Molecular Basis Of Behavior Research Articles

MicroRNA-Dependent Control of Sensory Neuron Function Regulates Posture Behavior in Drosophila.

All what we see, touch, hear, taste, or smell must first be detected by the sensory elements of our nervous system. Sensory neurons, therefore, represent a critical component in all neural circuits and their correct function is essential for the generation of behavior and adaptation to the environment. Here, we report that the evolutionarily-conserved microRNA (miRNA) miR-263b plays a key behavioral role in Drosophila melanogaster through effects on the function of larval sensory neurons. Several independent experiments (in 50:50 male:female populations) support this finding: first, miRNA expression analysis, via reporter expression and fluorescent-activated cell sorting (FACS)-quantitative PCR (qPCR) analysis, demonstrate miR-263b expression in larval sensory neurons. Second, behavioral tests in miR-263b null mutants show defects in self-righting, an innate and evolutionarily conserved posture-control behavior that allows larvae to rectify their position if turned upside-down. Third, competitive inhibition of miR-263b in sensory neurons using a miR-263b “sponge” leads to self-righting defects. Fourth, systematic analysis of sensory neurons in miR-263b mutants shows no detectable morphologic defects in their stereotypic pattern, while genetically-encoded calcium sensors expressed in the sensory domain reveal a reduction in neural activity in miR-263b mutants. Fifth, miR-263b null mutants show reduced “touch-response” behavior and a compromised response to sound, both characteristic of larval sensory deficits. Furthermore, bioinformatic miRNA target analysis, gene expression assays, and behavioral phenocopy experiments suggest that miR-263b might exert its effects, at least in part, through repression of the basic helix-loop-helix (bHLH) transcription factor Atonal. Altogether, our study suggests a model in which miRNA-dependent control of transcription factor expression affects sensory function and behavior.SIGNIFICANCE STATEMENT Sensory neurons are key to neural circuit function, but how these neurons acquire their specific properties is not well understood. Here, we examine this problem, focusing on the roles played by microRNAs (miRNAs). Using Drosophila, we demonstrate that the evolutionarily-conserved miRNA miR-263b controls sensory neuron function allowing the animal to perform an adaptive, elaborate three-dimensional movement. Our work thus shows that microRNAs can control complex motor behaviors by modulating sensory neuron physiology, and suggests that similar miRNA-dependent mechanisms may operate in other species. The work contributes to advance the understanding of the molecular basis of behavior and the biological roles of microRNAs within the nervous system.

Unc-4 acts to promote neuronal identity and development of the take-off circuit in the Drosophila CNS.

The Drosophila ventral nerve cord (VNC) is composed of thousands of neurons born from a set of individually identifiable stem cells. The VNC harbors neuronal circuits required to execute key behaviors, such as flying and walking. Leveraging the lineage-based functional organization of the VNC, we investigated the developmental and molecular basis of behavior by focusing on lineage-specific functions of the homeodomain transcription factor, Unc-4. We found that Unc-4 functions in lineage 11A to promote cholinergic neurotransmitter identity and suppress the GABA fate. In lineage 7B, Unc-4 promotes proper neuronal projections to the leg neuropil and a specific flight-related take-off behavior. We also uncovered that Unc-4 acts peripherally to promote proprioceptive sensory organ development and the execution of specific leg-related behaviors. Through time-dependent conditional knock-out of Unc-4, we found that its function is required during development, but not in the adult, to regulate the above events.

MeCP2 Deficiency Disrupts Kainate-Induced Presynaptic Plasticity in the Mossy Fiber Projections in the Hippocampus.

