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1.  Cortical Odor Processing in Health and Disease 
Progress in brain research  2014;208:275-305.
The olfactory system has a rich cortical representation, including a large archicortical component present in most vertebrates, and in mammals neocortical components including the entorhinal and orbitofrontal cortices. Together, these cortical components contribute to normal odor perception and memory. They help transform the physicochemical features of volatile molecules inhaled or exhaled through the nose into the perception of odor objects with rich associative and hedonic aspects. This chapter focuses on how olfactory cortical areas contribute to odor perception and begins to explore why odor perception is so sensitive to disease and pathology. Odor perception is disrupted by a wide range of disorders including Alzheimer’s disease, Parkinson’s disease, schizophrenia, depression, autism, and early life exposure to toxins. This olfactory deficit often occurs despite maintained functioning in other sensory systems. Does the unusual network of olfactory cortical structures contribute to this sensitivity?
PMCID: PMC4284974  PMID: 24767487
piriform cortex; orbitofrontal cortex; entorhinal cortex; mediodorsal thalamus; odor perception
2.  Glutamatergic Transmission Aberration: A Major Cause of Behavioral Deficits in a Murine Model of Down's Syndrome 
The Journal of Neuroscience  2014;34(15):5099-5106.
Trisomy 21, or Down's syndrome (DS), is the most common genetic cause of intellectual disability. Altered neurotransmission in the brains of DS patients leads to hippocampus-dependent learning and memory deficiency. Although genetic mouse models have provided important insights into the genes and mechanisms responsible for DS-specific changes, the molecular mechanisms leading to memory deficits are not clear. We investigated whether the segmental trisomy model of DS, Ts[Rb(12.1716)]2Cje (Ts2), exhibits hippocampal glutamatergic transmission abnormalities and whether these alterations cause behavioral deficits. Behavioral assays demonstrated that Ts2 mice display a deficit in nest building behavior, a measure of hippocampus-dependent nonlearned behavior, as well as dysfunctional hippocampus-dependent spatial memory tested in the object-placement and the Y-maze spontaneous alternation tasks. Magnetic resonance spectra measured in the hippocampi revealed a significantly lower glutamate concentration in Ts2 as compared with normal disomic (2N) littermates. The glutamate deficit accompanied hippocampal NMDA receptor1 (NMDA-R1) mRNA and protein expression level downregulation in Ts2 compared with 2N mice. In concert with these alterations, paired-pulse analyses suggested enhanced synaptic inhibition and/or lack of facilitation in the dentate gyrus of Ts2 compared with 2N mice. Ts2 mice also exhibited disrupted synaptic plasticity in slice recordings of the hippocampal CA1 region. Collectively, these findings imply that deficits in glutamate and NMDA-R1 may be responsible for impairments in synaptic plasticity in the hippocampus associated with behavioral dysfunctions in Ts2 mice. Thus, these findings suggest that glutamatergic deficits have a significant role in causing intellectual disabilities in DS.
PMCID: PMC3983795  PMID: 24719089
Down's syndrome; glutamate; LTP; NMDA receptors; spatial memory
3.  Slow-Wave Sleep-Imposed Replay Modulates Both Strength and Precision of Memory 
The Journal of Neuroscience  2014;34(15):5134-5142.
