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. Author manuscript; available in PMC: 2024 Feb 1.
Published in final edited form as: Behav Neurosci. 2022 Sep 8;137(1):29–40. doi: 10.1037/bne0000525

Rhesus monkeys with damage to amygdala or orbitofrontal cortex perform well on novelty-based memory tasks

Joshua L Krasney 1, Joseph R Manns 1, Andrew M Kazama 1, Jocelyne Bachevalier 1,2
PMCID: PMC9899092  NIHMSID: NIHMS1864529  PMID: 36074577

Abstract

The amygdala and orbitofrontal cortex (OFC) are interconnected regions that serve as key nodes in brain circuits supporting social and affective behaviors. An important question that has come into focus is whether these regions also play a fundamental role in responding to novelty. One possibility is that these regions are important for discriminating novel from familiar stimuli. An alternative possibility is that these regions contribute to affective responses to stimuli in novelty-based tasks. For example, the amygdala and OFC could contribute to assessing novel stimuli as being threatening or previously selected stimuli as having reward value. The present study tested rhesus macaque monkeys with damage to the amygdala or OFC, along with sham-operated control monkeys, across six variants of novelty-based memory tasks. The results showed that monkeys with damage to the amygdala or OFC performed better overall than control monkeys across the tasks. The results indicated that neither region was likely to be essential for discriminating novel from familiar stimuli. Instead, the findings suggested that the improved performance observed in novelty-based tasks following damage to these regions was more likely attributable to influences on affect.

The amygdala and orbitofrontal cortex (OFC) are key nodes in brain circuits supporting social and affective behaviors (Morrison et al., 2011; Adolphs et al., 1994; Machado and Bachevalier, 2008). In macaque monkeys, the regions exhibit dense bidirectional connections with each other and both project to many of the same other brain regions. Specifically, among projections to the frontal lobe, the amygdala preferentially projects to portions of the OFC and receives moderate to strong return projections from the same areas (Aggleton, 1985; Ghashghaei et al., 2007; Pandya et al., 1981). Moreover, both the amygdala and OFC receive direct sensory inputs from multiple modalities (Morecraft et al., 1992; Price et al., 1987). Further, both regions bidirectionally connect with extra-amygdalar areas of the medial temporal lobe and with the hypothalamus (Cavada et al., 2000; Price and Amaral, 1981; Amaral et al., 1982; Bachevalier and Mishkin, 1994; Bachevalier and Nemanic, 2008; Wang and Barbas, 2018). Thus, both regions are well positioned to integrate memory and multimodal sensory inputs and subsequently modulate memory, emotional regulation, and decision making.

The complementary functions of the amygdala and OFC in monkeys are becoming clearer, though uncertainties remain. The amygdala is conventionally viewed as a key node involved in processing affective salience, defined here as the attention and arousal elicited by a stimulus (Janak and Tye, 2015). The OFC is conventionally viewed as a key node involved in maintaining an updated representation of the relative reward value associated with a stimulus (Tremblay and Schultz, 1999) as well as in regulating emotion in support of decision making (Machado and Bachevalier, 2006). Further, interactions between the amygdala and OFC have been shown to be important for updating the value of stimuli after changing their associated outcome (Saddoris et al., 2005; Morrison et al., 2011). However, more recently, data from monkeys and humans have raised the possibility that both the amygdala and OFC are important for responding to the novelty of stimuli separate from affective or reward information typically thought to depend on these brain regions (Petrides, 2007; Wilson and Rolls, 1993; Weierich et al., 2010; Blackford et al., 2010). Whether either region plays an essential role in producing normal responses to novel stimuli remains uncertain.

Determining the importance of the amygdala and OFC for responding to novelty requires the use of memory tasks, as a stimulus’ relative novelty is a function of one’s memory, or lack thereof, for the stimulus. However, neither the amygdala nor the OFC are thought to be essential for remembering individual stimuli in terms of reactivation of representations of those previously-encountered items (Mishkin, 1978; Meunier et al., 1997). Instead, the question is whether the amygdala or OFC are essential for normal responses to the newness, unexpectedness, or unusualness of novel stimuli. In addition to the prerequisite memory load, novelty-based memory tasks can differ in terms of the use of appetitive rewards, complexity of procedure, and type of stimuli, such as objects or locations. Thus, assessing performance across multiple tasks would be important to identify common trends in responding to novel stimuli that generalize across tasks. As such, the current study will test monkeys with lesions to the amygdala or OFC on a battery of novelty-based memory tasks to determine whether either region is necessary for processing novelty.

To assess the importance of the amygdala and OFC for responding to novelty, the current study compared the performance of rhesus macaque monkeys with lesions to either region to control monkeys across several novelty-based memory tasks. The tasks included a range of study-test memory intervals, spatial and nonspatial stimuli, as well as rewarded decisions and spontaneous looking preferences. The results showed that monkeys with lesions to either the amygdala or OFC performed well across all tasks. Indeed, when comparing performance across tasks, monkeys with lesions to either region actually performed better than monkeys in the control group. The results suggested that both structures do play a role in normal novelty processing, but that their roles likely differ from current proposals that would have predicted impaired performance on the tasks.

Method

All procedures were approved by the Institutional Animal Care and Use Committee of the University of Texas Health Science Center, Houston, carried out in accordance with the National Institute of Health Guide for the Care and Use of Laboratory Animals and conformed to the NIH Guide for the care and use of Laboratory Animals (HHS publication 85–23, 1985). All efforts were made to minimize the number of animals used, as well as their pain and suffering.

