section_path: Mechanism/Neurocircuitry in mammals/Pheromones and contagion
section_name: Pheromones and contagion
paragraph_text: 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 and earthworms, and four years later also found in mammals, both mice and rats. 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. 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. The experiment also showed that the bees' fear-induced pain tolerance was mediated by an endorphin.
  
  By using the forced swimming test in rats as a model of fear-induction, the first mammalian "alarm substance" was found. 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.
  
  In 1993 a connection between alarm chemosignals in mice and their immune response was found. Pheromone production in mice was found to be associated with or mediated by the pituitary gland in 1994.
  
  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. Further experiments showed that when a rat perceived alarm pheromones, it increased its defensive and risk assessment behavior, 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).
  
  The neurocircuit for how rats perceive alarm pheromones was shown to be related to the hypothalamus, brainstem, and amygdalae, 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.
  
  Alarm pheromone-induced anxiety in rats has been used to evaluate the degree to which anxiolytics can alleviate anxiety in humans. For this, the change in the 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 agonist or CP-154,526, a corticotropin-releasing hormone antagonist.
  
  Faulty development of odor discrimination impairs the perception of pheromones and pheromone-related behavior, like aggressive behavior and mating in male rats: The enzyme 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 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.
  
  Lastly, alleviation of an acute fear response because a friendly peer (or in biological language: an affiliative conspecific) 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. 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. "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 habituate to threats is suggested by the fact that the disturbed colonies also decreased their foraging.
  
  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 compositions and affect rates of energy and material exchange in an ecological community. Thus pheromones generate structure in a food web and play critical roles in maintaining natural systems.