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Neuroscience Letters

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The neuroscience of adaptive thermoregulation

Michael J. Angilletta Jr.a,⁎, Jacob P. Youngblooda, Lauren K. Neela, John M. VandenBrooksb

a School of Life Sciences, Arizona State University, Tempe, AZ 85287, USAbDepartment of Physiology, Midwestern University, Glendale, AZ 85308, USA

A R T I C L E I N F O

Keywords:AmygdalaHypothalamusPlasticityPre-optic areaSet-point temperature

A B S T R A C T

The nervous system acts as a biological thermostat by controlling behaviors that regulate the warming andcooling of animals. We review the structures responsible for thermoregulation in three model species: round-worms (Caenorhabditis elegans), flies (Drosophila melanogaster), and rats (Rattus novegicus). We then consideradditional features of the nervous system required to explain adaptive plasticity of the set-point temperature andthe precision of thermoregulation. Because animals use resources such as energy, water, and oxygen to ther-moregulate, the nervous system monitors the abundance of these resources and adjusts the strategy of ther-moregulation accordingly. Starvation, dehydration, or hypoxemia alter the activity of temperature-sensitiveneurons in the pre-optic area of the hypothalamus. Other regions of the brain work in conjunction with thehypothalamus to promote adaptive plasticity of thermoregulation. For example, the amygdala likely inhibitsneurons of the pre-optic area, overriding thermoregulation when a risk of predation or a threat of aggressionexists. Moreover, the hippocampus enables an animal to remember microhabitats that enable safe and effectivethermoregulation. In ectothermic animals, such as C. elegans and D. melanogaster, the nervous system can alterset-point temperatures as the environmental temperatures change. To build on this knowledge, neuroscientistscan use experimental evolution to study adaptation of neural phenotypes in controlled thermal environments. Amicroevolutionary perspective would leverage our understanding of ecological processes to predict the originand maintenance of neural phenotypes by natural selection.

1. Introduction

Bathing in radiation from a clear sky and hot sand, a shovel-nosedlizard rhythmically shifts from side to side, balancing on two limbs at atime. Convection causes its airborne limbs to cool sufficiently before itsother limbs conduct too much heat from the ground. When performedcarefully, this dance extends the lizard’s time on the surface, searchingfor food. No one who has witnessed this event can question the role ofbehavior in thermoregulation. Neuroscientists seek to explain how thenervous system orchestrates behaviors such as the dance of a shovel-nosed lizard. As evolutionary ecologists, however, we want to knowhow the design of the nervous system affects the fitness of an animal inits natural environment. Yet, surprisingly little information exists aboutthe neural control of thermoregulation beyond a few model organisms.Moreover, current models of neural control leave us unable to explainsome common thermoregulatory behaviors. In other words, we know alot about why animals thermoregulate but not nearly as much abouthow their nervous systems control this behavior. Undoubtedly, this si-tuation reflects the challenges of teasing apart intricate systems withlimited resources. And we realize that more resources will always be

channeled toward research on the fevers of humans than the dances oflizards. Nonetheless, the situation might also reflect an oversight on thepart of neuroscience, which has been criticized for lacking an evolu-tionary perspective. In the words of Mitra [114], “Darwin’s theory ofnatural selection, arguably the most important theoretical framework inbiology, is prominent by its absence in modern neuroscience.”

In this review, we offer ecological and evolutionary perspectives onthermoregulation that raise new questions about its neural control. Byno means do we intend to masquerade as neuroscientists. Rather, welean heavily on previous reviews of neural mechanisms in model or-ganisms to summarize the basic model of a biological thermostat[21,71,121]. This model captures the indirect effects of afferent neu-rons on physiological and behavioral processes, which feed back ne-gatively to regulate body temperature. We then focus on patterns ofthermoregulation that fall outside the purview of a simple thermostat:1) shifting the set-point temperature according to supplies of food,water, and oxygen (dialing the thermostat up or down); 2) inhibitingthermoregulation when the cost exceeds the benefit (turning the ther-mostat off); and 3) choosing the most efficient behavioral or physio-logical response in the environmental context (deciding which system

https://doi.org/10.1016/j.neulet.2018.10.046Received 4 September 2018; Received in revised form 17 October 2018; Accepted 21 October 2018

⁎ Corresponding author.E-mail address: ma@asu.edu (M.J. Angilletta).

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Available online 25 October 20180304-3940/ © 2018 Elsevier B.V. All rights reserved.

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of heating or cooling to activate). We then briefly explore how thenervous system coordinates changes in thermal tolerance and the set-point temperature. Finally, we outline the steps needed to develop amicroevolutionary perspective on neurobiology with the hope thatmore neuroscientists will conduct evolutionary experiments with modelorganisms. To make this review accessible to a broad audience, weaimed to provide a conceptual synthesis rather than a detailed de-scription of mechanisms. Further elaboration of mechanisms can befound in the references provided.

