Functional connectivity between anterior cingulate cortex and orbitofrontal cortex during value-based decision making.

There is a growing body of evidence showing that the anterior cingulate (ACC) and the orbitofrontal (OFC) cortex are both essential for reinforcement-guided decision making. Focusing on functional connectivity approach through coherence, we studied whether communication between the ACC and OFC through neural synchronization is a necessary stage for performing value-based decision making. We used a T-maze task with a differential reward (Large vs. small reward) and cost (long vs. short waiting time) and simultaneously recorded local field potentials (LFP) from the ACC and OFC. Task-dependent synchronization in theta/low beta (4-20 Hz) frequency bands were observed between areas when rats chose the higher over the lower reward. This synchronization was significantly poorer when rats chose lower rewards or passively performed the task. High-gamma (80-100 Hz) synchrony between areas was also observed, however, it was not dependent on the animal's decision. Our results propose that synchronization between the ACC and OFC in the low-frequency range is necessary during value-based decision making.

Feature integration, attention, and fixations during visual search.

We argue that mechanistic premises of "item-based" theories are not invalidated by the fixation-based approach. We use item-based theories to propose an account that does not advocate strict serial item processing and integrates fixations. The main focus of this account is feature integration within fixations. We also suggest that perceptual load determines the size of the fixations.

Neural and neurochemical basis of reinforcement-guided decision making.

Decision making is an adaptive behavior that takes into account several internal and external input variables and leads to the choice of a course of action over other available and often competing alternatives. While it has been studied in diverse fields ranging from mathematics, economics, ecology, and ethology to psychology and neuroscience, recent cross talk among perspectives from different fields has yielded novel descriptions of decision processes. Reinforcement-guided decision making models are based on economic and reinforcement learning theories, and their focus is on the maximization of acquired benefit over a defined period of time. Studies based on reinforcement-guided decision making have implicated a large network of neural circuits across the brain. This network includes a wide range of cortical (e.g., orbitofrontal cortex and anterior cingulate cortex) and subcortical (e.g., nucleus accumbens and subthalamic nucleus) brain areas and uses several neurotransmitter systems (e.g., dopaminergic and serotonergic systems) to communicate and process decision-related information. This review discusses distinct as well as overlapping contributions of these networks and neurotransmitter systems to the processing of decision making. We end the review by touching on neural circuitry and neuromodulatory regulation of exploratory decision making.

High-Efficiency Recognition and Identification of Disulfide Bonded Peptides in Rat Neuropeptidome Using Targeted Electron Transfer Dissociation Tandem Mass Spectrometry.

The main goal of the present study is to develop a method to recognize and identify endogenous intrachain disulfide bonded peptide, which are rarely sequenced in current peptidomics studies. In order to achieve highly efficient detection of these peptides in a neuropeptidome analysis, we alkylated the peptides, mined the raw mass spectrometry data, and then recognized the candidates of untreated disulfide bonded peptides from unalkylated peptide extracts. After removing more than 90% features, targeted electron transfer dissociation fragmentation was performed for detecting and fragmenting disulfide bonded peptides, and even most of them were present in low abundance in the original sample. Diverse endogenous disulfide bonded peptides were then detected and sequenced, opening up new perspectives for comprehensively understanding the response of a neuropeptidome.

Partially dissociable roles of OFC and ACC in stimulus-guided and action-guided decision making.

Recently, the functional specialization of prefrontal areas of the brain, and, specifically, the functional dissociation of the orbitofrontal cortex (OFC) and the anterior cingulate cortex (ACC), during decision making have become a particular focus of research. A number of neuropsychological and lesion studies have shown that the OFC and ACC have dissociable functions in various dimensions of decision making, which are supported by their different anatomical connections. A recent single-neuron study, however, described a more complex picture of the functional dissociation between these two frontal regions during decision making. Here, I discuss the results of that study and consider alternative interpretations in connection with other findings.

Insecticide activity of essential oils of Mentha longifolia, Pulicaria gnaphalodes and Achillea wilhelmsii against two stored product pests, the flour beetle, Tribolium castaneum, and the cowpea weevil, Callosobruchus maculatus.

