Impaired Object Recognition Research Articles

Prolonged reversal of the phencyclidine-induced impairment in novel object recognition by a serotonin (5-HT)1A-dependent mechanism

Many acute treatments transiently reverse the deficit in novel object recognition (NOR) produced by subchronic treatment with the N-methyl-d-aspartate receptor non-competitive antagonist, phencyclidine (PCP), in rodents. Treatments which restore NOR for prolonged periods after subchronic PCP treatment may have greater relevance for treating the cognitive impairment in schizophrenia than those which restore NOR transiently. We examined the ability of post-PCP subchronic lurasidone, an atypical APD with potent serotonin (5-HT)1A partial agonism and subchronic tandospirone, a selective 5-HT1A partial agonist, to enable prolonged reversal of the subchronic PCP-induced NOR deficit. Rats treated with subchronic PCP (2mg/kg, twice daily for 7 days) or vehicle, followed by a 7day washout period were subsequently administered lurasidone or tandospirone twice daily for 7 days (day 15–21), and tested for NOR weekly for up to two additional weeks. Subchronic lurasidone (1, but not 0.1mg/kg) or tandospirone (5, but not 0.6mg/kg) significantly reversed the PCP-induced NOR deficit at 24h and 7days after the last injection, respectively. The effect of lurasidone persisted for one more week (day 36, 14 days after the last lurasidone dose), while tandospirone-treated rats were able to perform NOR at 7, but not 14, days after the last tandospirone dose. Co-administration of WAY100635 (0.6mg/kg), a 5-HT1A antagonist, with lurasidone, blocked the ability of lurasidone to restore NOR, suggesting that 5-HT1A receptor stimulation is necessary for lurasidone to reverse the effects of PCP. The role of dopamine, GABA and the MAPK/ERK signalling pathway in the persistent, but not indefinite, restoration of NOR is discussed.

Ventral simultanagnosia and prosopagnosia for unfamiliar faces due to a right posterior superior temporal sulcus and angular gyrus lesion

We report a patient with ventral simultanagnosia, prosopagnosia for “unfamiliar faces” (dorsal prosopagnosia), spatial agraphia, and constructional disorder, particularly on the left spatial side, due to a lesion in the right posterior superior and middle temporal gyri and angular gyrus. The patient showed impairment of fundamental visual and visuospatial recognition, such as in object size, configuration, and horizontal point location, which probably underlay the mechanism of simultanagnosia and prosopagnosia. This case also suggests that the coexistence of simultanagnosia and prosopagnosia results from a right hemispheric insult, and damage to the temporoparietal area interrupts the incorporation of spatial information into object recognition. This disconnection of information flow, together with impaired object recognition per se, may impair the parallel processing of multiple objects, leading to object-by-object or part-by-part recognition.

The group II metabotropic glutamate receptor agonist LY379268 reduces toluene-induced enhancement of brain-stimulation reward and behavioral disturbances.

Toluene, a widely abused solvent with demonstrated addictive potential in humans, hasbeen reported to negatively modulate N-methyl-D-aspartate receptors (NMDARs) and alter glutamatergicneurotransmission. The group II metabotropic glutamate receptor (mGluR) agonist LY379268 has beenshown to regulate glutamate release transmission and NMDAR function and block toluene-induced locomotorhyperactivity. However, remaining unknown is whether group II mGluRs are involved in the toluene-induced reward-facilitating effect and other behavioral manifestations. The present study evaluated the effects of LY379268 on toluene-induced reward enhancement, motor incoordination, recognition memory impairment, and social interaction deficits. Our data demonstrated that LY379268 significantly reversed the toluene-induced lowering of intracranial self-stimulation (ICSS) thresholds and impairments in novel object recognition, rotarod performance, and social interaction with different potencies. These results indicate a negative modulatory role of group II mGluRs in acute toluene-induced reward-facilitating and behavioral effects and suggest that group II mGluR agonists may have therapeutic potential for toluene addiction and the prevention of toluene intoxication caused by occupational or intentional exposure.

Therapeutic hypothermia and hypoxia-ischemia in the term-equivalent neonatal rat: characterization of a translational preclinical model.

