RESUMO
Oxidative stress generating DNA damage has been shown to be a key characteristic in Alzheimer's disease (AD). However, how it affects the pathogenesis of AD is not yet fully understood. Neil3 is a DNA glycosylase initiating repair of oxidative DNA base lesions and with a distinct expression pattern in proliferating cells. In brain, its function has been linked to hippocampal-dependent memory and to induction of neurogenesis after stroke and in prion disease. Here, we generated a novel AD mouse model deficient for Neil3 to study the impact of impaired oxidative base lesion repair on the pathogenesis of AD. Our results demonstrate an age-dependent decrease in amyloid-ß (Aß) plaque deposition in female Neil3-deficient AD mice, whereas no significant difference was observed in male mice. Furthermore, male but not female Neil3-deficient AD mice show reduced neural stem cell proliferation in the adult hippocampus and impaired working memory compared to controls. These effects seem to be independent of DNA repair as both sexes show increased level of oxidative base lesions in the hippocampus upon loss of Neil3. Thus, our findings suggest an age- and sex-dependent role of Neil3 in the progression of AD by altering cerebral Aß accumulation and promoting adult hippocampal neurogenesis to maintain cognitive function.
Assuntos
Doença de Alzheimer , DNA Glicosilases , Masculino , Feminino , Camundongos , Animais , Doença de Alzheimer/genética , DNA Glicosilases/genética , Neurogênese/genética , Modelos Animais de Doenças , Placa Amiloide/genética , Peptídeos beta-Amiloides/genética , Transtornos da MemóriaRESUMO
Recent investigations of the rat posterior parietal cortex (PPC) suggest that this region plays a central role in action control together with the frontal cortical areas. Posterior parietal-frontal cortical connections have been described in rats, but little is known about whether these connections are topographically organized as in the primate. Here, we injected retrograde and anterograde tracers into subdivisions of PPC as well as the frontal midline and orbital cortical areas to explore possible topographies within their connections. We found that PPC projects to several frontal cortical areas, largely reciprocating the densest input received from the same areas. All PPC subdivisions are strongly connected with the secondary motor cortex (M2) in a topographically organized manner. The medial subdivision (medial posterior parietal cortex, mPPC) has a dense reciprocal connection with the most caudal portion of M2 (cM2), whereas the lateral subdivision (lateral posterior parietal cortex, lPPC) and the caudolateral subdivision (PtP) are reciprocally connected with the intermediate rostrocaudal portion of M2 (iM2). Sparser reciprocal connections were seen with anterior cingulate area 24b. mPPC connects with rostral, and lPPC and PtP connect with caudal parts of 24b, respectively. There are virtually no connections with area 24a, nor with prelimbic or infralimbic cortex. PPC and orbitofrontal cortices are also connected, showing a gradient such that mPPC entertains reciprocal connections mainly with the ventral orbitofrontal cortex (OFC), whereas lPPC and PtP are preferentially connected with medial and central portions of ventrolateral OFC, respectively. Our results thus indicate that the connections of PPC with frontal cortices are organized in a topographical fashion, supporting functional heterogeneity within PPC and frontal cortices.
RESUMO
Experts have long warned against psychotherapy with psychopathic offenders out of a fear that they will beguile therapists into believing they have been rehabilitated, only to commit new offenses upon release. Yet the question is not whether to communicate with psychopathic offenders, but rather how to do so in a way which can facilitate real change. In this article, we ask: What can we learn about psychopathic offenders by studying their communication? We review the literature and describe how psychopathy is manifested in communication, how psychopathy can be understood based on this communication, and how therapists may communicate with psychopaths to create change and avoid being fooled. We recommend that therapists do not withdraw from psychopathic offenders but rather study their communication more carefully.
