Object-place-context learning impairment correlates with spatial learning impairment in aged Long-Evans rats.

The hippocampal formation is vulnerable to the process of normal aging. In humans, the extent of this age-related deterioration varies among individuals. Long-Evans rats replicate these individual differences as they age, and therefore they serve as a valuable model system to study aging in the absence of neurodegenerative diseases. In the Morris water maze, aged memory-unimpaired (AU) rats navigate to remembered goal locations as effectively as young rats and demonstrate minimal alterations in physiological markers of synaptic plasticity, whereas aged memory-impaired (AI) rats show impairments in both spatial navigation skills and cellular and molecular markers of plasticity. The present study investigates whether another cognitive domain is affected similarly to navigation in aged Long-Evans rats. We tested the ability of young, AU, and AI animals to recognize novel object-place-context (OPC) configurations and found that performance on the novel OPC recognition paradigm was significantly correlated with performance on the Morris water maze. In the first OPC test, young and AU rats, but not AI rats, successfully recognized and preferentially explored objects in novel OPC configurations. In a second test with new OPC configurations, all age groups showed similar OPC associative recognition memory. The results demonstrated similarities in the behavioral expression of associative, episodic-like memory between young and AU rats and revealed age-related, individual differences in functional decline in both navigation and episodic-like memory abilities.

Individual differences in age-related neurocognitive outcomes: within-subject assessment of memory for odors.

Cognitive decline is a common feature of aging, particularly in memory domains supported by the medial temporal lobe (MTL). The ability to identify intervention strategies to treat or prevent this decline is challenging due to substantial variability between adults in terms of age of onset, rate and severity of decline, and many factors that could influence cognitive reserve. These factors can be somewhat mitigated by use of within-subject designs. Aged outbred Long-Evans rats have proven useful for identifying translationally relevant substrates contributing to age-related decline in MTL-dependent memory. In this population, some animals show reliable impairment on MTL-dependent tasks while others perform within the range of young adult rats. However, currently there are relatively few within-subject behavior protocols for assessing MTL function over time, and most require extensive training and appetitive motivation for associative learning. In the current study, we aimed to test whether water maze learning impairments in aged Long-Evans rats would be predictive of delayed recognition memory impairments and whether these odor memory impairments would be stable within subjects over multiple rounds of testing.

Structural and functional consequences of PAX6 mutations in the brain: Implications for aniridia.

The paired-box 6 (PAX6) gene encodes a highly conserved transcription factor essential for the proper development of the eye and brain. Heterozygous loss-of-function mutations in PAX6 are causal for a condition known as aniridia in humans and the Small eye phenotype in mice. Aniridia is characterized by iris hypoplasia and other ocular abnormalities, but recent evidence of neuroanatomical, sensory, and cognitive impairments in this population has emerged, indicating brain-related phenotypes as a prevalent feature of the disorder. Determining the neurophysiological origins of brain-related phenotypes in this disorder presents a substantial challenge, as the majority of extra-ocular traits in aniridia demonstrate a high degree of heterogeneity. Here, we summarize and integrate findings from human and rodent model studies, which have focused on neuroanatomical and functional consequences of PAX6 mutations. We highlight novel findings from PAX6 central nervous system studies in adult mammals, and integrate these findings into what we know about PAX6's role in development of the central nervous system. This review presents the current literature in the field in order to inform clinical application, discusses what is needed in future studies, and highlights PAX6 as a lens through which to understand genetic disorders affecting the human nervous system.

Significance of inhibitory recruitment in aging with preserved cognition: limiting gamma-aminobutyric acid type A α5 function produces memory impairment.