Odor perception is hypothesized to be an experience-dependent process involving the encoding of odor objects by distributed olfactory cortical ensembles. Olfactory cortical neurons coactivated by a specific pattern of odorant evoked input become linked through association fiber synaptic plasticity, creating a template of the familiar odor. In this way, experience and memory play an important role in odor perception and discrimination. In other systems, memory consolidation occurs partially via slow-wave sleep (SWS)-dependent replay of activity patterns originally evoked during waking. SWS is ideal for replay given hyporesponsive sensory systems, and thus reduced interference. Here, using artificial patterns of olfactory bulb stimulation in a fear conditioning procedure in the rat, we tested the effects of imposed post-training replay during SWS and waking on strength and precision of pattern memory. The results show that imposed replay during post-training SWS enhanced the subsequent strength of memory, whereas the identical replay during waking induced extinction. The magnitude of this enhancement was dependent on the timing of imposed replay relative to cortical sharp-waves. Imposed SWS replay of stimuli, which differed from the conditioned stimulus, did not affect conditioned stimulus memory strength but induced generalization of the fear memory to novel artificial patterns. Finally, post-training disruption of piriform cortex intracortical association fiber synapses, hypothesized to be critical for experience-dependent odor coding, also impaired subsequent memory precision but not strength. These results suggest that SWS replay in the olfactory cortex enhances memory consolidation, and that memory precision is dependent on the fidelity of that replay.
PMCID: PMC3983797  PMID: 24719093
memory; odor memory; odor object; olfaction; piriform cortex; sleep
4.  Spared Piriform Cortical Single-Unit Odor Processing and Odor Discrimination in the Tg2576 Mouse Model of Alzheimer's Disease 
PLoS ONE  2014;9(9):e106431.
Alzheimer's disease is a neurodegenerative disorder that is the most common cause of dementia in the elderly today. One of the earliest reported signs of Alzheimer's disease is olfactory dysfunction, which may manifest in a variety of ways. The present study sought to address this issue by investigating odor coding in the anterior piriform cortex, the primary cortical region involved in higher order olfactory function, and how it relates to performance on olfactory behavioral tasks. An olfactory habituation task was performed on cohorts of transgenic and age-matched wild-type mice at 3, 6 and 12 months of age. These animals were then anesthetized and acute, single-unit electrophysiology was performed in the anterior piriform cortex. In addition, in a separate group of animals, a longitudinal odor discrimination task was conducted from 3–12 months of age. Results showed that while odor habituation was impaired at all ages, Tg2576 performed comparably to age-matched wild-type mice on the olfactory discrimination task. The behavioral data mirrored intact anterior piriform cortex single-unit odor responses and receptive fields in Tg2576, which were comparable to wild-type at all age groups. The present results suggest that odor processing in the olfactory cortex and basic odor discrimination is especially robust in the face of amyloid β precursor protein (AβPP) over-expression and advancing amyloid β (Aβ) pathology. Odor identification deficits known to emerge early in Alzheimer's disease progression, therefore, may reflect impairments in linking the odor percept to associated labels in cortical regions upstream of the primary olfactory pathway, rather than in the basic odor processing itself.
PMCID: PMC4152226  PMID: 25181487
5.  Lung Function Profiles among Individuals with Nonmalignant Asbestos-related Disorders 
Safety and Health at Work  2014;5(4):234-237.
Inhalation of asbestos fibers can lead to adverse health effects on the lungs. This study describes lung function profiles among individuals with nonmalignant asbestos-related disorders (ARDs).
The study population was from the Workers' Compensation (Dust Diseases) Board of New South Wales, Sydney, Australia. Lung function measurements were conducted in males with asbestosis (n = 26), diffuse pleural thickening (DPT; n = 129), asbestosis and DPT (n = 14), pleural plaques only (n = 160) and also apparently healthy individuals with a history of asbestos exposure (n = 248). Standardized spirometric and single-breath diffusing capacity for carbon monoxide (DLCO) measurements were used.
Mean age [standard deviation (SD)] was 66.7 (10.3) years for all participants. Current and ex-smokers among all participants comprised about 9.0% and 54.8%, respectively. Median pack-years (SD) of smoking for ex- and current-smokers were 22.7 (19.9). Overall 222 participants (38.6%) and 139 participants (24.2%) had forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) measurements < 80% predicted, and 217 participants (37.7%) had FEV1/FVC results < 70%. A total of 249 individuals (43.8%) had DLco values < 80% predicted and only 75 (13.2%) had DLco/VA results < 80% predicted. A total of 147 participants (25.6%) had peak expiratory flow (PEF) measurements < 80% predicted. The presence of ARDs lowered the lung function measurements compared to those of healthy individuals exposed to asbestos.