BackgroundHypoxic-ischemic encephalopathy (HIE) is a major cause of morbidity in survivors. Therapeutic hypothermia (TH) is the only available intervention, but the protection is incomplete. Preclinical studies of HIE/TH in the rodent have relied on the postnatal day (P) 7 rat whose brain approximates a 32–36 week gestation infant, less relevant for these studies. We propose that HIE and TH in the term-equivalent P10 rat will be more translational.MethodsP10–11 rat pups were subjected to unilateral hypoxia-ischemia (HI) and 4 hours recovery in normothermic (N) or hypothermic (TH) conditions. Brain damage was assessed longitudinally at 24 hours, 2 and 12 weeks. Motor function was assessed with the beam walk; recognition memory was measured by novel object recognition.ResultsNeuroprotection with TH was apparent at 2 and 12 weeks in both moderately and severely damaged animals. TH improved motor function in moderate, but not severe damage. Impaired object recognition occurred with severe damage with no evidence of protection of TH.ConclusionThis adaptation of the immature rat model of HI provides a reproducible platform to further study HIE/TH in which individual animals are followed longitudinally to provide a useful translational preclinical model.

Psychosocial predator-based animal model of PTSD produces physiological and behavioral sequelae and a traumatic memory four months following stress onset

We have a well-established animal model of PTSD composed of predator exposure administered in conjunction with social instability that produces PTSD-like behavioral and physiological abnormalities one month after stress initiation. Here, we assessed whether the PTSD-like effects would persist for at least 4months after the initiation of the psychosocial stress regimen. Adult male Sprague–Dawley rats were exposed to either 2 or 3 predator-based fear conditioning sessions. During each session, rats were placed in a chamber for a 3-min period that terminated with a 30-s tone, followed by 1h of immobilization of the rats during cat exposure (Day 1). All rats in the stress groups received a second fear conditioning session 10days later (Day 11). Half of the stress rats received a third fear conditioning session 3weeks later (Day 32). The two cat-exposed groups were also exposed to daily unstable housing conditions for the entire duration of the psychosocial stress regimen. The control group received stable (conventional) housing conditions and an equivalent amount of chamber exposure on Days 1, 11 and 32, without cat exposure. Behavioral testing commenced for all groups on Day 116. The stress groups demonstrated increased anxiety on the elevated plus maze, impaired object recognition memory and robust contextual and cued fear conditioned memory 3months after the last conditioning session. Combined data from the two stress groups revealed lower post-stress corticosterone levels and greater diastolic blood pressure relative to the control group. These findings indicate that predator-based psychosocial stress produces persistent PTSD-like physiological and behavioral abnormalities that may provide insight into the neurobiological and endocrine sequelae in traumatized people with PTSD.

Do I know you? Examining face and object memory in frontotemporal dementia

The ability to perceive, learn and recognise faces is a complex ability, which is key to successful social interactions. This ability is proposed to be coordinated by neural regions in the occipital and temporal lobes, specialised for face perception and memory. While previous studies have suggested that memory for faces is compromised in some dementia syndromes, it remains unclear whether this simply reflects more generalised memory deficits. Here, we examined basic face perception (Identity-Matching), face recognition (Cambridge Face Memory Task) and object recognition (Cambridge Car Memory Task) in 11 semantic dementia (SD) patients (8 left-lateralised, 3 right-lateralised) and 13 behavioural-variant frontotemporal dementia (bvFTD) patients, compared with 11 controls. On the Identity-Matching task, bvFTD were impaired compared to controls, with a similar trend observed in the SD group. Importantly, both bvFTD and SD also demonstrated impaired face recognition. In contrast, only bvFTD showed impaired object recognition, with SD performing within normal limits on this task. Voxel-based morphometry analyses revealed that Identity-Matching and face recognition were associated with partly dissociable regions including the fusiform cortex and anterior temporal lobe. Object-memory was associated with thalamic integrity in the bvFTD group only. These results reveal that face perception and face memory deficits are common in bvFTD and SD, and have been previously underestimated. These deficits are due to neurodegeneration of key regions within the ‘core’ and ‘extended’ face processing system, providing convergent evidence of the neural regions supporting face perception. From a clinical perspective, impaired ability to recognise faces is common in bvFTD and SD and therefore strategies to improve face perception and memory may be beneficial for these patients.

Impairments in cognition and neural precursor cell proliferation in mice expressing constitutively active glycogen synthase kinase-3.

