Conceptual difference between SIH and infectious fever

SIH refers to a significant increase in basal body temperature, and its nature is usually short or medium in duration; followed by a gradual return to basal temperature, once the stimulus or the perceived stressful situation dissipates (^{Oka et al., 2001}).

In this context, ^{Bittencourt et al., (2015)}, with the objective of determining the thermal response to stress stimuli in birds through telemetric records; they evaluated pigeons (Columbia livia) exposed to stressful stimuli. It was observed that the transfer from the cage, visual isolation and tonic immobility, caused an increase in body temperature for 10-20 minutes and subsequently it was possible to decrease significantly. Thus, with this observation it was determined that temperature is a parameter associated with stress, but according to what the authors observed, it can also show specific attributes to characterize the stressor based on its type, direction and species. On the other hand, it has been observed that when the individual is repeatedly exposed to a stressful stimulus and can express a behavioral pattern similar to depression, chronic hyperthermia occurs that is low-grade and persistent (^{Oka, 2018}).

This has been related to a conditioned hyperthermia form, which refers to the increase in temperature caused by previous experiences during early or youthful age, due to an aversive memory between a certain stimulus and situation (^{Oka, 2018}). An example of this is that if an animal receives an electric shock that is unfamiliar, a behavioral and autonomic response associated with fear is triggered when it is exposed again to the same stimulus ((^{Thompson et al., 2012}; ^{Wellman et al., 2016}). In contrast, hyperthermia caused by infectious processes is called fever and it is a cardinal response typically related to sepsis or microorganism presence in the body (^{Evans et al., 2015}). Unlike SIH, fever involves a high energy cost, since to produce a 1 ºC increase in body temperature, a 10- 15% increase in metabolic rate is required (^{Young and Saxena, 2014} ).

As can be seen, it is clear that from a conceptual analysis, there is a difference between the possible causes of temperature increase in the body; however, both signaling tracks share a neuronal pathway that modulates thermal response.

Temperature hypothalamic modulation in SIH and fever

Although stress encompasses a series of both behavioral and physiological responses in order to face a stressful event (^{Yaribeygi et al., 2017}), to understand the response to stress, whether infectious or emotional in origin; it is necessary to understand the physiological response that is triggered to assess how animal welfare is compromised (^{Lees et al., 2020}). In other words, when an individual faces a stressful event, different related physiological responses can be triggered, including an increase in body temperature ((^{Vinkers et al., 2009}) and metabolic consequences could be different. proposed that both in humans and animals, stress perception seems to correlate with high activity in the Autonomous Nervous System (ANS) and with stress high levels (such as anxiety or fear), generating an increase in the frequency heart rate and body temperature level (^{Bi, 2014}; ^{Houtepen et al., 2011}). For this reason, it has been considered as a physiological response associated with stress degree experienced by the body (^{Lees et al., 2020}).

Emotional stress or fever increases body temperature through independent cytokine and prostaglandin E2 (PGE2) mechanisms. Thus, the systemic administration of non-steroidal analgesics (NSAIDs), such as phenylbutazone or indomethacin, fails to inhibit this type of stress-induced hyperthermia (^{Zhang et al., 2010}). In contrast, drugs that possess anxiolytic properties, such as benzodiazepines and serotonin (5-HT) receptor agonists, such as buspirone and flesinoxane, do have effects on reducing the magnitude of stress- induced hyperthermia (^{Rygula et al., 2008}; ^{Vinkers et al., 2010}).

These findings have shown that ANS, over the whole sympathetic nervous system (SNSi) influences temperature modulation while main effector organs are BAT and blood vessels (^{Nakamura, 2015}). In the first case it is controlled by SNSi innervation through β3 adrenoreceptors, which are predominantly expressed, and in some studies it has been shown that the hypothalamic-medullary glutamatergic signal is the one that drives sympathetic thermogenesis in BAT (^{Kataoka et al., 2014}). On the contrary, in the blood vessels there is a decrease in heat loss by radiation, due to cutaneous vasoconstriction, which is measured by a sympathetic response of α adrenoreceptors that generate the decrease in dermal blood flow ((^{Nakamura, 2015}; ^{Ikoma et al., 2018})

Additionally, the hypothalamic-pituitary-adrenal (HPA) axis is activated, generating the stimulating hormone neurosecretion of the adrenal cortex, which in turn increases the secretion of glucocorticoids in the adrenal cortex; action that stimulates two catabolic events: gluconeogenesis and lipolysis, which contributes to increasing thermogenic activity (^{Oka, 2018}; ^{Wang et al., 2015}). Likewise, during stress perception, a moderate tachycardia is induced without decreasing the stroke volume, thereby providing support to increase necessary oxygen supply for BAT consumption and distribute heat to the rest of the body. This process has been called “cardiac thermogenesis” (^{Morrison, 2011}).

