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.

All-or-none disconnection of pyramidal inputs onto parvalbumin-positive interneurons gates ocular dominance plasticity.

Disinhibition is an obligatory initial step in the remodeling of cortical circuits by sensory experience. Our investigation on disinhibitory mechanisms in the classical model of ocular dominance plasticity uncovered an unexpected form of experience-dependent circuit plasticity. In the layer 2/3 of mouse visual cortex, monocular deprivation triggers a complete, "all-or-none," elimination of connections from pyramidal cells onto nearby parvalbumin-positive interneurons (Pyr→PV). This binary form of circuit plasticity is unique, as it is transient, local, and discrete. It lasts only 1 d, and it does not manifest as widespread changes in synaptic strength; rather, only about half of local connections are lost, and the remaining ones are not affected in strength. Mechanistically, the deprivation-induced loss of Pyr→PV is contingent on a reduction of the protein neuropentraxin2. Functionally, the loss of Pyr→PV is absolutely necessary for ocular dominance plasticity, a canonical model of deprivation-induced model of cortical remodeling. We surmise, therefore, that this all-or-none loss of local Pyr→PV circuitry gates experience-dependent cortical plasticity.

Heterogeneity of Age-Related Neural Hyperactivity along the CA3 Transverse Axis.

Age-related memory deficits are correlated with neural hyperactivity in the CA3 region of the hippocampus. Abnormal CA3 hyperactivity in aged rats has been proposed to contribute to an imbalance between pattern separation and pattern completion, resulting in overly rigid representations. Recent evidence of functional heterogeneity along the CA3 transverse axis suggests that proximal CA3 supports pattern separation while distal CA3 supports pattern completion. It is not known whether age-related CA3 hyperactivity is uniformly represented along the CA3 transverse axis. We examined the firing rates of CA3 neurons from young and aged, male, Long-Evans rats along the CA3 transverse axis. Consistent with prior studies, young CA3 cells showed an increasing gradient in mean firing rate from proximal to distal CA3. However, aged CA3 cells showed an opposite, decreasing trend, in that CA3 cells in aged rats were hyperactive in proximal CA3, but possibly hypoactive in distal CA3, compared with young (Y) rats. We suggest that, in combination with altered inputs from the entorhinal cortex and dentate gyrus (DG), the proximal CA3 region of aged rats may switch from its normal function that reflects the pattern separation output of the DG and instead performs a computation that reflects an abnormal bias toward pattern completion. In parallel, distal CA3 of aged rats may create weaker attractor basins that promote abnormal, bistable representations under certain conditions.SIGNIFICANCE STATEMENT Prior work suggested that age-related CA3 hyperactivity enhances pattern completion, resulting in rigid representations. Implicit in prior studies is the notion that hyperactivity is present throughout a functionally homogeneous CA3 network. However, more recent work has demonstrated functional heterogeneity along the CA3 transverse axis, in that proximal CA3 is involved in pattern separation and distal CA3 is involved in pattern completion. Here, we show that age-related hyperactivity is present only in proximal CA3, with potential hypoactivity in distal CA3. This result provides new insight in the role of CA3 in age-related memory impairments, suggesting that the rigid representations in aging result primarily from dysfunction of computational circuits involving the dentate gyrus (DG) and proximal CA3.

Effect of aging differs for memory of object identity and object position within a spatial context.

There has been considerable focus on investigating age-related memory changes in cognitively healthy older adults, in the absence of neurodegenerative disorders. Previous studies have reported age-related domain-specific changes in older adults, showing increased difficulty encoding and processing object information but minimal to no impairment in processing spatial information compared with younger adults. However, few of these studies have examined age-related changes in the encoding of concurrently presented object and spatial stimuli, specifically the integration of both spatial and nonspatial (object) information. To more closely resemble real-life memory encoding and the integration of both spatial and nonspatial information, the current study developed a new experimental paradigm with novel environments that allowed for the placement of different objects in different positions within the environment. The results show that older adults have decreased performance in recognizing changes of the object position within the spatial context but no significant differences in recognizing changes in the identity of the object within the spatial context compared with younger adults. These findings suggest there may be potential age-related differences in the mechanisms underlying the representations of complex environments and furthermore, the integration of spatial and nonspatial information may be differentially processed relative to independent and isolated representations of object and spatial information.

Using internal memory representations in associative learning to study hallucination-like phenomenon.