Subjects

Subjects were 11 young-adult male rhesus monkeys (M. mulatta), aged 3.5–4.0 years at the beginning of behavioral testing. Animals were randomly assigned to one of the following three experimental groups: sham-operated control (C; n = 5), bilateral neurotoxic amygdala lesion (A-ibo; n = 3), and bilateral aspiration orbitofrontal lesion (O-asp; n = 3). Animals were housed individually at the University of Texas Medical School Animal Care Facility, given water ad libitum and fed daily with fresh fruit, vegetables and high-protein monkey chow (Lab Diet #5045, PMI Nutrition International Inc., Brentwood, MO). Animal housing rooms were maintained on a 12-h light:12-h dark cycle.

Neuroimaging and Surgical Procedures

All surgical procedures have been previously described in detail (Machado and Bachevalier, 2007, 2008). Briefly, monkeys received pre-surgical MRI scans of the brain (T1-weighed high-resolution structural scan) that were used to either calculate the coordinates of the injection sites within the amygdala for Group A-ibo or to visualize the sulcal borders of the target region for cortical aspiration lesions in Group O-asp. Animals were sedated (intubated with ketamine hydrochloride, 10 mg/kg, i.m., followed by inhalation of isoflurane gas, 1.0–2.0%, v/v, to effect). Each animal’s head was secured in a stereotaxic apparatus and his body was placed on a heating pad to allow temperature regulation. They were treated with Emla cream to reduce ear and eye pain caused by pressure from the head-restraint device and received ophthalmic ointment to prevent ocular dryness. Animals also received an intravenous drip solution containing 0.45% sodium chloride to maintain hydration. Vital signs and expired CO2 were monitored throughout the neuroimaging and surgical procedure until the animal began to awaken from anesthesia. As the animal began to awaken, intubation was removed but veterinarians and staff continued to monitor the animal until he fully recovered from anesthesia. Following the MRI scans, animals were kept anesthetized in the stereotaxic apparatus and brought immediately to the surgical suite where they were prepared for the surgical procedure, which were performed under aseptic conditions. For all surgeries, the scalp was shaved, and an injection of local anesthetic (Marcain 25%, 1.5 mL) was administered subcutaneously beneath the incision line. An incision of the skin was made that extended from the mid-orbital ridge to the occiput. The skin, connective tissue and the temporal muscles were then retracted to expose the bone.

Amygdala lesions targeted all amygdaloid nuclei. A total of 12–15-injection sites (2 mm apart on all three planes) were selected for each amygdala. Small bilateral craniotomies and dura slits were made bilaterally to allow the needle of the 10-μL Hamilton syringe, held by a Kopf electrode manipulator (David Kopf Instruments, Tujunga, CA), to be lowered to the appropriate injection coordinates. Two Hamilton syringes were filled with ibotenic acid (Biosearch Technologies, Novato, CA, 10 mg ⁄ mL in phosphate buffered saline, pH 7.4) and used to inject 0.2 to 0.6 μL ibotenic acid (0.2 uL ⁄ minute) at each site selected for each hemisphere. After each injection, a 3-min delay ensued to permit diffusion of the neurotoxin and minimize its spread along the needle track during retraction of the needles.

Orbitofrontal cortex lesions targeted those areas of the ventral frontal cortex that are heavily interconnected with the amygdala (Amaral, Price, Pitkanen, Carmichael, 1992; Ghashghaei, Hilgetag, Barbas, 2007), namely areas 11 and 13 (as defined by Carmichael and Price, 1994). The extent of areas 11 and 13 included the cortical mantel between the following surface landmarks. The anterior border was a line joining the anterior tips of the medial and lateral orbital sulci. The posterior border was a line joining the medial bank of the lateral orbital sulcus and the olfactory stria just anterior to its division into the medial and lateral olfactory tracts. The medial border followed the olfactory stria, and the lateral border followed the medial bank of the lateral orbital sulcus from its anterior tip to the posterior border of the lesion. With the aid of a surgical microscope and using 21- and 23-gauge suckers, the cortical tissue contained within these limits was gently aspirated until the white matter beneath could be seen.

For sham lesions, bilateral craniotomies were made at the level of the orbitofrontal cortex in each hemisphere and the dura was cut to expose the surface of the brain, but no needle was inserted and no injections were made.

After completion of all three types of surgeries (described above), the wound was closed in anatomical layers and animals were recovered from anesthesia. Beginning 12 h prior to and continuing for 1 week after surgery, all operated monkeys were treated with dexamethasone sodium phosphate (0.4 mg/kg, i.m.) and Cephazolin (Bristol-Myers Squibb, 25 mg/kg, i.m.) to reduce inflammation and protect against infection, respectively. For 3 days after surgery, the monkeys also received an analgesic (acetaminophen 10 mg/kg, p.o.).

Histology-based Lesion Assessment

The extent of lesions was assessed on post-mortem histological sections collected when the animals were 7–9 years of age. Animals were sedated with Ketamine HCl (10mg/kg, i.m.), then deeply anesthetized with Nembutal (15 mg/kg, i.v.), followed by sodium pentobarbital (25 mg/kg, i.v.) and perfused transcardially, first with 0.9% saline and then with 4% paraformaldehyde at pH 7.4. Brains were removed and taken through a series of ascending sucrose solutions in 0.1M phosphate buffer at 4°C, then frozen in dry ice and sliced at 50 μm on a freezing microtome with a freezing stage (Model 860; American Optical Corp., Lorton, VA). A series of sections at 500 μm intervals was processed with a Nissl stain to visualize cell bodies and a second series was processed with Gallyas silver stain to visualize fiber tracts.

For each lesion type, histological slices throughout the target structures (i.e., amygdala or orbitofrontal cortex) were matched to a series of drawings of coronal histological sections from a normal adult rhesus monkey brain (J. Bachevalier, unpublished data) at 1 mm intervals. The extent of cellular loss (amygdala) or tissue damaged (orbitofrontal cortex) in target structures as well as adjacent tissue was visually identified on each section and plotted onto the corresponding drawings of the brain of the normal adult monkey. The surface area (in pixels) of damage to both the target structures and adjacent areas was measured using ImageJ® software (http://rsb.info.nih.gov/ij/). The total volume of cell loss for each structure was calculated from the measured surface areas in each hemisphere (Gundersen and Jensen, 1987), and expressed as a percentage of the normal volume for that structure (detailed in Nemanic et al., 2002). The extent of cell loss to each target structure and to adjacent tissue is presented in Table 1.

