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.
alcohol; FASD; neural circuit; brain development; excitation/inhibition balance; neurodegeneration
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.
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.
Titanium dioxide; Nanoparticle; Lactate dehydrogenase; Cytotoxicity; Protein binding
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.
olfaction; circadian rhythms; Bmal1 gene; oscillator; Period2 gene
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.
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.
asbestos; asbestos-related diseases; elimination; international collaboration; pleural plaques
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.
FASD; behavior; olfactory; lithium; neuroprotection
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.
Ethanol consumption during pregnancy can lead to FetalAlcohol Spectrum Disorder (FASD), which consists of the complete spectrum of developmental deficits including neurological dysfunction. FASD is associated with a variety of neurobehavioral disturbances dependent on the age and duration of exposure. Ethanol exposure in neonatal rodents can alsoinduce widespread apoptotic neurodegeneration and long-lasting behavioral abnormalities similar to FASD. The developmental stage of neonatal rodent brains that are at the peak of synaptogenesis is equivalent to the third trimester of human gestation.
Male and female C57BL/6By mice were injected with ethanol (20%, 2.5g/kg, two s.c. injections) or an equal volume of saline (controls) on postnatal day 7 (P7). Animals were allowed to mature and at 3 months were tested on an olfactory habituation task known to be dependent on piriform cortex function, a hippocampal-dependent object place memory task, and used for electrophysiological testing of spontaneous and odor-evoked local field potential (LFP) activity in the olfactory bulb, piriform cortex and dorsal hippocampus.
P7 ethanol induced widespread cell death within 1 day of exposure, with highest levels in the neocortex, intermediate levels in the dorsal hippocampus and relatively low levels in the primary olfactory system.No impairment of odor investigation or odor habituation was detected in P7 ethanol exposed 3 months old mice compared to saline controls. However, hippocampal-dependent object place memory was significantly impaired in the P7 ethanol treated adult mice. Odor-evoked LFP activity was enhanced throughout the olfacto-hippocampal pathway, primarily within the theta frequency band, although the hippocampus also showed elevated evoked delta frequency activity. In addition, functional coherence between the piriform cortex and olfactory bulb and between the piriform cortex and dorsal hippocampus was enhanced in the beta frequency range in P7 ethanol treated adult mice compared to controls.
P7 ethanol induces an immediate wave of regionally selective cell death followed by long-lasting, changes in local circuit and regional network function that are accompanied by changes in neurobehavioral performance. The results suggest that both the activity of local neural circuits within a brain region and the flow of information between brain regions can be modified by early alcohol exposure which may contribute to long-lasting behavioral abnormalities known to rely on those circuits.
Fetal Alcohol Spectrum Disorders; Olfactory bulb; Piriform cortex; Hippocampus; Local field potentials; Memory; Alcohol
Orienting responses are physiological and active behavioral reactions evoked by novel stimulus perception and are critical for survival. We explored whether odor orienting responses are impacted throughout both adulthood and normal and pathological aging in mice. Novel odor investigation (including duration and bout numbers) and its subsequent habituation as assayed in the odor habituation task were preserved in adult C57BL/6J mice up to 12mo of age with <6% variability between age groups in investigation time. Separately, using whole-body plethysmography we found that both spontaneous respiration and odor-evoked sniffing behaviors were strikingly preserved in wildtype (WT) mice up to 26mo of age. In contrast, mice accumulating amyloid-β protein in the brain by means of overexpressing mutations in the human amyloid precursor protein gene (APP) showed preserved spontaneous respiration up to 12mo, but starting at 14mo showed significant differences from WT. Similar to WTs, odor-evoked sniffing was not impacted in APP mice up to 26mo. These results show that odor-orienting responses are minimally impacted throughout aging in mice, and suggest that the olfactomotor network is mostly spared of insults due to aging.
