Impairment Of Novel Object Recognition Research Articles

Low-Dose Interleukin-2 Reverses Traumatic Brain Injury-Induced Cognitive Deficit and Pain.

Despite the high prevalence, mild traumatic brain injury (mTBI)-induced chronic headache and cognitive deficits are poorly understood and lack effective treatments. Low-dose interleukin-2 (LD-IL-2) treatment soon after mTBI or overexpressing IL-2 in brain astrocytes prior to injury protects mice from developing post-traumatic headache (PTH)-related behaviors and cognitive decline. The present study addresses a clinically relevant knowledge gap: whether LD-IL-2 treatment long after the initial injury is still effective for chronic PTH and cognitive deficits. mTBI was induced by a noninvasive closed-head weight drop method. LD-IL-2 was administered 4-6 weeks post-mTBI to assess its effects on chronic PTH-related facial mechanical hypersensitivity as well as mTBI-induced impairment in novel object recognition and object location tests. Endogenous regulatory T (Treg) cells were depleted to investigate the mechanism of action of LD-IL-2. Delayed LD-IL-2 treatment abolished chronic PTH-related behaviors. It also completely reversed mTBI-induced cognitive impairment in both male and female mice. Treg cell depletion not only prolonged PTH-related behaviors but also abolished the effects of LD-IL-2. Interestingly, LD-IL-2 treatment significantly increased the number of Treg cells in dura but not in brain tissues. These results suggest that the beneficial effects of LD-IL-2 treatment are mediated through the expansion of meningeal Treg cells. Collectively, our study identifies Treg as a cellular target and LD-IL-2 as a promising therapy for both chronic PTH and mTBI-induced cognitive impairment for both males and females, with a wide therapeutic time window and the potential of reducing polypharmacy in mTBI treatment. ANN NEUROL 2024.

Acute physical exercise prevents memory amnesia caused by protein synthesis inhibition in rats' hippocampus

The benefits of physical exercise (PE) on memory consolidation have been well-documented in both healthy and memory-impaired animals. However, the underlying mechanisms through which PE exerts these effects are still unclear. In this study, we aimed to investigate the role of hippocampal protein synthesis in memory modulation by acute PE in rats. After novel object recognition (NOR) training, rats were subjected to a 30-min moderate-intensity acute PE on the treadmill, while control animals did not undergo any procedures. Using anisomycin (ANI) and rapamycin (RAPA), compounds that inhibit protein synthesis through different mechanisms, we manipulated protein synthesis in the CA1 region of the hippocampus to examine its contribution to memory consolidation. Memory was assessed on days 1, 7, and 14 post-training. Our results showed that inhibiting protein synthesis by ANI or RAPA impaired NOR memory consolidation in control animals. However, acute PE prevented this impairment without affecting memory persistence. We also evaluated brain-derived neurotrophic factor (BDNF) levels after acute PE at 0.5h, 2h, and 12h afterward and found no differences in levels compared to animals that did not engage in acute PE or were only habituated to the treadmill. Therefore, our findings suggest that acute PE could serve as a non-pharmacological intervention to enhance memory consolidation and prevent memory loss in conditions associated with hippocampal protein synthesis inhibition. This mechanism appears not to depend on BDNF synthesis in the early hours after exercise.

Astaxanthin and DHA Supplementation Modulates the Maternal Undernutrition-induced Impairment of Cognitive Behavior and Synaptic Plasticity in Adult Life of Offspring's -Exploring the Molecular Mechanism.