Table 1.

Extent of Lesions

Group A-ibo Amygdala Entorhinal Perirhinal
L R AVG W L R AVG W L R AVG W
A-ibo-7 76.41 69.48 72.94 53.09 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00
A-ibo-8 26.17 26.1 26.14 6.83 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00
A-ibo-9 25.42 35.14 30.28 8.93 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00
Mean 42.67 43.57 43.12 22.95 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00
Group O-asp Areas 11–13 Area 12 AI
L R AVG W L R AVG W L R AVG W
O-asp-4 91.04 83.64 87.34 76.14 26.74 21.68 24.21 5.80 19.53 18.28 18.92 3.57
O-asp-5 72.22 83.33 77.77 60.18 8.69 26.63 17.66 2.31 20.08 17.76 18.92 3.57
O-asp-6 89.91 96.42 93.17 86.69 10.59 30.34 20.47 3.21 10.50 13.72 12.11 1.44
Mean 84.39 87.79 86.09 74.34 15.34 26.23 20.78 3.77 16.70 16.59 16.65 2.86
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Note. Data are the estimated percentage of cell loss as assessed from postmortem histological thionin stained sections for animals with neurotoxic amygdala lesions (Group A-ibo) and those with aspiration lesions of orbitofrontal areas 11 and 13 (Group O-asp). L, Percentage of cell loss to the left hemisphere; R, percentage of cell loss to the right hemisphere; Avg, average of L plus R percent damage; W: L*R/100 = weighted index as defined by Hodos and Bobko (1984). Areas 11, 12, and 13, and agranular insular (AI) are cytoarchitectonic subregions of the macaque orbitofrontal cortex as defined by Carmichael and Price (1994).

Behavioral Testing Procedures

All animals in this study had the same prior training history. All animals were behaviorally trained prior to this study on the Human Intruder task measuring behavioral reactivity to threatening stimuli (Machado and Bachevalier, 2008), food preference and devaluation/reinforce task (Machado and Bachevalier, 2007), preferential viewing tasks (Zeamer et al., 2008), discrimination tasks (Kazama and Bachevalier, 2009), and a spatial delayed alternation task (Heuer and Bachevalier, unpublished data). All behavioral procedures have been previously detailed in Heuer and Bachevalier (2011) or Zeamer and colleagues (2010) and will be briefly described below. All three A-ibo and all three O-asp monkeys participated in all tasks. Two control monkeys did not participate in the SMS and VPC tasks, with one monkey discontinuing due to behavioral problems and the second monkey discontinuing due to euthanasia following an untreatable illness.

Apparatus and Stimuli

Figure 1 outlines the 4 tasks used in the current study. Monkeys were tested in a dimly lit room with a white noise generator to mask peripheral sounds. Stimuli were presented on two trays or a monitor. One tray included three indented food wells (2 cm diameter, 1 cm deep, and spaced 13 cm apart) in a single centered row, used to test the delayed non-matching-to-sample (DNMS) task. A second tray included 19 food wells (2 cm diameter and spaced 7 cm apart) oriented in a top and bottom row of 6 wells with a middle row of 7 wells, used for the object memory span (OMS) and spatial memory span (SMS) tasks. A 19” monitor was positioned at the monkey’s eye level with a video camera (Sony Digital8 TRV-140) mounted above the screen to capture the monkey’s eye movements for the visual paired-comparison (VPC) task. Output from the camera was fed into a time/date generator connected to a VCR (JVC HR-S4800U) to record eye movements and fed into a TV screen to monitor the monkey’s looking behavior.

Figure 1.

Figure 1.

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Schematic of the tasks. A) Delayed Non-Matching-to-Sample (DNMS) task. Open circles represent empty food wells, and crosses represent rewarded objects. B) Visual Paired-Comparison (VPC) task. C) Object Memory Span (OMS) task. The novel and repeat object spans used similar procedures, but novel spans used novel objects and repeat spans reused objects. Open circles represent empty food wells, and crosses represent rewarded objects. D) Spatial Memory Span (SMS) task. The novel and repeat spatial spans used similar procedures, but novel spans used novel locations and repeat spans reused locations. Open circles represent empty food wells, and crosses represent rewarded objects. The objects illustrated in panels A, B, and C are color pictures selected from a pool of 800,000 clipart images (Nova Art Explosion 800,000 Clip Art). ITI = inter-trial interval.

Stimuli for the DNMS task were pulled from a collection of 1,000 objects that differed in sizes, shapes, and colors. Objects were novel to the monkeys before testing. Stimuli for the OMS task were pulled from a separate set of 500 objects never previously encountered. Stimuli for the SMS task included 19 identical round red checker pieces. Stimuli for the VPC task were colored photos that differed in sizes, shapes, and textures pulled from a collection of 800,000 clipart images (Nova Art Explosion 800,000 Clip Art). Pairs were matched for size and brightness but varied in shapes, textures, and colors.

Delayed non-matching-to-sample (DNMS) task

Figure 1A depicts the DNMS task. The same testing procedures for this task have been previously published (Bachevalier et al., 1999; Heuer and Bachevalier, 2011). The task started with an acquisition phase in which a sample object covered a food reward in the central well. The test phase ensued after 10 s in which the familiar sample object and baited novel object were pseudorandomly presented in the lateral wells. Trials were separated by 30 s, with each trial using unique objects. Monkeys performed 20 trials per day until they reached criterion of 90 correct responses in 100 consecutive trials. Once reaching criterion, monkeys underwent performance tests comprised of 100 trials at delays of 30, 60, and 120 s and 50 trials at a delay of 600 s.

