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, 35 (39), 13323-35

Bidirectional Modulation of Recognition Memory

Affiliations

Bidirectional Modulation of Recognition Memory

Jonathan W Ho et al. J Neurosci.

Abstract

Perirhinal cortex (PER) has a well established role in the familiarity-based recognition of individual items and objects. For example, animals and humans with perirhinal damage are unable to distinguish familiar from novel objects in recognition memory tasks. In the normal brain, perirhinal neurons respond to novelty and familiarity by increasing or decreasing firing rates. Recent work also implicates oscillatory activity in the low-beta and low-gamma frequency bands in sensory detection, perception, and recognition. Using optogenetic methods in a spontaneous object exploration (SOR) task, we altered recognition memory performance in rats. In the SOR task, normal rats preferentially explore novel images over familiar ones. We modulated exploratory behavior in this task by optically stimulating channelrhodopsin-expressing perirhinal neurons at various frequencies while rats looked at novel or familiar 2D images. Stimulation at 30-40 Hz during looking caused rats to treat a familiar image as if it were novel by increasing time looking at the image. Stimulation at 30-40 Hz was not effective in increasing exploration of novel images. Stimulation at 10-15 Hz caused animals to treat a novel image as familiar by decreasing time looking at the image, but did not affect looking times for images that were already familiar. We conclude that optical stimulation of PER at different frequencies can alter visual recognition memory bidirectionally. Significance statement: Recognition of novelty and familiarity are important for learning, memory, and decision making. Perirhinal cortex (PER) has a well established role in the familiarity-based recognition of individual items and objects, but how novelty and familiarity are encoded and transmitted in the brain is not known. Perirhinal neurons respond to novelty and familiarity by changing firing rates, but recent work suggests that brain oscillations may also be important for recognition. In this study, we showed that stimulation of the PER could increase or decrease exploration of novel and familiar images depending on the frequency of stimulation. Our findings suggest that optical stimulation of PER at specific frequencies can predictably alter recognition memory.

Keywords: brain oscillations; familiarity; novelty; optogenetics; perirhinal; vision.