Lung function measurement differs in individuals with different ARDs. Monitoring of lung function among asbestos-exposed populations is a simple means of facilitating earlier interventions.
PMCID: PMC4266811  PMID: 25516818
asbestos; asbestosis; diffuse pleural thickening; pleural plaques; lung function
6.  Titanium Dioxide Exposure Induces Acute Eosinophilic Lung Inflammation in Rabbits 
Industrial Health  2014;52(4):289-295.
Titanium dioxide (TiO2) is increasingly widely used in industrial, commercial and home products. TiO2 aggravates respiratory symptoms by induction of pulmonary inflammation although the mechanisms have not been well investigated. We aimed to investigate lung inflammation in rabbits after intratracheal instillation of P25 TiO2. One ml of 10, 50 and 250 µg of P25 TiO2 was instilled into one of the lungs of rabbits, chest computed-tomography was performed, and bronchoalveolar lavage (BAL) fluid was collected before, at 1 and 24 h after P25 TiO2 exposure. Changes in inflammatory cells in the BAL fluids were measured. Lung pathological assay was also carried out at 24 h after P25 TiO2 exposure. Ground glass opacities were noted in both lungs 1 h after P25 TiO2 and saline (control) instillation. Although the control lung showed complete resolution at 24 h, the lung exposed to P25 TiO2 showed persistent ground glass opacities at 24 h. The eosinophil counts in BAL fluid were significantly increased after P25 TiO2 exposure. P25 TiO2 induced a dose dependent increase of eosinophils in BAL fluid but no significant differences in neutrophil and lymphocyte cell counts were detected. The present findings suggest that P25 TiO2 induces lung inflammation in rabbits which is associated with eosinophilic inflammation.
PMCID: PMC4243014  PMID: 24705802
Allergy; Eosinophil; Inflammation; P25 TiO2 nanoparticle
Neuroscience letters  2013;545:50-53.
Pattern separation plays an important role in perception and memory. In olfaction, pattern separation is critical component of piriform cortical odor processing contributing to behavioral perception of overlapping odor mixtures. Previous work has demonstrated that odor discrimination ability is modulated by acetylcholine. Here, we extended this previous work by using a distinct, well characterized complex odor stimulus set that has been shown to differentially involve pattern separation processes within piriform cortex. We find that the cholinergic muscarinic receptor agonist oxotremorine facilitates the acquisition of odor discrimination. Furthermore, the muscarinic receptor antagonist scopolamine impairs acquisition of odor discrimination even if the antagonist is limited to the piriform cortex. Finally, acetylcholine effects are most robust during discrimination acquisition, with minimal effects during expression.
PMCID: PMC3682214  PMID: 23624024
Odor discrimination; pattern separation; acetylcholine; piriform cortex; odor memory; perceptual learning
8.  Lateral Entorhinal Modulation of Piriform Cortical Activity and Fine Odor Discrimination 
The Journal of Neuroscience  2013;33(33):13449-13459.
The lateral entorhinal cortex (LEC) receives direct input from olfactory bulb mitral cells and piriform cortical pyramidal cells and is the gateway for olfactory input to the hippocampus. However, the LEC also projects back to the piriform cortex and olfactory bulb. Activity in the LEC is shaped by input from the perirhinal cortices, hippocampus, and amygdala, and thus could provide a rich contextual modulation of cortical odor processing. The present study further explored LEC feedback to anterior piriform cortex by examining how LEC top-down input modulates anterior piriform cortex odor evoked activity in rats. Retrograde viral tracing confirmed rich LEC projections to both the olfactory bulb and piriform cortices. In anesthetized rats, reversible lesions of the ipsilateral LEC increased anterior piriform cortical single-unit spontaneous activity. In awake animals performing an odor discrimination task, unilateral LEC reversible lesions enhanced ipsilateral piriform cortical local field potential oscillations during odor sampling, with minimal impact on contralateral activity. Bilateral LEC reversible lesions impaired discrimination performance on a well learned, difficult odor discrimination task, but had no impact on a well learned simple odor discrimination task. The simple discrimination task was impaired by bilateral reversible lesions of the anterior piriform cortex. Given the known function of LEC in working memory and multisensory integration, these results suggest it may serve as a powerful top-down modulator of olfactory cortical function and odor perception. Furthermore, the results provide potential insight into how neuropathology in the entorhinal cortex could contribute to early olfactory deficits seen in Alzheimer's disease.
