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NG2 glia, also known as oligodendrocyte precursor cells (OPCs), play an important role in proliferation and give rise to myelinating oligodendrocytes during early brain development. In contrast to other glial cell types, the most intriguing aspect of NG2 glia is their ability to directly sense synaptic inputs from neurons. However, whether this synaptic interaction is bidirectional or unidirectional, or its physiological relevance has not yet been clarified. Here, we report that NG2 glia form synaptic complexes with hippocampal interneurons and that selective photostimulation of NG2 glia (expressing channelrhodopsin-2) functionally drives GABA release and enhances inhibitory synaptic transmission onto proximal interneurons in a microcircuit. The mechanism involves GAD67 biosynthesis and VAMP-2 containing vesicular exocytosis. Further, behavioral assays demonstrate that NG2 glia photoactivation triggers anxiety-like behavior in vivo and contributes to chronic social defeat stress. Nerve/glial antigen 2 (NG2) glia can sense synaptic inputs from neurons. Here, the authors show NG2 glia form functional GABAergic synapses by regulating inhibitory synaptic transmission onto adjacent hippocampal interneurons, and activation of NG2 glia induces anxiety-like behaviour in a mouse model of chronic social defeat stress.

Major depressive disorder is a devastating psychiatric disease that afflicts up to 17% of the world’s population. Postmortem brain analyses and imaging studies of patients with depression have implicated basal lateral amygdala (BLA) dysfunction in the pathophysiology of depression. However, the circuit and molecular mechanisms through which BLA neurons modulate depressive behavior are largely uncharacterized. Here, in mice, we identified that BLA cholecystokinin (CCK) glutamatergic neurons mediated negative reinforcement via D2 medium spiny neurons (MSNs) in the nucleus accumbens (NAc) and that chronic social defeat selectively potentiated excitatory transmission of the CCKBLA–D2NAc circuit in susceptible mice via reduction of presynaptic cannabinoid type-1 receptor (CB1R). Knockdown of CB1R in the CCKBLA–D2NAc circuit elevated synaptic activity and promoted stress susceptibility. Notably, selective inhibition of the CCKBLA–D2NAc circuit or administration of synthetic cannabinoids in the NAc was sufficient to produce antidepressant-like effects. Overall, our studies reveal the circuit and molecular mechanisms of depression.Activating cannabinoid receptors in a newly identified neural circuit ameliorates depressive-like behaviors in mice.

The lateral parabrachial nucleus (LPBN) is known to relay noxious information to the amygdala for processing affective responses. However, it is unclear whether the LPBN actively processes neuropathic pain characterized by persistent hyperalgesia with aversive emotional responses. Here we report that neuropathic pain-like hypersensitivity induced by common peroneal nerve (CPN) ligation increases nociceptive stimulation-induced responses in glutamatergic LPBN neurons. Optogenetic activation of GABAergic LPBN neurons does not affect basal nociception, but alleviates neuropathic pain-like behavior. Optogenetic activation of glutamatergic or inhibition of GABAergic LPBN neurons induces neuropathic pain-like behavior in naïve mice. Inhibition of glutamatergic LPBN neurons alleviates both basal nociception and neuropathic pain-like hypersensitivity. Repetitive pharmacogenetic activation of glutamatergic or GABAergic LPBN neurons respectively mimics or prevents the development of CPN ligation-induced neuropathic pain-like hypersensitivity. These findings indicate that a delicate balance between excitatory and inhibitory LPBN neuronal activity governs the development and maintenance of neuropathic pain. The parabrachial nucleus (PBN) projects to the amygdala, and contributes to affective aspects of neuropathic pain. Here the authors demonstrate that the lateral parabrachial nucleus (LPBN) contributes to hypersensitivity in a mouse model of neuropathic pain.

Ketamine, an N -methyl- d -aspartate receptor (NMDAR) antagonist 1 , has revolutionized the treatment of depression because of its potent, rapid and sustained antidepressant effects 2 – 4 . Although the elimination half-life of ketamine is only 13 min in mice 5 , its antidepressant activities can last for at least 24 h 6 – 9 . This large discrepancy poses an interesting basic biological question and has strong clinical implications. Here we demonstrate that after a single systemic injection, ketamine continues to suppress burst firing and block NMDARs in the lateral habenula (LHb) for up to 24 h. This long inhibition of NMDARs is not due to endocytosis but depends on the use-dependent trapping of ketamine in NMDARs. The rate of untrapping is regulated by neural activity. Harnessing the dynamic equilibrium of ketamine–NMDAR interactions by activating the LHb and opening local NMDARs at different plasma ketamine concentrations, we were able to either shorten or prolong the antidepressant effects of ketamine in vivo. These results provide new insights into the causal mechanisms of the sustained antidepressant effects of ketamine. The ability to modulate the duration of ketamine action based on the biophysical properties of ketamine–NMDAR interactions opens up new opportunities for the therapeutic use of ketamine. The discrepancy between the short half-life of ketamine and its long-lasting effects is due to ketamine being trapped in NMDA receptors, and its release depends on neural activity in the lateral habenula.

