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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., (© 2024 The Author(s). Advanced Healthcare Materials published by Wiley‐VCH GmbH.)

Background: Continuous waveform monitoring is standard-of-care for patients at risk for or with critically illness. Derived from waveforms, heart rate, respiratory rate and blood pressure variability contain useful diagnostic and prognostic information; and when combined with machine learning, can provide predictive indices relating to severity of illness and/or reduced physiologic reserve. Integration of predictive models into clinical decision support software (CDSS) tools represents a potential evolution of monitoring., Methods: We perform a review and analysis of the multidisciplinary steps required to develop and rigorously evaluate predictive clinical decision support tools based on monitoring., Results: Development and evaluation of waveform-based variability-derived predictive models involves a multistep, multidisciplinary approach. The stepwise processes involves data science (data collection, waveform processing, variability analysis, statistical analysis, machine learning, predictive modelling), CDSS development (iterative research prototype evolution to commercial tool), and clinical research (observational and interventional implementation studies, followed by feasibility then definitive randomized controlled trials), and poses unique challenges (including technical, analytical, psychological, regulatory and commercial)., Conclusions: The proposed roadmap provides guidance for the development and evaluation of novel predictive CDSS tools with potential to help transform monitoring and improve care., Competing Interests: Declarations. Conflict interest: Dr. Andrew Seely is the founder and CEO of Therapeutic Monitoring Systems (TMS) which holds licensing rights to several patents related to variability-derived clinical decision support, where both Andrew Seely and Christophe Herry are patent authors related to this work. Dr. A. Seely discloses the conflict of interest (CoI) in all grants, publications, presentations, and other public communication, and submits a CoI management agreement to Ottawa Hospital Research Institute annually., (© 2024. The Author(s).)

Importance: Extubation Advisor (EA) is a novel software tool that generates a synoptic report for each Spontaneous Breathing Trial (SBT) conducted to inform extubation decision-making., Objectives: To assess bedside EA implementation, perceptions of utility, and identify barriers and facilitators of use., Design, Setting and Participants: We conducted a phase I mixed-methods interventional study in three mixed intensive care unit (ICUs) in two academic hospitals. We interviewed critical care physicians (MDs) and respiratory therapists (RTs) regarding user-centered design principles and usability., Analysis: We evaluated our ability to consent participants (feasibility threshold 50%), capture complete data (threshold 90%), generate and review EA reports in real-time (thresholds 75% and 80%, respectively), and MD perception of tool usefulness (6-point Likert scale). We analyzed interview transcripts using inductive coding to identify facilitators and barriers to EA implementation and perceived benefit of tool use., Results: We enrolled 31 patients who underwent 70 SBTs. Although consent rates [31/31 (100%], complete data capture [68/68 (100%)], and EA report generation [68/70 (97.1%)] exceeded feasibility thresholds, reports were reviewed by MDs for [55/70 (78.6%)] SBTs. Mean MD usefulness score was 4.0/6. Based on feedback obtained from 36 interviews (15 MDs, 21 RTs), we revised the EA report twice and identified facilitators (ability to track patient progress, enhance extubation decision-making, and provide support in resource-limited settings) and barriers (resource constraints, need for education) to tool implementation. Half of respondents (9 MDs, 9 RTs; combined 50%) perceived definite or potential benefit to EA tool use., Conclusion: This is the first study of a waveform-based variability-derived, predictive clinical decision support tool evaluated in adult ICUs. Our findings support the feasibility of integrating the EA tool into bedside workflow. Clinical trials are needed to assess the utility of the EA tool in practice and its impact on extubation decision-making and outcomes., Trial Registration: NCT04708509., Competing Interests: Declaration of Conflicting InterestsDr A Seely and Dr C Herry are named on a patent related to Extubation Advisor technology described in this paper. Dr Seely is founder and board chairman of Therapeutic Monitoring Systems, a company founded to help research, develop, and commercialize clinical decision support tools based on variability analysis, including Extubation Advisor.

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., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

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., (© 2024. The Author(s).)

The selection and optimization of appropriate adaptive responses depends on interoceptive and exteroceptive stimuli as well as on the animal's ability to switch from one behavioral strategy to another. Although growing evidence indicate that dopamine D2R-mediated signaling events ensure the selection of the appropriate strategy for each specific situation, the underlying neural circuits through which they mediate these effects are poorly characterized. Here, we investigated the role of D2R signaling in a mesolimbic neuronal subpopulation expressing the Wolfram syndrome 1 (Wfs1) gene. This subpopulation is located within the nucleus accumbens, the central amygdala, the bed nucleus of the stria terminalis, and the tail of the striatum, all brain regions critical for the regulation of emotions and motivated behaviors. Using a mouse model carrying a temporally controlled deletion of D2R in WFS1-neurons, we demonstrate that intact D2R signaling in this neuronal population is necessary to regulate homeostasis-dependent food-seeking behaviors in both male and female mice. In addition, we found that reduced D2R signaling in WFS1-neurons impaired active avoidance learning and innate escape responses. Collectively, these findings identify a yet undocumented role for D2R signaling in WFS1-neurons as a novel effector through which dopamine optimizes appetitive behaviors and regulates defensive behaviors., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The medial prefrontal cortex (mPFC) is at the core of numerous psychiatric conditions, including fear and anxiety-related disorders. Whereas an abundance of evidence suggests a crucial role of the mPFC in regulating fear behaviour, the precise role of the mPFC in this process is not yet entirely clear. While studies at the single-cell level have demonstrated the involvement of this area in various aspects of fear processing, such as the encoding of threat-related cues and fear expression, an increasingly prevalent idea in the systems neuroscience field is that populations of neurons are, in fact, the essential unit of computation in many integrative brain regions such as prefrontal areas. What mPFC neuronal populations represent when we face threats? To address this question, we performed electrophysiological single-unit population recordings in the dorsal mPFC while mice faced threat-predicting cues eliciting defensive behaviours, and performed pharmacological and optogenetic inactivations of this area and the amygdala. Our data indicated that the presence of threat-predicting cues induces a stable coding dynamics of internally driven representations in the dorsal mPFC, necessary to drive learned defensive behaviours. Moreover, these neural population representations primary reflect learned associations rather than specific defensive behaviours, and the construct of such representations relies on the functional integrity of the amygdala.