Olfaction; Neurodegeneration; Alzheimer’s disease; amyloid-beta; APP; orienting; respiration
The unique vulnerability of the olfactory system to Alzheimer’s disease (AD) provides a quintessential translational tool for understanding mechanisms of synaptic dysfunction and pathological progression in the disease. Using the Tg2576 mouse model of β-amyloidosis, we show aberrant, hyperactive olfactory network activity begins early in life, prior to detectable behavioral impairments or comparable hippocampal dysfunction and at a time when Aβ deposition is restricted to the olfactory bulb (OB). Hyperactive odor-evoked activity in the piriform cortex (PCX) and increased OB-PCX functional connectivity emerged at a time coinciding with olfactory behavior impairments. This hyperactive activity persisted until later-life when the network converted to a hyporesponsive state. This conversion was Aβ-dependent, as liver-x-receptor agonist treatment to promote Aβ degradation, rescued the hyporesponsive state and olfactory behavior. These data lend evidence to a novel working model of olfactory dysfunction in AD and, complimentary to other recent works, suggest that disease-relevant network dysfunction is highly dynamic and region specific, yet with lasting effects on cognition and behavior.
Neural network; olfactory bulb; olfactory cortex; Amyloid-β; APP
Learning to adapt to a complex and fluctuating environment requires the ability to adjust neural representations of sensory stimuli. Through pattern completion processes, cortical networks can reconstruct familiar patterns from degraded input patterns, while pattern separation processes allow discrimination of even highly overlapping inputs. Here we show that the balance between pattern separation and completion is experience-dependent. Rats given extensive training with overlapping complex odorant mixtures show improved behavioral discrimination ability and enhanced cortical ensemble pattern separation. In contrast, behavioral training to disregard normally detectable differences between overlapping mixtures results in impaired cortical ensemble pattern separation (enhanced pattern completion) and impaired discrimination. This bidirectional effect was not found in the olfactory bulb, and may be due to plasticity within olfactory cortex itself. Thus pattern recognition, and the balance between pattern separation and completion, is highly malleable based on task demands and occurs in concert with changes in perceptual performance.
The extensive autophagic-lysosomal pathology in Alzheimer disease (AD) brain has revealed a major defect in the proteolytic clearance of autophagy substrates. Autophagy failure contributes on several levels to AD pathogenesis and has become an important therapeutic target for AD and other neurodegenerative diseases. We recently observed broad therapeutic effects of stimulating autophagic-lysosomal proteolysis in the TgCRND8 mouse model of AD that exhibits defective proteolytic clearance of autophagic substrates, robust intralysosomal amyloid-β peptide (Aβ) accumulation, extracellular β-amyloid deposition and cognitive deficits. By genetically deleting the lysosomal cysteine protease inhibitor, cystatin B (CstB), to selectively restore depressed cathepsin activities, we substantially cleared Aβ, ubiquitinated proteins and other autophagic substrates from autolysosomes/lysosomes and rescued autophagic-lysosomal pathology, as well as reduced total Aβ40/42 levels and extracellular amyloid deposition, highlighting the underappreciated importance of the lysosomal system for Aβ clearance. Most importantly, lysosomal remediation prevented the marked learning and memory deficits in TgCRND8 mice. Our findings underscore the pathogenic significance of autophagic-lysosomal dysfunction in AD and demonstrate the value of reversing this dysfunction as an innovative therapeutic strategy for AD.
autophagy; lysosome; cathepsin; cystatin B; proteolysis; Alzheimer disease; transgenic
The false-suffocation hypothesis of panic disorder (Klein, 1993) suggested δ-opioid receptors as a possible source of the respiratory dysfunction manifested in panic attacks occurring in panic disorder (Preter and Klein, 2008). This study sought to determine if a lack of δ-opioid receptors in a mouse model affects respiratory response to elevated CO2, and whether the response is modulated by benzodiazepines, which are widely used to treat panic disorder. In a whole-body plethysmograph, respiratory responses to 5% CO2 were compared between δ-opioid receptor knockout mice and wild-type mice after saline, diazepam (1 mg/kg), and alprazolam (0.3 mg/kg) injection. The results show that lack of δ-opioid receptors does not affect normal response to elevated CO2, but does prevent benzodiazepines from modulating that response. Thus, in the presence of benzodiazepine agonists, respiratory responses to elevated CO2 were enhanced in δ-opioid receptor knockout mice compared to wild-type mice. This suggests an interplay between benzodiazepine receptors and δ-opioid receptors in regulating the respiratory effects of elevated CO2, which might be related to CO2 induced panic.
