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There is only one known portal system in the mammalian brain - that of the pituitary gland, first identified in 1933 by Popa and Fielding. Here we describe a second portal pathway in the mouse linking the capillary vessels of the brain’s clock suprachiasmatic nucleus (SCN) to those of the organum vasculosum of the lamina terminalis (OVLT), a circumventricular organ. The localized blood vessels of portal pathways enable small amounts of important secretions to reach their specialized targets in high concentrations without dilution in the general circulatory system. These brain clock portal vessels point to an entirely new route and targets for secreted SCN signals, and potentially restructures our understanding of brain communication pathways.

 

Zinc is important in neurogenesis, but excessive levels can cause apoptosis and other pathologies leading to cognitive impairments. Mast cells are present in many brain regions including the hippocampus, an area rich in vesicular zinc. Mast cells contain zinc‐rich granules and a well‐developed mechanism for uptake of zinc ions; both features point to the potential for a role in zinc homeostasis. Prior work using the Timm stain supported this hypothesis, as increased labile zinc was detected in the hippocampus of mast cell‐deficient mice compared to wild‐type mice while no differences in total zinc were found between the two genotypes in the whole brain or other tissues. The current report further examines differences in zinc homeostasis between wild‐type and mast cell‐deficient mice by exploring the zinc transporter ZnT3, which transports labile zinc into synaptic vesicles. The first study used immunocytochemistry to localize ZnT3 within the mossy fibre layer of the hippocampus to determine whether there was differential expression of ZnT3 in wild‐type versus mast cell‐deficient mice. The second study used inductively coupled plasma mass spectrometry (ICP‐MS) to determine total zinc content in the whole dentate gyrus of the two genotypes. The immunocytochemical results indicate that there are higher levels of ZnT3 localized to the mossy fibre layer of the dentate gyrus of mast cell‐deficient mice than in wild‐type mice. TheICP‐MSdata reveal no differences in total zinc in dentate gyrus as a whole. The results are consistent with the hypothesis that mast cells participate in zinc homeostasis at the level of synaptic vesicles.

 

Dopamine has been implicated in circadian timing underlying the food entrainable oscillator (FEO) circuitry and overexpression of the dopamine D2 receptor (D2R) in the striatum has been reported to reduce motivation to obtain food rewards in operant tasks. In the present study, we explored both of these mechanisms by examining food anticipatory activity (FAA) in dopamine D2 receptor‐overexpressing (D2R‐OE) mice under various durations of food availability. First, we noted that at baseline, there were no differences between D2R‐OEmice and their littermates in activity level, food intake, and body weight or in circadian activity. Under conditions of very restricted food availability (4 or 6 hr), both genotypes displayedFAA. In contrast, under 8‐hr food availability, control mice showedFAA, but D2R‐OEmice did not. Normalization of D2R by administration of doxycycline, a tetracycline analogue, rescuedFAAunder 8‐hr restricted food. We next tested for circadian regulation ofFAA. When given ad libitum access to food, neither D2R‐OEnor controls were active during the daytime. However, after an interval of food restriction, all mice showed elevated locomotor activity at the time of previous food availability in the day, indicating circadian timing of anticipatory activity. In summary, motivation is reduced in D2R‐OEmice but circadian timing behavior is not affected. We conclude that an increase in striatal D2R reducesFAAby modulating motivation and not by acting on a clock mechanism.

 

A map of central nervous system organization based on vascular networks or angiomes1 provides a layer of organization distinct from familiar neural networks or connectomes. As a well-established example, the capillary networks of the pituitary portal system enable a route for small amounts of neurochemical signals to reach local targets by traveling along specialized pathways, thereby avoiding dilution in the systemic circulation. Anatomical studies provided the first evidence of this vascular pathway in the brain. Specifically, Popa and Fielding identified a portal pathway linking the hypothalamus and the pituitary gland. Their anatomical work was based on hematoxylin and eosin-stained sections of the human brain. They also extensively discussed previous studies of this brain region. Based on the available literature and the appearance of India ink in the hypothalamus after it had been injected into the anterior pituitary, they vigorously argued that the direction of blood flow was from the pituitary gland to the hypothalamus 

