Deficits In Olfactory Memory Research Articles

Olfactory Dysfunction Associated with Cognitive Decline in an Elderly Population

ABSTRACT Background In many neurological disorders, including Alzheimer disease, early olfactory dysfunction is observed. Objective In order to determine if deficits in olfactory memory are present in the elderly and if olfactory dysfunction correlates with cognitive impairment in the aging population, olfactory testing has been done on seniors from the NuAge cohort accepting to participate in the Olfactory Response Cognition and Aging (ORCA) secondary sub-study. The t-Mini Mental Statement Examination and the Telephone Interview for Cognitive Status tests were done to assess cognition levels. Results Overall, 94% of the ORCA cohort displayed olfactory dysfunction. Deficits in olfactory memory were also present. A correlation was observed between olfactory function and cognitive test scores. Moreover, in women who smoked, there was an association between olfactory memory and cognitive scores. Conclusion Our results suggest that olfactory dysfunction may predict impending cognitive decline and highlights the need for olfactory training in seniors to improve olfaction and overall well-being.

Effects of caloric restriction on monoaminergic neurotransmission, peripheral hormones, and olfactory memory in aged rats

Aging is associated with a reduced ability to identify and discriminate scents, and olfactory dysfunction has been linked to preclinical stages of neurodegenerative diseases in humans. Moreover, emerging evidence suggests that smell-driven behaviors are regulated by hormones like insulin or leptin, and by metabolic parameters like glucose, which in turn may influence monoaminergic neurotransmission in brain areas related to cognition. Several studies have suggested that dietary interventions like caloric restriction (CR) can mitigate the age-induced decline in memory by modifying metabolic parameters and brain monoaminergic levels. The present study explored the effects of CR on age-dependent olfactory memory deficits, as well as their relationship with peripheral leptin, insulin and glucose levels, and brain monoamines. To this end, aged rats (24-months-old) fed on a CR diet or with ad libitum access to food, and adult rats (3–4 months), were trained in an odor discrimination task (ODT). The peripheral plasma levels of insulin, leptin, and glucose, and of monoamines and metabolites/precursors in brain areas related to olfactory learning and memory processes, such as the striatum and frontal cortex (FC), were determined. The data obtained indicated that CR attenuated the age-dependent decline in olfactory sensitivity in old animals fed ad libitum, which was correlated with the performance in ODT retention trial, as well as with leptin plasma levels. CR enhanced dopamine levels in the striatum, while it attenuated the age-related decline in serotonin levels in the striatum and FC. Such findings support a positive effect of CR on age-dependent olfactory sensitivity decline and dysfunctions in brain monoamine levels.

Inducible and conditional activation of ERK5 MAP kinase rescues mice from cadmium-induced olfactory memory deficits

Cadmium (Cd) is a heavy metal that is one of the most toxic environmental pollutants throughout the world. We previously reported that Cd exposure impairs olfactory memory in mice. However, the underlying mechanisms for its neurotoxicity for olfactory function are not well understood. Since adult Subventricular zone (SVZ) and Olfactory Bulb (OB) neurogenesis contributes to olfaction, olfactory memory defects caused by Cd may be due to inhibition of neurogenesis. In this study, using bromodeoxyuridine (BrdU) labeling and immunohistochemistry, we found that 0.6 mg/L Cd exposure through drinking water impaired adult SVZ/OB neurogenesis in C57BL/6 mice. To determine if the inhibition of olfactory memory by Cd can be reversed by stimulating adult neurogenesis, we utilized the transgenic caMEK5 mouse strain to conditional stimulate of adult neurogenesis by activating the endogenous ERK5 MAP kinase signaling pathway. This was accomplished by conditionally induced expression of active MEK5 (caMEK5) in adult neural stem/progenitor cells. The caMEK5 mice were exposed to 0.6 mg/L Cd for 38 weeks, and tamoxifen was administered to induce caMEK5 expression and stimulate adult SVZ/OB neurogenesis during Cd exposure. Short-term olfactory memory test and sand-digging based, odor-cued olfactory learning and memory test were conducted after Cd and tamoxifen treatments to examine their effects on olfaction. Here we report that Cd exposure impaired short-term olfactory memory and odor-cued associative learning and memory in mice. Furthermore, the Cd-impaired olfactory memory deficits were rescued by the tamoxifen-induction of caMEK5 expression. This suggests that Cd exposure impairs olfactory function by affecting adult SVZ/OB neurogenesis in mice.

