Tracking defensive states with prefrontal dynorphin-expressing neurons.

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.

CA3 hippocampal synaptic plasticity supports ripple physiology during memory consolidation.

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.

Prefrontal circuits encode both general danger and specific threat representations.

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.

N-3 PUFA deficiency disrupts oligodendrocyte maturation and myelin integrity during brain development.

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.

The advent of fear conditioning as an animal model of post-traumatic stress disorder: Learning from the past to shape the future of PTSD research.

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.

Memories of Opiate Withdrawal Emotional States Correlate with Specific Gamma Oscillations in the Nucleus Accumbens.

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.

Prefrontal neuronal assemblies temporally control fear behaviour.

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.

4-Hz oscillations synchronize prefrontal-amygdala circuits during fear behavior.

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.

Neuronal Circuits for Fear Expression and Recovery: Recent Advances and Potential Therapeutic Strategies.

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.

Review, mapping and analysis of the agricultural plastic waste generation and consolidation in Europe.

A review of agricultural plastic waste generation and consolidation in Europe is presented. A detailed geographical mapping of the agricultural plastic use and waste generation in Europe was conducted focusing on areas of high concentration of agricultural plastics. Quantitative data and analysis of the agricultural plastic waste generation by category, geographical distribution and compositional range, and physical characteristics of the agricultural plastic waste per use and the temporal distribution of the waste generation are presented. Data were collected and cross-checked from a variety of sources, including European, national and regional services and organizations, local agronomists, retailers and farmers, importers and converters. Missing data were estimated indirectly based on the recorded cultivated areas and the characteristics of the agricultural plastics commonly used in the particular regions. The temporal distribution, the composition and physical characteristics of the agricultural plastic waste streams were mapped by category and by application. This study represents the first systematic effort to map and analyse agricultural plastic waste generation and consolidation in Europe.

Optic flow stimuli update anterodorsal thalamus head direction neuronal activity in rats.

Head direction (HD) neurons fire selectively according to head orientation in the yaw plane relative to environmental landmark cues. Head movements provoke optic field flow signals that enter the vestibular nuclei, indicating head velocity, and hence angular displacements. To test whether optic field flow alone affects the directional firing of HD neurons, rats walked about on a circular platform as a spot array was projected onto the surrounding floor-to-ceiling cylindrical black curtain. Directional responses in the anterodorsal thalamus of four rats remained stable as they moved about with the point field but in the absence of landmark cues. Then, the spherical projector was rotated about its yaw axis at 4.5°/s for ∼90 s. In 27 sessions the mean drift speed of the preferred directions (PDs) was 1.48°/s (SD=0.78°/s; range: 0.15 to 2.88°/s). Thus, optic flow stimulation entrained PDs, albeit at drift speeds slower than the field rotation. This could be due to conflicts with vestibular, motor command, and efferent copy signals. After field rotation ended, 20/27 PDs drifted back to within 45° of the initial values over several minutes, generally following the shortest path to return to the initial value. Poststimulation drifts could change speed and/or direction, with mean speeds of 0.68±0.64°/s (range 0 to 1.36°/s). Since the HD cell pathway (containing anterodorsal thalamus) is the only known projection of head direction information to entorhinal grid cells and hippocampal place cells, yaw plane optic flow signals likely influence representations in this spatial reference coordinate system for orientation and navigation.

Why am I lost without dopamine? Effects of 6-OHDA lesion on the encoding of reward and decision process in CA3.

There is growing evidence that Parkinson's disease, generally characterized by motor symptoms, also causes cognitive impairment such as spatial disorientation. The hippocampus is a critical structure for spatial navigation and receives sparse but comprehensive dopamine (DA) innervation. DA loss is known to be the cause of Parkinson's disease and therefore it has been hypothesized that the associated spatial disorientation could result from hippocampal dysfunction. Because DA is involved in the prediction of reward expectation, it is possible to infer that spatial disorientation in DA depleted subjects results from the loss of the ability to detect the rewarding features within the environment. Amongst hippocampal formation subdivisions, CA3 properties such as the high liability of its place fields make it a serious candidate for interfacing DA reward system and spatial information encoding. We addressed this issue using multiple electrode recordings of CA3 in normal and dopamine depleted rats performing a spatial learning in a Y-maze. Our data confirm that DA is essential to spatial learning as its depletion results in spatial impairments. The present work also shows that CA3 involvement in the detection of spatial feature contextual significance is under DA control. Finally, it also shows that CA3 contributes to the decision making processes of navigation tasks. The data also reveal a lateralization effect of DA depletion underlined by neural correlates.