Maternal nutrition was recognized as a significant part of brain growth and maturation in most mammalian species. Timely intervention with suitable nutraceuticals would provide long-term health benefits. We aim to unravel the molecular mechanisms of perinatal undernutrition-induced impairments in cognition and synaptic plasticity, employing animal model based on dietary nutraceutical supplementation. We treated undernourished dams at their gestational, lactational, and at both the time point with Astaxanthin (AsX) and Docosahexaenoic acid (DHA), and their pups were used as experimental animals. We evaluated the cognitive function by subjecting the pups to behavioral tests in their adult life. In addition, we assessed the expression of genes in the hippocampus related to cognitive function and synaptic plasticity. Our results showed downregulation of Brain-derived neurotrophic factor (BDNF), Neurotrophin-3 (NT-3), cAMP response-element-binding protein (CREB), and uncoupling protein-2 (UCP2) gene expression in pups born to undernourished dams in their adult life, which AsX and DHA modulated. Maternal AsX and DHA supplementation ameliorated the undernutrition-induced learning impairment in novel object recognition (NOR) tests and partially baited radial arm maze (RAM) tasks in offspring's. The expressions of Synapsin-1 and PSD-95 decreased in perinatally undernourished groups compared to control and AsX-DHA treated groups at CA1, CA2, CA3, and DG. AsX and DHA supplementation upregulated BDNF, NT-3, CREB, and UCP2 gene expressions in perinatally undernourished rats, which are involved in intracellular signaling cascades like Ras, PI3K, and PLC. The results of our study give new insights into neuronal differentiation, survival, and plasticity, indicating that the perinatal period is the critical time for reversing maternal undernutrition-induced cognitive impairment in offspring's.

Abstract 7451: Translational models of ovarian cancer-associated cognitive impairment and chemotherapy-induced peripheral neuropathy

Abstract Cisplatin is widely used to treat ovarian malignancies, and over 70% of ovarian cancer patients report experiencing cancer-related cognitive impairment (CRCI) and chemotherapy-induced peripheral neuropathy (CIPN) during and after chemotherapy treatment. Most pre-clinical CRCI/CIPN studies have been conducted on non-tumor bearing rodents. We developed two novel clinically relevant models of CRCI/CIPN: (1) the ID8 syngeneic mouse model in B6(Cg)-Tyrc-2J/J female mice, and (2) the SKOV3.ip1 ovarian cancer xenograft model in female Cr:NIH-RNU rats. We examined cognitive function and serum cytokine levels with respect to cancer progression and/or in response to cisplatin. B6 female mice were injected with 107 ID8 cells or 0.9% saline, i.p. Mice received cisplatin (2.3 mg/kg/day, i.p.) or 0.9% saline (OvT+CIS, OvT+VEH, respectively) for 5d, followed by 5d of rest for two cycles. RNU rats were injected with 107 SKOV3.ip1 cells or 0.9% saline, i.p. Rats received cisplatin (5 mg/kg, i.p) or 0.9% saline (OvT+CIS, OvT+VEH, respectively) every other week for four cycles. OvT+CIS and OvT+VEH mice and rats showed impairments in novel object recognition (NOR), with discrimination ratios ≤0.5. Cisplatin transiently increased hyperalgesia in OvT+CIS mice, which persisted longitudinally in OvT+VEH mice. Serum cytokine levels were elevated in OvT+VEH mice (IL-2, IL-10, INFγ) and OvT+VEH rats (IL-4, IL-10) compared to OvT+CIS (P<0.05). Ovarian cancer may evoke progressive sensory and neurocognitive deficits and increase systemic pro-inflammatory cytokine levels in the absence of chemotherapy. Future studies will address hyperalgesia and cognitive differences between healthy control and ovarian cancer models +/- cisplatin, and biological mechanisms underlying CRCI and CIPN. Citation Format: Naomi Lomeli, Donovan Argueta, Diana C. Pearre, Javier Lepe, Kalpna Gupta, Daniela A. Bota. Translational models of ovarian cancer-associated cognitive impairment and chemotherapy-induced peripheral neuropathy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7451.

Memory impairment induced by aluminum nanoparticles is associated with hippocampal IL-1 and IBA-1 upregulation in mice

ABSTRACT Objectives Increasing evidence indicates a link between aluminum (Al) intake and Alzheimer’s disease (AD). The main entry of Al into the human body is through oral route, and in the digestive tract, under the influence of the pH change, Al can be transformed into Al nanoparticles (Al-NP). However, studies related to the effect of Al-NP on the brain are limited and need further investigation. Neuro-inflammation is considered as one of the principal features of AD. Microglial activation and expression of the inflammatory cytokine IL-1β (interleukin-1β) in the brain have been used as hallmarks of brain inflammation. Therefore, in the present study, the hippocampal levels of ionized calcium-binding adaptor molecule 1 (IBA-1), as the marker of microglia activation, and IL-1β were assessed. Methods Adult male NMRI mice were treated with Al-NP (5 or 10 mg/kg) for 5 days. A novel object recognition (NOR) test was used to assess memory. Following cognitive assessments, the hippocampal tissues were isolated to analyze the levels of IL-1β and IBA-1 as well as beta actin proteins using western blot technique. Results Al-NP in both doses of 5 and 10 mg/kg impaired NOR memory in mice. In addition, Al-NP increased IL-1β and IBA-1 in the hippocampus. Discussion These findings indicate that the memory impairing effect of Al-NP coincides with hippocampal inflammation. According to the proposed relationship between AD and Al toxicity, this study can increase the knowledge about the toxic effects of Al-NP and highlight the need to limit the use of this nanoparticle.