Intact olfactory memory in the 5xFAD mouse model of Alzheimer’s disease from 3 to 15 months of age

Alzheimer’s disease (AD) is an age-related neurodegenerative disorder that causes profound cognitive dysfunction. Deficits in olfactory memory occur in early stages of AD and may be useful in AD diagnosis. The 5xFAD mouse is a commonly used model of AD, as it develops neuropathology, cognitive and sensori-motor dysfunctions similar to those seen in AD. However, olfactory memory dysfunction has not been studied adequately or in detail in 5xFAD mice. Furthermore, despite sex differences in AD prevalence and symptom presentation, few studies using 5xFAD mice have examined sex differences in learning and memory. Therefore, we tested olfactory memory in male and female 5xFAD mice from 3 to 15 months of age using a conditioned odour preference task. Olfactory memory was not impaired in male or female 5xFAD mice at any age tested, nor were there any sex differences. Because early-onset impairments in very long-term (remote) memory have been reported in 5xFAD mice, we trained a group of mice at 3 months of age and tested olfactory memory 90 days later. Very long-term olfactory memory in 5xFAD mice was not impaired, nor was their ability to perform the discrimination task with new odourants. Examination of brains from 5xFAD mice confirmed extensive Aβ-plaque deposition spanning the olfactory memory system, including the olfactory bulb, hippocampus, amygdala and piriform cortex. Overall this study indicates that male and female 5xFAD mice do not develop olfactory memory deficits, despite extensive Aβ deposition within the olfactory-memory regions of the brain.

Gad67 haploinsufficiency reduces amyloid pathology and rescues olfactory memory deficits in a mouse model of Alzheimer\u2019s disease

BackgroundAlzheimer’s disease (AD) is the most common age-related neurodegenerative disorder, affecting millions of people worldwide. Although dysfunction of multiple neurotransmitter systems including cholinergic, glutamatergic and GABAergic systems has been associated with AD progression the underlying mechanisms remain elusive. We and others have recently found that GABA content is elevated in AD brains and linked to cognitive deficits in AD mouse models. The glutamic acid decarboxylase 67 (GAD67) is the major enzyme converting glutamate into GABA and has been implied in a number of neurological disorders such as epilepsy and schizophrenia. However, whether Gad67 is involved in AD pathology has not been well studied. Here, we investigate the functional role of GAD67 in an AD mouse model with Gad67 haploinsufficiency that is caused by replacing one allele of Gad67 with green fluorescent protein (GFP) gene during generation of GAD67-GFP mice.MethodsTo genetically reduce GAD67 in AD mouse brains, we crossed the Gad67 haploinsufficient mice (GAD67-GFP+/−) with 5xFAD mice (harboring 5 human familial AD mutations in APP and PS1 genes) to generate a new line of bigenic mice. Immunostaining, ELISA, electrophysiology and behavior test were applied to compare the difference between groups.ResultsWe found that reduction of GAD67 resulted in a significant decrease of amyloid β production in 5xFAD mice. Concurrently, the abnormal astrocytic GABA and tonic GABA currents, as well as the microglial reactivity were significantly reduced in the 5xFAD mice with Gad67 haploinsufficiency. Importantly, the olfactory memory deficit of 5xFAD mice was rescued by Gad67 haploinsufficiency.ConclusionsOur results demonstrate that GAD67 plays an important role in AD pathology, suggesting that GAD67 may be a potential drug target for modulating the progress of AD.

Fus1 KO Mouse As a Model of Oxidative Stress-Mediated Sporadic Alzheimer's Disease: Circadian Disruption and Long-Term Spatial and Olfactory Memory Impairments.