Brain glycogen synthase kinase-3 (GSK3) is hyperactive in several neurological conditions that involve impairments in both cognition and neurogenesis. This raises the hypotheses that hyperactive GSK3 may directly contribute to impaired cognition, and that this may be related to deficiencies in neural precursor cells (NPC). To study the effects of hyperactive GSK3 in the absence of disease influences, we compared adult hippocampal NPC proliferation and performance in three cognitive tasks in male and female wild-type (WT) mice and GSK3 knockin mice, which express constitutively active GSK3. NPC proliferation was ~40% deficient in both male and female GSK3 knockin mice compared with WT mice. Environmental enrichment (EE) increased NPC proliferation in male, but not female, GSK3 knockin mice and WT mice. Male and female GSK3 knockin mice exhibited impairments in novel object recognition, temporal order memory, and coordinate spatial processing compared with gender-matched WT mice. EE restored impaired novel object recognition and temporal ordering in both sexes of GSK3 knockin mice, indicating that this repair was not dependent on NPC proliferation, which was not increased by EE in female GSK3 knockin mice. Acute 1 h pretreatment with the GSK3 inhibitor TDZD-8 also improved novel object recognition and temporal ordering in male and female GSK3 knockin mice. These findings demonstrate that hyperactive GSK3 is sufficient to impair adult hippocampal NPC proliferation and to impair performance in three cognitive tasks in both male and female mice, but these changes in NPC proliferation do not directly regulate novel object recognition and temporal ordering tasks.

Binge ethanol exposure during adolescence leads to a persistent loss of neurogenesis in the dorsal and ventral hippocampus that is associated with impaired adult cognitive functioning.

Adolescence is a developmental period that coincides with the maturation of adult cognitive faculties. Binge drinking is common during adolescence and can impact brain maturation. Using a rodent model of adolescent intermittent ethanol (AIE; 5.0 g/kg, i.g., 20% EtOH w/v; 2 days on/2 days off from postnatal day [P]25 to P55), we discovered that AIE treatment reduced neurogenesis (i.e., doublecortin-immunoreactive [DCX + IR] cells) in both the dorsal and ventral hippocampal dentate gyrus of late adolescent (P56) male Wistar rats that persisted during abstinence into adulthood (P220). This reduction in neurogenesis was accompanied by a concomitant reduction in proliferating cells (Ki-67) and an increase in cell death (cleaved caspase-3). In the hippocampus, AIE treatment induced a long-term upregulation of neuroimmune genes, including Toll-like receptor 4 (TLR4) and its endogenous agonist high-mobility group box 1 as well as several proinflammatory signaling molecules. Administration of lipopolysaccharide, a gram-negative endotoxin agonist at TLR4, to young adult rats (P70) produced a similar reduction of DCX + IR cells that was observed in AIE-treated animals. Behaviorally, AIE treatment impaired object recognition on the novel object recognition task when assessed from P163 to P165. Interestingly, object recognition memory was positively correlated with DCX + IR in both the dorsal and ventral hippocampal dentate gyrus while latency to enter the center of the apparatus was negatively correlated with DCX + IR in the ventral dentate gyrus. Together, these data reveal that adolescent binge ethanol exposure persistently inhibits neurogenesis throughout the hippocampus, possibly through neuroimmune mechanisms, which might contribute to altered adult cognitive and emotive function.

Hippocampal Infusion of Zeta Inhibitory Peptide Impairs Recent, but Not Remote, Recognition Memory in Rats.

Spatial memory in rodents can be erased following the infusion of zeta inhibitory peptide (ZIP) into the dorsal hippocampus via indwelling guide cannulas. It is believed that ZIP impairs spatial memory by reversing established late-phase long-term potentiation (LTP). However, it is unclear whether other forms of hippocampus-dependent memory, such as recognition memory, are also supported by hippocampal LTP. In the current study, we tested recognition memory in rats following hippocampal ZIP infusion. In order to combat the limited targeting of infusions via cannula, we implemented a stereotaxic approach for infusing ZIP throughout the dorsal, intermediate, and ventral hippocampus. Rats infused with ZIP 3–7 days after training on the novel object recognition task exhibited impaired object recognition memory compared to control rats (those infused with aCSF). In contrast, rats infused with ZIP 1 month after training performed similar to control rats. The ability to form new memories after ZIP infusions remained intact. We suggest that enhanced recognition memory for recent events is supported by hippocampal LTP, which can be reversed by hippocampal ZIP infusion.