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., (© 2023. The Author(s).)

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., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Take-Home Message: During short bouts of light-to-vigorous exercise in the heat, controlled and uncomplicated hypertension did not significantly modulate HRV in physically active individuals. These findings can be used to refine guidance on use of exercise for hypertension management in the heat., Competing Interests: The authors declare there are no competing interests.

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., (© 2023. Springer Nature Limited.)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Vivien, El Azraoui, Lheraux, Lanore, Aouizerate, Herry, Humeau and Bienvenu.)

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., Competing Interests: Conflict of interest statement Nothing declared., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

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.

The dentate gyrus is one of the only brain regions that continues its development after birth in rodents. Adolescence is a very sensitive period during which cognitive competences are programmed. We investigated the role of dentate granule neurons (DGNs) born during adolescence in spatial memory and compared them with those generated earlier in life (in embryos or neonates) or during adulthood by combining functional imaging, retroviral and optogenetic tools to tag and silence DGNs. By imaging DGNs expressing Zif268, a proxy for neuronal activity, we found that neurons generated in adolescent rats (and not embryos or neonates) are transiently involved in spatial memory processing. In contrast, adult-generated DGNs are recruited at a later time point when animals are older. A causal relationship between the temporal origin of DGNs and spatial memory was confirmed by silencing DGNs in behaving animals. Our results demonstrate that the emergence of spatial memory depends on neurons born during adolescence, a function later assumed by neurons generated during adulthood., (© 2021. The Author(s).)

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., Competing Interests: Declaration of interests B.A. received speaker’s honoraria and/or a travel allowance from Lundbeck, Janssen-Cilag, Sanofi, and Eli Lilly. He has served on the advisory board of Janssen-Cilag., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Fear extinction is an adaptive process whereby defensive responses are attenuated following repeated experience of prior fear-related stimuli without harm. The formation of extinction memories involves interactions between various corticolimbic structures, resulting in reduced central amygdala (CEA) output. Recent studies show, however, the CEA is not merely an output relay of fear responses but contains multiple neuronal subpopulations that interact to calibrate levels of fear responding. Here, by integrating behavioural, in vivo electrophysiological, anatomical and optogenetic approaches in mice we demonstrate that fear extinction produces reversible, stimulus- and context-specific changes in neuronal responses to conditioned stimuli in functionally and genetically defined cell types in the lateral (CEl) and medial (CEm) CEA. Moreover, we show these alterations are absent when extinction is deficient and that selective silencing of protein kinase C delta-expressing (PKCδ) CEl neurons impairs fear extinction. Our findings identify CEA inhibitory microcircuits that act as critical elements within the brain networks mediating fear extinction.

Coping with threatening situations requires both identifying stimuli that predict danger and selecting adaptive behavioural responses to survive 1 . The dorsomedial prefrontal cortex (dmPFC) is a critical structure that is involved in the regulation of threat-related behaviour 2-4 . However, it is unclear how threat-predicting stimuli and defensive behaviours are associated within prefrontal networks to successfully drive adaptive responses. Here we used a combination of extracellular recordings, neuronal decoding approaches, pharmacological and optogenetic manipulations to show that, in mice, threat representations and the initiation of avoidance behaviour are dynamically encoded in the overall population activity of dmPFC neurons. Our data indicate that although dmPFC population activity at stimulus onset encodes sustained threat representations driven by the amygdala, it does not predict action outcome. By contrast, transient dmPFC population activity before the initiation of action reliably predicts avoided from non-avoided trials. Accordingly, optogenetic inhibition of prefrontal activity constrained the selection of adaptive defensive responses in a time-dependent manner. These results reveal that the adaptive selection of defensive responses relies on a dynamic process of information linking threats with defensive actions, unfolding within prefrontal networks., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Brain-body interactions are thought to be essential in emotions but their physiological basis remains poorly understood. In mice, regular 4 Hz breathing appears during freezing after cue-fear conditioning. Here we show that the olfactory bulb (OB) transmits this rhythm to the dorsomedial prefrontal cortex (dmPFC) where it organizes neural activity. Reduction of the respiratory-related 4 Hz oscillation, via bulbectomy or optogenetic perturbation of the OB, reduces freezing. Behavioural modelling shows that this is due to a specific reduction in freezing maintenance without impacting its initiation, thus dissociating these two phenomena. dmPFC LFP and firing patterns support the region's specific function in freezing maintenance. In particular, population analysis reveals that network activity tracks 4 Hz power dynamics during freezing and reaches a stable state at 4 Hz peak that lasts until freezing termination. These results provide a potential mechanism and a functional role for bodily feedback in emotions and therefore shed light on the historical James-Cannon debate.