Acute physical exercise improves recognition memory via locus coeruleus activation but not via ventral tegmental area activation

Both animals and humans have been studied to explore the impact of acute physical exercise (PE) on memory. In rats, a single session of PE enhances the persistence of novel object recognition (NOR) memory, which depends on dopamine and noradrenaline activity in the hippocampus. However, limited research has examined the involvement of other brain regions in this phenomenon. In this study, we investigated the role of the ventral tegmental area (VTA) and locus coeruleus (LC) in modulating the persistence of NOR memory induced by acute PE. After NOR training, some animals underwent a 30 min treadmill PE session, followed by infusion of either vehicle (VEH) or muscimol (MUS) in either the VTA or LC. Other animals did not undergo PE and only received VEH, MUS, or NMDA within the same time window. We evaluated memory recall 1, 7, and 14 days later. Acute PE promoted memory persistence for up to 14 days afterward, similar to NMDA glutamatergic stimulation of the VTA or LC. Moreover, only the LC region was required for the memory improvement induced by acute PE since blocking this region with MUS impaired NOR encoding. Our findings suggest that acute PE can improve learning within a closed time window, and this effect depends on LC, but not VTA, activity.

Agmatine prevents the memory impairment and the dysfunction of hippocampal GSK-3β and ERK signaling induced by aluminum nanoparticle in mice.

The growing usage of aluminum nanoparticles (Al-NP) and their exposure may influence body function. Considering the proposed relationship between Al and the pathogenesis of Alzheimer's disease and the concern about the effect of this nanoparticle on brain health and cognitive function, the use of neuroprotective agents might be helpful. According to the reported neuroprotective effects of agmatine, in the present study, the possible protective effect of agmatine was assessed in mice model of Al-NP-induced memory impairment. In addition, due to the roles of hippocampal Glycogen synthase kinase-3 beta (GSK-3β) and ERK signaling in memory and its disorders, these pathways were also investigated. Al-NP (10 mg/kg/p.o.) with/without agmatine (5 or 10 mg/kg/i.p.) was administered to adult male NMRI mice for 5 days. Novel object recognition (NOR) test session was used to assess cognitive function. Following the behavioral assessments, the hippocampi were used to determine the phosphorylated and total levels of GSK-3β and ERK as well as GAPDH using western blot analysis. The results showed that Al-NP impaired NOR memory in mice while agmatine 10 mg/kg prevented the memory deficit induced by Al-NP. Furthermore, Al-NP activated GSK-3β as well as ERK signals within the hippocampus while agmatine prevented the effects of Al-NP on GSK-3β and ERK signals within the hippocampus. Besides supporting the neuroprotective effects of agmatine, these findings suggest the possibility of the connection of hippocampal GSK-3β and ERK signaling in the neuroprotective effect of this polyamine against Al-NP.

Sex differences in the effects of mild traumatic brain injury and progesterone treatment on anxiety-like behavior and fear conditioning in rats

