A circuit from dorsal hippocampal CA3 to parvafox nucleus mediates chronic social defeat stress-induced deficits in preference for social novelty.

The preference for social novelty is crucial to the social life of humans and rodents. However, the neural mechanisms underlying social novelty preference are poorly understood. Here, we found that chronic social defeat stress (CSDS) reduced the preference for social novelty in mice by impairing the response of CaMKIIα+ neurons in the CA3 region of dorsal hippocampus (dCA3) during approach to an unfamiliar mouse. The deficits of social novelty preference in CSDS-treated mice were reversed by activating the output from dCA3 to the GABAergic neurons in the lateral septum (LS). The activation of GABAergic projection from LS recruited a circuit that inhibited the Foxb1+ neurons in the parvafox nucleus (PFN), which drove social avoidance by projecting to the lateral periaqueductal gray (lPAG). These results suggest that a previously unidentified circuit of dCA3CaMKIIα+→LSGABA+→PFNFoxb1+→lPAG mediates the deficits of social novelty preference induced by CSDS.

The effects of Kctd12, an auxiliary subunit of GABAB receptor in dentate gyrus on behavioral response to chronic social defeat stress in mice.

Adaptive responses to stress are critical to enhance physical and mental well-being, but excessive or prolonged stress may cause inadaptability and increase the risks of psychiatric disorders, such as depression. GABABR signaling is fundamental to brain function and has been identified in neuropsychiatric disorders. KCTD12 is a critical auxiliary subunit in GABABR signaling, but its role in mental disorders, such as depression is unclear. In the present study, we used a well-validated mice model, chronic social defeat stress (CSDS) to investigate behavioral responses to stress and explore the role of Kctd12 in stress response, as well as the relevant mechanisms. We found that CSDS increased the expression of Kctd12 in the dentate gyrus (DG), a subregion of hippocampus. Overexpression of Kctd12 in DG induced higher responsiveness to acute stress and increased vulnerability to social stress in mice, whereas knock-down of Kctd12 in DG prevented the social avoidance. Furthermore, an increased expression of GABAB receptor 2 (GB2) in the DG of CSDS-treated mice was observed, and CGP35348, an antagonist of GABABR, improved the stress-induced behavior responses along with suppressing the excess expression of Kctd12. In addition, Kctd12 regulated the excitability of granule cell in DG, and the stimulation of neuronal activity by silencing Kctd12 contributed to the antidepressant-like effect of fluoxetine. These findings identify that the Kctd12 in DG works as a critical mediator of stress responses, providing a promising therapeutic target in stress-related psychiatric disorders, including depression.

Microglia: A Central Player in Depression.

Microglia are the major immune cells in the central nervous system and play a key role in the normal function of the brain. Microglia exhibit functional diversity, and they control the inflammation in central nervous system through releasing inflammatory cytokine, clearing apoptotic cells via phagocytosis, regulating synaptic plasticity and the formation of neural network by synapse pruning. Recent studies have strongly indicated that the microglial dysfunction is associated with a variety of neuropsychiatric diseases such as depression, which have been termed as "microgliopathy". The emergency of advanced technologies and tools has enabled us to comprehensively understand the role of microglia in physiology and pathology, and growing studies have targetted microglia to explore the treatment of neuropsychiatric diseases. Here, we describe the key progress of microglia research, and review the recent developments in the understanding of the role of microglia in physiology and etiology of depression.

Angiotensin-Converting Enzyme Inhibitor Rapidly Ameliorates Depressive-Type Behaviors via Bradykinin-Dependent Activation of Mammalian Target of Rapamycin Complex 1.

BACKGROUND: Angiotensin-converting enzyme inhibitors (ACEIs) are widely prescribed antihypertensive agents. Intriguingly, case reports and clinical trials have indicated that ACEIs, including captopril and lisinopril, may have a rapid mood-elevating effect in certain patients, but few experimental studies have investigated their value as fast-onset antidepressants. METHODS: The present study consisted of a series of experiments using biochemical assays, immunohistochemistry, and behavioral techniques to examine the effect and mechanism of captopril on depressive-like behavior in 2 animal models, the chronic unpredictable stress model and the chronic social defeat stress model. RESULTS: Captopril (19.5 or 39 mg/kg, intraperitoneal injection) exerted rapid antidepressant activity in mice treated under the chronic unpredictable stress model and mice treated under the chronic social defeat stress model. Pharmacokinetic analysis revealed that captopril crossed the blood-brain barrier and that lisinopril, another ACEI with better blood-brain barrier permeability, exerted a faster and longer-lasting effect at a same molar equivalent dose. This antidepressant effect seemed to be independent of the renin-angiotensin system, but dependent on the bradykinin (BK) system, since the decreased BK detected in the stressed mice could be reversed by captopril. The hypofunction of the downstream effector of BK, Cdc42 (cell division control protein 42) homolog, contributed to the stress-induced loss of dendritic spines, which was rapidly reversed by captopril via activating the mTORC1 (mammalian target of rapamycin complex 1) pathway. CONCLUSIONS: Our findings indicate that the BK-dependent activation of mTORC1 may represent a promising mechanism underlying antidepressant pharmacology. Considering their affordability and availability, ACEIs may emerge as a novel fast-onset antidepressant, especially for patients with comorbid depression and hypertension.

