Anti-CD49d Ab treatment ameliorates age-associated inflammatory response and mitigates CD8 T-cell cytotoxicity after traumatic brain injury.

Patients aged 65 years and older account for an increasing proportion of patients with traumatic brain injury (TBI). Older TBI patients experience increased morbidity and mortality compared to their younger counterparts. Our prior data demonstrated that by blocking α4 integrin, anti-CD49d antibody (aCD49d Ab) abrogates CD8 T-cell infiltration into the injured brain, improves survival, and attenuates neurocognitive deficits.

antiCD49d Ab treatment ameliorates age-associated inflammatory response and mitigates CD8+ T-cell cytotoxicity after traumatic brain injury.

Unlabelled: Patients aged 65 years and older account for an increasing proportion of patients with traumatic brain injury (TBI). Older TBI patients experience increased morbidity and mortality compared to their younger counterparts. Our prior data demonstrated that by blocking α4 integrin, anti-CD49d antibody (aCD49d Ab) abrogates CD8+ T-cell infiltration into the injured brain, improves survival, and attenuates neurocognitive deficits.

ANTI-CD49D ANTIBODY TREATMENT IMPROVES SURVIVAL AND ATTENUATES NEUROCOGNITIVE DEFICITS AFTER TRAUMATIC BRAIN INJURY IN AGED MICE.

Patients 65 years and older account for an increasing proportion of traumatic brain injury (TBI) patients. Aged TBI patients experience increased morbidity and mortality compared with young TBI patients. We previously demonstrated a marked accumulation of CD8 + T-cells within the brains of aged TBI mice compared with young TBI mice.

Brain activity studied with magnetic resonance imaging in awake rabbits.

We reviewed fMRI experiments from our previous work in conscious rabbits, an experimental preparation that is advantageous for measuring brain activation that is free of anesthetic modulation and which can address questions in a variety of areas in sensory, cognitive, and pharmacological neuroscience research. Rabbits do not struggle or move for several hours while sitting with their heads restrained inside the horizontal bore of a magnet. This greatly reduces movement artifacts in magnetic resonance (MR) images in comparison to other experimental animals such as rodents, cats, and monkeys.

The TgF344-AD rat: behavioral and proteomic changes associated with aging and protein expression in a transgenic rat model of Alzheimer's disease.

Animal models of Alzheimer's Disease (AD) are attractive tools for preclinical, prodromal drug testing. The TgF344-AD (Tg) rat exhibits cognitive deficits and 5 major hallmarks of AD. Here we show that spatial water maze (WMZ) memory deficits and proteomic differences in dorsal CA1 were present in young Tg rats.

Learning-related changes in cellular activity within mouse dentate gyrus during trace eyeblink conditioning.

Because the dentate gyrus serves as the first site for information processing in the hippocampal trisynaptic circuit, it an important structure for the formation of associative memories. Previous findings in rabbit had recorded populations of cells within dentate gyrus that may bridge the temporal gap between stimuli to support memory formation during trace eyeblink conditioning, an associative learning task. However, this previous work was unable to identify the types of cells demonstrating this type of activity.

Diet-induced Alzheimer's-like syndrome in the rabbit.

Introduction: Although mouse models of Alzheimer's disease (AD) have increased our understanding of the molecular basis of the disease, none of those models represent late-onset Alzheimer's Disease which accounts for >90% of AD cases, and no therapeutics developed in the mouse (with the possible exceptions of aduhelm/aducanumab and gantenerumab) have succeeded in preventing or reversing the disease. This technology has allowed much progress in understanding the molecular basis of AD. To further enhance our understanding, we used wild-type rabbit (with a nearly identical amino acid sequence for amyloid as in humans) to model LOAD by stressing risk factors including age, hypercholesterolemia, and elevated blood glucose levels (BGLs), upon an ε3-like isoform of apolipoprotein.

Differential neuropathology and functional outcome after equivalent traumatic brain injury in aged versus young adult mice.

The CDC estimate that nearly 3 million Americans sustain a traumatic brain injury (TBI) each year. Even when medical comorbidities are accounted for, age is an independent risk factor for poor outcome after TBI. Nonetheless, few studies have examined the pathophysiology of age-linked biologic outcomes in TBI.

Cognitive aging is associated with redistribution of synaptic weights in the hippocampus.

