The Role of Leptin in the Development of Energy Homeostatic Systems and the Maintenance of Body Weight

LEP is a pleiotropic gene and the actions of leptin extend well beyond simply acting as the signal of the size of adipose tissue stores originally proposed. This is a discussion of the multi-system interactions of leptin with the development of the neural systems regulating energy stores, and the subsequent maintenance of energy stores throughout the lifespan. The prenatal, perinatal, and later postnatal effects of leptin on systems regulating body energy stores and on the energy stores themselves are heavily influenced by the nutritional environment which leptin exposure occurs. This review discusses the prenatal and perinatal roles of leptin in establishing the neuronal circuitry and other systems relevant to the adiposity set-point (or “threshold”) and the role of leptin in maintaining weight homeostasis in adulthood. Therapeutic manipulation of the intrauterine environment, use of leptin sensitizing agents, and identification of specific cohorts who may be more responsive to leptin or other means of activating the leptin signaling pathway are ripe areas for future research.

Gating of Ion Channels

Excitable cells, such as neurons and muscles, use ion channels to generate electrical and chemical signals that underlie their functions. Examples include the electrical signals underlying the complex neuronal circuitry in the brain, the secretion of hormones and neurotransmitters, skeletal and cardiac muscle contraction, and the signaling events that lead to fertility. Because of their pivotal role in cellular signaling and electrical excitability, a major goal in modern biology has been to determine the physical properties that control and modulate ion channel function. This chapter briefly reviews classical works about the gating of ion channels. Furthermore, it discusses some innovative approaches that when combined with biophysical and mathematical simulations have contributed to the current understanding of channel gating.

The tectonigral pathway regulates appetitive locomotion in predatory hunting in mice

Appetitive locomotion is essential for animals to approach rewards, such as food and prey. The neuronal circuitry controlling appetitive locomotion is unclear. In a goal-directed behavior—predatory hunting, we show an excitatory brain circuit from the superior colliculus (SC) to the substantia nigra pars compacta (SNc) to enhance appetitive locomotion in mice. This tectonigral pathway transmits locomotion-speed signals to dopamine neurons and triggers dopamine release in the dorsal striatum. Synaptic inactivation of this pathway impairs appetitive locomotion but not defensive locomotion. Conversely, activation of this pathway increases the speed and frequency of approach during predatory hunting, an effect that depends on the activities of SNc dopamine neurons. Together, these data reveal that the SC regulates locomotion-speed signals to SNc dopamine neurons to enhance appetitive locomotion in mice.

Sexual Dimorphism in Aggression: Sex-Specific Fighting Strategies Across Species

Aggressive behavior is thought to have evolved as a strategy for gaining access to resources such as territory, food, and potential mates. Across species, secondary sexual characteristics such as competitive aggression and territoriality are considered male-specific behaviors. However, although female–female aggression is often a behavior that is displayed almost exclusively to protect the offspring, multiple examples of female–female competitive aggression have been reported in both invertebrate and vertebrate species. Moreover, cases of intersexual aggression have been observed in a variety of species. Genetically tractable model systems such as mice, zebrafish, and fruit flies have proven extremely valuable for studying the underlying neuronal circuitry and the genetic architecture of aggressive behavior under laboratory conditions. However, most studies lack ethological or ecological perspectives and the behavioral patterns available are limited. The goal of this review is to discuss each of these forms of aggression, male intrasexual aggression, intersexual aggression and female intrasexual aggression in the context of the most common genetic animal models and discuss examples of these behaviors in other species.

Hormonal control of motivational circuitry orchestrates the transition to sexuality in Drosophila

Newborns and hatchlings can perform incredibly sophisticated behaviors, but many animals abstain from sexual activity at the beginning of life. Hormonal changes have long been known to drive both physical and behavioral changes during adolescence, leading to the largely untested assumption that sexuality emerges from organizational changes to neuronal circuitry. We show that the transition to sexuality in male Drosophila is controlled by hormonal changes, but this regulation is functional rather than structural. In very young males, a broadly acting hormone directly inhibits the activity of three courtship-motivating circuit elements, ensuring the complete suppression of sexual motivation and behavior. Blocking or overriding these inhibitory mechanisms evokes immediate and robust sexual behavior from very young and otherwise asexual males. Similarities to mammalian adolescence suggest a general principle in which hormonal changes gate the transition to sexuality not by constructing new circuitry but by permitting activity in otherwise latent motivational circuit elements.