Studies of Pavlovian conditioning have enriched our understanding of how relations among events can adaptively guide behavior through the formation and use of internal mental representations. In this review, we illustrate how internal representations flexibly integrate new updated information in reinforcer revaluation to influence relationships to impact actions and outcomes. We highlight representation-mediated learning to show the similarities in properties and functions between internally generated and directly activated representations, and how normal perception of internal representations could contribute to hallucinations. Converging evidence emerges from recent behavioral and neural activation studies using animal models of schizophrenia as well as clinical studies in patients to support increased tendencies in these populations to evoke internal representations from prior associative experience that approximate hallucination-like percepts. The heightened propensity is dependent on dopaminergic activation which is known to be sensitive to hippocampal overexcitability, a condition that has been observed in patients with psychosis. This presents a network that overlaps with cognitive neural circuits and offers a fresh approach for the development of therapeutic interventions targeting psychosis.

Metabotropic Glutamate Receptors Induce a Form of LTP Controlled by Translation and Arc Signaling in the Hippocampus.

Activity-dependent bidirectional modifications of excitatory synaptic strength are essential for learning and storage on new memories. Research on bidirectional synaptic plasticity has largely focused on long-term potentiation (LTP) and long-term depression (LTD) mechanisms that rely on the activation of NMDA receptors. In principle, metabotropic glutamate receptors (mGluRs) are also suitable to convert synaptic activity into intracellular signals for synaptic modification. Indeed, dysfunction of a form of LTD that depends on Type I mGluRs (mGluR-LTD), but not NMDARs, has been implicated in learning deficits in aging and mouse models of several neurological conditions, including Fragile X syndrome and Alzheimer's disease. To determine whether mGluR activation can also induce LTP in the absence of NMDAR activation, we examined in hippocampal slices from rats and mice, an NMDAR-independent form of LTP previously characterized as dependent on voltage-gated Ca(2+) channels. We found that this form of LTP requires activation of Type I mGluRs and, like mGluR-LTD but unlike NMDAR-dependent plasticity, depends crucially on protein synthesis controlled by fragile X mental retardation protein and on Arc signaling. Based on these observations, we propose the coexistence of two distinct activity-dependent systems of bidirectional synaptic plasticity: one that is based on the activity of NMDARs and the other one based on the activation of mGluRs. SIGNIFICANCE STATEMENT: Bidirectional changes of synaptic strength are crucial for the encoding of new memories. Currently, the only activity-dependent mechanism known to support such bidirectional changes are long-term potentiation (LTP) and long-term depression (LTD) forms that relay on the activation of NMDA receptors. Metabotropic glutamate receptors (mGluRs) are, in principle, also suitable to trigger bidirectional synaptic modifications. However, only the mGluR-dependent form of LTD has been characterized. Here we report that an NMDAR-independent form of LTP, initially characterized as dependent on voltage-gated Ca(2+) channels, also requires the activation of mGluRs. These finding suggest the coexistence of two distinct activity-dependent systems of bidirectional synaptic plasticity: one that is based on the activity of NMDARs and the other one based on the activation of mGluRs.

Cognitive and motivational deficits together with prefrontal oxidative stress in a mouse model for neuropsychiatric illness.

Guided by features of molecular, cellular, and circuit dysfunction affecting the prefrontal cortex in clinical investigations, we targeted prefrontal cortex in studies of a model for neuropsychiatric illness using transgenic mice expressing a putative dominant-negative disrupted in schizophrenia 1 (DN-DISC1). We detected marked augmentation of GAPDH-seven in absentia homolog Siah protein binding in the DISC1 mice, a major hallmark of a nuclear GAPDH cascade that is activated in response to oxidative stress. Furthermore, deficits were observed in well-defined tests for the cognitive control of adaptive behavior using reversal learning and reinforcer devaluation paradigms. These deficits occurred even though DN-DISC1 mice showed intact performance in simple associative learning and normal responses in consumption of reward. In an additional series of assessments, motivational functions also were impoverished in DN-DISC1 mice, including tests of the dynamic modulation of reward value by effortful action, progressive ratio performance, and social behavior. Augmentation of an oxidative stress-associated cascade (e.g., a nuclear GAPDH cascade) points to an underlying condition that may contribute to the profile of cognitive and motivational impairments in DN-DISC1 mice by affecting the functional integrity of the prefrontal cortex and dysfunction within its connected networks. As such, this model should be useful for further preclinical research and drug discovery efforts relevant to the burden of prefrontal dysfunction in neuropsychiatric illness.

Inositol polyphosphate multikinase is a transcriptional coactivator required for immediate early gene induction.