Background: The minimum duration of pulselessness required before organ donation after circulatory determination of death has not been well studied., Methods: We conducted a prospective observational study of the incidence and timing of resumption of cardiac electrical and pulsatile activity in adults who died after planned withdrawal of life-sustaining measures in 20 intensive care units in three countries. Patients were intended to be monitored for 30 minutes after determination of death. Clinicians at the bedside reported resumption of cardiac activity prospectively. Continuous blood-pressure and electrocardiographic (ECG) waveforms were recorded and reviewed retrospectively to confirm bedside observations and to determine whether there were additional instances of resumption of cardiac activity., Results: A total of 1999 patients were screened, and 631 were included in the study. Clinically reported resumption of cardiac activity, respiratory movement, or both that was confirmed by waveform analysis occurred in 5 patients (1%). Retrospective analysis of ECG and blood-pressure waveforms from 480 patients identified 67 instances (14%) with resumption of cardiac activity after a period of pulselessness, including the 5 reported by bedside clinicians. The longest duration after pulselessness before resumption of cardiac activity was 4 minutes 20 seconds. The last QRS complex coincided with the last arterial pulse in 19% of the patients., Conclusions: After withdrawal of life-sustaining measures, transient resumption of at least one cycle of cardiac activity after pulselessness occurred in 14% of patients according to retrospective analysis of waveforms; only 1% of such resumptions were identified at the bedside. These events occurred within 4 minutes 20 seconds after a period of pulselessness. (Funded by the Canadian Institutes for Health Research and others.)., (Copyright © 2021 Massachusetts Medical Society.)

Categorization is based on cognitive mechanisms allowing the development of internal representations of the environment that guide behavior. This study tests the influence of emotions on categorization in adolescents and young adults. After a mood induction (negative, positive, or neutral), we compared how 68 adolescents aged 13 to 15 and 57 young adults aged 21 to 29 categorized emotional concepts using a lexical emotional categorization task. Participants had to choose which of three associates, of different emotional valence (positive, negative or neutral), was more similar to a target concept. The aim of this study was to determine if adolescents rely on the emotional dimension in categorization more than adults. The results show that the emotional state can influence the cognitive process of categorization in adolescence, particularly in the negative mood.

The behavioral repertoire of an organism can be highly diverse, spanning from social to defensive. How an animal efficiently switches between distinct behaviors is a fundamental question whose inquiry will provide insights into the mechanisms that are necessary for an organism's survival. Previous work aimed at identifying the neural systems responsible for defensive behaviors, such as freezing, has demonstrated critical interactions between the prefrontal cortex and amygdala. Indeed, this foundational research has provided an indispensable anatomical framework that investigators are now using to understand the physiological mechanisms of defined neural circuits within the prefrontal cortex that code for the rapid and flexible expression of defensive behaviors. Here we review recent findings demonstrating temporal and rate coding mechanisms of freezing behavior in the prefrontal cortex. We hypothesize that anatomical features, such as target structure and cortical layer, as well as the nature of the information to be coded, may be critical factors determining the coding scheme. Furthermore, detailed behavioral analyses may reveal subtypes of defensive behaviors that represent the principle factor governing coding selection., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Declarative memory formation depends on the hippocampus and declines in aging. Two functions of the hippocampus, temporal binding and relational organization (Rawlins and Tsaltas, 1983; Eichenbaum et al. , 1992 ; Cohen et al. , 1997 ), are known to decline in aging (Leal and Yassa, 2015). However, in the literature distinct procedures have been used to study these two functions. Here, we describe the experimental procedures used to investigate how these two processes are related in the formation of declarative memory and how they are compromised in aging ( Sellami et al. , 2017 ). First, we studied temporal binding using a one-trial learning procedure: trace fear conditioning. It is classical Pavlovian conditioning requiring temporal binding since a brief temporal gap separates the conditioned stimulus (CS) and unconditioned stimulus (US) presentations. We combined the trace fear condition procedure with an optogenetic approach, and we showed that the temporal binding relies on dorsal (d)CA1 activity over temporal gaps. Then, we studied the interaction between temporal binding and relational organization in declarative memory formation using a two-phase radial-maze task in mice and its virtual analog in humans. The behavioral procedure comprises an initial learning phase where subjects learned the constant rewarding /no rewarding valence of each arm, followed by a test phase where the reward contingencies among the arms remained unchanged but where the arms were recombined to assess flexibility, a cardinal property of declarative memory. We demonstrated that dCA1-dependent temporal binding is necessary for the development of a relational organization of memories that allows flexible declarative memory expression. Furthermore, in aging, the degradation of declarative memory is due to a reduction of temporal binding capacity that prevents relation organization., (Copyright © 2018 The Authors; exclusive licensee Bio-protocol LLC.)

