularly when the activity is elevated in comparison to resting level; modulatory inputs are enhanced. Prolonged activation of glucocorticoid receptors can implicate the integrity of neuronal circuits by allowing considerable influx of calcium ions during depolarization. Of the gonadal hormones, estradiol mainly exerts excitatory actions, in both a rapid and a delayed mode. Progesterone on the other hand is predominantly inhibitory, usually with a short delay in onset. The effect of androgens on neuronal excitability has not yet been studied in great detail. Finally, neurosteroids and A-ring reduced steroids in general induce rapid effects on firing patterns, probably by acting on ligand gated ion channels. The diverse actions of steroid hormones on single cell activity have consequences for the excitability in local circuits in which these cells participate. This is illustrated in this review for two processes that depend on circuit rather than single cell function, i.e., long term potentiation and epilepsy. The diverging character of steroid hormones with regard to the time frame, space, and nature of their effects is also reflected in the functional processes that are linked to the activity of the networks responding to steroids. In this way steroid hormones add an essentially new aspect to the regulation of functional processes in the brain, during physiological conditions but also when networks are implicated during diseases and disorders. Future research on steroid modulation of cellular excitability will gain considerably from attempts to either link the changed excitability to the underlying molecular events or study the effects on cellular activity in close connection with behavioral functions.

Animals↗

Sleep after spatial learning promotes covert reorganization of brain activity.

Sleep promotes the integration of recently acquired spatial memories into cerebral networks for the long term. In this study, we examined how sleep deprivation hinders this consolidation process. Using functional MRI, we mapped regional cerebral activity during place-finding navigation in a virtual town, immediately after learning and 3 days later, in subjects either allowed regular sleep (RS) or totally sleep-deprived (TSD) on the first posttraining night. At immediate and delayed retrieval, place-finding navigation elicited increased brain activity in an extended hippocampo-neocortical network in both RS and TSD subjects. Behavioral performance was equivalent between groups. However, striatal navigation-related activity increased more at delayed retrieval in RS than in TSD subjects. Furthermore, correlations between striatal response and behavioral performance, as well as functional connectivity between the striatum and the hippocampus, were modulated by posttraining sleep. These data suggest that brain activity is restructured during sleep in such a way that navigation in the virtual environment, initially related to a hippocampus-dependent spatial strategy, becomes progressively contingent in part on a response-based strategy mediated by the striatum. Both neural strategies eventually relate to equivalent performance levels, indicating that covert reorganization of brain patterns underlying navigation after sleep is not necessarily accompanied by overt changes in behavior.

Adult↗

Infrared-guided laser stimulation of neurons in brain slices.

Infrared-guided laser stimulation is a new technique that allows precise and rapid stimulation of visualized neurons in brain slices. Infrared imaging of neurons with a new contrast system is combined with the photolytic release of caged neurotransmitters by an ultraviolet (UV) laser. Addition of caged neurotransmitters to the superfusion medium of neurons in brain slices allows local excitation in the micrometer range with a focused spot of UV light. In this way, the distribution of glutamate or gamma-aminobutyric acid (GABA) receptors on neuronal dendrites can be mapped. Furthermore, this technique can be used to map the connectivity of neuronal networks through the controlled stimulation of neighboring neurons. Because the laser stimulation can be performed much faster than can paired recording, it is also possible to search for synaptic connections between distant neurons that have a low probability of connectivity.

Animals↗

Zona incerta: Substrate for contralateral interconnectivity in the thalamus of rats.

We have shown previously that the zona incerta (ZI), a small nucleus deriving from the ventral thalamus, has extensive ipsilateral connections with the higher order and intralaminar nuclei of the dorsal thalamus and that there are many ipsilateral interconnections between the different cytoarchitectonic sectors of the ZI. In this study, we explore the contralateral connections that the ZI has with its opposing nucleus as well as with the other nuclei of the thalamus. Injections of biotinylated dextran or cholera toxin subunit B were made into each of the different ZI sectors (rostral, dorsal, ventral, and caudal) and into intralaminar and higher order dorsal thalamic nuclei of Sprague-Dawley rats by using stereotaxic coordinates. Brains were fixed in aldehyde and processed using standard methods. Our results show that, after injections limited to a given ZI sector, labelled terminal-like elements and cells were seen across the other sectors of the ZI of the contralateral side. Furthermore, after each of these ZI injections, labelling was seen in the intralaminar (e.g., parafascicular, central lateral, and central medial) and higher order (e.g., posterior thalamic, lateral posterior, and lateral dorsal) nuclei of the contralateral side. These patterns of labelling were confirmed after tracer injections into intralaminar and higher order nuclei; after such injections, labelling was seen in the contralateral ZI. In all cases, there was labelling on the ipsilateral side as well, and this was generally heavier than on the contralateral side. Overall, our results indicate that there is a network of interconnections between the ZI of both sides of the thalamus and that the ZI has contralateral connections with the intralaminar and higher order nuclei. Hence, the ZI furnishes a substrate that spreads activity to both sides of the brain.

