Non-cognitive Behaviors Research Articles

High-fat diet negatively affects brain markers, cognitive behaviors, and noncognitive behaviors in the rTg4510 tau mouse model

Alzheimer's disease (AD) drastically impacts cognitive and noncognitive behaviors in both humans and animal models. Two hallmark proteins in AD, amyloid-β plaques and tau neurofibrillary tangles, accumulate in regions of the brain critical for learning and memory, including the hippocampus. Poor dietary choices have been shown to exacerbate cognitive deficits seen in AD. In this study, we assessed the effects of a high-fat diet (HFD - 60 kcal% fat) on cognitive & noncognitive behaviors as well as on brain markers in the rTg4510 tau mouse model. While all mice learned the Morris Water Maze (MWM) task, it was noted that on the last day of acquisition female tau mice had a significantly higher latency to find the platform than male tau mice (p < 0.01). Mice given the HFD spent significantly less time in the target quadrant than those given a control diet (CD) (p < 0.05). Tau mice showed impaired burrowing (p < 0.05) and nesting behaviors (p < 0.001) compared to WT mice and HFD administration worsened burrowing in tau mice. Tau mice exhibited greater levels of glial fibrillary acidic protein (GFAP) (p < 0.05) and significantly less hippocampal cell density than WT mice (p < 0.001). We observed trends of HFD mice having greater levels of GFAP and greater average tangle size than CD mice. These results highlight the importance of dietary choices, especially in older populations more susceptible to AD and its effects.

Effects of Psycho-educational Program Alone and Combined with Reminiscence Therapy on Depression, Cognitive and Non-cognitive Behaviors among Patients with Dementia

Effects of Psycho-educational Program Alone and Combined with Reminiscence Therapy on Depression, Cognitive and Non-cognitive Behaviors among Patients with Dementia

Grit and Self-Efficacy on Growth Mindset- A Review Based Analysis

Purpose: Grit signifies a student's competence that endures after stumbling academic blocks. The trait Grit is closely identified with mindset. Students who believe that their shortcomings result from their fixed mental models, find no use nor reason to attempt again. Individuals with such rigid attitudes are believed to have a fixed mindset. On the contrary, students with a growth mindset are more likely to be resilient and have more grit. On the contrary, individuals who are mentally tough and strong are likely to be considered to have a growth mindset. According to previous research, grit is a question of nature and nurture. People need to build a growth attitude in order to become grittier. Design/Methodology/Approach: More than 100 research papers, articles, and journals were reviewed systematically to identify gaps, identify conflicts in previous studies, and for the purpose of foundation of knowledge on current topic. A systematic review of literature uses a meticulous and transparent methodology for research synthesis, with the aim of evaluating and, where feasible, diminishing bias in the findings. This review is based on careful and systematic scrutinization of the above-mentioned keywords and their combinations thereof. Electronic databases like Google Scholar, Research gate, Academia, Srinivas Publication and Mendeley/Elsevier with open access journals were perused. Results/ Findings: The relevant reviews indicate that people with a higher level of a growth mindset exhibit an equally high level of self-efficacy than pupils who had a more rigid perspective. Several literatures suggest that grit is associated with improved participation and better performance in a school environment. Students with a fixed mindset have a strong notion that their innate intelligence is limited preventing them from reaching their desired goals. This results in a hopeless ‘giving up’ attitude with a deep-rooted fear of failure. Whereas a growth mindset person marches forward with confidence. Their thoughts and beliefs are controlled by them. They understand that every person is brilliant in their own way which can be built, changed, and developed over time with the necessary components of will and effort. Few studies highlight different intervention models to improve fixed mindset of students. Few other studies suggest that practitioners could find a difference in the increase of grit with effective and committed goal settings which eventually would lead to an increased level of mindset in the right direction. Originality/Value: This study is a prequel for the original study on grit, self-efficacy, and mindset modification for the professional success of Industrial Training Institute Students. This intervention-based study has been recommended by few previous studies. In all originality, the experimental study would largely impact the young adults, their cognition and non-cognitive behavior with a developed growth mindset. Type of Paper: Systematic Literature Review-Based Analysis.

