Mapping and Deciphering Neural Codes of NMDA Receptor-Dependent Fear Memory Engrams in the Hippocampus
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{"title"=>"Mapping and deciphering neural codes of NMDA receptor-dependent fear memory engrams in the hippocampus", "type"=>"journal", "authors"=>[{"first_name"=>"Hongmiao", "last_name"=>"Zhang", "scopus_author_id"=>"56080215600"}, {"first_name"=>"Guifen", "last_name"=>"Chen", "scopus_author_id"=>"55546323600"}, {"first_name"=>"Hui", "last_name"=>"Kuang", "scopus_author_id"=>"24776153000"}, {"first_name"=>"Joe Z.", "last_name"=>"Tsien", "scopus_author_id"=>"7003786684"}], "year"=>2013, "source"=>"PLoS ONE", "identifiers"=>{"isbn"=>"1932-6203 (Electronic)\\n1932-6203 (Linking)", "doi"=>"10.1371/journal.pone.0079454", "pui"=>"372438548", "sgr"=>"84896722968", "scopus"=>"2-s2.0-84896722968", "pmid"=>"24302990", "issn"=>"19326203"}, "id"=>"fa151a3a-fecf-3413-9f7a-857fc89d91d6", "abstract"=>"Mapping and decoding brain activity patterns underlying learning and memory represents both great interest and immense challenge. At present, very little is known regarding many of the very basic questions regarding the neural codes of memory: are fear memories retrieved during the freezing state or non-freezing state of the animals? How do individual memory traces give arise to a holistic, real-time associative memory engram? How are memory codes regulated by synaptic plasticity? Here, by applying high-density electrode arrays and dimensionality-reduction decoding algorithms, we investigate hippocampal CA1 activity patterns of trace fear conditioning memory code in inducible NMDA receptor knockout mice and their control littermates. Our analyses showed that the conditioned tone (CS) and unconditioned foot-shock (US) can evoke hippocampal ensemble responses in control and mutant mice. Yet, temporal formats and contents of CA1 fear memory engrams differ significantly between the genotypes. The mutant mice with disabled NMDA receptor plasticity failed to generate CS-to-US or US-to-CS associative memory traces. Moreover, the mutant CA1 region lacked memory traces for \"what at when\" information that predicts the timing relationship between the conditioned tone and the foot shock. The degraded associative fear memory engram is further manifested in its lack of intertwined and alternating temporal association between CS and US memory traces that are characteristic to the holistic memory recall in the wild-type animals. Therefore, our study has decoded real-time memory contents, timing relationship between CS and US, and temporal organizing patterns of fear memory engrams and demonstrated how hippocampal memory codes are regulated by NMDA receptor synaptic plasticity.", "link"=>"http://www.mendeley.com/research/mapping-deciphering-neural-codes-nmda-receptordependent-fear-memory-engrams-hippocampus", "reader_count"=>29, "reader_count_by_academic_status"=>{"Librarian"=>1, "Researcher"=>8, "Student > Doctoral Student"=>3, "Student > Ph. D. Student"=>6, "Student > Postgraduate"=>2, "Student > Master"=>2, "Other"=>1, "Student > Bachelor"=>4, "Professor"=>2}, "reader_count_by_user_role"=>{"Librarian"=>1, "Researcher"=>8, "Student > Doctoral Student"=>3, "Student > Ph. D. Student"=>6, "Student > Postgraduate"=>2, "Student > Master"=>2, "Other"=>1, "Student > Bachelor"=>4, "Professor"=>2}, "reader_count_by_subject_area"=>{"Agricultural and Biological Sciences"=>14, "Neuroscience"=>4, "Business, Management and Accounting"=>1, "Psychology"=>4, "Social Sciences"=>1, "Computer Science"=>4, "Economics, Econometrics and Finance"=>1}, "reader_count_by_subdiscipline"=>{"Neuroscience"=>{"Neuroscience"=>4}, "Social Sciences"=>{"Social Sciences"=>1}, "Psychology"=>{"Psychology"=>4}, "Economics, Econometrics and Finance"=>{"Economics, Econometrics and Finance"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>14}, "Computer Science"=>{"Computer Science"=>4}, "Business, Management and Accounting"=>{"Business, Management and Accounting"=>1}}, "reader_count_by_country"=>{"United States"=>4, "Japan"=>1, "United Kingdom"=>1, "France"=>1, "Spain"=>1}, "group_count"=>2}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1296215"], "description"=>"<p>(<b>A</b>) The characteristic oscillations confirm the recording happened in the hippocampal CA1 region of a representative control mouse. The top panel shows a representative channel of local field potential (LFP) recorded during sleep, and the filtered LFP shows high-frequency ripple (100–250 Hz). The lower panels show the raw LFP and LFP_theta (4–12 Hz) recorded when the animal was active exploring. Scale bar: 0.5 mV and 0.1 sec. (<b>B</b>) Sharp wave associated ripple (top panel) and theta oscillations (bottom panel) were also observed in the CA1 of the