Object Recognition Deficits Research Articles

Two distinct enriched housings differentially ameliorate object and place recognition deficits in a rat model of schizophrenia

Schizophrenia is a psychiatric disorder characterized by cognitive dysfunctions. These dysfunctions significantly impact the daily lives of schizophrenic patients, yet effective interventions remain scarce. In this study, we explored the effects of two enriched housing types—cognitive and physical—on cognitive dysfunctions in a rat model of schizophrenia. Male neonatal Wistar-Imamichi rats were administered MK-801, a noncompetitive NMDAR antagonist, twice daily from postnatal day (PND) 7 to PND 20. Physical enrichment ameliorated memory deficits in both object and place recognition tests, while cognitive enrichment primarily improved object recognition performance. Our findings suggest that exercise therapy could be a potential approach to address cognitive dysfunctions in schizophrenia patients.

Dysregulating mTORC1-4E-BP2 signaling in GABAergic interneurons impairs hippocampus-dependent learning and memory.

Memory formation is contingent on molecular and structural changes in neurons in response to learning stimuli-a process known as neuronal plasticity. The initiation step of mRNA translation is a gatekeeper of long-term memory by controlling the production of plasticity-related proteins in the brain. The mechanistic target of rapamycin complex 1 (mTORC1) controls mRNA translation, mainly through phosphorylation of the eukaryotic initiation factor 4E (eIF4E)-binding proteins (4E-BPs) and ribosomal protein S6 kinases (S6Ks). mTORC1 signaling decreases throughout brain development, starting from the early postnatal period. Here, we discovered that in mice, the age-dependent decrease in mTORC1 signaling occurs selectively in excitatory but not inhibitory neurons. Using a gene conditional knockout (cKO) strategy, we demonstrate that either up- or downregulating the mTORC1-4E-BP2 axis in GAD65 inhibitory interneurons, but not excitatory neurons, results in long-term object recognition and object location memory deficits. Our data indicate that the mTORC1 pathway in inhibitory but not excitatory neurons plays a key role in memory formation.

Nanoencapsulated Curcumin: Enhanced Efficacy in Reversing Memory Loss in An Alzheimer Disease Model.

Investigating new drugs or formulations that target Alzheimer disease (AD) is critical for advancing therapeutic interventions. Therefore, this study aimed to assess the effectiveness of nanoencapsulated curcumin (NC Curc) in alleviating memory impairment, oxidative stress, and neuroinflammation in a validated AD model. Male Wistar rats were given bilateral intracerebroventricular injections of either saline or streptozotocin (STZ) (3 mg/3 µL/site) to establish the AD model (day 0). On day 22, daily oral administrations of curcumin (6 mg/kg), NC Curc (6 mg/kg), or a vehicle (unloaded NC) were initiated and continued for 14 days. NC Curc significantly reversed memory deficits in object recognition and inhibitory avoidance tests induced by STZ. Both formulations of curcumin attenuated elevated acetylcholinesterase activity caused by STZ. Importantly, NC Curc alone effectively mitigated STZ-induced oxidative stress. Additionally, NC Curc treatment normalized GFAP levels, suggesting a potential reduction in neuroinflammation in STZ-treated rats. Our findings indicate that NC Curc improves memory in an AD rat model, highlighting its enhanced therapeutic effects compared to unencapsulated curcumin. This research significantly contributes to understanding the therapeutic and neurorestorative potential of NC Curc in AD, particularly in reversing pathophysiological changes.

Impaired cortical neuronal homeostasis and cognition after diffuse traumatic brain injury are dependent on microglia and type I interferon responses.