PMCID: PMC3742931  PMID: 23946403
9.  Chronic anti-murine Aβ immunization preserves odor guided behaviors in an Alzheimer's β-amyloidosis model 
Behavioural brain research  2012;237:96-102.
Olfaction is often impaired in Alzheimer‟s disease (AD) and is also dysfunctional in mouse models of the disease. We recently demonstrated that short-term passive anti-murine-Aβ immunization can rescue olfactory behavior in the Tg2576 mouse model overexpressing a human mutation of the amyloid precursor protein (APP) after β-amyloid deposition. Here we tested the ability to preserve normal olfactory behaviors by means of long-term passive anti-murine-Aβ immunization. Seven-month-old Tg2576 and non-transgenic littermate (NTg) mice were IP-injected biweekly with the m3.2 murine-Aβ-specific antibody until 16 months of age when mice were tested in the odor habituation test. While Tg2576 mice treated with a control antibody showed elevations in odor investigation times and impaired odor habituation compared to NTg, olfactory behavior was preserved to NTg levels in m3.2-immunized Tg2576 mice. Immunized Tg2576 mice had significantly less β-amyloid immunolabeling in the olfactory bulb and entorhinal cortex, yet showed elevations in Thioflavin-S labeled plaques in the piriform cortex. No detectable changes in APP metabolite levels other than Aβ were found following m3.2 immunization. These results demonstrate efficacy of chronic, long-term anti-murine-Aβ m3.2 immunization in preserving normal odor-guided behaviors in a human APP Tg model. Further, these results provide mechanistic insights into olfactory dysfunction as a biomarker for AD by yielding evidence that focal reductions of Aβ may be sufficient to preserve olfaction.
PMCID: PMC3500395  PMID: 23000537
Olfaction; Neurodegeneration; Alzheimer's disease; amyloid-beta; APP; immunization
10.  Immunization targeting a minor plaque constituent clears β-amyloid and rescues behavioral deficits in an Alzheimer's disease mouse model 
Neurobiology of aging  2012;34(1):137-145.
While anti-human-Aβ immunotherapy clears brain β-amyloid plaques in Alzheimer's disease (AD), targeting additional brain plaque constituents to promote clearance has not been attempted. Endogenous murine Aβ is a minor β-amyloid plaque component in amyloid precursor protein transgenic AD models, which we show is ~2–8% of the total accumulated Aβ in various human APP transgenic mice. Murine Aβ co-deposits and co-localizes with human Aβ in amyloid plaques and the two Aβ species co-immunoprecipitate together from brain extracts. In the human APP transgenic mice Tg2576, passive immunization for eight weeks with a murine-Aβ-specific antibody reduced β-plaque pathology, robustly decreasing both murine and human Aβ levels. The immunized mice additionally showed improvements in two behavioral assays, odor habituation and nesting behavior. We conclude that passive anti-murine-Aβ immunization clears β-amyloid plaque pathology – including the major human Aβ component – and decreases behavioral deficits, arguing that targeting minor, endogenous brain plaque constituents can be beneficial, broadening the range of plaque-associated targets for AD therapeutics.
