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 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:
Westernization of dietary habits has led to a progressive reduction in dietary intake of n-3 polyunsaturated fatty acids (n-3 PUFAs). Low maternal intake of n-3 PUFAs has been linked to neurodevelopmental disorders, conditions in which myelination processes are abnormal, leading to defects in brain functional connectivity. Only little is known about the role of n-3 PUFAs in oligodendrocyte physiology and white matter development. Here, we show that lifelong n-3 PUFA deficiency disrupts oligodendrocytes maturation and myelination processes during the postnatal period in mice. This has long-term deleterious consequences on white matter organization and hippocampus-prefrontal functional connectivity in adults, associated with cognitive and emotional disorders. Promoting developmental myelination with clemastine, a first-generation histamine antagonist and enhancer of oligodendrocyte precursor cell differentiation, rescues memory deficits in n-3 PUFA deficient animals. Our findings identify a novel mechanism through which n-3 PUFA deficiency alters brain functions by disrupting oligodendrocyte maturation and brain myelination during the neurodevelopmental period.

Abstract:
Translational research on post-traumatic stress disorder (PTSD) has produced limited improvements in clinical practice. Fear conditioning (FC) is one of the dominant animal models of PTSD. In fact, FC is used in many different ways to model PTSD. The variety of FC-based models is ill defined, creating confusion and conceptual vagueness, which in turn impedes translation into the clinic. This article takes a historical and conceptual approach to provide a comprehensive picture of current research and help reorient the research focus. This work historically reviews the variety of models that have emerged from the initial association of PTSD with FC, highlighting conceptual pitfalls that have limited the translation of animal research into clinical advances. We then provide some guidance on how future translational research could benefit from conceptual and technological improvements to translate basic findings in patients. This objective will require transdisciplinary approaches and should involve physicians, engineers, philosophers, and neuroscientists.

Abstract:
Affective memories associated with the negative emotional state experienced during opiate withdrawal are central in maintaining drug taking, seeking, and relapse. Nucleus accumbens (NAC) is a key structure for both acute withdrawal and withdrawal memories reactivation, but the NAC neuron coding properties underpinning the expression of these memories remain largely unknown. Here we aimed at deciphering the role of NAC neurons in the encoding and retrieval of opiate withdrawal memory. Chronic single neuron and local field potentials recordings were performed in morphine-dependent rats and placebo controls. Animals were subjected to an unbiased conditioned placed aversion protocol with one compartment (CS+) paired with naloxone-precipitated withdrawal, a second compartment with saline injection (CS-), and a third being neutral (no pairing). After conditioning, animals displayed a typical place aversion for CS+ and developed a preference for CS- characteristic of safety learning. We found that distinct NAC neurons code for CS+ or CS-. Both populations also displayed highly specific oscillatory dynamics, CS+ and CS- neurons, respectively, following 80 Hz (G80) and 60 Hz (G60) local field potential gamma rhythms. Finally, we found that the balance between G60 and G80 rhythms strongly correlated both with the ongoing behavior of the animal and the strength of the conditioning. We demonstrate here that the aversive and preferred environments are underpinned by distinct groups of NAC neurons as well as specific oscillatory dynamics. This suggest that G60/G80 interplay-established through the conditioning process-serves as a robust and versatile mechanism for a fine coding of the environment emotional weight.

Abstract:
Precise spike timing through the coordination and synchronization of neuronal assemblies is an efficient and flexible coding mechanism for sensory and cognitive processing. In cortical and subcortical areas, the formation of cell assemblies critically depends on neuronal oscillations, which can precisely control the timing of spiking activity. Whereas this form of coding has been described for sensory processing and spatial learning, its role in encoding emotional behaviour remains unknown. Fear behaviour relies on the activation of distributed structures, among which the dorsal medial prefrontal cortex (dmPFC) is known to be critical for fear memory expression. In the dmPFC, the phasic activation of neurons to threat-predicting cues, a spike-rate coding mechanism, correlates with conditioned fear responses and supports the discrimination between aversive and neutral stimuli. However, this mechanism does not account for freezing observed outside stimuli presentations, and the contribution of a general spike-time coding mechanism for freezing in the dmPFC remains to be established. Here we use a combination of single-unit and local field potential recordings along with optogenetic manipulations to show that, in the dmPFC, expression of conditioned fear is causally related to the organization of neurons into functional assemblies. During fear behaviour, the development of 4 Hz oscillations coincides with the activation of assemblies nested in the ascending phase of the oscillation. The selective optogenetic inhibition of dmPFC neurons during the ascending or descending phases of this oscillation blocks and promotes conditioned fear responses, respectively. These results identify a novel phase-specific coding mechanism, which dynamically regulates the development of dmPFC assemblies to control the precise timing of fear responses.

Abstract:
Fear expression relies on the coordinated activity of prefrontal and amygdala circuits, yet the mechanisms allowing long-range network synchronization during fear remain unknown. Using a combination of extracellular recordings, pharmacological and optogenetic manipulations, we found that freezing, a behavioral expression of fear, temporally coincided with the development of sustained, internally generated 4-Hz oscillations in prefrontal-amygdala circuits. 4-Hz oscillations predict freezing onset and offset and synchronize prefrontal-amygdala circuits. Optogenetic induction of prefrontal 4-Hz oscillations coordinates prefrontal-amygdala activity and elicits fear behavior. These results unravel a sustained oscillatory mechanism mediating prefrontal-amygdala coupling during fear behavior.

Abstract:
Recent technological developments, such as single unit recordings coupled to optogenetic approaches, have provided unprecedented knowledge about the precise neuronal circuits contributing to the expression and recovery of conditioned fear behavior. These data have provided an understanding of the contributions of distinct brain regions such as the amygdala, prefrontal cortex, hippocampus, and periaqueductal gray matter to the control of conditioned fear behavior. Notably, the precise manipulation and identification of specific cell types by optogenetic techniques have provided novel avenues to establish causal links between changes in neuronal activity that develop in dedicated neuronal structures and the short and long-lasting expression of conditioned fear memories. In this review, we provide an update on the key neuronal circuits and cell types mediating conditioned fear expression and recovery and how these new discoveries might refine therapeutic approaches for psychiatric conditions such as anxiety disorders and posttraumatic stress disorder.