Multifunctional interneurons in behavioral circuits of the medicinal leech

We are using the medicinal leech to study the neuronal basis of behavioral choice. In particular, we are recording from neurons, both extracellularly and intracellularly, in preparations that can express three different behaviors: the shortening reflex, crawling and swimming. We have found that particular mechanosensory neurons can elicit any of the behaviors, and that the movements are produced by just four sets of muscles, each controlled by a small number of motor neurons. Hence, there must be three different pattern-generating neuronal circuits, each of which can be activated by the same set of sensory neurons. We are studying how the choice is made among the three behaviors by recording, while one behavior is being performed, from neurons known to be involved in the initiation of the other two. We have found that an interneuron, cell 204, which is known to initiate and maintain swimming, is also active during shortening and crawling. The activity level in this interneuron can influence whether a mechanosensory stimulus produces shortening or swimming. The neuronal mechanisms by which this choice is normally effected awaits further elucidation of the circuits that elicit and generate shortening and crawling.     

Development of behavior and learning inAplysia

Summary A set of fundamental issues in neuroethology concerns the neural mechanisms underlying behavior and behavioral plasticity. We have recently analyzed these issues by combining a simple systems approach in the marine molluscAplysia with a developmental analysis aimed at examining the emergence and maturation of different forms of behavior and learning. We have focussed on two kinds of questions: 1) How are specific neural circuits developmentally assembled to mediate different types of behaviors? and 2) how is plasticity integrated with these circuits to give rise to different forms of learning? From our analysis of the development of learning and memory inAplysia, several themes have emerged: 1) Different forms of learning emerge according to different developmental timetables. 2) Cellular analogs of learning have the same developmental timetables as their respective forms of behavioral learing. 3) An analysis of non-decremented responses prior to the emergence of sensitization reveals a novel inhibitory process on both behavioral and cellular levels. 4) Sensitization emerges simultaneously in diverse response systems, suggesting an underlying general process. 5) A widespread proliferation of central neurons occurs in the same developmental stage as the emergence of sensitization, raising the possibility that some aspect of the trigger for neuronal proliferation may also contribute to the expression of sensitization.     

Neurotrophins and neuronal differentiation in the central nervous system

The central nervous system requires the proper formation of exquisitely precise circuits to function properly. These neuronal circuits are assembled during development by the formation of synaptic connections between hundreds of thousands of differentiating neurons. For these circuits to form correctly, neurons must elaborate precisely patterned axonal and dendritic arbors. Although the cellular and molecular mechanisms that guide neuronal differentiation and formation of connections remain mostly unknown, the neurotrophins have emerged recently as attractive candidates for regulating neuronal differentiation in the developing brain. The experiments reviewed here provide strong support for a bifunctional role for the neurotrophins in axonal and dendritic growth and are consistent with the exciting possibility that the neurotrophins might mediate activity-dependent synaptic plasticity.     

Development of behavior and learning in Aplysia

A set of fundamental issues in neuroethology concerns the neural mechanisms underlying behavior and behavioral plasticity. We have recently analyzed these issues by combining a simple systems approach in the marine mollusc Aplysia with a developmental analysis aimed at examining the emergence and maturation of different forms of behavior and learning. We have focussed on two kinds of questions: 1) How are specific neural circuits developmentally assembled to mediate different types of behaviors? and 2) how is plasticity integrated with these circuits to give rise to different forms of learning? From our analysis of the development of learning and memory in Aplysia, several themes have emerged: 1) Different forms of learning emerge according to different developmental timetables. 2) Cellular analogs of learning have the same developmental timetables as their respective forms of behavioral learning. 3) An analysis of non-decremented responses prior to the emergence of sensitization reveals a novel inhibitory process on both behavioral and cellular levels. 4) Sensitization emerges simultaneously in diverse response systems, suggesting an underlying general process. 5) A widespread proliferation of central neurons occurs in the same developmental stage as the emergence of sensitization, raising the possibility that some aspect of the trigger for neuronal proliferation may also contribute to the expression of sensitization.     