Left Tactile Agnosia Amelioration by Prism Adaptation Sustains Unilateral Spatial Neglect-Based Hypothesis

Objective: Left tactile agnosia has never been described as part of the neglect syndrome so far. We observed two patients with left tactile agnosia, following a right hemisphere stroke and test if impairment in their unilateral tactile object recognition could be due to Unilateral Spatial Neglect. Method: patients were submitted to three different experimental tests assessing the tactile recognition of micro and macro structural characteristics of shapes, the number of hands' explorative movements and the effects of prism adaptation on tactile object recognition impairment. Results: patients showed a left tactile agnosia, which was neither related to impairment in microstructural nor macrostructural recognition of shapes. Similarly to controls, patients performed more exploratory movements with the left hand, which resulted to be impaired in object recognition, suggesting that tactile apraxia was not the cause of this tactile agnosia. After 10 days treatment with prism adaptation procedure, both neglect symptoms and left tactile agnosia improved. Conclusions: The absence of other causes of left tactile agnosia and the efficacy of prism adaptation on it, support the functional relation between tactile agnosia and tactile neglect.

Evidence for a specific role for muscarinic receptors in crossmodal object recognition in rats

Acetylcholine (ACh) has been implicated in numerous cognitive functions, including multisensory feature binding. In the present study, we systematically assessed the involvement of cholinergic muscarinic receptors in several variations of an object recognition task for rats. In the standard spontaneous object recognition (SOR) task, tactile and visual properties of objects were freely available throughout the sample and choice phases. In the tactile- and visual-only unimodal SOR tasks, exploration in both phases was restricted to tactile and visual information, respectively. For the basic crossmodal object recognition (CMOR) task, sample object exploration was limited to tactile features, whereas choice objects were available only in the visual domain. In Experiment 1, pre-sample systemic administration of scopolamine (0.2mg/kg) disrupted performance on standard SOR, both unimodal SOR tasks, and basic CMOR, consistent with a role for muscarinic receptors in memory encoding. Conversely, in Experiment 2, pre-choice systemic scopolamine selectively impaired object recognition on the CMOR task. For Experiment 3, the inclusion of multimodal, but not unimodal pre-exposure to the to-be-remembered objects prevented scopolamine from disrupting performance on the CMOR task when given prior to the choice phase. These results suggest that ACh is necessary during the choice phase of the CMOR task to facilitate the binding of object features across sensory modalities, a function that is not required for the other tasks assessed. Multimodal object pre-exposure might preclude the requisite contribution of ACh in the choice phase by allowing rats to bind important visual and tactile object information prior to testing.

α4β2 nicotinic receptor stimulation of the GABAergic system within the orbitofrontal cortex ameliorates the severe crossmodal object recognition impairment in ketamine-treated rats: Implications for cognitive dysfunction in schizophrenia

Schizophrenia is associated with atypical multisensory integration. Rats treated sub-chronically with NMDA receptor antagonists to model schizophrenia are severely impaired on a tactile-to-visual crossmodal object recognition (CMOR) task, and this deficit is reversed by systemic nicotine. The current study assessed the receptor specificity of the ameliorative effect of nicotine in the CMOR task, as well as the potential for nicotinic receptor (nAChR) interactions with GABA and glutamate. Male Long-Evans rats were treated sub-chronically for 10 days with ketamine or saline and then tested on the CMOR task after a 10-day washout. Systemic nicotine given before the sample phase of the CMOR task reversed the ketamine-induced impairment, but this effect was blocked by co-administration of the GABAA receptor antagonist bicuculline at a dosage that itself did not cause impairment. Pre-sample systemic co-administration of the NMDA receptor antagonist MK-801 did not block the remediating effect of nicotine in ketamine-treated rats. The selective α7 nAChR agonist GTS-21 and α4β2 nAChR agonist ABT-418 were also tested, with only the latter reversing the ketamine impairment dose-dependently; bicuculline also blocked this effect. Similarly, infusions of nicotine or ABT-418 into the orbitofrontal cortex (OFC) reversed the CMOR impairment in ketamine-treated rats, and systemic bicuculline blocked the effect of intra-OFC ABT-418. These results suggest that nicotine-induced agonism of α4β2 nAChRs within the OFC ameliorates CMOR deficits in ketamine-treated rats via stimulation of the GABAergic system. The findings of this research may have important implications for understanding the nature and potential treatment of cognitive impairment in schizophrenia.

