Major depressive disorder:hypothesis,mechanism,prevention and treatment

Worldwide,the incidence of major depressive disorder(MDD)is increasing annually,resulting in greater economic and social burdens.Moreover,the pathological mechanisms of MDD and the mechanisms underlying the effects of pharmacological treatments for MDD are complex and unclear,and additional diagnostic and therapeutic strategies for MDD still are needed.The currently widely accepted theories of MDD pathogenesis include the neurotransmitter and receptor hypothesis,hypothalamicpituitary-adrenal(HPA)axis hypothesis,cytokine hypothesis,neuroplasticity hypothesis and systemic influence hypothesis,but these hypothesis cannot completely explain the pathological mechanism of MDD.Even it is still hard to adopt only one hypothesis to completely reveal the pathogenesis of MDD,thus in recent years,great progress has been made in elucidating the roles of multiple organ interactions in the pathogenesis MDD and identifying novel therapeutic approaches and multitarget modulatory strategies,further revealing the disease features of MDD.Furthermore,some newly discovered potential pharmacological targets and newly studied antidepressants have attracted widespread attention,some reagents have even been approved for clinical treatment and some novel therapeutic methods such as phototherapy and acupuncture have been discovered to have effective improvement for the depressive symptoms.In this work,we comprehensively summarize the latest research on the pathogenesis and diagnosis of MDD,preventive approaches and therapeutic medicines,as well as the related clinical trials.

Extent of mismatch between the period of circadian clocks and light/dark cycles determines time-to-emergence in fruit flies

Circadian clocks time developmental stages of fruit flies Drosophila melanogaster, while light/dark （LD） cycles delimit emergence of adults, conceding only during the ＂allowed gate.＂ Previous studies have revealed that time-to-emergence can be altered by mutations in the core clock gene period （per）, or by altering the length of LD cycles. Since this evidence came from studies on genetically manipulated flies, or on flies maintained under LD cycles with limited range of periods, inferences that can be drawn are limited. Moreover, the extent of shortening or lengthening of time-to-emergence re- mains yet unknown. In order to pursue this further, we assayed time-to-emergence of D. rnelanogaster under 12 different LD cycles as well as in constant light （LL） and constant dark conditions （DD）. Time-to-emergence in flies occurred earlier under LL than in LD cycles and DD. Among the LD cycles, time-to-emergence occurred earlier under T4-T8, followed by T36-T48, and then T12-T32, suggesting that egg-to-emergence duration in flies becomes shorter when the length of LD cycles deviates from 24 h, bearing a strong positive and a marginally negative correlation with day length, for values shorter and longer than 24 h, respectively. These results suggest that the extent of mismatch between the period of circadian clocks and environmental cycles determines the time-to-emergence in Drosophila.

Purinergic Signaling in the Central Nervous System in Health and Disease

The existence of purinergic signaling—the idea that almost all cells of the animal/human organism are able to communicate with each other via extracellular purines—was proposed by Geoffrey Burnstock(1929-2020)in 1972[1-3].The purinergic system includes the following constituents:(1)the four main purines:adenosine triphosphate(ATP)and its metabolites,adenosine diphosphate(ADP),adenosine monophosphate(AMP),and adenosine(ADO);(2)three key enzymes,the ectonucleoside triphosphate diphosphohydrolases(E-NTPDases:NTPDase1/CD39),ectonucleotide pyrophosphatase/phosphodiesterases(E-NPP),and ecto-5’-nucleotidase(E-5’-nucleotidase/CD73),which decompose ATP into ADP,AMP,and ADO.

Astrocytes in human central nervous system diseases: a frontier for new therapies

Astroglia are a broad class of neural parenchymal cells primarily dedicated to homoeostasis and defence of the central nervous system(CNS).Astroglia contribute to the pathophysiology of all neurological and neuropsychiatric disorders in ways that can be either beneficial or detrimental to disorder outcome.Pathophysiological changes in astroglia can be primary or secondary and can result in gain or loss of functions.Astroglia respond to external,non-cell autonomous signals associated with any form of CNS pathology by undergoing complex and variable changes in their structure,molecular expression,and function.In addition,internally driven,cell autonomous changes of astroglial innate properties can lead to CNS pathologies.Astroglial pathophysiology is complex,with different pathophysiological cell states and cell phenotypes that are context-specific and vary with disorder,disorder-stage,comorbidities,age,and sex.Here,we classify astroglial pathophysiology into(i)reactive astrogliosis,(ii)astroglial atrophy with loss of function,(iii)astroglial degeneration and death,and(iv)astrocytopathies characterised by aberrant forms that drive disease.We review astroglial pathophysiology across the spectrum of human CNS diseases and disorders,including neurotrauma,stroke,neuroinfection,autoimmune attack and epilepsy,as well as neurodevelopmental,neurodegenerative,metabolic and neuropsychiatric disorders.Characterising cellular and molecular mechanisms of astroglial pathophysiology represents a new frontier to identify novel therapeutic strategies.

PROK2–PROKR2 Signaling:New Contributor to Pleasant Touch

Pleasant touch sensation derived from hugging,cuddling,holding hands,or massage therapy can provide powerful benefits for patients with psychiatric disorders and play a crucial role in reducing pain,alleviating stress,and strengthening social bonds.Revealing the underlying mechanisms of pleasant touch is an attractive topic in neuroscience[1].The peripheral pathway for pleasant touch is mainly coded by C-tactile(CT)afferents,activated by touches with velocities between 1 and 10cm/s[2].

Decoupling SERT-nNOS Interaction to Generate Fast-Onset Antidepressants

Major depressive disorder(MDD)is one of the most common psychiatric disorders,and~4.7%of the world's population has an onset of depression in any one-year period.It causes constant distress,impairs social function and physiological health,and even leads to suicide[1].Numerous studies support the classic monoamine hypothesis of depressive episodes.The majority of clinical antidepressants have been developed on the basis of this hypothesis to increase 5-hydroxytryptamine(5-HT).

TASK-3:New Target for Pain-Relief

Morphine and other opioids are among the most effective analgesics for treating pain.However,drug dependence and other deleterious side effects of opioids have limited their clinical applicability.Recent studies suggest that the use of opioids for pain control may even exacerbate disease outcomes in some pain-producing conditions,such as acute pancreatitis[1].

CNMa-CNMa receptor at microbiome-gut-brain axis:novel target to regulate feeding decision

A recent study published in Nature by Kim et al.discovers that the CNMamide(CNMa)-CNMa receptor(CNMaR)axis plays a crucial regulatory role in response to deprivation of diet-and microbiome-derived amino acid in Drosophila.In detail,gut enterocytes detect and respond to protein limitation through upregulating CNMa expression and communicating with CNMaR-expressing neurons in the brain(Fig.1).