Evolution of the dynamic properties of the cortex-basal ganglia network after dopaminergic depletion in rats.

It is well established that parkinsonian syndrome is associated with alterations of neuronal activity temporal pattern basal ganglia (BG). An increase in synchronized oscillations has been observed in different BG nuclei in Parkinson's disease patients as well as animal models such as 6-hydroxydopamine treated rats. We recently demonstrated that this increase in oscillatory synchronization is present during high-voltage spindles (HVS) probably underpinned by the disorganization of cortex-BG interactions. Here we investigated the time course of both oscillatory and motor alterations. For that purpose we performed daily simultaneous recordings of neuronal activity in motor cortex, striatum and substantia nigra pars reticulata (SNr), before and after 6-hydroxydopamine lesion in awake rats. After a brief non-dopamine-specific desynchronization, oscillatory activity first increased during HVS followed by progressive motor impairment and the shortening of SNr activation delay. While the oscillatory firing increase reflects dopaminergic depletion, response alteration in SNr neurons is closely related to motor symptom.

Power fluctuations in beta and gamma frequencies in rat globus pallidus: association with specific phases of slow oscillations and differential modulation by dopamine D1 and D2 receptors.

Modulation of oscillatory activity through basal ganglia-cortical loops in specific frequency bands is thought to reflect specific functional states of neural networks. A specific negative correlation between beta and gamma sub-bands has been demonstrated in human basal ganglia and may be key for normal basal ganglia function. However, these studies were limited to Parkinson's disease patients. To confirm that this interaction is a feature of normal basal ganglia, we recorded local field potential (LFP) from electrodes in globus pallidus (GP) of intact rats. We found significant negative correlation between specific frequencies within gamma (≈ 60 Hz) and beta (≈ 14 Hz) bands. Furthermore, we show that fluctuations in power at these frequencies are differentially nested within slow (≈ 3 Hz) oscillations in the delta band, showing maximum power at distinct and different phases of delta. These results suggest a hierarchical organization of LFP frequencies in the rat GP, in which a low-frequency signal in the basal ganglia can predict the timing and interaction of power fluctuations across higher frequencies. Finally, we found that dopamine D(1) and D(2) receptor antagonists differentially affected power in gamma and beta bands and also had different effects on correlation between them and the nesting within delta, indicating an important role for endogenous dopamine acting on direct and indirect pathway neurons in the maintenance of the hierarchical organization of frequency bands. Disruption of this hierarchical organization and subsequent disordered beta-gamma balance in basal ganglia disorders such as Parkinson's disease may be important in the pathogenesis of their symptoms.

Cortical effects of subthalamic stimulation correlate with behavioral recovery from dopamine antagonist induced akinesia.

High-frequency stimulation of around 130 Hz delivered to the subthalamic nucleus (STN-DBS [deep brain stimulation]) is an effective treatment of Parkinson's disease (PD), but the mechanisms of its therapeutic effect remain obscure. Recently, it has been shown in anaesthetized rats that STN-DBS antidromically activates cortical neurons with coincident reduction of the cortical slow wave oscillations that occur in this preparation. Here we extend this work; recording the effect of STN-DBS upon cortical EEG and akinesia, in unanesthetized rats rendered cataleptic by acute dopaminergic blockade. STN-DBS-like stimulation resulted in a short latency, presumed antidromic, evoked potential in the cortex. In cataleptic animals, there was a significant increase in the power of beta oscillations in the electroencephalography which was reversed by stimulation that evoked the cortical response. We also observed a significant rescue of motor function, with the level of akinesia (bar test score) being inversely correlated to the amplitude of the evoked potential (R2 = 0.84). These data confirm that (probably antidromic) short latency cortical responses occur in the awake animal and that these are associated with reductions in abnormal cortical oscillations characteristic of PD and with improvements in akinesia. Our results raise the possibility that STN-DBS reduces PD oscillations and symptoms through antidromic cortical activation.