Behaviors that rely on the hippocampus are particularly susceptible to chronological aging, with many aged animals (including humans) maintaining cognition at a young adult-like level, but many others the same age showing marked impairments. It is unclear whether the ability to maintain cognition over time is attributable to brain maintenance, sufficient cognitive reserve, compensatory changes in network function, or some combination thereof. While network dysfunction within the hippocampal circuit of aged, learning-impaired animals is well-documented, its neurobiological substrates remain elusive.

Intact Female Mice Acquire Trace Eyeblink Conditioning Faster than Male and Ovariectomized Female Mice.

Female subjects have been widely excluded from past neuroscience work because of a number of biases, including the notion that cycling sex hormones increase variability. However, it is necessary to conduct behavioral research in mice that includes both sexes as mice are typically used for developing and evaluating future therapeutics. Understanding sex differences in learning is fundamental for the development of targeted therapies for numerous neurologic and neurodegenerative disorders, including Alzheimer's disease, which is more prevalent in females than males.

Aβ oligomer induced cognitive impairment and evaluation of ACU193-MNS-based MRI in rabbit.

Introduction: Amyloid-beta oligomers (AβOs) accumulate in Alzheimer's disease and may instigate neuronal pathology and cognitive impairment. We examined the ability of a new probe for molecular magnetic resonance imaging (MRI) to detect AβOs in vivo, and we tested the behavioral impact of AβOs injected in rabbits, a species with an amino acid sequence that is nearly identical to the human sequence.

Methods: Intracerebroventricular (ICV) injection with stabilized AβOs was performed.

Detection of memory- and learning-related brain connectivity changes following trace eyeblink-conditioning using resting-state functional magnetic resonance imaging in the awake rabbit.

Animal imaging studies have the potential to further establish resting-state fMRI (rs-fMRI) and enable its validation for clinical use. The rabbit subjects used in this work are an ideal model system for studying learning and behavior and are also an excellent established test subject for awake scanning given their natural tolerance for restraint. We found that analysis of rs-fMRI conducted on a cohort of rabbits undergoing eyeblink conditioning can reveal functional brain connectivity changes associated with learning, and that rs-fMRI can be used to capture differences between subjects with different levels of cognitive performance.

Intrinsic Excitability Increase in Cerebellar Purkinje Cells after Delay Eye-Blink Conditioning in Mice.

Cerebellar-based learning is thought to rely on synaptic plasticity, particularly at synaptic inputs to Purkinje cells. Recently, however, other complementary mechanisms have been identified. Intrinsic plasticity is one such mechanism, and depends in part on the downregulation of calcium-dependent SK-type K channels, which contribute to a medium-slow afterhyperpolarization (AHP) after spike bursts, regulating membrane excitability.

Conditioned Contextual Freezing is A Neurobehavioral Biomarker of Axonal Injury Indicated by Reduced Fractional Anisotropy in A Mouse Model of Blast-Induced Mild Traumatic Brain Injury.

Mild traumatic brain injury (TBI) is an important public health problem generated by closed head injury. This study is focused on the impact of blast-induced mild TBI on auditory trace and delay fear conditioning, models of declarative and non-declarative memory, respectively, and the correlation of conditioned freezing and fractional anisotropy, a measure of axonal state. A supersonic helium pressure wave was generated by a shock tube to blast 8-week-old male mice on Day 1 for 1.

Genetic Ablation of Neural Progenitor Cells Impairs Acquisition of Trace Eyeblink Conditioning.

Adult-born neurons are believed to play a role in memory formation by providing enhanced plasticity to the hippocampus. Past studies have demonstrated that reduction of neurogenesis impairs associative learning, but these experiments used irradiation or neurotoxic substances, which may have had unintended off-target effects. Therefore, to investigate the role of these adult-born neurons more precisely, we used nestin-HSV-TK transgenic mice (Nes-TK) to selectively ablate newborn neurons.

Differential responsivity of neurons in perirhinal cortex, lateral entorhinal cortex, and dentate gyrus during time-bridging learning.

Many studies have focused on the function of hippocampal region CA1 as a critical site for associative memory, but much less is known about changes in the afferents to CA1. Here we report the activity of multiple single neurons from perirhinal and entorhinal cortex and from dentate gyrus during trace eyeblink conditioning as well as consolidated recall, and in pseudo-conditioned control rabbits. We also report an analysis of theta activity filtered from the local field potential (LFP).

Non-comedogenic and non-acnegenic claim substantiation.

There are currently two methods to evaluate comedogenecity. One is the inexpensive human model developed by Mills and Kligman and modified by others. The second is the more costly human clinical trial, which is the gold standard for comedogenesis and to which the human model is compared.