Lion's Mane (Hericium erinaceus) Exerts Anxiolytic Effects in the rTg4510 Tau Mouse Model.

Alzheimer’s disease (AD) significantly impairs the life of an individual both cognitively and behaviorally. Tau and beta-amyloid (Aβ) proteins are major contributors to the etiology of AD. This study used mice modeling AD through the presence of tau pathology to assess the effects of Hericium erinaceus (H. erinaceus), also known as Lion’s mane, on cognitive and non-cognitive behaviors. Despite neurocognitive and neurobiological effects of H. erinaceus being seen in both healthy and transgenic mice, no research to date has explored its effects on mice with solely tau pathology. In this study, mice were placed on a diet supplemented with H. erinaceus or a standard rodent diet for 4.5 months in order to determine the effect of this medicinal mushroom on behavior. Tau mice given H. erinaceus had significantly shorter latencies to enter the center of the open field (OF) (p < 0.05) and spent significantly more time in the open arms of the elevated zero maze (EZM) (p < 0.001) compared to tau control mice. Mice given H. erinaceus spent significantly more time in the open arms of and made more head dips in the elevated zero maze (EZM) (p < 0.05). While H. erinaceus had anxiolytic effects, no improvements were seen in spatial memory or activities of daily living. These findings provide additional support for the anxiolytic effects of H. erinaceus and point to its potential benefit as a therapeutic for anxiety in AD.

Neuropathological and behavioral features of an APP/PS1/MAPT (6xTg) transgenic model of Alzheimer’s disease

Alzheimer's disease is associated with various brain dysfunctions, including memory impairment, neuronal loss, astrocyte activation, amyloid-β plaques, and neurofibrillary tangles. Transgenic animal models of Alzheimer's disease have proven to be invaluable for the basic research of Alzheimer's disease. However, Alzheimer's disease mouse models developed so far do not fully recapitulate the pathological and behavioral features reminiscent of Alzheimer's disease in humans. Here, we investigated the neurobehavioral sequelae in the novel 6xTg mouse model of Alzheimer's disease, which was developed by incorporating human tau containing P301L mutation in the widely used 5xFAD mouse model of Alzheimer's disease. At 11-months-old, 6xTg mice displayed the core pathological processes found in Alzheimer's disease, including accumulation of amyloid-β plaque, extensive neuronal loss, elevated level of astrocyte activation, and abnormal tau phosphorylation in the brain. At 9 to 11-months-old, 6xTg mice exhibited both cognitive and non-cognitive behavioral impairments relevant to Alzheimer’s disease, including memory loss, hyperlocomotion, anxiety-like behavior, depression-like behavior, and reduced sensorimotor gating. Our data suggest that the aged 6xTg mouse model of Alzheimer's disease presents pathological and cognitive-behavioral features reminiscent of Alzheimer's disease in humans. Thus, the 6xTg mouse model of Alzheimer's disease may be a valuable model for studying Alzheimer’s disease-relevant non-cognitive behaviors.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13041-022-00933-8.

Attitudes, Behavior and Relations in the Early School Years

In the early school years, the emphasis is more and more on cognitive output factors. Non-cognitive development is receiving less attention than before, though such factors are important determinants of academic success. This study aims at answering two questions: (1) How do young children perform on a number of non-cognitive characteristics, more specifically, attitudes, behavior, and relationships? (2) Are there any differences with regard to those characteristics according to the pupils’ social and ethnic/immigrant background? To answer the questions, data from the Dutch large-scale cohort study COOL5-18 were analyzed. The main sample included nearly 6500 grade 2 pupils (6-year-olds). Teachers answered questions about their pupils’ attitudes, behavior, and relationships. One- and two-way analyses of variance were employed, and effect sizes were computed. The results showed that the teachers rated their pupil’s work attitude as lower than their behavior and popularity. They were more positive regarding their relationship with the pupils. More important was that there were differences according to the pupils’ social and ethnic/immigrant backgrounds: ethnic minority/immigrant pupils scored less positive on all non-cognitive characteristics than native Dutch pupils, and the higher the parental educational level, the more favorable their children performed on the non-cognitive characteristics. These findings are discussed and possible solutions are presented.

