Metabolic determinants of Alzheimer’s disease: A focus on thermoregulation

Alzheimer’s disease (AD) is a complex age-related neurodegenerative disease, associated with central and peripheral metabolic anomalies, such as impaired glucose utilization and insulin resistance. These observations led to a considerable interest not only in lifestyle-related interventions, but also in repurposing insulin and other anti-diabetic drugs to prevent or treat dementia. Body temperature is the oldest known metabolic readout and mechanisms underlying its maintenance fail in the elderly, when the incidence of AD rises. This raises the possibility that an age-associated thermoregulatory deficit contributes to energy failure underlying AD pathogenesis. Brown adipose tissue (BAT) plays a central role in thermogenesis and maintenance of body temperature. In recent years, the modulation of BAT activity has been increasingly demonstrated to regulate energy expenditure, insulin sensitivity and glucose utilization, which could also provide benefits for AD. Here, we review the evidence linking thermoregulation, BAT and insulin-related metabolic defects with AD, and we propose mechanisms through which correcting thermoregulatory impairments could slow the progression and delay the onset of AD.     

To cool or not to cool? Intestinal coccidians disrupt the behavioral hypothermia of lizards in response to tick infestation

It is generally accepted that parasites exert negative effects on their hosts and that natural selection favors specific host responses that mitigate this impact. It is also known that some components of the host immune system often co-evolve with parasite antigens resulting in a host-parasite arms race. In addition to immunological components of the anti-parasitic response, host behavioral responses are also important in this arms race and natural selection may favor avoidance strategies that preclude contact with parasites, or shifts in the host’s thermoregulatory strategy to combat active infections (e.g., behavioral fever). Ticks are widespread parasites with direct and indirect costs on their vertebrate hosts. Their saliva provokes hemolysis in the blood of their hosts and can transmit a plethora of tick-borne pathogens. We enquired whether tick infestation by Ixodes pacificus can provoke a thermoregulatory response in Sceloporus occidentalis. For this, we compared the thermoregulatory behavior of tick-infested lizards against tick-infested lizards co-infected with two different species of coccidians (Lankesterella occidentalis and Acroeimeria sceloporis). After this, lizards were kept in individual terraria with a basking spot and fed ad libitum. We found that tick-infested lizards sought cooler temperatures in proportion to their tick load, and this response was independent of the co-infection status by L. occidentalis. This was consistent in April and June (when tick loads were significantly lower) and suggests a conservative strategy to save energy which might have been selected to overcome tick infestations during phenological peaks of this parasite. However, this behavior was not observed in lizards co-infected with A. sceloporis, suggesting that co-infection with this intestinal parasite prompt lizards to be active. Cost of tick infestation was confirmed because housed lizards lost weight at a constant ratio to initial tick load, independently of other infections. The broader implications of these findings are discussed in the context of climate change.     

Intermittent exercise-heat exposures and intense physical activity sustain heat acclimation adaptations

Objectives

To determine if intermittent exercise-heat exposures (IHE) every fifth day sustain heat acclimation (HA) adaptations 25?days after initial HA.

Release of norepinephrine from the rat's hypothalamus perfused with alcohol: Relation to body temperature

The activity of norepinephrine (NE), within the thermosensitive region of the anterior hypothalamic, pre-optic area (AH/POA) of the rat was examined in relation to changes in core temperature produced by ethyl alcohol. Following stereotaxic implantation of push-pull guide tubes, a specific site in the AH/POA, reactive or non-reactive to NE, was labeled with 1.0 μl of [³H]-NE. Alcohol in a concentration of 2.75% or 5.5% was then perfused locally at the same site by push-pull cannulae or administered peripherally in a dose of 2.0 g/kg. In control experiments, artificial CSF was perfused alone. The perfusion of alcohol enhanced or delayed the release of [³H]-NE in AH/POA or failed to alter the efflux of the catecholamine, with the specific response dependent principally on the: (1) anatomical site of hypothalamic perfusion, (2) concentration of alcohol, and (3) interval of perfusion itself. During the perfusion of alcohol within a very circumscribed region in the AH/POA, vasodilatation, as reflected by an increase in skin temperature, and a hypothermia of short latency, occurred. The change in core temperature was usually accompanied by a delay in the efflux of [³H]-NE. After the peripheral administration of 2.0 g/kg alcohol, an alteration in NE efflux from the AH/POA was also induced during the course of a hypothermic response accompanied by vasodilatation. These results suggest that alcohol exerts a direct central effect on nerve cells comprising the thermoregulatory mechanism located within the hypothalamus. Further, the well-known thermolytic effect of alcohol could be mediated in part by noradrenergic synapses within AH/POA, by means of their phasic release of NE.     