Profound induction of immediate early genes (IEGs) by neural activation is a critical determinant for plasticity in the brain, but intervening molecular signals are not well characterized. We demonstrate that inositol polyphosphate multikinase (IPMK) acts noncatalytically as a transcriptional coactivator to mediate induction of numerous IEGs. IEG induction by electroconvulsive stimulation is virtually abolished in the brains of IPMK-deleted mice, which also display deficits in spatial memory. Neural activity stimulates binding of IPMK to the histone acetyltransferase CBP and enhances its recruitment to IEG promoters. Interestingly, IPMK regulation of CBP recruitment and IEG induction does not require its catalytic activities. Dominant-negative constructs, which prevent IPMK-CBP binding, substantially decrease IEG induction. As IPMK is ubiquitously expressed, its epigenetic regulation of IEGs may influence diverse nonneural and neural biologic processes.

Integrity of mGluR-LTD in the associative/commissural inputs to CA3 correlates with successful aging in rats.

The impact of aging on cognitive capabilities varies among individuals ranging from significant impairment to preservation of function on par with younger adults. Research on the neural basis for age-related memory decline has focused primarily on the CA1 region of the hippocampus. However, recent studies in elderly human and rodents indicate that individual differences in cognitive aging are more strongly tied to functional alterations in CA3 circuits. To examine synaptic plasticity in the CA3 region, we used aged rats behaviorally characterized in a hippocampal-dependent task to evaluate the status of long-term potentiation and long-term depression (LTP and LTD) in the associative/commissural pathway (A/C → CA3), which provides the majority of excitatory input to CA3 pyramidal neurons. We found that, unlike in CA1 synapses, in A/C → CA3 LTP is minimally affected by age. However, two forms of LTD, involving NMDA and metabotropic glutamate receptors (mGluR), are both greatly reduced in age-impaired rats. Age-unimpaired rats, in contrast, had intact mGluR LTD. These findings indicate that the integrity of mGluR-LTD at A/C → CA3 inputs may play a crucial role in maintaining the performance of CA3 circuitry in aging.

Age-associated changes in hippocampal-dependent cognition in Diversity Outbred mice.

Episodic memory impairment due to aging has been linked to hippocampal dysfunction. Evidence exists for alterations in specific circuits within the hippocampal system that are closely coupled to individual differences in the presence and severity of such memory loss. Here, we used the newly developed Diversity Outbred (DO) mouse that was designed to model the genetic diversity in human populations. Young and aged DO mice were tested in a hippocampal-dependent water maze task. Young mice showed higher proficiency and more robust memory compared to the overall performance of aged mice. A substantial number of the older mice, however, performed on par with the normative performance of the younger mice. Stereological quantification of somatostatin-immunoreactive neurons in the dentate hilus showed that high-performing young and unimpaired aged mice had similar numbers of somatostatin-positive interneurons, while aged mice that were impaired in the spatial task had significantly fewer such neurons. These data in the DO model tie loss of hilar inhibitory network integrity to age-related memory impairment, paralleling data in other rodent models.

A fine balance: Regulation of hippocampal Arc/Arg3.1 transcription, translation and degradation in a rat model of normal cognitive aging.

Memory decline is a common feature of aging. Expression of the immediate-early gene Arc is necessary for normal long-term memory, and although experience dependent Arc transcription is reportedly reduced in the aged rat hippocampus, it has not been clear whether this effect is an invariant consequence of growing older, or a finding linked specifically to age-related memory impairment. Here we show that experience dependent Arc mRNA expression in the hippocampus fails selectively among aged rats with spatial memory deficits. While these findings are consistent with the possibility that blunted Arc transcription contributes to cognitive aging, we also found increased basal ARC protein levels in the CA1 field of the hippocampus in aged rats with memory impairment, together with a loss of the experience dependent increase observed in young and unimpaired aged rats. Follow-up analysis revealed that increased basal translation and blunted ubiquitin mediated degradation may contribute to increased basal ARC protein levels noted in memory impaired aged rats. These findings indicate that Arc expression is regulated at multiple levels, and that several of these mechanisms are altered in cognitively impaired aged rats. Defining the influence of these alterations on the spatial and temporal fidelity of synapse specific, memory-related plasticity in the aged hippocampus is an important challenge.

The HOPE4MCI study: A randomized double-blind assessment of AGB101 for the treatment of MCI due to AD.