Throughout this review, we emphasize the role of phenotypicplasticity in thermoregulation. Phenotypic plasticity refers to variationin the phenotype caused by variation in the environment experiencedby a genotype [149,173,177]. Plasticity occurs at all levels of thephenotype, including changes in cells, tissues, and organs [133]. Thus,the plasticity of an organismal phenotype (e.g., the body temperature ofan animal) could involve plasticity of a cellular phenotype (e.g., thelong-term potentiation of a neuron). We discuss how the plasticity ofneural phenotypes influences the behavior and physiology of thermo-regulation. Such plasticity can occur either once during development orrepeatedly throughout life [133]. Although many forms of neuralplasticity are reversible, we caution that sometimes insufficient dataexist to infer the flexibility of a phenotype over the life of an organism[4].

2. The biological thermostat: a basic model of thermoregulation

Thermoregulation involves sensory input in the central or periph-eral nervous system, integration by the brain or spinal cord, and motoroutput that causes negative feedback through heating or cooling[113,121,124,142,153]. Yet, the complexity of structures responsiblefor these functions differs among groups of animals.

Consider the afferent pathways for thermoregulation in three spe-cies of model organisms, illustrated in Fig. 1: roundworms (Cae-norhabditis elegans), flies (Drosophila melanogaster), and rats (Rattus no-vegicus). The microscopic roundworm has the simplest system, in whicha pair of peripheral neurons in the bilateral amphids (AFD neurons)sense a change in temperature and synapse directly with interneuronsthat initiate a behavioral response [71,100,116,119,127]. In flies,thermosensing occurs through transient receptor potential channels andgustatory receptors in the antennae, which communicate with glo-meruli in the posterior antennal lobe of the brain [65,77,126,155,165].These neurons synapse with others in the calyx of the mushroom bodyand the edge of the lateral horn, where a subset of axons extendsventrally and terminates in the posterior lateral protocerebrum [59].Finally, rats have an even more complex pathway for neural control.These animals use transient receptor potential channels in the skin andabdomen to send information to neurons in the dorsal horn of the spinalcord [109,121,176]. The dorsal horn communicates through neuronsthat terminate in the lateral parabrachial nucleus of the pons [120].Finally, neurons of the pons synapse with others in the preoptic area,anterior hypothalamus, and the dorsomedial hypothalamus[50,148,185]. By integrating information at multiple sites in the brain,larger animals can respond more precisely to warming or coolingthroughout the body.

The complexity of each species’ sensory processes is mirrored intheir motor output. Tiny animals such as C. elegans and D. melanogasterheat and cool so fast that they must switch microclimates to thermo-regulate [162]. Consequently, roundworms rely on turning and trackingto locate microclimates that offer preferred temperatures [71,100].Flies behave similarly but have the advantage of flight, which enablesthem to rapidly escape stressful temperatures [181,182]. Additionally,these insects can open spiracles and increase ventilation to evapora-tively cool [42], but this strategy must be a last resort given the dearthof discretionary water in such a tiny animal. Larger animals, such asrats, heat or cool heterogeneously and slowly. These animals effectivelyregulate heat flux by adjusting posture, circulation, conductance,

evaporation, and metabolism; moreover, these responses occur in asequence that confers the greatest thermoregulatory benefit for the leastenergetic cost [162]. When thermal receptors in the skin detect cooling,rats increase blood flow to the core as a feed-forward mechanism toslow cooling [142]. Subsequent cooling causes piloerector muscles tocontract, reducing heat loss by conduction through fur. Only whenthese mechanisms fail to counteract cooling does non-shivering orshivering thermogenesis kick in. Similarly, warming leads to a species-specific sequence of responses, which may include vasodilation,sweating, and panting. The pre-optic area of the hypothalamus controlthese thermoregulatory behaviors in amphibians, reptiles, and birds, aswell as mammals [10,19,22].

Given the remarkable diversity of animals on Earth, insights from afew species create an illusion of generality worth challenging [76]. Ratsdiffer from flies and worms in more ways than size. For instance, ratsare endothermic whereas flies, worms, and most other animals are ec-tothermic. Ectothermic animals thermoregulate without the benefit (orcost) of thermogenesis. Instead, these animals must choose micro-climates and adopt postures that confer the heat flux needed to main-tain a suitable core temperature. Because temperatures can vary over

Fig. 1. The neural pathways responsible for thermoregulation in three species:Caenorhabditis elegans (top), Drosophila melanogaster (middle), and Rattus nor-vegicus (bottom). Boxes represent anatomical regions within the peripheral orcentral nervous system. Circles and lines represent neurons that communicateinformation between regions. Red and blue neurons are warm-sensitive andcold-sensitive, respectively. See text for a detailed description of each system.Image of D. melanogaster created by B. Nuhanen.

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the surface of a large ectotherm, the brain registers which parts of thebody are warming or cooling most rapidly and adjusts posture ac-cordingly. What better way to appreciate the elegance of this processthan by watching a shovel-nosed lizard dance in the desert? Unlessneuroscience expands its focus to other species, we will never knowhow brains coordinate these complex behaviors. Still, our knowledge ofthe biological thermostat in model organisms provides enough foun-dation to think about the neural control of adaptive thermoregulation.