Positive and Negative Selective Allosteric Modulators of α5 GABAA Receptors: Effects on Emotionality, Motivation, and Motor Function in the 5xFAD Model of Alzheimer's Disease.

Positive and negative allosteric modulators of α5 GABAA receptors (PAM and NAM, respectively) are worthy of investigation as putative treatments of Alzheimer's disease (AD). However, their potential to modify a dynamic range of behaviors in AD models needs to be systematically examined. The study aimed to assess effects of MP-III-022 as PAM and PWZ-029 as NAM on emotional reactivity, motivation, and motor function, as well as on gene expression of GABRA2, GABRA3 and GABRA5 subunit of GABAA receptors in prefrontal cortex (PFC) and hippocampus (HC) in 5xFAD mice, as an early-onset transgenic AD model. The 6-month-old 5xFAD transgenic and non-transgenic mice of both genders underwent a battery of reflexes and behavioral tests (sensorimotor tests, elevated plus maze, and open field) after 10-day intraperitoneal treatment with MP-III-022, PWZ-029, or solvent. The behavioral battery was followed by qPCR analysis of gene expression. MP-III-022 induced a decline in motor function, while PWZ-029 further decreased emotionality of transgenic males, as compared to the transgenic control. No interfering effects on non-cognitive behavior were observed in female mice. In HC, both treatments reversed reciprocal GABRA2 and GABRA3 changes in transgenic females. In PFC, MP-III-022 decreased GABRA5 in both genders, while PWZ-029 increased GABRA2 in male transgenic animals. Gender-dependent protracted effects of PAMs and NAMs in AD model, with detrimental impact on motor capabilities of PAM, and attenuation of emotionality elicited by NAM in transgenic males, were revealed. This favors future research of α5 GABAA receptor modulation in females as more promising.

Noncognitive species-typical and home-cage behavioral alterations in conditional presenilin 1/presenilin 2 double knockout mice

Impairments in activities of daily living (ADL) are common clinical symptoms of human Alzheimer’s disease (AD). Describing the ADL in AD animal models might provide more insights into the mechanism/treatment of the disease. Here, we demonstrated that the forebrain presenilin 1(Psen1)/presenilin 2 (Psen2) conditional double knockout (DKO) mice exhibited deficits in nest building, marble burying and food burrowing starting at 3 months old and worsening at later ages. At 4 months of age, spontaneous activities in the home cage were also impaired in DKO mice, including physically demanding activities, habituation-like behaviors, and nourishment behaviors during the first two hours in the dark phase. These results indicated that loss of function of Psen1 and Psen2 in mice impaired a series of noncognitive behaviors in the early phase of neurodegeneration. This observation suggests that DKO mice are an ideal model for further mechanistic studies of Psen1 and Psen2 functions in regulating noncognitive behaviors.

Chronic Mild Unpredictable Stress and High-Fat Diet Given during Adolescence Impact Both Cognitive and Noncognitive Behaviors in Young Adult Mice.

Stress and diet are intricately linked, and they often interact in a negative fashion. Increases in stress can lead to poor food choices; adolescence is a period that is often accompanied by increased levels of stress. Stress and poor dietary choices can affect learning and memory; it is important to understand their combined effects when occurring during crucial developmental periods. Here, we present evidence that chronic mild unpredictable stress (CMUS) and high-fat diet (HFD) impact both cognitive and noncognitive behaviors when assessed after four weeks of manipulation in four-week old mice. CMUS mice had increased anxiety in the open field test (OFT) (p = 0.01) and spent more time in the open arms of the elevated zero maze (EZM) (p < 0.01). HFD administration was shown to interact with CMUS to impair spatial memory in the Morris Water Maze (MWM) (p < 0.05). Stress and diet also led to disturbances in non-cognitive behaviors: CMUS led to significantly more burrowing (p < 0.05) and HFD administration led to the poorer nest construction (p < 0.05). These findings allow for researchers to assess how modifying lifestyle factors (including diet and stress) during adolescence can serve as a potential strategy to improve cognition in young adulthood.

Dim Light at Night Induced Neurodegeneration and Ameliorative Effect of Curcumin.

