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Coping with threatening situations requires both identifying stimuli that predict danger and selecting adaptive behavioural responses to survive1. The dorsomedial prefrontal cortex (dmPFC) is a critical structure that is involved in the regulation of threat-related behaviour2,3,4. 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.

Coping with threatening situations requires both identifying stimuli that predict danger and selecting adaptive behavioural responses to survive

The brain’s ability to associate different stimuli is vital to long-term memory, but how neural ensembles encode associative memories is unknown. Here we studied how cell ensembles in the basal and lateral amygdala (BLA) encode associations between conditioned and unconditioned stimuli (CS, US). Using a miniature fluorescence microscope, we tracked BLA ensemble neural Ca2+ dynamics during fear learning and extinction over six days in behaving mice. Fear conditioning induced both up- and down-regulation of individual cells’ CS-evoked responses. This bi-directional plasticity mainly occurred after conditioning and reshaped the CS ensemble neural representation to gain similarity to the US-representation. During extinction training with repetitive CS presentations, the CS-representation became more distinctive without reverting to its original form. Throughout, the strength of the ensemble-encoded CS-US association predicted each mouse’s level of behavioral conditioning. These findings support a supervised learning model in which activation of the US-representation guides the transformation of the CS-representation.

OBJECTIVE: To demonstrate that ephrin-B2 (the ligand of EphB2 receptor) antagonizes the pathogenic effects of patients' N-methyl-D-aspartate receptor (NMDAR) antibodies on memory and synaptic plasticity. METHODS: One hundred twenty-two C57BL/6J mice infused with cerebrospinal fluid (CSF) from patients with anti-NMDAR encephalitis or controls, with or without ephrin-B2, were investigated. CSF was infused through ventricular catheters connected to subcutaneous osmotic pumps over 14 days. Memory, behavioral tasks, locomotor activity, presence of human antibodies specifically bound to hippocampal NMDAR, and antibody effects on the density of cell-surface and synaptic NMDAR and EphB2 were examined at different time points using reported techniques. Short- and long-term synaptic plasticity were determined in acute brain sections; the Schaffer collateral pathway was stimulated and the field excitatory postsynaptic potentials were recorded in the CA1 region of the hippocampus. RESULTS: Mice infused with patients' CSF, but not control CSF, developed progressive memory deficit and depressive-like behavior along with deposits of NMDAR antibodies in the hippocampus. These findings were associated with a decrease of the density of cell-surface and synaptic NMDAR and EphB2, and marked impairment of long-term synaptic plasticity without altering short-term plasticity. Administration of ephrin-B2 prevented the pathogenic effects of the antibodies in all the investigated paradigms assessing memory, depressive-like behavior, density of cell-surface and synaptic NMDAR and EphB2, and long-term synaptic plasticity. INTERPRETATION: Administration of ephrin-B2 prevents the pathogenic effects of anti-NMDAR encephalitis antibodies on memory and behavior, levels of cell-surface NMDAR, and synaptic plasticity. These findings reveal a strategy beyond immunotherapy to antagonize patients' antibody effects. Ann Neurol 2016; 80: 388-400. This study was supported, in part, by Instituto Carlos III/FEDER (FIS 15/00377 [to F.G.], FIS 14/00203 and CIBERER [to J.D.], and RETICS-RTA and RD12/0028/0023 [to R.M.]), NIH RO1NS077851 (to J.D.), MINECO (SAF2014-59648-P; to R.M.), European Commission (HEALTH-F2-2013-602891; to R.M.), Fundació Cellex (to J.D.), the Netherlands Organisation for Scientific Research (NWO, Veni incentive; to M.T.), an Erasmus MC fellowship (to M.T.), and the German Research Council (DFG; GE 2519/3-1 and CRC-TR 166/1 B2 [to C.G.])

Spatial navigation is one of the most frequently used behavioral paradigms to study memory formation in rodents. Commonly used tasks to study memory are labor-intensive, preventing the simultaneous testing of multiple animals and tend to yield a low number of trials, curtailing the statistical power. Moreover, they are not tailored to be combined with neurophysiology because they are not based on overt stereotyped behavioral responses that can be precisely timed. Here we present the 8-port maze task to study long-term memory formation and recall during spatial navigation. The task consists of a learning session during which mice need to find the rewarding port that changes from day to day. Following learning, there is a 2 hr recall session during which mice report the location of the memorized rewarding port. During the recall sessions, the animals repeatedly report the remembered port over many trials (up to ~20) without receiving reward (i.e. no positive feedback). Interestingly, mice also show memory regarding ports learned on previous days (up to 72 hours). We have been able to pharmacologically manipulate these memories individually. The 8-port maze task required minimal human intervention, allowing simultaneous and unsupervised testing of several mice, yielding a high number of recall trials per session over many days (up to 200). In addition, the task is compatible with neural activity recordings. Our novel methodology opens the door to investigate with high statistical power the mechanisms underlying long-term memories during formation and recall behavior, something that has not been previously achieved with other tasks.