knockout mouse hippocampus. (<b>C-D</b>) Automatic spike sorting was performed with KlustaKwik method and followed by manual cutting and merging in MClust program. Spike clusters for a typical stereotrode were shown with the energy of the two channels of a stereotrode. The stereotrode waveforms of each unit are shown in the inserts. Stable recordings were confirmed as judged by the distribution of spike clusters and spike waveforms of each individual unit at the beginning (<b>C</b>) and end (<b>D</b>) of the recording whole session. L-ratio and Isolation distances were used to quantitatively measure the quality of sorted units. The L-ratios of the four units shown here were 0.2077, 0.0233, 0.1987 and 0.1220, respectively, and the Isolation distances were 21.0224, 63.8598, 25.2531 and 31.7989, respectively.</p>", "links"=>[], "tags"=>["units", "potentials", "hippocampal", "ca1", "behaving"], "article_id"=>862871, "categories"=>["Biological Sciences", "Science Policy"], "users"=>["Hongmiao Zhang", "Guifen Chen", "Hui Kuang", "Joe Z. Tsien"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0079454.g001"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Recording_of_single_units_and_local_field_potentials_in_the_hippocampal_CA1_region_of_freely_behaving_mice_/862871", "title"=>"Recording of single units and local field potentials in the hippocampal CA1 region of freely behaving mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-11-26 04:03:05"}
  • {"files"=>["https://ndownloader.figshare.com/files/1296217"], "description"=>"<p>(<b>A</b>) Illustration of tone-shock trace fear conditioned memory. A 2-sec neutral tone precedes a mild foot-shock (0.3 sec) with a 20-sec time trace interval. Seven pairings were given. (<b>B</b>) Immediate freezing during learning and contextual freezing during 1-hr contextual memory recall. There was a significant difference in contextual freezing between the control (<i>n</i> = 4, 52%±6%) and mutant mice (<i>n = </i>5, 21%±5%). Error bars represent SEM; *<i>p<</i>0.05. (<b>C</b>) Impaired trace fear retention in the mutant group as compared to the control group. Freezing prior to recall tone and after the tone at 1-hr trace recall in the control and mutant mice. The tone was presented for seven times (trials) with a 1–3 min random time interval. There was a significant difference in tone-induced freezing between control (51%±7%) and knockout mice (31%±4%), **<i>p<</i>0.01.</p>", "links"=>[], "tags"=>["performances"], "article_id"=>862873, "categories"=>["Biological Sciences", "Science Policy"], "users"=>["Hongmiao Zhang", "Guifen Chen", "Hui Kuang", "Joe Z. Tsien"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0079454.g002"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Behavior_performances_in_fear_conditioning_/862873", "title"=>"Behavior performances in fear conditioning.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-11-26 04:03:05"}
  • {"files"=>["https://ndownloader.figshare.com/files/1296219"], "description"=>"<p>(<b>A</b>) Spike rasters of simultaneously recorded 243 CA1 units from a control mouse in response to the conditioned tone and foot-shock during training. (<b>B</b>) A representative unit only responded to CS during learning. (<b>C</b>) A representative unit responded only to CS-paired foot shock during learning. (<b>D</b>) A representative unit responded to both CS and tone-paired US, but not to CS during recall. (<b>E</b>) A representative unit responded to CS and US during pairing as well as to recall tone. Within each panel, upper subplot is peri-event raster; each short vertical tick presents a spike. Spike activities are aligned at the time when stimuli were delivered. Lower subplot shows histogram calculated with 100 msec temporal windows.</p>", "links"=>[], "tags"=>["responses"], "article_id"=>862875, "categories"=>["Biological Sciences", "Science Policy"], "users"=>["Hongmiao Zhang", "Guifen Chen", "Hui Kuang", "Joe Z. Tsien"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0079454.g003"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_CA1_responses_to_fear_conditioning_/862875", "title"=>"CA1 responses to fear conditioning.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-11-26 04:03:05"}
