Abstract:
Dye-based fluorescent organic nanoparticles are a specific class of nanoparticles obtained by nanoprecipitation in water of pure dyes only. While the photophysical and colloidal properties of the nanoparticles strongly depend on the nature of the aggregated dyes, their excellent brightness in the visible and in the near infrared make these nanoparticles a unique and versatile platform for in vivo application. This article examines the promising utilization of these nanoparticles for in vivo optogenetics applications. Their photophysical properties as well as their biocompatibility and their capacity to activate Chrimson opsin in vivo through the fluorescence reabsorption process are demonstrated. Additionally, an illustrative example of employing these nanoparticles in fear reduction in mice through closed-loop stimulation is presented. Through an optogenetic methodology, the nanoparticles demonstrate an ability to selectively manipulate neurons implicated in the fear response and diminish the latter. Dye-based fluorescent organic nanoparticles represent a promising and innovative strategy for optogenetic applications, holding substantial potential in the domain of translational neuroscience. This work paves the way for novel therapeutic modalities for neurological and neuropsychiatric disorders.

Abstract:
The dynamic suppression of threat-related behavior as a function of environmental constraint is critical for survival in mammals, yet the neurobiological underpinnings remain largely unknown. In this issue of Neuron, Wang et al.(1) identified prefrontal dynorphin-expressing neurons as key elements for tracking threat-related behavioral states and regulating fear suppression.

Abstract:
The dentate gyrus (DG) of the hippocampus is a mosaic of dentate granule neurons (DGNs) accumulated throughout life. While many studies focused on the morpho-functional properties of adult-born DGNs, much less is known about DGNs generated during development, and in particular those born during embryogenesis. One of the main reasons for this gap is the lack of methods available to specifically label and manipulate embryonically-born DGNs. Here, we have assessed the relevance of the Penk(Cre) mouse line as a genetic model to target this embryonically-born population. In young animals, Penk(Cre) expression allows to tag neurons in the DG with positional, morphological and electrophysiological properties characteristic of DGNs born during the embryonic period. In addition, Penk(Cre)+ cells in the DG are distributed in both blades along the entire septo-temporal axis. This model thus offers new possibilities to explore the functions of this underexplored population of embryonically-born DGNs.

Abstract:
The consolidation of recent memories depends on memory replays, also called ripples, generated within the hippocampus during slow-wave sleep, and whose inactivation leads to memory impairment. For now, the mobilisation, localisation and importance of synaptic plasticity events associated to ripples are largely unknown. To tackle this question, we used cell surface AMPAR immobilisation to block post-synaptic LTP within the hippocampal region of male mice during a spatial memory task, and show that: 1- hippocampal synaptic plasticity is engaged during consolidation, but is dispensable during encoding or retrieval. 2- Plasticity blockade during sleep results in apparent forgetting of the encoded rule. 3- In vivo ripple recordings show a strong effect of AMPAR immobilisation when a rule has been recently encoded. 4- In situ investigation suggests that plasticity at CA3-CA3 recurrent synapses supports ripple generation. We thus propose that post-synaptic AMPAR mobility at CA3 recurrent synapses is necessary for ripple-dependent rule consolidation.

Abstract:
Behavioral adaptation to potential threats requires both a global representation of danger to prepare the organism to react in a timely manner but also the identification of specific threatening situations to select the appropriate behavioral responses. The prefrontal cortex is known to control threat-related behaviors, yet it is unknown whether it encodes global defensive states and/or the identity of specific threatening encounters. Using a new behavioral paradigm that exposes mice to different threatening situations, we show that the dorsomedial prefrontal cortex (dmPFC) encodes a general representation of danger while simultaneously encoding a specific neuronal representation of each threat. Importantly, the global representation of danger persisted in error trials that instead lacked specific threat identity representations. Consistently, optogenetic prefrontal inhibition impaired overall behavioral performance and discrimination of different threatening situations without any bias toward active or passive behaviors. Together, these data indicate that the prefrontal cortex encodes both a global representation of danger and specific representations of threat identity to control the selection of defensive behaviors.

