Behavior-related neuronal reactions and dynamics of neuronal activity

Functionally, behavior-related discharges of associative neurons are an efferent flow of pulses continuously generated over the course of each behavioral act of an animal. However, predominant research approaches are based on the "stimulus - reaction" principle. Analysis of the dynamics of unit activity in monkeys during performance of a multi-step behavioral complex showed that differences related to different behavioral acts consist in composition changes in the active neurons (or their recombination) rather than in a number of responsive cells or involvement of action-specific neurons. Each combination of active neurons ensures the distribution of efferent signals characteristic of the given combination. These findings suggest the addressing coding of the efferent neuronal signals.     

Embryonic neuronal transplantation

Foetal neurones transplanted within the adult mammalian central nervous system survive and differentiate. Study of such transplants has yielded insights into the function, development and plasticity of brain structures, and suggests promising new therapies for a number of neurological disorders.     

The neuronal zootype

We present an hypothesis, derived from the zootype concept of Slack, Holland and Graham. The main point of this hypothesis is to postulate that the primordial function of the zootype genes is to design an appropriate neuronal network in bilaterian animals, by controlling the genes involved in the specificity of the axon pathways. This would be the primary function of the zootype genes in development and their primitive function in evolution. The hypothesis is discussed in view of the current knowledge on the Hox genes, their evolution, their genomic organisation, their expression and their targets.     

HIV-related neuronal injury

Perhaps as many as 25–50% of adult patients and children with acquired immunodeficiency syndrome (AIDS) eventually suffer from neurological manifestations, including dysfunction of cognition, movement, and sensation. How can human immunodeficiency virus type 1 (HIV-1) result in neuronal damage if neurons themselves are for all intents and purposes not infected by the virus? this article reviews a series of experiments leading to a hypothesis that accounts at least in part for the neurotoxicity observed in the brains of AIDS patients. There is growing support for the existence of HIV- or immune-related toxins that lead indirectly to the injury or demise of neurons via a potentially complex web of interactions among macrophages (or microglia), astrocytes, and neurons. HIV-infected monocytoid cells (macrophages, microglia, or monocytes), after interacting with astrocytes, secrete eicosanoids, i.e., arachidonic acid and its metabolites, including platelet-activating factor. Macrophages activated by HIV-1 envelope protein gp 120 also appear to release arachidonic acid and its metabolites. In addition, interferon-γ (IFN-γ) stimulation of macrophages induces release of the glutamate-like agonist, quinolinate. Furthermore, HIV-infected macrophage production of cytokines, including TNF-α and IL1-β, contributes to astrogliosis. A final common pathway for neuronal susceptibility appears to be operative, similar to that observed in stroke, trauma, epilepsy, neuropathic pain, and several neurodegenerative diseases, possibly including Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis. This mechanism involves the activation of voltage-dependent Ca²⁺ channels andN-methyl-d-aspartate (NMDA) receptor-operated channels, and, therefore, offers hope for future pharmacological intervention. This article focuses on clinically tolerated calcium channel antagonists and NMDA antagonists with the potential for trials in humans with AIDS dementia in the near future.     

Nonclassical neuronal communications

Examples from classical neuronal communications are discussed in the light of biochemical and anatomical data. These are the nonsynaptic axo-axonic interactions of the enkephalinergic neurons on nerve terminals of peptidergic primary sensory afferents and dopaminergic nigrostriatal fibers. Examples of dendrites as presynaptic sites are discussed in three very different situations, namely, the dopaminergic dendrites of the substantia nigra neurons, the gamma-aminobutyric acid--ergic dendrites involved in reciprocal dendro-dendritic synapses in the olfactory bulb, and the peripheral branches of the substance P-containing primary sensory neurons.     

The regulation and role of neuronal gap junctions during neuronal injury

In the mammalian CNS, excessive release of glutamate and overactivation of glutamate receptors are responsible for the secondary (delayed) neuronal death following neuronal injury, including ischemia, traumatic brain injury (TBI) and epilepsy. The coupling of neurons by gap junctions (electrical synapses) increases during neuronal injury. In a recent study with the use of in vivo and in vitro models of cortical ischemia in mice, we have demonstrated that the ischemic increase in neuronal gap junction coupling is regulated by glutamate via group II metabotropic glutamate receptors (mGluR). Specifically, we found that activation of group II mGluRs increases background levels of neuronal gap junction coupling and expression of connexin 36 (Cx36; neuronal gap junction protein), whereas inactivation of group II mGluRs prevents the ischemia-mediated increases in the coupling and Cx36 expression. Using the analysis of neuronal death, we also established that inactivation of group II mGluRs or genetic elimination of Cx36 both dramatically reduce ischemic neuronal death in vitro and in vivo. Similar results were obtained using in vitro models of TBI and epilepsy. Our study demonstrated that mechanisms for the injury-mediated increase in neuronal gap junction coupling are part of the mechanisms for glutamate-dependent neuronal death.     