Neuropsychiatric complications including depression and cognitive decline develop in the years after traumatic brain injury (TBI), negatively affecting quality of life. Microglial and type 1 interferon (IFN-I) responses are associated with the transition from acute to chronic neuroinflammation after diffuse TBI in mice. Thus, the purpose of this study was to determine if impaired neuronal homeostasis and increased IFN-I responses intersected after TBI to cause cognitive impairment. Here, the RNA profile of neurons and microglia after TBI (single nucleus RNA-sequencing) with or without microglia depletion (CSF1R antagonist) was assessed 7 dpi. There was a TBI-dependent suppression of cortical neuronal homeostasis with reductions in CREB signaling, synaptogenesis, and synaptic migration and increases in RhoGDI and PTEN signaling (Ingenuity Pathway Analysis). Microglial depletion reversed 50% of TBI-induced gene changes in cortical neurons depending on subtype. Moreover, the microglial RNA signature 7 dpi was associated with increased stimulator of interferon genes (STING) activation and IFN-I responses. Therefore, we sought to reduce IFN-I signaling after TBI using STING knockout mice and a STING antagonist, chloroquine (CQ). TBI-associated cognitive deficits in novel object location and recognition (NOL/NOR) tasks at 7 and 30 dpi were STING dependent. In addition, TBI-induced STING expression, microglial morphological restructuring, inflammatory (Tnf, Cd68, Ccl2) and IFN-related (Irf3, Irf7, Ifi27) gene expression in the cortex were attenuated in STINGKO mice. CQ also reversed TBI-induced cognitive deficits and reduced TBI-induced inflammatory (Tnf, Cd68, Ccl2) and IFN (Irf7, Sting) cortical gene expression. Collectively, reducing IFN-I signaling after TBI with STING-dependent interventions attenuated the prolonged microglial activation and cognitive impairment.

(2R,6R)-Hydroxynorketamine Treatment of Rats Exposed to Repetitive Low-Level Blast Injury.

Many military veterans who experienced blast-related traumatic brain injuries (TBIs) in the conflicts in Iraq and Afghanistan suffer from chronic cognitive and mental health problems, including post-traumatic stress disorder (PTSD). Male rats subjected to repetitive low-level blast exposure develop chronic cognitive and PTSD-related traits that develop in a delayed manner. Ketamine has received attention as a treatment for refractory depression and PTSD. (2R,6R)-hydroxynorketamine [(2R,6R)-HNK] is a ketamine metabolite that exerts rapid antidepressant actions. (2R,6R)-HNK has become of clinical interest because of its favorable side-effect profile, low abuse potential, and oral route of administration. We treated three cohorts of blast-exposed rats with (2R,6R)-HNK, beginning 7-11 months after blast exposure, a time when the behavioral phenotype is established. Each cohort consisted of groups (n = 10-13/group) as follows: 1) Sham-exposed treated with saline, 2) blast-exposed treated with saline, and 3) blast-exposed treated with a single dose of 20 mg/kg of (2R,6R)-HNK. (2R,6R)-HNK rescued blast-induced deficits in novel object recognition (NOR) and anxiety-related features in the elevated zero maze (EZM) in all three cohorts. Exaggerated acoustic startle was reversed in cohort 1, but not in cohort 3. (2R,6R)-HNK effects were still present in the EZM 12 days after administration in cohort 1 and 27 days after administration in NOR testing of cohorts 2 and 3. (2R,6R)-HNK may be beneficial for the neurobehavioral syndromes that follow blast exposure in military veterans. Additional studies will be needed to determine whether higher doses or more extended treatment regimens may be more effective.

A Comparative Study of the Impact of NO-Related Agents on MK-801- or Scopolamine-Induced Cognitive Impairments in the Morris Water Maze

Learning and memory deficits accompany numerous brain dysfunctions, including schizophrenia and Alzheimer's disease (AD), and many studies point to the role of nitric oxide (NO) in these processes. The present investigations constitute the follow-up of our previous research, in which we investigated the activity of NO releasers and a selective inhibitor of neuronal NO synthase (nNOS) to prevent short-term memory deficits in novel object recognition and T-maze. Here, the ability of the compounds to prevent the induction of long-term memory deficits by MK-801 or scopolamine administration was investigated. The Morris Water Maze test, a reliable and valid test of spatial learning and memory, was used, in which escape latency in the acquisition phase and nine different parameters in the retention phase were measured. A fast NO releaser (spermine NONOate), a slow NO releaser (DETA NONOate), and a nNOS inhibitor, N(ω)-propyl-L-arginine (NPLA), were used. The compounds were administered i.p. at a dose range of 0.05-0.5 mg/kg. All compounds prevented learning deficits in the acquisition phase and reversed reference memory deficits in the retention phase of the scopolamine-treated mice. Spermine NONOate was the least effective. In contrast, the drugs poorly antagonised MK-801-induced deficits, and only the administration of DETA NONOate induced some improvements in the retention trial.

Hemispheric Patterns of Recruitment of Object Processing Regions in Early Alzheimer's Disease: A Study Along the Entire Ventral Stream.

