Editing Toxoplasmosis (section)

=== Rodents ===
Infection with ''T. gondii'' has been shown to [[Behavior-altering parasites and parasitoids|alter the behavior]] of mice and rats in ways thought to increase the rodents' chances of being preyed upon by cats.<ref name=Webster_2010/><ref name=Webster_2007>{{cite journal |last1=Webster |first1=J. P. |title=The Effect of Toxoplasma gondii on Animal Behavior: Playing Cat and Mouse |journal=Schizophrenia Bulletin |date=19 March 2007 |volume=33 |issue=3 |pages=752–756 |doi=10.1093/schbul/sbl073 |pmid=17218613 |pmc=2526137 }}</ref><ref name=Berdoy_2000>{{cite journal |last1=Berdoy |first1=M. |last2=Webster |first2=J. P. |last3=Macdonald |first3=D. W. | title = Fatal attraction in rats infected with ''Toxoplasma gondii'' | journal = Proceedings of the Royal Society B: Biological Sciences | volume = 267 | issue = 1452 | pages = 1591–1594 | date = August 7, 2000 | pmid = 11007336 | pmc = 1690701 | doi = 10.1098/rspb.2000.1182 }}</ref> Infected rodents show a reduction in their innate aversion to cat odors; while uninfected mice and rats will generally avoid areas marked with cat [[urine]] or with cat body odor, this avoidance is reduced or eliminated in infected animals.<ref name=Webster_2010 /><ref name=Berdoy_2000 /><ref name=Vyas2007BehavioralChanges>{{cite journal |vauthors=Vyas A, Kim SK, Giacomini N, Boothroyd JC, Sapolsky RM | title = Behavioral changes induced by ''Toxoplasma'' infection of rodents are highly specific to aversion of cat odors | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 104 | issue = 15 | pages = 6442–6447 | date = April 10, 2007 | pmid = 17404235 | pmc = 1851063 | doi = 10.1073/pnas.0608310104 | bibcode = 2007PNAS..104.6442V | doi-access = free }}</ref> Moreover, some evidence suggests this loss of aversion may be specific to feline odors: when given a choice between two [[predator]] odors (cat or [[mink]]), infected rodents show a significantly stronger preference to cat odors than do uninfected [[control (experiment)|controls]].<ref name="Xiao_2012">{{cite journal |vauthors=Xiao J, Kannan G, Jones-Brando L, Brannock C, Krasnova IN, Cadet JL, Pletnikov M, Yolken RH | title = Sex-specific changes in gene expression and behavior induced by chronic ''Toxoplasma'' infection in mice | journal = Neuroscience | volume = 206 | pages = 39–48 | date = March 29, 2012 | pmid = 22240252 | doi = 10.1016/j.neuroscience.2011.12.051 | s2cid = 24725619 }}</ref><ref name=Lamberton2008>{{cite journal |vauthors=Lamberton PH, Donnelly CA, Webster JP | title = Specificity of the''Toxoplasma gondii''-altered behaviour to definitive versus non-definitive host predation risk | journal = Parasitology | volume = 135 | issue = 10 | pages = 1143–1150 | date = September 2008 | pmid = 18620624 | doi = 10.1017/S0031182008004666 | s2cid = 21601830 }}</ref>

In rodents, ''T.&nbsp;gondii''–induced behavioral changes occur through [[chromatin remodeling|epigenetic remodeling]] in neurons associated with observed behaviors;<ref name="TG Masterpiece review" /><ref name="Masterpiece of epigenetic engineering" /> for example, it modifies [[epigenetic methylation]] to induce hypomethylation of [[arginine vasopressin]]-related genes in the medial amygdala to greatly decrease predator aversion.