Critical reviews in neurobiology最新文献

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.

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.

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.

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.

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.

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.

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 naïv

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.