Neuroscientists and ecologists share an interest in the set-pointtemperature of the biological thermostat, or the temperature that theanimal attempts to maintain. Deviation from this temperature triggersthe nervous system to activate processes that limit or reverse heat fluxbetween the animal and its environment. Ideally, neuroscientists wouldmeasure the set point of a brain directly, but ecologists often infer setpoints from the range of body temperatures selected in laboratory ex-periments [21]. When designed properly, a thermal gradient in thelaboratory enables an animal to choose any temperature with little orno cost [4]. The statistical distribution of body temperatures selected ina thermal gradient reflect behavioral set points. Even when this dis-tribution has a clear mode, an animal frequently permits its tempera-ture to rise above or below this mode. Such behaviors led researchers topropose that ectotherms have two neural set points for thermoregula-tion (upper and lower), which determine the range of body tempera-tures [15]. Indeed, animals possess warm-sensitive neurons and cold-sensitive neurons that initiate behavioral responses at each extreme[74]. If behavioral set points in a thermal gradient reflect neural setpoints, we can infer a change in neural control from a change in thebody temperatures selected by an animal. Similarly, we can infer var-iation in neural control among populations or species when comparingtheir behaviors in thermal gradients. Such experiments provide awealth of data with which we can generate hypotheses about theplasticity and evolution of neural control.

3. Expanding the thermostat model to explain adaptive plasticity

Although a biological thermostat captures the essential elements ofthermoregulation, this model cannot account for changes in bodytemperature predicted by evolutionary theory [6,16,90,151]. Each or-ganism must have a certain body temperature to maximize its rate ofsurvival and reproduction [88]. At the same time, thermoregulationrequires time, energy, and risk—costs that offset the benefits. As a costof thermoregulation increases, an animal should shift its set point(s) toreduce this cost and thus maximize the net benefit [4,6]. Under few, ifany, circumstances should we expect the thermostat to remain static.Indeed, anyone who owns a home knows that adjusting the mechanicalthermostat will save money. Not surprisingly, natural selection grantedother animals the same thrifty behavior. Under extreme conditions,animals even turn off the thermostat entirely [36,180]. To captureadaptive changes in body temperature, we must expand the model of abiological thermostat by adding neural plasticity, in which experiencealters activity of temperature-sensitive neurons [132].

To start, we must convert the set-point temperature from a para-meter to a variable, which depends on physiological or environmentalfactors. This type of model has successfully explained the causes offever in rats [121,125]. Prior to fever, bacterial cells and immune cellsrelease pyrogens, which are chaperoned across the blood-brain barrierto reach hypothalamic neurons [41] or bind directly to receptors in themidline of the preoptic area [148]. Pyrogens in the blood also triggerthe release of secondary pyrogens by endothelial cells of the blood-brain barrier [41]. Binding pyrogens in the preoptic area influences thefeed-forward system starting in the skin and feedback system starting inthe central nervous system [41]. In the preoptic area, pyrogens reducethe frequency of action potentials in warm-activated neurons [25,132],preventing these neurons from activating effectors for heat loss. As a neteffect, metabolic heating continues until the hypothalamus reaches ahigher set-point temperature.

Similarly, animals alter their set-point temperatures when facedwith either high energetic demand [26,90,130,152] or low energysupply [27,86,108,130]. For example, small mammals and birds canenter torpor on a daily or seasonal basis in response to declining energysupply or environmental temperature [38]. During torpor, both the set-point temperature and the metabolic rate of the animal drop, loweringthe energetic cost of thermoregulation. By supplementing heat or food,researchers caused mammals to forego torpor or reduce its duration andintensity [62,78,99]. In rodents, both leptin and triiodothyronine (T3)trigger the hypothalamus to initiate torpor as energy supply declines[13]. Researchers induced torpor by blocking leptin receptors [37] ormanipulating the concentration of T3 [14,44]. These hormones altergene expression in anorexigenic and orexigenic centers of the hy-pothalamus [44], which presumably transmit information to warm-sensitive and cold-sensitive neurons of the hypothalamus [46]. Theregulation of genes that stimulate appetite differs between seasonaltorpor and daily torpor. Seasonal torpor, induced by fasting, causesdownregulation of orexigenic genes [44], suggesting that animals enterseasonal torpor from a state of negative energy balance. However, dailytorpor does not involve a downregulation of these genes.

Both daily and seasonal torpor involve a reduction in the set-pointtemperature and the sensitivity of the set point [163]. During torpor,the hypothalamus must respond differently to sensory input, similar tohow heat acclimation lowers the threshold for sweating [8]. Severalresearchers have suggested that the hippocampus, the medial septalnucleus, and the diagonal band of Broca influence hibernation[52,81,128]. As animals enter torpor, the pre-optic area must cool tosuccessively lower temperatures before shivering occurs [82], fa-cilitated by a transient lowering of the set-point temperature. However,the overarching control of these systems has yet to be determined [52].Because the physiological state of the animal determines the depth andduration of torpor in a given environment, the brain likely exhibitsplasticity to ensure that metabolic rate and body temperature dropwhen the cost of thermogenesis outweighs the benefit.