Biological systems have a variety of time-keeping mechanisms ranging from molecular clocks within cells to a complex interconnected unit across an entire organism. The suprachiasmatic nucleus, comprising interconnected oscillatory neurons, serves as a master-clock in mammals. The ubiquity of such systems indicates an evolutionary benefit that outweighs the cost of establishing and maintaining them, but little is known about the process of evolutionary development. To begin to address this shortfall, we introduce and analyse a new evolutionary game theoretic framework modelling the behaviour and evolution of systems of coupled oscillators. Each oscillator is characterized by a pair of dynamic behavioural dimensions, a phase and a communication strategy, along which evolution occurs. We measure success of mutations by comparing the benefit of synchronization balanced against the cost of connections between the oscillators. Despite the simple set-up, this model exhibits non-trivial behaviours mimicking several different classical games—the Prisoner’s Dilemma, snowdrift games, coordination games—as the landscape of the oscillators changes over time. Across many situations, we find a surprisingly simple characterization of synchronization through connectivity and communication: if the benefit of synchronization is greater than twice the cost, the system will evolve towards complete communication and phase synchronization. 

Background Steroids are lipid hormones that reach bodily tissues through the systemic circulation, and play a major role in reproduction, metabolism, and homeostasis. All of these functions and steroids themselves are under the regulation of the circadian timing system (CTS) and its cellular/molecular underpinnings. In health, cells throughout the body coordinate their daily activities to optimize responses to signals from the CTS and steroids. Misalignment of responses to these signals produces dysfunction and underlies many pathologies. Questions Addressed To explore relationships between the CTS and circulating steroids, we examine the brain clock located in the suprachiasmatic nucleus (SCN), the daily fluctuations in plasma steroids, the mechanisms producing regularly recurring fluctuations, and the actions of steroids on their receptors within the SCN. The goal is to understand the relationship between temporal control of steroid secretion and how rhythmic changes in steroids impact the SCN, which in turn modulate behavior and physiology. Evidence Surveyed The CTS is a multi-level organization producing recurrent feedback loops that operate on several time scales. We review the evidence showing that the CTS modulates the timing of secretions from the level of the hypothalamus to the steroidogenic gonadal and adrenal glands, and at specific sites within steroidogenic pathways. The SCN determines the timing of steroid hormones that then act on their cognate receptors within the brain clock. In addition, some compartments of the body-wide CTS are impacted by signals derived from food, stress, exercise etc. These in turn act on steroidogenesis to either align or misalign CTS oscillators. Finally this review provides a comprehensive exploration of the broad contribution of steroid receptors in the SCN and how these receptors in turn impact peripheral responses. Conclusion The hypothesis emerging from the recognition of steroid receptors in the SCN is that mutual shaping of responses occurs between the brain clock and fluctuating plasma steroid levels. 

The mammalian suprachiasmatic nucleus (SCN) comprises about 20,000 interconnected oscillatory neurons that create and maintain a robust circadian signal which matches to external light cues. Here, we use an evolutionary game theoretic framework to explore how evolutionary constraints can influence the synchronization of the system under various assumptions on the connection topology, contributing to the understanding of the structure of interneuron connectivity. Our basic model represents the SCN as a network of agents each with two properties—a phase and a flag that determines if it communicates with its neighbors or not. Communication comes at a cost to the agent, but synchronization of phases with its neighbors bears a benefit. Earlier work shows that when we have “all-to-all” connectivity, where every agent potentially communicates with every other agent, there is often a simple trade-off that leads to complete communication and synchronization of the system: the benefit must be greater than twice the cost. This trade-off for all-to-all connectivity gives us a baseline to compare to when looking at other topologies. Using simulations, we compare three plausible topologies to the all-to-all case, finding that convergence to synchronous dynamics occurs in all considered topologies under similar benefit and cost trade-offs. Consequently, sparser, less biologically costly topologies are reasonable evolutionary outcomes for organisms that develop a synchronizable oscillatory network. Our simulations also shed light on constraints imposed by the time scale on which we observe the SCN to arise in mammals. We find two conditions that allow for a synchronizable system to arise in relatively few generations. First, the benefits of connectivity must outweigh the cost of facilitating the connectivity in the network. Second, the game at the core of the model needs to be more cooperative than antagonistic games such as the Prisoner’s Dilemma. These results again imply that evolutionary pressure may have driven the system towards sparser topologies, as they are less costly to create and maintain. Last, our simulations indicate that models based on the mutualism game fare the best in uptake of communication and synchronization compared to more antagonistic games such as the Prisoner’s Dilemma.