Insufficient advances in the development of effective therapeutic treatments of sporadic Alzheimer's Disease (sAD) to date are largely due to the lack of sAD-relevant animal models. While the vast majority of models do recapitulate AD's hallmarks of plaques and tangles by virtue of tau and/or beta amyloid overexpression, these models do not reflect the fact that in sAD (unlike familial AD) these genes are not risk factors per se and that other mechanisms like oxidative stress, metabolic dysregulation and inflammation play key roles in AD etiology. Here we characterize and propose the Fus1 KO mice that lack a mitochondrial protein Fus1/Tusc2 as a new sAD model. To establish sAD relevance, we assessed sAD related deficits in Fus1 KO and WT adult mice of 4–5 months old, the equivalent human age when the earliest cognitive and olfactory sAD symptoms arise. Fus1 KO mice showed oxidative stress (increased levels of ROS, decreased levels of PRDX1), disruption of metabolic homeostasis (decreased levels of ACC2, increased phosphorylation of AMPK), autophagy (decreased levels of LC3-II), PKC (decreased levels of RACK1) and calcium signaling (decreased levels of Calb2) in the olfactory bulb and/or hippocampus. Mice were behaviorally tested using objective and accurate video tracking (Noldus), in which Fus1 KO mice showed clear deficits in olfactory memory (decreased habituation/cross-habituation in the short and long term), olfactory guided navigation memory (inability to reduce their latency to find the hidden cookie), spatial memory (learning impairments on finding the platform in the Morris water maze) and showed more sleep time during the diurnal cycle. Fus1 KO mice did not show clear deficits in olfactory perception (cross-habituation), association memory (passive avoidance) or in species-typical behavior (nest building) and no increased anxiety (open field, light-dark box) or depression/anhedonia (sucrose preference) at this relatively young age. These neurobehavioral deficits of the Fus1 KO mice at this relatively young age are highly relevant to sAD, making them suitable for effective research on pharmacological targets in the context of early intervention of sAD.

4-Hydroxyisophthalic acid from Decalepis hamiltonii rescues the neurobehavioral deficit in transgenic Drosophila model of taupathies

Oxidative stress is one of the major etiological factors implicated in pathogenesis of neurodegenerative diseases. Since neurons are more sensitive to oxidative damage there is an increasing interest in developing novel antioxidant therapies, especially herbal preparations due to their safety profile and high efficiency. In this regard, the neuroprotective potential of a novel antioxidant compound, 4-hydroxyisophthalic acid (4-HIPA) isolated from aqueous extract of Decalepis hamiltonii roots was examined using transgenic Drosophila model of taupathy expressing wild-type and mutant forms of 2N4R isoform of human microtubule associated protein tau (MAPT). Taupathy model flies showed cognitive deficits in olfactory memory and deteriorated circadian rhythm of locomotory activities. Administration of 0.1 mg/ml 4-HIPA, markedly enhanced their olfactory memory performance and restored circadian rhythmicity of the transgenic flies locomotory behavior to the normal range. The mechanism of action that underlies 4-HIPA neuroprotection involves enhancement in efficiency of cellular antioxidant defense system by means of elevation in antioxidant enzyme activities and attenuation of oxidative stress. The molecule could positively affect the activity of neurotransmitter enzymes, which in turn enhances neuronal function and ameliorates the Tau-induced neurobehavioral deficits. Our findings showed that 4-HIPA can be considered as a suitable therapeutic candidate for drug development towards treatment of neurodegenerative disorders.

D-cycloserine in Prelimbic Cortex Reverses Scopolamine-Induced Deficits in Olfactory Memory in Rats