It is a well-known fact that following a proper routine light/dark or diurnal rhythm controls almost all biological processes. With the introduction of modern lighting and artificial illumination systems, continuous exposure to light at night may lead to the disruption of diurnal rhythm. However, the effect of light during the night on brain anatomy, physiology, and human body functions is less explored and poorly understood. In this study, we have evaluated the effect of exposure to dim light (5 lux) at night (dLAN) on Swiss Albino mice over a duration of three consecutive weeks. Results have revealed that exposure to dLAN led to an impairment of cognitive and non-cognitive behaviour, oxidative stress–mediated elevation of lipid peroxidation, and reduction of superoxide dismutase and catalase activity. It also led to the downregulation of hippocampal proteins (BDNF, Synapsin II and DCX) at both protein and mRNA level. Additionally, there was downregulation of CREB and SIRT1 mRNAs and neurodegeneration-associated miRNA21a-5p and miRNA34a-5p. The pyramidal and cortical neurons started showing pyknotic and chromatolysis characteristics. However, a dose of curcumin administered to the mice positively modulated these parameters in our experimental animals. We proposed the modulatory role of curcumin in addressing the deleterious effects of dLAN.

The Rap1 small GTPase is a critical mediator of the effects of stress on prefrontal cortical dysfunction.

The neural molecular and biochemical response to stress is a distinct physiological process, and multiple lines of evidence indicate that the prefrontal cortex (PFC) is particularly sensitive to, and afflicted by, exposure to stress. Largely through this PFC dysfunction, stress has a characterized role in facilitating cognitive impairment, which is often dissociable from its effects on non-cognitive behaviors. The Rap1 small GTPase pathway has emerged as a commonly disrupted intracellular target in neuropsychiatric conditions, whether it be via alterations in Rap1 expression or through alterations in the expression of direct and specific upstream Rap1 activators and inhibitors. Here we demonstrate that escalating, intermittent stress increases Rap1 in mouse PFC synapses, results in cognitive impairments, and reduces the preponderance of mature dendritic spines in PFC neurons. Using viral-mediated gene transfer, we reveal that the hyper-induction of Rap1 in the PFC is sufficient to drive stress-relevant cognitive and synaptic phenotypes. These findings point to Rap1 as a critical mediator of stress-driven neuronal and behavioral pathology and highlight a previously unrecognized involvement for Rap1 in novelty-driven PFC engagement.

Development and treatment of aggression in individuals with dementia

Abstract Behavioral and psychological symptoms of dementia (BPSD) are a group of non-cognitive symptoms and behaviors that often occur with a diagnosis of dementia. Aggression is the most prevalent and serious of these noncognitive symptoms. However, the development and treatment of aggression in this population are not always clear and the type of dementia does not further help to clarify this problem. There are biological, psychosocial, and environmental factors that attribute to the development of aggression, but identification has proven difficult due to the homogeneity of symptoms. Few studies have compared the type of aggression across the four most common types of dementia: Alzheimer's Disease (AD), vascular dementia (VaD), dementia with Lewy body (DLB) and frontotemporal dementia (FTD). Results indicated that those with AD are more likely to be physically aggressive, but other factors play a role in how and why it is exhibited. Treatment for aggression in dementia has focused on pharmacological and nonpharmacological methods. Atypical antipsychotics are the most frequently prescribed, nevertheless, these medications come with severe risks. The more recent Nonpharmacological treatments have shown promising results shown in conjunction with psychosocial approaches. Aggression in dementia is associated with a variety of factors and can be treated in multiple ways. Future research is needed in terms of identifying the etiology and presentation of aggression in AD, VaD, DLB, and FTD, developing safe pharmacologic treatments, and evidence-based nonpharmacological methods.

