Delay-dependent cholinergic modulation of visual short-term memory in rhesus macaques.

Cholinergic neuromodulation is known to play a key role in visual working memory (VWM) - keeping relevant stimulus representations available for cognitive processes for short time periods (up to a few minutes). Despite the growing body of evidence on how the neural and cognitive mechanisms of VWM dynamically change over retention time, there is mixed evidence available on cholinergic effects as a function of VWM delay period in non-human primates. Using the delayed matching to sample VWM task in rhesus macaques (N = 6), we aimed to characterize VWM maintenance in terms of performance changes as a function of delay duration (across a wide range of delays from 1 to 76 s). Then, we studied how cholinergic neuromodulation influences VWM maintenance using the muscarinic receptor antagonist scopolamine administered alone as transient amnestic treatment, and in combination with two doses of the acetylcholinesterase inhibitor donepezil, a widely used Alzheimer's medication probing for the reversal of scopolamine-induced impairments. Results indicate that scopolamine-induced impairments of VWM maintenance are delay-dependent and specifically affect the 15-33 s time range, suggesting that scopolamine worsens the normal decay of VWM with the passage of time. Donepezil partially rescued the observed scopolamine-induced impairments of VWM performance. These results provide strong behavioral evidence for the role of increased cholinergic tone and muscarinic neuromodulation in the maintenance of VWM beyond a few seconds, in line with our current knowledge on the role of muscarinic acetylcholine receptors in sustained neural activity during VWM delay periods.

Generative modelling of the thalamo-cortical circuit mechanisms underlying the neurophysiological effects of ketamine.

Cortical recordings of task-induced oscillations following subanaesthetic ketamine administration demonstrate alterations in amplitude, including increases at high-frequencies (gamma) and reductions at low frequencies (theta, alpha). To investigate the population-level interactions underlying these changes, we implemented a thalamo-cortical model (TCM) capable of recapitulating broadband spectral responses. Compared with an existing cortex-only 4-population model, Bayesian Model Selection preferred the TCM. The model was able to accurately and significantly recapitulate ketamine-induced reductions in alpha amplitude and increases in gamma amplitude. Parameter analysis revealed no change in receptor time-constants but significant increases in select synaptic connectivity with ketamine. Significantly increased connections included both AMPA and NMDA mediated connections from layer 2/3 superficial pyramidal cells to inhibitory interneurons and both GABAA and NMDA mediated within-population gain control of layer 5 pyramidal cells. These results support the use of extended generative models for explaining oscillatory data and provide in silico support for ketamine's ability to alter local coupling mediated by NMDA, AMPA and GABA-A.

Blockage of NMDA- and GABA(A) Receptors Improves Working Memory Selectivity of Primate Prefrontal Neurons.

The ongoing activity of prefrontal neurons after a stimulus has disappeared is considered a neuronal correlate of working memory. It depends on the delicate but poorly understood interplay between excitatory glutamatergic and inhibitory GABAergic receptor effects. We administered the NMDA receptor antagonist MK-801 and the GABA(A) receptor antagonist bicuculline methiodide while recording cellular activity in PFC of male rhesus monkeys performing a delayed decision task requiring working memory. The blockade of GABA(A) receptors strongly improved the selectivity of the neurons' delay activity, causing an increase in signal-to-noise ratio during working memory periods as well as an enhancement of the neurons' coding selectivity. The blockade of NMDA receptors resulted in a slight enhancement of selectivity and encoding capacity of the neurons. Our findings emphasize the delicate and more complex than expected interplay of excitatory and inhibitory transmitter systems in modulating working memory coding in prefrontal circuits.SIGNIFICANCE STATEMENT Ongoing delay activity of prefrontal neurons constitutes a neuronal correlate of working memory. However, how this delay activity is generated by the delicate interplay of synaptic excitation and inhibition is unknown. We probed the effects of excitatory neurotransmitter glutamate and inhibitory neurotransmitter GABA in regulating delay activity in rhesus monkeys performing a delayed decision task requiring working memory. Surprisingly, the blockade of both glutamatergic NMDA and GABA(A) receptors improved neuronal selectivity of delay activity, causing an increase in neuronal signal-to-noise ratio. Moreover, individual neurons were similarly affected by blockade of both receptors. This emphasizes the delicate and more complex than expected interplay of excitatory and inhibitory transmitter systems in modulating working memory coding in prefrontal circuits.