Ectothermic animals also tune their set-point temperature to theirenergetic state but for a different reason. Digestion and growth dependon an animal’s temperature. After feeding, an animal grows fastest at arelatively high temperature. Conversely, a starving animal can reduceits loss of mass by keeping a lower temperature. Thus, the optimaltemperature for growth increases with an increase in food consumption[54,86]. To take advantage of this effect, many animals raise theirtemperature after feeding and drop it after fasting. For example, locustsadjust their set-point temperature between 32 and 38 °C depending onthe need for digestion. Feeding causes body temperature to rise and fallwithin 90min. The peak temperature of a locust during digestion in-creases linearly with the amount of food ingested (Fig. 2). Given whatwe know about the mammalian nervous system, we presume that theset point changes because of information conveyed by afferent neuronsin the digestive system, which detect either stretching of the stomach ornutrients in the intestine [91,113,144,170,179].

Fig. 2. The mean body temperature of locusts in a thermal gradient dependedon the amount of food ingested within the previous 24 h. Heat contours depictthe relative frequency of locusts at each body temperature. The wavy white linedenotes the range of food intake in which preferred temperature varied.Adapted from [39].

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Dehydration also alters the set points of endotherms and ectothermsin opposite but predictable directions [21]. When dehydrated, en-dotherms raise the set point to reduce the water needed for evaporativecooling [32,112]; however, ectotherms lower their set point to pas-sively minimize evaporative water loss [3,95]. Experimentally raisingthe tonicity or decreasing the volume of plasma in mammals also raisesthe threshold temperature for sweating [109]. Ablation of lamina ter-minalis eliminated this plastic response to dehydration [178]. Theplasticity of the set-point temperature for these responses likely in-volves the preoptic area of the hypothalamus, which contains neuronsthat sense osmolarity as well as temperature [110]. In rats, a localchange in osmolarity in the hypothalamus alters the activity of ther-mosensitive neurons, but not that of other neurons [109]. Although themechanism linking these neurons remains unclear, McKinley and col-leagues speculated that neurons of the median preoptic nucleus inhibitthe activity of thermosensitive neurons in the pre-optic area of thehypothalamus [109].

Oxygen supply limits performance at high temperatures, becausewarmer animals require more oxygen to sustain aerobic metabolism[66,136,172]. For this reason, ectothermic animals select lower tem-peratures when exposed to severe hypoxia [20,28,31,80,85,98]. Astudy of rats suggests that endothermic animals do the same [30]. Whenchallenged with hypoxia, rats reduced their body temperature from37.5 to 35.7 °C within a day. Faced with the combined stress of hypoxiaand cold, rats cooled to 34.1 °C in the same period. Importantly, ratsmaintained a body temperature of 37.3 °C when exposed to coldwithout hypoxia; therefore, rats would have paid the cost of thermo-regulating in the cold if the oxygen supply were sufficient for thermo-genesis. After several days of hypoxia, rats return to a set-point tem-perature closer to their normal one [30], suggesting that acclimation oforgans that deliver or consume oxygen compensates for the poorsupply.

Although hypoxemia generally reduces the set-point temperature ofan animal, our knowledge of the neural mechanisms appears limited torats. The thermoregulatory response to hypoxemia involves sensoryneurons that respond to the deficit of circulating oxygen [160,164].Neurons in the pre-optic area release adenosine, serotonin, dopamine,and nitric oxide, which cause other neurons of the pre-optic area toelevate cAMP and cGMP, which enhance the propensity for action po-tentials in warm-sensitive neurons during excitation and thus lowersthe set-point temperature. [21,160,161]. Presumably, these in-tracellular signals lower the set point by triggering changes that en-hance the activity of warm-sensitive neurons. At the same time, thebrain may release carbon monoxide to counter this response, pre-venting the set point from dropping low enough to cause prolongeddamage [21]. As acclimation to hypoxia reduces the intensity of hy-poxemia, the falling concentration of chemical messengers in the pre-optic neurons would reverse the plasticity of hypothalamic neurons andraise the set-point temperature. Along with responses to food andwater, these responses to oxygen supply demonstrate that adaptivethermoregulation depends on neural plasticity.

