The Role of Cerebellar Intrinsic Neuronal Excitability, Synaptic Plasticity, and Perineuronal Nets in Eyeblink Conditioning.

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.

Highlighting the value of Alzheimer's disease-focused registries: lessons learned from cancer surveillance.

Like cancer, Alzheimer's disease and related dementias (ADRD) comprise a global health burden that can benefit tremendously from the power of disease registry data. With an aging population, the incidence, treatment, and mortality from ADRD is increasing and changing rapidly. In the same way that current cancer registries work toward prevention and control, so do ADRD registries.

Health Disparities in Appalachian and Other Rural Communities.

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.

Eyeblink tract tracing with two strains of herpes simplex virus 1.

Background: Neuroinvasive herpes simplex-1 (HSV-1) isolates including H129 and McIntyre cross at or near synapses labeling higher-order neurons directly connected to infected cells. H129 spreads predominately in the anterograde direction while McIntyre strains spread only in the retrograde direction. However, it is unknown if neurons are functional once infected with derivatives of H129 or McIntyre.

Disruption of rat deep cerebellar perineuronal net alters eyeblink conditioning and neuronal electrophysiology.

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.

Changes in cerebellar intrinsic neuronal excitability and synaptic plasticity result from 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.

Inactivation of the interpositus nucleus during unpaired extinction does not prevent extinction of conditioned eyeblink responses or conditioning-specific reflex modification.

For almost 75 years, classical eyeblink conditioning has been an invaluable tool for assessing associative learning processes across many species, thanks to its high translatability and well-defined neural circuitry. Our laboratory has adapted the paradigm to extensively detail associative changes in the rabbit reflexive eyeblink response (unconditioned response, UR), characterized by postconditioning increases in the frequency, size, and latency of the UR when the periorbital shock unconditioned stimulus (US) is presented alone, termed conditioning-specific reflex modification (CRM). Because the shape and timing of CRM closely resembles the conditioned eyeblink response (CR) to the tone conditioned stimulus (CS), we previously tested whether CRs and CRM share a common neural substrate, the interpositus nucleus of the cerebellum (IP), and found that IP inactivation during conditioning blocked the development of both CRs and the timing aspect of CRM.

Changes in membrane properties of rat deep cerebellar nuclear projection neurons during acquisition of eyeblink conditioning.

Previous studies have shown changes in membrane properties of neurons in rat deep cerebellar nuclei (DCN) as a function of development, but due to technical difficulties in obtaining viable DCN slices from adult animals, it remains unclear whether there are learning-related alterations in the membrane properties of DCN neurons in adult rats. This study was designed to record from identified DCN cells in cerebellar slices from postnatal day 25-26 (P25-26) rats that had a relatively mature sensory nervous system and were able to acquire learning as a result of tone-shock eyeblink conditioning (EBC) and to document resulting changes in electrophysiological properties. After electromyographic electrode implantation at P21 and inoculation with a fluorescent pseudorabies virus (PRV-152) at P22-23, rats received either four sessions of paired delay EBC or unpaired stimulus presentations with a tone conditioned stimulus and a shock unconditioned stimulus or sat in the training chamber without stimulus presentations.

Inactivation of the interpositus nucleus blocks the acquisition of conditioned responses and timing changes in conditioning-specific reflex modification of the rabbit eyeblink response.

Conditioning-specific reflex modification (CRM) of the rabbit eyeblink response is an associative phenomenon characterized by increases in the frequency, size, and peak latency of the reflexive unconditioned eyeblink response (UR) when the periorbital shock unconditioned stimulus (US) is presented alone following conditioning, particularly to lower intensity USs that produced minimal responding prior to conditioning. Previous work has shown that CRM shares many commonalities with the conditioned eyeblink response (CR) including a similar response topography, suggesting the two may share similar neural substrates. The following study examined the hypothesis that the interpositus nucleus (IP) of the cerebellum, an essential part of the neural circuitry of eyeblink conditioning, is also required for the acquisition of CRM.

Sex differences in a rabbit eyeblink conditioning model of PTSD.