Zerumbone ameliorates behavioral impairments and neuropathology in transgenic APP/PS1 mice by suppressing MAPK signaling

BackgroundAlzheimer’s disease (AD) is a major clinical problem, but there is a distinct lack of effective therapeutic drugs for this disease. We investigated the potential therapeutic effects of zerumbone, a subtropical ginger sesquiterpene, in transgenic APP/PS1 mice, rodent models of AD which exhibit cerebral amyloidosis and neuroinflammation.MethodsThe N9 microglial cell line and primary microglial cells were cultured to investigate the effects of zerumbone on microglia. APP/PS1 mice were treated with zerumbone, and non-cognitive and cognitive behavioral impairments were assessed and compared between the treatment and control groups. The animals were then sacrificed, and tissues were collected for further analysis. The potential therapeutic mechanism of zerumbone and the signaling pathways involved were also investigated by RT-PCR, western blot, nitric oxide detection, enzyme-linked immunosorbent assay, immunohistochemistry, immunofluorescence, and flow cytometry analysis.ResultsZerumbone suppressed the expression of pro-inflammatory cytokines and induced a switch in microglial phenotype from the classic inflammatory phenotype to the alternative anti-inflammatory phenotype by inhibiting the mitogen-activated protein kinase (MAPK)/nuclear factor-kappa B signaling pathway in vitro. After a treatment period of 20 days, zerumbone significantly ameliorated deficits in both non-cognitive and cognitive behaviors in transgenic APP/PS1 mice. Zerumbone significantly reduced β-amyloid deposition and attenuated pro-inflammatory microglial activation in the cortex and hippocampus. Interestingly, zerumbone significantly increased the proportion of anti-inflammatory microglia among all activated microglia, potentially contributing to reduced β-amyloid deposition by enhancing phagocytosis. Meanwhile, zerumbone also reduced the expression of key molecules of the MAPK pathway, such as p38 and extracellular signal-regulated kinase.ConclusionsOverall, zerumbone effectively ameliorated behavioral impairments, attenuated neuroinflammation, and reduced β-amyloid deposition in transgenic APP/PS1 mice. Zerumbone exhibited substantial anti-inflammatory activity in microglial cells and induced a phenotypic switch in microglia from the pro-inflammatory phenotype to the anti-inflammatory phenotype by inhibiting the MAPK signaling pathway, which may play an important role in its neuroprotective effects. Our results suggest that zerumbone is a potential therapeutic agent for human neuroinflammatory and neurodegenerative diseases, in particular AD.

Improvement of APOE4-dependent non-cognitive behavioural traits by postnatal cholinergic stimulation in female mice

The apolipoprotein E (APOE) ε4 allele hastens cognitive decline, but other non-cognitive behaviours, as well as underpinning interactions with the cholinergic system, have not been systematically addressed. Both C57BL/6 and humanised apoE4 female mice were transiently exposed to subclinical doses (0 or 1 mg/kg body weight) of the cholinesterase inhibitor chlorpyrifos (CPF), a widely-used pesticide, from postnatal days 10–15. At 5 months of age, we assessed the impact of APOE4 genotype, postnatal CPF exposure and APOE4 x CPF interactions on anxiety (open field and light-dark tests), stereotypes (digging test) and neophobia (sucrose preference test), as well as on high-fat diet (HFD)-seeking and consumption (scheduled-feeding paradigm). We found that control APOE4 female carriers displayed a robust anxiety-like phenotype, which was accompanied by exaggerated stereotypes and a subtle neophobic response to rewarding foods. In parallel, we observed an amplified “wanting” response for HFD in these mice, which did not entail enhanced “liking”. Notably, postnatal CPF ameliorated the anxiety-like and the heightened HFD-seeking responses in adult apoE4 female mice, while caused them to gain weight steadily compared to control peers. In turn, an early-life transient exposure to CPF fostered the over-consumption of HFD during adulthood without affecting how much this reward was “wanted” or the total caloric intake. These data reveal a role for CPF towards fostering “unhealthy” dietary choices. We conclude that the APOE4 genotype modulates non-cognitive behaviours and we provide support for an APOE4-dependent cholinergic dysfunction.