Δ9-Tetrahydrocannabinol During Encoding Impairs Perceptual Details yet Spares Context Effects on Episodic Memory.

BACKGROUND: With the growing acceptance of cannabis use, it is crucial to understand the drug's effects on episodic memory accuracy and distortion. We investigated the impact of the administration of Δ9-tetrahydrocannabinol (THC), the main psychoactive constituent of cannabis, on a context-based memory illusion. METHODS: In a double-blind, placebo-controlled, within-subjects design, healthy infrequent cannabis users (N = 24) memorized object pictures that were superimposed over scenes (e.g., gray cat on beach) after pretreatment with placebo or THC (15 mg oral). Two days later under sober conditions, memory for the object pictures was tested by asking participants to discriminate between previously seen objects or perceptually similar lures (e.g., different gray cat). Context reinstatement was manipulated by presenting objects on their original or different scenes (e.g., beach or forest). RESULTS: THC impaired memory for perceptual details of objects compared with placebo, and the context illusion was obtained in each condition: context reinstatement increased high-confidence false recognition along with correct recognition of previously seen objects. Although THC did not interact with these context effects overall, post hoc analyses showed that THC magnified the context illusion when objects were semantically congruent with their encoding contexts but abolished the context illusion when objects were incongruent with their encoding contexts. CONCLUSIONS: These results are consistent with the hypothesis that THC impairs the encoding of specific object information more than item-context associations. As a result, THC may spare the distorting effects of context reinstatement on memory. In fact, THC may increase these distorting effects under conditions when objects are semantically congruent with context.

Neuroprotective role of naringenin against methylmercury induced cognitive impairment and mitochondrial damage in a mouse model.

Human exposure to organomercurials like methylmercury (MeHg) may occur by consumption of contaminated seafood, affecting various vital organs especially, brain contributing to neuro disorders. The citrus flavanone, naringenin (NAR) has shown strong antioxidant and anti-inflammatory effects and therefore may exert cytoprotective effect against xenobiotic agents. Herein, we investigated the neuroprotective role of NAR against MeHg induced functional changes in mitochondria, neuronal cell death and cognitive impairment in a mouse model. A neurotoxic dose of MeHg (4 mg/kg.b.wt.) was administered orally to mice for 15 days. This resulted in the reduction of GSH and GST, an increase in mitochondrial DNA damage and memory impairment. On the contrary, NAR pre-treatment (100 mg/kg.b.wt.), helped in lowering the oxidative burden which in turn maintained mitochondrial function and prevented induced neuronal cell death, ultimately improving the cognitive impairment. As MeHg intoxication occurs chronically, consumption of the dietary components rich in NAR may have its positive human health impact, ultimately improving the quality of life.

Development of an "object category recognition" task for mice: Involvement of muscarinic acetylcholine receptors.

Recent research suggests that rats are capable of object categorization-like processes. To study whether mice possess similar abilities, we developed a spontaneous one-trial object category recognition (OCR) task. Based on the spontaneous object recognition paradigm, mice discriminated between two otherwise equally novel objects, one from a novel category and one from a studied category. During the sample phase, mice were exposed to two different exemplars from the same category. After a retention delay, they explored a third (i.e., novel) object from that sampled category and an object from a novel category in a choice phase. Mice preferentially explored the novel category object, taken as an index of category recognition, in this OCR task when a 30-min retention delay was used. Extensive preexposure to category exemplar objects also enhanced subsequent task performance across a longer (1-h) retention delay at which mice without preexposure did not demonstrate evidence for category recognition. Prechoice administration of the acetylcholine muscarinic receptor antagonist, scopolamine, disrupted OCR performance with or without preexposure, implicating acetylcholine in category recognition. The current study presents a valuable new rodent task for the study of the mechanistic basis of categorization-like processes and its potential relevance to common cognitive disorders. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Exploring Object Discrimination in Zebrafish: Behavioral Performance and Scopolamine-Induced Cognitive Deficits at Different Retention Intervals.

