The effects of cholesterol on learning and memory Schreurs, Bernard G.
Neuroscience & biobehavioral reviews/Neuroscience and biobehavioral reviews,
07/2010, Letnik:
34, Številka:
8
Journal Article
Recenzirano
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Cholesterol is vital to normal brain function including learning and memory but that involvement is as complex as the synthesis, metabolism and excretion of cholesterol itself. Dietary cholesterol ...influences learning tasks from water maze to fear conditioning even though cholesterol does not cross the blood brain barrier. Excess cholesterol has many consequences including peripheral pathology that can signal brain via cholesterol metabolites, pro-inflammatory mediators and antioxidant processes. Manipulations of cholesterol within the central nervous system through genetic, pharmacological, or metabolic means circumvent the blood brain barrier and affect learning and memory but often in animals already otherwise compromised. The human literature is no less complex. Cholesterol reduction using statins improves memory in some cases but not others. There is also controversy over statin use to alleviate memory problems in Alzheimer's disease. Correlations of cholesterol and cognitive function are mixed and association studies find some genetic polymorphisms are related to cognitive function but others are not. In sum, the field is in flux with a number of seemingly contradictory results and many complexities. Nevertheless, understanding cholesterol effects on learning and memory is too important to ignore.
•Purkinje cell intrinsic membrane excitability increases after eyeblink conditioning.•These changes may result from changes in potassium channels.•Purkinje cell synaptic plasticity increases after ...eyeblink conditioning.•Membrane excitability in deep cerebellar nuclei increases after eyeblink conditioning.•Both intrinsic and synaptic plasticity are required for eyeblink conditioning.
There is a long history of research documenting plasticity in the cerebellum as well as the role of the cerebellum in learning and memory. Recordings in slices of cerebellum have provided evidence of long-term depression and long-term potentiation at several excitatory and inhibitory synapses. Lesions and recordings show the cerebellum is crucial for eyeblink conditioning and it appears changes in both synaptic and membrane plasticity are involved. In addition to its role in fine motor control, there is growing consensus that the cerebellum is crucial for perceptual, cognitive, and emotional functions. In the current review, we explore the evidence that eyeblink conditioning results in significant changes in intrinsic membrane excitability as well as synaptic plasticity in Purkinje cells of the cerebellar cortex in rabbits and changes in intrinsic membrane excitability in principal neurons of the deep cerebellar nuclei in rats.
Despite the crucial role played by cholesterol and copper in nutrition and normal brain function, recent evidence indicates that they may both be important factors in the etiology of Alzheimer's ...disease (AD). Here we provide critical evidence for the role of cholesterol and copper in AD by showing that the addition of trace amounts of copper (0.12 ppm) to water given to cholesterol-fed rabbits can induce β-amyloid (Aβ) accumulation, including senile plaque-like structures in the hippocampus and temporal lobe, and can significantly retard the ability of rabbits to learn a difficult trace conditioning task. The Aβ deposits do not affect the ability of rabbits to detect or respond to the training stimuli nor to learn a simpler delay conditioning task. Trace amounts of copper in drinking water may influence clearance of Aβ from the brain at the level of the interface between the blood and cerebrovasculature and combined with high cholesterol may be a key component to the accumulation of Aβ in the brain, having a significant impact on learning and memory. Cholesterol-fed rabbits have at least 12 pathological markers seen in AD, suggesting that the cholesterol-fed rabbit is a good animal model for studying AD.
Post-traumatic stress disorder (PTSD) is a learning-based anxiety disorder with significant public health challenges due to difficulties in treating the complex, multiple symptomology. We have ...developed an animal model of PTSD, based on Pavlovian eyeblink conditioning in rabbits, that addresses two key features: conditioned responses (CRs) to cues associated with an aversive event and a form of conditioned hyperarousal referred to as conditioning-specific reflex modification (CRM). We have found previously that unpaired extinction is ideal for reducing both CRs and CRM simultaneously and shows sensitivity to systemic serotonergic and glutamatergic manipulations. The following study aimed to extend our work to examine the role of the noradrenergic system, dysregulation of which is strongly implicated as part of the neurobiology of PTSD and which may also play a role in the balance shift from fear reconsolidation to extinction during treatment. The goal of the following two studies was to examine whether the β-adrenergic receptor antagonist propranolol combined with either a full or brief course of unpaired extinction treatment could enhance extinction of CRs and/or CRM. Results showed a within-session facilitation of propranolol on extinction of CRs, particularly during the first extinction session, and a short-term enhancement of extinction of CRM when extinction treatment was brief. However, neither benefit translated to long-term extinction retention for the majority of subjects. Findings suggest that propranolol may provide the most therapeutic benefit in situations of high arousal early in treatment, which may be more important for future patient compliance rather than long-term treatment outcomes.