  • {"files"=>["https://ndownloader.figshare.com/files/1296221"], "description"=>"<p>(<b>A</b>) Hierarchical clustering method revealed categorical and combinatorial response patterns in recorded CA1 units from the control mice. Nonresponsive units and units responded to CS and US during learning and to the conditioned tone at recall were listed vertically (a total of 1147 units from 5 five control mice). (<b>B</b>) Global responses of all recorded CA1 units from the knockout mice (a total of 1153 units from 5 five knockout mice). Color scale bars indicate the logarithm transformed responsiveness of hippocampal units averaged over seven trials (see <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0079454#s4\" target=\"_blank\">Methods</a>).</p>", "links"=>[], "tags"=>["conditioning", "responses", "recorded", "hippocampal", "ca1"], "article_id"=>862877, "categories"=>["Biological Sciences", "Science Policy"], "users"=>["Hongmiao Zhang", "Guifen Chen", "Hui Kuang", "Joe Z. Tsien"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0079454.g004"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Overview_of_fear_conditioning_responses_of_recorded_hippocampal_CA1_cell_populations_/862877", "title"=>"Overview of fear conditioning responses of recorded hippocampal CA1 cell populations.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-11-26 04:03:05"}
  • {"files"=>["https://ndownloader.figshare.com/files/1296222"], "description"=>"<p>(<b>A</b>) From spike trains of CA1 units, firing rates in two 250 msec windows after stimuli presentation was extracted. (<b>B</b>) After binned and normalized, firing rates were transformed to measure to neural responses. The matrix of normalized response from CA1 units corresponding to the sampling points (all repetitions of CS or US or Rest) was obtained. (<b>C</b>) The covariance matrix can be determined by between-class matrix and within-class matrix, which were obtained from population responses matrix. (<b>D</b>) The discriminant projection vectors are determined by the eigenvalue decomposition of covariance matrix. (<b>E</b>) Transfer matrix was constructed with the corresponding eigenvectors as columns and were sorted in the descend order of the eigenvalues. (<b>F</b>) Neural ensemble responses are then projected to form event- and resting state- clusters in MDA pattern encoding subspaces by transfer matrix. The top three most discriminant subspaces (MDA1-3) are plotted for intuitive visualization. A sliding-window technique can be further applied to calculate transient ensemble states of neural activity (using 20 millisecond steps), thereby tracking dynamic evolution of ensemble trajectories in time throughout the entire recording experiments.</p>", "links"=>[], "tags"=>["discriminant", "projecting", "neural", "ensemble", "responses", "encoding"], "article_id"=>862878, "categories"=>["Biological Sciences", "Science Policy"], "users"=>["Hongmiao Zhang", "Guifen Chen", "Hui Kuang", "Joe Z. Tsien"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0079454.g005"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Schematic_illustration_of_Multiple_Discriminant_analysis_MDA_method_for_projecting_neural_ensemble_responses_to_pattern_encoding_subspaces_/862878", "title"=>"Schematic illustration of Multiple Discriminant analysis (MDA) method for projecting neural ensemble responses to pattern encoding subspaces.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-11-26 04:03:05"}
  • {"files"=>["https://ndownloader.figshare.com/files/1296225"], "description"=>"<p>(<b>A</b>) MDA projection of CA1 ensemble firing patterns in two representative control mice (left and right plots, respectively). Ensemble activity patterns form distinct states for the rest period prior to CS (dots, grey ellipsoid), conditioned tone state (CS, square, blue ellipsoid) and CS-paired foot-shock state (US, circle, red ellipsoid). The top three most discriminant subspaces were plotted to show the encoding patterns revealed by MDA-based dimensionality-reduction method. (<b>B</b>) MDA projection of CA1 ensemble firing patterns from two representative knockout mice (left and right plots, respectively). (<b>C</b>) Discriminant distances between points within the Rest cluster, separation distances between the Rest and CS or US clusters, or between the CS and US clusters. Distances were calculated by averaging the mean distances between point to point belonging to different clusters or the same cluster (Rest) over animals. (Student <i>t-</i>test, **<i>p<</i>0.01). The knockout mice can still form CS and US ensemble representation, but exhibited lower pattern separation at the CA1 level.</p>", "links"=>[], "tags"=>["ensemble", "representations", "resting", "cs-paired", "states", "knockout"], "article_id"=>862881, "categories"=>["Biological Sciences", "Science Policy"], "users"=>["Hongmiao Zhang", "Guifen Chen", "Hui Kuang", "Joe Z. Tsien"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0079454.g006"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_CA1_ensemble_representations_for_the_resting_state_CS_and_CS_paired_US_states_in_control_and_knockout_mice_/862881", "title"=>"CA1 ensemble representations for the resting state, CS, and CS-paired US states in control and knockout mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-11-26 04:03:05"}