The object discrimination test allows the testing of different memory retention periods. However, few behavioral endpoints have been measured in fish species such that retention is often assessed using a single parameter (time spent in object area). Here, we aimed to explore the object discrimination test in zebrafish by assessing their behavioral performance after 1 or 24 h retention interval periods. To characterize putative interaction-like behaviors, fish were tested in the absence or presence of scopolamine (1 h before test session). Zebrafish were habituated for 3 consecutive days in the experimental tank, and training session was performed for 10 min using two identical nonpreferred objects (black cube or sphere). After the retention intervals, a familiar object was replaced by a novel object (test session, 10 min). Fish were also exposed to the novel tank diving test to assess locomotion and anxiety-like behaviors. At 1 h retention interval, animals performed more circular-like investigation near the familiar object, whereas 24 h after training session, a prominent rapid investigation was observed when animals explore the nonfamiliar object. Because scopolamine abolished these phenotypes, as well as the increased time spent in the novel object area during the test without changing locomotion and anxiety-related parameters, the behavioral responses described here may predictively reflect interaction-like behaviors involved in object discrimination memory in zebrafish models.

D-Cycloserine Improves Difficult Discriminations in a Pattern Separation Task in Alzheimer's Disease Patients with Dementia.

Recent fMRI studies in human identified that pattern separation ability is associated with increased activity in the hippocampal dentate gyrus (DG), whereas no such DG changes are seen during pattern completion. Disruption to neurogenesis in the DG has been associated with Alzheimer's disease (AD). In a post-hoc analysis of two large unsuccessful AD clinical trials, we examined the effect of D-cycloserine (DCS) on a specific object pattern separation measure, a component of the picture recognition task from the Cognitive Drug Research (CDR) system. This task yields a measure of pattern separation and a measure of pattern completion. Study data were available for 756 AD patients with dementia, randomized to several doses of DCS. Data were available at week 2, 6, 14, and 26 for 732, 707, 653, and 559 patients, respectively. None of the DCS doses had a statistically significant benefit over placebo on pattern completion. However, the DCS 15 mg BID dose significantly increased accuracy over placebo on the pattern separation measure by 5.1%. Further, the magnitude of the benefit of DCS 15 mg BID over placebo was almost doubled relative to the whole study population in a subset of patients whose pattern separation scores were≥2 standard deviations poorer than the CDR norm of age-matched healthy individuals at baseline. These post-hoc analyses suggest a potential value of the pattern separation task for evaluating compounds promoting neurogenesis. Further, the use of a restrictive pattern separation eligibility criterion might facilitate signal detection.

Reversible Inactivation of Different Millimeter-Scale Regions of Primate IT Results in Different Patterns of Core Object Recognition Deficits.

Extensive research suggests that the inferior temporal (IT) population supports visual object recognition behavior. However, causal evidence for this hypothesis has been equivocal, particularly beyond the specific case of face-selective subregions of IT. Here, we directly tested this hypothesis by pharmacologically inactivating individual, millimeter-scale subregions of IT while monkeys performed several core object recognition subtasks, interleaved trial-by trial. First, we observed that IT inactivation resulted in reliable contralateral-biased subtask-selective behavioral deficits. Moreover, inactivating different IT subregions resulted in different patterns of subtask deficits, predicted by each subregion's neuronal object discriminability. Finally, the similarity between different inactivation effects was tightly related to the anatomical distance between corresponding inactivation sites. Taken together, these results provide direct evidence that the IT cortex causally supports general core object recognition and that the underlying IT coding dimensions are topographically organized.

GABAergic and cholinergic modulation of repetition suppression in inferior temporal cortex.

Neurons in many brain areas of different species reduce their response when a stimulus is repeated. Such adaptation or repetition suppression is prevalent in inferior temporal (IT) cortex. The mechanisms underlying repetition suppression in IT are still poorly understood. Studies in rodents and in-vitro experiments suggest that acetylcholine and GABA can contribute to repetition suppression by interacting with fatigue-related or local adaptation mechanisms. Here, we examined the contribution of cholinergic and GABAergic mechanisms to repetition suppression in macaque IT, using an adaptation paradigm in which familiar images were presented successively with a short interstimulus interval. We found that intracortical local injections of acetylcholine and of the GABAA receptor antagonist Gabazine both increased repetition suppression in awake macaque IT. The increased repetition suppression was observed for both spiking activity and local field potential power. The latter was present mainly for frequencies below 50 Hz, spectral bands that typically do not show consistent repetition suppression in IT. Although increased with drug application, repetition suppression remained stimulus selective. These findings agree with the hypothesis that repetition suppression of IT neurons mainly results from suppressed input from upstream and other IT neurons but depend less on intrinsic neuronal fatigue.

