Biased 5-HT1A receptor agonists F13714 and NLX-101 differentially affect pattern separation and neuronal plasticity in rats after acute and chronic treatment.

Pattern separation is a hippocampal process in which highly similar stimuli are recognized as separate representations, and deficits could lead to memory impairments in neuropsychiatric disorders such as schizophrenia. The 5-HT1A receptor (5-HT1AR) is believed to be involved in these hippocampal pattern separation processes. However, in the dorsal raphe nucleus (DRN), the 5-HT1AR is expressed as a somatodendritic autoreceptor, negatively regulates serotonergic signaling, and could thereby counteract the effects of hippocampal postsynaptic 5-HT1A receptors. Therefore, this study aims to identify how pre- and post-synaptic 5-HT1AR activity affects pattern separation. Object pattern separation (OPS) performance was measured in male Wistar rats after both acute and chronic treatment (i.p.) with 5-HT1AR biased agonists F13714 (0.0025 mg/kg acutely, 0.02 mg/kg/day chronically) or NLX-101 (0.08 mg/kg acutely, 0.32 mg/kg/day chronically), which preferentially activate autoreceptors or postsynaptic receptors respectively, for 14 days. Body temperature - a functional correlate of hypothalamic 5-HT1AR stimulation - was measured daily. Additionally, 5-HT1AR density (DRN) and plasticity markers (hippocampus) were assessed. Acute treatment with F13714 impaired OPS performance, whereas chronic treatment normalized this, and a drop in body temperature was found from day 4 onwards. NLX-101 enhanced OPS performance acutely and chronically, and caused an acute drop in body temperature. Chronic NLX-101 treatment increased doublecortin positive neurons in the dorsal hippocampus, while chronic treatment with F13714 resulted in a downregulation of 5-HT1A autoreceptors, which likely reversed the acute impairment in OPS performance. Chronic treatment with NLX-101 appears to have therapeutic potential to improve brain plasticity and OPS performance.

A complex mTOR response in habituation paradigms for a social signal in adult songbirds.

Nonassociative learning is considered simple because it depends on presentation of a single stimulus, but it likely reflects complex molecular signaling. To advance understanding of the molecular mechanisms of one form of nonassociative learning, habituation, for ethologically relevant signals we examined song recognition learning in adult zebra finches. These colonial songbirds learn the unique song of individuals, which helps establish and maintain mate and other social bonds, and informs appropriate behavioral interactions with specific birds. We leveraged prior work demonstrating behavioral habituation for individual songs, and extended the molecular framework correlated with this behavior by investigating the mechanistic Target of Rapamycin (mTOR) signaling cascade. We hypothesized that mTOR may contribute to habituation because it integrates a variety of upstream signals and enhances associative learning, and it crosstalks with another cascade previously associated with habituation, ERK/ZENK. To begin probing for a possible role for mTOR in song recognition learning, we used a combination of song playback paradigms and bidirectional dysregulation of mTORC1 activation. We found that mTOR demonstrates the molecular signatures of a habituation mechanism, and that its manipulation reveals the complexity of processes that may be invoked during nonassociative learning. These results thus expand the molecular targets for habituation studies and raise new questions about neural processing of complex natural signals.

Wave-Like Dose-Dependence of the Stimulating Effects of Dimebon on Cognition in a Wide Dose Range.

Comparison of the cognition-stimulating effects of Dimebon in a wide dose range revealed a non-monotonic and nontrivial wave-like dose-dependence of its activity. Positive results were obtained at low (0.02-0.05 mg/kg) or high (5-10 mg/kg) doses of Dimebon, while intermediate doses were ineffective. This type of the dose dependence of the pharmacological effect can indicate that the substance has several targets. This fact should be taken into consideration when selecting the doses and concentrations of the substance and its analogues for further studies, and for planning treatment schemes and administration doses in clinical studies.

Effects of resveratrol on memory performance, hippocampus connectivity and microstructure in older adults - A randomized controlled trial.