PMCID: PMC3426627  PMID: 22608241
Alzheimer's disease; Aβ; co-deposition; immunization; immunotherapy
11.  Sleep and olfactory cortical plasticity 
In many systems, sleep plays a vital role in memory consolidation and synaptic homeostasis. These processes together help store information of biological significance and reset synaptic circuits to facilitate acquisition of information in the future. In this review, we describe recent evidence of sleep-dependent changes in olfactory system structure and function which contribute to odor memory and perception. During slow-wave sleep, the piriform cortex becomes hypo-responsive to odor stimulation and instead displays sharp-wave activity similar to that observed within the hippocampal formation. Furthermore, the functional connectivity between the piriform cortex and other cortical and limbic regions is enhanced during slow-wave sleep compared to waking. This combination of conditions may allow odor memory consolidation to occur during a state of reduced external interference and facilitate association of odor memories with stored hedonic and contextual cues. Evidence consistent with sleep-dependent odor replay within olfactory cortical circuits is presented. These data suggest that both the strength and precision of odor memories is sleep-dependent. The work further emphasizes the critical role of synaptic plasticity and memory in not only odor memory but also basic odor perception. The work also suggests a possible link between sleep disturbances that are frequently co-morbid with a wide range of pathologies including Alzheimer’s disease, schizophrenia and depression and the known olfactory impairments associated with those disorders.
PMCID: PMC4001050  PMID: 24795585
olfaction; piriform cortex; slow-wave sleep; odor memory; odor perception; memory consolidation
12.  Differential memory persistence of odor mixture and components in newborn rabbits: competition between the whole and its parts 
Interacting with the mother during the daily nursing, newborn rabbits experience her body odor cues. In particular, the mammary pheromone (MP) contained in rabbit milk triggers the typical behavior which helps to localize and seize the nipples. It also promotes the very rapid appetitive learning of simple or complex stimuli (odorants or mixtures) through associative conditioning. We previously showed that 24 h after MP-induced conditioning to odorants A (ethyl isobutyrate) or B (ethyl maltol), newborn rabbits perceive the AB mixture in a weak configural way, i.e., they perceive the odor of the AB configuration in addition to the odors of the elements. Moreover, after conditioning to the mixture, elimination of the memories of A and B does not affect the memory of AB, suggesting independent elemental and configural memories of the mixture. Here, we evaluated whether configural memory persistence differs from elemental one. First, whereas 1 or 3-day-old pups conditioned to A or B maintained their responsiveness to the conditioned odorant for 4 days, those conditioned to AB did not respond to the mixture after the same retention period. Second, the pups conditioned to AB still responded to A and B 4 days after conditioning, which indicates stronger retention of the elements than of the configuration when all information are learned together. Third, we determined whether the memory of the elements competes with the memory of the configuration: after conditioning to AB, when the memories of A and B were erased using pharmacological treatment, the memory of the mixture was extended to day 5. Thus, newborn rabbits have access to both elemental and configural information in certain odor mixtures, and competition between these distinct representations of the mixture influences the persistence of their memories. Such effects certainly occur in the natural context of mother-pup interactions and may contribute to early acquisition of knowledge about the surroundings.
PMCID: PMC4059275  PMID: 24982622
Oryctolagus cuniculus; newborn; odor mixture; configural perception; stimulus representation; retention; memory persistence
13.  Habituation mechanisms and their importance for cognitive function 
PMCID: PMC4288050  PMID: 25620920
habituation; sensorimotor gating; sensory filtering; synaptic mechanisms; behavioral plasticity; learning and memory
14.  Hazardous Metal Pollution in the Republic of Fiji and the Need to Elicit Human Exposure 
The fact that hazardous metals do not bio-degrade or bio-deteriorate translates to long-lasting environmental effects. In the context of evidently rapid global industrialization, this ought to warrant serious caution, particularly in developing countries. In the Republic of Fiji, a developing country in the South Pacific, several different environmental studies over the past 20 years have shown levels of lead, copper, zinc and iron in sediments of the Suva Harbor to be 6.2, 3.9, 3.3 and 2.1 times more than the accepted background reference levels, respectively. High levels of mercury have also been reported in lagoon shellfish. These data inevitably warrant thorough assessment of the waste practices of industries located upstream from the estuaries, but in addition, an exposure and health impact assessment has never been conducted. Relevant government departments are duty-bound, at least to the general public that reside in and consume seafood from the vicinities of the Suva Harbor, to investigate possible human effects of the elevated hazardous metal concentrations found consistently in 20 years of surface sediment analysis. Furthermore, pollution of the intermediate food web with hazardous metals should be investigated, regardless of whether human effects are eventually confirmed present or not.
