Neural network of bipolar disorder: Toward integration of neuroimaging and neurocircuit-based treatment strategies.

Bipolar disorder (BD) is a complex psychiatric disorder characterized by dysfunctions in three domains including emotional processing, cognitive processing, and psychomotor dimensions. However, the neural underpinnings underlying these clinical profiles are not well understood. Based on the reported data, we hypothesized that (i) the core neuropathology in BD is damage in fronto-limbic network, which is associated with emotional dysfunction; (ii) changes in intrinsic brain network, such as sensorimotor network, salience network, default-mode network, central executive network are associated with impaired cognition function; and (iii) beyond the dopaminergic-driven basal ganglia-thalamo-cortical motor circuit modulated by other neurotransmitter systems, such as serotonin (subcortical-cortical modulation), the sensorimotor network and related motor function modulated by other non-motor networks such as the default-mode network are involved in psychomotor function. In this review, we propose a neurocircuit-based clinical characteristics and taxonomy to guide the treatment of BD. We draw on findings from neuropsychological and neuroimaging studies in BD and link variations in these clinical profiles to underlying neurocircuit dysfunctions. We consider pharmacological, psychotherapy, and neuromodulatory treatments that could target those specific neurocircuit dysfunctions in BD. Finally, it is suggested that the methods of testing the neurocircuit-based taxonomy and important limitations to this approach should be considered in future.

Effect of circular RNA, mmu_circ_0000296, on neuronal apoptosis in chronic cerebral ischaemia via the miR-194-5p/Runx3/Sirt1 axis.

Chronic cerebral ischaemia (CCI) is a common pathological disorder, which is associated with various diseases, such as cerebral arteriosclerosis and vascular dementia, resulting in neurological dysfunction. As a type of non-coding RNA, circular RNA is involved in regulating the occurrence and development of diseases, such as ischaemic brain injury. Here, we found that HT22 cells and hippocampus treated with CCI had low expression of circ_0000296, Runx3, Sirt1, but high expression of miR-194-5p. Overexpression of circ_0000296, Runx3, Sirt1, and silenced miR-194-5p significantly inhibited neuronal apoptosis induced by CCI. This study demonstrated that circ_0000296 specifically bound to miR-194-5p; miR-194-5p bound to the 3'UTR region of Runx3 mRNA; Runx3 directly bound to the promoter region of Sirt1, enhancing its transcriptional activity. Overexpression of circ_0000296 by miR-194-5p reduced the negative regulatory effect of miR-194-5p on Runx3, promoted the transcriptional effect of Runx3 on Sirt1, and inhibited neuronal apoptosis induced by CCI. mmu_circ_0000296 plays an important role in regulating neuronal apoptosis induced by CCI through miR-194-5p/Runx3/Sirt1 pathway.

Correction: Mechanism of Snhg8/miR-384/Hoxa13/FAM3A axis regulating neuronal apoptosis in ischemic mice model.

Following the publication of this article, the authors realized there was an error in Figure 6H in which two versions of the figure appear.This does not impact the conclusions of the article.

Mechanism of Snhg8/miR-384/Hoxa13/FAM3A axis regulating neuronal apoptosis in ischemic mice model.

Long noncoding RNAs, a subgroup of noncoding RNAs, are implicated in ischemic brain injury. The expression levels of Snhg8, miR-384, Hoxa13, and FAM3A were measured in chronic cerebral ischemia-induced HT22 cells and hippocampal tissues. The role of the Snhg8/miR-384/Hoxa13/FAM3A axis was evaluated in chronic cerebral ischemia models in vivo and in vitro. In this study, we found that Snhg8 and Hoxa13 were downregulated, while miR-384 was upregulated in chronic cerebral ischemia-induced HT22 cells and hippocampal tissues. Overexpression of Snhg8 and Hoxa13, and silencing of miR-384, all inhibited chronic cerebral ischemia-induced apoptosis of HT22 cells. Moreover, Snhg8 bound to miR-384 in a sequence-dependent manner and there was a reciprocal repression between Snhg8 and miR-384. Besides, overexpression of miR-384 impaired Hoxa13 expression by targeting its 3'UTR and regulated chronic cerebral ischemia-induced neuronal apoptosis. Hoxa13 bound to the promoter of FAM3A and enhanced its promotor activity, which regulated chronic cerebral ischemia-induced neuronal apoptosis. Remarkably, the in vivo experiments demonstrated that Snhg8 overexpression combined with miR-384 knockdown led to an anti-apoptosis effect. These results reveal that the Snhg8/miR-384/Hoxa13/FAM3A axis plays a critical role in the regulation of chronic cerebral ischemia-induced neuronal apoptosis.

Cerebellar Purkinje cell neurodegeneration after cardiac arrest: effect of therapeutic hypothermia.

AIMS: The cerebellum is among the brain regions most vulnerable to damage caused by cardiac arrest, and cerebellar Purkinje cell loss may contribute to neurologic dysfunction, including post-hypoxic myoclonus. However, it remains unknown whether cerebellar Purkinje cells are protected by post-cardiac arrest therapeutic hypothermia (TH). Therefore, we examined the effect of post-cardiac arrest TH onset and duration on cerebellar Purkinje cell loss. METHODS: Samples from a previously published study of post-cardiac arrest TH were utilized for the present analysis. Adult male rats subjected to asphyxial cardiac arrest and cardiopulmonary resuscitation were block randomized to normothermia (37.0°C) or TH (33.0°C) initiated 0, 1, 4, or 8h after return of spontaneous circulation (ROSC) and maintained for 24 or 48 h. Cerebella from rats surviving 7 days after ROSC were processed for histology and immunohistochemistry. Purkinje cell density was quantified in Nissl-stained sections of the primary fissure of the cerebellar vermis. RESULTS: With post-cardiac arrest normothermia, Purkinje cell density in the primary fissure was severely reduced compared to sham-injured controls (3.8 ± 1.8 cells mm(-1) vs. 35.9 ± 2.4 cells mm(-1), p<0.001). TH moderately improved Purkinje cell survival in all groups combined (14.0 ± 5.6 cells mm(-1), p<0.001 compared to normothermia). There was no statistical difference in Purkinje cell protection based on TH onset time or duration. CONCLUSION: These results indicate that post-cardiac arrest TH protects selectively vulnerable cerebellar Purkinje cells within a broad therapeutic window. The potential clinical implications for improving Purkinje cell survival require further investigation.