INTRODUCTION: The polyphenol resveratrol has been suggested to exert beneficial effects on memory and the aging hippocampus due to calorie-restriction mimicking effects. However, the evidence based on human interventional studies is scarce. We therefore aimed to determine the effects of resveratrol on memory performance, and to identify potential underlying mechanisms using a broad array of blood-based biomarkers as well as hippocampus connectivity and microstructure assessed with ultra-high field magnetic resonance imaging (UHF-MRI). METHODS: In this double-blind, randomized controlled trial, 60 elderly participants (60-79 years) with a wide body-mass index (BMI) range of 21-37 kg/m2 were randomized to receive either resveratrol (200 mg/day) or placebo for 26 weeks (registered at ClinicalTrials.gov: NCT02621554). Baseline and follow-up assessments included the California Verbal Learning Task (CVLT, main outcome), the ModBent task, anthropometry, markers of glucose and lipid metabolism, inflammation and neurotrophins derived from fasting blood, multimodal neuroimaging at 3 and 7 T, and questionnaires to assess confounding factors. RESULTS: Multivariate repeated-measures ANOVA did not detect significant time by group effects for CVLT performance. There was a trend for preserved pattern recognition memory after resveratrol, while performance decreased in the placebo group (n.s., p = 0.07). Further exploratory analyses showed increases in both groups over time in body fat, cholesterol, fasting glucose, interleukin 6, high sensitive C-reactive protein, tumor necrosis factor alpha and in mean diffusivity of the subiculum and presubiculum, as well as decreases in physical activity, brain-derived neurotrophic factor and insulin-like growth factor 1 at follow-up, which were partly more pronounced after resveratrol. DISCUSSION: This interventional study failed to show significant improvements in verbal memory after 6 months of resveratrol in healthy elderly with a wide BMI range. A non-significant trend emerged for positive effects on pattern recognition memory, while possible confounding effects of unfavorable changes in lifestyle behavior, neurotrophins and inflammatory markers occurred. Our findings also indicate the feasibility to detect (un)healthy aging-related changes in measures of hippocampus microstructure after 6 months using 7T diffusion MRI. More studies incorporating a longer duration and larger sample size are needed to determine if resveratrol enhances memory performance in healthy older adults.

The Dynamic Multisensory Engram: Neural Circuitry Underlying Crossmodal Object Recognition in Rats Changes with the Nature of Object Experience.

Rats, humans, and monkeys demonstrate robust crossmodal object recognition (CMOR), identifying objects across sensory modalities. We have shown that rats' performance of a spontaneous tactile-to-visual CMOR task requires functional integration of perirhinal (PRh) and posterior parietal (PPC) cortices, which seemingly provide visual and tactile object feature processing, respectively. However, research with primates has suggested that PRh is sufficient for multisensory object representation. We tested this hypothesis in rats using a modification of the CMOR task in which multimodal preexposure to the to-be-remembered objects significantly facilitates performance. In the original CMOR task, with no preexposure, reversible lesions of PRh or PPC produced patterns of impairment consistent with modality-specific contributions. Conversely, in the CMOR task with preexposure, PPC lesions had no effect, whereas PRh involvement was robust, proving necessary for phases of the task that did not require PRh activity when rats did not have preexposure; this pattern was supported by results from c-fos imaging. We suggest that multimodal preexposure alters the circuitry responsible for object recognition, in this case obviating the need for PPC contributions and expanding PRh involvement, consistent with the polymodal nature of PRh connections and results from primates indicating a key role for PRh in multisensory object representation. These findings have significant implications for our understanding of multisensory information processing, suggesting that the nature of an individual's past experience with an object strongly determines the brain circuitry involved in representing that object's multisensory features in memory. SIGNIFICANCE STATEMENT: The ability to integrate information from multiple sensory modalities is crucial to the survival of organisms living in complex environments. Appropriate responses to behaviorally relevant objects are informed by integration of multisensory object features. We used crossmodal object recognition tasks in rats to study the neurobiological basis of multisensory object representation. When rats had no prior exposure to the to-be-remembered objects, the spontaneous ability to recognize objects across sensory modalities relied on functional interaction between multiple cortical regions. However, prior multisensory exploration of the task-relevant objects remapped cortical contributions, negating the involvement of one region and significantly expanding the role of another. This finding emphasizes the dynamic nature of cortical representation of objects in relation to past experience.

