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1. Hypothalamic hormone deficiency enables physiological anorexia in ground squirrels during hibernation

   https://doi.org/10.1038/s41467-024-49996-2  

   Mohr, Sarah M; DaiPra, Rafael; Platt, Maryann P; Feketa, Viktor V; Shanabrough, Marya; Varela, Luis; Kristant, Ashley; Cao, Haoran; Merriman, Dana K; Horvath, Tamas L; et al (July 2024, Nature Communications)

   Mammalian hibernators survive prolonged periods of cold and resource scarcity by temporarily modulating normal physiological functions, but the mechanisms underlying these adaptations are poorly understood. The hibernation cycle of thirteen-lined ground squirrels (Ictidomys tridecemlineatus) lasts for 5–7 months and comprises weeks of hypometabolic, hypothermic torpor interspersed with 24–48-h periods of an active-like interbout arousal (IBA) state. We show that ground squirrels, who endure the entire hibernation season without food, have negligible hunger during IBAs. These squirrels exhibit reversible inhibition of the hypothalamic feeding center, such that hypothalamic arcuate nucleus neurons exhibit reduced sensitivity to the orexigenic and anorexigenic effects of ghrelin and leptin, respectively. However, hypothalamic infusion of thyroid hormone during an IBA is sufficient to rescue hibernation anorexia. Our results reveal that thyroid hormone deficiency underlies hibernation anorexia and demonstrate the functional flexibility of the hypothalamic feeding center. 

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2. Estrogen Receptor Beta Mediates the Dipsogenic Effect of Estradiol in Ovariectomized Female Rats

   https://doi.org/10.1159/000530962  

   Santollo, Jessica; Edwards, Andrea A. (May 2023, Neuroendocrinology)

   Although the fluid inhibitory effects of estradiol are well characterized, a dipsogenic role of the hormone was recently identified. In ovariectomized (OVX) rats, unstimulated water intake, in the absence of food, was increased after estradiol treatment. The goals for these experiments were to further characterize the fluid enhancing effects of estradiol by determining the estrogen receptor subtype mediating the dipsogenic effect, examining saline intake, and testing for a dipsogenic effect of estradiol in male rats. Pharmacological activation of estrogen receptor beta (ERβ) increased water intake, in the absence of food, and was associated with changes in postingestive feedback signals. Surprisingly, activation of ERα reduced water intake even in the absence of food. A follow-up study demonstrated that when food was available, co-activation of ERα and ERβ reduced water intake, but when food was not available water intake was increased. In addition, in OVX rats, estradiol increased saline intake through changes in postingestive and orosensory feedback signals. Finally, although estradiol decreased water intake in male rats with access to food, estradiol had no effect on water intake in the absence of food. These results demonstrate that the dipsogenic effect is mediated by ERβ, the fluid enhancing effects of estradiol generalize to saline, and is limited to females, which implies that a feminized brain is necessary for estradiol to increase water intake. These findings will aid in guiding future studies focused on elucidating the neuronal mechanisms that allow estradiol to both increase and decrease fluid intake. 

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3. Circadian Synchrony: Sleep, Nutrition, and Physical Activity

   Healy, Kelly L.; Morris, Andrew R.; Liu, Andrew C. (October 2021, Frontiers in network physiology)

   The circadian clock in mammals regulates the sleep/wake cycle and many associated behavioral and physiological processes. The cellular clock mechanism involves a transcriptional negative feedback loop that gives rise to circadian rhythms in gene expression with an approximately 24-hour periodicity. To maintain system robustness, clocks throughout the body must be synchronized and their functions coordinated. In mammals, the master clock is located in the suprachiasmatic nucleus (SCN) of the hypothalamus. The SCN is entrained to the light/dark cycle through photic signal transduction and subsequent induction of core clock gene expression. The SCN in turn relays the time-of-day information to clocks in peripheral tissues. While the SCN is highly responsive to photic cues, peripheral clocks are more sensitive to non-photic resetting cues such as nutrients, body temperature, and neuroendocrine hormones. For example, feeding/fasting and physical activity can entrain peripheral clocks through signaling pathways and subsequent regulation of core clock genes and proteins. As such, timing of food intake and physical activity matters. In an ideal world, the sleep/wake and feeding/fasting cycles are synchronized to the light/dark cycle. However, asynchronous environmental cues, such as those experienced by shift workers and frequent travelers, often lead to misalignment between the master and peripheral clocks. Emerging evidence suggests that the resulting circadian disruption is associated with various diseases and chronic conditions that further circadian desynchrony and accelerate disease progression. In this review, we discuss how sleep, nutrition, and physical activity synchronize circadian clocks and how chronomedicine may offer novel strategies for disease intervention. 