  • {"files"=>["https://ndownloader.figshare.com/files/1296226"], "description"=>"<p>(<b>A</b>) Sixty-sec spike raster of 243 simultaneously recorded CA1 units from a control mouse during the first CS/US pairing. Yellow strips indicate the sliding MDA window. (<b>B</b>) MDA dimensionality-reduction statistical projection method show distinct CA1 ensemble patterns (as ellipsoid clusters) represent the Rest (grey), CS (blue) and US (red) activated states. The boundaries of each ellipsoid reflect the 2σ boundaries with Gaussian distributions in the MDA space. Each dot within an ellipsoid shown the MDA subspaces is a statistical result for the ensemble of the simultaneously recorded units from a single trial. The sliding-window method provides the 20-msec resolution of continuous transient ensemble trajectories (or dynamic traces) in response to the CS or US events. A simple CS and US trace during the trial were shown, respectively. The arrows indicate the moving directions of the ensemble trajectories. (<b>C</b>) A CS-to-US associative trace (left) and a US-to-CS associative trace (right) were elicited by the tone or foot shock, respectively, at the 2nd CS/US pairing in the same control mouse. (<b>D</b>) A simple CS trace (left) and US trace (right) in the mutant mouse at the 1st trial. (<b>E</b>) A robust CS or US trace was produced by tone or foot shock, respectively, during the 2nd CS/US pairing trial in the same knockout animal. (<b>F</b>) The occurrences of US-to-CS associative traces triggered by the CS-paired foot shock in all seven trials from the five control mice (left panel) and five knockout mice (right panel). The blue rectangles indicate that the simple US traces produced by paired foot-shock, whereas the red rectangles indicate the US-to-CS associative traces were elicited by the US presentation. (<b>G</b>) The occurrences of CS-to-US associative traces triggered by the tone in all seven trials from the five control mice (left matrix) and five knockout mice (right matrix). The blue rectangles indicate that the simple CS traces produced by paired CS, whereas the red rectangles indicate the CS-to-US associative traces were elicited by the CS presentation during learning.</p>", "links"=>[], "tags"=>["cs", "traces", "us-to-cs", "cs-to-us", "associative"], "article_id"=>862882, "categories"=>["Biological Sciences", "Science Policy"], "users"=>["Hongmiao Zhang", "Guifen Chen", "Hui Kuang", "Joe Z. Tsien"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0079454.g007"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Real_time_CS_and_US_simple_traces_and_US_to_CS_or_CS_to_US_associative_traces_during_learning_/862882", "title"=>"Real-time CS and US simple traces and US-to-CS or CS-to-US associative traces during learning.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-11-26 04:03:05"}
  • {"files"=>["https://ndownloader.figshare.com/files/1296227"], "description"=>"<p>(<b>A)</b> Reverberation of real-time ensemble traces during the CS/US pairings. The black bar on the top of the spike raster (100 simultaneously recorded CA1 units were selected for illustration) indicates the non-freezing state, whereas the orange bar indicates the freezing state of the animal during learning. The reverberation of various ensemble traces is shown at the bottom of the raster: CS trace, blue triangle; US trace, red triangle; US-to-CS associative trace, red diamond; CS-to-US associative trace, blue diamond. (<b>B</b>) Examples of reverberated CS, US, US-to-CS, and CS-to-US traces during the learning phase. (<b>C</b>) Increased on-line reverberations of various traces in a representative control mouse over seven CS-US pairing trials. CS and US stimulation time windows are shown by the blue bar and the vertical line, respectively. (<b>D</b>) Example of sporadic on-line reverberations from a knockout mouse over the seven pairing trials, with associative traces rarely showing reverberation. (<b>E</b>) Average on-line reverberations per trial in control and mutant groups (Wilcoxon rank sum test, ***<i>p<</i>0.001). Left plot for total reverberation numbers in control and mutant groups. Right panel for each type of reverberated traces (genotype difference: Wilcoxon rank sum test, *<i>p<</i>0.05, ***<i>p<</i>0.001). (<b>F</b>) Compositions of reverberation numbers for each trace type (CS, US, US-to-CS and CS-to-US) in control and mutant groups. (<b>G</b>) Trial-dependent increases in on-line reverberation of both simple and associative traces in the control but not in the mutant groups (<i>n</i> = 5 for each group). Student <i>t</i>-test, **<i>p<</i>0.01. (<b>H</b>) Increased on-line reverberation of associative traces (CS-to-US and US-to-CS traces combined) in the control, but not mutant mice (<i>n</i> = 5 for each group). Student <i>t</i>-test, *<i>p<</i>0.05, error bars represent SEM. (<b>I</b>) The increase in the numbers of learning pattern reverberations was correlated with the increase in the amounts of immediate freezing during this learning phase in control mice (<i>r</i> = 0.84, <i>p<</i>0.05). (<b>J</b>) Lower level of freezing responses and learning pattern reverberations in knockout mice (<i>r</i> = 0.28, <i>p</i> > 0.05).