Methyl cytosine binding protein 2 (MeCP2) is a structural chromosomal protein involved in the regulation of gene expression. Mutations in the gene encoding MeCP2 result in Rett Syndrome (RTT), a pervasive neurodevelopmental disorder. RTT is one of few autism spectrum disorders whose cause was identified as a single gene mutation. Remarkably, abnormal levels of MeCP2 have been associated to other neurodevelopmental disorders, as well as neuropsychiatric disorders. Therefore, many studies have been oriented to investigate the role of MeCP2 in the nervous system. In the present work, we explore cellular and molecular mechanisms affecting synaptic plasticity events in vivo in the hippocampus of MeCP2 mutant mice. While most studies addressed postsynaptic defects in the absence of MeCP2, we took advantage of an in vivo activity-paradigm (seizures), two models of MeCP2 deficiency, and neurobiological assays to reveal novel defects in presynaptic structural plasticity in the hippocampus in RTT rodent models. These approaches allowed us to determine that MeCP2 mutations alter presynaptic components, i.e., disrupts the plastic response of mossy fibers to synaptic activity and results in reduced axonal growth which is correlated with imbalanced trophic and guidance support, associated with aberrant expression of brain-derived neurotrophic factor and semaphorin 3F. Our results also revealed that adult-born granule cells recapitulate maturational defects that have been only shown at early postnatal ages. As these cells do not mature timely, they may not integrate properly into the adult hippocampal circuitry. Finally, we performed a hippocampal-dependent test that revealed defective spatial memory in these mice. Altogether, our studies establish a model that allows us to evaluate the effect of the manipulation of specific pathways involved in axonal guidance, synaptogenesis, or maturation in specific circuits and correlate it with changes in behavior. Understanding the mechanisms underlying the neuronal compromise caused by mutations in MeCP2 could provide information on the pathogenic mechanism of autistic spectrum disorders and improve our understanding of brain development and molecular basis of behavior.

<em>Aplysia</em> Ganglia Preparation for Electrophysiological and Molecular Analyses of Single Neurons

A major challenge in neurobiology is to understand the molecular underpinnings of neural circuitry that govern a specific behavior. Once the specific molecular mechanisms are identified, new therapeutic strategies can be developed to treat abnormalities in specific behaviors caused by degenerative diseases or aging of the nervous system. The marine snail Aplysia californica is well suited for the investigations of cellular and molecular basis of behavior because neural circuitry underlying a specific behavior could be easily determined and the individual components of the circuitry could be easily manipulated. These advantages of Aplysia have led to several fundamental discoveries of neurobiology of learning and memory. Here we describe a preparation of the Aplysia nervous system for the electrophysiological and molecular analyses of individual neurons. Briefly, ganglion dissected from the nervous system is exposed to protease to remove the ganglion sheath such that neurons are exposed but retain neuronal activity as in the intact animal. This preparation is used to carry out electrophysiological measurements of single or multiple neurons. Importantly, following the recording using a simple methodology, the neurons could be isolated directly from the ganglia for gene expression analysis. These protocols were used to carry out simultaneous electrophysiological recordings from L7 and R15 neurons, study their response to acetylcholine and quantitating expression of CREB1 gene in isolated single L7, L11, R15, and R2 neurons of Aplysia.

Balance within the Neurexin Trans-Synaptic Connexus Stabilizes Behavioral Control

Autism spectrum disorder (ASD) is characterized by a broad spectrum of behavioral deficits of unknown etiology. ASD associated mutations implicate numerous neurological pathways including a common association with the neurexin trans-synaptic connexus (NTSC) which regulates neuronal cell-adhesion, neuronal circuitry, and neurotransmission. Comparable DNA lesions affecting the NTSC, however, associate with a diversity of behavioral deficits within and without the autism spectrum including a very strong association with Tourette syndrome. The NTSC is comprised of numerous post-synaptic ligands competing for trans-synaptic connection with one of the many different neurexin receptors yet no apparent association exists between specific NTSC molecules/complexes and specific behavioral deficits. Together these findings indicate a fundamental role for NTSC-balance in stabilizing pre-behavioral control. Further molecular and clinical characterization and stratification of ASD and TS on the basis of NTSC status will help elucidate the molecular basis of behavior – and define how the NTSC functions in combination with other molecular determinates to strengthen behavioral control and specify behavioral deficits.

The Promise of Evolutionary Systems Biology: Lessons from Bacterial Chemotaxis

Bacterial chemotaxis and the signaling networks underlying it provide us with a model system for studying the molecular basis of behavior and information processing. Although chemotaxis is well characterized at both the phenotype and genotype levels in the model organism Escherichia coli, it is not yet possible to predict chemotaxis behavior in diverse bacteria on the basis of their environment or genome sequence. Moreover, we still cannot propose a plausible evolutionary trajectory from minimal systems to present-day chemotaxis networks. The analysis of all sequenced bacterial genomes provides a prediction of their chemotaxis networks and reveals substantial structural diversity. Additionally, it uncovers a set of previously unknown proteins that could be the "missing" link between complex present-day chemotaxis networks and simpler, ancestral systems composed of a few proteins. Further evaluation of these findings with experimental and modeling studies will allow us to distill evolutionary design principles in chemotaxis signaling networks.