Objective: The utility of fetal heart rate (FHR) monitoring can only be achieved with an acquisition sampling rate that preserves the underlying physiological information on the millisecond time scale (1000 Hz rather than 4 Hz). For such acquisition, fetal ECG (fECG) is required, rather than the ultrasound to derive FHR. We tested one recently developed algorithm, SAVER, and two widely applied algorithms to extract fECG from a single-channel maternal ECG signal recorded over the xyphoid process rather than the routine abdominal signal., Approach: At 126dG, ECG was attached to near-term ewe and fetal shoulders, manubrium and xyphoid processes (n  =  12). fECG served as the ground-truth to which the fetal ECG signal extracted from the simultaneously-acquired maternal ECG was compared. All fetuses were in good health during surgery (pH 7.29  ±  0.03, pO 2 33.2  ±  8.4, pCO 2 56.0  ±  7.8, O 2 Sat 78.3  ±  7.6, lactate 2.8  ±  0.6, BE  -0.3  ±  2.4)., Main Result: In all animals, single lead fECG extraction algorithm could not extract fECG from the maternal ECG signal over the xyphoid process with the F1 less than 50%., Significance: The applied fECG extraction algorithms might be unsuitable for the maternal ECG signal over the xyphoid process, or the latter does not contain strong enough fECG signal, although the lead is near the mother's abdomen. Fetal sheep model is widely used to mimic various fetal conditions, yet ECG recordings in a public data set form are not available to test the predictive ability of fECG and FHR. We are making this data set openly available to other researchers to foster non-invasive fECG acquisition in this animal model.

Survival critically depends on selecting appropriate defensive or exploratory behaviors and is strongly influenced by the surrounding environment. Contextual discrimination is a fundamental process that is thought to depend on the prefrontal cortex to integrate sensory information from the environment and regulate adaptive responses to threat during uncertainty. However, the precise prefrontal circuits necessary for discriminating a previously threatening context from a neutral context remain unknown. Using a combination of single-unit recordings and optogenetic manipulations, we identified a neuronal subpopulation in the dorsal medial prefrontal cortex (dmPFC) that projects to the lateral and ventrolateral periaqueductal gray (l/vlPAG) and is selectively activated during contextual fear discrimination. Moreover, optogenetic activation and inhibition of this neuronal population promoted contextual fear discrimination and generalization, respectively. Our results identify a subpopulation of dmPFC-l/vlPAG-projecting neurons that control switching between different emotional states during contextual discrimination., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Temporal binding, the process that enables association between discontiguous stimuli in memory, and relational organization, a process that enables the flexibility of declarative memories, are both hippocampus-dependent and decline in aging. However, how these two processes are related in supporting declarative memory formation and how they are compromised in age-related memory loss remain hypothetical. We here identify a causal link between these two features of declarative memory: Temporal binding is a necessary condition for the relational organization of discontiguous events. We demonstrate that the formation of a relational memory is limited by the capability of temporal binding, which depends on dorsal (d)CA1 activity over time intervals and diminishes in aging. Conversely, relational representation is successful even in aged individuals when the demand on temporal binding is minimized, showing that relational/declarative memory per se is not impaired in aging. Thus, bridging temporal intervals by dCA1 activity is a critical foundation of relational representation, and a deterioration of this mechanism is responsible for the age-associated memory impairment., Competing Interests: The authors declare no conflict of interest.

Background: Orexins are hypothalamic neuropeptides recently involved in the regulation of emotional memory. The basolateral amygdala, an area orchestrating fear memory processes, appears to be modulated by orexin transmission during fear extinction. However, the neuronal types within the basolateral amygdala involved in this modulation remain to be elucidated., Methods: We used retrograde tracing combined with immunofluorescence techniques in mice to identify basolateral amygdala projection neurons and cell subpopulations in this brain region influenced by orexin transmission during contextual fear extinction consolidation., Results: Treatment with the orexin-1 receptor antagonist SB334867 increased the activity of basolateral amygdala neurons projecting to infralimbic medial prefrontal cortex during fear extinction. GABAergic interneurons expressing calbindin, but not parvalbumin, were also activated by orexin-1 receptor antagonism in the basolateral amygdala., Conclusions: These data identify neuronal circuits and cell populations of the amygdala associated with the facilitation of fear extinction consolidation induced by the orexin-1 receptor antagonist SB334867., (© The Author 2017. Published by Oxford University Press on behalf of CINP.)

Accurate predatory behavior requires coordination between pursuit activity and prey consumption, yet the underlying neuronal circuits are unknown. A novel study published in this issue of Cell identifies two coordinated circuits emanating from the central amygdala that control the efficiency of prey capture and the ability to deliver fatal bites to prey., (Copyright © 2017. Published by Elsevier Inc.)

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.

Survival in threatening situations depends on the selection and rapid execution of an appropriate active or passive defensive response, yet the underlying brain circuitry is not understood. Here we use circuit-based optogenetic, in vivo and in vitro electrophysiological, and neuroanatomical tracing methods to define midbrain periaqueductal grey circuits for specific defensive behaviours. We identify an inhibitory pathway from the central nucleus of the amygdala to the ventrolateral periaqueductal grey that produces freezing by disinhibition of ventrolateral periaqueductal grey excitatory outputs to pre-motor targets in the magnocellular nucleus of the medulla. In addition, we provide evidence for anatomical and functional interaction of this freezing pathway with long-range and local circuits mediating flight. Our data define the neuronal circuitry underlying the execution of freezing, an evolutionarily conserved defensive behaviour, which is expressed by many species including fish, rodents and primates. In humans, dysregulation of this 'survival circuit' has been implicated in anxiety-related disorders.