Molecular neurophysiology of taste in <Emphasis Type="Italic">Drosophila</Emphasis>

The recent identification of candidate receptor genes for sweet, umami and bitter taste in mammals has opened a door to elucidate the molecular and neuronal mechanisms of taste. Drosophila provides a suitable system to study the molecular, physiological and behavioral aspects of taste, as sophisticated molecular genetic techniques can be applied. A gene family for putative gustatory receptors has been found in the Drosophila genome. We discuss here current knowledge of the gustatory physiology of Drosophila. Taste cells in insects are primary sensory neurons whereupon each receptor neuron responds to either sugar, salt or water. We found that particular tarsal gustatory sensilla respond to bitter compounds. Electrophysiological studies indicate that gustatory sensilla on the labellum and tarsi are heterogeneous in terms of their taste sensitivity. Determination of the molecular bases for this heterogeneity could lead to an understanding of how the sensory information is processed in the brain and how this in turn is linked to behavior.Received 12 May 2003; received after revision 9 June 2003; accepted 13 June 2003     

Escape behavior in the cockroach: Distributed neural processing

Summary Escape reactions are often considered to be among the simplest behaviors. The nerve circuits guiding these reactions are also generally thought to be simple. For instance, in several species a single interneuron is sufficient to trigger normal escape. The evasive response of the cockroach, however, appears to be more complex both behaviorally and physiologically. In this review, several complications of the behavior are pointed out, based on a recent computer-graphic analysis of the leg movements. Next described is the cooperative role of several interneurons-not just one-in evoking an escape turn away from the stimulus. A model of this multicellular code for stimulus direction is then presented that correctly predicts the turning behavior under many different experimental conditions. Finally, an overall scheme of the information processing for escape behavior is presented.     

Escape behavior in the cockroach: distributed neural processing

Escape reactions are often considered to be among the simplest behaviors. The nerve circuits guiding these reactions are also generally thought to be simple. For instance, in several species a single interneuron is sufficient to trigger normal escape. The evasive response of the cockroach, however, appears to be more complex both behaviorally and physiologically. In this review, several complications of the behavior are pointed out, based on a recent computer-graphic analysis of the leg movements. Next described is the cooperative role of several interneurons--not just one--in evoking an escape turn away from the stimulus. A model of this multicellular code for stimulus direction is then presented that correctly predicts the turning behavior under many different experimental conditions. Finally, an overall scheme of the information processing for escape behavior is presented.     

Neurodegeneration changes in primary central nervous system neurons transfected with the Alzheimer-associated neuronal thread protein gene

The AD7c-NTP gene is over-expressed in brains with Alzheimer's disease (AD), and increased levels of the corresponding protein are detectable in cortical neurons, brain tissue extracts, cerebrospinal fluid, and urine beginning early in the course of AD neurodegeneration. In the present study, we utilized a novel method to transfect post-mitotic primary neuronal cell cultures, and demonstrated that over-expression of the AD7c-NTP gene causes cell death and neuritic sprouting, two prominent abnormalities associated with AD. These results provide further evidence that aberrantly increas-ed AD7c-NTP expression may have a role in AD-type neurodegeneration. In addition, we demonstrate that primary post-mitotic neurons can be efficiently transfected with conventional recombinant plasmid DNA to evaluate the effects of gene over-expression in relevant in vitro models. Received 31 January 2001; received after revision 31 March 2001; accepted 4 April 2001     

Physiological arousal: a role for hypothalamic systems

The lateral hypothalamus (LH) has long been known as a homeostasis center of the brain that modulates feeding behavior, arousal and reward. The hypocretins (Hcrts, also called orexins) and melanin-concentrating hormone (MCH) are neuropeptides produced in two intermingled populations of a few thousand neurons in the LH. The Hcrts have a prominent role in regulating the stability of arousal, since Hcrt system deficiency leads to narcolepsy. MCH is an important modulator of energy balance, as MCH system deficiency in mice leads to leanness and increased metabolism. Recently, MCH has been proposed to modulate rapid eye movement sleep in rodents. In this review, we propose a working model of the cross-talk between Hcrt and MCH circuits that may provide an arousal balance system to regulate complex goal-oriented behaviors.     

Analysis of synaptic integration using the laser photoinactivation technique

Summary Crickets (and many other insects) have two antenna-like appendages at the rear of their abdomen, each of which is covered with hundreds of filiform hairs resembling the bristles on a bottle brush. Deflection of these filiform hairs by wind currents activates mechanosensory neurons at the base of the hairs. The axons from these sensory neurons project into the terminal abdominal ganglion to form a topographic representation (or map) containing information about the direction, velocity and acceleration of wind currents around the animal. Information is extracted from this map by primary sensory interneurons that are also located within the terminal abdominal ganglion. In this paper, we review the progress that has been made toward understanding the mechanisms underlying directional sensitivity of an identified sensory interneuron in the cricket,Acheta domesticus. The response properties of the cell have been found to depend to a large extent upon the structure of its dendritic branches, which determines its synaptic connectivity with the sensory afferents in the map of wind space and the relative efficacy of its different synaptic inputs.     