•Propranolol facilitates within-session extinction of conditioned eyeblink responses.•Propranolol enhances extinction of conditioned hyperarousal short-term.•Propranolol provides the most benefit early in extinction when arousal level high.•Propranolol may improve compliance rather than long-term treatment outcomes.
Hypercholesterolemia has been implicated in numerous health problems from cardiovascular disease to neurodegeneration. High serum cholesterol levels in midlife have been associated with an increased ...risk of developing Alzheimer's disease (AD) later in life which suggests that the pathways leading to AD pathology might be activated decades before the symptoms of the disease are detected. Cholesterol-fed animals, particularly cholesterol-fed rabbits, exhibit brain pathology similar to the changes found in brains of AD patients. Dietary cholesterol, which cannot pass the blood-brain barrier, is thought to influence central nervous system homeostasis by increased transport of its circulatory breakdown product, 27-hydroxycholesterol (27-OHC), into the brain. 27-OHC is an endogenous selective estrogen receptor modulator. Estrogen-mediated non-reproductive functions require estrogen receptors (ERs) and include modulation of mitochondrial function and structure, as well as regulation of synaptogenesis in the brain. ERs are located in brain areas affected early in AD pathogenesis, including the hippocampus. Here we report that increase in serum cholesterol, induced by feeding rabbits a high-cholesterol diet, is associated with higher levels of 27-OHC in the brain as well as increased levels of neurodegeneration in the hippocampus. Furthermore, these results are accompanied by changes in expression of ERs in the hippocampus as well as a decrease in hippocampal mitochondria. These findings provide an important insight into one of the possible mechanisms involved in the development of AD, and shed light on the processes that may antedate amyloid-β and tau phosphorylation changes currently hypothesized to cause AD symptomology and pathology.
Purpose
Older adults living in rural areas may face barriers to obtaining a diagnosis of Alzheimer's disease and related disorders (ADRD). We sought to examine rural‐urban differences in prevalence ...of ADRD among Medicare beneficiaries in Kentucky and West Virginia, 2 contiguous, geographically similar states with large rural areas and aged populations.
Methods
We used Centers for Medicare and Medicaid Services Public Use Files data from 2007 to 2013 to assess prevalence of ADRD at the county level among all Medicare beneficiaries in each state. Rural‐Urban Continuum Codes were used to classify counties as rural or urban. We used Poisson regression to estimate unadjusted and adjusted prevalence ratios. Primary analyses focused on 2013 data and were repeated for 2007 to 2012. This study was completely ecologic.
Findings
After adjusting for state, average beneficiary age, percent of female beneficiaries, percent of beneficiaries eligible for Medicaid in each county, Central Appalachian county, percent of age‐eligible residents enrolled in Medicare, and percent of residents under age 65 enrolled in Medicare in our adjusted models, we found that 2013 ADRD diagnostic prevalence was 11% lower in rural counties (95% CI: 9%‐13%).
Conclusions
Medicare beneficiaries in rural counties in Kentucky and West Virginia may be underdiagnosed with respect to ADRD. However, due to the ecologic design, and evidence of a younger, more heavily male beneficiary population in some rural areas, further studies using individual‐level data are needed to confirm the results.