Combined serotonin (5-HT)1A agonism, 5-HT2A and dopamine D2 receptor antagonism reproduces atypical antipsychotic drug effects on phencyclidine-impaired novel object recognition in rats

Subchronic administration of an N-methyl-d-aspartate receptor (NMDAR) antagonist, e.g. phencyclidine (PCP), produces prolonged impairment of novel object recognition (NOR), suggesting they constitute a hypoglutamate-based model of cognitive impairment in schizophrenia (CIS). Acute administration of atypical, e.g. lurasidone, but not typical antipsychotic drugs (APDs), e.g. haloperidol, are able to restore NOR following PCP (acute reversal model). Furthermore, atypical APDs, when co-administered with PCP, have been shown to prevent development of NOR deficits (prevention model). Most atypical, but not typical APDs, are more potent 5-HT2A receptor inverse agonists than dopamine (DA) D2 antagonists, and have been shown to enhance cortical and hippocampal efflux and to be direct or indirect 5-HT1A agonists in vivo. To further clarify the importance of these actions to the restoration of NOR by atypical APDs, sub-effective or non-effective doses of combinations of the 5-HT1A partial agonist (tandospirone), the 5-HT2A inverse agonist (pimavanserin), or the D2 antagonist (haloperidol), as well as the combination of all three agents, were studied in the acute reversal and prevention PCP models of CIS. Only the combination of all three agents restored NOR and prevented the development of PCP-induced deficit. Thus, this triple combination of 5-HT1A agonism, 5-HT2A antagonism/inverse agonism, and D2 antagonism is able to mimic the ability of atypical APDs to prevent or ameliorate the PCP-induced NOR deficit, possibly by stimulating signaling cascades from D1 and 5-HT1A receptor stimulation, modulated by D2 and 5-HT2A receptor antagonism.

Beta2 oscillations (23-30Hz) in the mouse hippocampus during novel object recognition.

The oscillatory activity of hippocampal neuronal networks is believed to play a role in memory acquisition and consolidation. Particular focus has been given to characterising theta (4-12Hz), gamma (40-100Hz) and ripple (150-250Hz) oscillations. Beyond these well-described network states, few studies have investigated hippocampal beta2 (23-30Hz) activity in vivo and its link to behaviour. A previous sudy showed that the exploration of novel environments may lead to the appearance of beta2 oscillations in the mouse hippocampus. In the present study we characterised hippocampal beta2 oscillations in mice during an object recognition task. We found prominent bursts of beta2 oscillations in the beginning of novel exploration sessions (four new objects), which could be readily observed by spectral analysis and visual inspection of local field potentials. Beta2 modulated hippocampal but not neocortical neurons and its power decreased along the session. We also found increased beta2 power in the beginning of a second exploration session performed 24h later in a slightly modified environment (two new, two familiar objects), but to a lesser extent than in the first session. However, the increase in beta2 power in the second exploration session became similar to the first session when we pharmacologically impaired object recognition in a new set of experiments performed 1week later. Our results suggest that hippocampal beta2 activity is associated with a dynamic network state tuned for novelty detection and which may allow new learning to occur.

Effect of miroestrol on ovariectomy-induced cognitive impairment and lipid peroxidation in mouse brain

Miroestrol (MR) is a phytoestrogen isolated from Pueraria candollei var. mirifica (KwaoKrueaKhao), a Thai medicinal plant used for rejuvenation. We examined the effects of MR on cognitive function, oxidative brain damage, and the expression of genes encoding brain-derived neurotrophic factor (BDNF) and cyclic AMP-responsive element-binding protein (CREB), factors implicated in neurogenesis and synaptic plasticity, in ovariectomized (OVX) mice. OVX decreased serum 17β-estradiol level and uterine weight. OVX also impaired object recognition performance in the novel object recognition test and spatial cognitive performance in the Y-maze test and the water maze test. Daily treatment of MR dose-dependently attenuated OVX-induced cognitive dysfunction. Moreover, OVX mice had a significantly increased level of thiobarbituric acid-reactive substances, and down-regulated expression levels of BDNF and CREB mRNAs in the hippocampus and frontal cortex. MR treatment as well as hormone replacement therapy with 17β-estradiol significantly reversed these neurochemical alterations caused by OVX. These results suggest that MR ameliorates cognitive deficits in OVX animals via attenuation of OVX-induced oxidative stress and down-regulation of BDNF and CREB mRNA transcription in the brain. Our findings raise the possibility that MR and Pueraria candollei var. mirifica, the plant of origin of MR, may have a beneficial effect on cognitive deficits like AD in which menopause/ovariectomy are implicated as risk factors.