Investigation of neural response patterns along the entire network of functionally defined object recognition ventral stream regions in Alzheimer's disease (AD) is surprisingly lacking. We aimed to investigate putative functional reorganization along a wide-ranging network of known regions in the ventral visual stream in mild AD. Overall we investigated 6 regions of interest (5 of which were not investigated before), in 19 AD patients and 19 controls, in both hemispheres along the ventral visual stream: Fusiform Face Area, Fusiform Body Area, Extrastriate Body Area, Lateral Occipital Cortex, Parahippocampal Place Area, and Visual Word Form Area, while assessing object recognition performance. We found group differences in dprime measures for all object categories, corroborating generalized deficits in object recognition. Concerning neural responses, we found region dependent group differences respecting a priori expected Hemispheric asymmetries. Patients showed significantly decreased BOLD responses in the right hemisphere-biased Fusiform Body Area, and lower left hemisphere responses in the Visual Word Form Area (with a priori known left hemispheric bias), consistent with deficits in body shape and word/pseudoword processing deficits. This hemispheric dominance related effects were preserved when controlling for performance differences. Whole brain analysis during the recognition task showed enhanced activity in AD group of left dorsolateral prefrontal cortex, left cingulate gyrus, and in the posterior cingulate cortex- a hotspot of amyloid-β accumulation. These findings demonstrate region dependent respecting hemispheric dominance patterns activation changes in independently localized selective regions in mild AD, accompanied by putative compensatory activity of frontal and cingular networks.

The α2C-adrenoceptor antagonist JP-1302 controls behavioral parameters, tyrosine hydroxylase activity and receptor expression in a rat model of ketamine-induced schizophrenia-like deficits

Schizophrenia is a chronic disabling disease affecting 1 % of the population. Current antipsychotics have limited efficacy in mitigating the severity of the symptoms of the disease. Therefore, searching for new therapeutic targets is essential. Previous studies have shown that α2C-adrenoceptor antagonists may have antipsychotic and pro-cognitive effects. Therefore, the current study evaluates the behavioral and neurochemical effects of JP-1302, a selective α2C-adrenoceptor antagonist, in a model of schizophrenia-like deficits induced by sub-chronic ketamine (KET) administration.Here, we administered ketamine (25 mg/kg, i.p.) to male and female Wistar rats for eight consecutive days. On the last two days of ketamine administration, rats were pretreated with either JP-1302 (1-3-10 μmol/kg, i.p.), chlorpromazine (0.1 mg/kg, i.p.), or saline, and the behavioral tests were performed. Behaviors related to positive (locomotor activity), negative (social interaction), and cognitive (novel object recognition) symptoms of schizophrenia were assessed. Glutamate, glutamine, GABA levels, and α2C-adrenoceptor expression were measured in the frontal cortex and the hippocampus. Tyrosine hydroxylase immunocytochemical reactivity was also shown in the midbrain regions.Sub-chronic ketamine administration increased locomotor activity and produced robust social interaction and object recognition deficits, and JP-1302 significantly ameliorated ketamine-induced cognitive deficits. Ketamine induced a hyperdopaminergic activity in the striatum, which was reversed by the treatment with JP-1302. Also, the α2C-adrenoceptor expression was higher in the frontal cortex and hippocampus in the ketamine-treated rats.Our findings confirm that α2C-adrenoceptor antagonism may be a potential drug target for treating cognitive disorders related to schizophrenia.

Swimming exercise is a promising early intervention for autism-like behavior in Shank3 deletion rats.

SHANK3 is an important excitatory postsynaptic scaffold protein, and its mutations lead to genetic cause of neurodevelopmental diseases including autism spectrum disorders (ASD), Philan McDermid syndrome (PMS), and intellectual disability (ID). Early prevention and treatment are important for Shank3 gene mutation disease. Swimming has been proven to have a positive effect on neurodegenerative diseases. Shank3 gene exon 11-21 knockout rats were intervened by a 40 min/day, 5day/week for 8-week protocol. After the intervention, the rats were tested to behavioral measures such as learning and memory, and the volume and H-spectrum of the brain were measured using MRI; hippocampal dendritic spines were measured using Golgi staining and laser confocal. The results showed that Shank3-deficient rats had significant deficits in social memory, object recognition, and water maze learning decreased hippocampal volume and number of neurons, and lower levels of related scaffold proteins and receptor proteins were found in Shank3-deficient rats. It is suggested that early swimming exercise has a positive effect on Shank3 gene-deficient rats, which provides a new therapeutic strategy for the prevention and recovery of neurodevelopmental disorders.