Rabbit eyeblink conditioning is a well characterized model of associative learning. To identify specific neurons that are part of the eyeblink premotor pathway, a retrograde transsynaptic tracer ...(pseudorabies virus) was injected into the orbicularis oculi muscle. Four time points (3, 4, 4.5, and 5 d) were selected to identify sequential segments of the pathway and a map of labeled structures was generated. At 3 d, labeled first-order motor neurons were found in dorsolateral facial nucleus ipsilaterally. At 4 d, second-order premotor neurons were found in reticular nuclei, and sensory trigeminal, auditory, vestibular, and motor structures, including contralateral red nucleus. At 4.5 d, labeled third-order premotor neurons were found in the pons, midbrain, and cerebellum, including dorsolateral anterior interpositus nucleus and rostral fastigial nucleus. At 5 d, labeling revealed higher-order premotor structures. Labeled fourth-order Purkinje cells were found in ipsilateral cerebellar cortex in cerebellar lobule HVI and in lobule I. The former has been implicated in eyeblink conditioning and the latter in vestibular control. Labeled neurons in anterior interpositus were studied, using neurotransmitter immunoreactivity to classify individual cell types and delineate their interconnectivity. Labeled third-order premotor neurons were immunoreactive for glutamate and corresponded to large excitatory projection neurons. Labeled fourth-order premotor interneurons were immunoreactive for GABA (30%), glycine (18%), or both GABA and glycine (52%) and form a functional network within anterior interpositus involved in modulation of motor commands. These results identify a complete eyeblink premotor pathway, deep cerebellar interconnectivity, and specific neurons responsible for the generation of eyeblink responses.
Rural areas are home to a larger proportion of older adults and populations who age within these locales and suffer disproportionately from health, mental health, and economic disparities compared to ...their urban counterparts. This article will explore the disparities faced by persons that reside in rural communities across the lifespan. It will briefly discuss what is meant by rural. As a rural region at specific risk, the issues confronting those aging in Appalachia will be examined. Finally, best practices and future directions to combat health disparities among rural residents and elders will be discussed. This includes the Appalachian Gerontology Experiences: Advancing Diversity in Aging Research training program which recruits and trains minority and first-generation undergraduate students in aging and health disparity research.
Evidence is strong that, in addition to fine motor control, there is an important role for the cerebellum in cognition and emotion. The deep nuclei of the mammalian cerebellum also contain the ...highest density of perineural nets-mesh-like structures that surround neurons-in the brain, and it appears there may be a connection between these nets and cognitive processes, particularly learning and memory. Here, we review how the cerebellum is involved in eyeblink conditioning-a particularly well-understood form of learning and memory-and focus on the role of perineuronal nets in intrinsic membrane excitability and synaptic plasticity that underlie eyeblink conditioning. We explore the development and role of perineuronal nets and the in vivo and in vitro evidence that manipulations of the perineuronal net in the deep cerebellar nuclei affect eyeblink conditioning. Together, these findings provide evidence of an important role for perineuronal net in learning and memory.
•PNN in rat DCN shows developmental changes.•Application of ChABC in vivo and in vitro can digest PNN in rat DCN.•In vivo degradation of the PNN in the rat DCN has effects on EBC.•Vehicle rats have ...sex differences in EBC not present in the ChABC-infused animals.•PNN degradation alters membrane properties of rat DCN neurons.
The perineuronal net (PNN) is a specialized type of extracellular matrix found in the central nervous system. The PNN forms on fast spiking neurons during postnatal development but the ontogeny of PNN development has yet to be elucidated. By studying the development and prevalence of the PNN in the juvenile and adult rat brain, we may be able to understand the PNN’s role in development and learning and memory. We show that the PNN is fully developed in the deep cerebellar nuclei (DCN) of rats by P18. By using enzymatic digestion of the PNN with chondroitinase ABC (ChABC), we are able to study how digestion of the PNN affects cerebellar-dependent eyeblink conditioning in vivo and perform electrophysiological recordings from DCN neurons in vitro. In vivo degradation of the PNN resulted in significant differences in eyeblink conditioning amplitude and area. Female animals in the vehicle group demonstrated higher levels of conditioning as well as significantly higher post-probe conditioned responses compared to males in that group, differences not present in the ChABC group. In vitro, we found that DCN neurons with a disrupted PNN following exposure to ChABC had altered membrane properties, fewer rebound spikes, and decreased intrinsic excitability. Together, this study further elucidates the role of the PNN in cerebellar learning in the DCN and is the first to demonstrate PNN degradation may erase sex differences in delay conditioning.
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