Editing Fear (section)

====Pheromones and contagion====
In threatening situations, insects, aquatic organisms, birds, reptiles, and mammals emit odorant substances, initially called alarm substances, which are chemical signals now called alarm [[pheromones]]. This is to defend themselves and at the same time to inform members of the same species of danger and leads to observable behavior change like freezing, defensive behavior, or dispersion depending on circumstances and species. For example, stressed rats release odorant cues that cause other rats to move away from the source of the signal.

After the discovery of pheromones in 1959, alarm pheromones were first described in 1968 in ants<ref>{{cite journal | vauthors = Moser JC, Brownlee RC, Silverstein R | title = Alarm pheromones of the ant atta texana | journal = Journal of Insect Physiology | volume = 14 | issue = 4 | pages = 529–535 | date = April 1968 | pmid = 5649232 | doi = 10.1016/0022-1910(68)90068-1 | bibcode = 1968JInsP..14..529M }}</ref> and earthworms,<ref>{{cite journal | vauthors = Ressler RH, Cialdini RB, Ghoca ML, Kleist SM | title = Alarm pheromone in the earthworm Lumbricus terrestris | journal = Science | volume = 161 | issue = 3841 | pages = 597–599 | date = August 1968 | pmid = 5663305 | doi = 10.1126/science.161.3841.597 | s2cid = 30927186 | bibcode = 1968Sci...161..597R }}</ref> and four years later also found in mammals, both mice and rats.<ref>{{cite journal | vauthors = Rottman SJ, Snowdon CT | title = Demonstration and analysis of an alarm pheromone in mice | journal = Journal of Comparative and Physiological Psychology | volume = 81 | issue = 3 | pages = 483–490 | date = December 1972 | pmid = 4649187 | doi = 10.1037/h0033703 }}</ref> Over the next two decades, identification and characterization of these pheromones proceeded in all manner of insects and sea animals, including fish, but it was not until 1990 that more insight into mammalian alarm pheromones was gleaned.

In 1985, a link between odors released by stressed rats and [[pain perception]] was discovered: unstressed rats exposed to these odors developed opioid-mediated analgesia.<ref>{{cite journal | vauthors = Fanselow MS | title = Odors released by stressed rats produce opioid analgesia in unstressed rats | journal = Behavioral Neuroscience | volume = 99 | issue = 3 | pages = 589–592 | date = June 1985 | pmid = 3843728 | doi = 10.1037/0735-7044.99.3.589 }}</ref> In 1997, researchers found that bees became less responsive to pain after they had been stimulated with [[isoamyl acetate]], a chemical smelling of banana, and a component of bee alarm pheromone.<ref>{{cite journal | vauthors = Núñez J, Almeida L, Balderrama N, Giurfa M | title = Alarm pheromone induces stress analgesia via an opioid system in the honeybee | journal = Physiology & Behavior | volume = 63 | issue = 1 | pages = 75–80 | date = December 1997 | pmid = 9402618 | doi = 10.1016/s0031-9384(97)00391-0 | s2cid = 8788442 }}</ref> The experiment also showed that the bees' fear-induced [[pain tolerance]] was mediated by an [[endorphin]].

By using the [[Behavioural despair test|forced swimming test]] in rats as a model of fear-induction, the first mammalian "alarm substance" was found.<ref>{{cite journal | vauthors = Abel EL, Bilitzke PJ | title = A possible alarm substance in the forced swimming test | journal = Physiology & Behavior | volume = 48 | issue = 2 | pages = 233–239 | date = August 1990 | pmid = 2255725 | doi = 10.1016/0031-9384(90)90306-o | s2cid = 22994036 }}</ref> In 1991, this "alarm substance" was shown to fulfill criteria for pheromones: well-defined behavioral effect, species specificity, minimal influence of experience and control for nonspecific arousal. Rat activity testing with the alarm pheromone, and their preference/avoidance for odors from cylinders containing the pheromone, showed that the pheromone had very low [[Volatility (chemistry)|volatility]].<ref>{{cite journal | vauthors = Abel EL | title = Alarm substance emitted by rats in the forced-swim test is a low volatile pheromone | journal = Physiology & Behavior | volume = 50 | issue = 4 | pages = 723–727 | date = October 1991 | pmid = 1775546 | doi = 10.1016/0031-9384(91)90009-d | s2cid = 41044786 }}</ref>

In 1993 a connection between alarm chemosignals in mice and their [[immune system|immune response]] was found.<ref>{{cite journal | vauthors = Cocke R, Moynihan JA, Cohen N, Grota LJ, Ader R | title = Exposure to conspecific alarm chemosignals alters immune responses in BALB/c mice | journal = Brain, Behavior, and Immunity | volume = 7 | issue = 1 | pages = 36–46 | date = March 1993 | pmid = 8471798 | doi = 10.1006/brbi.1993.1004 | s2cid = 7196539 | title-link = BALB/c mice }}</ref> Pheromone production in mice was found to be associated with or mediated by the [[pituitary gland]] in 1994.<ref>{{cite journal | vauthors = Abel EL | title = The pituitary mediates production or release of an alarm chemosignal in rats | journal = Hormones and Behavior | volume = 28 | issue = 2 | pages = 139–145 | date = June 1994 | pmid = 7927280 | doi = 10.1006/hbeh.1994.1011 | s2cid = 11844089 }}</ref>