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4. Viral rescue of magnocellular vasopressin cells in adolescent Brattleboro rats ameliorates diabetes insipidus, but not the hypoaroused phenotype

   https://doi.org/10.1038/s41598-019-44776-1  

   Schatz, K. C.; Brown, L. M.; Barrett, A. R.; Roth, L. C.; Grinevich, V.; Paul, M. J. (June 2019, Scientific Reports)

   Abstract Dysregulated arousal often accompanies neurodevelopmental disorders such as attention deficit hyperactivity disorder and autism spectrum disorder. Recently, we have found that adolescent homozygous Brattleboro (Hom) rats, which contain a mutation in the arginine vasopressin (AVP) gene, exhibit lower behavioral arousal than their heterozygous (Het) littermates in the open field test. This hypoaroused phenotype could be due to loss of AVP in magnocellular cells that supply AVP to the peripheral circulation and project to limbic structures or parvocellular cells that regulate the stress axis and other central targets. Alternatively, hypoarousal could be a side effect of diabetes insipidus – polydipsia and polyuria seen in Hom rats due to loss of AVP facilitation of water reabsorption in the kidney. We developed a viral-rescue approach to “cure” magnocellular AVP cells of their Brattleboro mutation. Infusion of a recombinant adeno-associated virus (rAAV) containing a functionalAvpgene and promoter (rAAV-AVP) rescued AVP within magnocellular cells and fiber projections of the paraventricular nucleus of the hypothalamus (PVN) of male and female adolescent Hom rats. Furthermore, water intake was markedly reduced, ameliorating the symptoms of diabetes insipidus. In contrast, open field activity was unaffected. These findings indicate that the hyporaoused phenotype of adolescent Hom rats is not due to the loss of AVP function in magnocellular cells or a side effect of diabetes insipidus, but favors the hypothesis that central, parvocellular AVP mechanisms underlie the regulation of arousal during adolescence. 

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5. Mild hypoxia exposure impacts peripheral serotonin uptake and degradation in Gulf toadfish ( Opsanus beta )

   https://doi.org/10.1242/jeb.244064  

   Sebastiani, John; Sabatelli, Allyson; McDonald, M. Danielle (July 2022, Journal of Experimental Biology)

   ABSTRACT Plasma serotonin (5-hydroxytryptamine, 5-HT) homeostasis is maintained through the combined processes of uptake (via the 5-HT transporter SERT, and others), degradation (via monoamine oxidase, MAO) and excretion. Previous studies have shown that inhibiting SERT, which would inhibit 5-HT uptake and degradation, attenuates parts of the cardiovascular hypoxia reflex in gulf toadfish (Opsanus beta), suggesting that these 5-HT clearance processes may be important during hypoxia exposure. Therefore, the goal of this experiment was to determine the effects of mild hypoxia on 5-HT uptake and degradation in the peripheral tissues of toadfish. We hypothesized that 5-HT uptake and degradation would be upregulated during hypoxia, resulting in lower plasma 5-HT, with uptake occurring in the gill, heart, liver and kidney. Fish were exposed to normoxia (97.6% O2 saturation, 155.6 Torr) or 2 min, 40 min or 24 h mild hypoxia (50% O2 saturation, ∼80 Torr), then injected with radiolabeled [3H]5-HT before blood, urine, bile and tissues were sampled. Plasma 5-HT levels were reduced by 40% after 40 min of hypoxia exposure and persisted through 24 h. 5-HT uptake by the gill was upregulated following 2 min of hypoxia exposure, and degradation in the gill was upregulated at 40 min and 24 h. Interestingly, there was no change in 5-HT uptake by the heart and degradation in the heart decreased by 58% within 2 min of hypoxia exposure and by 85% at 24 h. These results suggest that 5-HT clearance is upregulated during hypoxia and is likely driven, in part, by mechanisms within the gill and not the heart. 

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