Specific effects of the dopamine synaptic transmission modulator on the activity of sensomotor cortical neurons in a wakeful animal, performing a conditioned reflex are discussed. First, specific responses in the neocortical neurons after application of glutamate agonists and antagonists and gamma aminobutyric acid are described and then the effect of dopamine, its agonists and antagonists and amantadine, a dopamine releaser, on the background and induced pulse activities in the cortical neurons, as well as on specific characteristics of conditioned reflex motor responses, such as latency and intensity are analyzed in detail.
This article attempts to show why classical conceptual views of the brain that can be found in any neuroscience textbook are not capable of providing an adequate explanation of brain-initiated normal and pathological behaviors and why the classical view should therefore be replaced with a new concept of the brain. The major reason for the inadequacy of the classical model is its explanation of the relationship between structure and function in the brain. This article introduces a new brain concept based on two discoveries: the discovery of the neural network computational principle and the discovery of the generic functional organization of hierarchical neural optimal control systems. A neural optimal control system is a learning system that possesses a model of the behavior of its controlled object. A hierarchy of neural optimal control systems is functionally organized in such a way that a higher level neural optimal control system treats a lower one as its controlled object and creates a model of its behavior. The ability of the new conceptual brain model to explain brain mechanisms of normal and pathological behaviors is demonstrated through the examples of spinal reflexes and central pattern generators, the cerebellum, skeletomotor cortico-basal ganglia-thalamocortical loop, and Parkinson's disease and some other brain disorders. In this article, a new understanding of the relationship between structure and function in the brain is introduced. This article also discusses organizational and educational changes in the neurosciences that may be necessary to accelerate a broad acceptance of this new concept of the brain.
Hepatitis-C virus (HCV) has infected an estimated 130 million people worldwide, most of whom are chronically infected. Infection is marked by both treatment- and non-treatment-related psychiatric symptoms. Symptoms associated with antiretroviral therapy, interferon-alpha (IFN-alpha), include acute confusional states, delirium, depression, irritability, and even mania. These psychiatric symptoms are further complicated by the high rate of substance abuse and comorbid HIV infection inherent to this population. Even in the absence of IFN-alpha therapy, comorbid depression, cognitive decline, and especially fatigue are common in patients suffering HCV. These comorbidities have significant effects on both treatments and outcomes, and thus are reviewed herein.
Methylphenidate is the drug most often used to treat attention deficit/hyperactivity disorder (ADHD), a common behavioral disorder of children and young adults. The objectives of this study are (1) to use two different experimental assays of measuring animal activity--the wheel-running activity and the computerized open field--to establish which is more sensitive to acute and repetitive methylphenidate (MPD) administration and (2) to determine whether repetitive MPD treatment elicits adverse effects such as tolerance and behavioral sensitization. The dose-response protocol of MPD (0.6, 2.5, and 10.0 mg/kg) administration was performed in three groups of animals, with an additional saline control group as follows: single saline injection as the control/baseline followed by 6 consecutive days of MPD injections (0.6, 2.5, or 10.0 mg/kg MPD), 3 days of washout, and a day of MPD rechallenge. In general, the two different activity assays showed similar observations for the acute effect of MPD by eliciting increases in activity in a dose-dependent manner. The groups receiving repetitive 0.6 and 2.5 mg/kg MPD tested in the open-field assay exhibited further increase in activity that can be interpreted as behavioral sensitization, whereas the groups receiving 10 mg/kg MPD exhibited a reduction in activity, suggesting that tolerance was developed to the drug. All the groups (0.6, 2.5, and 10.0 mg/kg MPD) tested following repetitive MPD in the wheel-running assay exhibited a further increase in their activity, for example, all the groups exhibited behavioral sensitization. These different observations were interpreted as potentially measuring different kinds of locomotor activity.