Sensing the fuels: glucose and lipid signaling in the CNS controlling energy homeostasis

The central nervous system (CNS) is capable of gathering information on the body’s nutritional state and it implements appropriate behavioral and metabolic responses to changes in fuel availability. This feedback signaling of peripheral tissues ensures the maintenance of energy homeostasis. The hypothalamus is a primary site of convergence and integration for these nutrient-related feedback signals, which include central and peripheral neuronal inputs as well as hormonal signals. Increasing evidence indicates that glucose and lipids are detected by specialized fuel-sensing neurons that are integrated in these hypothalamic neuronal circuits. The purpose of this review is to outline the current understanding of fuel-sensing mechanisms in the hypothalamus, to integrate the recent findings in this field, and to address the potential role of dysregulation in these pathways in the development of obesity and type 2 diabetes mellitus.     

Coaxing bone marrow stromal mesenchymal stem cells towards neuronal differentiation: progress and uncertainties

Multipotent adult stem cells capable of developing into particular neuronal cell types have great potential for autologous cell replacement therapy for central nervous system neurodegenerative disorders and traumatic injury. Bone marrow-derived stromal mesenchymal stem cells (BMSCs) appear to be attractive starting materials. One question is whether BMSCs could be coaxed to differentiate in vitro along neuronal or glial lineages that would aid their functional integration post-transplantation, while reducing the risk of malignant transformation. Recent works suggest that BMSCs could indeed be differentiated in vitro to exhibit some cellular and physiological characteristics of neural cell lineages, but it is not likely to be achievable with simple chemical treatments. We discussed recent findings pertaining to efforts in neuronal differentiation of BMSCs in vitro, and results obtained when these were transplanted in vivo. Received 19 January 2006; received after revision 24 February 2006; accepted 12 April 2006     

On the ORigin of smell: odorant receptors in insects

Olfaction, the sense of smell, depends on large, divergent families of odorant receptors that detect odour stimuli in the nose and transform them into patterns of neuronal activity that are recognised in the brain. The olfactory circuits in mammals and insects display striking similarities in their sensory physiology and neuroanatomy, which has suggested that odours are perceived by a conserved mechanism. Here I review recent revelations of significant structural and functional differences between the Drosophila and mammalian odorant receptor proteins and discuss the implications for our understanding of the evolutionary and molecular biology of the insect odorant receptors. Received 23 March 2006; accepted 28 April 2006     

二进神经网络表达奇偶校验问题的隐元最小数目上界

二进神经网络采用线性分类,是结构简单又易于实现的一类神经网络,在许多应用领域中都有重要研究价值.对于单隐层二进神经网络,目前隐层规模的确定问题仍然没有明确的研究结论.本文在研究隐层规模问题的过程中,提出了布尔空间的最多孤立样本问题.在二进神经网络隐层神经元各自表达一个"与"关系,所有隐层神经元通过输出元形成"或"关系的情况下,证明了实现最多孤立样本问题需2n?1个隐层神经元.更重要的是,指出了n元奇偶校验问题和最多孤立样本结构的等价性.进一步地,通过引入隐层抑制神经元将隐元数目降为n,说明了抑制神经元在二进神经网络中的重要作用.最后,在Hamming球与SP函数的基础上,揭示出抑制神经元和n元奇偶校验问题的逻辑关系,并给出了奇偶校验问题的逻辑式表达.     

Tachykinins and their functions in the gastrointestinal tract

In the gastrointestinal tract, tachykinins are peptide neurotransmitters in nerve circuits that regulate intestinal motility, secretion, and vascular functions. Tachykinins also contribute to transmission from spinal afferents that innervate the gastrointestinal tract and have roles in the responses of the intestine to inflammation. Tachykinins coexist with acetylcholine, the primary transmitter of excitatory neurons innervating the muscle, and act as a co-neurotransmitter of excitatory neurons. Excitatory transmission is mediated through NK1 receptors (primarily on interstitial cells of Cajal) and NK2 receptors on the muscle. Tachykinins participate in slow excitatory transmission at neuro-neuronal synapses, through NK1 and NK3 receptors, in both ascending and descending pathways affecting motility. Activation of receptors (NK1 and NK2) on the epithelium causes fluid secretion. Tachykinin receptors on immune cells are activated during inflammation of the gut. Finally, tachykinins are released from the central terminals of gastrointestinal afferent neurons in the spinal cord, particularly in nociceptive pathways. Received 24 March 2007; received after revision 30 August 2007; accepted 14 September 2007     