Abstract:
Despite the popularity of fiber photometry (FP), its integration with operant behavior paradigms is progressing slowly. This can be attributed to the complex protocols in operant behavior - resulting in a combination of diverse non-predictable behavioral responses and scheduled events, thereby complicating data analysis. To overcome this, we developed Pyfiber, an open-source python library which facilitates the merge of FP with operant behavior by relating changes in fluorescent signals within a neuronal population to behavioral responses and events. Pyfiber helps to 1. Extract events and responses that occur in operant behavior, 2. Extract and process the FP signals, 3. Select events of interest and align them to the corresponding FP signals, 4. Apply appropriate signal normalization and analysis according to the type of events, 5. Run analysis on multiple individuals and sessions, 6. Collect results in an easily readable format. Pyfiber is suitable for use with many different fluorescent sensors and operant behavior protocols. It was developed using Doric lenses FP systems and Imetronic behavioral systems, but it possesses the capability to process data from alternative systems. This work sets a solid foundation for analyzing the relationship between different dimensions of complex behavioral paradigms with fluorescent signals from brain regions of interest.

Abstract:
Imbalance between excitation and inhibition in the cerebral cortex is one of the main theories in neuropsychiatric disorder pathophysiology. Cortical inhibition is finely regulated by a variety of highly specialized GABAergic interneuron types, which are thought to organize neural network activities. Among interneurons, axo-axonic cells are unique in making synapses with the axon initial segment of pyramidal neurons. Alterations of axo-axonic cells have been proposed to be implicated in disorders including epilepsy, schizophrenia and autism spectrum disorder. However, evidence for the alteration of axo-axonic cells in disease has only been examined in narrative reviews. By performing a systematic review of studies investigating axo-axonic cells and axo-axonic communication in epilepsy, schizophrenia and autism spectrum disorder, we outline convergent findings and discrepancies in the literature. Overall, the implication of axo-axonic cells in neuropsychiatric disorders might have been overstated. Additional work is needed to assess initial, mostly indirect findings, and to unravel how defects in axo-axonic cells translates to cortical dysregulation and, in turn, to pathological states.

Abstract:
Descending control from the brain to the spinal cord shapes our pain experience, ranging from powerful analgesia to extreme sensitivity. Increasing evidence from both preclinical and clinical studies points to an imbalance toward descending facilitation as a substrate of pathological pain, but the underlying mechanisms remain unknown. We used an optogenetic approach to manipulate serotonin (5-HT) neurons of the nucleus raphe magnus that project to the dorsal horn of the spinal cord. We found that 5-HT neurons exert an analgesic action in naïve mice that becomes proalgesic in an experimental model of neuropathic pain. We show that spinal KCC2 hypofunction turns this descending inhibitory control into paradoxical facilitation; KCC2 enhancers restored 5-HT-mediated descending inhibition and analgesia. Last, combining selective serotonin reuptake inhibitors (SSRIs) with a KCC2 enhancer yields effective analgesia against nerve injury-induced pain hypersensitivity. This uncovers a previously unidentified therapeutic path for SSRIs against neuropathic pain.

Abstract:
Our understanding of the neuronal circuits and mechanisms of defensive systems has been primarily dominated by studies focusing on the contribution of individual cells in the processing of threat-predictive cues, defensive responses, the extinction of such responses and the contextual modulation of threat-related behavior. These studies have been key in establishing threat-related circuits and mechanisms. Yet, they fall short in answering long-standing questions related to the integrative processing of distinct threatening cues, behavioral states induced by threat-related events, or the bridging from sensory processing of threat-related cues to specific defensive responses. Recent conceptual and technical developments has allowed the monitoring of large populations of neurons, which in addition to advanced analytic tools, have improved our understanding of how collective neuronal activity supports threat-related behaviors. In this review, we discuss the current knowledge of neuronal population codes within threat-related networks, in the context of aversive motivated behavior and the study of defensive systems.

Abstract:
Prevalence, symptoms, and treatment of depression suggest that major depressive disorders (MDD) present sex differences. Social stress-induced neurovascular pathology is associated with depressive symptoms in male mice; however, this association is unclear in females. Here, we report that chronic social and subchronic variable stress promotes blood-brain barrier (BBB) alterations in mood-related brain regions of female mice. Targeted disruption of the BBB in the female prefrontal cortex (PFC) induces anxiety- and depression-like behaviours. By comparing the endothelium cell-specific transcriptomic profiling of the mouse male and female PFC, we identify several pathways and genes involved in maladaptive stress responses and resilience to stress. Furthermore, we confirm that the BBB in the PFC of stressed female mice is leaky. Then, we identify circulating vascular biomarkers of chronic stress, such as soluble E-selectin. Similar changes in circulating soluble E-selectin, BBB gene expression and morphology can be found in blood serum and postmortem brain samples from women diagnosed with MDD. Altogether, we propose that BBB dysfunction plays an important role in modulating stress responses in female mice and possibly MDD.