RESUMO
We present here the first evidence of the much-predicted double dissociation between the effect of stress on cognitive skills [executive functions (EFs)] dependent on prefrontal cortex (PFC) by catechol-O-methyltransferase (COMT) genotype. The COMT gene polymorphism with methionine (Met) at codon 158 results in more dopamine (DA) in PFC and generally better EFs, while with valine (Val) at codon 158 the result is less PFC DA and generally poorer EFs. Many have predicted that mild stress, by raising PFC DA levels should aid EFs of COMT-Vals (bringing their PFC DA levels up, closer to optimal) and impair EFs of COMT-Mets (raising their PFC DA levels past optimal). We tested 140 men and women in a within-subject crossover design using extremely mild social evaluative stress. On trials requiring EFs (incongruent trials) of the Flanker/Reverse Flanker task, COMT-Val158 homozygotes performed better when mildly stressed than when calmer, while COMT-Met158 carriers performed worse when mildly stressed. Two other teams previously tried to obtain this, but only found stress impairing EFs of COMT-Mets, not improving EFs of COMT-Vals. Perhaps we found both because we used a much milder stressor. Evidently, the bandwidth for stress having a facilitative effect on EFs is exceedingly narrow.
Assuntos
Catecol O-Metiltransferase/genética , Função Executiva/fisiologia , Córtex Pré-Frontal/fisiologia , Estresse Psicológico , Adulto , Feminino , Genótipo , Humanos , Masculino , Polimorfismo de Nucleotídeo ÚnicoRESUMO
In an evolutionary context, trusted signals or cues provide individuals with the opportunity to manipulate them to their advantage by deceiving others. The deceived can then respond to the deception by either ignoring the signals or cues or evolving means of deception-detection. If the latter happens, it can result in an arms race between deception and detection. Here, we formally analyse these possibilities in the context of cue-mimicry in prey-predator interactions. We demonstrate that two extrinsic parameters control whether and for how long an arms race continues: the benefits of deception, and the cost of ignoring signals and cues and having an indiscriminate response. As long as the cost of new forms of deception is less than its benefits and the cost of new forms of detection is less than the cost of an indiscriminate response, an arms race results in the perpetual evolution of better forms of detection and deception. When novel forms of deception or detection become too costly to evolve, the population settles on a polymorphic equilibrium involving multiple strategies of deception and honesty, and multiple strategies of detection and trust.
Assuntos
Comportamento Animal , Mimetismo Biológico , Sinais (Psicologia) , Animais , EnganaçãoRESUMO
Concussion is a serious health concern. Concussion in athletes is of particular interest with respect to the relationship of concussion exposure to risk of chronic traumatic encephalopathy (CTE), a neurodegenerative condition associated with altered cognitive and psychiatric functions and profound tauopathy. However, much remains to be learned about factors other than cumulative exposure that could influence concussion pathogenesis. Approximately 20% of CTE cases report a history of substance use including androgenic-anabolic steroids (AAS). How acute, chronic, or historical AAS use may affect the vulnerability of the brain to concussion is unknown. We therefore tested whether antecedent AAS exposure in young, male C57Bl/6 mice affects acute behavioral and neuropathological responses to mild traumatic brain injury (TBI) induced with the CHIMERA (Closed Head Impact Model of Engineered Rotational Acceleration) platform. Male C57Bl/6 mice received either vehicle or a cocktail of three AAS (testosterone, nandrolone and 17α-methyltestosterone) from 8-16 weeks of age. At the end of the 7th week of treatment, mice underwent two closed-head TBI or sham procedures spaced 24 h apart using CHIMERA. Post-repetitive TBI (rTBI) behavior was assessed for 7 d followed by tissue collection. AAS treatment induced the expected physiological changes including increased body weight, testicular atrophy, aggression and downregulation of brain 5-HT1B receptor expression. rTBI induced behavioral deficits, widespread axonal injury and white matter microgliosis. While AAS treatment did not worsen post-rTBI behavioral changes, AAS-treated mice exhibited significantly exacerbated axonal injury and microgliosis, indicating that AAS exposure can alter neuronal and innate immune responses to concussive TBI.
Assuntos
Anabolizantes/farmacologia , Androgênios/farmacologia , Axônios/efeitos dos fármacos , Axônios/patologia , Concussão Encefálica/complicações , Lesão Encefálica Crônica/patologia , Esteroides/farmacologia , Animais , Concussão Encefálica/patologia , Lesões Encefálicas/complicações , Lesões Encefálicas/patologia , Lesão Encefálica Crônica/complicações , Modelos Animais de Doenças , Progressão da Doença , Masculino , Metiltestosterona/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Nandrolona/farmacologia , Testosterona/análogos & derivados , Testosterona/farmacologia , Fatores de TempoRESUMO
The apolipoprotein E (APOE) gene is the most highly associated susceptibility locus for late onset Alzheimer's Disease (AD), and augmenting the beneficial physiological functions of apoE is a proposed therapeutic strategy. In a high throughput phenotypic screen for small molecules that enhance apoE secretion from human CCF-STTG1 astrocytoma cells, we show the chrysanthemic ester 82879 robustly increases expressed apoE up to 9.4-fold and secreted apoE up to 6-fold and is associated with increased total cholesterol in conditioned media. Compound 82879 is unique as structural analogues, including pyrethroid esters, show no effect on apoE expression or secretion. 82879 also stimulates liver x receptor (LXR) target genes including ATP binding cassette A1 (ABCA1), LXRα and inducible degrader of low density lipoprotein receptor (IDOL) at both mRNA and protein levels. In particular, the lipid transporter ABCA1 was increased by up to 10.6-fold upon 82879 treatment. The findings from CCF-STTG1 cells were confirmed in primary human astrocytes from three donors, where increased apoE and ABCA1 was observed along with elevated secretion of high-density lipoprotein (HDL)-like apoE particles. Nuclear receptor transactivation assays revealed modest direct LXR agonism by compound 82879, yet 10 µM of 82879 significantly upregulated apoE mRNA in mouse embryonic fibroblasts (MEFs) depleted of both LXRα and LXRß, demonstrating that 82879 can also induce apoE expression independent of LXR transactivation. By contrast, deletion of LXRs in MEFs completely blocked mRNA changes in ABCA1 even at 10 µM of 82879, indicating the ability of 82879 to stimulate ABCA1 expression is entirely dependent on LXR transactivation. Taken together, compound 82879 is a novel chrysanthemic ester capable of modulating apoE secretion as well as apoE-associated lipid metabolic pathways in astrocytes, which is structurally and mechanistically distinct from known LXR agonists.