Activation of AMPK-dependent autophagy in the nucleus accumbens opposes cocaine-induced behaviors of mice.

Cocaine is a strong central nervous system stimulant, which can induce drug addiction. Previous studies have reported that cocaine-induced autophagy is involved in neuroinflammation and cell death. However, the role of autophagy in psychomotor sensitivity to cocaine has not been explored. Here, we reported that D1 receptor -CaMKII-AMPK-FoxO3a signaling pathway was involved in acute cocaine application-induced autophagy in the nucleus accumbens (NAc) both in vitro and in vivo. Furthermore, we found that knockdown of the ATG5 gene in the NAc augmented behavioral response to cocaine, and induction of autophagy in the NAc with rapamycin attenuated cocaine-induced behavioral response, which was coincident with the alterations of dendritic spine density in neurons of NAc. These results suggest that cocaine exposure leads to the induction of autophagy, which is a protective mechanism against behavioral response to cocaine of male mice.

Reactive Sulfur Species Emerge as Gliotransmitters to Support Memory via Sulfuration-Dependent Gating of NR2A-Containing N-Methyl-d-Aspartate Subtype Glutamate Receptor Function.

AIMS: Astrocytes have been revealed as a controller of synaptic plasticity and memory via releasing gliotransmitters. Our recent findings showed that reactive sulfur species (RSS), including hydrogen sulfide (H2S) and polysulfide (H2Sn), regulated the availability of d-serine, which is a well-known gliotransmitter that is involved in synaptic plasticity. An interesting question is whether RSS, which are small molecules, can function as direct gliotransmitters to integrate astrocyte-neuron interactions throughout the memory process. RESULTS: We found that hippocampal RSS level increased significantly in response to learning. We further demonstrated that the activity-triggered RSS signal controlled memory formation by using pharmacological and genetic approaches. The RSS-supporting memory was primarily conferred by enzymes that were mainly located in astrocytes, including cystathionine ß-synthase (CBS) and mercaptopyruvate sulfurtransferase (3-MST), and the memory-promoting effects were mostly dependent on sulfration of the NR2A subunit of N-methyl-d-aspartate subtype glutamate receptors (NMDARs). Further, RSS were demonstrated to buffer the strong inhibitory effect of synaptically released zinc on NR2A-containing NMDARs. Innovation and Conclusion: These results suggest that glial-derived RSS signals can serve as direct gliotransmitters that regulate memory formation through the redox modulation of postsynaptic receptors; this conclusion will enrich the gliotransmission hypothesis.

Rapid Antidepressant Effect of Hydrogen Sulfide: Evidence for Activation of mTORC1-TrkB-AMPA Receptor Pathways.

AIMS: We asked whether hydrogen sulfide (H2S), as the third gaseous mediator, provided fast antidepressant effect on major depressive disorders and underlying mechanisms. RESULTS: The decreased level of H2S was detected in the hippocampus of chronic unpredictable mild stress (CUMS)-treated rats. Acute administration of H2S either by H2S inhalation or by the donor NaHS produced a rapid antidepressant-like behavioral effect. Further investigation demonstrated that this effect of H2S was mediated by reversing the CUMS-induced decrease in dendritic spine density and required the activation of mammalian target of rapamycin (mTOR)C1 and neurotrophic TrkB receptors, which proceeded to increase synaptic protein expression, including postsynaptic density protein 95, synaptophysin, and α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor GluR1/2 subunit. INNOVATION: This study provides the first direct evidence for detecting the decreased H2S in hippocampus of CUMS rats and the biological significance of H2S in treating major depression. CONCLUSION: Our data demonstrate that H2S activates mTORC1 signaling cascades and thereby produces fast-onset antidepressant effect. The study provides a profound insight into H2S or its donors as potent preventive and therapeutic agents for intervention of depression. Antioxid. Redox Signal. 27, 472-488.