Brexpiprazole II: antipsychotic-like and procognitive effects of a novel serotonin-dopamine activity modulator.

Brexpiprazole (OPC-34712, 7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}quinolin-2(1H)-one) is a novel serotonin-dopamine activity modulator with partial agonist activity at serotonin 1A (5-HT1A) and D2/3 receptors, combined with potent antagonist effects on 5-HT2A, α1B-, and α2C-adrenergic receptors. Brexpiprazole inhibited conditioned avoidance response (ED50 = 6.0 mg/kg), apomorphine- or d-amphetamine-induced hyperactivity (ED50 = 2.3 and 0.90, respectively), and apomorphine-induced stereotypy (ED50 = 2.9) in rats at clinically relevant D2 receptor occupancies. Brexpiprazole also potently inhibited apomorphine-induced eye blinking in monkeys. The results suggest that brexpiprazole has antipsychotic potential. Brexpiprazole induced catalepsy (ED50 = 20) well above clinically relevant D2 receptor occupancies, suggesting a low risk for extrapyramidal side effects. Subchronic treatment with phencyclidine (PCP) induced cognitive impairment in both novel object recognition (NOR) and attentional set-shifting (ID-ED) tests in rats. Brexpiprazole reversed the PCP-induced cognitive impairment in the NOR test at 1.0 and 3.0 mg/kg, and in the ID-ED test at 1.0 mg/kg. However, aripiprazole (10 mg/kg) was ineffective in both tests, despite achieving relevant D2 occupancies. In the NOR test, the 5-HT1A agonist buspirone and the 5-HT2A antagonist M100907 [(R)-(2,3-dimethoxyphenyl)[1-(4-fluorophenethyl)piperidin-4-yl]methanol] partially but significantly reversed PCP-induced impairment. Furthermore, the effect of brexpiprazole was reversed by cotreatment with the 5-HT1A antagonist WAY100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide maleate). The results indicate that brexpiprazole has antipsychotic-like activity and robust efficacy in relevant models of cognitive impairment associated with schizophrenia. The effects of brexpiprazole in the cognitive tests are superior to those of aripiprazole. We propose that the pharmacologic profile of brexpiprazole be based on its balanced effects on 5-HT1A, D2, and 5-HT2A receptors, with possible modulating activity through additional monoamine receptors.

A modified controlled cortical impact technique to model mild traumatic brain injury mechanics in mice.

For the past 25 years, controlled cortical impact (CCI) has been a useful tool in traumatic brain injury (TBI) research, creating injury patterns that includes primary contusion, neuronal loss, and traumatic axonal damage. However, when CCI was first developed, very little was known on the underlying biomechanics of mild TBI. This paper uses information generated from recent computational models of mild TBI in humans to alter CCI and better reflect the biomechanical conditions of mild TBI. Using a finite element model of CCI in the mouse, we adjusted three primary features of CCI: the speed of the impact to achieve strain rates within the range associated with mild TBI, the shape, and material of the impounder to minimize strain concentrations in the brain, and the impact depth to control the peak deformation that occurred in the cortex and hippocampus. For these modified cortical impact conditions, we observed peak strains and strain rates throughout the brain were significantly reduced and consistent with estimated strains and strain rates observed in human mild TBI. We saw breakdown of the blood–brain barrier but no primary hemorrhage. Moreover, neuronal degeneration, axonal injury, and both astrocytic and microglia reactivity were observed up to 8 days after injury. Significant deficits in rotarod performance appeared early after injury, but we observed no impairment in spatial object recognition or contextual fear conditioning response 5 and 8 days after injury, respectively. Together, these data show that simulating the biomechanical conditions of mild TBI with a modified cortical impact technique produces regions of cellular reactivity and neuronal loss that coincide with only a transient behavioral impairment.