DNA Hypermethylation Induced by L-Methionine Leads to Oligodendroglial and Myelin Deficits and Schizophrenia-Like Behaviors in Adolescent Mice

Increasing evidence has demonstrated that in addition to dysfunction of neuronal circuitry, oligodendroglial dysfunction and/or disruption of white matter integrity are found in the brains of patients with schizophrenia. DNA methylation, a well-established risk factor for schizophrenia, has been demonstrated to cause neuronal dysfunction; however, whether dysregulation of DNA methylation contributes to oligodendroglial/myelin deficits in the pathogenesis of schizophrenia remains unclear. In the present study, by using L-methionine-treated mice, we confirmed that mice with DNA hypermethylation exhibited an anxious phenotype, impaired sociability, and sensorimotor gating deficits. Notably, DNA hypermethylation in oligodendroglial cells led to dysregulation of multiple oligodendroglia-specific transcription factors, which indicated disruption of the transcriptional architecture. Furthermore, DNA hypermethylation caused a reduction of oligodendroglial lineage cells and myelin integrity in the frontal white matter of mice. Taken together, these results indicate that DNA hypermethylation leads to oligodendroglial and/or myelin deficits, which may, at least in part, contribute to schizophrenia-like behaviors in mice. This study provides new insights into the possibility that precise modulation of DNA methylation status in oligodendroglia could be beneficial for the white matter pathology in schizophrenia.

A viral toolbox for conditional and transneuronal gene expression in zebrafish

Zebrafish are an important model in systems neuroscience but a key limitation is the lack of viral tools to interrogate the structure and function of neuronal circuitry. We developed methods for efficient gene transfer and retrograde tracing by herpes simplex viruses (HSV1), for conditional HSV1-mediated gene expression using the Gal4/UAS system, and for transneuronal tracing by rabies viruses. This toolbox creates new opportunities to visualize and manipulate specific sets of neurons through the combination of genetic and viral approaches in zebrafish.

Ghrelin-Mediated Regeneration and Plasticity After Nervous System Injury

The nervous system is highly vulnerable to different factors which may cause injury followed by an acute or chronic neurodegeneration. Injury involves a loss of extracellular matrix integrity, neuronal circuitry disintegration, and impairment of synaptic activity and plasticity. Application of pleiotropic molecules initiating extracellular matrix reorganization and stimulating neuronal plasticity could prevent propagation of the degeneration into the tissue surrounding the injury. To find an omnipotent therapeutic molecule, however, seems to be a fairly ambitious task, given the complex demands of the regenerating nervous system that need to be fulfilled. Among the vast number of candidates examined so far, the neuropeptide and hormone ghrelin holds within a very promising therapeutic potential with its ability to cross the blood-brain barrier, to balance metabolic processes, and to stimulate neurorepair and neuroactivity. Compared with its well-established systemic effects in treatment of metabolism-related disorders, the therapeutic potential of ghrelin on neuroregeneration upon injury has received lesser appreciation though. Here, we discuss emerging concepts of ghrelin as an omnipotent player unleashing developmentally related molecular cues and morphogenic cascades, which could attenuate and/or counteract acute and chronic neurodegeneration.

Neuronal circuits overcome imbalance in excitation and inhibition by adjusting connection numbers

The interplay between excitation and inhibition is crucial for neuronal circuitry in the brain. Inhibitory cell fractions in the neocortex and hippocampus are typically maintained at 15 to 30%, which is assumed to be important for stable dynamics. We have studied systematically the role of precisely controlled excitatory/inhibitory (E/I) cellular ratios on network activity using mice hippocampal cultures. Surprisingly, networks with varying E/I ratios maintain stable bursting dynamics. Interburst intervals remain constant for most ratios, except in the extremes of 0 to 10% and 90 to 100% inhibitory cells. Single-cell recordings and modeling suggest that networks adapt to chronic alterations of E/I compositions by balancing E/I connectivity. Gradual blockade of inhibition substantiates the agreement between the model and experiment and defines its limits. Combining measurements of population and single-cell activity with theoretical modeling, we provide a clearer picture of how E/I balance is preserved and where it fails in living neuronal networks.