Objective Up to 44% of particulates of food-grade titanium dioxide (TiO 2 ) are in nanoscale, while the effect and combined effect of which with other substances on intestinal barrier haven’t been fully understood yet. This study is aimed to study the effect of two kinds of TiO 2 nanoparticles (TiO 2 NPs and TiO 2 MPs) on intestinal barrier functions, to reveal the combined effect of TiO 2 NPs and Lipopolysaccharide (LPS) on intestinal barrier. Methods Male ICR mice were randomly divided into 18 groups (3 feed types * 3 exposure length * 2 LPS dosage) and were fed with normal or TiO 2 -mixed feed (containing 1% (mass fraction, w/w) TiO 2 NPs or TiO 2 MPs) for 1, 3, 6 months, followed by a single oral administration of 0 or 10 mg/(kg body weight) LPS. Four hours later, the transportation of TiO 2 , the intestinal barrier functions and the inflammatory response were evaluated. Results Both TiO 2 notably increased the intestinal villi height / crypt depth ratios after 1 and 3 months of exposure, and increased the expression of ileal tight junction proteins (ZO-1 and occludin) after 1 month of exposure. After 6 months of exposure, TiO 2 NPs led to reduced feed consumption, TiO 2 MPs caused spare microvilli in small intestine and elevated Ti content in the blood cells. The intestinal permeability didn’t change in both TiO 2 exposed groups. After LPS administration, we observed altered intestinal villi height / crypt depth ratios, lowered intestinal permeability (DAO) and upregulated expression of ileal ZO-1 in both (TiO 2 +LPS) exposed groups. There are no significant changes of ileal or serum cytokines except for a higher serum TNF-α level in LPS treated group. The antagonistic effect was found between TiO 2 NPs and LPS, but there are complicated interactions between TiO 2 MPs and LPS. Conclusion Long-term intake of food additive TiO 2 could alter the intestinal epithelial structure without influencing intestinal barrier function. Co-exposure of TiO 2 and LPS would enhance intestinal barrier function without causing notable inflammatory responses, and there is antagonistic effect between TiO 2 NPs and LPS. All the minor effects observed might associate with the gentle exposure method where TiO 2 being ingested with feed.

Flight, an active fear response to imminent threat, is dependent on the rapid risk assessment of sensory information processed by the cortex. The thalamic reticular nucleus (TRN) filters information between the cortex and the thalamus, but whether it participates in the regulation of flight behavior remains largely unknown. Here, we report that activation of parvalbumin-expressing neurons in the limbic TRN, but not those in the sensory TRN, mediates flight. Glutamatergic inputs from the cingulate cortex (Cg) selectively activate the limbic TRN, which in turn inhibits the intermediodorsal thalamic nucleus (IMD). Activation of this Cg→limbic TRN→IMD circuit results in inhibition of the IMD and produces flight behavior. Conversely, removal of inhibition onto the IMD results in more freezing and less flight, suggesting that the IMD may function as a pro-freeze center. Overall, these findings reveal a novel corticothalamic circuit through the TRN that controls the flight response.Dong, Wang et al. uncover a circuit linking Glu+cingulate inputs→PV+ neurons in the limbic thalamic reticular nucleus→intermediodorsal thalamic nucleus, and show that this cortico-intrathalamic circuit is a component of the fear circuitry and controls flight behavior in mice.

The amygdala, one of the most studied brain structures, integrates brain-wide heterogeneous inputs and governs multidimensional outputs to control diverse behaviors central to survival, yet how amygdalar input-output neuronal circuits are organized remains unclear. Using a simplified cell-type- and projection-specific retrograde transsynaptic tracing technique, we scrutinized brain-wide afferent inputs of four major output neuronal groups in the amygdalar basolateral complex (BLA) that project to the bed nucleus of the stria terminals (BNST), ventral hippocampus (vHPC), medial prefrontal cortex (mPFC) and nucleus accumbens (NAc), respectively. Brain-wide input-output quantitative analysis unveils that BLA efferent neurons receive a diverse array of afferents with varied input weights and predominant contextual representation. Notably, the afferents received by BNST-, vHPC-, mPFC- and NAc-projecting BLA neurons exhibit virtually identical origins and input weights. These results indicate that the organization of amygdalar BLA input-output neuronal circuits follows the input-dependent and output-independent principles, ideal for integrating brain-wide diverse afferent stimuli to control parallel efferent actions. The data provide the objective basis for improving the virtual reality exposure therapy for anxiety disorders and validate the simplified cell-type- and projection-specific retrograde transsynaptic tracing method.