Essential oils extracted from the foliage of Mentha longifolia (L.) (Lamiales: Lamiaceae) and Pulicaria gnaphalodes Ventenat (Asterales: Asteraceae), and flowers of Achillea wilhelmsii C. Koch (Asterales: Asteraceae) were tested in the laboratory for volatile toxicity against two storedproduct insects, the flour beetle, Tribolium castaneum Herbst (Coleoptera: Tenebrionidae) and the cowpea weevil, Callosobruchus maculatus F. (Coleoptera: Bruchidae). The chemical composition of the isolated oils was examined by gas chromatography-mass spectrometry. InM longifolia, the major compounds were piperitenon (43.9%), tripal (14.3%), oxathiane (9.3%), piperiton oxide (5.9%), and d-limonene (4.3%). In P. gnaphalodes, the major compounds were chrysanthenyl acetate (22.38%), 2L -4L-dihydroxy eicosane (18.5%), verbenol (16.59%), dehydroaromadendrene (12.54%), ß-pinen (6.43%), and 1,8 cineol (5.6%). In A. wilhelmsii, the major compounds were 1,8 cineole (13.03%), caranol (8.26%), alpha pinene (6%), farnesyl acetate (6%), and p-cymene (6%). C maculatus was more susceptible to the tested plant products than T castaneum. The oils of the three plants displayed the same insecticidal activity against C. maculatus based on LC(50) values (between 1.54µl/L air in P. gnaphalodes, and 2.65 µl/L air in A. wilhelmsii). While the oils of A. wilhelmsii and M. longifolia showed the same strong insecticidal activity against T. castaneum (LC(50) = 10.02 and 13.05 µl/L air, respectively), the oil of P. gnaphalodes revealed poor activity against the insect (LC(50) = 297.9 µl/L air). These results suggested that essential oils from the tested plants could be used as potential control agents for stored-product insects.

Paradoxical neuronal hyperexcitability in a mouse model of mitochondrial pyruvate import deficiency.

Neuronal excitation imposes a high demand of ATP in neurons. Most of the ATP derives primarily from pyruvate-mediated oxidative phosphorylation, a process that relies on import of pyruvate into mitochondria occuring exclusively via the mitochondrial pyruvate carrier (MPC). To investigate whether deficient oxidative phosphorylation impacts neuron excitability, we generated a mouse strain carrying a conditional deletion of MPC1, an essential subunit of the MPC, specifically in adult glutamatergic neurons. We found that, despite decreased levels of oxidative phosphorylation and decreased mitochondrial membrane potential in these excitatory neurons, mice were normal at rest. Surprisingly, in response to mild inhibition of GABA mediated synaptic activity, they rapidly developed severe seizures and died, whereas under similar conditions the behavior of control mice remained unchanged. We report that neurons with a deficient MPC were intrinsically hyperexcitable as a consequence of impaired calcium homeostasis, which reduced M-type potassium channel activity. Provision of ketone bodies restored energy status, calcium homeostasis and M-channel activity and attenuated seizures in animals fed a ketogenic diet. Our results provide an explanation for the seizures that frequently accompany a large number of neuropathologies, including cerebral ischemia and diverse mitochondriopathies, in which neurons experience an energy deficit.

Cold hardiness and supercooling capacity in the overwintering larvae of the codling moth, Cydia pomonella.

The codling moth, Cydia pomonella L. (Lepidoptera: Tortricidae), a worldwide apple pest, is classified as a freeze-intolerant organism and one of the most cold-tolerant pests. The objectives of this study were to examine the supercooling point of overwintering and non-diapausing larvae of C. pomonella as an index of its cold hardiness, and to assess larval mortality following 24 h exposure to extreme low temperatures ranging from -5 to -25 degrees C. The mean (+/-SE) supercooling point for feeding larvae (third through fifth instars) was -12.4 +/- 1.1 degrees C. The mean supercooling point for cocooned, non-diapausing larvae (i.e., non-feeding stages) decreased as the days that the arvae were cocooned increased and changed between -15.1 +/- 1.2 degrees C for one to two day cocooned arvae and -19.2 +/- 1.8 degrees C for less than five day cocooned larvae. The mean (+/-SE) supercooling point for other non-feeding stages containing pupae and overwintering larvae were -19.9 +/- 1.0 degrees C and -20.2 +/- 0.2 degrees C, respectively. Mean supercooling points of C. pomonella larvae were significantly lower during the winter months than the summer months, and sex had no effect on the supercooling point of C. pomonella larvae. The mortality of larvae increased significantly after individuals were exposed to temperatures below the mean supercooling point of the population. The supercooling point was a good predictor of cold hardiness.