Intermediate filaments (IFs), along with microfilaments and microtubules, comprise the three intracellular filaments identified in eukaryotic cells to date. Together, these three distinct filamentous networks act in a dynamic and tightly interconnected fashion to comprise the eukaryotic cytoskeleton. As such, they are involved in a number of essential and diverse cellular processes, including division, molecular transport, and the maintenance of structural integrity in the face of mechanical stress. Underscoring the ubiquitous importance of IF proteins to the normal function of cellular systems, mutations in IF-encoding genes that affect the structure, function, or regulation of these proteins are commonly found in association with a range of heritable genetic diseases. The diversity of IF-related disease is indeed as wide as the distribution of IF proteins themselves, effecting the development of a broad range of disease phenotypes. Here we review, with specific reference to recent developments in the correlation of genotype with phenotype, how the perturbation of IF networks can elicit the development of human neurological disease.
Delta-9-tetrahydrocannabinol (THC) is the primary psycho-active ingredient in Cannabis spp., the most widely used illicit drug in the United States. THC is an exogenous agonist of the central cannabinoid receptor (CB1), one of the most abundant G-coupled receptors in the mammalian brain. Although CB1 receptors are distributed throughout the brain, they are found at very high levels in the cerebellum. Despite the variety of disturbances associated with acute cannabis intoxication, including altered short-term memory, dissociation of thoughts, motor impairments, and paranoia, among others, a reliable index of cannabinoid system function has in large part eluded scientists. Thus, there is a demand in contemporary clinical neuroscience for methods sensitive to cannabinoid system function, not only for assessing how cannabis use influences human information processing, but also to assess the involvement of the endocannabinoid system (ECS) in clinical disease and evaluate the effects of CB1-based drug therapies. The purpose of the present article, therefore, is to address this current need by integrating two separate literatures. The first literature demonstrates that the ECS mediates synaptic plasticity, specifically, long-term depression (LTD) of parallel fibers at the parallel fiber-Purkinje junction in the cerebellar cortex. The second literature suggests that LTD at this junction is necessary for the acquisition of the primary dependent variable in delay eyeblink conditioning (EBC)--the exhibition of temporally measured conditioned responses. These two literatures are integrated by proposing an updated EBC circuit that incorporates the CB1 receptor and the endogenous cannabinoids. Finally, the implications of the model is discussed in consideration of recent evidence from CB1 knockout mice, human cannabis users, and schizophrenia patients, with the expectation that translational research on the cannabinoid system will be advanced.
An argument is made that small-vessel stroke, which usually results in lacunar infarction, is a serious medical problem. Therefore, it is surprising that only a few animal models exist that mimic small-vessel stroke and that these models have not been used for a systematic investigation of the genesis of lacunar infarctions. We make a case that the modified pial vessel class II disruption model mimics certain important aspects of lacunar infarctions, namely cavitation caused specifically by ischemia of smaller vessels. We found evidence that upregulation of inflammatory properties within a few days of inducing lesions prevents repopulation of the lesion with reactive astrocytes. We propose that this is the key mechanism by which cavitation occurs weeks later. We also found that treatment with minocycline after induction of lesions but before cavitation prevented the formation of the fluid-filled cavity. Rather than being walled off, the lesion apparently became part of the brain parenchyma and consisted of reactive astrocytes. We conclude that this new model can be used to investigate the mechanism of lacune formation and its prevention.