Animals↗

Differential connections of the temporal pole with the orbital and medial prefrontal networks in macaque monkeys.

Previous studies indicate that the orbital and medial prefrontal cortex (OMPFC) is organized into "orbital" and "medial" networks, which have distinct connections with cortical, limbic, and subcortical structures. In this study, retrograde and anterograde tracer experiments in monkeys demonstrated differential connections between the medial and orbital networks and the dorsal and ventral parts of the temporal pole. The dorsal part, including dysgranular and granular areas (TGdd and TGdg), is reciprocally connected with the medial network areas on the medial wall and gyrus rectus (areas 10m, 10o, 11m, 13a, 14c, 14r, 25, and 32) and on the lateral orbital surface (areas Iai and 12o). The strongest connections are with areas 10m (caudal part), 14c, 14r, 25, 32, and Iai. The agranular temporal pole (TGa) is connected with several areas, but most strongly with medial network area 25. The granular area around the superior temporal sulcus (TGsts) and the ventral dysgranular and granular areas (TGvd and TGvg) are reciprocally connected with the orbital network (especially areas 11l, 13b, 13l, 13m, Ial, Iam, and Iapm). TGsts is strongly connected with the entire orbital network, whereas areas TGvd and TGvg have lighter and more limited connections. Intrinsic connections within the temporal pole are also restricted to dorsal or ventral parts. Together with evidence that the dorsal and ventral temporal pole are differentially connected to auditory and visual areas of the superior and inferior temporal cortex, the results indicate separate connections between these systems and the medial and orbital prefrontal networks.

Animals↗

[Changes in the emotional processing in depressive patients: a study with functional magnetoresonance tomography under the employment of pictures with affective contents].

OBJECTIVE: The influence of emotional contents on brain activation was examined using functional magnetic resonance tomography (fMRT). METHOD: Aquiring 100 EPI-measurements of the whole brain, series of positive and negative pictures from the International Affective Picture System (IAPS) were shown to eight depressed males and to healthy controls. RESULTS: In depression, there was an overactivation in hippocampal area during positive stimulation, whereas an overactivation of amygdala, orbital and prefrontal regions was seen during negative stimulation. CONCLUSIONS: These results emphasize the importance of functional interaction between the neural network associated with emotion. We could show that depression is connected to dysregulation and disturbed functional connectivity during emotional processing.

Adult↗

The Thyroid-Brain Network: Exploring Inflammation, Immune Mechanisms and Common Triggers in Thyroid-Related Neurological Dysfunction.

Autoimmune thyroid diseases (AITD), including Hashimoto's thyroiditis and Graves' disease, represent the most prevalent endocrine disorders worldwide, affecting hundreds of millions with profound but often under recognized neurological consequences. There are emerging lines of evidence establishing inflammation and immunity as the critical missing link connecting peripheral thyroid dysfunction to central nervous system manifestations. Thyroid hormones function as essential neuromodulators governing neurodevelopment, synaptic plasticity, and cognitive processing through integrated genomic and non-genomic mechanisms, with region-specific cerebral metabolic disturbances correlating with distinct neuropsychiatric symptoms. The immunological perspective reveals that AITD propagates neuroinflammation through convergent pathways: molecular mimicry enabling cross-reactivity between thyroid and neural antigens, cytokine-mediated disruption of neurotransmitter metabolism, HMGB1-driven glial activation, and blood-brain barrier compromise facilitating immune cell infiltration. The thyroid-gut-microbiota axis emerges as a critical mediator wherein dysbiosis perpetuates both thyroid autoimmunity and neuroinflammation through impaired serotonin precursor availability and increased intestinal permeability. Mitochondrial dysfunction represents an energetic common denominator, as thyroid hormone dysregulation directly impairs oxidative phosphorylation, producing region-specific cerebral metabolic disturbances. Simultaneous compromise of monoamine systems, cholinergic signaling abnormalities, and glutamate excitotoxicity creates a particularly toxic neurochemical state in untreated thyroid dysfunction. Common triggers such as psychological stress, gut dysbiosis, and mitochondrial impairment may activate interconnected pathways that simultaneously compromise thyroid and brain function, revealing that these disorders share fundamental mechanistic origins. These insights have been discussed in the current review to enhance the understanding of thyroid-brain function, the core mechanisms and consequences of functional deficits.