In this sense, SNSi neurons integrate signals from different brain regions, so that neurons specialized in thermogenesis for BAT and vasoconstriction are predominantly found in the rostral medullary raphe region (rMR), which involves the nucleus of raphe pallidus rostral and raphe magnus (^{Nakamura, 2004}; ^{Nakamura et al., 2005}). Likewise, ^{Nakamura (2015)} reports that through nanoinjections use of drugs in vivo in the rat brain and evaluations by thermotelemetry, it was demonstrated that both rMR and the dorsomedial hypothalamus (DMH) mediate stress-induced thermogenesis. Possible brain regions that are involved in SIH include the prefrontal cortex, medial amygdala, lateral habenula, and orexin-containing neurons (^{Oka, 2018}). Therefore, being these regions in which neurons that contain the vesicular glutamate transporter (VGLUT 3) are expressed, they have been identified as glutamatergic neurons (^{Nakamura, 2004}).

^{Stornetta et al., (2005)} observed that through the histological and immune-reactive detection of VGLUT 3 mRNA in medullary raphe, 89% of neurons showed both marker expression; therefore, VGLUT 3 neurons contain receptors for both serotonin and GABA. This observation indicates that glutamatergic receptor activation participate in thermal response modulation to acute stress (^{Horiuchi et al., 2004}). In contrast, when glutamate receptor blockade in rMR is exerted with the GABA inhibitor use as such as muscimol, not only thermogenesis, but also hyperthermia and tachycardia due to stress are inhibited (^{Kataoka et al., 2014}; ^{Nakamura, 2015}) (Figure 1).

Figure 1 Temperature modulation and mechanisms related to SIH development 

On the contrary, in fever induced by infection and inflammation, the increase in temperature is considered a common response in sick patients, through interaction of exogenous pyrogens by pathogenic microorganism presence with interleukin (IL) - 1, IL- 6 and tumor necrosis factor α (TNF-α) (^{Walter et al., 2016}). These inducers stimulate the production of pro-inflammatory cytokines, which act directly in the preoptic area of the hypothalamus (POA), the organum vasculosum neuronal pathway of the terminalis lamina (^{Schortgen, 2012}). An area that is highly vascularized and lacks a blood-brain barrier, which allows it to be stimulated very easily (^{Walter et al., 2016}).

Likewise, prostaglandin PGE2, which is produced in endothelial cells at the brain level, becomes the main pyrogenic mediator of fever (^{Engström et al., 2012}). However, this chemical mediator can also be produced by hematopoietic cells after the activation of the Toll 4 receptor (TLR4) mediated by lipopolysaccharides (LPS) of bacteria, which, when in contact with the blood-brain barrier, initiate the thermal elevation known as fever (^{Hasday et al., 2014}; ^{Saper et al., 2012}). PGE2 acts on the POA by slowing down the firing speed of heat-sensitive neurons, causing an increase in body temperature, favoring febrile states (^{Clarke and Pörtner, 2010}) (Figure 2) .This evidence makes infectious fever is associated with elevated inflammatory markers, which can be attenuated with non- opioid NSAIDs, such as paracetamol, by blocking cyclooxygenase 3 at the brain level, thus decreasing the synthesis of PGE2 (^{Olivier et al., 2003}; ^{Jahr and Lee, 2010}).

Figure 2 Comparison of temperature modulation during infectious fever and SIH development 

Therefore, there is a great similarity between infectious fever and SIH, since in both cases the mediation pathway is given by POA, due to the abundance of excitatory glutamatergic neurons. However, the difference between the two phenomena is the origin that will trigger the hyperthermia response, which can be serotoninergic and glutamatergic, as in SIH; while for infectious origin fever, the temperature increases will correspond to the presence of exogenous pyrogens (Figure 2).

Modulating factors of stress-induced thermal response

There are several factors that must be taken into account for the stress-induced thermal cascade to be generated, including:

b) Species and sex

Similar to what occurs in the face of stressor nature, the morpho-physiological and behavioral differences also have an effect on thermal response modulation (^{Oka, 2018}).