PMCID: PMC3909747  PMID: 24498594
Developing countries; Fiji; Hazardous metals; Hazardous metal poisoning; Hazardous metal pollution; Industrialization
15.  Odor-evoked activity in the mouse lateral entorhinal cortex 
Neuroscience  2012;223:12-20.
The entorhinal cortex is a brain area with multiple reciprocal connections to the hippocampus, amygdala, perirhinal cortex, olfactory bulb and piriform cortex. As such, it is thought to play a large role in the olfactory memory process. The present study is the first to compare lateral entorhinal and anterior piriform cortex odor-evoked single-unit and local field potential activity in mouse. Recordings were made in urethane-anesthetized mice that were administered a range of 3 pure odors and 3 overlapping odor mixtures. Results show that spontaneous as well as odor-evoked unit activity was lower in lateral entorhinal versus piriform cortex. In addition, units in lateral entorhinal cortex were responsive to a more restricted set of odors compared to piriform. Conversely, odor-evoked power change in local field potential activity was greater in the lateral entorhinal cortex in the theta band than in piriform. The highly odor-specific and restricted firing in lateral entorhinal cortex suggests that it may play a role in modulating odor-specific, experience- and state-dependent olfactory coding.
PMCID: PMC3455128  PMID: 22871522
Olfaction; Piriform cortex; Lateral entorhinal cortex; Single-Unit; Mouse
16.  Long-Lasting Neural Circuit Dysfunction Following Developmental Ethanol Exposure 
Brain sciences  2013;3(2):704-727.
Fetal Alcohol Spectrum Disorder (FASD) is a general diagnosis for those exhibiting long-lasting neurobehavioral and cognitive deficiencies as a result of fetal alcohol exposure. It is among the most common causes of mental deficits today. Those impacted are left to rely on advances in our understanding of the nature of early alcohol-induced disorders toward human therapies. Research findings over the last decade have developed a model where ethanol-induced neurodegeneration impacts early neural circuit development, thereby perpetuating subsequent integration and plasticity in vulnerable brain regions. Here we review our current knowledge of FASD neuropathology based on discoveries of long-lasting neurophysiological effects of acute developmental ethanol exposure in animal models. We discuss the important balance between synaptic excitation and inhibition in normal neural network function, and relate the significance of that balance to human FASD as well as related disease states. Finally, we postulate that excitation/inhibition imbalance caused by early ethanol-induced neurodegeneration results in perturbed local and regional network signaling and therefore neurobehavioral pathology.
PMCID: PMC3767176  PMID: 24027632
alcohol; FASD; neural circuit; brain development; excitation/inhibition balance; neurodegeneration
17.  Response to Comments on “ApoE-Directed Therapeutics Rapidly Clear β-Amyloid and Reverse Deficits in AD Mouse Models” 
Science (New York, N.Y.)  2013;340(6135):924-92g.
The data reported in the Technical Comments by Fitz et al., Price et al., Tesseur et al., and Veeraraghavalu et al. replicate and validate our central conclusion that bexarotene stimulates the clearance of soluble β-amyloid peptides and results in the reversal of behavioral deficits in mouse models of Alzheimer’s disease (AD). The basis of the inability to reproduce the drug-stimulated microglial-mediated reduction in plaque burden is unexplained. However, we concluded that plaque burden is functionally unrelated to improved cognition and memory elicited by bexarotene.