Voluntary running does not reduce neuroinflammation or improve non-cognitive behavior in the 5xFAD mouse model of Alzheimer\u2019s disease

Physical exercise has been suggested to reduce the risk of developing Alzheimer’s disease (AD) as well as ameliorate the progression of the disease. However, we recently published results from two large epidemiological studies showing no such beneficial effects on the development of AD. In addition, long-term, voluntary running in the 5xFAD mouse model of AD did not affect levels of soluble amyloid beta (Aβ), synaptic proteins or cognitive function. In this follow-up study, we investigate whether running could impact other pathological aspects of the disease, such as insoluble Aβ levels, the neuroinflammatory response and non-cognitive behavioral impairments. We investigated the effects of 24 weeks of voluntary wheel running in female 5xFAD mice (n = 30) starting at 2–3 months of age, before substantial extracellular plaque formation. Running mice developed hindlimb clasping earlier (p = 0.009) compared to sedentary controls. Further, running exacerbated the exploratory behavior in Elevated plus maze (p = 0.001) and anxiety in Open field (p = 0.024) tests. Additionally, microglia, cytokines and insoluble Aβ levels were not affected. Taken together, our findings suggest that voluntary wheel running is not a beneficial intervention to halt disease progression in 5xFAD mice.

Zataria multiflora could improve hippocampal tau protein and TNFα levels and cognitive behavior defects in a rat model of Alzheimer's disease.

Zataria multiflora (ZM) is a plant with ethnopharmacological value which was recently tested to reduce symptoms of Alzheimer's disease (AD). The aim of the present study was to determine the effect of ZM essential oil on spatial cognitive and noncognitive behavior, as well as hippocampal tau protein and tumor necrosis factor alpha (TNFα) concentrations in rats with AD. Thirty-five adult male Sprague Dawley rats (300±30 g) were randomly divided into 5 groups: control (intact rats); sham (received intracerebroventricular (ICV) microinjection of normal saline); AD control (rats with AD that did not receive any treatment); vehicle control (rats with AD that orally received tween-80, 5% (ZM essential oil vehicle) for 20 days) and experimental (rats with AD that orally received ZM essential oil 100 µl/kg/day for 20 days). AD was induced by bidirectional microinjection of β amyloid 1-42 (10 µg/2µl). Tau protein and TNFα concentrations were measured by ELISA methods. Spatial cognitive and noncognitive behavior were determined by Morris water maze (MWM) test. ZM essential oil significantly improved latency time, time spent in the target quarter and cognitive behavior of rats with AD compared to control and sham groups (p<0.05). Hippocampal tau protein and TNFα concentrations were significantly higher in both AD control and vehicle groups compared to control and sham groups respectively (p<0.01 and p<0.001), administration of ZM essential oil reduced these parameters as compared to AD control and vehicle groups respectively (p<0.01 and p<0.001). ZM essential oil improves spatial learning and memory of rats with AD as assessed by MWM test. These effects are associated with decreased concentrations of hippocampal tau protein and TNFα.

Differential effects of post-training scopolamine on spatial and non-spatial learning tasks in mice

Muscarinic antagonist scopolamine has been extensively used to model amnesia in lab rodents, but most studies have focused on the effects of pre-training scopolamine administration. Here, we examined post-training scopolamine administration in C57BL/6JRj mice. Learning was assessed in three different procedures: odour discrimination in a digging paradigm, visual discrimination in a touchscreen-based setup, and spatial learning in the Morris water maze. Scopolamine administration affected performance in the odour discrimination task. More specifically, scopolamine decreased perseverance, which facilitated reversal learning. Similar results were obtained in the visual discrimination task, but scopolamine did not affect performance in the spatial learning task. It is unlikely that these results can be explained by non-memory-related cognitive effects (e.g., attention), non-cognitive behaviours (e.g., locomotor activity) or peripheral side-effects (e.g., mydriasis). They likely relate to the various neuropharmacological actions of scopolamine.

Comparing the effect of the novel ionic cocrystal of lithium salicylate proline (LISPRO) with lithium carbonate and lithium salicylate on memory and behavior in female APPswe/PS1dE9 Alzheimer's mice.