Journal Article↗

Functional neuroimaging of emotional learning and autonomic reactions.

This article provides a selective overview of the functional neuroimaging literature with an emphasis on emotional activation processes. Emotions are fast and flexible response systems that provide basic tendencies for adaptive action. From the range of involved component functions, we first discuss selected automatic mechanisms that control basic adaptational changes. Second, we illustrate how neuroimaging work has contributed to the mapping of the network components associated with basic emotion families (fear, anger, disgust, happiness), and secondary dimensional concepts that organise the meaning space for subjective experience and verbal labels (emotional valence, activity/intensity, approach/withdrawal, etc.). Third, results and methodological difficulties are discussed in view of own neuroimaging experiments that investigated the component functions involved in emotional learning. The amygdala, prefrontal cortex, and striatum form a network of reciprocal connections that show topographically distinct patterns of activity as a correlate of up and down regulation processes during an emotional episode. Emotional modulations of other brain systems have attracted recent research interests. Emotional neuroimaging calls for more representative designs that highlight the modulatory influences of regulation strategies and socio-cultural factors responsible for inhibitory control and extinction. We conclude by emphasising the relevance of the temporal process dynamics of emotional activations that may provide improved prediction of individual differences in emotionality.

Animals↗

Role of semaphorins in the adult nervous system.

In the developing nervous system, extending axons are directed towards their appropriate targets by a myriad of attractive and repulsive guidance cues. Work in the past decade has significantly advanced our understanding of these molecules and has made it increasingly clear that their function is not limited to the guidance of growing axons during embryogenesis. Axon guidance cues fulfill additional roles in angiogenesis, cell migration and the immune system, and often display sustained expression in adulthood. Here we focus on the semaphorin (Sema) family and review their proposed functions in the adult nervous system. Several semaphorin family members continue to be expressed in the adult brain and spinal cord, and increasing evidence indicates that their expression is regulated upon nervous system injury in rodents and in neuropathology in humans. The available evidence suggests that semaphorins might significantly contribute to the maintenance and stability of neuronal networks. Furthermore, semaphorins could play important roles in the regeneration, or failure thereof, of neuronal connections. In the future, genetic manipulation of semaphorins and their receptors in the adult intact and injured nervous system should provide a deeper insight into the mechanisms by which semaphorin signaling contributes to structural plasticity and regeneration in the adult brain.

Animals↗

Primary cell culture of LHRH neurones from embryonic olfactory placode in the sheep (Ovis aries).

The aim of this study was to establish an in vitro model of ovine luteinizing hormone-releasing hormone (LHRH) neurones. Olfactory placodes from 26 day-old sheep embryos (E26) were used for explant culture. Cultures were maintained successfully up to 35 days, but were usually used at 17 days for immunocytochemistry. LHRH and neuronal markers such as neurofilament (NF) were detected by immunocytochemistry within and/or outside the explant. Three main types of LHRH positive cells are described: (1) neuroblastic LHRH and NF immunoreactive cells with round cell body and very short neurites found mainly within the explant, (2) migrating LHRH bipolar neurones with an fusiform cell body, found outside the explant, (3) network LHRH neuron, bipolar or multipolar with long neurites connecting other LHRH neurons. Cell morphology was very similar to that which has been described in the adult sheep brain. These results strongly suggest that LHRH neurones in the sheep originate from the olfactory placode. This mode may represent a useful tool to study LHRH neurones directly in the sheep.

Animals↗

A simulation model for compensatory plasticity in the prefrontal cortex inducing a cortico-cortical dysconnection in early brain development.

In the present work, an abstract prefrontal cortex simulation model is used to predict compensatory structural alterations of the cortico-cortical connectivity pattern in the normal and pathologic forebrain maturation. The simulation network shows different representative courses of morphogenesis when developing undisturbed or when suffering from disturbing excitatory afferences. The simulative results could be affirmed by an immuno-histochemical study, revealing a qualitatively comparable development of the glutamatergic projection fibre density in gerbils (Meriones unguiculatus) after juvenile and adult methamphetamine intoxication. The simulation model further allows to consider different rearing conditions (enriched-environment model), and claims contradictory effects of an equal disturbance after enriched or impoverished rearing which are in accordance with the experimental findings.

Animals↗