Postoperative cognitive dysfunction depends on the type of surgery (684.6)

The risk of postoperative cognitive dysfunction (POCD) is higher after cardiac surgery compared to non‐cardiac surgery. The objective of this study was to compare POCD after cardiac and non‐cardiac surgery in rats as tool to study the underlying mechanisms.Male Wistar rats received abdominal surgery with ischemia‐reperfusion (i.r.) of the upper mesenteric artery (A‐S, n=12) or cardiac surgery with i.r. of the left coronary artery (MI‐S, n=12). Controls remained naive (C: n=12), received only anesthesia (A: n=12) or sham thorax surgery (T‐S, n=12). Weight loss accounted for severity of surgery. On postoperative day 10 to 14, cognition was assessed in the novel object and location test and Morris water maze (MWM).Location recognition was impaired in A‐S and MI‐S. Only A‐S displayed impaired spatial memory in the MWM, whereas only MI‐S displayed impaired object recognition and cognitive flexibility in the MWM. T‐S or A did not cause any cognitive impairment. All surgical procedures induced weight loss. MI‐S lost more weight than A‐S.Abdominal surgery only impaired spatial cognition, whereas cardiac surgery led to a more generalized cognitive dysfunction, indicating POCD depends on the type of surgery. Analysis of (neuro)inflammatory markers may reveal the basis of these findings and thus provide valuable insight in the mechanisms underlying POCD.

Postoperative cognitive dysfunction: effects of previous pathology (684.7)

Surgery patients may experience postoperative cognitive dysfunction (POCD), potentially depending on age and pre‐operative health status. The study objective was to research the effect of prior infection on POCD in aged rats.Cognitive function after abdominal surgery was compared between healthy aged (AH, 18 months) and aged rats that had recovered from an active mycoplasma infection (AI). Healthy young rats (YH, 3 months) and un‐operated rats served as control. Cognition was assessed 10 ‐ 14 days post‐surgery in the novel object ( NO) and location (NL) test and the Morris water maze (MWM).Cognitive performance of AH was comparable to YH. In these groups surgery only led to a decline in spatial memory. AI showed impaired spatial learning and memory and impaired cognitive flexibility compared to YH, which was further impaired following surgery. Additionally, surgery led to impaired object recognition in AI. Velocity in the MWM did not differ significantly between groups.Age in itself did not lead to cognitive impairment. In healthy young and aged rats abdominal surgery only impaired spatial, hippocampal dependent, cognition. Prior infection however caused cognitive impairment and more generalized and severe POCD in aged rats, indicating that patients with a history of infection may be more prone to develop POCD. Analysis of (neuro)inflammatory markers may provide insight in the influence of prior infection on POCD.

Elevation of endogenous anandamide impairs LTP, learning, and memory through CB1 receptor signaling in mice

In rodents, many exogenous and endogenous cannabinoids, such as anandamide (AEA) and 2-arachidonyl glycerol (2-AG), have been shown to play an important role in certain hippocampal memory processes. However, the mechanisms by which endogenous AEA regulate this processes are not well understood. Here the effects of AEA on long-term potentiation (LTP), hippocampal-dependent learning and memory tasks, pERK1/2, pCaMKIV, and pCREB signaling events in both cannabinoid receptor type 1 (CB1R) wild-type (WT) and knockout (KO) mice were assessed following administration of URB597, an inhibitor of the fatty acid amide hydrolase (FAAH). Acute administration of URB597 enhanced AEA levels without affecting the levels of 2-AG or CB1R in the hippocampus and neocortex as compared to vehicle. In hippocampal slices, URB597 impaired LTP in CB1R WT but not in KO littermates. URB597 impaired object recognition, spontaneous alternation and spatial memory in the Y-maze test in CB1R WT mice but not in KO mice. Furthermore, URB597 enhanced ERK phosphorylation in WT without affecting total ERK levels in WT or KO mice. URB597 impaired CaMKIV and CREB phosphorylation in WT but not in KO mice. CB1R KO mice have a lower pCaMKIV/CaMKIV ratio and higher pCREB/CREB ratio as compared to WT littermates. Our results indicate that pharmacologically elevated AEA impair LTP, learning and memory and inhibit CaMKIV and CREB phosphorylation, via the activation of CB1Rs. Collectively, these findings also suggest that pharmacological elevation of AEA beyond normal concentrations is also detrimental for the underlying physiological responses.