Mild traumatic brain injuries (mild TBIs) commonly occur in young adults of both sexes, oftentimes in high-stress environments. In humans, sex differences have been observed in the development of post-concussive anxiety and PTSD-like behaviors. Progesterone, a sex steroid that has neuroprotective properties, restores cognitive function in animal models following more severe TBI, but its effectiveness in preventing the psychological symptoms associated with mild TBI has not been evaluated. Using a model of mild TBI that pairs a social stressor (social defeat) with weight drop, male and naturally estrous-cycling female rats were treated with 4 mg/kg progesterone or vehicle once daily for 5 days after injury. Behavioral measures, including elevated plus maze (EPM), contextual fear conditioning, and novel object recognition (NOR) were assessed following progesterone treatment. Anxiety-like behavior was increased by mild TBI in male rats, with a smaller effect seen in female rats in the diestrus phase at the time of EPM testing. In contrast, mild TBI impaired fear learning in female rats in estrus at the time of fear acquisition. Progesterone treatment failed to attenuate post-mild TBI anxiety-like behavior in either sex. Furthermore, progesterone increased fear conditioning and impaired NOR discrimination in male rats, independent of TBI status. Overall, both sex and estrous cycle contributed to psychological outcomes following mild TBI, which were not ameliorated by post-TBI progesterone. This suggests sex steroids play an important role as a moderator of the expression of mild TBI-induced psychological symptoms, rather than as a potential treatment for their underlying etiology.

Handling prevents and reverses cognitive deficits induced by sub-chronic phencyclidine in a model for schizophrenia in rats

Treatments for schizophrenia are not effective in ameliorating cognitive deficits. Therefore, novel therapies are needed to treat cognitive impairments associated with schizophrenia (CIAS), which are modelled in rats through administration of sub-chronic phencyclidine (scPCP). We have previously shown that enrichment via voluntary exercise prevents and reverses impairments in novel object recognition (NOR) in this model.The present study aimed to investigate if handling could prevent delay-induced NOR deficits and prevent and reverse scPCP-induced NOR deficits.Two cohorts of adult female Lister Hooded rats were used. In experiment one, handling (five minutes/day, five days/week for two weeks), took place before scPCP administration (2 mg/kg, i.p. twice-daily for seven days). NOR tests were conducted at two, four, and seven weeks post-handling with a one-minute inter-trial interval (ITI) and at five weeks post-dosing with a six-hour ITI. In experiment two, rats were handled after scPCP administration and tested immediately in the one-minute ITI NOR task and again at two weeks post-handling.In both handling regimens, the scPCP control groups failed to discriminate novelty, conversely the scPCP handled groups significantly discriminated in this task. In the 6 h ITI test, vehicle control and scPCP control failed to discriminate novelty; however, the vehicle handled and scPCP handled groups did significantly discriminate.Handling rats prevented and reversed scPCP-induced deficits and prevented delay-induced NOR deficits. These findings add to evidence that environmental enrichment is a viable treatment for cognitive deficits in rodent tests and models of relevance to schizophrenia, with potential to translate into effective treatments for CIAS.

NCMP-18. NEUROLOGICAL SEQUELAE IN THE ID8 OVARIAN CANCER MOUSE MODEL: P38/JNK MAPK INHIBITION AS A POTENTIAL THERAPEUTIC FOR CANCER-RELATED COGNITIVE IMPAIRMENTS AND CHEMOTHERAPY-INDUCED PERIPHERAL NEUROPATHY

Abstract OBJECTIVES Chemotherapy-related cognitive impairment (CRCI) and chemotherapy-induced peripheral neuropathy (CIPN) are neurological sequelae of platinum-based chemotherapy. To examine the contribution of cancer itself and additional neurological impairment with chemotherapy, we used the ID8 syngeneic ovarian cancer mouse model and assessed cognition and hyperalgesia +/- cisplatin treatment. We examined the effect of p38 and c-JUN N-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) inhibition on cisplatin-induced neuronal damage. METHODS B6 female mice were injected with 107 ID8 cells or 0.9% saline, i.p. Mice received cisplatin (2.3 m¬¬¬g/kg/day, i.p.) or 0.9% saline (OvT+CIS, OvT+VEH, respectively) for 5d, followed by 5d of rest for two cycles. Cognition was assessed longitudinally at 69d by the open field test (OFT), novel object recognition (NOR) at 75d and 104d, and novel place recognition (NPR) at 106d post-ID8 implantation. Hyperalgesia was assessed at 113d. Primary mouse and rat hippocampal neurons were pre-treated with VX-745 or SP600125, followed by cisplatin, and neuronal morphology was assessed. RESULTS OvT+VEH mice had detectable abdominal tumors 90d post-implantation. At 75d, OvT+VEH and OvT+CIS had impairments in NOR, with discrimination ratios (DR)= 0.52, 0.51, respectively. OvT+VEH showed trending differences vs. OvT+CIS (DR=0.39, DR=0.62, p=0.079) on NOR on 104d, and impairments on NPR on 106d (DR=0.41, DR=0.63, p=0.03). Cisplatin decreased mechanical (p< 0.05) and cold hyperalgesia (p< 0.07, n.s.) in OvT+CIS vs. OvT+VEH. VX-745 and SP600125 pre-treatment in mouse and rat hippocampal neurons prevented cisplatin-induced dendritic branching and spine density loss (p< 0.05). DISCUSSION While cisplatin transiently increased anxiogenic behavior, cognitive impairments, and hyperalgesia in OvT+CIS, these deficits persisted longitudinally in OvT+VEH, suggesting ovarian cancer may evoke sensory and progressive neurocognitive deficits in the absence of chemotherapy. Future studies will address hyperalgesia and cognitive differences between healthy control and ovarian cancer mice +/- cisplatin, and whether VX-745 and SP600125 administration ameliorates CRCI/CIPN in this model.