4. Fear overrides thermoregulation

Although changing the set point will reduce the cost of thermo-regulation, an animal should abandon thermoregulation entirely whenthe cost becomes extreme [90]. The greatest cost of thermoregulationoccurs when behaviors such as basking or shuttling attract the attentionof a predator or the aggression of a competitor. For ectotherms, whichrely primarily on movement between microclimates to regulate bodytemperature, one easily notices the switch between behaviors thatregulate heat flux and behaviors that reduce risk. For example, larvalnewts spent less time in warm patches when dragonfly nymphs werepresent [75]. Similarly, grasshoppers in the wild shifted their baskingsites when predators were excluded [134]. Even artificial cues of pre-dation risk can temporarily eliminate thermoregulatory behavior. For

example, lizards avoided preferred microclimates when these sites weremarked with the scent of a predatory snake, but not when marked witha control substance [51,83]. In another experiment, lizards thermo-regulated precisely except when a physical model of a hawk was flownoverhead [145]. This tradeoff between vigilance and thermoregulationoccurs in endotherms as well as ectotherms. For instance, small birdsavoided basking in sunlight and abandoned heat-conserving postureswhen vulnerable to predators [33,34]. As with predation risk, aggres-sion between members of the same species can also suppress thermo-regulatory behavior [17,51,146]. When an animal switch from ther-moregulation to vigilance, its temperature comes to an equilibriumdetermined by its current microclimate [12]. The loss of benefits nor-mally conferred by thermoregulation can have a long-term impact onperformance. For instance, lizards in risky environments grew moreslowly compared to lizards in a safe environments, by avoiding theexposed microhabitats needed to thermoregulate effectively [51].

To explain the switch between thermoregulation and vigilance, wemust further expand our model of a biological thermostat to include aneural pathway that inhibits hypothalamic neurons or overrides theireffects on behavior (Fig. 3). At the moment, we can only infer such amodel from studies of fear in rats. When exposed to cat odor, a ratmonitors its environment by extending its head from a safe location[48]. At the same time, vasoconstriction reduces blood flow to the limbsand non-shivering thermogenesis raises the temperature of the dorsalsurface [174]. Aggression from a competing rat also causes warming bynon-shivering thermogenesis [115]. These behaviors, although uniqueto rats, rely on connections among the thalamus, amygdala, and hy-pothalamus that might reflect a more general model of fear [131]. Theneural control of fear begins when the amygdala receives informationabout the environment from the thalamus. Neurons in the medialamygdala communicate with an integrated circuit in the hypothalamus,including neurons of the dorsomedial hypothalamus [48]. This regionof the hypothalamus also contains neurons that trigger non-shiveringthermogenesis and cutaneous vasoconstriction [50]. Although eachspecies responds differently to fear, experiments with rats and othermammals have established a connection between the amygdala and thehypothalamus [159], which might inhibit thermoregulatory behaviorsin vertebrates with homologous structures [118].

A model of inhibition by fear must also account for the manner inwhich vigilance subsides and thermoregulation resumes. A threat ofpredation usually causes an animal to seek refuge for some period. For

Fig. 3. When threatened by predation, sensory input comes to the thalamus,which contains neurons that activate a center responsible for fear in theamygdala. Boxes represent anatomical regions within the peripheral or centralnervous system. Circles and lines represent neurons that communicate in-formation between regions. Red and blue neurons are warm-sensitive and cold-sensitive, respectively. In rats, the amygdala communicate with neurons in thepre-optic area of the hypothalamus, including those responsible for thermo-regulation. We hypothesize that fear causes neurons in the amygdala (shown inpurple) to inhibit the function of temperature-sensitive neurons in the pre-opticarea.

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ectotherms, time spent in a refuge usually means cooling below theoptimal temperature for physiological performance. The time spent in aburrow depends on the temperature of the burrow (the cost of cooling)and the intensity of the threat (the benefit of hiding). In one experi-ment, a researcher approached tortoises to simulate a threat of preda-tion; all tortoises took refuge in a burrow, but cooler burrows causedtortoises to emerge earlier [137]. This observation suggests a model inwhich inhibition from the amygdala prevent thermoregulation until thethermoreceptors in the hypothalamus reach a certain level of activity.All else being equal, the hypothalamus will reach this level of activitysooner in a colder refuge. However, this model cannot account for otherpatterns of vigilance. For instance, when lizards were chased by amechanical predator, they extended the duration of hiding with eachsuccessive attack [135]. Because lizards entered the refuge at a lowerbody temperature each time, one might expect them to spend less timein the refuge before the hypothalamus reactivates thermoregulatorybehaviors. Instead, lizards spent more time hiding with each successiveattack (Fig. 4). This phenomenon requires stronger inhibition of ther-moregulation with each attack. Similarly, lizards living in a risky en-vironment fled sooner and hid longer than did lizards living in a safeenvironment [47], suggesting the intensity of fear depends on experi-ence.

Again, we can look to studies of rodents for ideas about how thebrain modulates the fear that overrides thermoregulation. Researcherstaught rats to associate fear of cat odor or electric shock with otherelements of their environment [158]. Subsequent exposure to asso-ciated cues causes the anterior pituitary to release adrenocorticotropichormone, which ultimately elevates cortisol in the plasma [122]. Thisconditioning involves plasticity of neurons in the amygdala, which re-ceive signals from the hippocampus [8,131]. NMDA receptors andvoltage-gated channels permit more calcium to enter these neurons,triggering intracellular signals, including protein kinases [131]. Thesesignals alter gene expression in the neurons of the amygdala, resultingin long-term potentiation [147]. In this way, an animal can learn todiscriminate a mild threat from a severe one.