Neurons in the medial superior olive process sound-localization cues via binaural coincidence detection, in which excitatory synaptic inputs from each ear are segregated onto different branches of a bipolar dendritic structure and summed at the soma and axon with submillisecond time resolution. Although synaptic timing and dynamics critically shape this computation, synaptic interactions with intrinsic ion channels have received less attention. Using paired somatic and dendritic patch-clamp recordings in gerbil brainstem slices together with compartmental modeling, we found that activation of K(v)1 channels by dendritic excitatory postsynaptic potentials (EPSPs) accelerated membrane repolarization in a voltage-dependent manner and actively improved the time resolution of synaptic integration. We found that a somatically biased gradient of K(v)1 channels underlies the degree of compensation for passive cable filtering during propagation of EPSPs in dendrites. Thus, both the spatial distribution and properties of K(v)1 channels are important for preserving binaural synaptic timing.

During long-term memory formation, cellular and molecular processes reshape how individual neurons respond to specific patterns of synaptic input. It remains poorly understood how such changes impact information processing across networks of mammalian neurons. To observe how networks encode, store, and retrieve information, neuroscientists must track the dynamics of large ensembles of individual cells in behaving animals, over timescales commensurate with long-term memory. Fluorescence Ca(2+)-imaging techniques can monitor hundreds of neurons in behaving mice, opening exciting avenues for studies of learning and memory at the network level. Genetically encoded Ca(2+) indicators allow neurons to be targeted by genetic type or connectivity. Chronic animal preparations permit repeated imaging of neural Ca(2+) dynamics over multiple weeks. Together, these capabilities should enable unprecedented analyses of how ensemble neural codes evolve throughout memory processing and provide new insights into how memories are organized in the brain.

Songbirds produce their vocalizations by means of a vocal organ called syrinx. A relatively small number of parameters are cyclically changed in order to produce a song. These time-dependent parameters are generated by a set of hierarchically organized neural nuclei. In this work we use theoretical tools in order to test the hypothesis that some aspects of the phrase structure in a song can be the result of the nonlinear response of some of these nuclei to a basic regular syllabic oscillation. We propose simple rate models for the activities displayed by the nuclei and inspect their dynamics. Fil: Jercog, Pablo. University of New York; Estados Unidos Fil: Trevisan, Marcos Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Física de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Física de Buenos Aires; Argentina Fil: Mindlin, Bernardo Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Física de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Física de Buenos Aires; Argentina

In order to localize sounds in the environment, the auditory system detects and encodes differences in signals between each ear. The exquisite sensitivity of auditory brain stem neurons to the differences in rise time of the excitation signals from the two ears allows for neuronal encoding of microsecond interaural time differences., Low-frequency sound localization depends on the neural computation of interaural time differences (ITD) and relies on neurons in the auditory brain stem that integrate synaptic inputs delivered by the ipsi- and contralateral auditory pathways that start at the two ears. The first auditory neurons that respond selectively to ITD are found in the medial superior olivary nucleus (MSO). We identified a new mechanism for ITD coding using a brain slice preparation that preserves the binaural inputs to the MSO. There was an internal latency difference for the two excitatory pathways that would, if left uncompensated, position the ITD response function too far outside the physiological range to be useful for estimating ITD. We demonstrate, and support using a biophysically based computational model, that a bilateral asymmetry in excitatory post-synaptic potential (EPSP) slopes provides a robust compensatory delay mechanism due to differential activation of low threshold potassium conductance on these inputs and permits MSO neurons to encode physiological ITDs. We suggest, more generally, that the dependence of spike probability on rate of depolarization, as in these auditory neurons, provides a mechanism for temporal order discrimination between EPSPs., Author Summary Animals can locate the source of a sound by detecting microsecond differences in the arrival time of sound at the two ears. Neurons encoding these interaural time differences (ITDs) receive an excitatory synaptic input from each ear. They can perform a microsecond computation with excitatory synapses that have millisecond time scale because they are extremely sensitive to the input's “rise time,” the time taken to reach the peak of the synaptic input. Current theories assume that the biophysical properties of the two inputs are identical. We challenge this assumption by showing that the rise times of excitatory synaptic potentials driven by the ipsilateral ear are faster than those driven by the contralateral ear. Further, we present a computational model demonstrating that this disparity in rise times, together with the neurons' sensitivity to excitation's rise time, can endow ITD-encoding with microsecond resolution in the biologically relevant range. Our analysis also resolves a timing mismatch. The difference between contralateral and ipsilateral latencies is substantially larger than the relevant ITD range. We show how the rise time disparity compensates for this mismatch. Generalizing, we suggest that phasic-firing neurons—those that respond to rapidly, but not to slowly, changing stimuli—are selective to the temporal ordering of brief inputs. In a coincidence-detection computation the neuron will respond more robustly when a faster input leads a slower one, even if the inputs are brief and have similar amplitudes.