</p>", "links"=>[], "tags"=>["on-line", "reverberations", "acquired", "ca1", "traces"], "article_id"=>862883, "categories"=>["Biological Sciences", "Science Policy"], "users"=>["Hongmiao Zhang", "Guifen Chen", "Hui Kuang", "Joe Z. Tsien"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0079454.g008"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Immediate_on_line_reverberations_of_newly_acquired_CA1_traces_during_learning_phase_/862883", "title"=>"Immediate on-line reverberations of newly acquired CA1 traces during learning phase.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-11-26 04:03:05"}
  • {"files"=>["https://ndownloader.figshare.com/files/1296229"], "description"=>"<p>(<b>A</b>) Spike raster of 56 CS-responding units corresponding to a CS trace reverberation (left). This particular reverberated CS ensemble trace is shown in MDA plot prior to spike training shuffle (left MDA plot); selective degradation of this CS trace after shuffling of these units’ spikes (middle MDA plot), but not affected by shuffling of randomly selected 56 non-responsive units (right MDA plot). (<b>B</b>) Spike raster of 49 US responsive units corresponding to a US trace reverberation. This reverberated trace is shown in MDA plot prior to shuffle (left MDA plot); selective degradation of this US trace after shuffling of these units’ spikes (middle MDA plot), but not affected by shuffling of randomly selected 49 non-responsive units (right MDA plot). (<b>C</b>) Spike raster of 44 responsive units corresponding to a US-to-CS associative trace reverberation. This reverberated associative trace is shown in MDA plot prior to shuffle (left MDA plot); selective degradation of this trace after shuffling of these units’ spikes (middle MDA plot), but not affected by shuffling of randomly selected 44 non-responsive units (right MDA plot). (<b>D</b>) Spike raster of 43 responsive units corresponding to a CS-to-US associative trace reverberation. This reverberated trace is shown in MDA plot prior to shuffle (left MDA plot); selective degradation of this trace after shuffling of these units’ spikes (middle MDA plot), but not affected by shuffling of randomly selected 49 non-responsive units (right MDA plot). Arrows show the moving direction of the trajectories.</p>", "links"=>[], "tags"=>["ensemble", "ca1", "units", "encoding", "associative", "traces", "contributions", "Real-time", "trajectories", "mda"], "article_id"=>862885, "categories"=>["Biological Sciences", "Science Policy"], "users"=>["Hongmiao Zhang", "Guifen Chen", "Hui Kuang", "Joe Z. Tsien"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0079454.g009"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Activated_ensemble_CA1_units_encoding_simple_or_associative_traces_during_reverberations_and_their_contributions_to_real_time_ensemble_trajectories_described_in_MDA_encoding_subspaces_/862885", "title"=>"Activated ensemble CA1 units encoding simple or associative traces during reverberations, and their contributions to real-time ensemble trajectories described in MDA encoding subspaces.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-11-26 04:03:05"}
  • {"files"=>["https://ndownloader.figshare.com/files/1296230"], "description"=>"<p>(<b>A</b>) An example of various memory traces being retrieved during the 60-sec traced fear recall test in a control mouse (1-hr retention). A conditioned tone (2-sec) was presented without the reinforcing foot shock. The black bar on the top of spike raster indicates the non-freezing state, whereas the orange bar indicates the freezing state of the animal. Colored triangles or diamonds at the bottom indicate the various moments at which those memory traces were retrieved. (<b>B</b>) Examples of each type of memory traces retrieved during the traced recall. (<b>C</b>) Various memory traces being retrieved over all seven tone trials from a representative control mouse. Symbols: simple CS trace, blue triangle; simple US trace, red triangle; US-to-CS associative trace, red diamond; CS-to-US associative trace, blue diamond. The time window for recalling the anticipated foot shock memory is illustrated by dotted rectangle (18.5-24.5 seconds after the termination of the conditioned tone. Please note the simple or associative foot-shock traces at this time period. (<b>D</b>) Greatly reduced numbers of memory traces