Visual paired-comparison (VPC) task

Figure 1B depicts the VPC task. The same testing procedures for this task have been previously published (Zeamer et al., 2010). The task started with a familiarization phase in which monkeys looked at a photo in the center of the screen for 30 s as assessed by the experimenter. After a delay of 10, 30, 60, 120, or 86400 s, which were randomly intermixed within testing sessions, monkeys performed two retention tests separated by 5 s. Each retention test involved presenting the familiar photo 12 cm next to a novel photo for 5 s, starting when the monkey first looked at either photo. The novel photo was pseudorandomly positioned on the left or right for the first retention test and opposite for the second retention test. A black screen was shown for all delay epochs. Monkeys performed 10 trials of each delay, with 6–10 trials tested each day. Trials were separated by 30 s, with food reward provided during random intertrial intervals to motivate monkeys to continue focusing on the screen. Performance was calculated as percent of time looking at the novel object relative to the familiar object [novel/ (novel + familiar) × 100].

Object memory span (OMS) task

Figure 1C depicts the OMS task. The same testing procedures for this task have been previously published (Heuer and Bachevalier, 2011). Each day, monkeys performed eight novel-spans that each used 19 novel objects. Each day, monkeys also performed the same two repeat-spans that each reused 19 objects in the same order. Locations of objects on the tray were varied across trials each day for both novel and repeat spans to prevent monkeys using a spatial strategy. Spans were separated by 30 s, with novel- and repeat-spans randomly intermixed. Trial 1 for each span involved a novel object covering a reward in one of the 19 wells. After receiving the reward and waiting 10 s, Trial 2 involved placing the familiar object in a novel well location and a baited novel object in a different location. After receiving the reward and waiting 10 s, Trial 3 involved placing the two familiar objects in novel well locations and a baited novel object in a different location. Trials continued until the monkey made an error by choosing a familiar object. The number of novel objects chosen before selecting a familiar object constituted the object memory span. Monkeys performed 10 daily sessions, totaling 80 novel-spans and 10 presentations of the two repeat-spans. Each monkey’s performance for each day was averaged separately for the eight novel-spans and two repeat-spans.

Spatial memory span (SMS) task

Figure 1D depicts the SMS task. The same testing procedures for this task have been previously published (Heuer and Bachevalier, 2011). Procedures for the SMS and OMS tasks were similar, except identical red plaques were used rather than objects, and novel locations were rewarded rather than novel objects. Each day, monkeys performed eight novel-spans that each rewarded a unique sequence of wells. Monkeys also performed two repeat-spans that each rewarded the same sequence of wells each day. Spans were separated by 30 s, with novel- and repeat-spans randomly intermixed. Trial 1 for each span involved a plaque covering a reward in one of the 19 wells. After receiving the reward and waiting 10 s, Trial 2 involved placing a plaque over the same well without a reward and another plaque over a baited novel well. After receiving the reward and waiting 10 s, Trial 3 involved placing plaques over the two previous wells without a reward and another plaque over a baited novel well. Trials continued until the monkey made an error by choosing a previous well. The number of novel locations chosen before selecting a previous location constituted the spatial memory span. Monkeys performed 10 daily sessions, totaling 80 novel-spans and 10 presentations of the two repeat-spans. Each monkey’s performance for each day was averaged separately for the eight novel-spans and two repeat-spans.

Data Analysis

Data were analyzed using MATLAB (MathWorks; Natick, MA). The DNMS and VPC tasks were analyzed using ANOVAs (function fitrm) in which lesion condition was a between-subjects effect and study-test delay was a within-subject effect. The OMS and SMS tasks were analyzed using ANOVAs (function fitrm) in which lesion condition was a between-subjects effect and test day was a within-subject effect. For both memory span tasks, performance for the novel-spans and repeat-spans was evaluated separately. Partial eta-squared (ηp2) values were calculated as an estimate of effect size. In particular, an effect size for lesion condition was calculated as the sum of squared errors for the effect of lesion divided by the sum of squared errors for the effect of lesion plus the sum of squared overall errors [SSlesion/(SSlesion+SSerror)]. For each analysis, calculation of effects for three levels (A-ibo, O-asp, and C) of the lesion condition were followed by more specific calculation of effects for each of the lesioned groups relative to the sham control group (A-ibo vs. C; O-asp vs. C). The data are available upon request.

Results

Lesion Extent

Table 1 provides a summary of the percentage of intended and unintended damage (cell loss) for each type of lesions. For the amygdala lesions, extent of cell loss is described and illustrated below. Illustrations of the cell loss and fiber damage have previously been published for each case of Group O-asp in Kazama and colleagues (2009), and thus only a brief summary will be given below for that lesion group.

The neurotoxic amygdala injections resulted in bilateral cell loss largely confined to the amygdaloid nuclei, averaging 27–73% (Table 1). Briefly, in case A-ibo-7, the cell loss was dense bilaterally (76% on the left and 69% on the right) and located in almost all amygdaloid nuclei bilaterally and in the anterior portion of the hippocampus (average: 4%). Slight sparing was noted in the anterior portion of the lateral aspect of the lateral nuclei on the right and in the medial nuclei on the left. For the other two cases, the cell loss did not extend to the entire amygdaloid nuclei bilaterally and did not affect the structures adjacent to the amygdala. For case A-ibo-8, the cell loss was located mostly in the dorsal portion of the amygdala bilaterally (averaging 26% on each side) and included the central nucleus and the dorsal portion of the lateral and basolateral nuclei on the left and the central nucleus and the dorsal portion of the basolateral nucleus on the right (see Figure 2). For case A-ibo-9, the cell loss was located along almost all antero-posterior extent of the amygdala in the central and lateral nuclei on the left, and in the central and basal accessory and medial aspect of the basolateral nuclei on the right. Thus, although the amygdala lesions targeted all amygdaloid nuclei, the produced lesions for each subject were smaller than the intended lesions and did not extend to adjacent perirhinal or entorhinal cortical areas.