5. Efferent mechanisms depend on the environmental context

When an animal desires to warm or cool, certain behaviors yieldbetter results than others. Consider an experiment in which lizards weregiven the option of standing on a hot surface or basking under a brightlight [18]. The researchers rigged the experiment such that lizards

would warm to an equilibrium of 38 °C in either half of the arena;however, lizards would warm about 50% faster by absorbing radiationfrom the light than by conducting heat from the rock. Prior to the ex-periment, lizards were given a chance to explore the arena and discoverthe potential for thermoregulation. During the experiment, lizardschose to bask under the light 57% of the time, which did not differsignificantly from 50%. Next, the researchers raised the equilibrialtemperature on both sides of the arena to 50 °C. Under this lethalcondition, a lizard standing on the hot surface would warm nearly threetimes as fast as a lizard basking under the light. Remarkably, lizardsknew to prefer the side conferring slower warming, moving to the lightabout 66% of the time. Thus, a lizard assessed its surroundings andinitiated the more effective of two thermoregulatory behaviors. Thisbehavior likely relied on the TRPA1 channels, which sense the rate ofwarming in lizards and other animals [2,99]. This sensory informationcould have directly triggered the behavior during the experiment orindirectly conditioned this behavior when lizards explored the arenabefore the experiment.

Endotherms can also differentiate between mechanisms of thermo-regulation that confer greater or lesser benefits in the present context.As with ectotherms, this conclusion comes from studies of behavior inthermal arenas. In one study, rats could enter a reward zone in thearena to trigger a blast of warm or cold air; without this behavior, thetemperature inside the arena remained outside the thermoneutral zone[35]. Rats quickly learned to trigger a comforting blast of air by en-tering the reward zone. When the background air was cold and foodwas absent, the cost of metabolic warming was greater than the cost ofseeking the reward zone. As expected, rats regularly entered the rewardzone to release warm air under these conditions [184]. However, whenthe background air was warm or food was present, rats relied primarilyon non-shivering thermogenesis instead of shuttling behavior. Thesedistinct thermoregulatory strategies indicate that rats learned to as-sociate the reward zone with a certain heat flux and behaved accordingto their body temperature and nutritional state.

Animals might learn to associate certain thermoregulatory beha-viors with environmental cues in a similar way that they learn to as-sociate fear (see Section 5). Researchers have conditioned rats to as-sociate the fear of an electric shock with a visual or auditory cue [8,11].After conditioning, the cue alone would elicit the freezing behavior andnon-shivering thermogenesis normally triggered by fear. Lesioning ei-ther the amygdala or the hippocampus prevented rats from learning tofreeze when threatened [8]. In particular, manipulations of the centralnucleus of the amygdala impair context-dependent learning of fear.However, Maren cautioned that other parts of the brain can generatecontext-dependent behavior in the absence of hippocampus andamygdala, although the stimulus for conditioning might need to beexaggerated [104]. He presented a model in which the cortex inducesfear in conditioned animals exposed to a related but novel stimulus(e.g., odor of fox instead of a cat). In a similar way, we imagine thatmany animals use visual cues to associate regions of their environmentwith the microclimates needed to thermoregulate. Through long-termpotentiation by the hippocampus, a rat can associate a place within acold arena with a refreshing blast of warm air [101,105]. Likewise, ahomologue of the hippocampus enables non-mammalian vertebrates,such as reptiles, to remember their environment and navigate adap-tively [123].

6. Animals should coordinate changes in thermal tolerance andthermoregulatory behavior

To remain adaptive, set-point temperatures must correspond to thethermal tolerance of a species [74]. Most endothermic species regulatetheir body temperature within a degree or two [6]. However, mostectothermic species permit their temperature to vary over a range, oftenreferred to as the range of preferred temperatures [46,84]. Based onthis pattern, Barber and Crawford [15] proposed that ectotherms use

Fig. 4. When threatened repeatedly, lizards hid for a longer duration with eachsuccessive attack. This pattern was observed in two treatments, which imposeddifferent energetic costs of hiding. The cost of hiding was manipulated bychanging the temperature of the refuge; a colder refuge imposed a higher en-ergetic cost. Redrawn from [135].

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upper and lower set points to respond to heating and cooling, respec-tively. A system based on double set points enables the range of pre-ferred temperatures to evolve according to the thermal limits of aspecies. Generalists, which tolerate a wide range of temperatures,should have wider set points and hence a broader range of preferredtemperatures than specialists should. Likewise, when an animal accli-mates to a change in temperature, both its thermal tolerance and itsthermoregulatory behavior should shift together [4,5,87]. Therefore,environments that select for plasticity of tolerance limits should alsoselect for plasticity of set-point temperatures.