Epileptic seizures are widely regarded to occur as a result of the excitation-inhibition imbalance from a neuro-centric view. Although astrocyte-neuron interactions are increasingly recognized in seizure, elementary questions about the causal role of astrocytes in seizure remain unanswered. Here we show that optogenetic activation of channelrhodopsin-2-expressing astrocytes effectively attenuates neocortical seizures in rodent models. This anti-seizure effect is independent from classical calcium signaling, and instead related to astrocytic Na + -K + -ATPase-mediated buffering K + , which activity-dependently inhibits firing in highly active pyramidal neurons during seizure. Compared with inhibition of pyramidal neurons, astrocyte stimulation exhibits anti-seizure effects with several advantages, including a wider therapeutic window, large-space efficacy, and minimal side effects. Finally, optogenetic-driven astrocytic Na + -K + -ATPase shows promising therapeutic effects in a chronic focal cortical dysplasia epilepsy model. Together, we uncover a promising anti-seizure strategy with optogenetic control of astrocytic Na + -K + -ATPase activity, providing alternative ideas and a potential target for the treatment of intractable epilepsy. Neocortical epilepsy is resistant to current treatments. Zhao et al. report that optogenetic stimulation of astrocytes effectively attenuates seizures via driving Na + -K + -ATPase, indicating a potential treatment strategy for intractable epilepsy.

Negative symptoms in schizophrenia strongly contribute to poor functional outcomes, however its pathogenesis is still unclear. Here, we found that histamine H 1 receptor (H 1 R) expression in basal forebrain (BF) cholinergic neurons was decreased in patients with schizophrenia having negative symptoms. Deletion of H 1 R gene in cholinergic neurons in mice resulted in functional deficiency of cholinergic projections from the BF to the prefrontal cortex and in the formation of sensorimotor gating deficit, social impairment and anhedonia-like behavior. These behavioral deficits can be rescued by re-expressing H 1 R or by chemogenetic activation of cholinergic neurons in the BF. Direct chemogenetic inhibition of BF cholinergic neurons produced such behavioral deficits and also increased the susceptibility to hyperlocomotion. Our results suggest that the H 1 R deficiency in BF cholinergic neurons is critical for sensorimotor gating deficit, social impairments and anhedonia-like behavior. This finding may help to understand the genetic and biochemical bases of negative symptoms in schizophrenia. Social impairment and anhedonia are common negative symptoms in patients with schizophrenia. Here, the authors show that the histamine H 1 receptor in cholinergic neurons in the basal forebrain has a critical role in sensorimotor gating, social behaviour, and anhedonia-like behaviour in mice.

Selective elimination of unwanted synapses is vital for the precise formation of neuronal circuits during development, but the underlying mechanisms remain unclear. Using inositol 1,4,5-trisphosphate receptor type 2 knockout (Itpr2−/−) mice to specifically disturb somatic Ca2+ signaling in astrocytes, we showed that developmental elimination of the ventral posteromedial nucleus relay synapse was impaired. Interestingly, intracerebroventricular injection of ATP, but not adenosine, rescued the deficit in synapse elimination in Itpr2−/− mice. Further studies showed that developmental synapse elimination was also impaired in P2ry1−/− mice and was not rescued by ATP, indicating a possible role of purinergic signaling. This hypothesis was confirmed by MRS-2365, a selective P2Y1 agonist, could also rescue the deficient of synapse elimination in Itpr2−/− mice. Our results uncovered a novel mechanism suggesting that astrocytes release ATP in an IP3R2-dependent manner to regulate synapse elimination. Neighbouring neurons connect to each other and share information through structures known as synapses. As the brain develops, many synapses turn out to be redundant. Just like trees in a garden that need to be trimmed, these redundant synapses must be pruned in order to form the right pattern of connections between different neurons. Brain cells called astrocytes play a key role in synaptic pruning, but it is unclear exactly how astrocytes coordinate this process. One important way in which astrocytes communicate with neurons is through a process called calcium signaling, in which the movement of calcium ions into or out of the cell sets off a cascade of activity inside the astrocytes. Yang et al. have now studied developing mice that lacked a gene that is essential for calcium signaling in astrocytes. Two weeks after they were born, these mice still had redundant synapses that are normally lost after birth. However, injecting the developing brain with a substance called ATP prevented this defect and allowed synapses to be correctly pruned. This is likely to be because astrocytes also use ATP to communicate with neurons, and ATP compensated for the missing calcium signaling. The experiments also uncovered the specific structure – called the P2Y1 receptor – on the outer surface of a neuron that ATP latches on to in order to help remove synapses. Further work is now needed to reveal how activating the P2Y1 receptor coordinates synaptic removal.