Beneficial effects of atypical antipsychotics on object recognition deficits after adolescent toluene exposure in mice: involvement of 5-HT1A receptors

ABSTRACT Background: Inhalant (e.g. toluene) misuse by adolescents has been linked to psychosis and persistent cognitive deficits. Identifying effective strategies to improve cognitive deficits following chronic toluene misuse is critical. 5-HT1A receptor has been proposed as a target for the treatment of cognitive deficits. Objectives: We compared the effects of antipsychotics on recognition deficits after adolescent toluene exposure in mice and elucidated the role of 5-HT1A receptors in the cognition-improving effects of antipsychotics. Methods: Male NMRI mice (n = 279) received one injection per day of either toluene (750 mg/kg) or corn oil at postnatal days 35–39 and 42–46. Thereafter, the acute and subchronic effects of haloperidol, aripiprazole, or clozapine on toluene-induced recognition deficits were evaluated by novel object recognition test. Results: Acute administration of aripiprazole (p < .05) and clozapine (p < .01), but not haloperidol, significantly attenuated the toluene-induced recognition deficits. Pretreatment with 5-HT1A receptor antagonist WAY -100,635 (p < .05) blocked their beneficial effects. Moreover, 5-HT1A receptor agonist buspirone (p < .01) ameliorated the toluene-induced recognition deficits, which was reversed by WAY -100,635 (p < .001). Finally, after repeated treatment with clozapine, aripiprazole, and buspirone daily for 14 days, the impaired object recognition in toluene-exposed mice was significantly improved (p < .05) and the beneficial effects lasted for at least 2 weeks (p < .05). Conclusions: The results indicate that clozapine and aripiprazole, which display 5-HT1A agonist properties, restored cognitive deficits in mice induced by adolescent toluene exposure. These findings suggest that these antipsychotics should be further explored as a potential treatment option for cognitive deficits in patients with psychosis associated with toluene exposure.

Cannabidiol in the treatment and prevention of Alzheimer’s disease – a comprehensive overview of in vitro and in vivo studies

Introduction and purpose. Dementia is a major public health problem. Alzheimer’s disease (AD) accounts for 60% of dementia cases. However, AD is currently considered as an incurable disorder and the only few drugs available for its treatment are mostly symptomatic. In the quest for novel drugs for this devastating disease, cannabidiol (CBD) has been recently gaining attention due to its multiple properties, such as an ability to interact with various receptors, anti-inflammatory and antioxidative effects and many more. The aim of this review article was to summarize findings on the effect of CBD on AD with a focus on molecular mechanisms of CBD’s action and therapeutic effects which it exerts.&#x0D; Description of the state of knowledge. In vitro studies, carried out on cell models of AD, showed anti-inflammatory and antioxidative properties of CBD through a suppression of pro-inflammatory genes and causing a reduction of production of, among others, nitric oxide. Moreover, CBD was proven to decrease amyloid β (Aβ) production, reduce formation and aggregation of tau fibrils, protect against microglial and Aβ-induced neurotoxicity and prevented the Aβ-induced deficit in long-term potentiation in hippocampus. In vivo studies, conducted mostly on mice models of AD, indicated that CBD improves memory and spatial learning, reverses deficit in social and object recognition, reduces anxiety-like behaviors and improves glucose metabolism. One study including humans demonstrated that CBD enhances cerebral blood flow in hippocampus. Currently there are two ongoing clinical trials on the use of CBD in AD-associated agitation.&#x0D; Conclusions. Both in vitro and in vivo studies indicate that cannabidiol appears promising in the treatment and prevention of Alzheimer’s disease.

Antipsychotic-like effects of fasudil, a Rho-kinase inhibitor, in a pharmacologic animal model of schizophrenia