Alzheimer's disease (AD) is characterized by progressive decline of cognition and associated neuropsychiatric signs including weight loss, anxiety, depression, agitation, and aggression, which is particularly pronounced in the female gender. Previously, we have shown that a novel ionic co-crystal of lithium salicylate proline (LISPRO) is an improved lithium formulation compared to the carbonate or salicylate form of lithium in terms of safety and efficacy in reducing AD pathology in Alzheimer's mice. The current study is designed to compare the prophylactic effects of LISPRO, lithium carbonate (LC), and lithium salicylate (LS) on cognitive and noncognitive impairments in female transgenic APPswe/PS1dE9 AD mice. Female APPswe/PS1dE9 mice at 4months of age were orally treated with low-dose LISPRO, LS, or LC for 9months at 2.25mmol lithium/kg/day followed by determination of body weight, growth of internal organs, and cognitive and noncognitive behavior. No significant differences in body or internal organ weight, anxiety or locomotor activity were found between lithium treated and untreated APPswe/PS1dE9 cohorts. LISPRO, LC, and LS prevented spatial cognitive decline, as determined by Morris water maze and depression as determined by tail suspension test. In addition, LISPRO treatment was superior in preventing associative memory decline determined by contextual fear conditioning and reducing irritability determined by touch escape test in comparison with LC and LS. In conclusion, low-dose LISPRO, LC, and LS treatment prevent spatial cognitive decline and depression-like behavior, while LISPRO prevented hippocampal-dependent associative memory decline and irritability in APPswe/PS1dE9 mice.

Phosphodiesterase 1b (PDE1B) Regulates Spatial and Contextual Memory in Hippocampus.

Augmentation of cyclic nucleotide signaling through inhibition of phosphodiesterase (PDE) activity has long been understood to enhance memory. Efforts in this domain have focused predominantly on PDE4, a cAMP-specific phosphodiesterase implicated in consolidation. But less is known about the function of other PDEs expressed in neuroanatomical regions critical to memory. The PDE1 isoforms are the only PDEs to regulate neuronal cAMP and cGMP levels in a Ca2+/Calmodulin (CaM) dependent manner. Here, we show that knock-down of PDE1B in hippocampus of adult mice enhances contextual and spatial memory without effect on non-cognitive behaviors. Pharmacological augmentation of memory in rats was observed with a selective inhibitor of PDE1 dosed before and immediately after training, but not with drug dosed either 1 h after training or before recall. Our data clearly demonstrate a role for the PDE1B isoforms as negative regulators of memory, and they implicate PDE1 in an early phase of consolidation, but not retrieval. Inhibition of PDE1B is a promising therapeutic mechanism for treating memory impairment.

A Novel hAPP/htau Mouse Model of Alzheimer's Disease: Inclusion of APP With Tau Exacerbates Behavioral Deficits and Zinc Administration Heightens Tangle Pathology

The brains of those with Alzheimer's disease have amyloid and tau pathology; thus, mice modeling AD should have both markers. In this study, we characterize offspring from the cross of the J20 (hAPP) and rTg4510 (htau) strains (referred to as dual Tg). Behavior was assessed at both 3.5 and 7 months, and biochemical differences were assessed at 8 months. Additionally, mice were placed on zinc (Zn) water or standard lab water in order to determine the role of this essential biometal. Behavioral measures examined cognition, emotion, and aspects of daily living. Transgenic mice (dual Tg and htau) showed significant deficits in spatial memory in the Barnes Maze at both 3.5 and 7 months compared to controls. At 7 months, dual Tg mice performed significantly worse than htau mice (p < 0.01). Open field and elevated zero maze (EZM) data indicated that dual Tg and htau mice displayed behavioral disinhibition compared to control mice at both 3.5 and 7 months (p < 0.001). Transgenic mice showed significant deficits in activities of daily living, including burrowing and nesting, at both 3.5 and 7 months compared to control mice (p < 0.01). Dual Tg mice built very poor nests, indicating that non-cognitive tasks are also impacted by AD. Overall, dual Tg mice demonstrated behavioral deficits earlier than those shown by the htau mice. In the brain, dual Tg mice had significantly less free Zn compared to control mice in both the dentate gyrus and the CA3 of the hippocampus (p < 0.01). Dual Tg mice had increased tangles and plaques in the hippocampus compared to htau mice and the dual Tg mice given Zn water displayed increased tangle pathology in the hippocampus compared to htau mice on Zn water (p < 0.05). The dual Tg mouse described here displays pathology reminiscent of the human AD condition and is impaired early on in both cognitive and non-cognitive behaviors. This new mouse model allows researchers to assess how both amyloid and tau in combination impact behavior and brain pathology.