SRI-32743, a novel allosteric modulator, attenuates HIV-1 Tat protein-induced inhibition of the dopamine transporter and alleviates the potentiation of cocaine reward in HIV-1 Tat transgenic mice

Cocaine abuse increases the incidence of HIV-1-associated neurocognitive disorders. We have demonstrated that HIV-1 transactivator of transcription (Tat) allosterically modulates dopamine (DA) reuptake through the human DA transporter (hDAT), potentially contributing to Tat-induced cognitive impairment and potentiation of cocaine conditioned place preference (CPP). This study determined the effects of a novel allosteric modulator of DAT, SRI-32743, on the interactions of HIV-1 Tat, DA, cocaine, and [3H]WIN35,428 with hDAT in vitro. SRI-32743 (50 nM) attenuated Tat-induced inhibition of [3H]DA uptake and decreased the cocaine-mediated dissociation of [3H]WIN35,428 binding in CHO cells expressing hDAT, suggesting a SRI-32743-mediated allosteric modulation of the Tat-DAT interaction. In further in vivo studies utilizing doxycycline-inducible Tat transgenic (iTat-tg) mice, 14 days of Tat expression significantly reduced the recognition index by 31.7% in the final phase of novel object recognition (NOR) and potentiated cocaine-CPP 2.7-fold compared to responses of vehicle-treated control iTat-tg mice. The Tat-induced NOR deficits and potentiation of cocaine-CPP were not observed in saline-treated iTat-tg or doxycycline-treated G-tg (Tat-null) mice. Systemic administration (i.p.) of SRI-32743 prior to behavioral testing ameliorated Tat-induced impairment of NOR (at a dose of 10 mg/kg) and the Tat-induced potentiation of cocaine-CPP (at doses of 1 or 10 mg/kg). These findings demonstrate that Tat and cocaine interactions with DAT may be regulated by compounds interacting at the DAT allosteric modulatory sites, suggesting a potential therapeutic intervention for HIV-infected patients with concurrent cocaine abuse.

Two distinct ways to form long-term object recognition memory during sleep and wakefulness

Memory consolidation is promoted by sleep. However, there is also evidence for consolidation into long-term memory during wakefulness via processes that preferentially affect nonhippocampal representations. We compared, in rats, the effects of 2-h postencoding periods of sleep and wakefulness on the formation of long-term memory for objects and their associated environmental contexts. We employed a novel-object recognition (NOR) task, using object exploration and exploratory rearing as behavioral indicators of these memories. Remote recall testing (after 1 wk) confirmed significant long-term NOR memory under both conditions, with NOR memory after sleep predicted by the occurrence of EEG spindle-slow oscillation coupling. Rats in the sleep group decreased their exploratory rearing at recall testing, revealing successful recall of the environmental context. By contrast, rats that stayed awake after encoding showed equally high levels of rearing upon remote testing as during encoding, indicating that context memory was lost. Disruption of hippocampal function during the postencoding interval (by muscimol administration) suppressed long-term NOR memory together with context memory formation when animals slept, but enhanced NOR memory when they were awake during this interval. Testing remote recall in a context different from that during encoding impaired NOR memory in the sleep condition, while exploratory rearing was increased. By contrast, NOR memory in the wake rats was preserved and actually superior to that after sleep. Our findings indicate two distinct modes of long-term memory formation: Sleep consolidation is hippocampus dependent and implicates event-context binding, whereas wake consolidation is impaired by hippocampal activation and strengthens context-independent representations.