Methotrexate causes persistent deficits in memory and executive function in a juvenile animal model.

Methotrexate is a dihydrofolate reductase inhibitor widely employed in curative treatment for children with acute lymphoblastic leukemia (ALL). However, methotrexate administration is also associated with persistent cognitive deficits among long-term childhood cancer survivors. Animal models of methotrexate-induced cognitive deficits have primarily utilized adult animals. The purpose of present study is to investigate the neurotoxicity of methotrexate in juvenile rats and its relevant mechanisms. The doses and schedule of systemic and intrathecal methotrexate, given from post-natal age 3-7 weeks, were chosen to model the effects of repeated methotrexate dosing on the developing brains of young children with ALL. This methotrexate regimen had no visible acute toxicity and no effect on growth. At 15 weeks of age (8 weeks after the last methotrexate dose) both spatial pattern memory and visual recognition memory were impaired. In addition, methotrexate-treated animals demonstrated impaired performance in the set-shifting assay, indicating decreased cognitive flexibility. Histopathological analysis demonstrated decreased cell proliferation in methotrexate-treated animals compared to controls, as well as changes in length and thickness of the corpus callosum. Moreover, methotrexate suppressed microglia activation and RANTES production. In conclusion, our study demonstrated that a clinically relevant regimen of systemic and intrathecal methotrexate induces persistent deficits in spatial pattern memory, visual recognition memory and executive function, lasting at least 8 weeks after the last injection. The mechanisms behind methotrexate-induced deficits are likely multifactorial and may relate to suppression of neurogenesis, alterations in neuroinflammation and microglial activation, and structural changes in the corpus callosum.

Trigonelline mitigates lipopolysaccharide-induced learning and memory impairment in the rat due to its anti-oxidative and anti-inflammatory effect.

Brain inflammation is associated with cognitive dysfunction, especially in elderly. Trigonelline is a plant alkaloid and a major component of coffee and fenugreek with anti-diabetic, antioxidant, anti-inflammatory, and neuroprotective effects. In this study, the beneficial effect of trigonelline against lipopolysaccharide (LPS)-induced cognitive decline was assessed in the rat. LPS was injected i.p. at a dose of 500 µg/kg to induce neuroinflammation and trigonelline was administered p.o. at doses of 20, 40, or 80 mg/kg/day 1 h after LPS that continued for one week. Trigonelline-treated LPS-challenged rats showed improved spatial recognition memory in Y maze, discrimination ratio in novel object discrimination test, and retention and recall in passive avoidance paradigm. Additionally, trigonelline lowered hippocampal malondialdehyde (MDA) and acetylcholinesterase (AChE) activity and improved superoxide dismutase (SOD), catalase, and glutathione (GSH). Furthermore, trigonelline depressed hippocampal nuclear factor-kappaB (NF-κB), toll-like receptor 4 (TLR4), and tumor necrosis factor α (TNF α) in LPS-challenged rats. All of the effects of trigonelline followed a dose-dependent pattern and in some aspects, it acted even better than the routinely-used anti-inflammatory drug dexamethasone. Collectively, trigonelline is capable to diminish LPS-induced cognitive decline via suppression of hippocampal oxidative stress and inflammation and appropriate modulation of NF-κB/TLR4 and AChE activity.

The role of the hippocampus in object discrimination based on visual features.

The role of rodent hippocampus has been intensively studied in different cognitive tasks. However, its role in discrimination of objects remains controversial due to conflicting findings. We tested whether the number and type of features available for the identification of objects might affect the strategy (hippocampal-independent vs. hippocampal-dependent) that rats adopt to solve object discrimination tasks. We trained rats to discriminate 2D visual objects presented on a computer screen. The objects were defined either by their shape only or by multiple-features (a combination of filling pattern and brightness in addition to the shape). Our data showed that objects displayed as simple geometric shapes are not discriminated by trained rats after their hippocampi had been bilaterally inactivated by the GABAA-agonist muscimol. On the other hand, objects containing a specific combination of non-geometric features in addition to the shape are discriminated even without the hippocampus. Our results suggest that the involvement of the hippocampus in visual object discrimination depends on the abundance of object's features.