retrieved in the knockout mice during 1-hr traced retention test. Please note the lack of the simple US or associative US-to-CS traces at this trace-interval time period. (<b>E</b>) The average memory trace retrieval rates in the control and knockout group during 1-hr trace recall test (the central red lines are the medians, the edges of the box are the 25th and 75th percentiles, each row of ‘x’ markers indicate the result of seven trials from one animal, small random numbers were added to avoid overlap of the markers; student <i>t</i>-test, **<i>p<</i>0.01). (<b>F</b>) Memory trace-time interval analysis revealed that trace recall in the control group has the characteristics of exponential decay distribution, indicating it occurred in a ‘bursting’ manner. (<b>G</b>) Memory trace retrieved in the mutant mice did not show tight an exponential decay process. The inter-trace intervals of control and mutant mice formed different distribution (Two-sample Kolmogorov-Smirnov test, <i>p = </i>5.3E-7). (<b>H</b>) Time distribution of US traces (include US simple trace and US-to-CS trace) in the control mice showed a distinct peak at about 22 second time-window at which a foot shock would be anticipated. This peak was absent in the mutant group. One way ANOVA test between two curve, <i>p = </i>1.9E-6. (<b>I</b>) Time distribution of CS traces did not reveal any significant peaks in either control mice or knockout mice. (<b>J</b>) The occurrence of real-time shock memory traces around the 20-sec traced interval time window (18.5–24.5 sec after the offset of the recall tone) for all seven trials in five control mice. Red rectangles represent the occurrences of the correct foot-shock memory traces, whereas blue squares indicate the absence of foot-shock memory traces at the time point. (<b>K</b>) Lack of memory traces for time relationship in predicting foot shock event and its timing in five knockout mice. There is a significant difference in recalling memory of time relationship between CS and US between genotypes. Wilcoxon rank sum test, <i>p<</i>0.01.</p>", "links"=>[], "tags"=>["traces", "retention"], "article_id"=>862886, "categories"=>["Biological Sciences", "Science Policy"], "users"=>["Hongmiao Zhang", "Guifen Chen", "Hui Kuang", "Joe Z. Tsien"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0079454.g010"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Real_time_fear_memory_traces_during_the_trace_retention_test_/862886", "title"=>"Real-time fear memory traces during the trace retention test.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-11-26 04:03:05"}
  • {"files"=>["https://ndownloader.figshare.com/files/1296233"], "description"=>"<p>(<b>A</b>) An example of various memory traces being retrieved during the 1-hr contextual fear recall test (first 60 sec shown here). The black bar on the top of spike raster illustrates the non-freezing state, whereas the orange bar indicates the freezing state of the animal. Note that the two initial memory traces were recalled ∼3–4 seconds before freezing behavior once the animal returned to the conditioning chamber. Colored triangles or diamonds at the bottom the raster indicate the moments at which those memory traces were retrieved. Memory traces were detected in both freezing and non-freezing states. (<b>B</b>) Examples of four types of memory traces retrieved during the contextual recall. (<b>C</b>) Memory traces retrieved over the first 60-sec of contextual retention tests in all five control mice. Symbols: simple CS trace, blue triangle; simple US trace, red triangle; US-to-CS associative trace, red diamond; CS-to-US associative trace, blue diamond. (<b>D</b>) Reduced numbers of memory traces during 1-hr contextual recall test in the five knockout mice. (<b>E</b>) Freezing responses correlated with memory trace retrievals in a control mouse in the 5-min contextual retention test. (<b>F</b>) Lower freezing and lower numbers of retrieved memory traces in a mutant mouse in the 5-min contextual test. (<b>G</b>) Linear regression analysis shows that at group level, averaged freezing responses also correlated with their averaged numbers of total pattern retrievals (<i>r<sup>2</sup></i> = 0.73, <i>p<</i>0.01). Each blue dot represents the data from a single control mouse and each red triangle represents the data from a single knockout mouse. (<b>H</b>) The total numbers of memory traces retrieved in the control and knockout mice (Wilcoxon rank sum test, **<i>p<</i>0.01; error bars represent SEM). The filled bar portion represents the associative memory traces retrieved during the contextual retention test. The knockout mice had few associative memory traces retrieved (Wilcoxon rank sum test, <i>p<</i>0.05). (<b>I</b>) Inter-memory trace-time interval analysis revealed that contextual recall in the control mice has the characteristics of exponential decay distribution. (<b>J</b>) Memory trace retrieved in the mutant mice did not show obvious exponential decay process temporal associativeness. There is significant difference between memory trace time distribution from control and mutant mice (two-sample Kolmogorov-Smirnov test, <i>p = </i>1.2E-7).