Impacts of a perinatal exposure to manganese coupled with maternal stress in rats: Learning, memory and attentional function in exposed offspring

The developmental effects of chemicals that co-occur in vulnerable populations with elevated psychological stress are of increasing concern to the public. To investigate these concerns, we developed a rodent model of co-occurring perinatal manipulations and conducted a series of cognitive assessments in male and female offspring. Manganese (Mn), a neurodevelopmental toxicant when exceeding physiological requirements, was delivered in the drinking water (0, 2, or 4 mg Mn/mL) of rats from gestational day (GD) 7 to postnatal day (PND) 22. A variable perinatal stress paradigm was applied to half of the animals from GD13 to PND9. Novel object recognition (NOR), Morris water maze (MWM), differential reinforcement of low-rates procedure (DRL) and cued and uncued choice reaction time (CRT) tests were used to assess cognitive functions in offspring. Mn (4 mg/mL) and stress impaired NOR in adolescent males but facilitated NOR performance in females. However, when stress and Mn were combined these effects were attenuated in both sexes. During training for the DRL, Mn (2 mg/mL) facilitated, while stress impaired, lever press learning in both sexes. Few effects related to the treatments were found on DRL or MWM. During cued CRT, Mn (2 and 4 mg/mL) and stress reduced accuracy in males, while stress and Mn (2 mg/mL) increased anticipatory responding and slowed decision time in both sexes. Stress combined with Mn (2 mg/mL) improved cued accuracy and decision time, and Mn attenuated the effect of stress on anticipatory responding in both sexes. Stress slowed female movement time but when combined with Mn (4 mg/mL) the effect of stress was attenuated. During uncued CRT, except for decision time (which replicated effects observed with the cued task), no other effects of Mn or its combination with stress occurred. Females remained negatively affected by stress in most uncued CRT performance measures, while stressed improved male uncued accuracy. Taken together these data do not support increased cognitive impairment produced by Mn when combined with stress. However, the effects of perinatal stress alone, on these cognitive functions may hinder the detection of effects due to chemical exposures and underscores the need to consider the psychological health and wellbeing of the mother and her environment in risk assessment for developmental neurotoxicity of chemicals.

Dihydromyricetin Improves Cognitive Impairments in d-Galactose-Induced Aging Mice through Regulating Oxidative Stress and Inhibition of Acetylcholinesterase.

Alzheimer's disease (AD) is a neurodegenerative disease with phenomena of cognitive impairments. Oxidative stress and cholinergic system dysfunction are two widely studied pathogenesis of AD. Dihydromyricetin (DMY) is a natural dihydroflavonol with many bioactivities. In this study, it is aimed to investigate the effects of DMY on cognitive impairment in d-galactose (d-gal) induced aging mice. Mice are intraperitoneally injected with d-gal for 16 weeks, and DMY is supplemented in drinking water. The results show that DMY significantly improves d-gal-induced cognitive impairments in novel object recognition and Y-maze studies. H&E and TUNEL staining show that DMY could improve histopathological changes and cell apoptosis in mice brain. DMY effectively induces the activities of catalase, superoxide dismutase and glutathione peroxidase, and reduces malondialdehyde level in mice brain and liver. Furthermore, DMY reduces cholinergic injury by inhibiting the activity of Acetylcholinesterase (AChE) in mice brain. In vitro studies show that DMY is a non-competitive inhibitor of AChE with IC50 value of 161.2µgmL-1 . DMY alleviates the cognitive impairments in d-gal-induced aging mice partly through regulating oxidative stress and inhibition of acetylcholinesterase.

Dietary Choline Protects Against Cognitive Decline After Surgery in Mice.

