Alzheimer's disease (AD) is a complex neurodegenerative disease in the elderly and the most common cause of human dementia. AD is characterized by accumulation of abnormal protein aggregates including amyloid plaques (composed of beta-amyloid (Aβ) peptides) and neurofibrillary tangles (formed by hyper-phosphorylated tau protein). Synaptic plasticity, neuroinflammation, calcium signaling etc. also show dysfunction in AD patients. Autophagy is an evolutionarily conserved lysosome-dependent cellular event in eukaryotes. It is closely linked to modulation of protein metabolism, through which damaged organelles and mis-folded proteins are degraded and then recycled to maintain protein homeostasis. Accumulating evidence has shown that impaired autophagy also contributes to AD pathogenesis. In the present review, we highlight the role of autophagy, including bulk and selective autophagy, in regulating metabolic circuits in AD pathogenesis. We also discuss the potential and future perspectives of autophagy-inducing strategies in AD therapeutics.

Mood disorders have multiple phenotypes and complex underlying biological mechanisms and, as such, there are no effective therapeutic strategies. A review of recent work on the role of astrocytes in mood disorders is thus warranted, which we embark on here. We argue that there is tremendous potential for novel strategies for therapeutic interventions based on the role of astrocytes. Astrocytes are traditionally considered to have supporting roles within the brain, yet emerging evidence has shown that astrocytes have more direct roles in influencing brain function. Notably, evidence from postmortem human brain tissues has highlighted changes in glial cell morphology, density and astrocyte-related biomarkers and genes following mood disorders, indicating astrocyte involvement in mood disorders. Findings from animal models strongly imply that astrocytes not only change astrocyte morphology and physiological characteristics but also influence neural circuits via synapse structure and formation. This review pays particular attention to interactions between astrocytes and neurons and argues that astrocyte dysfunction affects the monoaminergic system, excitatory–inhibitory balance and neurotrophic states of local networks. Together, these studies provide a foundation of knowledge about the exact role of astrocytes in mood disorders. Importantly, we then change the focus from neurons to glial cells and the interactions between the two, so that we can understand newly proposed mechanisms underlying mood disorders, and to identify more diagnostic indicators or effective targets for treatment of these diseases.

The prevailing view is that parvalbumin (PV) interneurons play modulatory roles in emotional response through local medium spiny projection neurons (MSNs). Here, we show that PV activity within the nucleus accumbens shell (sNAc) is required for producing anxiety-like avoidance when mice are under anxiogenic situations. Firing rates of sNAc^PV neurons were negatively correlated to exploration time in open arms (threatening environment). In addition, sNAc^PV neurons exhibited high excitability in a chronic stress mouse model, which generated excessive maladaptive avoidance behavior in an anxiogenic context. We also discovered a novel GABAergic pathway from the anterior dorsal bed nuclei of stria terminalis (adBNST) to sNAc^PV neurons. Optogenetic activation of these afferent terminals in sNAc produced an anxiolytic effect via GABA transmission. Next, we further demonstrated that chronic stressors attenuated the inhibitory synaptic transmission at adBNST^GABA → sNAc^PV synapses, which in turn explains the hyperexcitability of sNAc PV neurons on stressed models. Therefore, activation of these GABAergic afferents in sNAc rescued the excessive avoidance behavior related to an anxious state. Finally, we identified that the majority GABAergic input neurons, which innervate sNAc^PV cells, were expressing somatostatin (SOM), and also revealed that coordination between SOM- and PV- cells functioning in the BNST → NAc circuit has an inhibitory influence on anxiety-like responses. Our findings provide a potentially neurobiological basis for therapeutic interventions in pathological anxiety.