Large-Scale Networks for Auditory Sensory Gating in the Awake Mouse.

The amplitude of the brain response to a repeated auditory stimulus is diminished as compared to the response to the first tone (T1) for interstimulus intervals (ISI) lasting up to hundreds of milliseconds. This adaptation process, called auditory sensory gating (ASG), is altered in various psychiatric diseases including schizophrenia and is classically studied by focusing on early evoked cortical responses to the second tone (T2) using 500-ms ISI. However, mechanisms underlying ASG are still not well-understood. We investigated ASG in awake mice from the brainstem to cortex at variable ISIs (125-2000 ms) using high-density EEG and intracerebral recordings. While ASG decreases at longer ISIs, it is still present at durations (500-2000 ms) far beyond the time during which brain responses to T1 could still be detected. T1 induces a sequence of specific stable scalp EEG topographies that correspond to the successive activation of distinct neural networks lasting about 350 ms. These brain states remain unaltered if T2 is presented during this period, although T2 is processed by the brain, suggesting that ongoing networks of brain activity are active for longer than early evoked-potentials and are not overwritten by an upcoming new stimulus. Intracerebral recordings demonstrate that ASG is already present at the level of ventral cochlear nucleus (vCN) and inferior colliculus and is amplified across the hierarchy in bottom-up direction. This study uncovers the extended stability of sensory-evoked brain states and long duration of ASG, and sheds light on generators of ASG and possible interactions between bottom-up and top-down mechanisms.

Whole-Night Continuous Rocking Entrains Spontaneous Neural Oscillations with Benefits for Sleep and Memory.

Sensory processing continues during sleep and can influence brain oscillations. We previously showed that a gentle rocking stimulation (0.25 Hz), during an afternoon nap, facilitates wake-sleep transition and boosts endogenous brain oscillations (i.e., EEG spindles and slow oscillations [SOs]). Here, we tested the hypothesis that the rhythmic rocking stimulation synchronizes sleep oscillations, a neurophysiological mechanism referred to as "neural entrainment." We analyzed EEG brain responses related to the stimulation recorded from 18 participants while they had a full night of sleep on a rocking bed. Moreover, because sleep oscillations are considered of critical relevance for memory processes, we also investigated whether rocking influences overnight declarative memory consolidation. We first show that, compared to a stationary night, continuous rocking shortened the latency to non-REM (NREM) sleep and strengthened sleep maintenance, as indexed by increased NREM stage 3 (N3) duration and fewer arousals. These beneficial effects were paralleled by an increase in SOs and in slow and fast spindles during N3, without affecting the physiological SO-spindle phase coupling. We then confirm that, during the rocking night, overnight memory consolidation was enhanced and also correlated with the increase in fast spindles, whose co-occurrence with the SO up-state is considered to foster cortical synaptic plasticity. Finally, supporting the hypothesis that a rhythmic stimulation entrains sleep oscillations, we report a temporal clustering of spindles and SOs relative to the rocking cycle. Altogether, these findings demonstrate that a continuous rocking stimulation strengthens deep sleep via the neural entrainment of intrinsic sleep oscillations.

Reducing the time and dose of morphine application used in Marshall and Grahame-Smith method for induction of morphine tolerance and dependence in mice.

To induce morphine dependence, different programs have been used and a wide range of behaviors evaluated. A quantitative method based on mice withdrawal jumping behavior has been suggested and later described by Marshall and Grahame-Smith. The purpose of this work was to evaluate different aspects of this method using variations in doses and duration of the protocol. All experiments were done in three parallel methods according to the Marshall protocol: (i) except the dose of morphine (n=20) where we divided all morphine doses by two in first 3 days, (ii) 2-day (M100%-2D, n=14) and (iii) 1-day morphine application (M100%-1D; n=13). The results showed that only 50% doses of morphine that are used according to Marshall method is sufficient to induce morphine dependence whereas they are not able to induce tolerance. On the other hand, M100%-2D protocol could induce morphine tolerance but not dependence whereas M100%-1D group could induce neither morphine tolerance nor dependence in mice. Therefore, these simple modifications in dose and period of morphine application in Marshall method resulted in distinct protocols for induction of morphine tolerance and dependence along with saving of drug and time.

Repeated administration of nicotine attenuates the development of morphine tolerance and dependence in mice.