Figure 2.

Figure 2.

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Histological Gallyas fiber-stained coronal sections through mid-amygdala for the three cases with amygdala lesions. The areas highlighted with a black dashed line indicate sparing of fibers (darker areas) in areas where cell loss was almost complete.

The aspiration orbitofrontal lesions resulted in cortical cell loss largely confined bilaterally to areas 11 and 13, ranging from 77.7% to 93.2% (Table 1) and included all cortical layers. The extent of the orbitofrontal aspiration lesions is illustrated on the ventral view of the brain for the three cases in Figure 3. Unintended damage for all cases included small encroachment to area 12 (20%) laterally, agranuar insular cortex (17%) posteriorly, and area 10 (3%) anteriorly.

Figure 3.

Figure 3.

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Ventral views of the orbitofrontal cortex surface. Panel A depicts in gray the intended lesions to mainly target areas 11 and 13 as reconstructed onto a ventral view of an adult atlas brain. Panels B-D depict the extent of the cortical lesion for the three O-asp cases on a photograph of the orbitofrontal surface, revealing the exposed underlying white matter (highlighted within the black line) in the areas where the cortex was aspirated. Abbreviations: cs, Cingulate sulcus; G, gustatory cortex; Ia, insular (agranular); ias, inferior arcuate sulcus; los, lateral orbital sulcus; mos, medial orbital sulcus; Pir, piriform cortex; PrCO, precentral opercular area; ps, principal sulcus; rs, rostral sulcus; VP, ventral pallidum. Cytoarchitectonic fields are as described by Barbas and Pandya (1989), Amaral et al. (1992), and Carmichael and Price (1994).

A-ibo and O-asp groups performed well on the DNMS task

Figure 4 shows the results of the DNMS task. All three groups of monkeys performed similarly well (mean percent correct across delays ± SEM for C, A-ibo, and O-asp = 86.3 ± 1.7%, 89.1 ± 3.4%, and 86.0 ± 2.5%). For all monkey groups, there was a general decrease in performance for the longer study-test delays (effect of delay: F[3, 24] = 3.58; p = 0.029; ηp2 = 0.309). However, there was no statistically significant effect of lesion group (F[2, 8] = 0.45; p = 0.655; ηp2 = 0.100) and no interaction between group and delay (F[6, 24] = 0.07; p = 0.998; ηp2 = 0.017). Direct comparisons of overall performance between the sham control group and either the A-ibo group (F[1,6] = 0.69; p = 0.437; ηp2 = 0.103) or O-asp group (F[1,6] = 0.47; p = 0.935; ηp2 = 0.001) did not reveal statistically significant differences.

Figure 4.

Figure 4.

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Mean percentage of correct choices on the DNMS task for each lesion group. Error bars represent SEM. C = sham lesions, n = 5; A-ibo = neurotoxic amygdala lesions, n = 3; O-asp = aspiration orbitofrontal lesions, n = 3.

A-ibo and O-asp groups performed well on the VPC task

Figure 5 shows the results of the VPC task. All three groups of monkeys again performed similarly well (mean percent looking at novel objects across delays ± SEM for C, A-ibo, and O-asp = 67.2 ± 1.2%, 71.0 ± 2.5%, and 71.7% ± 1.7%). There was again an effect of study-test delay (F[4, 24] = 13.00; p < 0.001; ηp2 = 0.684) but no statistically significant effect of lesion group (F[2,6] = 1.71; p = 0.257; ηp2 = .364) or group by delay interaction (F[8, 24] = 0.40; p = 0.911; ηp2 = 0.117). Direct comparisons of overall performance between the sham control group and either the A-ibo group (F[1,4] = 1.88; p = 0.242; ηp2 = 0.320) or O-asp group (F[1,4] = 4.83; p = 0.093; ηp2 = 0.547) did not reveal statistically significant differences.

Figure 5.

Figure 5.

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Mean percentage of time looking at the novel object during the VPC task for each lesion group. Error bars represent SEM. C = sham lesions, n = 3; A-ibo = neurotoxic amygdala lesions, n = 3; O-asp = aspiration orbitofrontal lesions, n = 3.

A-ibo and O-asp groups performed well on the OMS task for novel and repeated objects

Figure 6 shows the results of the OMS task as a function of test day separately for novel object spans (Figure 6A) and repeat object spans (Figure 6B). For the novel object spans, the three lesion groups performed similarly on day 1, but the A-ibo and O-asp groups improved their performance across days at a faster rate as compared to the control group, a pattern reflected by a statistically significant group by day interaction (F[18, 72] = 2.81; p = 0.001; ηp2 = 0.413). There was also a significant effect of day (F[9,72] = 14.08; p < 0.001; ηp2 = 0.638) and an effect of lesion group that approached significance (F[2,8] = 3.52; p = 0.080; ηp2 = 0.468). Averaging across days, the A-ibo group (mean span ± SEM = 7.37 ± 1.49) and O-asp group (5.29 ± 0.65) performed better than the control group (4.11 ± 0.58). However, direct comparisons of overall performance between the sham control group and the A-ibo group fell just short of statistical significance (F[1,6] = 5.95; p = 0.051; ηp2 = 0.498), and a direct contrast between the sham control group and the O-asp group did not reveal a statistically significant difference (F[1,6] = 1.68; p = 0.242; ηp2 = 0.219).

Figure 6.

Figure 6.

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Mean percentage of correct novel objects chosen during the novel OMS (A) and repeat OMS (B) tasks for each lesion group. Error bars represent SEM. C = sham lesions, n = 5; A-ibo = neurotoxic amygdala lesions, n = 3; O-asp = aspiration orbitofrontal lesions, n = 3.