INTRODUCTION: In addition to the accumulation of amyloid plaques and neurofibrillary tangles, the presence of excess neural activity is a pathological hallmark of Alzheimer's disease (AD) and a prognostic indicator for progression of AD pathology and clinical/cognitive worsening in mild cognitive impairment due to Alzheimer's disease (MCI due to AD). The HOPE4MCI clinical study tested the efficacy of a therapeutic with demonstrated ability to normalize heightened neural activity in the hippocampus in a randomized controlled trial of 78 weeks duration in patients with MCI due to AD. METHODS: One hundred and sixty-four participants were randomized to placebo (n = 83) or AGB101 (n = 81), an extended-release formulation of low dose (220 mg) levetiracetam. The primary endpoint was the change in Clinical Dementia Rating Scale Sum of Boxes score (CDR-SB) comparing follow up at 18 months to baseline. The goal of the primary efficacy analysis was to estimate the difference between the AGB101 and placebo arms in the mean change of the primary endpoint. RESULTS: The mean change in CDR-SB was estimated to be 1.12 (95% confidence interval [CI]: 0.66, 1.69) for the AGB101 arm and 1.22 (95% CI: 0.75, 1.78) for the placebo arm. The estimated difference between arms is -0.10 (95% CI: -0.85, 0.58), which was not statistically significant. In a prespecified analysis, the difference was -0.45 (95% CI: -1.43, 0.53) for ApoE-4 noncarriers and -0.10 (95% CI: -0.92, 0.72) for apolipoprotein E (ApoE)-4 carriers. DISCUSSION: The possibility that ApoE-4 carriers and noncarriers will respond differently to therapeutic intervention is consistent with recently reported findings from biologics and the present results show further testing of AGB101 in patients with MCI due to AD who are noncarriers of the ApoeE-4 allele is warranted. Conclusions from the HOPE4MCI study are limited primarily due to the small sample size and results can only be regarded as a guide to future research.

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.

mGluR-dependent plasticity in rodent models of Alzheimer's disease.

Long-term potentiation (LTP) and depression (LTD) are currently the most comprehensive models of synaptic plasticity models to subserve learning and memory. In the CA1 region of the hippocampus LTP and LTD can be induced by the activation of either NMDA receptors or mGluR5 metabotropic glutamate receptors. Alterations in either form of synaptic plasticity, NMDAR-dependent or mGluR-dependent, are attractive candidates to contribute to learning deficits in conditions like Alzheimer's disease (AD) and aging. Research, however, has focused predominantly on NMDAR-dependent forms of LTP and LTD. Here we studied age-associated changes in mGluR-dependent LTP and LTD in the APP/PS1 mouse model of AD and in Octodon degu, a rodent model of aging that exhibits features of AD. At 2 months of age, APP/PS1 mouse exhibited robust mGluR-dependent LTP and LTD that was completely lost by the 8th month of age. The expression of mGluR protein in the hippocampus of APP/PS1 mice was not affected, consistent with previous findings indicating the uncoupling of the plasticity cascade from mGluR5 activation. In O. degu, the average mGluR-LTD magnitude is reduced by half by the 3 rd year of age. In aged O. degu individuals, the reduced mGluR-LTD correlated with reduced performance in a radial arm maze task. Altogether these findings support the idea that the preservation of mGluR-dependent synaptic plasticity is essential for the preservation of learning capacity during aging.

A specific amyloid-beta protein assembly in the brain impairs memory.

Memory function often declines with age, and is believed to deteriorate initially because of changes in synaptic function rather than loss of neurons. Some individuals then go on to develop Alzheimer's disease with neurodegeneration. Here we use Tg2576 mice, which express a human amyloid-beta precursor protein (APP) variant linked to Alzheimer's disease, to investigate the cause of memory decline in the absence of neurodegeneration or amyloid-beta protein amyloidosis. Young Tg2576 mice (< 6 months old) have normal memory and lack neuropathology, middle-aged mice (6-14 months old) develop memory deficits without neuronal loss, and old mice (> 14 months old) form abundant neuritic plaques containing amyloid-beta (refs 3-6). We found that memory deficits in middle-aged Tg2576 mice are caused by the extracellular accumulation of a 56-kDa soluble amyloid-beta assembly, which we term Abeta*56 (Abeta star 56). Abeta*56 purified from the brains of impaired Tg2576 mice disrupts memory when administered to young rats. We propose that Abeta*56 impairs memory independently of plaques or neuronal loss, and may contribute to cognitive deficits associated with Alzheimer's disease.

Cognitive decline is associated with reduced reelin expression in the entorhinal cortex of aged rats.