Posttraumatic stress disorder (PTSD) is a highly debilitating and prevalent psychological disorder. It is characterized by highly distressing intrusive trauma memories that are partly explained by fear conditioning. Despite efficient therapeutic approaches, a subset of PTSD patients displays spontaneous recurrence of traumatic memories after successful treatment. The development of animal behavioral models mimicking the individual variability in treatment outcome for PTSD patients represent therefore an important challenge as it allows for the identification of predicting factors of resilience or susceptibility to relapse. However, to date, only few animal behavioral models of long-lasting fear recovery have been developed and their predictive validity has not been tested directly. The objectives of this study were twofold. First we aimed to develop a simple animal behavioral model of long-lasting fear recovery based on auditory cued fear conditioning and extinction learning, which recapitulates the heterogeneity of fear responses observed in PTSD patients after successful treatment. Second we aimed at testing the predictive validity of our behavioral model and used to this purpose a translational approach based (i) on the demonstration of the efficiency of Eye Movement Desensitization and Reprocessing (EMDR) therapy to reduce conditioned fear responses in PTSD patients and (ii) on the implementation in our behavioral model of an electrical bilateral alternating stimulation of the eyelid which mimics the core feature of EMDR. Our data indicate that electrical bilateral alternating stimulation of the eyelid during extinction learning alleviates long-lasting fear recovery of conditioned fear responses and dramatically reduces inter-individual variability. These results demonstrate the face and predictive validity of our animal behavioral model and provide an interesting tool to understand the neurobiological underpinnings of long-lasting fear recovery., (Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.)

Objective: Necrotizing enterocolitis of the neonate is an acute inflammatory intestinal disease that can cause necrosis and sepsis. Chorioamnionitis is a risk factor of necrotizing enterocolitis. The gut represents the biggest vagus-innervated organ. Vagal activity can be measured via fetal heart rate variability. We hypothesized that fetal heart rate variability can detect fetuses with incipient gut inflammation., Design: Prospective animal study., Setting: University research laboratory., Subjects: Chronically instrumented near-term fetal sheep (n = 21)., Measurements and Main Results: Animals were surgically instrumented with vascular catheters and electrocardiogram to allow manipulation and recording from nonanesthetized animals. In 14 fetal sheep, inflammation was induced with lipopolysaccharide (IV) to mimic chorioamnionitis. Fetal arterial blood samples were drawn at selected time points over 54 hours post lipopolysaccharide for blood gas and cytokines (interleukin-6 and tumor necrosis factor-α enzymelinked immunosorbent assay). Fetal heart rateV was quantified throughout the experiment. The time-matched fetal heart rate variability measures were correlated to the levels of interleukin-6 and tumor necrosis factor-α. Upon necropsy, ionized calcium binding adaptor molecule 1+ (Iba1+), CD11c+ (M1), CD206+ (M2 macrophages), and occludin (leakiness marker) immunofluorescence in the terminal ileum was quantified along with regional Iba1+ signal in the brain (microglia). Interleukin-6 peaked at 3 hours post lipopolysaccharide accompanied by mild cardiovascular signs of sepsis. At 54 hours, we identified an increase in Iba1+ and, specifically, M1 macrophages in the ileum accompanied by increased leakiness, with no change in Iba1 signal in the brain. Preceding this change on tissue level, at 24 hours, a subset of nine fetal heart rate variability measures correlated exclusively to the Iba+ markers of ileal, but not brain, inflammation. An additional fetal heart rate variability measure, mean of the differences of R-R intervals, correlated uniquely to M1 ileum macrophages increasing due to lipopolysaccharide., Conclusions: We identified a unique subset of fetal heart rate variability measures reflecting 1.5 days ahead of time the levels of macrophage activation and increased leakiness in terminal ileum. We propose that such subset of fetal heart rate variability measures reflects brain-gut communication via the vagus nerve. Detecting such noninvasively obtainable organ-specific fetal heart rate variability signature of inflammation would alarm neonatologists about neonates at risk of developing necrotizing enterocolitis and sepsis. Clinical validation studies are required.

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.

This study describes a safe, reliable, and accessible means to measure heart rate (HR) and HR variability (HRV) and evaluates the use of HRV as a physiological correlate of stress in the Asian elephant. A probabilistic model indicates that HRV measurements may adequately distinguish between stressed and non-stressed elephants.

Background. Spontaneous breathing trials (SBTs) are standard of care in assessing extubation readiness; however, there are no universally accepted guidelines regarding their precise performance and reporting. Objective. To investigate variability in SBT practice across centres. Methods. Data from 680 patients undergoing 931 SBTs from eight North American centres from the Weaning and Variability Evaluation (WAVE) observational study were examined. SBT performance was analyzed with respect to ventilatory support, oxygen requirements, and sedation level using the Richmond Agitation Scale Score (RASS). The incidence of use of clinical extubation criteria and changes in physiologic parameters during an SBT were assessed. Results. The majority (80% and 78%) of SBTs used 5 cmH2O of ventilator support, although there was variability. A significant range in oxygenation was observed. RASS scores were variable, with RASS 0 ranging from 29% to 86% and 22% of SBTs performed in sedated patients (RASS < -2). Clinical extubation criteria were heterogeneous among centres. On average, there was no change in physiological variables during SBTs. Conclusion. The present study highlights variation in SBT performance and documentation across and within sites. With their impact on the accuracy of outcome prediction, these results support efforts to further clarify and standardize optimal SBT technique.

