Juvenile male rats display lower cortical metabolic capacity than females

Departments of Psychology, Pharmacology and Toxicology, University of Texas at Austin, 1 University Station A8000, Austin, TX 78712, USA.
Neuroscience Letters (Impact Factor: 2.03). 09/2008; 440(3):255-9. DOI: 10.1016/j.neulet.2008.05.104
Source: PubMed


The juvenile brain undergoes marked maturational changes accompanied by major sex hormone changes. In particular, sex differences in neural substrates could underlie male-specific dysfunction in behavioral responses related to the prefrontal cortex. Sex differences in regional metabolic capacity of the cerebral cortex were investigated in juvenile Sprague-Dawley rats. At 6 weeks of age the brains were processed for quantitative histochemistry of cytochrome oxidase, a rate-limiting enzyme in cellular respiration, which is an index of brain metabolic capacity. Quantitative image analysis revealed a main effect of sex with males displaying lower regional metabolic capacity than females in the dorsolateral and orbital prefrontal cortex and in the posterior parietal cortex. In addition, males separated for 6 h/day from their mothers as pups showed greater ambulatory behavior in the novel open field and higher metabolism in the posterior parietal cortex relative to males separated for 15 min/day. This is the first study to show sex differences in brain metabolic capacity in regions such as the prefrontal cortex that may be hypometabolic in juvenile males relative to females.

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    • "We have previously demonstrated that adolescent Sprague-Dawley males and females show sex differences in brain CO activity (Spivey et al., 2008a), particularly in the prefrontal and posterior parietal cortical regions. Some neurochemical changes in the brain resulting from maternal separation have been reported to be sex-dependent. "
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    ABSTRACT: This is the first study to assess the effects of mother-infant separation on regional metabolic capacity in the preweanling rat brain. Mother-infant separation is generally known to be stressful for rat pups. Holtzman adolescent rats show a depressive-like behavioral phenotype after maternal separation during the preweanling period. However, information is lacking on the effects of maternal separation on the brains of rat pups. We addressed this issue by mapping the brains of preweanling Holtzman rat pups using cytochrome oxidase histochemistry, which reflects long-term changes in brain metabolic capacity, following two weeks of repeated, prolonged maternal separation, and compared this to both early handled and non-handled pups. Quantitative image analysis revealed that maternal separation reduced cytochrome oxidase activity in the medial prefrontal cortex and nucleus accumbens shell. Maternal separation reduced prefrontal cytochrome oxidase to a greater degree in female pups than in males. Early handling reduced cytochrome oxidase activity in the posterior parietal cortex, ventral tegmental area, and subiculum, but increased cytochrome oxidase activity in the lateral frontal cortex. The sex-dependent effects of early handling on cytochrome oxidase activity were limited to the medial prefrontal cortex. Regardless of separation group, females had greater cytochrome oxidase activity in the habenula and ventral tegmental area compared to males. These findings suggest that early life mother-infant separation results in dysfunction of prefrontal and mesolimbic regions in the preweanling rat brain that may contribute to behavioral changes later in life.
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    ABSTRACT: Käesolevas väitekirjas vaadeldakse kaht püsivatel käitumuslikel fenotüüpidel põhinevat ja üht geneetilist loomkatsemudelit, mis on mõeldud afektiivsete protsesside kaudu haavatavamate katseloomade väljavalimiseks või tekitamiseks. Emotsionaalselt haavatavamad loomad võimaldavad valiidsemalt reprodutseerida inimese depressioonilaadset seisundit. Esimene kahel polaarsel käitumisfenotüübil põhinev loomkatsemudel on uudiskastis vähe- ja palju-uudistavad rotid ja teine on eksperimentaatori-poolse manuaalse stimulatsiooni ehk kõdistamise poolt esilekutsutud 50-kHz sagedusel esitatud ultrahelihäälitsuste hulga põhjal eristatud vähe ja palju 50-kHz sagedusel häälitsevad rotid. Kolmadaks mudeliks oli heterosügootne hiire nokautmudel, kus hiirel oli välja lülitatud vesikulaarse glutamaadi transporteri 1 (VGLUT1) geeni üks kahest alleelist. Selline manipulatsioon suurendab glutamaadi/gamma-aminovõihappe suhet kesknärvisüsteemis ja sellist endofenotüüpi on leitud ka meeleoluhäretega inimestel. Kõigis kolmes mudelis rakendati loomadele kroonilist muutlikku stressi depressiooni-laadse afektiivse seisundi esilekutsumiseks ning mõõdeti oksüdatiivset ajumetabolismi tsütokroom c oksüdaasi histokeemia abil. Vähe 50-kHz-häälitsevad isasrotid osutusid läbitestitud käitumuslikest fenotüüpidest stressi poolt enim haavatavateks. Kroonilise muutliku stressi tagajärjel arenes neil anhedoonia ning nad eelistasid passiivseid toimetulekustrateegiaid, lisaks esines neil rohkem stressijärgseid ajumetabolismi regionaalseid muutusi. Väheuudistavad rotid olid teiseks käitumuslikuks fenotüübiks, kellel esinesid mõned paljulubavad stressijärgsed käitumise muutused, kuid mitte nii selgelt, nagu vähe 50-kHz-häälitsevatel isastel. VGLUT1 geeni osalise nokaudiga hiirtel suurenes samuti anhedoonia kroonilise muutliku stressi tagajärjel ning mitmes käitumiskatses paistsid nad abitumad kui geneetiliselt muundamata hiired. Emaste rottide kroonilise muutliku stressi taluvusvõime oli käitumiskatsetes suurem võrreldes isastega ning neil esines ka vähem stressijärgseid ajumetabolismi regionaalseid Two animal models of affective vulnerability based on the selection for stable behavioural phenotypes and one based on the genetic manipulation are discussed in the thesis. Use of animals exhibiting affective vulnerability adds validity to models of human mood disorders. The first animal model was based on the selection in the exploratory box test for rats with low and high exploratory phenotype. In the second animal model, the selection for opposing behavioural phenotypes was based on the number 50-kHz ultrasonic vocalisations (USVs) emitted upon manual playful stimulation of a juvenile rat by experimenter or 'tickling'. Heterozygous knockout of the vesicular glutamate transporter 1 (VGLUT1) in mice was the third animal model, in which one of VGLUT1 gene alleles was inactivated. Partial VGLUT1 gene inactivation increases glutamate to GABA ratio in the central nervous system - an endophenotype of human mood disorders observed in some clinical samples. In all three models, a chronic variable stress (CVS) was employed to elicit depressive-like state in the experimental subjects, and their cerebral oxidative metabolism was measured via cytochrome c oxidase histochemistry - a biomarker for long-term neuronal energy demand. From the presented behavioural phenotypes, low 50-kHz USV emitting male rats seem to be the most vulnerable to stressful stimulation. They co-express symptoms of anhedonia and passive coping strategies and show discrete changes in cerebral oxidative metabolism. Low exploratory (LE) male rats is another behavioural phenotype that showed some promising stress-associated changes in behaviour, however, behavioural profile of LE-rats is more ambiguous, and there was no unique changes in brain metabolic activity to CVS regimen. Female rats demonstrated a better stress-tolerance and had fewer CVS-associated changes in cytochrome c oxidase activity than male rats.
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