The regulation and role of neuronal gap junctions during neuronal injury

In the mammalian CNS, excessive release of glutamate and overactivation of glutamate receptors are responsible for the secondary (delayed) neuronal death following neuronal injury, including ischemia, traumatic brain injury (TBI) and epilepsy. The coupling of neurons by gap junctions (electrical synapses) increases during neuronal injury. In a recent study with the use of in vivo and in vitro models of cortical ischemia in mice, we have demonstrated that the ischemic increase in neuronal gap junction coupling is regulated by glutamate via group II metabotropic glutamate receptors (mGluR). Specifically, we found that activation of group II mGluRs increases background levels of neuronal gap junction coupling and expression of connexin 36 (Cx36; neuronal gap junction protein), whereas inactivation of group II mGluRs prevents the ischemia-mediated increases in the coupling and Cx36 expression. Using the analysis of neuronal death, we also established that inactivation of group II mGluRs or genetic elimination of Cx36 both dramatically reduce ischemic neuronal death in vitro and in vivo. Similar results were obtained using in vitro models of TBI and epilepsy. Our study demonstrated that mechanisms for the injury-mediated increase in neuronal gap junction coupling are part of the mechanisms for glutamate-dependent neuronal death.     

Targeted neuronal death affects neuronal replacement and vocal behavior in adult songbirds

In the high vocal center (HVC) of adult songbirds, increases in spontaneous neuronal replacement correlate with song changes and with cell death. We experimentally induced death of specific HVC neuron types in adult male zebra finches using targeted photolysis. Induced death of a projection neuron type that normally turns over resulted in compensatory replacement of the same type. Induced death of the normally nonreplaced type did not stimulate their replacement. In juveniles, death of the latter type increased recruitment of the replaceable kind. We infer that neuronal death regulates the recruitment of replaceable neurons. Song deteriorated in some birds only after elimination of replaceable neurons. Behavioral deficits were transient and followed by variable degrees of recovery. This raises the possibility that induced neuronal replacement can restore a learned behavior.     

Ageing and neuronal vulnerability

Everyone ages, but only some will develop a neurodegenerative disorder in the process. Disease might occur when cells fail to respond adaptively to age-related increases in oxidative, metabolic and ionic stress, thereby resulting in the accumulation of damaged proteins, DNA and membranes. Determinants of neuronal vulnerability might include cell size and location, metabolism of disease-specific proteins and a repertoire of signal transduction pathways and stress resistance mechanisms. Emerging evidence on protein interaction networks that monitor and respond to the normal ageing process suggests that successful neural ageing is possible for most people, but also cautions that cures for neurodegenerative disorders are unlikely in the near future.     

Plasticity of neuronal receptors

This article describes ways in which receptors, key components of signal propagation through a synapse, can mediate changes in that propagation. Changes occur at four levels: in the signal-transducing capability of a single receptor molecule, in the number of receptors per cell, in the subcellular placement of receptor molecules, and in the cytoarchitecture of receptor-rich regions. The ability of receptors to shift between different desired states is called plasticity, and such shifts can be long-lived as well as transient. In this article we focus on neuronal receptors, although key findings from a variety of cell systems are reported. Neuronal receptor plasticity may have a special role in the assembly as well as the adaptability of the nervous system.     

Self-stabilization of neuronal networks

Between the extreme views concerning ontogenesis (genetic vs. environmental determination), we use a moderate approach: a somehow pre-established neuronal model network reacts to activity deviations (reflecting input to be compensated), and stabilizes itself during a complex feed-back process. Morphogenesis is based on an algorithm formalizing the compensation theory of synaptogenesis (Wolff and Wagner 1983). This algorithm is applied to randomly connected McCulloch-Pitts networks that are able to maintain oscillations of their activity patterns over time. The algorithm can lead to networks which are morphogenetically stable but preserve self-maintained oscillations in activity. This is in contrast to most of the current models of synaptogenesis and synaptic modification based on Hebbian rules of plasticity. Hebbian networks are morphogenetically unstable without additional assumptions. The effects of compensation on structural and functional properties of the networks are described. It is concluded that the compensation theory of synaptogenesis can account for the development of morphogenetically stable neuronal networks out of randomly connected networks via selective stabilization and elimination of synapses.The logic of the compensation algorithm is based on experimental results. The present paper shows that the compensation theory can not only predict the behavior of synaptic populations (Wagner and Wolff, in preparation), but it can also describe the behavior of neurons interconnected in a network, with the resulting additional system properties. The neuronal interactions-leading to equilibrium in certain cases-are a self-organizing process in the sense that all decisions are performed on the individual cell level without knowing the overall network situation or goal.     

Metalloproteins and neuronal death

Neurodegenerative diseases include Alzheimer's and Parkinson's disease that are very common and other diseases that are notorious but occur less often such as Creutzfeldt-Jakob disease. In each case a protein is closely linked to the pathology of these diseases. These proteins include alpha-synuclein, the prion protein and Aβ. Despite first being discovered because of aggregates of these amyloidogenic proteins found in the brains of patients, these proteins all exist in the healthy brain where their normal function involves binding of metals. Recognition of these proteins as metalloproteins implies that the diseases they are associated with are possibly diseases with altered metal metabolism at their heart. This review considers the evidence that cell death in these diseases involves not just the aggregated proteins but also the metals they bind.     

Nucleokinesis in neuronal migration

Neuronal migration is a critical phase of nervous system development and can be divided into two distinct phases: extension of the leading process and movement of the cell body and nucleus (nucleokinesis). Nucleokinesis appears to require many of the same cytoskeletal and signaling molecules used in cell mitosis. Converging studies suggest it requires cytoplasmic dynein, cell polarity genes, and microtubule-associated proteins that coordinate microtubule remodeling. These coordinate first the positioning of the centrosome (microtubule organizing center) in the leading process in front of the nucleus and then the movement of the nucleus towards the centrosome. The positioning of the centrosome and the dynamic regulation that couples and uncouples the nucleus underlies directed migration of neurons.