Biology subjects

Yassa, M. A.

Publications and source records attributed to Yassa, M. A..

27 records · Page 2Linked to original sources

bioRxiv2022

Entorhinal-hippocampal circuit integrity is related to mnemonic discrimination and amyloid-β pathology in older adults

Mnemonic discrimination, a cognitive process that relies on hippocampal pattern separation, is one of the first memory domains to decline in aging and preclinical Alzheimers disease. We tested if functional connectivity (FC) within the entorhinal-hippocampal circuit, measured with high-resolution resting state fMRI, is associated with mnemonic discrimination and A{beta} pathology, measured with PET, in nondemented older adults. Low object mnemonic discrimination performance was specifically associated with increased FC between anterolateral entorhinal cortex (alEC) and dentate gyrus (DG)/CA3, supporting the importance of this connection to object memory. This hyperconnectivity between alEC-DG/CA3 was related to A{beta} pathology and decreased entorhinal cortex volume. In contrast, spatial mnemonic discrimination was not associated with altered FC. A{beta} was further associated with decreased FC and volume within hippocampal subfields. Our findings suggest that A{beta} may indirectly lead to memory impairment through entorhinal-hippocampal circuit dysfunction and neurodegeneration, and provide a mechanism for vulnerability of object mnemonic discrimination.

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bioRxiv2021

Awake ripples enhance emotional memory encoding in the human brain

Intracranial recordings from the human amygdala and the hippocampus during an emotional memory encoding and discrimination task reveal increased awake sharp-wave/ripples (aSWR) after encoding of emotional compared to neutral stimuli. Further, post-encoding aSWR-locked memory reinstatement in the amygdala and the hippocampus was predictive of later memory discrimination. These findings provide electrophysiological evidence that post-encoding aSWRs enhance memory for emotional events.

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bioRxiv2021

Early Life Adversity in Male Mice Sculpts Reward Circuits.

Early life adversity (ELA) comprises a wide variety of negative experiences during early life and has been linked to cognitive impairments, reduced experiences of pleasure (anhedonia), and other long-term consequences implying that ELA impacts the reward circuitry. In this study, we focused on the projections from the dorsal raphe (DR) to the ventral tegmental area (VTA) and on to the nucleus accumbens (NAcc), an important pathway within the reward circuit. We hypothesized that ELA alters connectivity within the DR-VTA- NAcc pathway, manifested behaviorally as anhedonia in adulthood. We used the limited bedding and nesting model to induce ELA in mice and measured reward-related behaviors in adulthood using the three-chamber social interaction and sucrose preference tests. High resolution ex vivo diffusion tensor imaging (DTI) was acquired and processed for regional DTI metrics, including tractography to assess circuit organization. We found brain-wide changes in radial diffusivity (RD) and altered connectivity of the reward circuit in the ELA group. DR-VTA-NAcc circuit tractography and axial diffusivity (AD) along this tract exhibited dispersed organization where AD was increased in the VTA segment. Behaviorally, ELA elicited an anhedonic phenotype in adulthood with decreased direct social approach and time spent with peer but no overt differences in sucrose preference test. Our findings suggest that reward circuits, assessed using DTI, are altered following ELA and that these changes may drive enduring reward deficits.

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bioRxiv2020

Brain Amyloid and the Transition to Dementia in Down Syndrome

INTRODUCTIONDown syndrome (DS) is associated with elevated risk for Alzheimers disease (AD) due to beta amyloid (A{beta}) lifelong accumulation. We hypothesized that the spatial distribution of brain A{beta} predicts future dementia conversion in individuals with DS. METHODSWe acquired 18F-Florbetapir PET scans from 19 nondemented individuals with DS at baseline and monitored them for four years, with five individuals transitioning to dementia. Machine learning classification determined features on 18F-Florbetapir standardized uptake value ratio (SUVR) maps that predicted transition. RESULTSIn addition to "AD signature" regions including the inferior parietal cortex, temporal lobes, and the cingulum, we found that A{beta} cortical binding in the prefrontal and superior frontal cortices distinguished subjects who transitioned to dementia. Classification did well in predicting transitioners. DISCUSSIONOur study suggests that specific regional profiles of brain amyloid in older adults with DS may predict cognitive decline and are informative in evaluating the risk for dementia. HighlightsO_LIRegional [18F]-Florbetapir PET predicts future transition to dementia in Downs Syndrome. C_LIO_LIIncreased amyloid in prefrontal, inferior parietal, superior frontal, rostral middle frontal, and posterior cingulate cortices detect transitioiners, with prefrontal and superior frontal being best overall. C_LIO_LIAmyloid PET-based classification able to discriminate between transitioners and non-transitioners. C_LI

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bioRxiv2020

CA1 20-40 Hz oscillatory dynamics reflect trial-specific information processing supporting nonspatial sequence memory

The hippocampus is known to play a critical role in processing information about temporal context. However, it remains unclear how hippocampal oscillations are involved, and how their functional organization is influenced by connectivity gradients. We examined local field potential activity in CA1 as rats performed a complex odor sequence memory task. We find that odor sequence processing epochs were characterized by increased power in the 4-8 Hz and 20-40 Hz range, with 20-40 Hz oscillations showing a power gradient increasing toward proximal CA1. Running epochs were characterized by increased power in the 8-12 Hz range and across higher frequency ranges (>24 Hz), with power gradients increasing toward proximal and distal CA1, respectively. Importantly, 20-40 Hz power increased with knowledge of the sequence and carried trial-type-specific information. These results suggest that 20-40 Hz oscillations are associated with trial-specific processing of nonspatial information critical for order memory judgments.

