Cerebral oxidative metabolism mapping in four genetic mouse models of anxiety and mood disorders

Abstract

The psychopathology of depression is highly complex and the outcome of studies on animal models is divergent. In order to find brain regions that could be metabolically distinctively active across a variety of mouse depression models and to compare the interconnectivity of brain regions of wild-type and such genetically modified mice, histochemical mapping of oxidative metabolism was performed by the measurement of cytochrome oxidase activity. We included mice with the heterozygous knockout of the vesicular glutamate transporter (VGLUT1 −/+ ), full knockout of the cannabinoid 1 receptor (CB1 −/− ), an anti-sense knockdown of the glucocorticoid receptor (GRi) and overexpression of the human 5-hydroxytryptamine transporter (h5-HTT). Altogether 76 mouse brains were studied to measure oxidative metabolism in one hundred brain regions, and the obtained dataset was submitted to a variety of machine learning algorithms and multidimensional scaling. Overall, the top brain regions having the largest contribution to classification into depression model were the lateroanterior hypothalamic nucleus, the anterior part of the basomedial amygdaloid nucleus, claustrum, the suprachiasmatic nucleus, the ventromedial hypothalamic nucleus, and the anterior hypothalamic area. In terms of the patterns of interregional relationship between wild-type and genetically modified mice there was little overall difference, while the most deviating brain regions were cortical amygdala and ventrolateral and ventral posteromedial thalamic nuclei. The GRi mice that most clearly differed from their controls exhibited deviation of connectivity for a number of brain regions, such as ventrolateral thalamic nucleus, the intermediate part of the lateral septal nucleus, the anteriodorsal part of the medial amygdaloid nucleus, the medial division of the central amygdaloid nucleus, ventral pallidum, nucleus of the vertical limb of the diagonal band, anteroventral parts of the thalamic nucleus and parts of the bed nucleus of the stria terminalis. Conclusively, the GRi mouse model was characterized by changes in the functional connectivity of the extended amygdala and stress response circuits. Cytochrome oxidase histochemistry cortex, CA1 field CA1 of hippocampus, CA2 field CA2 of hippocampus, CA3 field CA3 of hippocampus, FrA frontal association cortex, GP globus pallidus, IL infralimbic cortex, IPR interpeduncular nucleus rostral subnucleus, Lent lateral entorhinal cortex, LHb lateral habenular nucleus, LH lateral hypothalamic area, LO lateral orbital cortex, LPAG lateral periaqueductal gray, LPO lateral preoptic area, LSI lateral septal nucleus intermediate part, LA lateroanterior hypothalamic nucleus, LC locus coeruleus, MeAD medial amygdaloid nucleus anterior dorsal, MHb medial habenular nucleus, MM medial mammillary nucleus medial part, MO medial orbital cortex, MPA medial preoptic area, MPOM medial preoptic nucleus medial part, MS medial septal nucleus, MnPO median preoptic nucleus, MnR median raphe nucleus, MDL mediodorsal thalamic nucleus lateral pa...

AKT and MAPK signaling pathways in hippocampus reveals the pathogenesis of depression in four stress-induced models

“…The difference was that the intrinsic components of susceptibility in CSDS mice were largely dependent on epigenetic factors and early life environment [ 50 , 51 ], and that the BDNF het-Met variant confers a genetic predisposition to stress-related behaviors in response to applied stressors [ 52 ]. Meanwhile, a combined analysis of four genetic mouse models of affective disorders showed that the similarity between these models was highly correlated with regional oxidative metabolism revealed by cytochrome oxidase histochemistry, and different in that the GRi (glucocorticoid receptor) mouse model was characterized by several alterations in oxidative metabolism and altered functional connectivity of the extended amygdala and stress response circuit [ 53 ].…”

Comorbidity Network Analysis of Depression, Anxiety and Stress During the COVID-19 Pandemic

“…Symptom sad mood is closely related to abnormal brain connectivity in depression patients. It induces increased activation of the ventrolateral thalamus nucleus [43], while the abnormality of the ventral thalamus nucleus is the important abnormal brain regions of GRI model mice [44]. Besides depressive symptoms, stress symptom intolerable is the most important factor.…”

Early-life stress induces emotional and molecular alterations in female mice that are partially reversed by cannabidiol

“…Mitochondrial function as related to brain energy metabolism of limbic regions plays a pivotal role in stress responses, motivation, mood, and anxiety (Filiou and Sandi, 2019;Harro et al, 2011;Mällo et al, 2009;Matrov et al, 2019). In this regard, decreased oxidative metabolic capacity was found in the BLA, LA and BST of MSEW as compared to their SN.…”