Brain regions and neural circuits differ in their vulnerability to changes that occur during aging and in age-related neurodegenerative diseases. Among the areas that comprise the medial temporal lobe memory system, the layer II neurons of the entorhinal cortex, which form the perforant path input to the hippocampal formation, exhibit early alterations over the course of aging Reelin, a glycoprotein implicated in synaptic plasticity, is expressed by entorhinal cortical layer II neurons. Here, we report that an age-related reduction in reelin expression in the entorhinal cortex is associated with cognitive decline. Using immunohistochemistry and in situ hybridization, we observed decreases in the number of Reelin-immunoreactive cells and reelin messenger RNA expression in the lateral entorhinal cortex of aged rats that are cognitively impaired relative to young adults and aged rats with preserved cognitive abilities. The lateral entorhinal cortex of aged rats with cognitive impairment also exhibited changes in other molecular markers, including increased accumulation of phosphorylated tau and decreased synaptophysin immunoreactivity. Taken together, these findings suggest that reduced reelin expression, emanating from layer II entorhinal neurons, may contribute to network dysfunction that occurs during memory loss in aging.

Individual differences in neurocognitive aging in outbred male and female long-evans rats.

Individual differences in biology as well as experience and exposures throughout life may contribute risk or resilience to neurocognitive decline in aging. To investigate the role of sex as a biological variable in cognitive function due to normal aging, we used substantial cohorts of healthy male and female aged outbred rats maintained under similar conditions throughout life to assess whether both sexes display a similar distribution of individual differences in behavioral performance using a water maze task optimized to assess hippocampal-dependent cognition in aging. We found both aged male and female rats performed poorer than young adults overall, but with no performance differences between sex in either young adults or aged groups in memory probe tests. In addition, aged male and female rats had similar distributions of individual differences such that the same proportion of male and female performed on par with (intact memory) or outside of (impaired memory) the benchmark of young rats of their respective sex. The data support the use of this outbred model with biological diversity to study the neurobiology of aging trajectories for variation in cognitive outcomes in both male and females. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Lateral entorhinal cortex dysfunction in amnestic mild cognitive impairment.

The entorhinal cortex is the site of some of the earliest pathological changes in Alzheimer's disease, including neuronal, synaptic and volumetric loss. Specifically, the lateral entorhinal cortex shows significant accumulation of tau neurofibrillary tangles in the amnestic mild cognitive impairment (aMCI) phase of Alzheimer's disease. Although decreased entorhinal cortex activation has been observed in patients with aMCI in the context of impaired memory function, it remains unclear if functional changes in the entorhinal cortex can be localized to the lateral or medial entorhinal cortex. To assess subregion specific changes in the lateral and medial entorhinal cortex, patients with aMCI and healthy aged-matched control participants underwent high-resolution structural and functional magnetic resonance imaging. Patients with aMCI showed significantly reduced volume, and decreased activation localized to the lateral entorhinal cortex but not the medial entorhinal cortex. These results show that structural and functional changes associated with impaired memory function differentially engage the lateral entorhinal cortex in patients with aMCI, consistent with the locus of early disease related pathology.

Loss of functional heterogeneity along the CA3 transverse axis in aging.

Age-related deficits in pattern separation have been postulated to bias the output of hippocampal memory processing toward pattern completion, which can cause deficits in accurate memory retrieval. Although the CA3 region of the hippocampus is often conceptualized as a homogeneous network involved in pattern completion, growing evidence demonstrates a functional gradient in CA3 along the transverse axis, as pattern-separated outputs (dominant in the more proximal CA3) transition to pattern-completed outputs (dominant in the more distal CA3). We examined the neural representations along the CA3 transverse axis in young (Y), aged memory-unimpaired (AU), and aged memory-impaired (AI) rats when different changes were made to the environment. Functional heterogeneity in CA3 was observed in Y and AU rats when the environmental similarity was high (altered cues or altered environment shapes in the same room), with more orthogonalized representations in proximal CA3 than in distal CA3. In contrast, AI rats showed reduced orthogonalization in proximal CA3 but showed normal (i.e., generalized) representations in distal CA3, with little evidence of a functional gradient. Under experimental conditions when the environmental similarity was low (different rooms), representations in proximal and distal CA3 remapped in all rats, showing that CA3 of AI rats is able to encode distinctive representations for inputs with greater dissimilarity. These experiments support the hypotheses that the age-related bias toward hippocampal pattern completion is due to the loss in AI rats of the normal transition from pattern separation to pattern completion along the CA3 transverse axis.