This review critically examines progress in understanding the link between Alzheimer’s disease (AD) molecular pathogenesis and behavior, with an emphasis on the impact of amyloid-β. We present the argument that the AD research field requires more multi-faceted analyses into the impacts of Alzheimer’s pathogenesis which combine simultaneous molecular-, circuit-, and behavior-level approaches. Supporting this argument is a review of particular research utilizing similar, ‘systems-level’ methods in mouse models of AD. Related to this, a critique of common physiological and behavioral models is made – highlighting the likely usefulness of more refined and specific tools in understanding the relationship between candidate molecular pathologies and behavioral dysfunction. Finally, we propose challenges for future research which, if met, may greatly extend our current understanding of how AD molecular pathology impacts neural network function and behavior and possibly may lead to refinements in disease therapeutics.
Amyloid-β; APP; cognition; dementia; endocytosis; LTD; LTP; neural connectivity; presenilin; tau; rab5; synapse
While adult born neurons in the olfactory bulb (OB) and the dentate gyrus (DG) subregion of the hippocampus have fundamentally different properties, they may have more in common than meets the eye. Here, we propose that new granule cells in the OB and DG may function as modulators of principal neurons to influence pattern separation and that adult neurogenesis constitutes an adaptive mechanism to optimally encode contextual or olfactory information.
Objective. Iodine deficiency is defined by the goiter and the urinary iodine concentration. However, a lack of local thyroid volume reference data resulted in the vague definition of goiter, especially in school-aged children. The aim of this paper was to determine the thyroid volumes by ultrasonography in schoolchildren aged 6 to 12 years living in Cagayan areas in Philippine. Methods. Cross-sectional thyroid ultrasonographic data of 158 schoolchildren aged 6–12 years from Tuguegarao and Lagum in Cagayan valley, Philippine were used. Thyroid volumes were compared based on logistic issue and urban and rural area and compared with other previously reported data. Results. The mean values of thyroid volume in Tuguerago and Lagum were 2.99 ± 1.34 mL and 2.42 ± 0.92 mL. The thyroid size was significantly in association with age (P < 0.00), weight (P < 0.00), height (P < 0.00), and BSA (P < 0.00) by Pearson's correlation. The median thyroid volumes of schoolchildren investigated in this study were generally low compared to international reference data by age group but not by BSA. Conclusions. We propose for the first time local reference ultrasound values for thyroid volumes in 6–12 aged schoolchildren that should be used for monitoring iodine deficiency disorders.
To determine if previous exposure to bovine viral diarrhea virus (BVDV) and bovine herpes virus 1 (BHV-1) type 2 affects the onset of disease caused by Mycoplasma bovis, 6- to 8-month-old beef calves were exposed to BVDV or BHV-1 4 d prior to challenge with a suspension of 3 clinical isolates of M. bovis. Animals were observed for clinical signs of disease and at necropsy, percent abnormal lung tissue and presence of M. bovis were determined. Most animals pre-exposed to BHV-1 type 2 but not BVDV developed M. bovis-related respiratory illness. In a second trial, we determined that a 100-fold reduction in the number of M. bovis bacteria administered to BHV-1 exposed animals reduced the percentage of abnormal lung tissue but not the severity of clinical signs. We conclude that previous exposure to BHV-1 but not BVDV type 2 was a necessary cause of M. bovis-related respiratory diseases in our disease model.
The olfactory cortex encompasses several anatomically distinct regions each hypothesized to provide differential representation and processing of specific odors. Studies exploring whether or not the diversity of olfactory bulb input to olfactory cortices has functional meaning, however, are lacking. Here we tested whether two anatomically major olfactory cortical structures, the olfactory tubercle (OT) and piriform cortex (PCX), differ in their neural representation and processing dynamics of a small set of diverse odors by performing in vivo extracellular recordings from the OT and PCX of anesthetized mice. We found a wealth of similarities between structures, including odor-evoked response magnitudes, breadth of odor tuning, and odor-evoked firing latencies. In contrast, only few differences between structures were found, including spontaneous activity rates and odor signal-to-noise ratios. These results suggest that despite major anatomical differences in innervation by olfactory bulb mitral/tufted cells, the basic features of odor representation and processing, at least within this limited odor set, are similar within the OT and PCX. We predict that the olfactory code follows a distributed processing stream in transmitting behaviorally and perceptually-relevant information from low-level stations.