Changes in the brain and core temperatures in relation to the various arousal states in rats in the light and dark periods of the day

In rats, brain temperature (T _br) and core temperature (T _c) were recorded in parallel with the sleep-wake activity throughout the 24-h diurnal cycle, consisting of a 12-h light (L) and a 12-h dark (D) period. In order to characterize the temperature changes associated with the arousal states in the L and the D separately, (i) the average temperatures in wakefulness (W), non-rapid eye movement sleep (NREMS) and REM sleep (REMS), and at the transitions between the arousal states were calculated; (ii) the courses of temperatures before and after the transitions (falling asleep, awakening from NREMS or REMS, transition from NREMS to REMS) were determined; (iii) the rates of changes inT _br andT _c were calculated for each state; and (iv) the correlations between the temperatures and the overall length of each arousal state, and betweenT _br andT _c were studied.In both the L and D periods,T _br andT _c decreased at the beginning of NREMS, then levelled off, and increased slightly before awakening. Apart from short arousals which did not affect temperature,T _br andT _c increased in W, peaked 15–20 min after awakening, and declined significantly before the falling asleep. In REMS,T _br increased at a high rate, while a slight increase inT _c was evident in the L only. Correlations between the temperatures and the arousal states were found in both the L and the D. The courses ofT _br andT _c were also correlated.The results support the existence of characteristic changes in body temperature related to the arousal states in the rat.     

Dopamine and thermoregulation: An evaluation with special reference to dopaminergic pathways

The complex role of dopamine (DA) in the diencephalic mechanisms involved in the control of body temperature is reviewed and evaluated. In the context of the monoamine theory of thermoregulation, catecholaminergic synapses in the anterior hypothalamic pre-optic area, are proposed to mediate the pathways in the brain-stem which subserve heat dissipation. Within this theoretical framework, hypothalamic DA is considered to underlie a portion of the functional component of the heat loss system. This deduction is based on pharmacological studies in which both the catecholamine and receptor antagonists have been infused directly into the hypothalamus. In view of the action of DA applied to the substantia nigra and other subcortical structures, the unique anatomical circuitry of the central dopaminergic projections has also been analyzed in terms of specific connections within critical morphological regions related to thermal functions. In particular, the nigro-striatal pathway could be involved in the mediation of one or more of the different aspects of the thermoregulatory system integrating both autonomic and behavioral responses. Finally, an anatomical schema which portrays the suggested mechanisms of DA activity is presented.     

Potentiation of oxotremorine-induced hypothermia by alaproclate in PCA lesioned and non-lesioned rats

Stimulation of muscarinic cholinergic receptors with the highly potent and selective receptor agonist oxotremorine produced hypothermia in rats. Alaproclate, a purported selective serotonergic reuptake inhibitor, potentiated this response. Destruction of central presynaptic serotonergic terminals with the potent cytotoxin p-chloroamphetamine (PCA) failed to attenuate the hypothermic response to oxotremorine in alaproclate-pretreated animals. These results could be taken to suggest that alaproclate may act, at least in part, via a non-serotonergic mechanism to potentiate the oxotremorine-induced hypothermic response.This work was completed when Dr. Dilsaver was on the faculty of the Department of Psychiatry at the University of Michigan     

Venous structures associated with thermoregulation of phocid seal reproductive organs

Backgound: Seal reproductive systems are surrounded by thermogenic muscle and insulating blubber, suggesting elevated temperatures at the gonads and uterus. In the limbs of terrestrial mammals, cooled blood returning from superficial veins is mixed proximally with warm blood returning from deep veins. Thus, mixed cool-superficial and warmdeep venous blood from the hind limbs is returned to the central circulation. Methods: We describe structures observed in salvaged carcasses of harbor (Phoca vitulina), gray (Haliochoerus gryphus), harp (Phoca groendlandica), hooded (Cystophora cristata), and ringed (Phoca hispida) seals. Vessels were identified by dissection of injected and uninjected material. Results: In contrast to terrestrial mammals, phocid seals have anastomoses between the veins of the distal hind limb and the pelvis which allow large volumes of cool blood returning from the skin surface of the flipper to enter the gluteal, pelvic, or pudendo-epigastric veins. This provides a cool-superficial venous return that remains separate from the warm-deep venous return of the femoral veins. The cooled venous blood from the hind flippers supplies venous plexuses lining the inguinal region and the abdominal and pelvic cavities. Conclusions: Cooled blood may prevent hyperthermic insult to seal reproductive systems. © 1995 Wiley-Liss, Inc.     

Activation of the central cholinergic pathway increases post-exercise tail heat loss in rats

The aim of this study was to evaluate the effects of stimulation of the central cholinergic pathway on the regulation of post-exercise tail heat loss in rats. Either 2.0 μL of 25 × 10⁻³ M physostigmine (Phy) or 0.15 M NaCl solution (Sal) were injected into the right lateral cerebral ventricle of both resting (n = 8) and post-exercising rats (n = 6; 24 m min⁻¹; 25 min; 5% inclination). Tail temperature (T_tail) was measured using a thermistor taped to the tail, and intraperitoneal temperature, an index of core temperature (T_c), was recorded using a telemetry sensor implanted into the peritoneal cavity. In resting rats, Phy induced an increase in both T_tail (26.8 ± 0.3 °C Phy versus 25.2 ± 0.6 °C Sal; P < 0.05) and in heat loss index (0.26 ± 0.03 Phy versus 0.14 ± 0.05 Sal; P < 0.05; 30 min after injection), and a decrease in T_c compared to the Sal injection group (36.6 ± 0.2 °C Phy versus 37.0 ± 0.2 °C Sal; P < 0.05). In post-exercising rats, Phy injection attenuated the decrease in both T_tail (28.3 ± 0.8 °C Phy versus 26.4 ± 0.6 °C Sal; P < 0.05) and heat loss index (0.37 ± 0.07 Phy versus 0.19 ± 0.02 Sal; P < 0.05) without altering T_c. We conclude that activation of the central cholinergic pathway increases post-exercise tail heat loss in rats.