Dynamic changes in the cortex-basal ganglia network after dopamine depletion in the rat.

It is well established that parkinsonian syndrome is associated with alterations in the temporal pattern of neuronal activity and local field potentials in the basal ganglia (BG). An increase in synchronized oscillations has been observed in different BG nuclei in parkinsonian patients and animal models of this disease. However, the mechanisms underlying this phenomenon remain unclear. This study investigates the functional connectivity in the cortex-BG network of a rodent model of Parkinson's disease. Single neurons and local field potentials were simultaneously recorded in the motor cortex, the striatum, and the substantia nigra pars reticulata (SNr) of freely moving rats, and high-voltage spindles (HVSs) were used to compare signal transmission before and after dopaminergic depletion. It is shown that dopaminergic lesion results in a significant enhancement of oscillatory synchronization in the BG: the coherence between pairs of structures increased significantly and the percentage of oscillatory auto- and cross-correlograms. HVS episodes were also more numerous and longer. These changes were associated with a shortening of the latency of SNr response to cortical activation, from 40.5 +/- 4.8 to 10.2 +/- 1.07 ms. This result suggests that, in normal conditions, SNr neurons are likely to be driven by late inputs from the indirect pathway; however, after the lesion, their shorter latency also indicates an overactivation of the hyperdirect pathway. This study confirms that neuronal signal transmission is altered in the BG after dopamine depletion but also provides qualitative evidence for these changes at the cellular level.

Synchronous high-voltage spindles in the cortex-basal ganglia network of awake and unrestrained rats.

Synchronous oscillations in various frequency ranges have been recorded in several nuclei of the basal ganglia (BG) and are thought to be an information processing mechanism. High-voltage spindles (HVSs) are 5-13 Hz spike-and-wave oscillations, which are commonly recorded in rats and which have been reported in some recent studies where their occurrence in the BG has been investigated. We recorded single neurons and local field potentials (LFPs) simultaneously in the motor cortex, striatum and substantia nigra pars reticulata (SNr) of the freely moving rat. We took advantage of the high level of synchronization observed during HVSs to study signal transmission in the cortex-BG network in the awake animals. The results show that LFPs are synchronized in the motor cortex, striatum and SNr during HVS episodes and that the latter propagate from the cortex to the SNr via the striatum. Moreover, > 50% of single neurons in each of these structures are triggered by the HVS. Following the discharge of cortical cells, SNr neurons are first inhibited after approximately 19 ms and then activated after approximately 45 ms. This response is probably driven by the direct and indirect pathways, respectively, without any involvement of the hyperdirect pathway. Here, it is shown that cortex-BG connectivity can be studied using physiological signals in the freely moving animal as opposed to artificial stimulation under anaesthetized conditions. This opens the door to further studies under various experimental conditions, such as animal models of basal ganglia disorders.

In vivo analysis of proprioceptive coding and its antidromic modulation in the freely behaving crayfish.

Although sensory nerves in vitro are known to convey both orthodromic (sensory) and antidromic (putatively modulating) action potentials, in most cases very little is known about their bidirectional characteristics in intact animals. Here, we have investigated both the sensory coding properties and antidromic discharges that occur during real walking in the freely behaving crayfish. The activity of the sensory nerve innervating the proprioceptor CBCO, a chordotonal organ that monitors both angular movement and position of the coxo-basipodite (CB) joint, which is implicated in vertical leg movements, was recorded chronically along with the electromyographic activity of the muscles that control CB joint movements. Two wire electrodes placed on the sensory nerve were used to discriminate orthodromic from antidromic action potentials and thus allowed for analysis of both sensory coding and antidromic discharges. A distinction is proposed between 3 main classes of sensory neuron, according to their firing in relation to levator muscle activity during free walking. In parallel, we describe 2 types of antidromic activity: one produced exclusively during motor activity and a second produced both during and in the absence of motor activity. A negative correlation was found between the activity of sensory neurons in each of the 3 classes and identified antidromic discharges during walking. Finally, a state-dependent plasticity of CBCO nerve activity has been found by which the distribution of sensory orthodromic and antidromic activity changes with the physiological state of the biomechanical apparatus.