</p>", "links"=>[], "tags"=>["traces", "contextual", "retention"], "article_id"=>862889, "categories"=>["Biological Sciences", "Science Policy"], "users"=>["Hongmiao Zhang", "Guifen Chen", "Hui Kuang", "Joe Z. Tsien"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0079454.g011"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Real_time_fear_memory_traces_during_the_contextual_retention_test_/862889", "title"=>"Real-time fear memory traces during the contextual retention test.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-11-26 04:03:05"}
  • {"files"=>["https://ndownloader.figshare.com/files/1296235"], "description"=>"<p>(<b>A</b>) The intertwined memory trace retrievals (defined as retrievals between individually distinct memory traces, see underlined brackets) and alternating retrieval dynamics (defined as retrievals between distinct simple traces, upper brackets) were prevalent in all five control mice during the 5-min contextual recall. Symbols: CS trace, blue triangle; US trace, red triangle; US-to-CS associative trace, red diamond; CS-to-US associative trace, blue diamond. The intertwined retrievals between different traces within 7 sec time window are underlined, whereas alternating retrievals between US and CS or CS and US are marked by upper brackets. (<b>B</b>) Degraded memory codes in five mutant mice during 5-min contextual retention tests. Only KO #1 had five associative traces during the recall, all other mutants failed to produce such traces. Intertwined and alternating retrieval patterns were greatly diminished. (<b>C</b>) The intertwined memory retrieval in the control group (blue plots) during contextual recall follows an exponential decay process, indicating that intertwined memory traces were recalled in temporal clusters. The mutant mice were significantly impaired in the temporal association between recalled memory traces (Red plots) (two-sample Kolmogorov-Smirnov test, <i>p = </i>0.014). (<b>D</b>) Significant differences in the average occurrences of intertwined memory trace pairs between the control and knockout mice (Wilcoxon rank sum test, **<i>p<</i>0.01; error bars represent SD). (<b>E</b>) Numbers of various temporal structures of memory traces in single, doublet, triplet across the control and mutant mice during contextual recall. (<b>F</b>) The alternating retrieval for US simple trace followed with a simple CS memory trace or CS simple trace followed by a US memory trace in the control mice also exhibited exponential decay distribution, but not in the mutant mice (two-sample Kolmogorov-Smirnov test, <i>p = </i>0.0042). Trace interval for 50% temporally associational recall in the control is 3.6 sec for control mice and 8.2 sec for mutant mice. (<b>G</b>) Differences in the alternating retrieval rates between the control and knockout mice (Wilcoxon rank sum test, **<i>p<</i>0.01; error bars represent SD). To appreciate temporal associativeness of memory recalled, memory patterns from a control (Mouse #4) and mutant mouse (Mouse #3) were converted into audio clips of “Pavlovian memory symphony” (<a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0079454#pone.0079454.s001\" target=\"_blank\">Sound S1</a> and <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0079454#pone.0079454.s002\" target=\"_blank\">S2</a> correspondingly).</p>", "links"=>[], "tags"=>["ca1", "neural", "codes", "contextual"], "article_id"=>862890, "categories"=>["Biological Sciences", "Science Policy"], "users"=>["Hongmiao Zhang", "Guifen Chen", "Hui Kuang", "Joe Z. Tsien"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0079454.g012"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Temporal_map_of_CA1_fear_memory_neural_codes_underlying_contextual_memory_recall_/862890", "title"=>"Temporal map of CA1 fear memory neural codes underlying contextual memory recall.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-11-26 04:03:05"}