For the repeat object spans task, the pattern of performance was similar to the trends observed for the novel object spans. Specifically, there was evidence that the A-ibo and O-asp improved performance across days to a greater extent than the sham control group (group by day interaction: F[18, 72] = 2.411; p = 0.004; ηp2 = 0.376). There was also a significant effect of day (F[9,72] = 4.44; p < 0.001; ηp2 = 0.357) and a significant effect of lesion group (F[2,8] = 6.39; p = 0.022; ηp2 = 0.615). Averaging across days, the A-ibo group (5.75 ± 1.30) and O-asp group (3.32 ± 0.55) performed better than the control group (2.14 ± 0.41). Direct comparisons of overall performance between the sham control group and the A-ibo group revealed a statistically significant effect (F[1, 6] = 10.83; p = 0.017; ηp2 = 0.644), but the contrast between the O-asp and control groups did not (F[1, 6] = 3.02; p = 0.133; ηp2 = 0.335).

A-ibo and O-asp groups performed well on the SMS task for novel and repeated locations

Figure 7 shows the results of the SMS task as a function of test day separately for novel location spans (Figure 7A) and repeat location spans (Figure 7B). For the novel location spans, there was again a statistically significant group by day interaction (F[18, 54] = 1.86; p = 0.042; ηp2 = 0.382). There was also a significant effect of day (F[9,54] = 3.33; p = 0.003; ηp2 = 0.357) and an effect of lesion group that approached statistical significance (F[2,6] = 4.23; p = 0.071; ηp2 = 0.585). Averaging across days, the A-ibo group (3.11 ± 0.43) and O-asp group (2.34 ± 0.06) performed better than the control group (2.07 ± 0.12). Direct comparisons of overall performance between the sham control group and the A-ibo group revealed an effect that approached statistical significance (F[1, 4] = 5.33; p = 0.082; ηp2 = 0.571), but the contrast between the O-asp and control groups did not (F[1, 4] = 4.09; p = 0.133; ηp2 = 0.506).

Figure 7.

Figure 7.

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Mean percentage of correct novel locations chosen during the novel SMS (A) and repeat SMS (B) tasks for each lesion group. Error bars represent SEM. C = sham lesions, n = 3; A-ibo = neurotoxic amygdala lesions, n = 3; O-asp = aspiration orbitofrontal lesions, n = 3.

For the repeat location spans, the pattern of performance was similar to that observed for the novel location spans. There was an effect of lesion group that approached statistical significance (F[2,6] = 5.10; p = 0.051; ηp2 = 0.630), but the effect of day (F[9,54] = 0.75; p = 0.662; ηp2 = 0.111) and the group by day interaction (F[18,54] = 1.46; p = 0.144; ηp2 = 0.327) did not. Averaging across days, the A-ibo group (2.95 ± 0.38) and O-asp group (2.33 ± 0.07) performed better than the control group (1.91 ± 0.11). Direct comparisons of overall performance between the sham control group and the A-ibo group revealed an effect that approached statistical significance (F[1, 4] = 6.93; p = 0.058; ηp2 = 0.634), and the contrast between the O-asp and control groups was statistically significant (F[1, 4] = 9.84; p = 0.035; ηp2 = 0.711).

Across tasks, A-ibo and O-asp groups performed better than the control group

The monkeys in the A-ibo and O-asp lesion groups performed well on each task, significantly better than the control group in some instances. Moreover, in cases in which the direct comparison to the control group failed to reach statistical significance, the effect sizes were nevertheless often large. Table 2 shows the effect sizes (ηp2) of those direct group contrasts for the DNMS task, the VPC task, the OMS novel spans, the OMS repeat spans, the SMS novel spans, and the SMS repeat spans. In each case, the contrasts between the control group and each of the lesion groups focuses on the overall effect of group, averaging across delays or days. In order to compare effect sizes across tasks, a normalized effect size was calculated by Fisher Z transforming the square root of the ηp2 values. A positive sign was used to represent effects in which a lesion group (either A-ibo or O-asp) performed better than the control group, and a negative sign was used when either lesion group performed worse than the control group. The normalization procedure was necessary because ηp2 values are bounded (−1 to 1) and not normally distributed. The resulting normalized values were conceptually similar to Z-transformed Pearson’s r values. The mean normalized effect sizes were 0.839 (95% confidence interval = 0.524 to 1.154) for A-ibo versus control and 0.701 (95% confidence interval = 0.241 to 1.160) for O-asp versus control.

Table 2.

Sizes of Effects of Amygdala and Orbitofronal Lesions on Task Performance Relative to Control Group

A-ibo vs. C
 O-asp vs. C
Task Effect Size Normalized Effect Size Normalized
DNMS 0.103 0.333 −0.001 −0.035
VPC 0.320 0.641 0.547 0.950
OMS Novel 0.498 0.878 0.219 0.507
OMS Repeat 0.644 1.105 0.335 0.660
SMS Novel 0.571 0.986 0.506 0.890
SMS Repeat 0.634 1.088 0.711 1.232
Mean 0.462 0.839 0.386 0.701
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Note. Effect sizes are shown as ηp2 and refer to effect of group for direct contrasts either between the A-ibo and control groups or between the O-asp and control groups. The normalized values refer to the square root of the ηp2 values, which were then Fisher Z transformed. A positive value reflects better performance for the lesion group compared to the control group, and a negative value reflects better performance for the control group.