Role of Adaptation in C. elegans thermotaxis. Focus on “Short-Term Adaptation and Temporal Processing in the Cryophilic Response of Caenorabditis elegans”

From honeybee foraging to bird migration, the orientation of animals in their environments is vital for survival and provides opportunities for studying the neural mechanisms that underlie the perception and processing of sensory information. Temperature is a ubiquitous environmental variable that

Invertebrate studies and their ongoing contributions to neuroscience

Invertebrates have been deployed very successfully in experimental studies of the nervous system and neuromuscular junctions. Many important discoveries on axonal conduction, synaptic transmission, integrative neurobiology and behaviour have been made by investigations of these remarkable animals. Their advantages as model organisms for investigations of nervous systems include (a) the large diameter of neurons, glia and muscle cells of some invertebrates, thereby facilitating microelectrode recordings; (b) simple nervous systems with few neurons, enhancing the tractability of neuronal circuitry; and (c) well-defined behaviours, which lend themselves to physiological and genetic dissection. Genetic model organisms such as Drosophila melanogaster and Caenorhabditis elegans have provided powerful genetic approaches to central questions concerning nervous system development, learning and memory and the cellular and molecular basis of behaviour. The process of attributing function to particular gene products has been greatly accelerated in recent years with access to entire genome sequences and the application of reverse genetic (e.g. RNA interference, RNAi) and other post-genome technologies (e.g. microarrays). Studies of many other invertebrates, notably the honeybee (Apis mellifera), a nudibranch mollusc (Aplysia californica), locusts, lobsters, crabs, annelids and jellyfish have all assisted in the development of major concepts in neuroscience. The future is equally bright with ease of access to genome-wide reverse genetic technologies, and the development of optical recordings using voltage and intracellular calcium sensors genetically targeted to selected individual and groups of neurons.

Nematode Behaviour (ed. Gaugler, R. and Bilgrami, A. L.), pp. 432. CABI Publishing UK, 2004. ISBN 0 85199 818 6. £75.00 (US$140.00).

This book is dedicated to my Ph.D. advisor, Neil Croll (1941–1981), whose seminal text “The Behaviour of Nematodes” launched the field in 1970. The current effort is a thick, heavy tome when compared to Croll's slim and elegant little book, directly reflecting the explosion of interest in the topic, due in no small part to a single nematode Caenorhabiditis elegans. However, C. elegans is not the star of this book. The present effort is meant to be broad in its taxonomic scope, attempting to consolidate disparate nematode behaviours into a comprehensive up-to-date volume. Indeed, this is a formidable task in a world in which 4 out of every 5 metazoans is a nematode, and the end result is a bit uneven. To cover the taxonomic breadth, several chapters focused on simply describing proximate behaviours. Thus, Chapter 1 – Ecological and behavioural adaptations; Chapter 3 – Orientation; Chapter 4 – Feeding; Chapter 7 – Osmoregulation; and Chapter 8 – Physiological and biochemical basis of behaviour, were generally not synthetic, and read like catalogues of behaviour descriptors, often with little context on the natural history or biology of the responses. These chapters are not accessible to the non-specialist student, and their value lies primarily in their extensive literature searches. On the other hand, there are several wonderful pieces, including Chapter 5 – Reproductive behaviour and Chapter 6 – Ageing and development, whose compelling and clearly written stories cut across the artificial lines of plant, insect, animal, and parasite designations, to address the essence of our understanding of nematode behaviour. In this group, I particularly liked Chapter 2 – Locomotion, for the succinct incorporation of historical ideas into the growth of current thinking in this area. Chapter 9 – Molecular basis of behaviour, was an excellent presentation of behaviour in the C. elegans model system, and the authors did an outstanding job making the concepts and techniques in this high-tech area accessible to students of general biology. The remaining 4 chapters fell somewhere in the middle of the continuum. Overall, I think this a good effort, and I recommend this book for the shelves of every nematode biologist. It is valuable because of the sheer amount of information on nematode behaviour that it contains, and especially for the reference lists. For the 4 or 5 well-written chapters, this book is priceless!