Current antipsychotics used to treat schizophrenia have associated problems, including serious side effects and treatment resistance. We recently identified a significant association of schizophrenia with exonic copy number variations in the Rho GTPase activating protein 10 (ARHGAP10) gene using genome-wide analysis. ARHGAP10 encodes a RhoGAP superfamily member that is involved in small GTPase signaling. In mice, Arhgap10 gene variations result in RhoA/Rho-kinase pathway activation. We evaluated the pharmacokinetics of fasudil and hydroxyfasudil using liquid chromatography-tandem mass spectrometry in mice. The antipsychotic effects of fasudil on hyperlocomotion, social interaction deficits, prepulse inhibition deficits, and novel object recognition deficits were also investigated in a MK-801-treated pharmacological mouse schizophrenia model. Fasudil and its major metabolite, hydroxyfasudil, were detected in the brain at concentrations above their respective Ki values for Rho-kinase after intraperitoneal injection of 10 mg kg−1 fasudil. Fasudil improved the hyperlocomotion, social interaction deficits, prepulse inhibition deficits, and novel object recognition deficits in MK-801-treated mice in a dose-dependent manner. Following oral administration of fasudil, brain hydroxyfasudil was detected at concentration above the Ki value for Rho-kinase whilst fasudil was undetectable. MK-801-induced hyperlocomotion was also improved by oral fasudil administration. These results suggest that fasudil has antipsychotic-like effects on the MK-801-treated pharmacological mouse schizophrenia model. There are two isoforms in Rho-kinase, and further investigation is needed to clarify the isoforms involved in the antipsychotic-like effects of fasudil in the MK-801-treated mouse schizophrenia model.

Age-related loss of recognition memory and its correlation with hippocampal and perirhinal cortex changes in female Sprague Dawley rats

Ageing is associated with impaired performance in recognition memory, a process that consists of the discrimination of familiar and novel stimuli. Previous studies have shown the impact of ageing on object recognition memories. However, the early stages of memory impairment remain unknown. To fill this gap, we aimed at evaluating the ability of young (Y), middle-aged (MA), and senile (S) female Sprague-Dawley rats to retain 24 h long-term recognition memory. The MA cohort was included to characterise early memory deficits under two behavioural paradigms based on spontaneous location recognition (SLR) and spontaneous object recognition (SOR) tasks. In the SLR task, there was a markedly diminished novel discrimination capacity in the MA and S rats compared with the Y ones. In the SOR task, S rats evidenced a deterioration in novelty discrimination, while MA rats partially preserved the capacity to distinguish the new stimulus as compared with Y rats. Regarding early changes from MA to S rats, immunohistochemistry showed a marked decrease in the number and diameter of adult-born immature neurons in the Dentate Gyrus (DG) with a positive correlation with behavioural performance in the SLR task. Furthermore, we found a slight reduction in CA3 mature neurons and a decrease in the number of total microglia in the perirhinal cortex (Prh) in MA and S rats as compared with Y rats. As regards changes that were only observed in S rats, we found an increase in the number of total and reactive microglia in CA3 and a reduction in the number of total microglia in the DG. We conclude that spatial discrimination capacity could be affected earlier than feature discrimination capacity. We suggest that early depletion of neurogenesis in MA rats is involved in object location recognition deficits, whereas the disruption of microglial homeostasis in the Prh could be associated with object feature discrimination capacity.

Amitriptyline improves cognitive and neuronal function in a rat model that mimics dementia with lewy bodies

Dementia with Lewy bodies (DLB), a highly prevalent neurodegenerative disorder, causes motor and cognitive deficits. The main pathophysiologies of DLB are glutamate excitotoxicity and accumulation of Lewy bodies comprising α-synuclein (α-syn) and β-amyloid (Aβ). Amitriptyline (AMI) promotes expression of glutamate transporter-1 and glutamate reuptake. In this study, we measured the effects of AMI on behavioral and neuronal function in a DLB rat model. We used rivastigmine (RIVA) as a positive control. To establish the DLB rat model, male Wistar rats were stereotaxically injected with recombinant adenoassociated viral vector with the SNCA gene (10 μg/10 μL) and Aβ (5 μg/2.5 μL) into the left ventricle and prefrontal cortex, respectively. AMI (10 mg/kg/day, i.p.), RIVA (2 mg/kg/day, i.p.), or saline was injected intraperitoneally after surgery. From the 29th day, behavioral tests were performed to evaluate the motor and cognitive functions of the rats. Immunohistochemical staining was used to assess neuronal changes. We measured the α-syn level, number of newborn cells, and neuronal density in the hippocampus and in the nigrostriatal dopaminergic system. The DLB group exhibited deficit in object recognition. Both the AMI and RIVA treatments reversed these deficits. Histologically, the DLB rats exhibited cell loss in the substantia nigra pars compacta and in the hippocampal CA1 area. AMI reduced this cell loss, but RIVA did not. In addition, the DLB rats exhibited a lower number of newborn cells and higher α-syn levels in the dentate gyrus (DG). AMI did not affect α-syn accumulation but recovered neurogenesis in the DG of the rats, whereas RIVA reversed the α-syn accumulation but did not affect neurogenesis in the rats. We suggest that AMI may have potential for use in the treatment of DLB.