To determine whether these mean normalized effect sizes were greater than one would expect by chance, a random permutation analysis was performed in which the assignment of lesion or control group label was randomly shuffled across monkeys (shuffled A-ibo or C for A-ibo effect size and shuffled O-asp or C for O-asp effect size). A mean normalized effect size was calculated for the shuffled A-ibo versus control data and for the shuffled O-asp versus control data for each of 1,000 random shuffles of the data. Figure 8 shows the distribution of these random mean normalized effect sizes separately for A-ibo versus control and for O-asp versus control and highlights that the actual mean normalized effect size values (indicated by a star) lay outside these random distributions. Thus, the probability that the positive mean normalized effect sizes for A-ibo and O-asp lesions were due to random chance was less than 0.001 in both cases.

Figure 8.

Figure 8.

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Results of random shuffling procedure to determine if positive mean normalized effect sizes across tasks for O-asp versus control (O-asp vs. C) and A-ibo versus control (A-ibo vs. C) were greater than one would expect by chance. The distributions of black dots for both A-ibo and O-asp represent mean normalized effect sizes from 1,000 shuffles of monkeys’ group membership labels. Shaded rectangles represent the inner 95% of the random distribution. Zero represents similar performance between the two groups being compared. The stars represent the observed mean normalized effect sizes, which lay outside and above the random distributions in both cases. Thus, the positive mean effect sizes for both A-ibo and O-asp were unlikely (p < 0.001) to be due to chance.

Discussion

The key finding from the current study was that rhesus macaque monkeys with lesions to either the amygdala or OFC performed well across a series of novelty-based memory tasks. The monkeys with damage to the amygdala and the monkeys with damage to the OFC performed as well or better than the control monkeys across all tasks. Indeed, in some tasks, the effect sizes for the better-than-control results for both lesion groups were large. For both the monkeys with damage to the amygdala and the monkeys with damage to OFC, the mean effect sizes across all tasks relative to the control group were positive (indicating better than control performance) and were well outside the distribution of effect sizes one would have expected by chance alone. The tasks differed in terms of the study-test memory intervals (short and long), the type of stimuli (objects versus locations), and type of behavioral response (rewarded decisions versus spontaneous looking preferences). Thus, on average, damage to the amygdala or OFC significantly improved performance compared to control monkeys in a manner that generalized across the novelty-based memory tasks. The improvement in performance resulting from damage to either region suggests that both regions do normally serve a role in responding to novelty, though the current data suggest that these roles are unlikely to be attributable to a simple detection of novelty itself. The potential roles of the amygdala and OFC in responding to novelty are considered further below.

Amygdala lesions may have impacted reactions to novelty rather than novelty detection

Prior literature had raised the possibility that the amygdala could contribute to novelty-based memory tasks in at least two ways. First, many studies have demonstrated the importance of the amygdala in processing threatening or fear-inducing stimuli (Davis, 1992; LeDoux, 2000). Indeed, damage to the amygdala across rodents, monkeys, and humans has shown to impair typical reactions to threatening stimuli (Adolphs et al., 2005; Phelps and LeDoux, 2005; Machado et al., 2009). Some studies in monkeys have shown specifically that lesions to the amygdala reduced neophobia, leading to the suggestion that the amygdala might play an important role in responding to novel stimuli (Mason et al., 2006). The interpretation of this reduction in neophobia after lesions to the amygdala was interpreted as neutral stimuli potentially posing a threat to an animal due to the unexpectedness, unusualness, or ambiguity of novel stimuli. A second line of research has shown that amygdala activity is modulated by novel relative to familiar neutral stimuli (Wilson and Rolls, 1993; Weierich et al., 2010; Moses et al., 2005; Blackford et al., 2010), raising the possibility that the amygdala might contribute more directly to the discrimination between novel and familiar stimuli. Thus, prior to the current study, it was unclear whether the amygdala was important for novelty-based tasks because it contributed directly to the memory-based discrimination between new and old stimuli or because it mediated a subsequent hesitant response to the novelty.

The current data, which showed overall better novelty-based memory performance in monkeys with lesions to the amygdala as compared to control monkeys, indicated that the amygdala is not essential for discriminating novel from familiar stimuli. In contrast, the data were consistent with the possibility that the amygdala normally contributes to a hesitation towards novel stimuli. By this view, lesions of the amygdala could have attenuated any possible disinclination to look at or reach towards novel stimuli, thereby indirectly benefitting performance on tasks in which interaction with novel stimuli was a prerequisite for good performance.

An additional factor potentially contributing to the good performance by the monkeys with amygdala lesions was that the lesions were smaller than intended (Table 1). However, it seems unlikely that larger lesions would have led to impaired performance for three reasons. First, the monkeys with amygdala lesions performed statistically significantly better overall than the control monkeys (Figure 8). That is, the small lesions did not prevent detecting a significant impact of those lesions. Second, the same monkeys previously exhibited decreased aversive reactions to unfamiliar human intruders (Machado and Bachevalier, 2008). These prior results indicated that the lesions were sufficient to impair performance on a threat-based task, a finding that aligns with the interpretation of the present results that amygdala lesions attenuated neophobia. Third, the monkey with the most extensive lesions to the amygdala (A-ibo-7: 72.94% damage) performed as well or better on all six tasks compared to the other two monkeys with less extensive lesions to the amygdala (A-ibo-8: 26.14% damage; A-ibo-9: 35.14% damage). Specifically, as compared to A-ibo-8 and A-ibo-9, A-ibo-7 averaged higher VPC preference scores across delays (77.6% vs. 71.7 and 72.7%), higher DNMS scores across delays (93.3% vs. 91.8 and 82.3%), and averaged more spans across days on the OMS novel task (10.1 vs. 7.0 and 5.0), OMS repeat task (8.4 vs. 4.3 and 4.6), SMS novel task (4.1 vs. 2.5 and 2.8), and SMS repeat task (3.7 vs. 2.6 and 2.6). Thus, the smaller-than-intended amygdala lesions were nevertheless efficacious at statistically-significantly improving performance relative to control monkeys, and there was no indication that larger lesions would have led to an impairment on the current novelty-based memory tasks.