Figures

Figure 1.
Figure 1.
Experimental design and histology. a, Rat performing the SOR task. X represents the familiar image, i.e., presented in the sample and choice periods. Y represents the novel image, i.e., presented only in the choice period. A 5 min delay separated the two periods. b, Three experimental paradigms. In all paradigms, two identical images (XX) were always presented in the sample period. The standard configuration was XX→XY. In some experiments, the two sample images were both presented again at choice (XX→XX). In other experiments, two novel identical images were presented at choice (XX→YY). c, Expression of ChR2-EYFP (green) in a 30-μm-thick coronal section in caudal PER in a representative subject. Neurons are labeled with DAPI (blue). Position of the fiber is indicated. Scale bars: c, d, 250 μm d, Example of excitotoxic lesion for the same subject labeled for NeuN and counterstained for Nissl bodies. e, Schematic of the location of the tapered optical fiber. f, Contours showing locations of optical fiber tips. All fiber tips were located in caudal PER. The solid dots are for Study A and the open dots are for Study B. Scale bar, 500 μm. RS, Rhinal sulcus; 36p, caudal PER area 36.
Figure 2.
Figure 2.
Optical stimulation at 30 Hz results in increased exploration of familiar images. Paradigms used are shown above the bar graphs. Stimulation was paired with exploration of images (looking) in the choice period. Control conditions (CTL) are above the images and experimental conditions (EXP) are below the images. An empty box indicates no stimulation (NS). For CTL conditions, the laser was connected and operated exactly as in the EXP condition, but light was physically blocked from entering the fiber. Side was always counterbalanced, but for illustration purposes, choice images on the left and right represent familiar/novel (a, b) or familiar/familiar-paired images (c, d), respectively. Therefore, in all panels, the image and stimulation condition in which greater exploration was expected is shown on the right such that DR = (R − L)/(R + L). a, In CTL, as expected, rats (n = 7) preferentially explored the novel image. In EXP, when the familiar image was paired with 30 Hz optical stimulation, rats spent similar amounts of time exploring the paired familiar image and the novel image. The CTL DR was significantly higher than the EXP DR. b, Experiment in a was replicated with a second cohort of rats (n = 8). In CTL, again, rats explored the novel image more than the familiar one. In EXP, when looking at a familiar image was paired with 30 Hz stimulation, rats explored the familiar image more as if it were novel. c, In CTL, stimulation at 11 Hz does not decrease exploration of an already familiar stimulus. In EXP, stimulation at 30 Hz increased exploration of the paired familiar image (n = 6), showing that modulation of novelty exploratory behavior is frequency dependent. d, Replication of c except that NS is compared with 30 Hz (n = 8). Data are means ± normalized SEM. *p < 0.05; #p < 0.05 (t test), significant difference from zero.
Figure 3.
Figure 3.
Optical stimulation at 11 Hz results in decreased exploration of novel images. As for Figure 2, paradigms are shown above the bar graphs. Stimulation was paired with exploration of image(s) in the choice period (the two right panels in each set of four). Control conditions (CTL) are above the images and experimental conditions (EXP) are below. An empty box indicates no stimulation (NS). For CTL, the laser was connected and operated exactly as in the experimental condition, but light was physically blocked from entering the fiber. For illustration, left and right choice images represent familiar/novel images (a, b) or novel-paired/novel images (c, d), respectively. Therefore, in all panels, the image and stimulation condition in which greater exploration was expected is shown on the right such that DR = (R − L)/(R + L). a, In CTL, rats (n = 7) discriminated normally. In EXP, when optical stimulation at 11 Hz was paired with looking at the novel image, rats explored the familiar image and the novel paired image equally. b, Replication of a (n = 8). c, In CTL, rats (n = 6) explore the two novel images equally. In EXP, stimulation at 11 Hz decreased exploration of the paired novel image (n = 6). d, Replications of c (n = 8). Data are means ± normalized SEM. *p < 0.05; +p < 0.10 (rANOVA); #p < 0.05 (t test), significant difference from zero.
Figure 4.
Figure 4.
Screening for the most effective optical stimulation frequencies for decreasing exploration of novel images and increasing exploration of familiar images. a, The 10 and 15 Hz frequency stimulation were effective for decreasing exploration of novelty. In each trial, both images were novel and identical; one was not paired with optical stimulation (NS) and the other was paired with stimulation (5–60 Hz). DR = (NS − Stim)/(NS + Stim) such that a positive DR indicates an effective frequency. b, The 30 and 40 Hz frequency stimulation were effective for increasing exploration of familiar images. Both images used were familiar; one was paired with 10 Hz to ensure baseline familiarity and the other was paired with a range of stimulation frequencies (20–60 Hz). DR = (Stim − 10 Hz)/(Stim + 10 Hz) such that a positive DR indicated an effective frequency. Data are means ± SEM. #p < 0.05, one-tailed Student's t test (n = 4).
Figure 5.
Figure 5.
PER stimulation at 11 or 30 Hz does not result in place preference or avoidance. a, b, Schematic showing the floor patterns and dimensions of the horseshoe maze (a) and the V maze (b). c, Total exploration time for the unpaired (No Stim) and paired (Stim) sides of the mazes during the postconditioning test for 11 and 30 Hz (n = 7). d, Place preference scores for the rats during preconditioning and the postconditioning test for 11 and 30 Hz. Neither frequency resulted in a place preference or a place avoidance.
Figure 6.
Figure 6.
Responses of PER neurons to optical stimulation in vitro and in vivo. a, In vitro responses were recorded from 29 cells. Expressing cells generated large amplitude depolarizations with short latencies; one-third of such cells, including this one, reliably generated action potentials. Light stimuli (8 ms pulses) are indicated by tick marks. b, Example of synaptic responses to 10 Hz optical stimulation from a cell that did not express ChR2. c, ChR2-expressing and non-ChR2-expressing neurons were identifiable by the latency of light-evoked changes in membrane potential or current. (d), When steady depolarizing current was used to activate low-frequency spiking in a non-ChR2-expressing neuron, trains of light pulses triggered mixed effects, including stimulus-entrained spikes (at 10 Hz), net inhibition of baseline spiking (at 30 Hz), and poststimulus hyperpolarization and spike suppression. e, After termination of trains of light stimuli (10–40 Hz) the membrane of most neurons hyperpolarized for durations of 0.5–10 s (depending on train length and frequency). fh, In vivo activity during optical stimulation in PER. MUA 500 ms before and 500 ms during 11 Hz (f) and 30 Hz (g) stimulation in a virally transduced animal. h, Spiking activity during stimulation trials (20 trials per condition per rat) shows a frequency-dependent increase in activity during optogenetic stimulation in the transduced group (virus, n = 3), but not in the no virus group (n = 3). ***p < 0.001. Data are means + SEM.
Figure 7.
Figure 7.
Control experiments for effects on locomotor activity and differences in amount of light delivered. a, Optical stimulation at 11 or 30 Hz had no effect on locomotor activity (n = 5). b, Controlling for total light between 11 and 30 Hz conditions by compensating with pulse widths did not affect differential exploration (n = 6 for each condition). For both experiments, the DR = (time exploring in 30 Hz condition − time exploring in the 11 Hz condition)/(time exploring in 30 Hz condition + time exploring in the 11 Hz condition). The bar on the left shows the DR when pulses are 8 ms for both conditions. The bar on the right shows the DR when 30 Hz pulses are 4 ms and 11 Hz pulses are 12 ms. Data are means ± normalized SEM. ##p < 0.01, significant difference from zero, p < 0.05 (t test).

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