Clinical use of morphine in pain management is a controversial issue. Both nicotine and morphine are widely abused. So, investigating the interaction between nicotinic and opioid receptors is of great interest to both basic mechanistic and clinical view. We investigated the influence of repeated administration of nicotine on the development of morphine tolerance and dependence. Adult male albino mice were rendered dependent on morphine by subcutaneous (s.c.) injections three times daily for 3 days. Repeated intraperitoneal (i.p.) injection of nicotine (0.001-2 mg/kg) or saline (1 ml/kg) was performed 15 min prior to each morphine injection. Maximal possible effect (MPE%) of morphine (50 mg/kg; s.c.) was used on the fourth day as an index for the development of tolerance. Likewise, to assess the occurrence of dependence in drug-treated mice, naloxone (5 mg/kg; i.p.) was injected 2 h after the last dose of morphine. Repeated nicotine administration significantly attenuated the development of tolerance in a dose-dependent manner whereas it significantly decreased withdrawal jumping behavior in a biphasic profile (V-shape) manner. Furthermore, the central nicotinic receptor antagonist mecamylamine (0.01-0.1 mg/kg; i.p.) neither the peripheral nicotinic receptor antagonist hexamethonium (0.01 and 0.1 mg/kg; i.p.) nor the muscarinic receptor antagonist atropine (2.5-10 mg/kg; i.p.), dose-dependently antagonized both the inhibition of withdrawal jumping as well as increase in MPE% which was produced by repeated nicotine administration (0.1 mg/kg; i.p.). On the other hand, 3 days of solely nicotine treatment resulted in significant jumping behavior precipitated by naloxone after single morphine injection on the test day. The data suggests that the inhibitory effect of nicotine on the morphine tolerance and dependence is mediated by central nicotinic receptors and there is a cross-dependence between nicotine and morphine.

Interaction between cannabinoid compounds and diazepam on anxiety-like behaviour of mice.

Previous studies have suggested that cannabinoidergic system is involved in anxiety. However, a complete picture of cannabinoid association in the anxiety is still lacking. In the present study, we investigated the possible interaction between cannabinoidergic and GABAergic systems in the anxiety-like behaviour of mice. Intraperitoneal (i.p.) administration of the cannabinoid receptor agonist WIN55212-2 (0.25-5 mg/kg), the endocannabinoid transport inhibitor AM404 (0.25-2 mg/kg) and diazepam (0.25-8 mg/kg) dose dependently exhibited an anxiolytic effect evaluated in terms of increase in the percentage of time spent in the open arms in the elevated plus maze (EPM) test. Administration of certain fixed-ratio combinations (3:1 and 1:1) of WIN55212-2 and diazepam produced a synergistic anxiolytic effect, while the 1:3 combination produced an additive effect. In hole-board test, administration of certain ratios of WIN55212-2-diazepam combination significantly altered the animal behaviour compared to groups that received each drug alone. Co-administration of AM404 (1 and 2 mg/kg) and diazepam (0.5 mg/kg) abolished the anxiolytic effect of the former drug in EPM and the latter in hole-board test, respectively. The combination of an ineffective dose of the fatty acid amide hydrolase (FAAH) inhibitor, URB597 (0.3 mg/kg, i.p.) on anxiety-related responses with an ineffective dose of diazepam (0.25 mg/kg, i.p.) led to a synergistic effect. Co-administration of the CB1 receptor antagonist, AM251 (5 mg/kg) and an effective dose of diazepam (2 mg/kg, i.p.) attenuated diazepam-induced elevation of percentage of time spent in open arm, while lower dose of AM251 (0.5 mg/kg) failed to inhibit diazepam-induced anxiolytic effect. Taken together, the present study showed that co-administration of exogenous cannabinoids and diazepam produce additive or synergistic effect at different combinations. Moreover, it has been shown that enhancement of the function of endocannabinoids could increase the anxiolytic effect of diazepam.

Distinct Frequency Specialization for Detecting Dark Transients in Humans and Tree Shrews.

Despite well-known privileged perception of dark over light stimuli, it is unknown to what extent this dark dominance is maintained when visual transients occur in rapid succession, for example, during perception of moving stimuli. Here, we address this question using dark and light transients presented at different flicker frequencies. Although both human participants and tree shrews exhibited dark dominance for temporally modulated transients, these occurred at different flicker frequencies, namely, at 11 Hz in humans and 40 Hz and higher in tree shrews. Tree shrew V1 neuronal activity confirmed that differences between light and dark flicker were maximal at 40 Hz, corresponding closely to behavioral findings. These findings suggest large differences in flicker perception between humans and tree shrews, which may be related to the lifestyle of these species. A specialization for detecting dark transients at high temporal frequencies may thus be adaptive for tree shrews, which are particularly fast-moving small mammals.