Perioperative neurocognitive disorders (PNDs) are a common complication following procedures such as orthopedic surgery. Using a mouse model of tibial fracture and repair surgery, we have previously shown an increase in neuroinflammation and hippocampal-dependent cognitive deficits. These changes were ameliorated with the addition of a cholinergic agonist. Here, we sought to examine the effects of a high-choline diet for 3 weeks prior to tibial fracture surgery. We evaluated memory using novel object recognition (NOR) as well as young neurons and glial cell morphology at 1 day and 2 weeks post-surgery. At both time points, tibial fracture impaired NOR performance, and dietary choline rescued these impairments. Astrocytic density and hilar granule cells increased 1 day after tibial fracture, and these increases were partially blunted by dietary choline. An increase in young neurons in the subgranular zone of the dentate gyrus was found 2 weeks after tibial fracture. This increase was partially blunted by choline supplementation. This suggests that shortly after tibial fracture, hippocampal reorganization is a possible mechanism for acute impaired memory. These findings together suggest that non-pharmaceutical approaches, such as pre-surgical dietary intervention with choline, may be able to prevent PNDs.

Endogenous hippocampal, not peripheral, estradiol is the key factor affecting the novel object recognition abilities of female rats.

Estradiol (E2) is involved in the regulation of emotional behavior, cognitive function, and neuroplasticity. However, peripheral E2 and central E2 levels do not always fluctuate together. The relationships of peripheral and central E2 with cognitive function are not clear. The aim of this study was to investigate whether peripheral E2, hippocampal E2, or both play a critical role in novel object recognition (NOR), and whether Kalirin-7, an important regulator of spine plasticity, is involved in the modulation of E2 on cognitive behavior. Our results showed that ovariectomy (OVX) significantly reduced serum E2 levels in the 14 weeks following the procedure. However, hippocampal E2 levels did not decrease in the OVX group compared to the sham group until after 14 weeks. Consistent with the changes in hippocampal E2 levels, the investigation ratio in the NOR test and hippocampal Kalirin-7 expression was also not lower in the OVX group than in the sham group until 14 weeks after the procedure. To confirm the relationship between hippocampal E2 levels and NOR ability, we inhibited the production of hippocampal E2 via microinjection of letrozole (LTZ; an aromatase inhibitor) into the hippocampi of rats in the control group and 8-week OVX group. The data indicated that a reduction in E2 levels in the hippocampus significantly impaired NOR ability and simultaneously decreased Kalirin-7 levels in the hippocampus. In conclusion, our study strongly demonstrates that hippocampal E2, but not peripheral E2, plays a critical role in NOR ability and that Kalirin-7 may be involved in this mechanism. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Recovery From Repeat Mild Traumatic Brain Injury in Adolescent Rats Is Dependent on Pre-injury Activity State.

Adolescents and young adults have the highest incidence of mild traumatic brain injury (mTBI); sport-related activities are a major contributor. Roughly a third of these patients diagnosed with mTBI are estimated to have received a subsequent repeat mTBI (rTBI). Previously, animal studies have only modeled mTBI in sedentary animals. This study utilizes physical activity as a dependent variable prior to rTBI in adolescent rats by allowing voluntary exercise in males, establishing the rat athlete (rathlete). Rats were given access to locked or functional running wheels for 10 d prior to sham or rTBI injury. Following rTBI, rathletes were allowed voluntary access to running wheels beginning on different days post-injury: no run (rTBI+no run), immediate run (rTBI+Immed), or 3 day delay (rTBI+3dd). Rats were tested for motor and cognitive-behavioral (anxiety, social, memory) and mechanosensory (allodynia) dysfunction using a novel rat standardized concussion assessment tool on post-injury days 1,3,5,7, and 10. Protein expression of brain derived neurotrophic factor (BDNF) and proliferator-activated gamma coactivator 1-alpha (PGC1α) was measured in the parietal cortex, hippocampus, and gastrocnemius muscle. Sedentary shams displayed lower anxiety-like behaviors compared to rathlete shams on all testing days. BDNF and PGC1α levels increased in the parietal cortex and hippocampus with voluntary exercise. In rTBI rathletes, the rTBI+Immed group showed impaired social behavior, memory impairment in novel object recognition, and increased immobility compared to rathlete shams. All rats showed greater neuropathic mechanosensory sensitivity than previously published uninjured adults, with rTBI+3dd showing greatest sensitivity. These results demonstrate that voluntary exercise changes baseline functioning of the brain, and that among rTBI rathletes, delayed return to activity improved cognitive recovery.