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., (Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Fetal heart rate (FHR) sampling rate used on the bedside is equal or less than 4 Hz. Current FHR analysis methods fail to detect incipient fetal acidemia. In a fetal sheep model of human labour we showed that FHR sampling rates near 1000 Hz are needed to detect fetal acidemia. Trans-abdominal fetal ECG (t-a fECG) sampling FHR at 900 Hz combined with a complex signals bioinformatics approach showed promise in a human cohort. Here we validate this finding in a retrospective human cohort study by comparing the performance of the same bioinformatics approach to predict pH and BE at birth in the cohorts with FHR sampled either at 4 Hz or at 900 Hz.The 4 Hz FHR recording data sets consisted of the open access intrapartum CTG data base with n = 552 subjects used to develop the predictive model and another cohort of prospectively recruited n = 11 labouring women to then validate it. 900 Hz FHR data set comprised two prospectively recruited t-a fECG cohorts of n = 60 and n = 23 subjects. Recruitment criteria were similar across the cohorts. We have determined the goodness of fit (R(2)) and root mean square error (RMSE) as the performance indicators of the model on each cohort.The clinical characteristics of all cohorts were similar (gestational age 280   ±   8 d; gender 50% male; birth body weight 3.5   ±   0.5 kg; pH and BE at birth 7.25   ±   0.1 and  -5.7   ±   3.4 mmol L(  -  1), respectively; 1' and 5' Apgar scores at birth 8.5   ±   1.4 and 9.4   ±   0.6, respectively). The 4 Hz FHR cohort rendered-for pH and BE-R(2) = 0.26 and 0.2 and RMSE = 0.087 and 3.44, respectively. This could not be confirmed in the validation cohort for neither pH nor BE prediction. The 900 Hz FHR cohort rendered-for pH and BE-R(2) = 0.9 and 0.77 and RMSE = 0.03 and 1.70, respectively, and the pH prediction was validated.In our model, lower FHR sampling rate increased the predicted error range ~3-4 fold. We show that increasing FHR sampling rate to 900 Hz improves prediction of fetal pH and BE at birth. This should improve early identification of babies at risk of brain injury.

Over the past years, numerous studies have provided a clear understanding of the neuronal circuits and mechanisms involved in the formation, expression and extinction phases of conditioned cued fear memories. Yet, despite a strong clinical interest, a detailed understanding of these memory phases for contextual fear memories is still missing. Besides the well-known role of the hippocampus in encoding contextual fear behavior, growing evidence indicates that specific regions of the medial prefrontal cortex differentially regulate contextual fear acquisition and storage in both animals and humans that ultimately leads to expression of contextual fear memories. In this review, we provide a detailed description of the recent literature on the role of distinct prefrontal subregions in contextual fear behavior and provide a working model of the neuronal circuits involved in the acquisition, expression and generalization of contextual fear memories., (© 2014 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.)

How sensory information is transformed by learning into adaptive behaviors is a fundamental question in neuroscience. Studies of auditory fear conditioning have revealed much about the formation and expression of emotional memories and have provided important insights into this question. Classical work focused on the amygdala as a central structure for fear conditioning. Recent advances, however, have identified new circuits and neural coding strategies mediating fear learning and the expression of fear behaviors. One area of research has identified key brain regions and neuronal coding mechanisms that regulate the formation, specificity and strength of fear memories. Other work has discovered critical circuits and neuronal dynamics by which fear memories are expressed through a medial prefrontal cortex pathway and coordinated activity across interconnected brain regions. Here we review these recent advances alongside prior work to provide a working model of the extended circuits and neuronal coding mechanisms mediating fear learning and memory.

Variability analysis of respiratory waveforms has been shown to provide key insights into respiratory physiology and has been used successfully to predict clinical outcomes. The current standard for quality assessment of the capnogram signal relies on a visual analysis performed by an expert in order to identify waveform artifacts. Automated processing of capnograms is desirable in order to extract clinically useful features over extended periods of time in a patient monitoring environment. However, the proper interpretation of capnogram derived features depends upon the quality of the underlying waveform. In addition, the comparison of capnogram datasets across studies requires a more practical approach than a visual analysis and selection of high-quality breath data. This paper describes a system that automatically extracts breath-by-breath features from capnograms and estimates the quality of individual breaths derived from them. Segmented capnogram breaths were presented to expert annotators, who labeled the individual physiological breaths into normal and multiple abnormal breath types. All abnormal breath types were aggregated into the abnormal class for the purpose of this manuscript, with respiratory variability analysis as the end-application. A database of 11,526 breaths from over 300 patients was created, comprising around 35% abnormal breaths. Several simple classifiers were trained through a stratified repeated ten-fold cross-validation and tested on an unseen portion of the labeled breath database, using a subset of 15 features derived from each breath curve. Decision Tree, K-Nearest Neighbors (KNN) and Naive Bayes classifiers were close in terms of performance (AUC of 90%, 89% and 88% respectively), while using 7, 4 and 5 breath features, respectively. When compared to airflow derived timings, the 95% confidence interval on the mean difference in interbreath intervals was ± 0.18 s. This breath classification system provides a fast and robust pre-processing of continuous respiratory waveforms, thereby ensuring reliable variability analysis of breath-by-breath parameter time series.

