Neuroligins (NLGNs) are a family of postsynaptic adhesion molecules that bind to their presynaptic partners, neurexins, facilitating the formation and maintenance of synapses. In humans, there are five genes encoding NLGNs ( NLGN1-3 , NLGN4X , and NLGN4Y ), with NLGN1-3 having highly conserved counterparts in rodents, allowing these genes to be studied with high confidence of translational validity in mouse models. Human NLGN4X and 4Y were often assumed to serve similar functions because they share a 97% sequence homology, whereas mouse NLGN4-like is quite divergent. Many NLGN-mediated synaptic effects are modulated through post-translation modifications, which exert temporal and spatial control. In this report, we characterize a conserved phosphorylation site, serine 712, on NLGN4X and 4Y. Despite serine 712 being located in a highly conserved region between NLGN4X and 4Y, we observed kinase specificity. PKA exclusively phosphorylates NLGN4X S712, whereas Cdk5 phosphorylates S712 on both NLGN4X and 4Y. NL...

Epilepsy, affecting millions globally, often leads to significant cognitive and psychiatric comorbidities, particularly in children. Anxiety and depression are particularly prevalent, with roughly a quarter of pediatric epilepsy patients having a comorbid diagnosis. Current treatments inadequately address these issues. Adrenocorticotropic hormone (ACTH), a melanocortin peptide, has shown promise in mitigating deficits after early-life seizures (ELS), potentially through mechanisms beyond its canonical action on the melanocortin 2 receptor. This study explores the hypothesis that recurrent ELS is associated with long-term anxiety and that treatment with ACTH can prevent this anxiety through a mechanism that involves the melanocortin 4 receptor (MC4R) in the brain. Our findings reveal that ACTH ameliorates anxiety-like behavior associated with ELS, without altering seizure parameters, in wild-type but not in male and female MC4R knock-out mice. Our findings also show that knocking-in MC4R in either neurons o...

Recent findings have shifted the view of cholecystokinin (CCK) from being a cellular neuronal marker to being recognized as a crucial neuropeptide pivotal in synaptic plasticity and memory processes. Despite its now appreciated importance in various brain regions and abundance in the basal ganglia, its role in the striatum, which is vital for motor control, remains unclear. This study sought to fill this gap by performing a comprehensive investigation of the role of CCK in modulating striatal medium spiny neuron (MSN) membrane properties, as well as the secondary somatosensory cortex S2 to MSN synaptic transmission and plasticity in rodents. Using in vivo optopatch-clamp recording in mice on identified MSNs, we showed that the application of CCK receptor Type 2 (CCK2R) antagonists decreases corticostriatal transmission in both direct and indirect pathway MSNs. Moving to an ex vivo rat preparation to maximize experimental access, we showed that CCK2R inhibition impacts MSN membrane properties by reducing sp...

Central sensitization plays a critical role in bladder pain syndrome/interstitial cystitis (BPS/IC). Electroacupuncture (EA) nerve stimulation therapy has been broadly acknowledged as an effective means of alleviating chronic pathological pain. However, it remains to be explored whether EA is effective in mitigating pain-sensitive symptoms of BPS/IC and the mechanisms involved. This study aims to investigate the analgesic effect and mechanism of EA therapy. We employed several techniques: mechanical pain threshold tests to assess pain sensitivity, urodynamic studies to evaluate bladder function, western blotting for protein analysis, immunofluorescence for visualizing, and transcriptomics. A rat cystitis model was established through a systemic intraperitoneal injection with cyclophosphamide (CYP). EA therapy was executed by stimulating the deep part of the hypochondriac point. EA treatment was observed to effectively reduce mechanical allodynia, enhance urinary function, suppress the activation of microgl...

Motor skill learning enables organisms to interact effectively with their environment, relying on neural mechanisms that integrate sensory feedback with motor output. While sensory feedback, such as auditory cues linked to motor actions, enhances motor performance in humans, its mechanism of action is poorly understood. Developing a reliable animal model of augmented motor skill learning is crucial to begin dissecting the biological systems that underpin this enhancement. We hypothesized that continuous auditory feedback during a motor task would promote complex motor skill acquisition in mice. We developed a closed-loop system using DeepLabCut for real-time markerless tracking of mouse forepaw movements with high processing speed and low latency. By encoding forepaw movements into auditory tones of different frequencies, mice received continuous auditory feedback during a reaching task requiring vertical displacement of the left forepaw to a target. Adult mice were trained over 4 d with either auditory fe...

Neurons adapt to chronic activity changes by modifying synaptic properties, including neurotransmitter release. However, whether neuropeptide release via dense core vesicles (DCVs)—a distinct regulated secretory pathway—undergoes similar adaptation remains unclear. Here, we demonstrate that 24 h action potential blockade leads to significant DCV accumulation in primary mouse cortical neurons of both sexes. Reactivation with action potential trains induced enhanced Ca2+ influx and 700% more DCV exocytosis compared with control neurons. Notably, total DCV cargo protein levels were unchanged, while mRNA levels of corresponding genes were reduced. Blocking neurotransmitter release with Tetanus toxin induced DCV accumulation, similar to that induced by network silencing with TTX. Hence, chronic network silencing triggers increased DCV accumulation due to reduced exocytosis during silencing. These accumulated DCVs can be released upon reactivation resulting in a massive potentiation of DCV exocytosis, possibly c...

In the article “Comprehensive Characterization of a Subfamily of Ca2+-Binding Proteins in Mouse and Human Retinal Neurons at Single-Cell Resolution” by Jun-Bin Liu, He-Lan Yuan, Gong Zhang, and Jiang-Bin Ke …

Karen Ersche’s work focuses on the neurochemical processes underlying addictive behavior and how to translate these findings into therapies. Her findings have contributed to new behavioral and pharmacological approaches. For this work, she was awarded the Jacob P. Waletzky Award in 2017. What led you to study drug addiction, particularly cocaine addiction? My enthusiasm for drug addiction research is rooted in the potential it has to make a difference in people’s lives. Scientific advances have fundamentally changed the understanding of addiction from a deficit of character to a brain disorder, and I strongly believe it will also provide the pathway for developing more effective treatments. My research aims to tackle the problems surrounding cocaine addiction, which is a fairly common disorder in the United Kingdom with few effective treatments.

This is a playlist of 19 videos from the 2016 FENS-Hertie Winter School. Since the groundbreaking description of patient H.M. in the 1950's, our understanding of human memory and the mechanisms underlying memory functions has increased dramatically in the last decades. Through extensive interactions with leaders in the field, the 2016 FENS-Hertie Winter School provided a comprehensive overview of both the basic and the latest knowledge about memory functions and their underlying mechanisms in humans.

Emery Brown, professor of anesthesia at Harvard Medical School, discusses his career trajectory as a physician-scientist and his work-life balance. He delivered this talk during SfN’s Meet-the-Expert Series at Neuroscience 2017. The text below has been condensed and lightly edited and offer highlights from his talk. Listen to the audio recording above for the full remarks. Transitioning From Romance Languages to Circadian Rhythms I started out as an undergraduate at Harvard, majoring in romance languages. I knew I was going to go to medical school. I figured I would work for the World Health Organization, traveling around the world and stamping out diseases. However, in my sophomore year, my roommates concentrated in economics, and they talked like they understood the world. I then switched into economics, and in my junior year, I switched my major to applied mathematics. I also did an undergraduate thesis, and I wrote about studying outcomes from high-risk surgery. It was funded by the anesthesiology department at Massachusetts General Hospital. I didn't solve an earth-shattering problem, but it taught me how to formulate a problem, research it, and write it up.