Divergent Solutions to Visual Problem Solving across Mammalian Species.

Our understanding of the neurobiological underpinnings of learning and behavior relies on the use of invasive techniques, which necessitate the use of animal models. However, when different species learn the same task, to what degree are they actually producing the same behavior and engaging homologous neural circuitry? This question has received virtually no recent attention, even as the most powerful new methodologies for measuring and perturbing the nervous system have become increasingly dependent on the use of murine species. Here, we test humans, rats, monkeys, and an evolutionarily intermediate species, tree shrews, on a three alternative, forced choice, visual contrast discrimination task. As anticipated, learning rate, peak performance, and transfer across contrasts was lower in the rat compared to the other species. More interestingly, rats exhibited two major behavioral peculiarities: while monkeys and tree shrews based their choices largely on visual information, rats tended to base their choices on past reward history. Furthermore, as the task became more difficult, rats largely disengaged from the visual stimulus, reverting to innate spatial predispositions in order to collect rewards near chance probability. Our findings highlight the limitation of muridae as models for translational research, at least in the area of visually based decision making.

Cannabinoids induce apathetic and impulsive patterns of choice through CB1 receptors and TRPV1 channels.

Despite evidence from psychiatry and psychology clinics pointing to altered cognition and decision making following the consumption of cannabis, the effects of cannabis derivatives are still under dispute and the mechanisms of cannabinoid effects on cognition are not known. In this study, we used effort-based and delay-based decision tasks and showed that ACEA, a potent cannabinoid agonist induced apathetic and impulsive patterns of choice in rats in a dose-dependent manner when locally injected into the anterior cingulate cortex (ACC) and orbitofrontal cortex (OFC), respectively. Pre-treatment with AM251, a selective cannabinoid type 1 (CB1) receptor antagonist, reversed ACEA-induced impulsive and apathetic patterns of choice in doses higher than a minimally effective dose. Unlike CB1 receptor antagonist, pretreatment with capsazepine, a transient receptor potential vanilloid type 1 (TRPV1) channel antagonist, was effective only at an intermediary dose. Furthermore, capsazepine per se induced impulsivity and apathy at a high dose suggesting a basal tonic activation of TRPV1 channels that exist in the ACC and OFC to support cost-benefit decision making and to help avoid apathetic and impulsive patterns of decision making. Taken together, unlike previous reports supporting opposing roles for the CB1 receptors and TRPV1 channels in anxiety and panic behavior, our findings demonstrate a different sort of interaction between endocannabinoid and endovanilloid systems and suggest that both systems contribute to the cognitive disrupting effects of cannabinoids. Given prevalent occurrence of apathy and particularly impulsivity in psychiatric disorders, these results have significant implications for pharmacotherapy research targeting these receptors.

Role of glutamatergic receptors located in the nucleus raphe magnus on antinociceptive effect of morphine microinjected into the nucleus cuneiformis of rat.

Neurons in the nucleus cuneiformis (CnF), located just ventrolateral to the periaqueductal gray, project to medullary nucleus raphe magnus (NRM), which is a key medullary relay for descending pain modulation and is critically involved in opioid-induced analgesia. Previous studies have shown that antinociceptive response of CnF-microinjected morphine can be modulated by the specific subtypes of glutamatergic receptors within the CnF. In this study, we evaluated the role of NMDA and kainate/AMPA receptors that are widely distributed within the NRM on morphine-induced antinociception elicited from the CnF. Hundred and five male Wistar rats weighing 250-300 g were used. Morphine (10, 20 and 40 microg) and NMDA receptor antagonist, MK-801 (10 microg) or kainate/AMPA receptor antagonist, DNQX (0.5 microg) in 0.5 microl saline were stereotaxically microinjected into the CnF and NRM, respectively. The latency of tail-flick response was measured at set intervals (2, 7, 12, 17, 22, 27 min after microinjection) by using an automated tail-flick analgesiometer. The results showed that morphine microinjection into the CnF dose-dependently causes increase in tail-flick latency (TFL). MK-801 microinjected into the NRM, just 1 min before morphine injection into the CnF, significantly attenuated antinociceptive effects of morphine. On the other hand, DNQX microinjected into the NRM, significantly increased TFL after local application of morphine into the CnF. We suggest that morphine related antinociceptive effect elicited from the CnF is mediated, in part, by NMDA receptor at the level of the NRM whereas kainite/AMPA receptor has a net inhibitory influence at the same pathway.