Assessing mild cognitive impairment using object-location memory in immersive virtual environments.

Pathological changes in the medial temporal lobe (MTL) are found in the early stages of Alzheimer's disease (AD) and aging. The earliest pathological accumulation of tau colocalizes with the areas of the MTL involved in object processing as part of a wider anterolateral network. Here, we sought to assess the diagnostic potential of memory for object locations in iVR environments in individuals at high risk of AD dementia (amnestic mild cognitive impairment [aMCI] n = 23) as compared to age‐related cognitive decline. Consistent with our primary hypothesis that early AD would be associated with impaired object location, aMCI patients exhibited impaired spatial feature binding. Compared to both older (n = 24) and younger (n = 53) controls, aMCI patients, recalled object locations with significantly less accuracy (p < .001), with a trend toward an impaired identification of the object's correct context (p = .05). Importantly, these findings were not explained by deficits in object recognition (p = .6). These deficits differentiated aMCI from controls with greater accuracy (AUC = 0.89) than the standard neuropsychological tests. Within the aMCI group, 16 had CSF biomarkers indicative of their likely AD status (MCI+ n = 9 vs. MCI− n = 7). MCI+ showed lower accuracy in the object‐context association than MCI− (p = .03) suggesting a selective deficit in object‐context binding postulated to be associated with anterior‐temporal areas. MRI volumetric analysis across healthy older participants and aMCI revealed that test performance positively correlates with lateral entorhinal cortex volumes (p < .05) and hippocampus volumes (p < .01), consistent with their hypothesized role in binding contextual and spatial information with object identity. Our results indicate that tests relying on the anterolateral object processing stream, and in particular requiring successful binding of an object with spatial information, may aid detection of pre‐dementia AD due to the underlying early spread of tau pathology.

The effects of mango leaf extract during adolescence and adulthood in a rat model of schizophrenia.

There is evidence that in schizophrenia, imbalances in inflammatory and oxidative processes occur during pregnancy and in the early postnatal period, generating interest in the potential therapeutic efficacy of anti-inflammatory and antioxidant compounds. Mangiferin is a polyphenolic compound abundant in the leaves of Mangifera indica L. that has robust antioxidant and anti-inflammatory properties, making it a potential candidate for preventive or co-adjuvant therapy in schizophrenia. Hence, this study set-out to evaluate the effect of mango leaf extract (MLE) in a model of schizophrenia based on maternal immune activation, in which Poly I:C (4 mg/kg) is administered intravenously to pregnant rats. Young adult (postnatal day 60–70) or adolescent (postnatal day 35–49) male offspring received MLE (50 mg/kg of mangiferin) daily, and the effects of MLE in adolescence were compared to those of risperidone, assessing behavior, brain magnetic resonance imaging (MRI), and oxidative/inflammatory and antioxidant mediators in the adult offspring. MLE treatment in adulthood reversed the deficit in prepulse inhibition (PPI) but it failed to attenuate the sensitivity to amphetamine and the deficit in novel object recognition (NOR) induced. By contrast, adolescent MLE treatment prevented the sensorimotor gating deficit in the PPI test, producing an effect similar to that of risperidone. This MLE treatment also produced a reduction in grooming behavior, but it had no effect on anxiety or novel object recognition memory. MRI studies revealed that adolescent MLE administration partially counteracted the cortical shrinkage, and cerebellum and ventricle enlargement. In addition, MLE administration in adolescence reduced iNOS mediated inflammatory activation and it promoted the expression of biomarkers of compensatory antioxidant activity in the prefrontal cortex and hippocampus, as witnessed through the reduction of Keap1 and the accumulation of NRF2 and HO1. Together, these findings suggest that MLE might be an alternative therapeutic or preventive add-on strategy to improve the clinical expression of schizophrenia in adulthood, while also modifying the time course of this disease at earlier stages in populations at high-risk.