OFC lesions may have attenuated positive associations with familiar stimuli or negative responses to novel stimuli

Prior studies of the OFC had raised the possibility that it could contribute to novelty-based memory tasks in at least three ways. First, several studies in rodents and primates have suggested that the OFC is sensitive to the value of reinforcers (West et al., 2011; Rudebeck and Murray, 2011; O’Doherty et al., 2001; Gallagher et al., 1999). Indeed, the current monkeys with OFC lesions were previously reported to show deficits on reinforcer devaluation tasks (Machado and Bachevalier, 2007; Kazama and Bachevalier, 2009; Burke et al., 2014). Thus, in the present study, monkeys with OFC lesions may have performed particularly well on the DNMS, SMS, and OMS tasks because they were less inclined to return to the recently rewarded repeated items, which would represent incorrect choices in these tasks. Second, the current OFC group previously showed deficits in flexibly adjusting affective responses to varying levels of threatening stimuli (Machado and Bachevalier, 2008). Thus, paralleling one interpretation for the monkeys with amygdala lesions, monkeys with damage to the OFC may have performed well on novelty-based memory tasks because they were less sensitive to possible threat posed or negative affect elicited by the novel stimuli. Third, other studies have suggested that the OFC was important for discriminating novel from familiar stimuli and thus essential for the memory-based judgment (Petrides, 2007).

The present results weigh against the possibility that the OFC is necessary for discriminating novel from familiar stimuli. In particular, monkeys with damage to OFC showed, on average, better-than-control performance across tasks that required monkeys to identify the novel stimulus among one or more familiar stimuli. The current data cannot distinguish between the possibilities that OFC lesions beneficially biased those monkeys away from recently rewarded repeated stimuli versus towards potentially threatening novel stimuli. However, the good performance by the OFC monkeys on the VPC task, which involves spontaneously looking at novel stimuli in the absence of explicit rewards, might favor the possible reduction in negative association with novel stimuli for at least this task. In any case, the overall results from monkeys with damage to the OFC indicate that this region is not directly involved in discriminating novel from familiar stimuli. These results align with recent evidence in rats suggesting that inactivation of the OFC did not impair novel object recognition memory performance (Costa et al., 2022). The current results also support growing evidence that areas 11/13 of the OFC, the intended lesion locations, do not play an essential role in whether a stimulus is rewarded (i.e., reward contingency; Bachevalier et al., 2011). Instead, areas 11/13 may support maintaining a representation of the relative reward value among stimuli in the environment, with removal of this representation reducing the inclination to return to a recently rewarded repeated item (Kazama and Bachevalier, 2009).

Anatomical subregions within the OFC and amygdala

The amygdala and OFC are heterogenous brain regions (Swanson and Petrovich, 1998; Carmichael and Price, 1994). The amygdala in macaque monkeys includes thirteen subnuclei (Amaral et al., 1992), and the lesions in the present study targeted all subnuclei. Future studies in monkeys that target subsets of these nuclei could potentially reveal functional differences related to responding to novel stimuli. In particular, it is possible that subnuclei receiving many cortical inputs, such as the lateral nucleus, might contribute to novelty responses differently than subnuclei with direct projections to the hypothalamus, such as the central nucleus. The OFC in macaque monkeys includes distinct orbitofrontal (areas 11/13 and insular area [IA]) and “medial” (areas 14/10) regions based on internal anatomy and external connectivity (Bachevalier et al., 2011). The lesions in the present study targeted areas 11 and 13, which are interconnected with cortical areas associated with all sensory modalities and also exhibit dense bidirectional connections with the amygdala. Future studies would benefit from a direct comparison of effects of OFC lesions in areas 11 and 13 versus OFC lesions in areas 10 and 14, the latter exhibiting connections with autonomic areas and thus possibly being more important for emotional reactivity to novel stimuli rather than assessment of potential threat.

Summary

Taken together, the current results demonstrate that neither the amygdala nor the OFC are essential for good performance on novelty-based memory tasks. Nevertheless, the better-than-normal performance by monkeys with damage to these regions suggest that both the amygdala and OFC are normally involved in some way in novelty-based memory tasks. The interpretations offered here suggested that these regions may ordinarily play a role in secondary, affect-related responses rather than primary, memory-related processes. Further research will be required to clarify the exact nature of those affect-related responses and the extent to which the amygdala and OFC differentially contribute to those processes.

Acknowledgements

This work was supported by grants to JB from the National Institute of Mental Health (MH-58846; MH-100029), the National Institute of Child Health and Human Development (HD-35471; HD-090925), Autism Speaks Mentor-Based Predoctoral Fellowship to JB, Yerkes Base Grant NIH RR00165 supported by the Office of Research Infrastructure Programs/OD P51OD11132, and Center for Behavioral Neuroscience Grant NSF IBN-9876754. We thank the University of Texas Health Science Center at Houston veterinary and animal husbandry staff for expert animal care, Jairus O’Malley, Ernest Baskin, and Zachary Torrey for help with the behavioral testing of the animals, Roger E. Price and Belinda Rivera for the care and handling of animals during the MR imaging procedures, and Edward F. Jackson for assistance in neuroimaging techniques. Our appreciation also goes to Dr. Maria Alvarado; graduate students Drs. Shala Blue, Eric Heuer, Courtney Glavis-Bloom, Christopher Machado, Sarah Nemanic, Christa Payne, Jessica Raper, Alyson Zeamer; and the J.B. laboratory team that have participated in the neuroimaging and surgical procedures and the preparation of the histological material.

Footnotes

All authors declare no conflicts of interest.

CRediT Statement

JLK: Formal analysis, Visualization, Writing--original draft, Writing--review & editing; JRM: Formal analysis, Visualization, Writing--original draft, Writing--review & editing; AMK: Investigation, Methodology, Project administration, Supervision, Writing--review & editing; JB: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing--original draft, Writing--review & editing.

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