Safety assessment of Morus nigra L. leaves: Acute and subacute oral toxicity studies in Wistar rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Morus nigra L. is a plant native to Asia, and well adapted to the Brazilian climate. It is popularly known as "amoreira preta", and is part of the National List of Plants of Interest to the Brazilian Unified Health System. It is used in folk medicine mainly to soften the effects of menopause, as anti-inflammatory, antidiabetic and antihypertensive. However, information on safe doses and use is still precarious. AIM OF THE STUDY: To identify the chemical composition of the ethanolic extract of Morus nigra L. leaves (EEMN), as well as perform a toxicological study in male and female rats. MATERIALS AND METHODS: The chemical composition of the extract was performed by HPLC/DAD. In the acute study, the dose administered was 2000 mg/kg, and signs of toxicity and mortality was observed. In the sub-acute study, the extract was administered at doses of 500, 750 and 1000 mg/kg for 28 days. Behavioral changes, object recognition test, renal and hepatic tissue assessments, biochemical and hematological parameters were determined. The extract was administered orally to male and female rats in both studies. RESULTS: Quercetin and caffeic acid showed as major compounds in the extract. In the acute treatment, the extract was classified as safe (category 5), according to the protocol. In the subacute study, there was a decrease in AST in males (750 and 1000 mg/kg) and females (1000 mg/kg), reduction of total cholesterol in females (750 and 1000 mg/kg), and increase in renal and hepatic change the LPO levels. CONCLUSION: The present investigation showed that EEMN did not present significant toxic effects when administered orally. Moreover, presented a potentially protective action of organs and possesses hypocholesterolemic activity, thus, it is shown as a promising natural source to be used in pharmacology.

Erythropoietin improves object placement recognition memory in a time dependent manner in both, uninjured animals and fimbria-fornix-lesioned male rats.

An increasing number of reports sustain a possible role of erythropoietin (EPO) as neuroprotective agent. In two previous articles we have evaluated EPO as plasticity promoting agent, and to contribute the restoration of brain function affected by acquired damage. We have shown that EPO is able to induce an increased synaptic efficacy in vivo along with a plasticity promoting effect. In the Morris water maze EPO administration to fimbria-fornix lesioned male rats induces a significant improvement of their spatial memory, affected by the lesion. Singularly, EPO was only effective when administered shortly after training (10 min) but not after several hours (5 h), suggesting a specific EPO effect on time dependent plasticity process. In the present paper we have expanded this line of evidence using a low stress paradigm of object placement recognition in lesioned and healthy male rats. The memory trace in this model is short-lasting; animals could recognize the change in object position when tested 24 h after, but not 48 or 72 h after the acquisition session. EPO administration 10 min after acquisition significantly prolongs retention to, at least, 72 h in healthy rats. No effect was seen if EPO was administered 5 h after training, suggesting a specific EPO modulatory effect on the consolidation process. Remarkably, early EPO treatment to fimbria fornix lesioned animals reverts the memory deficit caused by the lesion. An increased expression of the plasticity related gene arc, was also confirmed in the hippocampus and the prefrontal cortex, that is likely to be involved in the behavioral improvement observed.

Effects of intranasal oxytocin on the attentional bias to emotional stimuli in patients with bulimia nervosa.

BACKGROUND: Bulimia nervosa (BN) is characterized by binge eating and emotional dysregulation including increased negative affectivity (anger, anxiety). The aim of this study was to examine the effect of oxytocin on attentional processes towards anger in patients with BN. METHOD: The study design consisted of a double-blind, placebo-controlled within-subject crossover, single dose experiment. Sixty-four women (31 patients with BN and 33 healthy comparisons) completed self-reported measures to evaluate emotional difficulties and were administered a single dose of intranasal oxytocin (40IU) or placebo followed by a visual probe detection task to examine attentional orienting to angry or happy faces. RESULTS: Patients with BN reported higher emotional dysregulation and more difficulties in controlling anger compared to the healthy comparison group. Patients with BN and the healthy women exhibited similar attentional bias to angry faces in the placebo condition. Intranasal oxytocin reduced the attentional bias towards angry faces in both the BN patients and the healthy women. CONCLUSIONS: We found that a single dose of oxytocin reduced vigilance towards angry faces in patients with BN as well as healthy women. The results showed that patients with BN are not different from healthy women in terms of vigilance towards threat.

Development of novel tasks for studying view-invariant object recognition in rodents: Sensitivity to scopolamine.