Male Spata19 knockout mice have behavioral disorders

ObjectivesSpata19 was one of genes involved in neurogenesis, which mutated in some psychiatric disorders. In the current study, using Spata19 knockout mice, we showed the effect of this gene inactivation on some behaviors of mice. MethodsTwenty-four wild-type (WT) and global Spata19 knockout (KO) mice were divided into four groups (Male: WT, n = 9 (6) | Male: KO, n = 5| Female: WT, n = 6| Female: KO, n = 4 (3)). Four of them died during the study. The behavior of these mice was compared with Open Field, Novel Object Recognition, Social Interaction Test and Forced Swimming Test. In these tests, respectively, time spent in centers and locomotor activity, number of smells, fighting and number of stops were evaluated. ResultsSpata19 gene inactivation had not any effect on the behavior of the female mice but in male mice showed greater locomotor activity and time spent in center of arena in the open field test, different coping behavior in Forced Swimming Test, aggressive behavior in Social Interaction Test and cognitive impairment in Novel Object Recognition. This behavioral difference in male KO vs. other mice was significant with a p-value less than 0.05. ConclusionsThe results showed that gene inactivation was involved in the development of behavioral disorders in males.

Aerobic exercise improves memory and prevents cognitive deficits of relevance to schizophrenia in an animal model.

Cognitive impairment associated with schizophrenia (CIAS) greatly reduces patients' functionality, and remains an unmet clinical need. The sub-chronic phencyclidine (scPCP) rat model is commonly employed in studying CIAS. We have previously shown that voluntary exercise reverses impairments in novel object recognition (NOR) induced by scPCP. However, there has not been a longitudinal study investigating the potential protective effects of exercise in a model of CIAS. This study aimed to investigate the pro-cognitive and protective effects of exercise on CIAS using the translational NOR and attentional set-shifting tasks (ASST). Female Lister Hooded rats were either exercised (wheel running for one hour per day, five days per week, for six weeks; n=20) or not (n=20) and then tested in a natural-forgetting NOR test. Rats in each group were then administered either PCP (2 mg/kg intraperitoneally (i.p.)) or saline solution (1 mL/kg i.p.) for seven days, followed by seven days washout. Three NOR tests were conducted immediately and two and nine weeks after washout, and a natural-forgetting NOR test was carried out again eight weeks post washout. Rats were trained and tested in ASST from week 6 to week 10 post washout. Non-exercised rats displayed a deficit in both of the natural-forgetting NOR tests, whereas exercised rats did not. The scPCP exercise group did not show the expected deficit in NOR at any time point, and had a significantly ameliorated deficit in the ASST compared to the scPCP control group. Voluntary exercise has long-lasting pro-cognitive and protective effects in two cognitive domains. Exercise improves cognition and could provide protection against CIAS.

Supplemental taurine during adolescence and early adulthood has sex-specific effects on cognition, behavior and neurotransmitter levels in C57BL/6J mice dependent on exposure window

The mammalian brain goes through final maturation during late adolescence and early adulthood with sex differences in timing. The key cellular processes, including changes in neurotransmitter receptor density and synaptic pruning, make this age uniquely vulnerable to neurotoxic insults. Teenagers and young adults are the major consumers of energy drinks, which contain high levels of taurine and caffeine. Taurine is one of the most abundant amino acids in the central nervous system, but the effects of supplemental taurine consumption during adolescence has not been well studied. We conducted an initial short-term exposure study with 0.12% taurine in drinking water and a long-term exposure dose-response study using 0.06 and 0.12% taurine in male and female C57BL/6J mice. We examined a broad range of cognitive functions and behaviors and measured neurotransmitter levels. We found no significant differences in anxiety, open field locomotor activity, or sensorimotor gating. However, we found impairments in novel object recognition and sex differences in Morris water maze. When taurine treatment stopped before behavioral experiments began, male mice had significant impairments in spatial learning and memory. In the dose-response study when taurine treatment continued throughout behavioral experiments, females had significant impairments. We also found sex differences in neurotransmitter levels with females having higher levels of glutamate, DOPAC and 5-HIAA. We conclude that both females and males are at risk from excess taurine consumption during final brain maturation.