Building Bridges through Science.

Science is ideally suited to connect people from different cultures and thereby foster mutual understanding. To promote international life science collaboration, we have launched "The Science Bridge" initiative. Our current project focuses on partnership between Western and Middle Eastern neuroscience communities.

The rabbit as a behavioral model system for magnetic resonance imaging.

Background: fMRI requires that subjects not move during image acquisition. This has been achieved by instructing people not to move, or by anesthetizing experimental animal subjects to induce immobility. We have demonstrated that a surgically implanted headbolt onto the skull of a rabbit allows their brain to be imaged comfortably while the animal is awake.

Whisker-signaled Eyeblink Classical Conditioning in Head-fixed Mice.

Eyeblink conditioning is a common paradigm for investigating the neural mechanisms underlying learning and memory. To better utilize the extensive repertoire of scientific techniques available to study learning and memory at the cellular level, it is ideal to have a stable cranial platform. Because mice do not readily tolerate restraint, they are usually trained while moving about freely in a chamber.

Pretrial functional connectivity differentiates behavioral outcomes during trace eyeblink conditioning in the rabbit.

Fluctuations in neural activity can produce states that facilitate and accelerate task-related performance. Acquisition of trace eyeblink conditioning (tEBC) in the rabbit is enhanced when trials are contingent on optimal pretrial activity in the hippocampus. Other regions which are essential for whisker-signaled tEBC, such as the cerebellar interpositus nucleus (IPN), somatosensory and prelimbic cortices, may also show optimal connectivity prior to successful performance.

Intrinsic connectivity of neural networks in the awake rabbit.

The way in which the brain is functionally connected into different networks has emerged as an important research topic in order to understand normal neural processing and signaling. Since some experimental manipulations are difficult or unethical to perform in humans, animal models are better suited to investigate this topic. Rabbits are a species that can undergo MRI scanning in an awake and conscious state with minimal preparation and habituation.

Activity-induced manganese-dependent MRI (AIM-MRI) and functional MRI in awake rabbits during somatosensory stimulation.

Activity-induced manganese-dependent MRI (AIM-MRI) is a powerful tool to track system-wide neural activity using high resolution, quantitative T1-weighted MRI in animal models and has significant advantages for investigating neural activity over other modalities including BOLD fMRI. With AIM-MRI, Mn(2+) ions enter neurons via voltage-gated calcium channels preferentially active during the time of experimental exposure. A broad range of AIM-MRI studies using different species studying different phenomena have been performed, but few of these studies provide a systematic evaluation of the factors influencing the detection of Mn(2+) such as dosage and the temporal characteristics of Mn(2+) uptake.

Eyeblink Conditioning and Novel Object Recognition in the Rabbit: Behavioral Paradigms for Assaying Psychiatric Diseases.

Analysis of data collected from behavioral paradigms has provided important information for understanding the etiology and progression of diseases that involve neural regions mediating abnormal behavior. The trace eyeblink conditioning (EBC) paradigm is particularly suited to examine cerebro-cerebellar interactions since the paradigm requires the cerebellum, forebrain, and awareness of the stimulus contingencies. Impairments in acquiring EBC have been noted in several neuropsychiatric conditions, including schizophrenia, Alzheimer's disease (AD), progressive supranuclear palsy, and post-traumatic stress disorder.

The impact of hippocampal lesions on trace-eyeblink conditioning and forebrain-cerebellar interactions.

Behavioral Neuroscience published a pivotal paper by Moyer, Deyo, and Disterhoft (1990) 25 years ago that described the impaired acquisition of trace-eyeblink conditioning in rabbits with complete removal of the hippocampus. As part of the Behavioral Neuroscience celebration commemorating the 30th anniversary of the journal, we reflect upon the impact of that study on understanding the role of the hippocampus, forebrain, and forebrain-cerebellar interactions that mediate acquisition and retention of trace-conditioned responses, and of declarative memory more globally. We discuss the expansion of the conditioning paradigm to species other than the rabbit, the heterogeneity of responses among hippocampal neurons during trace conditioning, the responsivity of hippocampal neurons following consolidation of conditioning, the role of awareness in conditioning, how blink conditioning can be used as a translational tool by assaying potential therapeutics for cognitive enhancement, how trace and delay classical conditioning may be used to investigate neurological disorders including Alzheimer's disease and schizophrenia, and how the 2 paradigms may be used to understand the relationship between declarative (explicit) and nondeclarative (implicit) memory systems.