In 2004, it was demonstrated that rats' alarm pheromones had different effects on the "recipient" rat (the rat perceiving the pheromone) depending which body region they were released from: Pheromone production from the face modified behavior in the recipient rat, e.g. caused sniffing or movement, whereas pheromone secreted from the rat's anal area induced [[autonomic nervous system]] stress responses, like an increase in core body temperature.<ref>{{cite journal | vauthors = Kiyokawa Y, Kikusui T, Takeuchi Y, Mori Y | title = Alarm pheromones with different functions are released from different regions of the body surface of male rats | journal = Chemical Senses | volume = 29 | issue = 1 | pages = 35–40 | date = January 2004 | pmid = 14752038 | doi = 10.1093/chemse/bjh004 | doi-access = free }}</ref> Further experiments showed that when a rat perceived alarm pheromones, it increased its defensive and risk assessment behavior,<ref>{{cite journal | vauthors = Kiyokawa Y, Shimozuru M, Kikusui T, Takeuchi Y, Mori Y | title = Alarm pheromone increases defensive and risk assessment behaviors in male rats | journal = Physiology & Behavior | volume = 87 | issue = 2 | pages = 383–387 | date = February 2006 | pmid = 16337975 | doi = 10.1016/j.physbeh.2005.11.003 | url = https://zenodo.org/record/853489 | url-status = live | access-date = 2017-08-30 | s2cid = 12780994 | archive-url = https://web.archive.org/web/20170830233838/https://zenodo.org/record/853489 | archive-date = 2017-08-30 }}</ref> and its acoustic [[startle reflex]] was enhanced.

It was not until 2011 that a link between severe pain, neuroinflammation and alarm pheromones release in rats was found: real time [[RT-PCR]] analysis of rat brain tissues indicated that shocking the footpad of a rat increased its production of [[proinflammatory cytokines]] in deep brain structures, namely of [[IL-1β]], heteronuclear [[Corticotropin-releasing hormone]] and [[c-fos]] mRNA expressions in both the [[paraventricular nucleus]] and the bed nucleus of the [[stria terminalis]], and it increased stress hormone levels in plasma ([[corticosterone]]).<ref>{{cite journal | vauthors = Arakawa H, Arakawa K, Blandino P, Deak T | title = The role of neuroinflammation in the release of aversive odor cues from footshock-stressed rats: Implications for the neural mechanism of alarm pheromone | journal = Psychoneuroendocrinology | volume = 36 | issue = 4 | pages = 557–568 | date = May 2011 | pmid = 20888127 | doi = 10.1016/j.psyneuen.2010.09.001 | s2cid = 24367179 }}</ref>

The [[emotion#neurocircuitry|neurocircuit]] for how rats perceive alarm pheromones was shown to be related to the [[hypothalamus]], [[brainstem]], and [[amygdala]]e, all of which are evolutionary ancient structures deep inside or in the case of the brainstem underneath the brain away from the cortex, and involved in the [[fight-or-flight response]], as is the case in humans.<ref>{{cite journal | vauthors = Kiyokawa Y, Kikusui T, Takeuchi Y, Mori Y | title = Mapping the neural circuit activated by alarm pheromone perception by c-Fos immunohistochemistry | journal = Brain Research | volume = 1043 | issue = 1–2 | pages = 145–154 | date = May 2005 | pmid = 15862528 | doi = 10.1016/j.brainres.2005.02.061 | url = https://zenodo.org/record/854830 | url-status = live | access-date = 2017-08-31 | s2cid = 41186952 | archive-url = https://web.archive.org/web/20170831131924/https://zenodo.org/record/854830 | archive-date = 2017-08-31 }}</ref>

Alarm pheromone-induced anxiety in rats has been used to evaluate the degree to which [[anxiolytic]]s can alleviate anxiety in humans. For this, the change in the [[startle response#acoustic startle reflex|acoustic startle reflex]] of rats with alarm pheromone-induced anxiety (i.e. reduction of defensiveness) has been measured. Pretreatment of rats with one of five anxiolytics used in clinical medicine was able to reduce their anxiety: namely [[midazolam]], [[phenelzine]] (a nonselective monoamine oxidase (MAO) inhibitor), [[propranolol]], a nonselective [[beta blocker]], [[clonidine]], an [[alpha-2 adrenergic receptor#agonist|alpha 2 adrenergic agonist]] or [[CP-154,526]], a [[corticotropin-releasing hormone antagonist]].<ref>{{cite journal | vauthors = Inagaki H, Kiyokawa Y, Takeuchi Y, Mori Y | title = The alarm pheromone in male rats as a unique anxiety model: psychopharmacological evidence using anxiolytics | journal = Pharmacology, Biochemistry, and Behavior | volume = 94 | issue = 4 | pages = 575–579 | date = February 2010 | pmid = 19969015 | doi = 10.1016/j.pbb.2009.11.013 | s2cid = 28194770 }}</ref>