We have developed a rabbit model of posttraumatic stress disorder (PTSD) which recapitulates several core features of PTSD, particularly hyperarousal and conditioned responding to trauma-associated cues. The work conducted with this model has all been done in male rabbits and, given sex differences in PTSD prevalence, it is important to expand our animal model of PTSD to include female rabbits to determine if they develop core features of PTSD, and if those core features can be treated. This is particularly important because, contrary to human studies, nearly all animal studies have found that males are consistently more vulnerable to various forms of acute and chronic stress than females.

Propranolol produces short-term facilitation of extinction in a rabbit model of post-traumatic stress disorder.

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.

Delayed unpaired extinction as a treatment for hyperarousal of the rabbit nictitating membrane response and its implications for treating PTSD.

Treatment for PTSD (Post-traumatic stress disorder) is rarely available immediately after trauma and often delayed for weeks or months after an event. In a rabbit eyeblink conditioning model of PTSD, we have previously shown that presentations of a tone conditioned stimulus (CS) and shock unconditioned stimulus (US) in an explicitly unpaired manner known as unpaired extinction is effective in reducing CS responding and US hyperarousal even if shock intensity is reduced eight-fold and elicits only minimal responding. Here we determined if delayed delivery of unpaired extinction would still be effective in extinguishing hyperarousal.

Grouping subjects based on conditioning criteria reveals differences in acquisition rates and in strength of conditioning-specific reflex modification.

Averaging behavioral data such as the nictitating membrane response (NMR) across subjects can conceal important individual and group differences. Analyses were conducted of NMR data from rabbits that were grouped based on the point during NMR conditioning when subjects produced 8 conditioned responses (CR) in a set of 10 trials. This resulted in five groups (Early Day 1, Late Day 1, Early Day 2, Late Day 2, Early Day 3) in which group differences in CR acquisition rates were found.

Effects of systemic glutamatergic manipulations on conditioned eyeblink responses and hyperarousal in a rabbit model of post-traumatic stress disorder.

Glutamatergic dysfunction is implicated in many neuropsychiatric conditions, including post-traumatic stress disorder (PTSD). Glutamate antagonists have shown some utility in treating PTSD symptoms, whereas glutamate agonists may facilitate cognitive behavioral therapy outcomes. We have developed an animal model of PTSD, based on conditioning of the rabbit's eyeblink response, 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).

Direct medical expenditures associated with Alzheimer's and related dementias (ADRD) in a nationally representative sample of older adults - an excess cost approach.

Objective: To estimate the excess direct annual healthcare expenditures associated with Alzheimer's and related dementias(ADRD) among community-dwelling older adults in the United States.

Methods: This retrospective cross-sectional study compared the annual healthcare expenditures between elderly individuals aged 65 years and older with ADRD (n = 662) and without ADRD (n = 13,398) using data from the Medical Expenditure Panel Survey (MEPS) for the years 2007, 2009, 2011 and 2013. Adjusted total annual medical expenditures was estimated using generalized linear model with gamma distribution and log link in 2013 U.

A High-Cholesterol Diet Increases 27-Hydroxycholesterol and Modifies Estrogen Receptor Expression and Neurodegeneration in Rabbit Hippocampus.

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.

Rural-Urban Differences in Alzheimer's Disease and Related Disorders Diagnostic Prevalence in Kentucky and West Virginia.

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.

Dietary high cholesterol and trace metals in the drinking water increase levels of ABCA1 in the rabbit hippocampus and temporal cortex.

Background: Cholesterol-fed rabbits have been documented to show increased amyloid-β (Aβ) deposits in the brain that can be exacerbated by the quality of drinking water especially if rabbits drink tap water or distilled water containing copper. One mechanism of cholesterol and Aβ clearance may be through the ATP-binding cassette transporter A1 (ABCA1).

Objective And Methods: Using an ABCA1 antibody, we determined the number of ABCA1-immunopositive neurons in three areas of rabbit brain as a function of feeding 2% cholesterol and providing tap water, distilled water, or distilled water to which aluminum, copper, or zinc was added.

Effects of extinction treatments on the reduction of conditioned responding and conditioned hyperarousal in a rabbit model of posttraumatic stress disorder (PTSD).