Fetal monitoring during labour currently fails to accurately detect acidemia. We developed a method to assess the multidimensional properties of fetal heart rate variability (fHRV) from trans-abdominal fetal electrocardiogram (fECG) during labour. We aimed to assess this novel bioinformatics approach for correlation between fHRV and neonatal pH or base excess (BE) at birth.We enrolled a prospective pilot cohort of uncomplicated singleton pregnancies at 38-42 weeks' gestation in Milan, Italy, and Liverpool, UK. Fetal monitoring was performed by standard cardiotocography. Simultaneously, with fECG (high sampling frequency) was recorded. To ensure clinician blinding, fECG information was not displayed. Data from the last 60 min preceding onset of second-stage labour were analyzed using clinically validated continuous individualized multiorgan variability analysis (CIMVA) software in 5 min overlapping windows. CIMVA allows simultaneous calculation of 101 fHRV measures across five fHRV signal analysis domains. We validated our mathematical prediction model internally with 80:20 cross-validation split, comparing results to cord pH and BE at birth.The cohort consisted of 60 women with neonatal pH values at birth ranging from 7.44 to 6.99 and BE from -0.3 to -18.7 mmol L(-1). Our model predicted pH from 30 fHRV measures (R(2) = 0.90, P < 0.001) and BE from 21 fHRV measures (R(2) = 0.77, P < 0.001).Novel bioinformatics approach (CIMVA) applied to fHRV derived from trans-abdominal fECG during labor correlated well with acid-base balance at birth. Further refinement and validation in larger cohorts are needed. These new measurements of fHRV might offer a new opportunity to predict fetal acid-base balance at birth.

Purpose: We evaluated the changes in core temperature, heart rate, and heart rate variability (HRV) during the induction and decay of heat acclimation., Methods: Ten males (23 ± 3 years; 79.5 ± 3.5 kg; 15.2 ± 4.5 percent body fat; 51.13 ± 4.61 mLO(2)∙kg(-1)∙min(-1) peak oxygen uptake) underwent a 14-day heat acclimation protocol comprising of 90-min cycling at ~50 % peak oxygen uptake at 40 °C and ~20 % relative humidity. Core temperature, heart rate, and 102 HRV measures were recorded during a heat tolerance test conducted at baseline (day 0) and at the end of the induction (day 14) and decay (day 28) phases., Results: Heat acclimation resulted in significantly reduced core temperature [rectal (χ (2) = 1298.14, p < 0.001); esophageal (χ (2) = 1069.88, p < 0.001)] and heart rate (χ (2) = 1230.17, p < 0.001). Following the decay phase, 26, 40, and 60 % of the heat acclimation-induced reductions in rectal temperature, esophageal temperature, and heart rate, respectively, were lost. Heat acclimation was accompanied by profound and broad changes in HRV: at the end of the induction phase, 75 of the 102 variability measures computed were significantly different (p < 0.001), compared to only 47 of the 102 at the end of the decay phase., Conclusions: Heat acclimation is accompanied by reduced core temperature, significant bradycardia, and marked alterations in HRV, which we interpret as being related to vagal dominance. The observed changes in core temperature persist for at least 2 weeks of non-exposure to heat, while the changes in heart rate and HRV decay faster and are only partly evident after 2 weeks of non-exposure to heat.

Extinction of auditory fear conditioning induces a temporary inhibition of conditioned fear responses that can spontaneously reappear with the passage of time. Several lines of evidence indicate that extinction learning relies on the recruitment of specific neuronal populations within the basolateral amygdala. In contrast, post-extinction spontaneous fear recovery is thought to result from deficits in the consolidation of extinction memory within prefrontal neuronal circuits. Interestingly, recent data indicates that the strength of gamma oscillations in the basolateral amygdala during auditory fear conditioning correlates with retrieval of conditioned fear responses. In the present manuscript we evaluated the hypothesis that post-extinction spontaneous fear recovery might depend on the maintenance of gamma oscillations within the basolateral amygdala by using single unit and local field potential recordings in behaving mice. Our results indicate that gamma oscillations in the basolateral amygdala were enhanced following fear conditioning, whereas during extinction learning gamma profiles were more heterogeneous despite similar extinction learning rates. Remarkably, variations in the strength of gamma power within the basolateral amygdala between early and late stages of extinction linearly predicted the level of post-extinction spontaneous fear recovery. These data suggest that maintenance of gamma oscillations in the basolateral amygdala during extinction learning is a strong predictive factor of long term spontaneous fear recovery., (Copyright © 2013 Elsevier Inc. All rights reserved.)

