in humans, there is evidence that depression-like symptoms beyond sickness behavior are also seen in non-human animals and that these symptoms often are accompanied by increased inflammation. primarily seen in experimental studies, these symptoms often take the form of states that appear similar to the helplessness, anxiety, anhedonia, and weight change seen in human depression. however, the degree to which these symptoms are comparable to human symptoms is unknown, with the full suite of cognitive symptoms associated with depression having yet to be found in any study of non-human animals. compared to the uncertainty about how the behaviors observed in non-human animals are experienced cognitively, there is much more evidence supporting the connection between inflammation and sickness behavior in non-human animals. as with humans, this is mainly seen experimentally, with injections of pro-inflammatory cytokines often resulting in sickness behavior and occasionally other depression-like symptoms. likewise, the ability for anti-inflammatories to reduce these symptoms is also seen in experimental studies as is seen in humans. medical explanations from immune response one explanation for the connection between inflammation and depression symptoms, is that depression is a disorder that stems from immune responses across the body. due in large part to the systems that bring them about both involving the same pro-inflammatory cytokines, the suggestion is that strong or prolonged immune responses allow for those with susceptibilities to depression to experience it outside of experiences with any other risk factors. of the ways this might happen, one is that those whose immune responses have been shifted to be pro-inflammatory without sufficient anti-inflammatory compensation have elevated risk of experiencing inflammation intense enough to cause depression. another suggestion is that variation in neurotransmitter production or receptors may also play a role in one's risk of experiencing inflammation-based depression if certain combinations result in increased risk of inflammation, similarly putting them at risk of maladaptive changes in brain chemistry. however, findings that depression and pro-inflammatory responses do not require the presence of the other for one to develop have led others to argue that the two conditions are often distinct, something which has been suggested to reduce the explanation's appeal to psychiatrists. evolutionary explanations pathogen host defense hypothesis one explanation that sees the connection between depression and inflammation as the result of adaptations is the pathogen host defense hypothesis (pathos-d), which proposes that depression is directly tied to immune responses. from this perspective, depression-like symptoms are thought to reduce energy consumption and reallocate resources so that one can mount a stronger immune defense, thereby reducing the organism's risk of death. in addition to this, both the reduction in activity and social withdrawal that often accompanies depression are also suggested to provide benefits by decreasing one's risk of encountering new pathogens or exposing kin or cooperative partners to one's illness, although they are likely of secondary importance. beyond serving as an explanation for the connection between depression and inflammation, pathos-d was also designed to account for the connection between social stressors and depression. by viewing social adversity as a recurrent cue of likely injury and infection risk across human evolutionary history, social stressors are incorporated into the hypothesis with the expectation that their presence can be used to inform the need to up-regulate immune function before the actual injury or infection risk occurs. as the risk of death in these situations was high ancestrally, false alarms in which social adversity results in one experiencing the costs of depression without any pathogen threat are expected to be common due to the greater costs of failing to respond to an actual threat. therefore, the benefits of depression in terms of reduced mortality are expected to outweigh the costs of depression throughout our evolutionary history both in terms of false alarms and the costs of depression in general. although serving as an explanation for the association between depression and increased inflammation levels, the host-defense hypothesis cannot currently explain many of the symptoms outside of reduced activity or social withdrawal. for example, both depression's connection to suicidality and the fact that depression symptoms often persist outside of illness or after a pathogen has been dealt with suggest that there is more to depression than its role as a coordinated immune defense. however, the host-defense hypothesis is not mutually exclusive with other explanations for these occurrences, and it is possible that illness symptoms can be co-opted for other purposes, such as signaling weakness and need for help. social signal transduction theory closely related to the host-defense hypothesis, the social signal transduction theory of depression also directly incorporates social stressors into its explanation for the connection between depression and up-regulated immune responses. however, compared to pathos-d, it emphasizes the role of depression as the body's way to prepare itself for the threat of future infection to a greater degree. it also differs in that while pathos-d still allows for many cases of depression to be adaptive in western, industrialized societies, the social signal transduction theory expects most instances to be maladaptive. this is due to the expectation that much of the cues indicating risk of injury are less relevant now due to both their lesser connection with violence and the fact that modern medicine has greatly reduced one's risk of death or long-term damage from infection. however, like pathos-d, the social signal transduction theory of depression has been suggested to be compatible with other explanations, with there being potential for both the cognitive and inflammatory symptoms of depression to be functional in times of social adversity. immune dysregulation hypothesis another explanation for the connection between depression and inflammation that emphasizes the role of environmental mismatch is the immune dysregulation hypothesis. the immune dysregulation hypothesis is based on the old friends hypothesis, which suggests that western, sanitary environments fail to provide sufficient microorganism exposure to train the immune system to tolerate safe or difficult to eradicate microorganisms, thereby resulting in greater prevalence of the pro-inflammatory phenotypes that typify autoimmune diseases. as depression is also associated with pro-inflammatory responses, the suggestion is that the causes of depression are little different from the causes of the autoimmune diseases it is largely co-morbid with, with sanitary environments increasing the risk of excessive inflammation in response to psychosocial stressors just as it is thought to with otherwise harmless microorganisms. however, evidence of increased inflammation among depressed individuals is also seen among the tsimané, which has been presented as challenge for the immune dysregulation hypothesis' expectation that this association is restricted to western environments. co-opted sickness behavior an additional explanation for the overlap in symptoms shared by depression and sickness behavior is that the neurobiology associated with sickness behavior was co-opted to result in melancholic symptoms outside of illness by other adaptations. based largely on the degree of overlap in symptoms major depression, sickness behavior, and starvation depression share, the argument is that sickness behavior likely evolved first due to its prevalence across animal species and the role infection plays as a major fitness threat. however, once the ability to down-regulate behavior to divert resources for immune function existed, the underlying mechanisms could then be used by other systems. this is thought to then allow for additional adaptations that add cognitive symptoms unique to melancholic depression to those stemming from normal sickness behavior. although likely consistent with any explanation of the evolution as major depression as the result of psychological adaptations, andrews and durisko present the co-option hypothesis as mainly consistent with the analytical rumination hypothesis. from this perspective, major depression is thought to often result in improved problem solving due to the redistribution of energy away from physical activity for increased rumination. as this is thought to be energetically costly, it therefore functions very similarly to sickness behavior with it both being adaptive for redistributing energy flows, differing primarily in whether increasing energy goes to cognition or immune defense.