Impact of therapeutic hypothermia onset and duration on survival, neurologic function, and neurodegeneration after cardiac arrest.

OBJECTIVE: Post-cardiac-arrest therapeutic hypothermia improves outcomes in comatose cardiac arrest survivors. This study tests the hypothesis that the efficacy of post-cardiac-arrest therapeutic hypothermia is dependent on the onset and duration of therapy. DESIGN: Prospective randomized laboratory investigation. SETTING: University research laboratory. SUBJECTS: A total of 268 male Long Evans rats. INTERVENTIONS: Post-cardiac-arrest therapeutic hypothermia. MEASUREMENTS AND MAIN RESULTS: Adult male Long Evans rats that achieved return of spontaneous circulation after a 10-min asphyxial cardiac arrest were block randomized to normothermia (37°C ± 1°C) or therapeutic hypothermia (33°C ± 1°C) initiated 0, 1, 4, or 8 hrs after return of spontaneous circulation and maintained for 24 or 48 hrs. Therapeutic hypothermia initiated 0, 1, 4, and 8 hrs after return of spontaneous circulation resulted in 7-day survival rates of 45%*, 36%*, 36%*, and 14%, respectively, compared to 17% for normothermic controls and survival with good neurologic function rates of 24%*, 24%*, 19%*, and 0%, respectively, compared to 2% for normothermic controls (*p < .05 vs. normothermia). These outcomes were not different when therapeutic hypothermia was maintained for 24 vs. 48 hrs. In contrast, hippocampal CA1 pyramidal neuron counts were 53% ± 27%*, 53% ± 19%*, 51% ± 24%*, and 65% ± 16%* of normal, respectively, when therapeutic hypothermia was initiated 0, 1, 4, or 8 hrs after return of spontaneous circulation compared to 9% in normothermic controls (*p < .01 vs. normothermia). Furthermore, surviving neuron counts were greater when therapeutic hypothermia was maintained for 48 hrs compared to 24 hrs (68% ± 15%* vs. 42% ± 22%, *p < .0001). CONCLUSIONS: In this study, post-cardiac-arrest therapeutic hypothermia resulted in comparable improvement of survival and survival with good neurologic function when initiated within 4 hrs after return of spontaneous circulation. However, histologic assessment of neuronal survival revealed a potentially broader therapeutic window and greater neuroprotection when therapeutic hypothermia was maintained for 48 vs. 24 hrs.

RNAi targeting micro-calpain increases neuron survival and preserves hippocampal function after global brain ischemia.

The calpain family of cysteine proteases has a well-established causal role in neuronal cell death following acute brain injury. However, the relative contribution of calpain isoforms has not been determined in in vivo models. Identification of the calpain isoform responsible for neuronal injury is particularly important given the differential role of calpain isoforms in normal physiology. This study evaluates the role of m-calpain and micro-calpain in an in vivo model of global brain ischemia. Adeno-associated viral vectors expressing short hairpin RNAs targeting the catalytic subunits of micro- or m-calpain were used to knockdown expression of the targeted isoforms in adult rat hippocampal CA1 pyramidal neurons. Knockdown of micro-calpain, but not m-calpain, prevented calpain activity 72 h after 6-min transient forebrain ischemia, increased long-term survival and protected hippocampal electrophysiological function. These findings represent the first in vivo evidence that reducing expression of an individual calpain isoform can decrease post-ischemic neuronal death and preserve hippocampal function.

Effects of atorvastatin on C-reactive protein secretions by adipocytes in hypercholesterolemic rabbits.

C-reactive protein (CRP) is a powerful predictor for coronary heart diseases. Recent study has revealed that adipocytes can produce CRP. Peroxisome proliferator-activated receptor (PPAR) gamma, an important nuclear transcriptional factor, can be predominately detected in adipocytes and exert several biological properties, including antiinflammatory effects. The authors investigated the effects of 2-week atorvastatin treatment on CRP secretions by adipocytes in hypercholesterolemic rabbits. CRP concentrations in serum and adipocytes culture supernatants were measured by latex particle-enhanced immunoturbidometric method. RT-PCR was used to evaluate PPARgamma mRNA expression. Two weeks of atorvastatin treatment resulted in significant reductions of circulating CRP concentrations, which were associated with CRP secretions in adipocytes (r = 0.688, P = 0.007). Meanwhile, CRP secretions in adipocytes were intimately related to low-density lipoprotein (LDL) cholesterol levels (r = 0.869, P < 0.001) and PPARgamma mRNA expressions in adipocytes (r = -0.857, P < 0.001). These data demonstrate that hypercholesterolemia may induce CRP secretions in adipocytes; short-term atorvastatin treatment reduces CRP secretions in adipocytes, possibly through lowering blood cholesterol levels and upregulating PPARgamma expressions in adipocytes. These findings enrich the pharmacological effects of statins and also enlighten the relationship between adipocytes and hypercholesterolemia.