Tone identification behavior in Rattus norvegicus: muscarinic receptor blockage lowers responsiveness in nontarget selective neurons, while nicotinic receptor blockage selectively lowers target responses.

Learning to associate a stimulus with reinforcement causes plasticity in primary sensory cortex. Neural activity caused by the associated stimulus is paired with reinforcement, but population analyses have not found a selective increase in response to that stimulus. Responses to other stimuli increase as much as, or more than, responses to the associated stimulus. Here, we applied population analysis at a new time point and additionally evaluated whether cholinergic receptor blockers interacted with the plastic changes in cortex. Three days of tone identification behavior caused responsiveness to increase broadly across primary auditory cortex, and target responses strengthened less than overall responsiveness. In pharmacology studies, behaviorally impairing doses of selective acetylcholine receptor blockers were administered during behavior. Neural responses were evaluated on the following day, while the blockers were absent. The muscarinic group, blocked by scopolamine, showed lower responsiveness and an increased response to the tone identification target that exceeded both the 3-day control group and task-naïve controls. Also, a selective increase in the late phase of the response to the tone identification stimulus emerged. Nicotinic receptor antagonism, with mecamylamine, more modestly lowered responses the following day and lowered target responses more than overall responses. Control acute studies demonstrated the muscarinic block did not acutely alter response rates, but the nicotinic block did. These results lead to the hypothesis that the decrease in the proportion of the population spiking response that is selective for the target may be explained by the balance between effects modulated by muscarinic and nicotinic receptors.

3',4'-Dihydroxyflavonol attenuates spatial learning and memory impairments in global cerebral ischemia.

OBJECTIVES: In the present study, effects of 3',4'-dihydroxyflavonol (DiOHF) on anxiety-like behavior, and learning and memory were investigated in a model of transient global cerebral ischemia and reperfusion. METHODS: The animals were assigned to sham-operated, ischemia, and two DiOHF-treated (10 mg/kg i.p.) groups. DiOHF was administered at 1 hour before and immediately after the ischemia. Male rats were subjected to bilateral common carotid artery occlusion to induce acute cerebral ischemia for 20 minutes, followed by reperfusion for 7 days. The openfield, elevated plus maze (EPM), and Morris water maze tests were used to evaluate the effects of DiOHF treatment on ischemia-induced locomotor activity, anxiety-like behavior, and spatial and recognition memory impairments, respectively. RESULTS: In the open field test, locomotor activity in the ischemic rats was not altered 6 days after the ischemia, nor was anxiety-like behavior, which was evaluated with the EPM (P > 0.05). In the water-maze test, cerebral ischemia significantly decreased the exploration time in the target quadrant, and the platform crossing counts were lower (P < 0.05) in the probe trial test; this memory impairment was significantly improved by DiOHF applied 1 hour before and immediately after ischemia (P < 0.05). DISCUSSION: All together, these findings suggest that DiOHF reverses spatial learning and memory deficits resulting from transient global ischemia but has no significant effect on anxiety-like behavior.

Cyclophosphamide impairs hippocampus-dependent learning and memory in adult mice: Possible involvement of hippocampal neurogenesis in chemotherapy-induced memory deficits.

Cyclophosphamide (CYP) is an anti-neoplastic agent as well as an immunosuppressive agent. In order to elucidate the alteration in adult hippocampal function following acute CYP treatment, hippocampus-related behavioral dysfunction and changes in adult hippocampal neurogenesis in CYP-treated (intraperitoneally, 40 mg/kg) mice (8-10-week-old ICR) were analyzed using hippocampus-dependent learning and memory tasks (passive avoidance and object recognition memory test) and immunohistochemical markers of neurogenesis (Ki-67 and doublecortin (DCX)). Compared to the vehicle-treated controls, mice trained at 12h after CYP injection showed significant memory deficits in passive avoidance and the object recognition memory test. The number of Ki-67- and DCX-positive cells began to decrease significantly at 12h post-injection, reaching the lowest level at 24h after CYP injection; however, this reverted gradually to the vehicle-treated control level between 2 and 10 days. We suggest that the administration of a chemotherapeutic agent in adult mice interrupts hippocampal functions, including learning and memory, possibly through the suppression of hippocampal neurogenesis.