High-frequency intake and high drug-induced seeking are associated with cocaine addiction in both human and animals. However, their relationships and neurobiological underpinnings remain hypothetical. The medial prefrontal cortex (mPFC), basolateral amygdala (BLA), and nucleus accumbens (NAc) have been shown to have a role in cocaine seeking. However, their involvement in regulating high-frequency intake and high cocaine-induced seeking is unclear. We manipulated frequency of cocaine self-administration and investigated whether it influenced cocaine seeking. The contribution of the aforementioned structures was evaluated using changes in expression of the immediate early gene c-Fos and targeted optogenetic manipulations. Rats that self-administered at High frequency (short inter-infusion intervals allowed by short time-out) showed higher cocaine-induced seeking than low frequency rats (long inter-infusions intervals imposed by long time-out), as measured with cocaine-induced reinstatement. c-Fos was enhanced in High frequency rats in the prelimbic (PL) and infralimbic (IL) areas of the mPFC, the BLA, and the NAc core and shell. Correlational analysis of c-Fos revealed that the PL was a critical node strongly correlated with both the IL and NAc core in High frequency rats. Targeted optogenetic inactivation of the PL decreased cocaine-induced reinstatement, but increased cocaine self-administration, in High frequency rats. In contrast, optogenetic activation of the PL had no effect on Low frequency rats. Thus, high-frequency intake promotes a PL-dependent control of cocaine seeking, with the PL exerting a facilitatory or inhibitory effect, depending on operant contingencies. Individual differences in cocaine-induced PL activation might be a source of vulnerability for poorly controlled cocaine-induced seeking and/or cocaine intake.

Learning is mediated by experience-dependent plasticity in neuronal circuits. Activity in neuronal circuits is tightly regulated by different subtypes of inhibitory interneurons, yet their role in learning is poorly understood. Using a combination of in vivo single-unit recordings and optogenetic manipulations, we show that in the mouse basolateral amygdala, interneurons expressing parvalbumin (PV) and somatostatin (SOM) bidirectionally control the acquisition of fear conditioning--a simple form of associative learning--through two distinct disinhibitory mechanisms. During an auditory cue, PV(+) interneurons are excited and indirectly disinhibit the dendrites of basolateral amygdala principal neurons via SOM(+) interneurons, thereby enhancing auditory responses and promoting cue-shock associations. During an aversive footshock, however, both PV(+) and SOM(+) interneurons are inhibited, which boosts postsynaptic footshock responses and gates learning. These results demonstrate that associative learning is dynamically regulated by the stimulus-specific activation of distinct disinhibitory microcircuits through precise interactions between different subtypes of local interneurons.

Introduction: Prolonged ventilation and failed extubation are associated with increased harm and cost. The added value of heart and respiratory rate variability (HRV and RRV) during spontaneous breathing trials (SBTs) to predict extubation failure remains unknown., Methods: We enrolled 721 patients in a multicenter (12 sites), prospective, observational study, evaluating clinical estimates of risk of extubation failure, physiologic measures recorded during SBTs, HRV and RRV recorded before and during the last SBT prior to extubation, and extubation outcomes. We excluded 287 patients because of protocol or technical violations, or poor data quality. Measures of variability (97 HRV, 82 RRV) were calculated from electrocardiogram and capnography waveforms followed by automated cleaning and variability analysis using Continuous Individualized Multiorgan Variability Analysis (CIMVA™) software. Repeated randomized subsampling with training, validation, and testing were used to derive and compare predictive models., Results: Of 434 patients with high-quality data, 51 (12%) failed extubation. Two HRV and eight RRV measures showed statistically significant association with extubation failure (P <0.0041, 5% false discovery rate). An ensemble average of five univariate logistic regression models using RRV during SBT, yielding a probability of extubation failure (called WAVE score), demonstrated optimal predictive capacity. With repeated random subsampling and testing, the model showed mean receiver operating characteristic area under the curve (ROC AUC) of 0.69, higher than heart rate (0.51), rapid shallow breathing index (RBSI; 0.61) and respiratory rate (0.63). After deriving a WAVE model based on all data, training-set performance demonstrated that the model increased its predictive power when applied to patients conventionally considered high risk: a WAVE score >0.5 in patients with RSBI >105 and perceived high risk of failure yielded a fold increase in risk of extubation failure of 3.0 (95% confidence interval (CI) 1.2 to 5.2) and 3.5 (95% CI 1.9 to 5.4), respectively., Conclusions: Altered HRV and RRV (during the SBT prior to extubation) are significantly associated with extubation failure. A predictive model using RRV during the last SBT provided optimal accuracy of prediction in all patients, with improved accuracy when combined with clinical impression or RSBI. This model requires a validation cohort to evaluate accuracy and generalizability., Trial Registration: ClinicalTrials.gov NCT01237886. Registered 13 October 2010.

Memories are acquired and encoded within large-scale neuronal networks spanning different brain areas. The anatomical and functional specificity of such long-range interactions and their role in learning is poorly understood. The amygdala and the medial prefrontal cortex (mPFC) are interconnected brain structures involved in the extinction of conditioned fear. Here, we show that a defined subpopulation of basal amygdala (BA) projection neurons targeting the prelimbic (PL) subdivision of mPFC is active during states of high fear, whereas BA neurons targeting the infralimbic (IL) subdivision are recruited, and exhibit cell-type-specific plasticity, during fear extinction. Pathway-specific optogenetic manipulations demonstrate that the activity balance between pathways is causally involved in fear extinction. Together, our findings demonstrate that, although intermingled locally, long-range connectivity defines distinct subpopulations of amygdala projection neurons and indicate that the formation of long-term extinction memories depends on the balance of activity between two defined amygdala-prefrontal pathways., (Copyright © 2014 Elsevier Inc. All rights reserved.)