Activation of cannabinoid system in anterior cingulate cortex and orbitofrontal cortex modulates cost-benefit decision making.

Despite the evidence for altered decision making in cannabis abusers, the role of the cannabinoid system in decision-making circuits has not been studied. Here, we examined the effects of cannabinoid modulation during cost-benefit decision making in the anterior cingulate cortex (ACC) and orbitofrontal cortex (OFC), key brain areas involved in decision making. We trained different groups of rats in a delay-based and an effort-based form of cost-benefit T-maze decision-making task. During test days, the rats received local injections of either vehicle or ACEA, a cannabinoid type-1 receptor (CB1R) agonist in the ACC or OFC. We measured spontaneous locomotor activity following the same treatments and characterized CB1Rs localization on different neuronal populations within these regions using immunohistochemistry. We showed that CB1R activation in the ACC impaired decision making such that rats were less willing to invest physical effort to gain high reward. Similarly, CB1R activation in the OFC induced impulsive pattern of choice such that rats preferred small immediate rewards to large delayed rewards. Control tasks ensured that the effects were specific for differential cost-benefit tasks. Furthermore, we characterized widespread colocalizations of CB1Rs on GABAergic axonal ends but few colocalizations on glutamatergic, dopaminergic, and serotonergic neuronal ends. These results provide first direct evidence that the cannabinoid system plays a critical role in regulating cost-benefit decision making in the ACC and OFC and implicate cannabinoid modulation of synaptic ends of predominantly interneurons and to a lesser degree other neuronal populations in these two frontal regions.

Fumigant and repellent properties of sesquiterpene-rich essential oil from Teucrium polium subsp. capitatum (L.).

OBJECTIVE: To test fumigant and repellent properties of sesquiterpene-rich essential oil from Teucrium polium subsp. capitatum (L.). METHODS: The fumigant toxicity test was performed at (27±1)°C, (65±5)% relative humidity, and under darkness condition and 24 h exposure time. The chemical composition of the isolated oils was examined by gas chromatography-mass spectrometry. RESULTS: The major compounds were α-cadinol (46.2%), caryophyllene oxide (25.9%), α muurolol epi (8.1%), cadalene (3.7%) and longiverbenone (2.9%). In all cases, considerable differences in mortality of insect to essential oil vapor were observed in different concentrations and exposure times. Callosobruchus maculatus (C. maculates) (LC50=148.9 µL/L air) was more susceptible to the tested plant product than Teucrium castaneum (T. castaneum) (LC50=360.2 µL/L air) based on LC50 values. In the present investigation, the concentration of 3 µL /mL acetone showed 60% and 52% repellency against T. casteneum and C. maculatus adults, respectively. CONCLUSIONS: The results suggests that sesquiterpene-rich essential oils from the tested plant could be used as a potential control agent for stored-product insects.

Tree shrews (Tupaia belangeri) exhibit novelty preference in the novel location memory task with 24-h retention periods.

Novelty preference is pervasive in mammalian species, and describes an inherent tendency to preferentially explore novelty. The novel location memory task studied here assesses the ability of animals to form accurate memories of a spatial configuration, consisting of several identical objects placed within an arena. Tree shrews were first familiarized with a particular object configuration during several sessions, and then an object was displaced during a test session. Tree shrews exhibited enhanced exploration when confronted with this novel configuration. The most reliable indicator associated with novelty preference was an enhancement in directed exploration towards the novel object, although we also observed a non-specific overall increase in exploration in one experiment. During the test session, we also observed an exploration of the location, which had previously been occupied by the displaced object, an effect termed empty quadrant. Our behavioral findings suggest multiple stages of spatial memory formation in tree shrews that are associated with various forms of behavioral responses to novelty. Reduced novelty preference has been linked to major depressive disorder in human patients. Given the established social conflict depression model in tree shrews, we anticipate that the study of the neural circuits of novelty preference and their malfunction during depression may have implications for understanding or treating depression in humans.