SLV330, a cannabinoid CB1 receptor antagonist, ameliorates deficits in the T-maze, object recognition and Social Recognition Tasks in rodents.

Cannabinoid CB(1) receptor (CB(1)R) signaling has been suggested to play an important role in the regulation of memory and cognition. In the present study, our aim was to investigate whether the CB(1)R antagonist SLV330 (doses ranging from 0.3 to 10mg/kg, given orally, p.o.) could ameliorate impairments in distinct aspects of cognition using different disruption models in both mice and rats. Effects of SLV330 were tested on working memory deficits in the T-maze Continuous Alternation Task (T-CAT) in mice; episodic memory deficits in the Object Recognition Task (ORT) and Social Recognition Task (SRT) in rats. The acetylcholinesterase inhibitor (AChEI) donepezil (Aricept, approved for symptomatic treatment of Alzheimer's disease) and nicotine were used as reference compounds. SLV330 markedly improved aging and scopolamine-induced memory deficits in the T-CAT in mice with a lowest effective dose (LED) of 1mg/kg p.o., while reversing the cognitive dysfunction induced by the N-methyl-D-aspartate (NMDA) antagonist dizocilpine (MK-801) only at the middle dose of 3mg/kg. In the ORT, we have found that combined administration of subthreshold doses of SLV330 (1mg/kg, p.o.) and the AChEI donepezil (0.1mg/kg, p.o.), that had no discernable effects on performance when given alone, enhanced memory performance in Wistar rats with deficits induced by the muscarinic antagonist scopolamine, suggestive of additive synergistic effects of SLV330 and donepezil on cognitive impairment. Finally, SLV330 was found to have cognition enhancing properties in a time delay paradigm in the SRT at a LED dose of 3mg/kg (p.o.). In conclusion, the CB(1)R antagonist SLV330 was found to clearly improve memory in several preclinical models for cognitive impairment.

MGlu5 antagonism impairs exploration and memory of spatial and non-spatial stimuli in rats.

Metabotropic glutamate receptor subtype 5 (mGlu5) has been implicated in memory processing in some but not all learning tasks. The reason why this receptor is involved in some tasks but not in others remains to be determined. The present experiments using rats examined effects of the mGlu5-antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP)--applied systemically i.p. (1-10mg/kg) or bilaterally into the prelimbic cortex (1-10 microg)---on the ability of rats to explore and remember new stimuli. A cross-maze, open field, and object recognition task were used to evaluate exploration and memory and it was found that: (1) locomotion during exploration of spatial environments and exploration time at novel objects were reduced by i.p. but not by prelimbic administration of MPEP, (2) spatial short-term memory was impaired in cross-maze and object discrimination was reduced after both types of administration, (3) long-term retention of spatial conditioning in the cross-maze was inhibited after i.p. applications which (4) also inhibited spontaneous alternation performance during maze-exploration. Reduced exploratory locomotion and exploration time after i.p. injections may have contributed to the observed retention impairments. However, the fact that prelimbic administration of MPEP inhibited retention without reducing exploration shows that memory formation was also impacted directly by prelimbic mGlu5 in both spatial and non-spatial learning.

Age-related vulnerability of pattern separation in C57BL/6J mice.