Elucidating the modulators of social behavioral is important in understanding the neural basis of behavior and in developing methods to enhance behavior in cases of disorder. The work here stems from the observation that the Alzheimer’s disease mouse model Tg2576, overexpressing human mutations of the amyloid-β precursor protein gene (APP) fails to construct nests when supplied paper towels in their home cages. Experiments using commercially available cotton nesting material found similar results. Additional experiments revealed that the genotype effect is progressively modulated by age in APP mice but not their WT counterparts. There was no effect of sex on nesting behavior in any group. Finally, this effect was independent of ambient temperature – even when subjected to a cold environment APP mice fail to build nests whereas WT mice do. These results suggest that the APP gene plays a role in affiliative behaviors and are discussed in relation to disorders characteristic of mutations in the APP gene and in affective dysfunction, including Alzheimer’s disease.
Affiliative behavior; Social behavior; Alzheimer’s disease; Amyloid beta; Biomarker
Since its designation in 1896 as a putative olfactory structure, the olfactory tubercle has received little attention in terms of elucidating its role in the processing and perception of odors. Instead, research on the olfactory tubercle has mostly focused on its relationship with the reward system. Here we provide a comprehensive review of research on the olfactory tubercle – with an emphasis on the likely role of this region in olfactory processing and its contributions to perception. Further, we propose several testable hypotheses regarding the likely involvement of the olfactory tubercle in both basic (odor detection, discrimination, parallel processing of olfactory information) and higher-order (social odor processing, hedonics, multi-modal integration) functions. Together, the information within this review highlights an understudied yet potentially critical component in central odor processing.
Arousal; Preference; Reward; Parallel-processing; Basal ganglia; Perception; Sensory integration; Olfactory cortex; Olfactory perception; Olfactory behavior; Sociosexual behavior
Autophagy, a major degradative pathway for proteins and organelles, is essential for survival of mature neurons. Extensive autophagic-lysosomal pathology in Alzheimer’s disease brain contributes to Alzheimer’s disease pathogenesis, although the underlying mechanisms are not well understood. Here, we identified and characterized marked intraneuronal amyloid-β peptide/amyloid and lysosomal system pathology in the Alzheimer’s disease mouse model TgCRND8 similar to that previously described in Alzheimer’s disease brains. We further establish that the basis for these pathologies involves defective proteolytic clearance of neuronal autophagic substrates including amyloid-β peptide. To establish the pathogenic significance of these abnormalities, we enhanced lysosomal cathepsin activities and rates of autophagic protein turnover in TgCRND8 mice by genetically deleting cystatin B, an endogenous inhibitor of lysosomal cysteine proteases. Cystatin B deletion rescued autophagic-lysosomal pathology, reduced abnormal accumulations of amyloid-β peptide, ubiquitinated proteins and other autophagic substrates within autolysosomes/lysosomes and reduced intraneuronal amyloid-β peptide. The amelioration of lysosomal function in TgCRND8 markedly decreased extracellular amyloid deposition and total brain amyloid-β peptide 40 and 42 levels, and prevented the development of deficits of learning and memory in fear conditioning and olfactory habituation tests. Our findings support the pathogenic significance of autophagic-lysosomal dysfunction in Alzheimer’s disease and indicate the potential value of restoring normal autophagy as an innovative therapeutic strategy for Alzheimer’s disease.
autophagy; lysosome; cystatin B; cathepsin; Alzheimer’s disease
Evaluation of imaging hardware represents a vital component of system design. In small-animal SPECT imaging, this evaluation has become increasingly difficult with the emergence of multi-pinhole apertures and adaptive, or patient-specific, imaging. This paper will describe two methods for hardware evaluation using reconstructed images. The first method is a rapid technique incorporating a system-specific non-linear, three-dimensional point response. This point response is easily computed and offers qualitative insight into an aperture’s resolution and artifact characteristics. The second method is an objective assessment of signal detection in lumpy backgrounds using the channelized Hotelling observer (CHO) with 3D Laguerre-Gauss and difference-of-Gaussian channels to calculate area under the receiver-operating characteristic curve (AUC). Previous work presented at this meeting described a unique, small-animal SPECT system (M3R) capable of operating under a myriad of hardware configurations and ideally suited for image quality studies. Measured system matrices were collected for several hardware configurations of M3R. The data used to implement these two methods was then generated by taking simulated objects through the measured system matrices. The results of these two methods comprise a combination of qualitative and quantitative analysis that is well-suited for hardware assessment.
SPECT; image quality; hardware evaluation; AUC; differential point-response function