Effects of methylene blue on electrical behavior of myenteric neurons

Summary Intracellular recording methods were used to investigate the action of methylene blue on electrical behavior of myenteric neurons in guinea pig small intestine. The neurophysiological studies were done in parallel with studies on contractile activity of the intestinal musculature. Methylene blue depolarized the membranes, increased the input resistance, augmented excitability and reduced postspike hyperpolarizing potentials in AH/Type 2 myenteric neurons. These effects, with the exception of suppression of postspike hyperpolarization, were reversed by exposure to elevated calcium. The mechanism of action of methylene blue appeared to be suppression of calcium-dependent potassium conductance in the neuronal membranes. The neuronal action of methylene blue was manifest as a release of excitatory neurontransmitter substances with evoked contraction of the small intestinal longitudinal muscle.     

Effects of methylene blue on electrical behavior of myenteric neurons

Intracellular recording methods were used to investigate the action of methylene blue on electrical behavior of myenteric neurons in guinea pig small intestine. The neurophysiological studies were done in parallel with studies on contractile activity of the intestinal musculature. Methylene blue depolarized the membranes, increased the input resistance, augmented excitability and reduced postspike hyperpolarizing potentials in AH/Type 2 myenteric neurons. These effects, with the exception of suppression of postspike hyperpolarization, were reversed by exposure to elevated calcium. The mechanism of action of methylene blue appeared to be suppression of calcium-dependent potassium conductance in the neuronal membranes. The neuronal action of methylene blue was manifest as a release of excitatory neurontransmitter substances which evoked contraction of the small intestinal longitudinal muscle.     

Molecular analysis of axonal target specificity and synapse formation

The development of neuronal connectivity requires the growth of axons to their target region and the formation of dendritic trees that extend into specific layers. Within the target region growth cones, the tips of extending axons are guided to finer target fields including specific subcellular compartments where they form synapses. In this article we highlight recent progress on molecular aspects of axonal subcellular target selection such as the axon initial segment or specific sublaminae of the vertebrate retina. We then discuss the very recent progress on the molecular analysis of synapse formation in the central nervous system, including the direction of differentiation into an inhibitory or excitatory synapse. Apparently, initial synaptic contacts are structurally and functionally modulated by neuronal activity, raising the question how neuronal activity can modify synaptic circuits. We therefore also focus on neural proteins that are up-regulated, secreted or converted by synaptic activity and, thus, might represent molecular candidates for experience-driven refinement or remodeling of synaptic connections. Received 5 July 2005; received after revision 19 August 2005; accepted 2 September 2005     

Principles of neural cell migration

Summary A basic property of immature neurons is their ability to change position from the place of their final mitotic division in proliferative centers of the developing brain to the specific positions they will occupy in a given structure of the adult nervous system. Proper acquisition of neuron position, attained through the process of active migration, ultimately affects a cell's morphology, synaptic connectivity and function. Although various classes of neurons may use different molecular cues to guide their migration to distant structures, a surface-mediated interaction between neighboring cells is considered essential for all types of migration. Disturbance of this cell-cell interaction may be important in several congenital and/or acquired brain abnormalities. The present article considers the basic mechanisms and principles of neuronal cell migration in the mammalian central nervous system.     

Homeostatic regulation of NCAM polysialylation is critical for correct synaptic targeting

During development, axonal projections have a remarkable ability to innervate correct dendritic subcompartments of their target neurons and to form regular neuronal circuits. Altered axonal targeting with formation of synapses on inappropriate neurons may result in neurodevelopmental sequelae, leading to psychiatric disorders. Here we show that altering the expression level of the polysialic acid moiety, which is a developmentally regulated, posttranslational modification of the neural cell adhesion molecule NCAM, critically affects correct circuit formation. Using a chemically modified sialic acid precursor (N-propyl-D: -mannosamine), we inhibited the polysialyltransferase ST8SiaII, the principal enzyme involved in polysialylation during development, at selected developmental time-points. This treatment altered NCAM polysialylation while NCAM expression was not affected. Altered polysialylation resulted in an aberrant mossy fiber projection that formed glutamatergic terminals on pyramidal neurons of the CA1 region in organotypic slice cultures and in vivo. Electrophysiological recordings revealed that the ectopic terminals on CA1 pyramids were functional and displayed characteristics of mossy fiber synapses. Moreover, ultrastructural examination indicated a "mossy fiber synapse"-like morphology. We thus conclude that homeostatic regulation of the amount of synthesized polysialic acid at specific developmental stages is essential for correct synaptic targeting and circuit formation during hippocampal development.