We have previously characterized a model of posttraumatic stress disorder (PTSD), based on classical conditioning of the rabbit nictitating membrane response (NMR), that focuses on 2 key PTSD-like features: conditioned responses to trauma-associated cues and hyperarousal. In addition to the development of conditioned NMRs (CRs) to a tone conditioned stimulus (CS) associated with a periorbital shock unconditioned stimulus (US), we have observed that rabbits also exhibit a conditioning-specific reflex modification (CRM) of the NMR that manifests as an exaggerated and more complex reflexive NMR to presentations of the US by itself, particularly to intensities that elicited little response prior to conditioning. Previous work has demonstrated that unpaired presentations of the CS and US are successful at extinguishing CRs and CRM simultaneously, even when a significantly weakened version of the US is utilized.

Eyeblink classical conditioning and post-traumatic stress disorder - a model systems approach.

Not everyone exposed to trauma suffers flashbacks, bad dreams, numbing, fear, anxiety, sleeplessness, hyper-vigilance, hyperarousal, or an inability to cope, but those who do may suffer from post-traumatic stress disorder (PTSD). PTSD is a major physical and mental health problem for military personnel and civilians exposed to trauma. There is still debate about the incidence and prevalence of PTSD especially among the military, but for those who are diagnosed, behavioral therapy and drug treatment strategies have proven to be less than effective.

Identification of the PS1 Thr147Ile Variant in a Family with Very Early Onset Dementia and Expressive Aphasia.

Background: Early onset dementias have variable clinical presentations and are often difficult to diagnose. We established a family pedigree that demonstrated consistent recurrence of very early onset dementia in successive generations.

Objective And Method: In order to refine the diagnosis in this family, we sequenced the exomes of two affected family members and relied on discrete filtering to identify disease genes and the corresponding causal variants.

Maturation of membrane properties of neurons in the rat deep cerebellar nuclei.

Patch clamp recordings of neurons in the adult rat deep cerebellar nuclei have been limited by the availability of viable brain slices. Using a new slicing technique, this study was designed to explore the maturation of membrane properties of neurons in the deep cerebellar nuclei (DCN)-an area involved in rat eyeblink conditioning. Compared to whole-cell current-clamp recordings in DCN in rat pups at postnatal day 16 (P16) to P21, recordings from weanling rats at P22-P40 revealed a number of significant changes including an increase in the amplitude of the afterhyperpolarization (AHP)-an index of membrane excitability which has been shown to be important for eyeblink conditioning-a prolonged interval between the first and second evoked action potential, and an increase in AHP amplitude for hyperpolarization-induced rebound spikes.

Dietary cholesterol degrades rabbit long term memory for discrimination learning but facilitates acquisition of discrimination reversal.

We have shown previously that feeding dietary cholesterol before learning can improve acquisition whereas feeding cholesterol after learning can degrade long term memory. To examine these different findings within a single paradigm, we fed groups of rabbits 2% cholesterol or normal chow with or without 0.12 ppm copper added to the drinking water following two-tone discrimination learning of the nictitating membrane response in which a 8-kHz tone (conditioned stimulus, CS+) was followed by air puff and a 1-kHz tone (CS-) was not.

Cholesterol and copper affect learning and memory in the rabbit.

A rabbit model of Alzheimer's disease based on feeding a cholesterol diet for eight weeks shows sixteen hallmarks of the disease including beta amyloid accumulation and learning and memory changes. Although we have shown that feeding 2% cholesterol and adding copper to the drinking water can retard learning, other studies have shown that feeding dietary cholesterol before learning can improve acquisition and feeding cholesterol after learning can degrade long-term memory. We explore the development of this model, the issues surrounding the role of copper, and the particular contributions of the late D.

Inactivation of the central nucleus of the amygdala blocks classical conditioning but not conditioning-specific reflex modification of rabbit heart rate.

Heart rate (HR) conditioning in rabbits is a widely used model of classical conditioning of autonomic responding that is noted for being similar to the development of conditioned heart rate slowing (bradycardia) in humans. We have shown previously that in addition to HR changes to a tone conditioned stimulus (CS), the HR reflex itself can undergo associative change called conditioning-specific reflex modification (CRM) that manifests when tested in the absence of the CS. Because CRM resembles the conditioned bradycardic response to the CS, we sought to determine if HR conditioning and CRM share a common neural substrate.