PMCID: PMC3714602  PMID: 23704556
18.  Binding of titanium dioxide nanoparticles to lactate dehydrogenase 
Measurement of released lactate dehydrogenase (LDH) activity, a commonly used marker of lethal cell injury in both in vitro and in vivo screenings, has been used to assess the cytotoxicity of nanoparticles (NPs), chemical compounds, and environmental factors. We have recently demonstrated that titanium dioxide (TiO2) particles bind to several serum proteins. In the present study we investigated the binding of TiO2 NPs to LDH.
Purified LDH was incubated with TiO2 NPs at 37°C for 1 h. The particles were then sedimented by centrifugation, and the activity and quantity of LDH in the supernatant and precipitated fraction were analyzed.
Incubation with TiO2 reduced the LDH activity in the supernatant in a dose-dependent manner, while LDH activity in the precipitated fraction increased in a dose-dependent manner. Moreover, sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis revealed a TiO2 dose-dependent reduction in the quantity of LDH protein in the supernatant and an increase of LDH in particulate re-suspensions.
These findings, although based on a purified form of LDH, suggest that TiO2 NPs bind to LDH, and consequently, TiO2 NP-induced toxicity could be underestimated by the LDH activity assay.
PMCID: PMC3390560  PMID: 21993949
Titanium dioxide; Nanoparticle; Lactate dehydrogenase; Cytotoxicity; Protein binding
19.  Long-Lasting Neural Circuit Dysfunction Following Developmental Ethanol Exposure 
Brain Sciences  2013;3(2):704-727.
Fetal Alcohol Spectrum Disorder (FASD) is a general diagnosis for those exhibiting long-lasting neurobehavioral and cognitive deficiencies as a result of fetal alcohol exposure. It is among the most common causes of mental deficits today. Those impacted are left to rely on advances in our understanding of the nature of early alcohol-induced disorders toward human therapies. Research findings over the last decade have developed a model where ethanol-induced neurodegeneration impacts early neural circuit development, thereby perpetuating subsequent integration and plasticity in vulnerable brain regions. Here we review our current knowledge of FASD neuropathology based on discoveries of long-lasting neurophysiological effects of acute developmental ethanol exposure in animal models. We discuss the important balance between synaptic excitation and inhibition in normal neural network function, and relate the significance of that balance to human FASD as well as related disease states. Finally, we postulate that excitation/inhibition imbalance caused by early ethanol-induced neurodegeneration results in perturbed local and regional network signaling and therefore neurobehavioral pathology.
PMCID: PMC3767176  PMID: 24027632
alcohol; FASD; neural circuit; brain development; excitation/inhibition balance; neurodegeneration
20.  Daily Rhythms in Olfactory Discrimination Depend on Clock Genes but Not the Suprachiasmatic Nucleus 
Journal of biological rhythms  2011;26(6):552-560.
The suprachiasmatic nucleus (SCN) regulates a wide range of daily behaviors and has been described as the master circadian pacemaker. The role of daily rhythmicity in other tissues, however, is unknown. We hypothesized that circadian changes in olfactory discrimination depend on a genetic circadian oscillator outside the SCN. We developed an automated assay to monitor olfactory discrimination in individual mice throughout the day. We found olfactory sensitivity increased approximately 6-fold from a minimum during the day to a peak in the early night. This circadian rhythm was maintained in SCN-lesioned mice and mice deficient for the Npas2 gene but was lost in mice lacking Bmal1 or both Per1 and Per2 genes. We conclude that daily rhythms in olfactory sensitivity depend on the expression of canonical clock genes. Olfaction is, thus, the first circadian behavior that is not based on locomotor activity and does not require the SCN.
PMCID: PMC3658462  PMID: 22215613
olfaction; circadian rhythms; Bmal1 gene; oscillator; Period2 gene
21.  ApoE-Directed Therapeutics Rapidly Clear β-Amyloid and Reverse Deficits in AD Mouse Models 
Science (New York, N.Y.)  2012;335(6075):1503-1506.
