In a developing nervous system, axonal arbors often undergo complex rearrangements before neural circuits attain their final innervation topology. In the lateral line sensory system of the zebrafish, developing sensory axons reorganize their terminal arborization patterns to establish precise neural microcircuits around the mechanosensory hair cells. However, a quantitative understanding of the changes in the sensory arbor morphology and the regulators behind the microcircuit assembly remain enigmatic. Here, we report that Semaphorin7A (Sema7A) acts as an important mediator of these processes. Utilizing a semi-automated three-dimensional neurite tracing methodology and computational techniques, we have identified and quantitatively analyzed distinct topological features that shape the network in wild-type and Sema7A loss-of-function mutants. In contrast to those of wild-type animals, the sensory axons in Sema7A mutants display aberrant arborizations with disorganized network topology and diminished contacts to hair cells. Moreover, ectopic expression of a secreted form of Sema7A by non-hair cells induces chemotropic guidance of sensory axons. Our findings propose that Sema7A likely functions both as a juxtracrine and as a secreted cue to pattern neural circuitry during sensory organ development.

Despite clinical data stretching over millennia, the neurobiological basis of the effectiveness of acupuncture in treating diseases of the central nervous system has remained elusive. Here, using an established model of acupuncture treatment in Parkinson\'s disease (PD) model mice, we show that peripheral acupuncture stimulation activates hypothalamic melanin-concentrating hormone (MCH) neurons via nerve conduction. We further identify two separate neural pathways originating from anatomically and electrophysiologically distinct MCH neuronal subpopulations, projecting to the substantia nigra and hippocampus, respectively. Through chemogenetic manipulation specifically targeting these MCH projections, their respective roles in mediating the acupuncture-induced motor recovery and memory improvements following PD onset are demonstrated, as well as the underlying mechanisms mediating recovery from dopaminergic neurodegeneration, reactive gliosis, and impaired hippocampal synaptic plasticity. Collectively, these MCH neurons constitute not only a circuit-based explanation for the therapeutic effectiveness of traditional acupuncture, but also a potential cellular target for treating both motor and non-motor PD symptoms.

Understanding how different neuronal types connect and communicate is critical to interpreting brain function and behavior. However, it has remained a formidable challenge to decipher the genetic underpinnings that dictate the specific connections formed between neuronal types. To address this, we propose a novel bilinear modeling approach that leverages the architecture similar to that of recommendation systems. Our model transforms the gene expressions of presynaptic and postsynaptic neuronal types, obtained from single-cell transcriptomics, into a covariance matrix. The objective is to construct this covariance matrix that closely mirrors a connectivity matrix, derived from connectomic data, reflecting the known anatomical connections between these neuronal types. When tested on a dataset of Caenorhabditis elegans, our model achieved a performance comparable to, if slightly better than, the previously proposed spatial connectome model (SCM) in reconstructing electrical synaptic connectivity based on gene expressions. Through a comparative analysis, our model not only captured all genetic interactions identified by the SCM but also inferred additional ones. Applied to a mouse retinal neuronal dataset, the bilinear model successfully recapitulated recognized connectivity motifs between bipolar cells and retinal ganglion cells, and provided interpretable insights into genetic interactions shaping the connectivity. Specifically, it identified unique genetic signatures associated with different connectivity motifs, including genes important to cell-cell adhesion and synapse formation, highlighting their role in orchestrating specific synaptic connections between these neurons. Our work establishes an innovative computational strategy for decoding the genetic programming of neuronal type connectivity. It not only sets a new benchmark for single-cell transcriptomic analysis of synaptic connections but also paves the way for mechanistic studies of neural circuit assembly and genetic manipulation of circuit wiring.

The nucleus of Darkschewitsch (ND), mainly composed of GABAergic neurons, is widely recognized as a component of the eye-movement controlling system. However, the functional contribution of ND GABAergic neurons (NDGABA) in animal behavior is largely unknown. Here, we show that NDGABA neurons were selectively activated by different types of fear stimuli, such as predator odor and foot shock. Optogenetic and chemogenetic manipulations revealed that NDGABA neurons mediate freezing behavior. Moreover, using circuit-based optogenetic and neuroanatomical tracing methods, we identified an excitatory pathway from the lateral periaqueductal gray (lPAG) to the ND that induces freezing by exciting ND inhibitory outputs to the motor-related gigantocellular reticular nucleus, ventral part (GiV). Together, these findings indicate the NDGABA population as a novel hub for controlling defensive response by relaying fearful information from the lPAG to GiV, a mechanism critical for understanding how the freezing behavior is encoded in the mammalian brain.