Aging is associated with impaired performance in behavioral pattern separation (PS) tasks based on similarities in object features and in object location. These deficits have been attributed to functional alterations in the dentate gyrus (DG)-CA3 region. Animal studies suggested a role of adult-born DG neurons in PS performance. The present study investigated the effect of aging in C57BL/6J mice performing PS tasks based on either object features or object location. At the age of 18 months or more, performance was severely impaired in both tasks. Spatial PS performance declined gradually over adult lifespan from 3 to 21 months. Subchronic treatment with the cognitive enhancer D-serine fully rescued spatial PS performance in 18-month-old mice and induced a modest increase in the number of 4-week-old adult-born cells in the DG. Performance of mice in these PS tasks shows an age dependence, which appears to translate well to that found in humans. This model should help in deciphering physiological changes underlying PS deficits and in identifying future therapeutic targets.

Male rats treated with subchronic PCP show intact olfaction and enhanced interest for a social odour in the olfactory habituation/dishabituation test.

The olfactory system participates in many sensory processes, and olfactory endophenotypes appear in a variety of neurological disorders such as Alzheimer's and Parkinson's disease, depression and schizophrenia. Social withdrawal is a core negative symptom of schizophrenia and animal models have proven to be invaluable for studying the neurobiological mechanisms and cognitive processes behind the formation of social relationships. The subchronic phencyclidine (PCP) rat model is a validated model for negative symptoms of schizophrenia, such as impaired sociability. However, the complete range of social behaviour and deficits in the model are still not fully understood. Intact rodent olfaction is essential for a wide range of social behaviour and disrupted olfactory function could have severe effects on social communication and recognition. In order to examine the olfactory ability of male rats treated with subchronic PCP, we conducted an olfactory habituation/dishabituation test including both non-social and social odours. The subchronic PCP-treated rats successfully recognized and discriminated among the odours, indicative of intact olfaction. Interestingly, the subchronic PCP-treated rats showed greater interest for a novel social odour compared to the saline-treated rats and the rationale remains to be elucidated. Our data indicate that subchronic PCP treatment does not disrupt olfactory function in male rats. By ruling out impaired olfaction as cause for the poor social interaction performance in subchronic PCP-treated rats, our data supports the use of NMDA receptor antagonists to model the negative symptoms of schizophrenia.

Hypericum perforatum chronic treatment affects cognitive parameters and brain neurotrophic factor levels.

OBJECTIVE: To evaluate the effects of Hypericum perforatum (hypericum) on cognitive behavior and neurotrophic factor levels in the brain of male and female rats. METHODS: Male and female Wistar rats were treated with hypericum or water during 28 days by gavage. The animals were then subjected to the open-field test, novel object recognition and step-down inhibitory avoidance test. Nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and glial cell-line derived neurotrophic factor (GDNF) levels were evaluated in the hippocampus and frontal cortex. RESULTS: Hypericum impaired the acquisition of short- and long-term aversive memory in male rats, evaluated in the inhibitory avoidance test. Female rats had no immediate memory acquisition and decreased short-term memory acquisition in the inhibitory avoidance test. Hypericum also decreased the recognition index of male rats in the object recognition test. Female rats did not recognize the new object in either the short-term or the long-term memory tasks. Hypericum decreased BDNF in the hippocampus of male and female rats. Hypericum also decreased NGF in the hippocampus of female rats. CONCLUSIONS: The long-term administration of hypericum appears to cause significant cognitive impairment in rats, possibly through a reduction in the levels of neurotrophic factors. This effect was more expressive in females than in males.

Performance of the odour span task is not impaired following inactivations of parietal cortex in rats.

Working memory (WM) is the ability to temporarily store information for use and manipulation. Working memory is thought to depend on a distributed set of higher cortical areas including the prefrontal and parietal cortex in primates while relatively little research has been conducted in rodents to elucidate the exact role of the parietal cortex (PC) in WM, particularly in relation to the construct of WM capacity. Previous work in our lab demonstrates that performance of the odour span task (OST), an olfactory incremental delayed nonmatching-to-sample task, relies on the medial prefrontal cortex (mPFC). However, the effects of inactivating the PC on the OST have not been studied. Therefore, the present experiment assessed the effects of inactivating the PC with the GABA receptor agonists muscimol/baclofen on performance of the OST. Infusions of muscimol/baclofen did not disrupt working memory performance, assessed by the mean number of odours each rat could remember before making an error on each day of testing. In contrast, performance of a positive control task, spontaneous cross-modal object recognition, was impaired by inactivating the PC. These results suggest that performance of the OST does not depend on the PC in rats. Our results are notable given past research demonstrating the importance of the parietal cortex for attentional processes and working memory in other tasks.