Repeated administration of rapastinel produces exceptionally prolonged rescue of memory deficits in phencyclidine-treated mice

Rapastinel, a positive N-methyl-D-aspartate receptor (NMDAR) modulator with rapid-acting antidepressant properties, rescues memory deficits in rodents. We have previously reported that a single intravenous dose of rapastinel, significantly, but only transiently, prevented and rescued deficits in the novel object recognition (NOR) test, a measure of episodic memory, produced by acute or subchronic administration of the NMDAR antagonists, phencyclidine (PCP) and ketamine. Here, we tested the ability of single and multiple subcutaneous doses per day of rapastinel to restore NOR and operant reversal learning (ORL) deficits in subchronic PCP-treated mice. Rapastinel, 1 or 3 mg/kg, administered subcutaneously, 30 min before NOR or ORL testing, respectively, transiently rescued both deficits in subchronic PCP mice. This effect of rapastinel on NOR and ORL was mammalian target of rapamycin (mTOR)-dependent. Most importantly, 1 mg/kg rapastinel given twice daily for 3 or 5 days, but not 1 day, restored NOR for at least 9 and 10 weeks, respectively, which is an indication of neuroplastic effects on learning and memory. Both rapastinel (3 mg/kg) and ketamine (30 mg/kg), moderately increased the efflux of dopamine, norepinephrine, and serotonin in medial prefrontal cortex; however, only ketamine increased cortical glutamate efflux. This observation was likely the basis for the contrasting effects of the two drugs on cognition.

Isoflurane Disrupts Postsynaptic Density-95 Protein Interactions Causing Neuronal Synapse Loss and Cognitive Impairment in Juvenile Mice via Canonical NO-mediated Protein Kinase-G Signaling.

Inhalational anesthetics are known to disrupt PDZ2 domain-mediated protein-protein interactions of the postsynaptic density (PSD)-95 protein. The aim of this study is to investigate the underlying mechanisms in response to early isoflurane exposure on synaptic PSD-95 PDZ2 domain disruption that altered spine densities and cognitive function. The authors hypothesized that activation of protein kinase-G by the components of nitric oxide (NO) signaling pathway constitutes a mechanism that prevents loss of early dendritic spines and synapse in neurons and cognitive impairment in mice in response to disruption of PDZ2 domain of the PSD-95 protein. Postnatal day 7 mice were exposed to 1.5% isoflurane for 4 h or injected with 8 mg/kg active PSD-95 wild-type PDZ2 peptide or soluble guanylyl cyclase activator YC-1 along with their respective controls. Primary neurons at 7 days in vitro were exposed to isoflurane or PSD-95 wild-type PDZ2 peptide for 4 h. Coimmunoprecipitation, spine density, synapses, cyclic guanosine monophosphate-dependent protein kinase activity, and novel object recognition memory were assessed. Exposure of isoflurane or PSD-95 wild-type PDZ2 peptide relative to controls causes the following. First, there is a decrease in PSD-95 coimmunoprecipitate relative to N-methyl-d-aspartate receptor subunits NR2A and NR2B precipitate (mean ± SD [in percentage of control]: isoflurane, 54.73 ± 16.52, P = 0.001; and PSD-95 wild-type PDZ2 peptide, 51.32 ± 12.93, P = 0.001). Second, there is a loss in spine density (mean ± SD [spine density per 10 µm]: control, 5.28 ± 0.56 vs. isoflurane, 2.23 ± 0.67, P < 0.0001; and PSD-95 mutant PDZ2 peptide, 4.74 ± 0.94 vs. PSD-95 wild-type PDZ2 peptide, 1.47 ± 0.87, P < 0.001) and a decrease in synaptic puncta (mean ± SD [in percentage of control]: isoflurane, 41.1 ± 14.38, P = 0.001; and PSD-95 wild-type PDZ2 peptide, 50.49 ± 14.31, P < 0.001). NO donor or cyclic guanosine monophosphate analog prevents the spines and synapse loss and decline in the cyclic guanosine monophosphate-dependent protein kinase activity, but this prevention was blocked by soluble guanylyl cyclase or protein kinase-G inhibitors in primary neurons. Third, there were deficits in object recognition at 5 weeks (mean ± SD [recognition index]: male, control, 64.08 ± 10.57 vs. isoflurane, 48.49 ± 13.41, P = 0.001, n = 60; and female, control, 67.13 ± 11.17 vs. isoflurane, 53.76 ± 6.64, P = 0.003, n = 58). Isoflurane-induced impairment in recognition memory was preventable by the introduction of YC-1. Activation of soluble guanylyl cyclase or protein kinase-G prevents isoflurane or PSD-95 wild-type PDZ2 peptide-induced loss of dendritic spines and synapse. Prevention of recognition memory with YC-1, a NO-independent activator of guanylyl cyclase, supports a role for the soluble guanylyl cyclase mediated protein kinase-G signaling in countering the effects of isoflurane-induced cognitive impairment.