Alzheimer’s disease (AD) is associated with impaired clearance of β-amyloid (Aβ) from the brain, a process normally facilitated by apolipoprotein E (apoE). ApoE expression is transcriptionally induced through the action of the nuclear receptors peroxisome proliferator–activated receptor gamma and liver X receptors in coordination with retinoid X receptors (RXRs). Oral administration of the RXR agonist bexarotene to a mouse model of AD resulted in enhanced clearance of soluble Aβ within hours in an apoE-dependent manner. Aβ plaque area was reduced more than 50% within just 72 hours. Furthermore, bexarotene stimulated the rapid reversal of cognitive, social, and olfactory deficits and improved neural circuit function. Thus, RXR activation stimulates physiological Aβ clearance mechanisms, resulting in the rapid reversal of a broad range of Aβ-induced deficits.
PMCID: PMC3651582  PMID: 22323736
23.  Awareness of Asbestos and Action Plans for Its Exposure can Help Lives Exposed to Asbestos 
Safety and Health at Work  2013;4(2):84-86.
Despite the fact that asbestos is a known carcinogen to humans, it is still used in industrialized countries, especially Asian countries. The global incidence of asbestos-related diseases (ARDs) due to the past use of asbestos, continues to increase, although many countries have adopted a total ban on asbestos use. The implementation of effective strategies to eliminate ARDs is therefore an important challenge in Asia, where asbestos is still mined and consumed. Collaborative efforts and strategies at the local and international levels are vital, in the pursuit toward the elimination of ARDs in this region.
PMCID: PMC3732141  PMID: 23961330
asbestos; asbestos-related diseases; elimination; international collaboration; pleural plaques
24.  Lithium prevents long-term neural and behavioral pathology induced by early alcohol exposure 
Neuroscience  2012;206:122-135.
Fetal alcohol exposure can cause developmental defects in offspring known as fetal alcohol spectrum disorder (FASD). FASD symptoms range from obvious facial deformities to changes in neuroanatomy and neurophysiology that disrupt normal brain function and behavior. Ethanol exposure at postnatal day 7 in C57BL/6 mice induces neuronal cell death and long-lasting neurobehavioral dysfunction. Previous work has demonstrated that early ethanol exposure impairs spatial memory task performance into adulthood, and perturbs local and interregional brain circuit integrity in the olfacto-hippocampal pathway. Here we pursue these findings to examine whether lithium prevents anatomical, neurophysiological and behavioral pathologies that result from early ethanol exposure. Lithium has neuroprotective properties that have been shown to prevent ethanol-induced apoptosis. Here we show that mice co-treated with lithium on the same day as ethanol exposure, exhibit dramatically reduced acute neurodegeneration in the hippocampus and retain hippocampal-dependent spatial memory as adults. Lithium co-treatment also blocked ethanol-induced disruption in synaptic plasticity in slice recordings of hippocampal CA1 in the adult mouse brain. Moreover, long-lasting dysfunctions caused by ethanol in olfacto-hippocampal networks, including sensory-evoked oscillations and resting state coherence, were prevented in mice co-treated with lithium. Together, these results provide behavioral and physiological evidence that lithium is capable of preventing or reducing immediate and long-term deleterious consequences of early ethanol exposure on brain function.
PMCID: PMC3294020  PMID: 22266347
FASD; behavior; olfactory; lithium; neuroprotection
Neuron  2011;72(4):506-519.
Natural odors, generally composed of many monomolecular components, are analyzed by peripheral receptors into component features and translated into spatiotemporal patterns of neural activity in the olfactory bulb. Here we will discuss the role of the olfactory cortex in the recognition, separation and completion of those odor-evoked patterns, and how these processes contribute to odor perception. Recent findings regarding the neural architecture, physiology and plasticity of the olfactory cortex, principally the piriform cortex, will be described in the context of how this paleocortical structure creates odor objects.
PMCID: PMC3223720  PMID: 22099455

Results 1-25 (105)