^{Dymon and Fewell (1998)}, evaluated the thermal response of male and female guinea pigs, against the exposure of a simulated open field, it was observed that neither the males nor the females developed SIH; however, in the case of females, there was a lower value of body temperature. This observation is in contrast to that reported in the study by ^{Dallmann et al., (2006)}, who found that social confrontation generates SIH, due to the increase in corticosterone, approximately between 10 to 30 minutes after exposure to the stressor. It should be noted that other authors have determined that SIH can be prolonged 60-120 minutes after the noxious stimulus, which was presented by performing an immune-staining analysis for the Fos receptor in the preoptic and periolivar nuclei (^{Veening et al., 2004}). This last evidence agrees with what was recently observed by ^{Lees et al., (2020)}, investigated the relationship between temperament traits, handling and SIH. To do this, they recorded the rectal temperature of 60 pure Angus breed steers, which were exposed to a standardized manipulation such as immobilization in the box for 30 seconds; also having a retention per group and immobilization in the sleeve for 60 seconds.

In this study, the temperaments evaluated were: agitator score, crush score, and flight speed. Their findings report that there was a moderate correlation between rectal temperature with flight speed and crush score (r = 0.37, r = 0.31). It is worth mentioning that, as observed by the authors, regardless of sex and temperament traits; rectal temperature showed a more significant relationship with time. It was concluded that the degree of expression or the increase in temperature is related to the animal species that presents it, probably due to a difference in receptor expression in the POA.

However, despite the fact that both in the guinea pig and in cattle, the evidence shows that there is no sex significant influence on SIH expression. Some studies have indicated that SIH is expressed to a greater extent in females. In this sense, ^{Rosinger et al., (2017)} mention that female rats have 1.3 ºC higher temperature than males. This could be due to a differential response of the HPA axis, in the face of stressors; possibly because estrogen can improve the function of this axis and therefore of the corticotropin-releasing hormone, which has been associated with the thermal effect (^{Oka, 2018}). In addition to this, it was recently observed in female mice that SIH occurred when the female was deprived of breeding; however, this effect did not show a correlation with circulating cortisol levels (^{Faraji and Metz, 2020}).

In summary, a significant difference has been observed between SIH response, in relation to species and sex; which can be explained by a difference in receptor expression the responsible for signaling the thermal response, although some studies do not provide sufficient data to establish a clear answer. Therefore, it is necessary to continue developing studies to answer these questions.

Participation of cardiac thermogenesis in the development and SIH modulation

Acute stress can affect cardiovascular functions, for example increasing blood pressure; therefore, it has been considered as a physiological impact factor in the development and modulation of SIH (^{Crestani, 2016}).

In relation to this and with the objective of determining the angiotensin II participation on the type1 Ang-II (AT1) both in homotypic and heterotypic emotional dysfunctions, ^{Costa- Ferreira et al., (2016)} compared the effect of an AT1 receptor antagonist (Losartan 30- mg/ kg/ day orally), on automatic and cardiovascular changes in rats. They observed that sympathetic tone increased in response to heart stressor, decreasing the cardiac parasympathetic activity, in addition, when a selective AT1 receptor blocker such as Losartan was administered, and the baroreflex deterioration was inhibited, as was the autonomic activity. Likewise, it was possible to identify the increase in levels of circulating corticosterone and a reduction in body weight. It was concluded that there is an important participation of AT1 in the autonomic changes caused by acute stress. This new evidence is additional to the modification of the cardiovascular pattern, due to α adrenoreceptor stimulation that generate a tachycardia in aversive situations (^{dos Reis et al., 2014}; ^{Crestani, 2016}).

On the other hand, it has been investigated whether social damping can inhibit SIH, since it has been observed that in male Wistar rats in the presence of a partner or a conspecific, stressor perception can be inhibited with the consequent reduction in SIH response (^{Kiyokawa et al., 2004}; ^{Lkhagvasuren and Oka, 2017}). However, it has recently been discovered that without the need for social contact, SIH response is inhibited due to the uptake of odors (^{Kiyokawa, 2015}); however, it is not yet clear whether the familiar odor effect could have the same answer to SIH.

In this context, ^{Kiyokawa et al., (2014)} studied familiarity effect with a conspecific on social damping intensity; for this, they evaluated the response of male Wistar rats housed with a family conspecific for 3 weeks. These same animals were subsequently exposed to a conditioned stimulus in a clean or scented control box with unknown or familiar conspecific. They observed that the subjects showed freezing and Fos expression in the paraventricular nucleus; but this response was nullified when they were exposed to a conspecific smell, showing a greater effect with the familiar smell. Thus, concluding that the smell of a familiar conspecific is more effective in socially dampening conditioned responses to fear.

For all the foregoing, the evidence indicates that probably the vascular changes produced by acute stress that affect the thermal response cannot be explained only with the HPA axis response and catecholamine secretion. Therefore, cardiovascular changes caused by stress may have more than one physiological pathway that can alter the temperature and worsen cardiovascular pathologies; however, these changes are inhibited by the conspecific presence, which in the future should be a field study to determine if inhibition follows the same feedback pathway at the neurological level.