Diffusion of transmitters in the synaptic cleft critically influences synaptic efficacy by affecting both the amplitude and the time course of quantal events, but the value of the diffusion constant is speculative. In this study, we use molecular dynamics simulations to determine how the spatial confinement and membrane charges affect the diffusion constants of glutamate- and water as well as general properties of their diffusion. The synaptic cleft is represented as the space enclosed by two single-wall carbon sheets. Both water and especially glutamate are concentrated near the pore wall, where the concentration of glutamate can reach 30-50 times the mean value and the concentration of water can reach 2-8 times the mean value. Such spatial profiles of glutamate contradict the classical notions of diffusion on which both continuous and Monte Carlo simulations are built. The layering of glutamate- and water molecules suggests that the interfacial glutamate-cleft wall (or water-cleft wall) interactions may critically regulate their diffusion in the cleft. Indeed, the effective longitudinal diffusion constant of glutamate is steeply dependent on the cleft width, but only when the cleft is very narrow (< 5 nm). Therefore, even for a cleft as narrow as at the glutamatergic synapse in the central nervous system, the effective diffusion constant of glutamate will not be much lower than free diffusion in the bulk solution due to confinement. The effective diffusion constant of water is considerably less sensitive to cleft width over the same range of cleft widths than is glutamate, but is also higher than that of glutamate. Finally, the layering of glutamate and water and their effective diffusion constants are largely independent of how the cleft wall is charged. In conclusion, in the confined space of the synaptic cleft, glutamate is layered near the wall. Consequently, its diffusion constant becomes dependent on the cleft width. However, the diffusion of glutamate is slower than its free diffusion in water only if the cleft is very narrow. If the width of the cleft is consistent with that determined by morphometric studies in the central nervous system, glutamate diffusion should not be slowed by confinement and is thus likely to be similar to that in free solution.
In keeping with previous observations in the CA1 and the somatosensory neocortex of the brain of rat, 20-min applications of 2-deoxy-D-glucose (2DG; 10 mM, replacing glucose) induced a long-term potentiation (LTP)-like enhancement of field excitatory synaptic potentials (fEPSPs) in the dentate region of hippocampal slices. The effects of 2DG were not identical at synapses of medial and lateral perforant paths (MPP and LPP). At MPP synapses, there was no post-2DG early depression of fEPSPs and the potentiation reached +78.6 +/- 5.7 % (+/- standard error of the mean) 40 min after the return to glucose. In the presence of 50 microM D-amino-phosphono valerate (APV; an N-methyl-D-aspartate [NMDA] receptor antagonist), a marked post-2DG depression appeared and the subsequent LTP was reduced to +34.7 +/- 2.8 % (for both 2DG- and APV-treatment P<0.001 by ANOVA-2W). At LPP synapses, even under control conditions, there was a sharp post-2DG depression followed by LTP (+62.2 +/- 5.7 %) and APV had little effect on either the post-2DG depression or LTP, reducing the latter by only 24 % [the 2DG treatment was very significant (P<0.001) but not the APV treatment]. Thus, 2DG evokes both NMDAR-dependent and -independent components of LTP in the perforant pathways. In view of these findings, the consumption of 2DG could have significant effects on synaptic plasticity and cognitive function.
The sensory relay synapses in the thalamus undergo extensive refinement during early life. Disruptions of spontaneous activity, but not sensory deprivation, can induce large-scale re-organization of neuronal connections in the thalamus. Recent studies also reveal an extended period of synaptic refinement in the visual and somatosensory relay synapses, where sensory deprivation produces some unexpected effects on synaptic remodeling. This article aims to provide a brief overview of recent findings and current ideas about the refinement of relay synapses in the thalamus.
Repetitive firing neuron or activation of synaptic transmission plays an important role in the modulation of synaptic efficacy, such as long-term potentiation (LTP) and long-term depression (LTD). These activity-dependent changes in synaptic efficacy are thought to be critical to learning and memory; however, the underlying mechanisms remain to be defined. Endogenous cannabinoids (eCBs) are diffusible modulators that are released from depolarized postsynaptic neurons and act on presynaptic terminals. Persistent release of eCBs can lead to long-term modulation of synaptic plasticity in the brain. Given a broad distribution of eCB receptors in the brain, the eCB signaling system could contribute to use-dependent modification of brain functions.