Surgical neuromodulation has witnessed significant progress in recent decades. Notably, deep brain stimulation (DBS), delivered precisely within therapeutic targets, has revolutionized the treatment of medication-refractory movement disorders and is now expanding for refractory psychiatric disorders, refractory epilepsy, and post-stroke motor recovery. In parallel, the advent of incisionless treatment with focused ultrasound ablation (FUSA) can offer patients life-changing symptomatic relief. Recent research has underscored the potential to further optimize DBS and FUSA outcomes by conceptualizing the therapeutic targets as critical nodes embedded within specific brain networks instead of strictly anatomical structures. This paradigm shift was facilitated by integrating two imaging modalities used regularly in brain connectomics research: diffusion MRI (dMRI) and functional MRI (fMRI). These advanced imaging techniques have helped optimize the targeting and programming techniques of surgical neuromodulation, all while holding immense promise for investigations into treating other neurological and psychiatric conditions. This review aims to provide a fundamental background of advanced imaging for clinicians and scientists, exploring the synergy between current and future approaches to neuromodulation as they relate to dMRI and fMRI capabilities. Focused research in this area is required to optimize existing, functional neurosurgical treatments while serving to build an investigative infrastructure to unlock novel targets to alleviate the burden of other neurological and psychiatric disorders.

Neuropeptide S (NPS) was postulated to be a wake-promoting neuropeptide with unknown mechanism, and a mutation in its receptor (NPSR1) causes the short sleep duration trait in humans. We investigated the role of different NPS+ nuclei in sleep/wake regulation. Loss-of-function and chemogenetic studies revealed that NPS+ neurons in the parabrachial nucleus (PB) are wake-promoting, whereas peri-locus coeruleus (peri-LC) NPS+ neurons are not important for sleep/wake modulation. Further, we found that a NPS+ nucleus in the central gray of the pons (CGPn) strongly promotes sleep. Fiber photometry recordings showed that NPS+ neurons are wake-active in the CGPn and wake/REM-sleep active in the PB and peri-LC. Blocking NPS-NPSR1 signaling or knockdown of Nps supported the function of the NPS-NPSR1 pathway in sleep/wake regulation. Together, these results reveal that NPS and NPS+ neurons play dichotomous roles in sleep/wake regulation at both the molecular and circuit levels.

Post-traumatic stress disorder (PTSD) is a stress-associated complex and debilitating psychiatric disorder due to an imbalance of neurotransmitters in response to traumatic events or fear. PTSD is characterized by re-experiencing, avoidance behavior, hyperarousal, negative emotions, insomnia, personality changes, and memory problems following exposure to severe trauma. However, the biological mechanisms and symptomatology underlying this disorder are still largely unknown or poorly understood. Considerable evidence shows that PTSD results from a dysfunction in highly conserved brain systems involved in regulating stress, anxiety, fear, and reward circuitry. This review provides a contemporary update about PTSD, including new data from the clinical and preclinical literature on stress, PTSD, and fear memory consolidation and extinction processes. First, we present an overview of well-established laboratory models of PTSD and discuss their clinical translational value for finding various treatments for PTSD. We then highlight the research progress on the neural circuits of fear and extinction-related behavior, including the prefrontal cortex, hippocampus, and amygdala. We further describe different molecular mechanisms, including GABAergic, glutamatergic, cholinergic, and neurotropic signaling, responsible for the structural and functional changes during fear acquisition and fear extinction processes in PTSD.