Reconsolidation of appetitive odor discrimination requires protein synthesis only when reactivation includes prediction error.

Reconsolidation theory has supported the notion that active memory is vulnerable to the effects of an amnesic agent. An extension of reconsolidation theory posits that active memory, while necessary for creating vulnerability in memory, is not sufficient. Prediction error (i.e., when expectation is inconsistent with reality) may be a key factor in the destabilization of memory. The present study examined the role of prediction error in appetitive memory reconsolidation. Rats learned to dig in cups of scented sand to retrieve buried sweet cereal rewards. Forty-eight hours following acquisition, a single reactivation trial was given during which a prediction error or no prediction error was included. The prediction error consisted of a single extinction trial, while the no prediction error condition consisted of an additional reinforced trial. Cycloheximide (CHX; 1 mg/kg) or vehicle (VEH: distilled water; 1 mg/kg) was administered intraperitoneally immediately following reactivation. One week following reactivation, rats received 2 nonreinforced test trials. Results showed longer latencies to dig for rats that received CHX following a prediction error (CHX/PE) compared to rats that received VEH (VEH/PE) or did not receive a prediction error (CHX/NoPE or VEH/NoPE). These results add to a growing literature demonstrating that protein synthesis is necessary in appetitive memory reconsolidation only when reactivation includes a prediction error. (PsycINFO Database Record

Change in Odor Identification Impairment is Associated with Improvement with Cholinesterase Inhibitor Treatment in Mild Cognitive Impairment.

BACKGROUND: Anticholinergic challenge can induce odor identification impairment that indicates Alzheimer's disease pathology. OBJECTIVE: To determine if decline in odor identification ability with anticholinergic challenge can predict improvement with donepezil, a cholinesterase inhibitor (ChEI), in patients with mild cognitive impairment (MCI). METHODS: At baseline, the University of Pennsylvania Smell identification Test (UPSIT) was administered before and after an anticholinergic atropine nasal spray challenge. Donepezil was started at 5 mg daily, increased to 10 mg daily if tolerated, and then the dose was kept constant for 52 weeks. Main outcomes were change in Selective Reminding Test (SRT) total immediate recall and ADAS-Cog total score from baseline to 26 and 52 weeks. RESULTS: In 37 participants, mean age 70.4 (SD 9.8) y, greater atropine-induced decrease in UPSIT score at baseline was associated with greater improvement in SRT total recall score from baseline to 26 and 52 weeks (p < 0.03). This effect remained after adjusting for time, age, education, gender, APOE ɛ4 status, and baseline cognitive score (p < 0.05). Decrease in UPSIT score was associated with global improvement (CIBIC-plus) over 52 weeks (p < 0.02). After excluding patients with congential anosmia, increase in UPSIT score from 0 to 8 weeks showed a trend-level association with improvement on the ADAS-Cog (p = 0.07). CONCLUSIONS: Anticholinergic challenge-induced odor identification decline was associated with cognitive improvement, and short-term improvement in odor identification tended to predict longer term cognitive improvement. These simple inexpensive strategies have the potential to improve selection of patients with MCI for ChEI treatment.

Low levels of chemical anthropogenic pollution may threaten amphibians by impairing predator recognition.