<ref name="TG Masterpiece review">{{cite journal | vauthors = Hari Dass SA, Vyas A | title = ''Toxoplasma gondii'' infection reduces predator aversion in rats through epigenetic modulation in the host medial amygdala | journal = Molecular Ecology | volume = 23 | issue = 24 | pages = 6114–6122 | date  = December 2014 | pmid = 25142402 | doi = 10.1111/mec.12888 | bibcode = 2014MolEc..23.6114H | s2cid = 45290208 }}</ref><ref name="Masterpiece of epigenetic engineering">{{cite journal | vauthors = Flegr J, Markoš A | title = Masterpiece of epigenetic engineering – how ''Toxoplasma gondii'' reprogrammes host brains to change fear to sexual attraction | journal = Molecular Ecology | volume = 23 | issue = 24 | pages = 5934–5936 | date  = December 2014 | pmid = 25532868 | doi = 10.1111/mec.13006 | bibcode = 2014MolEc..23.5934F | s2cid = 17253786 | doi-access = free }}</ref> Similar epigenetically induced behavioral changes have also been observed in mouse models of addiction, where changes in the expression of [[histone-modifying enzyme]]s via [[gene knockout]] or [[enzyme inhibition]] in specific neurons produced alterations in drug-related behaviors.<ref name="Amphetamine epigenetics">{{cite journal | vauthors =  McCowan TJ, Dhasarathy A, Carvelli L | title = The Epigenetic Mechanisms of Amphetamine | journal = Journal of Addiction and Prevention | date = February 2015 | issue = S1 | pages = 1–7 | pmc = 4955852 | quote = Epigenetic modifications caused by addictive drugs play an important role in neuronal plasticity and in drug-induced behavioral responses. Although few studies have investigated the effects of AMPH on gene regulation (Table 1), current data suggest that AMPH acts at multiple levels to alter histone/DNA interaction and to recruit transcription factors which ultimately cause repression of some genes and activation of other genes. Importantly, some studies have also correlated the epigenetic regulation induced by AMPH with the behavioral outcomes caused by this drug, suggesting therefore that epigenetics remodeling underlies the behavioral changes induced by AMPH. If this proves to be true, the use of specific drugs that inhibit histone acetylation, methylation or DNA methylation might be an important therapeutic alternative to prevent and/or reverse AMPH addiction and mitigate the side effects generate by AMPH when used to treat ADHD. | pmid=27453897 | volume=2015}}</ref><ref name="pmid25486626">{{cite journal | vauthors = Walker DM, Cates HM, Heller EA, Nestler EJ | title = Regulation of chromatin states by drugs of abuse | journal = Current Opinion in Neurobiology | volume = 30 | pages = 112–121 | date = February 2015 | pmid = 25486626 | doi = 10.1016/j.conb.2014.11.002 | pmc=4293340}}</ref><ref name="pmid23643695">{{cite journal|vauthors=Nestler EJ|title=Epigenetic mechanisms of drug addiction|journal=Neuropharmacology|volume=76|issue=Pt B|pages=259–268|date=January 2014|pmid=23643695|pmc=3766384|doi=10.1016/j.neuropharm.2013.04.004|quote=Short-term increases in histone acetylation generally promote behavioral responses to the drugs, while sustained increases oppose cocaine's effects, based on the actions of systemic or intra-NAc administration of HDAC inhibitors.&nbsp;...  Genetic or pharmacological blockade of G9a in the NAc potentiates behavioral responses to cocaine and opiates, whereas increasing G9a function exerts the opposite effect (Maze et al., 2010; Sun et al., 2012a). Such drug-induced downregulation of G9a and H3K9me2 also sensitizes animals to the deleterious effects of subsequent chronic stress (Covington et al., 2011). Downregulation of G9a increases the dendritic arborization of NAc neurons, and is associated with increased expression of numerous proteins implicated in synaptic function, which directly connects altered G9a/H3K9me2 in the synaptic plasticity associated with addiction (Maze et al., 2010).<p><!-- continuing quotation across paragraph break-->"G9a appears to be a critical control point for epigenetic regulation in NAc, as we know it functions in two negative feedback loops. It opposes the induction of ΔFosB, a long-lasting transcription factor important for drug addiction (Robison and Nestler, 2011), while ΔFosB in turn suppresses G9a expression (Maze et al., 2010; Sun et al., 2012a).