A significant interaction between N-methyl-D-aspartate (NMDA) and muscarinic receptors has been suggested in the modulation of learning and memory processes. The present study further investigates this issue and explores whether d-cycloserine (DCS), a partial agonist at the glycine binding site of the NMDA receptors that has been regarded as a cognitive enhancer, would reverse scopolamine (SCOP)-induced amnesia in two olfactory learning tasks when administered into the prelimbic cortex (PLC). Thus, in experiment 1, DCS (10 µg/site) was infused prior to acquisition of odor discrimination (ODT) and social transmission of food preference (STFP), which have been previously characterized as paradigms sensitive to PLC muscarinic blockade. Immediately after learning such tasks, SCOP was injected (20 µg/site) and the effects of both drugs (alone and combined) were tested in 24-h retention tests. To assess whether DCS effects may depend on the difficulty of the task, in the STFP the rats expressed their food preference either in a standard two-choice test (experiment 1) or a more challenging three-choice test (experiment 2). The results showed that bilateral intra-PLC infusions of SCOP markedly disrupted the ODT and STFP memory tests. Additionally, infusions of DCS alone into the PLC enhanced ODT but not STFP retention. However, the DCS treatment reversed SCOP-induced memory deficits in both tasks, and this effect seemed more apparent in ODT and 3-choice STFP. Such results support the interaction between the glutamatergic and the cholinergic systems in the PLC in such a way that positive modulation of the NMDA receptor/channel, through activation of the glycine binding site, may compensate dysfunction of muscarinic neurotransmission involved in stimulus-reward and relational learning tasks.

The arouser EPS8L3 Gene Is Critical for Normal Memory in Drosophila

The genetic mechanisms that influence memory formation and sensitivity to the effects of ethanol on behavior in Drosophila have some common elements. So far, these have centered on the cAMP/PKA signaling pathway, synapsin and fas2-dependent processes, pumilio-dependent regulators of translation, and a few other genes. However, there are several genes that are important for one or the other behaviors, suggesting that there is an incomplete overlap in the mechanisms that support memory and ethanol sensitive behaviors. The basis for this overlap is far from understood. We therefore examined memory in arouser (aru) mutant flies, which have recently been identified as having ethanol sensitivity deficits. The aru mutant flies showed memory deficits in both short-term place memory and olfactory memory tests. Flies with a revertant aru allele had wild-type levels of memory performance, arguing that the aru gene, encoding an EPS8L3 product, has a role in Drosophila memory formation. Furthermore, and interestingly, flies with the aru8–128 insertion allele had deficits in only one of two genetic backgrounds in place and olfactory memory tests. Flies with an aru imprecise excision allele had deficits in tests of olfactory memory. Quantitative measurements of aru EPS8L3 mRNA expression levels correlate decreased expression with deficits in olfactory memory while over expression is correlated with place memory deficits. Thus, mutations of the aru EPS8L3 gene interact with the alleles of a particular genetic background to regulate arouser expression and reveals a role of this gene in memory.

Locus coeruleus degeneration exacerbates olfactory deficits in APP/PS1 transgenic mice

Neuronal loss in the locus coeruleus (LC) is 1 of the early pathological events in Alzheimer's disease (AD). Projections of noradrenergic neurons of the LC innervate the olfactory bulb (OB). Because olfactory deficits have been reported in early AD, we investigated the effect of induced LC degeneration on olfactory memory and discrimination in an AD mouse model. LC degeneration was induced by treating APP/PS1 mice with N-(2-chloroethyl)-N-ethyl-bromo-benzylamine (DSP4) repeatedly between 3 and 12 months of age. Short term odor retention, ability for spontaneous habituation to an odor, and spontaneous odor discrimination were assessed by behavioral tests. DSP4 treatment in APP/PS1 mice resulted in an exacerbation of short term olfactory memory deficits and more discrete weakening of olfactory discrimination abilities, suggesting that LC degeneration contributes to olfactory deficits observed in AD. Importantly, DSP4 treatment also increased amyloid β (Aβ) deposition in the olfactory bulb of APP/PS1 mice, which correlated with olfactory memory, not with discrimination deficits.

P1-102: Evaluation of species-typical behavior, learning and memory in a single transgenic mouse model of Alzheimer's disease