Numerous aging studies have identified a shift in the excitatory/inhibitory (E/I) balance with heightened hippocampal neural activity associated with age-related memory impairment across species, including rats, monkeys, and humans. Neurobiological investigations directed at the hippocampal formation have demonstrated that unimpaired aged rats performing on par with young adult rats in a spatial memory task exhibit gene expression profiles, mechanisms for plasticity, and altered circuit/network function, which are distinct from younger rats. Particularly striking is a convergence of observational evidence that aged unimpaired rats augment recruitment of mechanisms associated with neural inhibition, a finding that may represent an adaptive homeostatic adjustment necessary to maintain neural plasticity and memory function in aging. In this study, we test the effect of limiting inhibition via administration of TB21007, a negative allosteric modulator of the alpha 5 subtype of gamma-aminobutyric acid type A α5 receptor, on a radial arm maze assessment of memory function. Impaired memory performance produced by this intervention in otherwise high-performing aged rats supports an adaptive role for gamma-aminobutyric acid in the functional maintenance of intact cognition in aging.

Aged rats with intact memory show distinctive recruitment in cortical regions relative to young adults in a cue mismatch task.

Similar to elderly humans, aged Long-Evans rats exhibit individual differences in performance on tasks that critically depend on the medial temporal lobe memory system. Although reduced memory performance is common, close to half of aged rats in this outbred rodent population perform within the range of young subjects, exhibiting a stable behavioral phenotype that may signal a resilience to memory decline. Increasing evidence from research on aging in the Long-Evans study population supports the existence of adaptive neural change rather than avoidance of detrimental effects of aging on the brain, indicating a malleability of brain function over the life span that may preserve optimal function. Augmenting prior work that centered on hippocampal function, the current study extends investigation to cortical regions functionally interconnected with the hippocampal formation, including medial temporal lobe cortices and posterior components of the default mode network. In response to an environmental manipulation that creates a mismatch in the expected cue orientation, aged rats with preserved memory show greater activation across an extended network of cortical regions as measured by immediate early gene expression. In contrast, young subjects, behaviorally similar to the aged rats in this study, show a more limited cortical response. This distinctive cortical recruitment in aged unimpaired rats, set against a background of comparable activation across hippocampal subregions, may represent adaptive cortical recruitment consistent with evidence in human studies of neurocognitive aging. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Aged rats with preserved memory dynamically recruit hippocampal inhibition in a local/global cue mismatch environment.

Similar to elderly humans, aged outbred Long-Evans rats exhibit individual differences in memory abilities, including a subset of aged rats that maintain memory function on par with young adults. Such individuals provide a basis for investigating mechanisms of resilience to age-related decline. The present study examined hippocampal gene expression in young adults and aged rats with preserved memory function under behavioral task conditions well established for assessing information processing central to the formation of episodic memory. Although behavioral measures and hippocampal gene induction associated with neural activity and synaptic plasticity were similar across age groups, a marker for inhibitory interneuron function in the hippocampal formation was distinctively increased only in aged rats but not in young adults. Because heightened hippocampal neural activity is associated with age-related memory impairment across species, including rats, monkeys, and humans, this finding may represent an adaptive homeostatic adjustment necessary to maintain neural plasticity and memory function in aging.

Genetic and Neurobiological Analyses of the Noradrenergic-like System in Vulnerability to Sugar Overconsumption Using a Drosophila Model.

Regular overconsumption of sugar is associated with obesity and type-2 diabetes, but how genetic factors contribute to variable sugar preferences and intake levels remains mostly unclear. Here we provide evidence for the usefulness of a Drosophila larva model to investigate genetic influence on vulnerability to sugar overconsumption. Using genetic and RNA interference approaches, we show that the activity of the Oamb gene, which encodes a receptor for octopamine (OA, the invertebrate homologue of norepinephrine), plays a major role in controlled sugar consumption. Furthermore, Oamb appears to suppress sugar food intake in fed larvae in an acute manner, and neurons expressing this Oamb receptor do not overlap with neurons expressing Octß3R, another OA receptor previously implicated in hunger-driven exuberant sugar intake. Together, these results suggest that two separate sub-circuits, defined by Oamb and Octß3R respectively, co-regulate sugar consumption according to changes in energy needs. We propose that the noradrenergic-like system defines an ancient regulatory mechanism for prevention of sugar overload.