Faulty development of odor discrimination impairs the [[perception]] of pheromones and pheromone-related behavior, like [[aggression|aggressive behavior]] and mating in male rats: The enzyme [[MAPK7|Mitogen-activated protein kinase 7]] (MAPK7) has been implicated in regulating the development of the olfactory bulb and odor discrimination and it is highly expressed in developing rat brains, but absent in most regions of adult rat brains. [[Conditional gene knockout|Conditional deletion]] of the MAPK7gene in mouse neural stem cells impairs several pheromone-mediated behaviors, including aggression and mating in male mice. These behavior impairments were not caused by a reduction in the level of testosterone, by physical immobility, by heightened fear or anxiety or by depression. Using mouse urine as a natural pheromone-containing solution, it has been shown that the impairment was associated with defective detection of related pheromones, and with changes in their inborn preference for pheromones related to sexual and reproductive activities.<ref>{{cite journal | vauthors = Zou J, Storm DR, Xia Z | title = Conditional deletion of ERK5 MAP kinase in the nervous system impairs pheromone information processing and pheromone-evoked behaviors | journal = PLOS ONE | volume = 8 | issue = 10 | page= e76901 | year = 2013 | pmid = 24130808 | pmc = 3793934 | doi = 10.1371/journal.pone.0076901 | bibcode = 2013PLoSO...876901Z | doi-access = free }}</ref>

Lastly, alleviation of an acute fear response because a friendly peer (or in biological language: an affiliative [[conspecific]]) [[tend and befriend|tends and befriends]] is called "[[social buffering]]". The term is in analogy to the 1985 "buffering" hypothesis in psychology, where [[social support]] has been proven to mitigate the negative health effects of alarm pheromone mediated distress.<ref>{{cite journal | vauthors = Cohen S, Wills TA | title = Stress, social support, and the buffering hypothesis | journal = Psychological Bulletin | volume = 98 | issue = 2 | pages = 310–357 | date = September 1985 | pmid = 3901065 | doi = 10.1037/0033-2909.98.2.310 | s2cid = 18137066 }}</ref> The role of a "social pheromone" is suggested by the recent discovery that olfactory signals are responsible in mediating the "social buffering" in male rats.<ref>{{cite journal | vauthors = Takahashi Y, Kiyokawa Y, Kodama Y, Arata S, Takeuchi Y, Mori Y | title = Olfactory signals mediate social buffering of conditioned fear responses in male rats | journal = Behavioural Brain Research | volume = 240 | pages = 46–51 | date = March 2013 | pmid = 23183219 | doi = 10.1016/j.bbr.2012.11.017 | url = https://zenodo.org/record/854828 | url-status = live | access-date = 2017-08-31 | s2cid = 30938917 | archive-url = https://web.archive.org/web/20170831133047/https://zenodo.org/record/854828 | archive-date = 2017-08-31 }}</ref> "Social buffering" was also observed to mitigate the conditioned fear responses of honeybees. A bee colony exposed to an environment of high threat of predation did not show increased aggression and aggressive-like gene expression patterns in individual bees, but decreased aggression. That the bees did not simply [[habituation|habituate]] to threats is suggested by the fact that the disturbed colonies also decreased their foraging.<ref>{{cite journal | vauthors = Rittschof CC, Robinson GE | title = Manipulation of colony environment modulates honey bee aggression and brain gene expression | journal = Genes, Brain and Behavior | volume = 12 | issue = 8 | pages = 802–811 | date = November 2013 | pmid = 24034579 | pmc = 3863782 | doi = 10.1111/gbb.12087 }}</ref>

Biologists have proposed in 2012 that fear pheromones evolved as molecules of "keystone significance", a term coined in analogy to [[keystone species]]. Pheromones may determine [[species richness|species compositions]] and affect rates of energy and material exchange in an [[community (ecology)|ecological community]]. Thus pheromones generate structure in a [[food web]] and play critical roles in maintaining [[Ecosystem health|natural systems]].<ref>{{cite journal | vauthors = Ferrer RP, Zimmer RK | title = Community ecology and the evolution of molecules of keystone significance | journal = The Biological Bulletin | volume = 223 | issue = 2 | pages = 167–177 | date = October 2012 | pmid = 23111129 | doi = 10.1086/BBLv223n2p167 | s2cid = 592393 }}</ref>