Transgenic mouse models are important for the study of genetic, neural and behavioral deficits found in Alzheimer's disease. We evaluated the behavior of the single transgenic Alzheimer's mouse strain B6.Cg-Tg(PDGFB-APPSwInd)20Lms/1J (JAX # 004661) and their wildtype littermate controls in tests of anxiety (marble burying, open field), species-typical behaviors (nest building), and learning and memory (novel object recognition/location, Morris water maze, conditioned odor preference) at 8, 12 and 16 months of age. There was no difference in the number of marbles buried in the marble-burying test at 8 or 12 months of age. At 8 months of age, the wildtype mice were more active in the open field than the transgenic mice, whereas at 12 months of age the transgenic mice spent more time in the center. There was a trend for transgenic mice to build poorer nests than their wildtype controls. There was no significant difference in learning and memory in the novel object location/recognition task, although the transgenic mice explored the objects longer than wildtype mice at 8 months of age. Transgenic mice performed worse than wildtype in latency to find the platform in the Morris water maze at 8 months of age and spent less time in the correct quadrant during the probe trial, indicating poorer memory. There was no difference in latency to the platform at 12 months of age, but transgenic mice still spent less time in the correct quadrant during the probe trial than wildtype mice. There was no difference in learning or remembering the odors in the conditioned odor preference test at 8 or 12 months of age. It appears that the B6.Cg-Tg(PDGFB-APPSwInd)20Lms/1J mice have deficits in spatial memory, as demonstrated by poor performance in the probe trial of the Morris water maze, but no deficits in olfactory memory or species-typical behavior at the ages tested.

Aging and Olfactory Recognition Memory: Effect of Encoding Strategies and Cognitive Abilities

The effects of two encoding manipulations on recognition memory for odors were examined in 20 young and 20 elderly males. Subjects were instructed to use two different encoding strategies: (1) labeling-plus-definition (i.e., naming the odor and giving a short description) and, (2) life-episode association (i.e., associating a memory of a life-episode with each odor). Results revealed that elderly subjects performed significantly worse than young subjects in the labeling-plus-definition condition, but not in the life-episode task in which they achieved a level of performance not significantly different from the young. Encoding specificity or precision did not significantly impact recognition memory for the odors in either group. Analysis of response bias revealed that, in the label-plus-definition condition, young subjects were more conservative in responding style, while more liberal in their responding in the life-episode condition. In contrast, elderly subjects exhibited nearly identical response bias across both encoding conditions. The results suggest that age-related deficits in olfactory memory may be strategy dependent.

Neuronal degeneration in rat cerebrocortical and olfactory regions during subchronic "binge" intoxication with ethanol: possible explanation for olfactory deficits in alcoholics.

Severe, repetitive ("binge") ethanol intoxication in adult rats (intragastric delivery 3 times daily for 4 days in a modification of the Majchrowicz method) precipitates neuronal degeneration in selected cerebral cortical regions involved in memory and olfaction, confirming the results of Switzer and colleagues (Anat. Rec. 202: 186a, 1982). Neuronal damage was visualized with the de Olmos cupric silver technique for degenerating neurons and processes (argyrophilia), and was quantitated by total counts and densities of argyrophilic cells/fields. The specificity of the degeneration provides a neuropathological basis for the olfactory memory deficits in chronic alcoholics. In highly intoxicated rats, argyrophilia was most extensive among hippocampal dentate gyrus granule cells, pyramidal neurons in layer 3 of the entorhinal cortex, and olfactory nerve terminals in the olfactory bulb. Degenerating pyramidal neurons were also consistently seen in the insular cortex and olfactory cortical regions, such as the piriform and perirhinal cortices. There were few argyrophilic neurons in the CA regions of the hippocampus and none in the cerebellum--regions generally shown to have cell loss in long-term ethanol feeding models--but degenerating mossy fibers in the CA2 region were observed. Degeneration was maximal before the peak period of abstinence symptoms in this model, because argyrophilic densities were no greater 36 hr, compared with 8 hr after the last ethanol dose. High blood ethanol levels were required, because argyrophilia, absent from isocaloric controls, also was only evident in ethanol-intoxicated rats with mean blood ethanol levels for days 2 to 4 above 300 mg/dl; however, it increased substantially between 350 and 550 mg/dl. The resemblance of the argyrophilic distribution to the regional neuropathology that occurs in experimental seizures indicates that the ethanol-induced degeneration may have an excitotoxic basis. Progressive reductions in the seizure threshold (e.g., kindling phenomena that have been documented during binge ethanol intoxication) might be associated with excitotoxic hyperactivity during the repetitive nadirs between high blood and brain ethanol peaks. However, direct toxic actions of ethanol or its metabolites could also be involved. Overall, the model should be useful for studying mechanisms of ethanol-induced selective cortical and olfactory brain damage.