The capacity to recognize objects from different view-points or angles, referred to as view-invariance, is an essential process that humans engage in daily. Currently, the ability to investigate the neurobiological underpinnings of this phenomenon is limited, as few ethologically valid view-invariant object recognition tasks exist for rodents. Here, we report two complementary, novel view-invariant object recognition tasks in which rodents physically interact with three-dimensional objects. Prior to experimentation, rats and mice were given extensive experience with a set of 'pre-exposure' objects. In a variant of the spontaneous object recognition task, novelty preference for pre-exposed or new objects was assessed at various angles of rotation (45°, 90° or 180°); unlike control rodents, for whom the objects were novel, rats and mice tested with pre-exposed objects did not discriminate between rotated and un-rotated objects in the choice phase, indicating substantial view-invariant object recognition. Secondly, using automated operant touchscreen chambers, rats were tested on pre-exposed or novel objects in a pairwise discrimination task, where the rewarded stimulus (S+) was rotated (180°) once rats had reached acquisition criterion; rats tested with pre-exposed objects re-acquired the pairwise discrimination following S+ rotation more effectively than those tested with new objects. Systemic scopolamine impaired performance on both tasks, suggesting involvement of acetylcholine at muscarinic receptors in view-invariant object processing. These tasks present novel means of studying the behavioral and neural bases of view-invariant object recognition in rodents.

Female sexual attractiveness and sex recognition in leopard gecko: Males are indiscriminate courters.

The nature and hormonal control of cues used for recognition of sex and reproductive status of conspecifics remain largely unstudied in reptiles. It has been proposed that production of a female attractiveness pheromone controlled by female ovarian hormones (and which is suppressed by male gonadal androgens) is necessary to elicit courtship in males. In the case of leopard gecko (Eublepharis macularius), it has been suggested that an individual is recognized as a male and attacked unless it produces female-specific stimuli in its skin and that females are attacked, not courted, while shedding. We tested the reactions of males to control males and control shedding and non-shedding females, castrated males, females treated with exogenous androgens (testosterone and dihydrotestosterone), and prepubertal individuals. The individuals with high androgen levels (i.e., control males and hormone-treated females) were attacked while animals in all the other groups were courted. Our results indicate that in leopard gecko hormonally controlled pheromones advertising female attractiveness are not required and that sex discrimination is based on the presence or absence of cues dependent on masculinization by male gonadal steroids.

Recombinant growth differentiation factor 11 influences short-term memory and enhances Sox2 expression in middle-aged mice.

Previous evidence suggests that a significant decline in cognitive ability begins during middle-age and continues to deteriorate with increase in age. Recent work has demonstrated the potential rejuvenation impact of growth differentiation factor-11 (GDF-11) in aged mice. We carried out experiments to evaluate the impact of a single dose of recombinant (rGDF-11) on short-term visual and spatial memory in middle-aged male mice. On the novel object recognition task, we observed middle-aged mice treated rGDF-11 showed improved performance on the novel object recognition task. However, middle-aged mice did not show increased expression of phosphorylated-Smad2/3, a downstream effector of GDF-11. We noted however that the expression of the transcription factor, Sox2 was increased within the dentate gyrus. Our data suggest that a single injection of rGDF-11 contributes to improvements in cognitive function of middle-aged animals, which may be critical in the preservation of short-term memory capacity in old age.

Histamine Enhances Theta-Coupled Spiking and Gamma Oscillations in the Medial Entorhinal Cortex Consistent With Successful Spatial Recognition.

Encoding of spatial information in the superficial layers of the medial entorhinal cortex (sMEC) involves theta-modulated spiking and gamma oscillations, as well as spatially tuned grid cells and border cells. Little is known about the role of the arousal-promoting histaminergic system in the modification of information encoded in the sMEC in vivo, and how such histamine-regulated information correlates with behavioral functions. Here, we show that histamine upregulates the neural excitability of a significant proportion of neurons (16.32%, 39.18%, and 52.94% at 30 µM, 300 µM, and 3 mM, respectively) and increases local theta (4-12 Hz) and gamma power (low: 25-48 Hz; high: 60-120 Hz) in the sMEC, through activation of histamine receptor types 1 and 3. During spatial exploration, the strength of theta-modulated firing of putative principal neurons and high gamma oscillations is enhanced about 2-fold by histamine. The histamine-mediated increase of theta phase-locking of spikes and high gamma power is consistent with successful spatial recognition. These results, for the first time, reveal possible mechanisms involving the arousal-promoting histaminergic system in the modulation of spatial cognition.