&nbsp;... Also, G9a is induced in NAc upon prolonged HDAC inhibition, which explains the paradoxical attenuation of cocaine's behavioral effects seen under these conditions, as noted above (Kennedy et al., 2013). GABAA receptor subunit genes are among those that are controlled by this feedback loop. Thus, chronic cocaine, or prolonged HDAC inhibition, induces several GABAA receptor subunits in NAc, which is associated with increased frequency of inhibitory postsynaptic currents (IPSCs). In striking contrast, combined exposure to cocaine and HDAC inhibition, which triggers the induction of G9a and increased global levels of H3K9me2, leads to blockade of GABAA receptor and IPSC regulation.</p>}}</ref> Widespread [[histone acetylation and deacetylation|histone–lysine acetylation]] in cortical [[astrocytes]] appears to be another epigenetic mechanism employed by ''T.&nbsp;gondii''.<ref name="T. Gondii has a HAT">{{cite journal |last1=Vanagas |first1=Laura |last2=Jeffers |first2=Victoria |last3=Bogado |first3=Silvina S |last4=Dalmasso |first4=Maria C |last5=Sullivan |first5=William J |last6=Angel |first6=Sergio O |title=''Toxoplasma'' histone acetylation remodelers as novel drug targets |journal=Expert Review of Anti-infective Therapy |date=October 2012 |volume=10 |issue=10 |pages=1189–1201 |doi=10.1586/eri.12.100 |pmid=23199404 |pmc=3581047 }}</ref><ref name="acetylation">{{cite journal | vauthors = Bouchut A, Chawla AR, Jeffers V, Hudmon A, Sullivan WJ | title = Proteome-wide lysine acetylation in cortical astrocytes and alterations that occur during infection with brain parasite ''Toxoplasma gondii'' | journal = PLOS ONE | volume = 10 | issue = 3 | pages = e0117966 | year = 2015 | pmid = 25786129 | pmc = 4364782 | doi = 10.1371/journal.pone.0117966 | bibcode = 2015PLoSO..1017966B | doi-access = free }}</ref>

''T. gondii''-infected rodents show a number of behavioral changes beyond altered responses to cat odors. Rats infected with the parasite show increased levels of activity and decreased [[neophobic]] behavior.<ref name=McConkey_2013>{{cite journal |vauthors=McConkey GA, Martin HL, Bristow GC, Webster JP | title = ''Toxoplasma gondii'' infection and behaviour – location, location, location? | journal = The Journal of Experimental Biology | volume = 216 | issue = Pt 1 | pages = 113–119 | date = January 1, 2013 | pmid = 23225873 | pmc = 3515035 | doi = 10.1242/jeb.074153 | bibcode = 2013JExpB.216..113M }}</ref> Similarly, infected mice show alterations in patterns of [[Animal locomotion|locomotion]] and exploratory behavior during experimental tests. These patterns include traveling greater distances, moving at higher speeds, accelerating for longer periods of time, and showing a decreased pause-time when placed in new arenas.<ref name=Afonso_2012>{{cite journal |vauthors=Afonso C, Paixão VB, Costa RM | title = Chronic ''Toxoplasma'' infection modifies the structure and the risk of host behavior | journal = PLOS ONE | volume = 7 | issue = 3 | pages = e32489 | year = 2012 | pmid = 22431975 | pmc = 3303785 | doi = 10.1371/journal.pone.0032489 | editor1-last = Hakimi | bibcode = 2012PLoSO...732489A | doi-access = free }}</ref> Infected rodents have also been shown to have lower [[anxiety (mood)|anxiety]], using traditional models such as [[elevated plus maze]]s, [[Open Field (animal test)|open field arenas]], and social interaction tests.<ref name=Afonso_2012 /><ref>{{cite journal |vauthors=Gonzalez LE, Rojnik B, Urrea F, Urdaneta H, Petrosino P, Colasante C, Pino S, Hernandez L | title = ''Toxoplasma gondii'' infection lower anxiety as measured in the plus-maze and social interaction tests in rats: A behavioral analysis | journal = Behavioural Brain Research | volume = 177 | issue = 1 | pages = 70–79 | date = February 12, 2007 | pmid = 17169442 | doi = 10.1016/j.bbr.2006.11.012 | s2cid = 33572709 }}</ref>