A capacity for plasticity should evolve in environments that changeslowly and predictably, such that a genotype can change its phenotypequickly enough to track the environment [61–63]. Therefore, seasonalchanges in temperature favor genotypes that tune their tolerance limitsthrough plasticity. This selective pressure was mimicked in recent ex-periments with D. melanogaster. Populations evolving in cages thatfluctuated between 16 and 25 °C diverged genetically from populationsevolving at a constant temperature, either 16 or 25 °C [183]. Genotypesfrom the fluctuating treatment evolved a greater capacity to tune theirmembrane fluidity [43] and thermal tolerance [96] when developing ateither low or high temperature. Based on this research, we expectplasticity of thermal tolerance in short-lived species from seasonal en-vironments, such as D. melanogaster [139] and C. elegans [150]. Tothermoregulate adaptively, these species would need to adjust their set-point temperatures according to environmental temperatures. Ecolo-gists refer to this coordination of physiological and behavioral pheno-types as coadaptation [7,24,87].

The developmental temperature of D. melanogaster sets its preferredtemperature in a way that supports the idea of coadaptation. Ten po-pulations of flies spent 10 generations at either 25, 27, or 30 °C [73].Afterward, flies from each population were acclimated to 25 °C forseveral days and placed in a thermal gradient. Flies from populationskept at 25 °C preferred the coolest part of the gradient, whereas fliesfrom populations at 30 °C preferred the warmest parts. Although someof this variation among populations was likely caused by develop-mental temperature, the acclimation period should have been sufficientto reduce environmental effects on preferred temperature. Indeed, D.melanogaster changes its preferred temperature rapidly during accli-mation to temperature and other environmental factors [49]. A popu-lation of flies maintained at 18 °C for 18 months preferred to lay eggs incolder regions of a thermal gradient than did a population of fliesmaintained at 25 °C [58]. Despite this difference, only 4 days of ex-posure to 25 °C during adulthood caused the preferred temperature torevert to 25 °C. Similarly, the preferred temperature shifted downwardwhen flies raised at 25 °C were exposed to 18 °C for just 4 days. Theseplastic changes in the set-point temperature would be adaptive if ac-climation to temperature altered the thermal tolerance of flies.

Acclimation of thermoregulatory behavior in D. melanogaster mightresemble diel patterns controlled by the circadian clock. Both the heattolerance and preferred temperature of flies follow a circadian rhythm,increasing throughout the day and decreasing at night [157,166]. Weknow that photoperiod triggers the shift in heat tolerance, because fliesentrained their diel cycle to light when this cue was decoupled fromtemperature [157]. Prior to dawn, small lateral ventral neurons sensepigment and activate dorsal neurons, the cells that regulate circadianshift in behavior [166]. Synaptic activity between ventral and dorsalneurons peaks before dawn. This diel cycle depends on thermosensitiveanterior cells that contact the small lateral ventral neurons [77]. De-tection of warming by dTRPA1 channels in the anterior cells occurs attemperatures just above the preferred body temperature. Knockdownexperiments confirmed that the neurotransmitter 5HT1B plays a role insynaptic transmission between anterior cells and the small lateralventral neurons. The morphology of the synapses varies throughout theday, which changes synaptic contacts with other neurons, controlled bycircadian clock. This plasticity of thermal preference occurs in-dependently of locomotor activity, as with diel patterns of body

temperature in mammals [140,141]. A similar form of neural plasticitymight explain how flies adjust their set-point temperature during de-velopment.

The thermoregulatory behavior of C. elegans also changes accordingto environmental temperature. Two types of plasticity happen on dif-ferent time-scales. Sensory adaptation of AFD neurons occurs withinminutes, but the set-point temperature for these neurons to commu-nicate with interneurons occurs within hours [79]. In this way, AFDneurons store information about recent experience, enhancing a worm’sability to compare recent and past experiences when traveling throughgradients of temperature [72,100]. The plasticity of AFD neurons de-pends on protein kinases, such as PKC-1, CMK-1 CaM-kinase, and DGK-3. PKC-1 facilitates exocytosis of vesicles in the synaptic cleft betweenthe AFD neuron and the AIY interneuron [79]. CMK-1 regulates tran-scription of genes, underscoring its role in the slower form of plasticity[72]. DGK-3 reduces the concentration of diacylglycerol, a secondarymessenger that affects the temperature required for synaptic activitybetween AFD and AIY neurons [23]. Mutational knockout of DGK-3prevented worms from changing the set point, but this behavior wasrescued by expressing a cDNA for DGK-3 [23]. These mechanisms ofneural plasticity in C. elegans, along with those in D. melanogaster,suggest that natural selection has favored genotypes that adjust theirpreferred temperatures according to thermal stresses imposed by theenvironment.

7. A call for evolutionary neuroscience

To date, most of neuroscience has focused on how nervous systemscontrol thermoregulation in model organisms, leaving little chance toinfer why these nervous systems work the way they do [76]. Althoughrecent pushes have been made to develop macroevolutionary perspec-tives on the nervous system [53,93,123,171], a microevolutionaryperspective requires a focus on genetic variation in neural control orneural plasticity within species. Any microevolutionary theory starts bydefining the genetic variants in a population and the fitness of thesevariants in specific environments. Such information is unlikely to comequickly or easily in neuroscience, even when focusing on species closelyrelated to the model organisms. But without this research, we cannotmove past the ‘stamp-collecting’ phase that dominated other disciplinesbefore they adopted an evolutionary perspective. With this in mind,how can we develop a microevolutionary perspective on the design andplasticity of biological thermostats?