Synapses mediated by gamma-aminobutyric acid (GABA) A receptors are notoriously altered during periods of enhanced activity. Since a loss of inhibitory tone is a basic cause of seizures and epilepsies, it is important to determine the underlying mechanisms and the way this could be alleviated or at least reduced. Alterations of the intracellular content of chloride are thought to be a major player in the sequence of events that follow episodes of hyperactivity. In this review, I discuss these mechanisms both in the adult and developing brain, relying on studies in which chloride and GABAergic currents were measured by electrophysiological and imaging techniques. The main conclusion is that in adult systems, status epilepticus induces a complete re-organization of the networks, with cell death, axonal growth, and glutamatergic neosynapse formation leading to an increased glutamatergic drive. This, in turn, will decrease the threshold of seizure generation and thus contribute to seizure generation. In contrast, GABAergic synapses are not readily "plastic" as the lost interneurones and synapses are not replaced. Somatostatin-positive 0-LM Interneurons that innervate the dendrites of the principal cells in the hippocampus degenerate selectively, leading to a loss of the inhibitory drive in the dendrites, whereas somatic projecting basket cells and somatic inhibitory drives are relatively spared. This imbalance leads to a reduction of the inhibitory strength that is necessary but not sufficient to generate ongoing seizures. An additional important factor is the persistent increase of the intracellular chloride concentration that leads to a long-lasting shift in the depolarizing direction of the actions of GABA that will also contribute to seizure generation. In the developing brain, a major source of seizure generation is the depolarizing and often excitatory actions of GABA due to a higher intracellular chloride concentration ([Cl-]I) in immature neurons, a property that has been confirmed in all developing systems and animal species studied. As a consequence, immature GABAergic synapses will excite targets and facilitate the emergence of seizures, in keeping with the well-known higher incidence of seizures in the developing brain. Using a unique preparation with two intact hippocampi placed in a three-compartment chamber in vitro, we have provided direct evidence that seizures beget seizures and that GABA signaling plays a central role in this phenomenon. Indeed, recurrent seizures triggered in one hippocampus by a convulsive agent propagate to the other hippocampus and transform the naive hippocampus into one that generates seizures once disconnected from the other hippocampus. This transformation is conditioned by the occurrence during the seizures of high-frequency oscillations (40 Hz and above). Interestingly, these oscillations are only produced when N-methyl-D-aspartate (NMDA-) and GABA receptors are operative and not blocked in the naïve hippocampus. Therefore, GABA-receptor antagonists are pro-convulsive in the developing brain but, in fact, anti-epileptic. This paradoxical conclusion has quite a few clinical implications that are discussed.
We have previously described a new endogenous phosphorylation mechanism that maintains ionotropic gamma-aminobutyric acid receptor (GABAAR) function and have shown that the kinase involved is the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH). This enzyme is closely associated with the receptor and phosphorylates the alpha1 subunit of the receptor. In a wealth of studies, a reduction in GABAergic neurotransmission has been suggested as a pathophysiological mechanism for human epilepsy. In this paper, we present evidence showing both reduced efficacy of this glycolysis-dependent GABAAR phosphorylation mechanism and of GABAergic inhibition in epileptogenic cortical tissue samples obtained during curative surgery of patients with partial seizures, as compared to non-epileptogenic human cortical tissue. This feature is not due to a reduction in the density of GABAAR alpha1 subunits in the epileptogenic tissue as evidenced by photoaffinity labeling. Maintaining the receptor in a phosphorylated state either by favoring the endogenous phosphorylation or by inhibiting a membrane-bound phosphatase sustains the GABAAR responses in the human epileptogenic cortex. The deficiency in endogenous phosphorylation and the associated decreased GABAAR function can account for transient failures of GABAergic inhibition and may favor seizure initiation and propagation. These findings suggest a functional link between epileptic pathology and the regional cerebral glucose hypometabolism observed in patients with partial epilepsies, since the dysfunction of the GABAergic mechanism is dependent on locally produced glycolytic ATP. They also point to new targets for developing molecules active in drug-resistant epilepsies.