Background: Supporting wellbeing beyond symptom reduction is necessary in trauma care. Research suggests increased posttraumatic growth (PTG) may promote wellbeing more effectively than posttraumatic stress disorder (PTSD) symptom reduction alone. Understanding neurobiological mechanisms of PTG would support PTG intervention development. However, most PTG research to-date has been cross-sectional data self-reported through surveys or interviews.Objective: Neural evidence of PTG and its coexistence with resilience and PTSD is limited. To advance neural PTG literature and contribute translational neuroscientific knowledge necessary to develop future objectively measurable neural-based PTG interventions.Method: Alpha frequency EEG and validated psychological inventories measuring PTG, resilience, and PTSD symptoms were collected from 30 trauma-exposed healthy adults amidst the COVID-19 pandemic. EEG data were collected using custom MNE-Python software, and a wireless OpenBCI 16-channel dry electrode EEG headset. Psychological inventory scores were analysed in SPSS Statistics and used to categorise the EEG data. Power spectral density analyses, t-tests and ANOVAs were conducted within EEGLab to identify brain activity differentiating high and low PTG, resilience, and PTSD symptoms.Results: Higher PTG was significantly differentiated from low PTG by higher alpha power in the left centro-temporal brain area around EEG electrode C3. A trend differentiating high PTG from PTSD was also indicated in this same location. Whole-scalp spectral topographies revealed alpha power EEG correlates of PTG, resilience and PTSD symptoms shared limited, but potentially meaningful similarities.Conclusion: This research provides the first comparative neural topographies of PTG, resilience and PTSD symptoms in the known literature. Results provide objective neural evidence supporting existing theory depicting PTG, resilience and PTSD as independent, yet co-occurring constructs. PTG neuromarker alpha C3 significantly delineated high from low PTG and warrants further investigation for potential clinical application. Findings provide foundation for future neural-based interventions and research for enhancing PTG in trauma-exposed individuals.
Objective translational study designed to increase neural understanding of posttraumatic growth (PTG) and provide a basis for future neural-based interventions to enhance PTG.Results provide neural evidence of PTG as an independent construct that coexists, and shares limited neural relatedness with resilience and PTSD symptoms.Increased PTG was significantly related to higher alpha power in the left centro-temporal brain area around EEG electrode C3: This finding warrants further investigation for potential clinical application.

Restricted repetitive behaviors (RRBs), which are associated with many different neurological and mental disorders, such as obsessive-compulsive disorder (OCD) and autism, are patterns of behavior with little variation and little obvious function. Paired Box 2 (Pax2) is a transcription factor that is expressed in many systems, including the kidney and the central nervous system. The protein that is encoded by Pax2 has been implicated in the development of the nervous system and neurodevelopmental disorders. In our previous study, Pax2 heterozygous gene knockout mice (Pax2+/- mice) showed abnormally increased self-grooming and impaired learning and memory abilities. However, it remains unclear which cell type is involved in this process. In this study, we deleted Pax2 only in the nervous system to determine the regulatory mechanism of Pax2 in RRBs.
In this study, Pax2 nervous system-specific knockout mice (Nestin-Pax2 mice) aged 6-8 weeks and Pax2 flox mice of the same age were recruited as the experimental group. Tamoxifen and vehicle were administered via intraperitoneal injection to induce Pax2 knockout after gene identification. Western blotting was used to detect Pax2 expression. After that, we assessed the general health of these two groups of mice. The self-grooming test, marble burying test and T-maze acquisition and reversal learning test were used to observe the lower-order and higher-order RRBs. The three-chamber test, Y-maze, and elevated plus-maze were used to assess social ability, spatial memory ability, and anxiety. Neural circuitry tracing and transcriptome sequencing (RNA-seq) were used to observe the abnormal neural circuitry, differentially expressed genes (DEGs) and signaling pathways affected by Pax2 gene knockout in the nervous system and the putative molecular mechanism.
(1) The Nestin-Pax2 mouse model was successfully constructed, and the Nestin-Pax2 mice showed decreased expression of Pax2. (2) Nestin-Pax2 mice showed increased self-grooming behavior and impaired T-maze reversal behavior compared with Pax2 flox mice. (3) An increased number of projection fibers can be found in the mPFC projecting to the CA1 and BLA, and a reduction in IGFBP2 can be found in the hippocampus of Nestin-Pax2 mice.
The results demonstrated that loss of Pax2 in the nervous system leads to restricted repetitive behaviors. The mechanism may be associated with impaired neural circuitry and a reduction in IGFBP2.

Neuronal synaptic junctions connect neurons to enable neuronal signal transmission in the nervous system. The proper establishment of synaptic connections required many adhesion molecules. Malfunctions of these adhesion molecules can result in neural development disorders and neuropsychiatric disorders. How specific synapses are established by various adhesion molecules for proper neural circuitry is a fundamental question of neuroscience. SynCAMs, also named CADMs, Necl, etc., are among the many adhesion proteins found in synapses. Here, we review the current understanding of the physical properties of SynCAMs and their roles in axon pathfinding, myelination, synaptogenesis, and synaptic plasticity. In addition, we discuss the involvement of SynCAMs in neuropsychiatric disorders. Finally, we propose that SynCAM functions can be better viewed and understood from the perspective of orientational cell adhesions (OCAs). In particular, we discuss the possibilities of how SynCAMs can be regulated at the cell-type specific expression, transcription variants, posttranslational modification, and subcellular localization to modulate the diversity of SynCAMs as OCA molecules. Being major components of the synapses, SynCAMs continue to be an important research topic of neuroscience, and many outstanding questions are waiting to be answered.