All quiet on the neuronal front: NMDA receptor inhibition by prion protein

The normal function of the prion protein (PrP)—the causative agent of mad cow or prion disease—has long remained out of reach. Deciphering PrP's function may help to unravel the complex chain of events triggered by PrP misfolding during prion disease. In this issue of the JCB, an exciting paper (Khosravani, H., Y. Zhang, S. Tsutsui, S. Hameed, C. Altier, J. Hamid, L. Chen, M. Villemaire, Z. Ali, F.R. Jirik, and G.W. Zamponi. 2008. J. Cell Biol. 181:551–565) connects diverse observations regarding PrP into a coherent framework whereby PrP dampens the activity of an N-methyl-D-aspartate (NMDA) receptor (NMDAR) subtype and reduces excitotoxic lesions. The findings of this study suggest that understanding the normal function of proteins associated with neurodegenerative disease may elucidate the molecular pathogenesis

Daily Timed Sexual Interaction Induces Moderate Anticipatory Activity in Mice

Anticipation of resource availability is a vital skill yet it is poorly understood in terms of neuronal circuitry. Rodents display robust anticipatory activity in the several hours preceding timed daily access to food when access is limited to a short temporal duration. We tested whether this anticipatory behavior could be generalized to timed daily social interaction by examining if singly housed male mice could anticipate either a daily novel female or a familiar female. We observed that anticipatory activity was moderate under both conditions, although both a novel female partner and sexual experience are moderate contributing factors to increasing anticipatory activity. In contrast, restricted access to running wheels did not produce any anticipatory activity, suggesting that an increase in activity during the scheduled access time was not sufficient to induce anticipation. To tease apart social versus sexual interaction, we tested the effect of exposing singly housed female mice to a familiar companion female mouse daily. The female mice did not show anticipatory activity for restricted female access, despite a large amount of social interaction, suggesting that daily timed social interaction between mice of the same gender is insufficient to induce anticipatory activity. Our study demonstrates that male mice will show anticipatory activity, albeit inconsistently, for a daily timed sexual encounter

Daily Scheduled High Fat Meals Moderately Entrain Behavioral Anticipatory Activity, Body Temperature, and Hypothalamic c-Fos Activation

When fed in restricted amounts, rodents show robust activity in the hours preceding expected meal delivery. This process, termed food anticipatory activity (FAA), is independent of the light-entrained clock, the suprachiasmatic nucleus, yet beyond this basic observation there is little agreement on the neuronal underpinnings of FAA. One complication in studying FAA using a calorie restriction model is that much of the brain is activated in response to this strong hunger signal. Thus, daily timed access to palatable meals in the presence of continuous access to standard chow has been employed as a model to study FAA in rats. In order to exploit the extensive genetic resources available in the murine system we extended this model to mice, which will anticipate rodent high fat diet but not chocolate or other sweet daily meals (Hsu, Patton, Mistlberger, and Steele; 2010, PLoS ONE e12903). In this study we test additional fatty meals, including peanut butter and cheese, both of which induced modest FAA. Measurement of core body temperature revealed a moderate preprandial increase in temperature in mice fed high fat diet but entrainment due to handling complicated interpretation of these results. Finally, we examined activation patterns of neurons by immunostaining for the immediate early gene c-Fos and observed a modest amount of entrainment of gene expression in the hypothalamus of mice fed a daily fatty palatable meal

Palatable Meal Anticipation in Mice

The ability to sense time and anticipate events is a critical skill in nature. Most efforts to understand the neural and molecular mechanisms of anticipatory behavior in rodents rely on daily restricted food access, which induces a robust increase of locomotor activity in anticipation of daily meal time. Interestingly, rats also show increased activity in anticipation of a daily palatable meal even when they have an ample food supply, suggesting a role for brain reward systems in anticipatory behavior, and providing an alternate model by which to study the neurobiology of anticipation in species, such as mice, that are less well adapted to "stuff and starve" feeding schedules. To extend this model to mice, and exploit molecular genetic resources available for that species, we tested the ability of wild-type mice to anticipate a daily palatable meal. We observed that mice with free access to regular chow and limited access to highly palatable snacks of chocolate or “Fruit Crunchies” avidly consumed the snack but did not show anticipatory locomotor activity as measured by running wheels or video-based behavioral analysis. However, male mice receiving a snack of high fat chow did show increased food bin entry prior to access time and a modest increase in activity in the two hours preceding the scheduled meal. Interestingly, female mice did not show anticipation of a daily high fat meal but did show increased activity at scheduled mealtime when that meal was withdrawn. These results indicate that anticipation of a scheduled food reward in mice is behavior, diet, and gender specific

Heat shock factor 1 regulates lifespan as distinct from disease onset in prion disease

Prion diseases are fatal, transmissible, neurodegenerative diseases caused by the misfolding of the prion protein (PrP). At present, the molecular pathways underlying prion-mediated neurotoxicity are largely unknown. We hypothesized that the transcriptional regulator of the stress response, heat shock factor 1 (HSF1), would play an important role in prion disease. Uninoculated HSF1 knockout (KO) mice used in our study do not show signs of neurodegeneration as assessed by survival, motor performance, or histopathology. When inoculated with Rocky Mountain Laboratory (RML) prions HSF1 KO mice had a dramatically shortened lifespan, succumbing to disease ≈20% faster than controls. Surprisingly, both the onset of home-cage behavioral symptoms and pathological alterations occurred at a similar time in HSF1 KO and control mice. The accumulation of proteinase K (PK)-resistant PrP also occurred with similar kinetics and prion infectivity accrued at an equal or slower rate. Thus, HSF1 provides an important protective function that is specifically manifest after the onset of behavioral symptoms of prion disease