Targeting Neural Hyperactivity as a Treatment to Stem Progression of Late-Onset Alzheimer's Disease.

Sporadic late-onset Alzheimer's disease (LOAD), the most common form of dementia in the elderly, causes progressive and severe loss of cognitive abilities. With greater numbers of people living to advanced ages, LOAD will increasingly burden both the healthcare system and society. There are currently no available disease-modifying therapies, and the failure of several recent pathology-based strategies has highlighted the urgent need for effective therapeutic targets. With aging as the greatest risk factor for LOAD, targeting mechanisms by which aging contributes to disease could prove an effective strategy to delay progression to clinical dementia by intervention in elderly individuals in an early prodromal stage of disease. Excess neural activity in the hippocampus, a recently described phenomenon associated with age-dependent memory loss, was first identified in animal models of aging and subsequently translated to clinical conditions of aging and early-stage LOAD. Critically, elevated activity was similarly localized to specific circuits within the hippocampal formation in aged animals and humans. Here we review evidence for hippocampal hyperactivity as a significant contributor to age-dependent cognitive decline and the progressive accumulation of pathology in LOAD. We also describe studies demonstrating the efficacy of reducing hyperactivity with an initial test therapy, levetiracetam (Keppra), an atypical antiepileptic. By targeting excess neural activity, levetiracetam may improve cognition and attenuate the accumulation of pathology contributing to progression to the dementia phase of LOAD.

Prevention of palatable diet-induced hyperphagia in rats by central injection of a VEGFR kinase inhibitor.

Our previous studies have demonstrated a critical role of a VEGFR-like signaling pathway in hunger-driven overeating of sugar-rich food in Drosophila larvae. In the current study, we investigate whether the VEGFR signaling mechanism plays a similar role in the feeding behavior of vertebrates using male Sprague Dawley rats. Young rats were treated intracerebroventrically (i.c.v.) with a single dose (2 µg) of VEGFR2 Tyrosine Kinase Inhibitor V (VTKI-V), an N-cyclopropylnaphthamide compound that selectively inhibits the kinase activity of VEGFR2 at subnanomolar concentrations. We find that animals treated with VTKI-V showed markedly attenuated overconsumption of palatable food that is sweet and fatty. The subsequent meal pattern analysis reveals that is achieved by consumption of smaller, shorter meals. Furthermore, i.c.v. injection of VTKI-V decreased body weight gain in animals fed with CHOW or palatable food. These inhibitory effects of the drug were detectable within 24h and persisted for at least five days. Given that body weight was affected by the drug regardless of diet while food intake was selectively altered in palatable diet fed animals, these results raise the possibility that i.c.v. injection of VTKI-V may interfere the functions of two separate VEGFR-mediated mechanisms: one promotes overconsumption of palatable food, and the other mediates body weight gain.

Octopamine-mediated circuit mechanism underlying controlled appetite for palatable food in Drosophila.

The easy accessibility of energy-rich palatable food makes it difficult to resist food temptation. Drosophila larvae are surrounded by sugar-rich food most of their lives, raising the question of how these animals modulate food-seeking behaviors in tune with physiological needs. Here we describe a circuit mechanism defined by neurons expressing tdc2-Gal4 (a tyrosine decarboxylase 2 promoter-directed driver) that selectively drives a distinct foraging strategy in food-deprived larvae. Stimulation of this otherwise functionally latent circuit in tdc2-Gal4 neurons was sufficient to induce exuberant feeding of liquid food in fed animals, whereas targeted lesions in a small subset of tdc2-Gal4 neurons in the subesophageal ganglion blocked hunger-driven increases in the feeding response. Furthermore, regulation of feeding rate enhancement by tdc2-Gal4 neurons requires a novel signaling mechanism involving the VEGF2-like receptor, octopamine, and its receptor. Our findings provide fresh insight for the neurobiology and evolution of appetitive motivation.