The 2003 Genetics Society of America Medal Jeffrey C. Hall

![Figure][1] Jeff Hall in the lab. THIS year’s GSA Medal is awarded to Jeffrey C. Hall for his seminal studies on the genetic and molecular bases of behavior in Drosophila. Over nearly 30 years, Hall has consolidated the field of Drosophila behavioral neurogenetics, which was initiated

The Emergent Ego: Complexity and Coevolution in the Psychoanalytic Process

Back to table of contents Previous article Next article Book Forum: PsychoanalysisFull AccessThe Emergent Ego: Complexity and Coevolution in the Psychoanalytic ProcessHAROLD I. EIST, M.D., HAROLD I. EISTSearch for more papers by this author, M.D., Bethesda, Md.Published Online:1 Mar 2001https://doi.org/10.1176/appi.ajp.158.3.505AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail In 1978, Stanley Palombo wrote Dreaming and Memory(1), a seminal volume that expanded understanding of dream function. He relied on empirical research in the sleep laboratory plus innovative integration of new neurobiological and computer science findings with current psychoanalytic ideas.Palombo’s new book skillfully continues these processes of integration and inclusion. He brings a new and lively version of psychoanalysis and psychoanalytic theory into the millennium as he combines modern evolutionary theory, computer models of evolution and information, complexity theory, neuroscience, and clinical psychoanalytic wisdom. This integration convincingly documents that psychoanalysis is quintessentially a biopsychosocial discipline that is alive, changing, growing, and relevant.Palombo challenges long-held, incorrect views that psychoanalysis is not science; that psychoanalysis deals with only outside influences on development (the one-way shaping of the individual through the pressures of learning and society on the drives or instincts, which create a dynamic, Möbius-strip effect) rather than the inner influences (the genetic or molecular bases of behavior); and that there is no way of measuring change in psychoanalysis. He does not get stuck at the level of molecular biology, however; rather, he recognizes the importance of the whole organism and the fact that change is reflected as an aspect of the organism. Palombo’s work is responsive to the important ideas of the sociobiologist Edmund O. Wilson, whom Jonathan Weiner (2) quoted as saying, “If everything else in biology is the product of evolution then surely we have to constantly examine and reexamine the human mind and human social behavior as products of evolution” (p. 220).Palombo argues compellingly that psychoanalysis induces changes within patients that are evolutionary in nature in that they alter adaptations from less effective to more effective. He also argues that these often small, nonlinear changes can lead to transformations with major enduring impact as new engrams. His views are in agreement with those of Eric Kandel, suggesting that the brain remains plastic throughout most of the life cycle and that new learning brought about by psychoanalysis can structurally alter the brain and the potential of the individual, which, like the brain, is changeable.Palombo points out that it is not essential for the reader to go through all of the chapters on computer models of self-sustaining and self-modifying systems to get the gist of his ideas and use them clinically. The concepts presented in these chapters are complex and require frequent rereadings and cogitation. However, reading these chapters is important not only as a strenuous mental exercise, which is good for the brain, but because they describe recent developments in post-Darwinian, modern evolutionary thinking. Evolution is often a glacial process, but it need not be, as documented in Jonathan Weiner’s exquisite volume, The Beak of the Finch(3), which Palombo refers to in this book and integrates into his ideas.Detailed clinical vignettes support the hypothesis that evolution is occurring in patients undergoing psychoanalytic treatment. Palombo’s writing also documents that he is a brilliant, creative thinker and one of the leading modern theory builders in psychoanalysis.For those interested in the advancement of psychoanalytic theory and understanding, for those desiring to break the intellectually stifling bonds of orthodoxy that have hurt psychoanalysis, for those feeling the need of a strong, intellectual, up-to-date perspective on psychoanalysis as an important science and an increasingly refined and clinically important art, this book is a major contribution. It richly deserves to be read.By Stanley R. Palombo, M.D. Madison, Conn., International Universities Press, 1999, 395 pp., $65.00.

Molecular analysis of behavior by gene transfer into neurons with herpes simplex vectors

One goal of neuroscience is to define the molecular and cellular basis for behavior and neurological diseases. A novel approach to this problem is based on the use of viral vectors to transfect specific genes into specific brain cell populations. This review focuses on herpes simplex-based vectors. Major advances have recently been made to improve the characteristics of these vectors, in particular to reduce their toxicity, to modulate the greatness and the time-course of transgene expression, to precisely target specific cell populations, and to transfer multiple genes. Much remains to be done to obtain robust and prolonged transgene expression. However, specific alterations in the behavior and in disease models have already been described following the herpes simplex vector-mediated expression of specific genes within highly localized brain areas. Therefore, this research strategy is likely to provide new clues on the cellular and molecular basis of behavior and of neurological diseases.