A novel allosteric PDE4B inhibitor T2409 improves mild cognitive impairment: involvement of cAMP related anti‐inflammatory pathway

Disorders affecting memory and cognition including Alzheimer’s disease (AD) affect millions of Americans. Although dozens of compounds have been reported for the treatment of mild cognitive deficits (MCI) in Alzheimer’s disease (AD), these drugs have not proven beneficial in ameliorating cognitive impairment in clinic. Phosphodiesterase 4B (PDE4B) plays a crucial role in the mediation of memory due to its primary role in hydrolyzing cyclic adenosine monophosphate (cAMP). However, the development of PDE4B inhibitors is challengeable due to the high conservation of the catalytic site of PDE4, across subtypes, to which classical inhibitors bind. The present study suggested that the newly synthesized allosteric inhibitor of PDE4, T2409, exhibits at least 150‐fold PDE4B selectivity. It exhibited low potency in a mouse surrogate model of emesis and nausea, suggesting its low side effects. Chronic treatment of T2409 for 14 days reversed cognitive and memory deficits in the novel object recognition and Morris water maze tests as evidenced by increased discrimination index and reduced the mean latency to platform via decreasing beta amyloid plaques both in the cortex and hippocampus in 8‐month‐old APP/PS1 mouse model of AD. Further study showed that these effects were related to decreased inflammatory factors, such as IL‐6, IL‐1β and TNF‐α, in the brain, and increased cAMP signaling dependent markers of neuroprotection associated with memory, such as p‐CREB and BDNF. These results accelerate the development of highly selective PDE4B inhibitors as novel treatments for illnesses that affect memory and cognitive function, such as AD.

Neuropathological fingerprints of survival, atrophy and language in primary progressive aphasia.

Primary progressive aphasia is a neurodegenerative disease that selectively impairs language without equivalent impairment of speech, memory or comportment. In 118 consecutive autopsies on patients with primary progressive aphasia, primary diagnosis was Alzheimer's disease neuropathological changes (ADNC) in 42%, corticobasal degeneration or progressive supranuclear palsy neuropathology in 24%, Pick's disease neuropathology in 10%, transactive response DNA binding proteinopathy type A [TDP(A)] in 10%, TDP(C) in 11% and infrequent entities in 3%. Survival was longest in TDP(C) (13.2 ± 2.6 years) and shortest in TDP(A) (7.1 ± 2.4 years). A subset of 68 right-handed participants entered longitudinal investigations. They were classified as logopenic, agrammatic/non-fluent or semantic by quantitative algorithms. Each variant had a preferred but not invariant neuropathological correlate. Seventy-seven per cent of logopenics had ADNC, 56% of agrammatics had corticobasal degeneration/progressive supranuclear palsy or Pick's disease and 89% of semantics had TDP(C). Word comprehension impairments had strong predictive power for determining underlying neuropathology positively for TDP(C) and negatively for ADNC. Cortical atrophy was smallest in corticobasal degeneration/progressive supranuclear palsy and largest in TDP(A). Atrophy encompassed posterior frontal but not temporoparietal cortex in corticobasal degeneration/progressive supranuclear palsy, anterior temporal but not frontoparietal cortex in TDP(C), temporofrontal but not parietal cortex in Pick's disease and all three lobes with ADNC or TDP(A). There were individual deviations from these group patterns, accounting for less frequent clinicopathologic associations. The one common denominator was progressive asymmetric atrophy overwhelmingly favouring the left hemisphere language network. Comparisons of ADNC in typical amnestic versus atypical aphasic dementia and of TDP in type A versus type C revealed fundamental biological and clinical differences, suggesting that members of each pair may constitute distinct clinicopathologic entities despite identical downstream proteinopathies. Individual TDP(C) participants with unilateral left temporal atrophy displayed word comprehension impairments without additional object recognition deficits, helping to dissociate semantic primary progressive aphasia from semantic dementia. When common and uncommon associations were considered in the set of 68 participants, one neuropathology was found to cause multiple clinical subtypes, and one subtype of primary progressive aphasia to be caused by multiple neuropathologies, but with different probabilities. Occasionally, expected clinical manifestations of atrophy sites were absent, probably reflecting individual peculiarities of language organization. The hemispheric asymmetry of neurodegeneration and resultant language impairment in primary progressive aphasia reflect complex interactions among the cellular affinities of the degenerative disease, the constitutive biology of language cortex, familial or developmental vulnerabilities of this network and potential idiosyncrasies of functional anatomy in the affected individual.