Recent studies suggest that direct mortality and physiological effects caused by pollutants are major contributing factors to global amphibian decline. However, even sublethal concentrations of pollutants could be harmful if they combined with other factors to cause high mortality in amphibians. Here we show that sublethal concentrations of pollutants can disrupt the ability of amphibian larvae to recognize predators, hence increasing their risk of predation. This effect is indeed much more important since very low amounts of pollutants are ubiquitous, and environmental efforts are mostly directed towards preventing lethal spills. We analyzed the effects of two common contaminants (humic acid and ammonium nitrate) on the ability of tadpoles of the western spadefoot toad (Pelobates cultripes) to recognize chemical cues from a common predator, nymphs of the dragonfly Anax imperator. We compared the swimming activity of tadpoles in the presence and absence of water-borne chemical cues from dragonflies at different concentrations of humic acid and ammonium nitrate. Tadpoles reduced swimming activity in response to predator cues in the absence of pollutants, whereas they remained unresponsive to these cues when either humic acid or ammonium nitrate was added to the water, even at low concentrations. Moreover, changes in tadpole activity associated with the pollutants themselves were non-significant, indicating no toxic effect. Alteration of the natural chemical environment of aquatic systems by pollutants may be an important contributing cause for declines in amphibian populations, even at sublethal concentrations.

Temporal decorrelation by SK channels enables efficient neural coding and perception of natural stimuli.

It is commonly assumed that neural systems efficiently process natural sensory input. However, the mechanisms by which such efficient processing is achieved, and the consequences for perception and behaviour remain poorly understood. Here we show that small conductance calcium-activated potassium (SK) channels enable efficient neural processing and perception of natural stimuli. Specifically, these channels allow for the high-pass filtering of sensory input, thereby removing temporal correlations or, equivalently, whitening frequency response power. Varying the degree of adaptation through pharmacological manipulation of SK channels reduced efficiency of coding of natural stimuli, which in turn gave rise to predictable changes in behavioural responses that were no longer matched to natural stimulus statistics. Our results thus demonstrate a novel mechanism by which the nervous system can implement efficient processing and perception of natural sensory input that is likely to be shared across systems and species.

Different dosing regimens of repeated ketamine administration have opposite effects on novelty processing in rats.

Repeated exposure to sub-anesthetic doses of ketamine in rats has been shown to induce cognitive deficits, as well as behavioral changes akin to the negative symptoms of schizophrenia, giving much face validity to the use of ketamine administration as a pharmacological model of schizophrenia. This study sought to further characterize the behavioral effects of two different ketamine pre-treatment regimens, focusing primarily on the effects of repeated ketamine administration on novelty processing, a capacity that is disrupted in schizophrenia. Rats received 5 or 14 intra-peritoneal injections of 30mg/kg ketamine or saline across 5 or 7days, respectively. They were then tested in an associative mismatch detection task to examine their ability to detect novel configurations of familiar audio-visual sequences. Furthermore, rats underwent a sequential novel object and novel object location exploration task. Subsequently, rats were also tested on the delayed matching to place T-maze task, sucrose preference task and locomotor tests involving administering a challenge dose of amphetamine (AMPH). The high-dose ketamine pre-treatment regimen elicited impairments in mismatch detection and working memory. In contrast, the low-dose ketamine pre-treatment regimen improved performance of novelty detection. In addition, low-dose ketamine pre-treated rats showed locomotor sensitization following an AMPH challenge, while the high-dose ketamine pre-treated rats showed an attenuated locomotor response to AMPH, compared to control rats. These findings demonstrate that different regimens of repeated ketamine administration induce alterations in novelty processing in opposite directions, and that differential neural adaptations occurring in the mesolimbic dopamine system may underlie these effects.

BDNF in the dentate gyrus is required for consolidation of "pattern-separated" memories.

Successful memory involves not only remembering information over time, but also keeping memories distinct and less confusable. The computational process for making representations for similar input patterns more distinct from each other has been referred to as "pattern separation." In this work, we developed a set of behavioral conditions that allowed us to manipulate the load for pattern separation at different stages of memory. Thus, we provide experimental evidence that a brain-derived neurotrophic factor (BDNF)-dependent pattern separation process occurs during the encoding/storage/consolidation, but not the retrieval stage of memory processing. We also found that a spontaneous increase in BDNF in the dentate gyrus of the hippocampus is associated with exposure to landmarks delineating similar, but not dissimilar, spatial locations, suggesting that BDNF is expressed on an "as-needed" basis for pattern separation.