Early in development, network activity in the hippocampus is characterized by giant depolarizing potentials (GDPs). These potentials consist of recurrent membrane depolarizations with superimposed fast action potentials separated by quiescent intervals. They are generated by the interplay of glutamate and gamma-aminobutyric acid (GABA) that, in the immediate postnatal period, is depolarizing and excitatory. Here, we review some recent data concerning the functional role of GDPs in shaping synaptic currents at low-probability mossy-fiber (MF)-CA3 synapses. A pairing procedure was used to correlate GDPs-associated calcium increase in the postsynaptic cell with stimulation of afferent inputs. The pairing protocol caused the appearance of synaptic responses or persistently enhanced the number of successes in "presynaptically" silent or low-probability synapses, respectively. In double-pulses experiments, this effect was associated with a significant reduction in the paired-pulse ratio and a significant increase in the inverse squared value of the coefficient of variation of response amplitude, suggesting that long-term potentiation (LTP) expression was due to the increased probability of transmitter released. In the absence of pairing, no significant changes in synaptic efficacy could be detected. When the interval between GDPs and MF stimulation was increased, the potentiating effect progressively declined and reached the control level in less than 4 s. Mossy-fiber responses were identified on the basis of their paired-pulse facilitation, short-term frequency facilitation, and sensitivity to the group III metabotropic glutamate receptor (mGluR) agonist, 2-amino-4-phosphonobutyric acid (L-AP4). Using these criteria, we found that MFs release mainly GAB A onto CA3 pyramidal cells or GABAergic interneurons. In line with their GABAergic nature, MF responses were blocked by the GABAA receptor antagonists bicuculline or gabazine and were potentiated by NO-711, a blocker of the GABA transporter GAT-1, and by flurazepam, an allosteric modulator of GABAA receptors. In addition, chemical stimulation of granule cell dendrites with glutamate in the presence of 6,7-dinitroquinoxaline-2,3-dione (DNQX) induced into target neurons barrages of L-AP4-sensitive GABAA-mediated postsynaptic currents, further supporting the GABAergic phenotype of granule cells. As in MF, pairing GDPs with Schaffer collateral stimulation induced a persistent potentiation of spontaneous and evoked alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-mediated responses at poorly developed CA3-CA1 synapses. This effect was mediated by an increase in calcium in the postsynaptic cell via voltage-dependent calcium channels activated by the depolarizing action of GABA during GDPs. We provide evidence also that, at these connections, cyclic AMP-dependent protein kinase A (PKA) is the signaling molecule necessary for enhancing synaptic efficacy, since GDPs-induced potentiation was prevented by the membrane permeable PKA inhibitor (PKI 14-22) applied in the bath or by the membrane impermeable form of PKI (PKI 6-22) applied via the patch pipette. In conclusion, it is suggested that GDPs translate specific patterns of pre- and postsynaptic activity into long-lasting changes in synaptic strength and stabilize synaptic connections, thus contributing to the structural refinement of the hippocampal circuit.
During neuronal development, gamma-aminobutyric acid (GABA), which is the principal inhibitory neurotransmitter in the mature brain, exerts a paradoxical depolarizing action that plays an important role in the generation of neuronal synaptic activities in the immature cortical structures and in the formation of the neuronal network. The depolarizing action of GABA is due to a differential organization of the chloride homeostasis system; in immature neurons it maintains an elevated intracellular chloride concentration ([Cl-]i), whereas in mature neurons it keeps [Cl-]i at relatively low levels. Several recent studies have shown that the function of chloride transporters during neuronal development extends beyond the simple maintenance of chloride homeostasis and might play an active role in neuronal growth and formation of synaptic connections. In the present manuscript, we summarize such evidence and discuss the perspectives in the study of the functional role of ion transporters in determining the mode of GABA actions.
The mammalian thoracolumbar spinal cord contains all the necessary elements to generate a rhythmic oscillatory activity that is transformed into locomotor commands to agonist and antagonist limb muscles to produce gait at various speed. This motor program is produced by interneurons in the ventral horn and can be readily recorded even with in vitro spinal cord preparations isolated from rats or mice (once dorsal afferents are stimulated or excitatory neuronchemicals applied). The locomotor program is continuously modulated and refined by afferent sensory inputs and by signals descending from brain centers. Nevertheless, this program is not the only type of rhythmic discharge produced by spinal networks. In fact, activation of metabotropic group I glutamate receptors or block of certain K+ currents by 4-aminopyridine generates non-locomotor discharges, and, at the same time, facilitates evoked locomotor activity, which then suppresses any other interfering rhythmicity. These findings suggest that accessory networks, activated by suitable stimuli, might be exploited to restore locomotor activity damaged by a lesion, an obvious goal for neuro-rehabilitation purposes. The structure of the locomotor networks appears to include a rhythm-generating circuit that drives a pattern formation circuit, commanding motoneurons to discharge appropriate signals to skeletal muscles. Studies with the K+-channel blocker tetraethylammonium have indicated that this hierarchical arrangement is preserved in vitro. Hence, isolated spinal cord preparations represent an interesting experimental tool to investigate new mechanisms to upregulate various components of locomotor networks, especially after the induction of experimental lesions.