  • {"files"=>["https://ndownloader.figshare.com/files/1296237"], "description"=>"<p>(<b>A</b>) The intertwined memory trace retrievals (underlined brackets) and alternating retrieval (upper brackets) map in a control mouse over seven tone-traced recall trials. Note the timed retrieval of foot shock memory traces around the 22-second time point after the onset of the conditioned tone. (<b>B</b>) Lack of temporally intertwined and alternating recall structures in memory codes of the knockout CA1 region during the tone-traced recall trials. (<b>C</b>) The intertwined memory retrieval in the control group during tone-traced recall exhibited clear exponential decay distribution, but not in the knockout mice (two-sample Kolmogorov-Smirnov test, <i>p = </i>0.0024). Time window for 50% temporally associational recall is 4.1 sec for control mice and 7.1 sec for mutant mice. (<b>D</b>) Significant reduction in intertwined memory retrievals during tone-traced recall in knockout mice as compared to the control group (Wilcoxon rank sum test, *<i>p<</i>0.05; error bars represent SD). (<b>E</b>) Average number of temporal structures of memory traces as single traces, doublet, triplet the control and mutant mice during trace recall. (<b>F</b>) The alternating retrieval between simple US trace and simple CS memory trace in the control mice exhibited an exponential decay distribution, suggesting that the retrieval occurred as clusters in time domain. Such temporal association is nearly absent in the mutant mice (two-sample Kolmogorov-Smirnov test, <i>p = </i>0.022). Trace interval for 50% temporally associational recall in the control is 3.8 sec for control mice and 6.6 sec for mutant mice. (<b>G</b>) Differences in alternating retrieval rates during tone-traced recall between the control and knockout mice (Wilcoxon rank sum test, *<i>p<</i>0.05; error bars represent SD).</p>", "links"=>[], "tags"=>["ca1", "neural", "codes", "tone-traced", "retention"], "article_id"=>862892, "categories"=>["Biological Sciences", "Science Policy"], "users"=>["Hongmiao Zhang", "Guifen Chen", "Hui Kuang", "Joe Z. Tsien"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0079454.g013"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Temporal_map_of_CA1_fear_memory_neural_codes_during_tone_traced_retention_test_/862892", "title"=>"Temporal map of CA1 fear memory neural codes during tone-traced retention test.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-11-26 04:03:05"}
  • {"files"=>["https://ndownloader.figshare.com/files/1296242", "https://ndownloader.figshare.com/files/1296243"], "description"=>"<div><p>Mapping and decoding brain activity patterns underlying learning and memory represents both great interest and immense challenge. At present, very little is known regarding many of the very basic questions regarding the neural codes of memory: are fear memories retrieved during the freezing state or non-freezing state of the animals? How do individual memory traces give arise to a holistic, real-time associative memory engram? How are memory codes regulated by synaptic plasticity? Here, by applying high-density electrode arrays and dimensionality-reduction decoding algorithms, we investigate hippocampal CA1 activity patterns of trace fear conditioning memory code in inducible NMDA receptor knockout mice and their control littermates. Our analyses showed that the conditioned tone (CS) and unconditioned foot-shock (US) can evoke hippocampal ensemble responses in control and mutant mice. Yet, temporal formats and contents of CA1 fear memory engrams differ significantly between the genotypes. The mutant mice with disabled NMDA receptor plasticity failed to generate CS-to-US or US-to-CS associative memory traces. Moreover, the mutant CA1 region lacked memory traces for “what at when” information that predicts the timing relationship between the conditioned tone and the foot shock. The degraded associative fear memory engram is further manifested in its lack of intertwined and alternating temporal association between CS and US memory traces that are characteristic to the holistic memory recall in the wild-type animals. Therefore, our study has decoded real-time memory contents, timing relationship between CS and US, and temporal organizing patterns of fear memory engrams and demonstrated how hippocampal memory codes are regulated by NMDA receptor synaptic plasticity.</p></div>", "links"=>[], "tags"=>["deciphering", "neural", "codes", "nmda", "receptor-dependent", "engrams"], "article_id"=>862897, "categories"=>["Biological Sciences", "Science Policy"], "users"=>["Hongmiao Zhang", "Guifen Chen", "Hui Kuang", "Joe Z. Tsien"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0079454.s001", "https://dx.doi.org/10.1371/journal.pone.0079454.s002"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Mapping_and_Deciphering_Neural_Codes_of_NMDA_Receptor_Dependent_Fear_Memory_Engrams_in_the_Hippocampus_/862897", "title"=>"Mapping and Deciphering Neural Codes of NMDA Receptor-Dependent Fear Memory Engrams in the Hippocampus", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2013-11-26 04:03:05"}

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Relative Metric

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