Classically, biologists have taken three approaches to study evolu-tion: 1) comparative analysis in a phylogenetic context, 2) directmeasures of phenotypic selection, and 3) experimental evolution in thelab [56,67–69,143]. Ironically, the most common approach for thestudy of evolution, comparative analysis, might be the most difficult touse in neuroscience. A comparative analysis require pairs of closelyrelated taxa that have experienced divergent selective pressures forlong periods, with each pair adding only one replicate to the analysis[57]. Thus, neuroscientists would have to repeat laborious experimentsin many species, some of which will differ distinctly from the modelorganisms in which molecular tools were developed.

Fortunately, neuroscientists can use experimental evolution to seehow nervous systems respond to natural selection. One of neu-roscience’s model organisms, D. melanogaster, has also been a work-horse for experimental evolution. Researchers have forced populationsof D. melanogaster to evolve at different temperatures with great suc-cess. In two separate experiments, a few years of natural selection atdifferent temperatures caused populations to diverge in behavior,physiology, and morphology [1,40,43,89,96,129]. Other researchersmaintained populations of flies that moved between patches at differenttemperatures [45]. Such populations could be kept in either constant orchanging gradients of temperature. These environments would relax orinduce selective pressure on thermoregulatory behavior, respectively.Then, neuroscientists could study the thermoregulatory behaviors and

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neural mechanisms of the resulting genotypes. To enhance the value ofexperimental evolution, researchers could start selection lines withknown frequencies of genotypes from the Drosophila Genetic ResearchPanel, a collection of more than 200 genotypes whose genomes havebeen sequenced [103]. These genotypes differ substantially in thermaltolerance [60,168,169] and in a wide range of behaviors [64,70,156].Therefore, populations created from these genotypes could be a valu-able model for studying the evolution of thermoregulatory behaviorand neural plasticity.

At the same time, biologists can quantify the fitness of neural mu-tants in the lab or field. This approach complements rather than re-places experimental evolution. Instead of manipulating the environ-ment and observing how natural selection shapes phenotypes, onemanipulates the phenotype and observes the effect on fitness. Biologistsmodel the relationship between the phenotype and fitness, termed aselection gradient, to predict evolutionary responses and test evolu-tionary models [9,55,92]. Targeted mutagenesis has long been used tosee how novel phenotypes influence the performance, survival, or re-production of a model organism, such as D. melanogaster [167]. Neu-roscientists already use targeted mutagenesis to alter the genes thatcontrol thermoregulation in Caenorhabditis and Drosophila [29,97]. Therecent development of CRISPR/Cas9 [102,175] has improved efforts touncover the genetic and physiological basis of behavior[107,111,117,138]. The next step would be to compare the perfor-mances of phenotypes under ecologically relevant conditions. For ex-ample, Lee and colleagues showed that the majority of flies carrying amutant allele of the pyrexia gene lost mobility when exposed briefly to40 °C, but flies with the wild-type allele rarely succumbed to this tem-perature [97]. Ideally, one would confirm the selective advantage of aphenotype in a natural environment [94] or a semi-natural enclosure[106]. Ecologists have used field experiments to contrast the perfor-mances of genotypes along environmental clines [78]. By selectivelymutating the genes involved in neural plasticity and studying theirimpact on fitness in the field, biologists could quantify the direction andstrength of natural selection neural traits.

Ecological and evolutionary theory offers a rich perspective for in-terpreting the design and plasticity of nervous systems [97,154].Models of adaptive plasticity, such as those discussed here, provide acontext in which to interpret neural mechanisms that underlie the di-versity of behaviors. At the same time, studies of neural plasticity inmodel organisms will continue to highlight constraints on the evolutionof behavior. Both neuroscientists and ecologists have much to learnabout behavior in general, and thermoregulation in particular. Fordecades, ecologists have treated thermoregulation as a black box to bequantified and compared in terms of means and variances. In theirdefense, no clear picture of neural control during thermoregulationexists, except for the biological thermostats of worms, flies, and rats.We hope this review opens a dialogue between ecologists and neu-roscientists that leads to integrative studies of thermoregulation by non-model organisms in natural environments. If not for curiosity alone, weshould pursue this goal because of global climate change, which hascreated ecological challenges rooted in neurobiology [97]. Thesechallenges stem from climatic effects on neural development and be-havioral thermoregulation, as well as selective pressures caused bynovel combinations of temperature, moisture, and acidity. Together, wecan face these challenges while exploring the ecological and evolu-tionary processes that generated the diversity of nervous systems.

Acknowledgements

We thank Jason Newbern and Elaina Gracheva for constructivecriticism of an early draft of the manuscript.

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