Food Anticipatory Activity on Circadian Time Scales Is Not Dependent on Central Serotonin: Evidence From Tryptophan Hydroxylase-2 and Serotonin Transporter Knockout Mice

A number of studies implicate biogenic amines in regulating circadian rhythms. In particular, dopamine and serotonin influence the entrainment of circadian rhythms to daily food availability. To study circadian entrainment to feeding, food availability is typically restricted to a short period within the light cycle daily. This results in a notable increase in pre-meal activity, termed “food anticipatory activity” (FAA), which typically develops within about 1 week of scheduled feeding. Several studies have implicated serotonin as a negative regulator of FAA: (1) aged rats treated with serotonin 5-HT2 and 3 receptor antagonists showed enhanced FAA, (2) mice lacking for the 2C serotonin receptor demonstrate enhanced FAA, and (3) pharmacologically increased serotonin levels suppressed FAA while decreased serotonin levels enhanced FAA in mice. We sought to confirm and extend these findings using genetic models with impairments in central serotonin production or re-uptake, but were surprised to find that both serotonin transporter (Slc6a4) and tryptophan hydroxylase-2 knockout mice demonstrated a normal behavioral response to timed, calorie restricted feeding. Our data suggest that FAA is largely independent of central serotonin and/or serotonin reuptake and that serotonin may not be a robust negative regulator of FAA

Halite as a Methane Sequestration Host: A Possible Explanation for Periodic Methane Release on Mars, and a Surface-accessible Source of Ancient Martian Carbon

We present the hypothesis that halite may play a role in methane sequestration on the martian surface. In terrestrial examples, halite deposits sequester large volumes of methane and chloromethane. Also, examples of chloromethane-bearing, approximately 4.5 Ga old halite from the Monahans meteorite show that this system is very stable unless the halite is damaged. On Mars, methane may be generated from carbonaceous material trapped in ancient halite deposits and sequestered. The methane may be released by damaging its halite host; either by aqueous alteration, aeolian abrasion, heating, or impact shock. Such a scenario may help to explain the appearance of short-lived releases of methane on the martian surface. The methane may be of either biogenic or abiogenic origin. If this scenario plays a significant role on Mars, then martian halite deposits may contain samples of organic compounds dating to the ancient desiccation of the planet, accessible at the surface for future sample return missions

Food Anticipatory Activity on Circadian Time Scales Is Not Dependent on Central Serotonin: Evidence From Tryptophan Hydroxylase-2 and Serotonin Transporter Knockout Mice

A number of studies implicate biogenic amines in regulating circadian rhythms. In particular, dopamine and serotonin influence the entrainment of circadian rhythms to daily food availability. To study circadian entrainment to feeding, food availability is typically restricted to a short period within the light cycle daily. This results in a notable increase in pre-meal activity, termed “food anticipatory activity” (FAA), which typically develops within about 1 week of scheduled feeding. Several studies have implicated serotonin as a negative regulator of FAA: (1) aged rats treated with serotonin 5-HT2 and 3 receptor antagonists showed enhanced FAA, (2) mice lacking for the 2C serotonin receptor demonstrate enhanced FAA, and (3) pharmacologically increased serotonin levels suppressed FAA while decreased serotonin levels enhanced FAA in mice. We sought to confirm and extend these findings using genetic models with impairments in central serotonin production or re-uptake, but were surprised to find that both serotonin transporter (Slc6a4) and tryptophan hydroxylase-2 knockout mice demonstrated a normal behavioral response to timed, calorie restricted feeding. Our data suggest that FAA is largely independent of central serotonin and/or serotonin reuptake and that serotonin may not be a robust negative regulator of FAA

Cholinergic Modulation of Locomotion and Striatal Dopamine Release Is Mediated by α6α4* Nicotinic Acetylcholine Receptors

Dopamine (DA) release in striatum is governed by firing rates of midbrain DA neurons, striatal cholinergic tone, and nicotinic ACh receptors (nAChRs) on DA presynaptic terminals. DA neurons selectively express α6* nAChRs, which show high ACh and nicotine sensitivity. To help identify nAChR subtypes that control DA transmission, we studied transgenic mice expressing hypersensitive α6^(L9’S*) receptors. α6^(L9’S) mice are hyperactive, travel greater distance, exhibit increased ambulatory behaviors such as walking, turning, and rearing, and show decreased pausing, hanging, drinking, and grooming. These effects were mediated by α6 α4* pentamers, as α6^(L9’S) mice lacking α4 subunits displayed essentially normal behavior. In α6^(L9’S) mice, receptor numbers are normal, but loss of α4 subunits leads to fewer and less sensitive α6* receptors. Gain-of-function nicotine-stimulated DA release from striatal synaptosomes requires α4 subunits, implicating α6α4β2* nAChRs in α6^(L9’S) mouse behaviors. In brain slices, we applied electrochemical measurements to study control of DA release by α6^(L9’S) nAChRs. Burst stimulation of DA fibers elicited increased DA release relative to single action potentials selectively in α6^(L9’S), but not WT or α4KO/ α6^(L9’S), mice. Thus, increased nAChR activity, like decreased activity, leads to enhanced extracellular DA release during phasic firing. Bursts may directly enhance DA release from α6^(L9’S) presynaptic terminals, as there was no difference in striatal DA receptor numbers or DA transporter levels or function in vitro. These results implicate α6α4β2* nAChRs in cholinergic control of DA transmission, and strongly suggest that these receptors are candidate drug targets for disorders involving the DA system