Aims: Chronic stress plays an important role in promoting the progression and migration of cancers. However, little is known of any direct impact on tumor progression related to the regulation of emotion‐related circuitry. The aim of this study was to explore the neural‐circuit mechanisms underlying stress‐induced progression of cancers and the impact of emotion‐related regulation of circuitry on tumor growth.Methods: Optogenetic manipulation was applied to unpredictable chronic mild stress (UCMS)–treated mice bearing breast tumor cell. The stress‐related hormones, tumor‐related cytokines, the tyrosine hydroxylase (TH)–positive neurons and their fibers, dopamine receptor–positive cells, and anxiety level were measured using ELISA, immunohistochemical staining, fluorescence in situ hybridization, and behavioral test, respectively.Results: By investigating breast cancer mouse models with a chronic mild stress model, optogenetic stimulation, and behavioral analysis, we show that chronic stress induced anxiety‐like behavior in mice and increased serum concentration of norepinephrine and corticosterone, hormones closely related to stress and anxiety. Optogenetic activation of VTA TH terminals in the mPFC rescued anxiety‐like behavior induced by chronic stress. Chronic stress resulted in marked progression of breast tumors, and repetitive optogenetic activation of VTA TH terminals in the mPFC significantly attenuated stress‐induced progression of breast cancers and reduced serum concentration of norepinephrine and corticosterone. Furthermore, there was a positive correlation between serum norepinephrine or corticosterone concentration and tumor size.Conclusions: These findings indicate a positive role of an emotion regulation circuit on the progression of breast cancer and reveal a link between stress, emotion regulation, and the progression of breast cancers. Our findings provide new insights pertinent to therapeutic interventions in the treatment of breast cancers.

Introduction and Aims: Alzheimer's disease (AD) is characterized by the abnormal accumulation of hyperphosphorylated tau proteins and amyloid‐beta (Aβ) peptides. Recent studies have shown that many microRNAs (miRNAs) are dysregulated in AD, and modulation of these miRNAs can influence the development of tau and Aβ pathology. The brain‐specific miRNA miR‐128, encoded by MIR128‐1 and MIR128‐2, is important for brain development and dysregulated in AD. In this study, the role of miR‐128 in tau and Aβ pathology as well as the regulatory mechanism underlying its dysregulation were investigated.Methods: The effect of miR‐128 on tau phosphorylation and Aβ accumulation was examined in AD cellular models through miR‐128 overexpression and inhibition. The therapeutic potential of miR‐128 in AD mouse model was assessed by comparing phenotypes of 5XFAD mice administered with miR‐128‐expressing AAVs with 5XFAD mice administered with control AAVs. Phenotypes examined included behavior, plaque load, and protein expression. The regulatory factor of miR‐128 transcription was identified through luciferase reporter assay and validated by siRNA knockdown and ChIP analysis.Results: Both gain‐of‐function and loss‐of‐function studies in AD cellular models reveal that miR‐128 represses tau phosphorylation and Aβ secretion. Subsequent investigations show that miR‐128 directly inhibits the expression of tau phosphorylation kinase GSK3β and Aβ modulators APPBP2 and mTOR. Upregulation of miR‐128 in the hippocampus of 5XFAD mice ameliorates learning and memory impairments, decreases plaque deposition, and enhances autophagic flux. We further demonstrated that C/EBPα transactivates MIR128‐1 transcription, while both C/EBPα and miR‐128 expression are inhibited by Aβ.Conclusion: Our findings suggest that miR‐128 suppresses AD pathogenesis, and could be a promising therapeutic target for AD. We also find a possible mechanism underlying the dysregulation of miR‐128 in AD, in which Aβ reduces miR‐128 expression by inhibiting C/EBPα.

Evidence shows that stress can promote the occurrence and development of tumors. In recent years, many studies have shown that stress-related hormones or peripheral neurotransmitters can promote the proliferation, survival, and angiogenesis of tumor cells and impair the body’s immune response, causing tumor cells to escape the “surveillance” of the immune system. However, the perception of stress occurs in the central nervous system (CNS) and the role of the central nervous system in tumor progression is still unclear, as are the underlying mechanisms. This review summarizes what is known of stress-related CNS-network activation during the stress response and the influence of the CNS on tumors and discusses available adjuvant treatment methods for cancer patients with negative emotional states, such as anxiety and depression.