Both long-lasting changes in synaptic function and long-term memory require gene expression. However, the molecular mechanisms by which gene expression is turned on are not fully understood. In this review, we highlight the role of the eukaryotic initiation factor 2 alpha (eIF2alpha) signalling pathway in long-term synaptic plasticity and memory.
Successful axon function is vital to the overall performance of the central nervous system (CNS). White matter (WM) axons are dependent on constant supply of oxygen and glucose to transmit signals with high fidelity. The optic nerve is a pure WM tract composed of completely myelinated axons while corpus callosum (CC) slices contain both gray and WM portions of the brain with a mixture of myelinated and unmyelinated axons. Axon function in both WM tracts is resistant to anoxia with a subset of axons able to survive exclusively on energy generated by glycolysis. In mouse optic nerves (MONs), removal of glucose during anoxia causes complete loss of axon function, implicating glucose as the sole source of energy. In contrast, in rat optic nerve (RON), anoxia causes rapid and complete loss of function. Because RON is about twice the diameter of MON, glucose diffusion during anoxia is inadequate. Increasing bath glucose concentration restores the ability of RON axons to persist during anoxia. Although in 10 mM glucose, MONs and CC slices exhibit identical resistance to anoxia, 30 mM glucose unmasks the greater resistance of CC axons suggesting unmyelinated axons and/or the smallest axons with the thinnest myelin sheath are resistant to anoxia. These results reveal that CNS WM is remarkably tolerant of anoxia although there is regional variability in their ability to function and survive anoxia. To achieve optimal protection of the CNS in various neurological diseases, it is critical to understand the properties of regional energy metabolisms and injury mechanisms for successful therapeutic approaches.
Krnjević, was an active member of the Croatian Peasant Party who, after the beginning of King Aleksandar's dictatorship and the formation of the Kingdom of Yugoslavia in 1929, moved his family to Geneva. During the 10 years that the family spent in Switzerland, Dr. Krnjevic became fl uent in French. The family returned to Zagreb in 1939, only to leave again in 1941, when the Germans invaded Yugoslavia. As a member of the Yu-goslav Government in exile, his father moved to England, but Dr. Krnjevic and his sister were sent for safety to Capetown, South Africa, where he learned the English language. After fi nishing high school, he moved to Great Britain at the beginning of 1944 and started his tertiary education in the medical school at Edinburgh University , graduating MBChB in 1949. At this point, he made the career decision to undertake PhD. training in the physiology department of the university under the supervision of David Whitteridge Dr. Krnjevic received an Honours BSc. in 1951 and PhD in 1953. His fi rst scientifi c publication was a proceedings paper in the Journal of Physiology (1952, 118 3P-4P), titled " The perfusion of the frog sciatic nerve with electro-lyte solutions " 1. This was followed by two full papers in 1954 on the perineural sheath as a diffusion barrier around peripheral nerves. All of these initial publications were under solo authorship. Post-doctoral studies took Dr. Krnjević and his wife, Jeanne, to the University of Washington in Seattle (1954-1956), where he continued his studies on Na and K ions in degenerating cat nerves; and where he also recorded age-dependent changes in somatosensory responses in the cortex of kittens. Dr. Krnjević then undertook a second post-doctoral position in the where he initiated research with R. Miledi on adrenaline and the failure of neuromuscular transmission and other publications on neuromuscu-lar transmission. Both also collaborated with D. R. Curtis on a project to record intracellularly from sacral motoneurons. While in Canberra, he