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bioRxiv2019

Integrity of the Uncinate Fasciculus Predicts Emotional Pattern Separation-Related fMRI Signals in the Hippocampal Dentate and CA3

Alterations in white matter integrity have been demonstrated in a number of psychiatric disorders that involve disruptions in emotional processing. One such pathway - the uncinate fasciculus (UF) - connects the orbitofrontal cortex (OFC) to the medial temporal lobes (MTL) and has been associated with early life adversity, maltreatment, anxiety, and depression. While it is purported to play a role in episodic memory and discrimination, its exact function remains poorly understood. We have previously described the role of the amygdala and dentate (DG)/CA3 fields of the hippocampus in the mnemonic discrimination of emotional experiences (i.e. emotional pattern separation). However, how this computation may be modulated by connectivity between the medial temporal lobes and the orbitofrontal cortex remains unknown. Here we ask the question of whether the uncinate fasciculus plays a role in influencing MTL subregional activity during emotional pattern separation. By combining diffusion imaging with high-resolution functional MRI, we found that reduced integrity of the UF is related to higher activation in the DG/CA3 subregions of the hippocampus during an emotional pattern separation task. We additionally report that higher levels of DG/CA3 activity are associated with poorer memory performance, suggesting that hyperexcitability in this network (which may be driven by CA3 recurrent collaterals) is associated with memory errors and that the UF may allow the OFC to exert inhibitory control on this network and improve discrimination of emotional experiences. This work provides novel mechanistic insight into the role of prefrontal interactions with the MTL, particularly in the context of emotional memory.

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bioRxiv2018

-Florbetapir PET: Towards Predicting Dementia in Adults with Down Syndrome

1. Background 1. Background 2. Methods 3. Results 4. Discussion 5. Conclusions References Individuals with Down syndrome (DS) have an increasing age-related prevalence of Alzheimers disease (AD). In DS, the triplication of amyloid precursor protein (APP) on chromosome 21 contributes to a life-long accumulation of brain amyloid (A{beta}) [1]. Dyshomeostasis of A{beta} has emerged as one of the most well-validated factors in the pathogenesis of AD [2]. By age 40 years, virtually all individuals with DS have amyloid plaques and tau tangles, hallmark pathologies that are characteristic of sporadic AD in the general population [3]. Dementia, while not inevitable in DS, increases significantly in prevalence with age to over 75% after age 65 years. [ ...

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bioRxiv2017

The ANTs Longitudinal Cortical Thickness Pipeline

Longitudinal studies of development and disease in the human brain have motivated the acquisition of large neuroimaging data sets and the concomitant development of robust methodological and statistical tools for quantifying neurostructural changes. Longitudinal-specific strategies for acquisition and processing have potentially significant benefits including more consistent estimates of intra-subject measurements while retaining predictive power. In this work, we introduce the open-source Advanced Normalization Tools (ANTs) registration-based cortical thickness longitudinal processing pipeline and its application to the first phase of the Alzheimers Disease Neuroimaging Initiative (ADNI-1) comprising over 600 subjects with multiple time points from baseline to 36 months. We demonstrate in these data that the single-subject template construction and same orientation processing results in a simultaneous minimization of residual variability and maximization of between-subject variability immediately estimable from a longitudinal mixed-effects modeling strategy. It is known from the statistical literature that optimizing these dual criteria leads to greater scientific interpretability in terms of tighter confidence intervals in calculated mean trends, smaller prediction intervals, and narrower confidence intervals for determining cross-sectional effects. This strategy is evaluated over the entire cortex, as defined by the Desikan-Killiany-Tourville labeling protocol, where comparisons are made with the cross-sectional and longitudinal FreeSurfer processing streams. Subsequent linear mixed effects modeling for identifying diagnostic groupings within the ADNI cohort is provided as supporting evidence for the utility of the proposed ANTs longitudinal framework which provides unbiased structural neuroimage processing and competitive to superior power for longitudinal structural change detection.

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bioRxiv2017

Anterolateral entorhinal-hippocampal imbalance in older adults disrupts object pattern separation

The entorhinal cortex (EC) is among the earliest brain areas to deteriorate in Alzheimers disease (AD). However, the extent to which functional properties of the EC are altered in the aging brain, even in the absence of clinical symptoms, is not understood. Recent human fMRI studies have identified a functional dissociation within the EC, similar to what is found in rodents. Here, we used high-resolution fMRI to identify a specific hypoactivity in the anterolateral EC (alEC) commensurate with major behavioral deficits on an object pattern separation task in asymptomatic older adults. Only subtle deficits were found in a comparable spatial condition, with no associated differences in posteromedial EC between young and older adults. We additionally link this condition to previously reported dentate/CA3 hyperactivity, both of which were associated with object mnemonic discrimination impairment. These results provide novel evidence of alEC-dentate/CA3 circuit dysfunction in cognitively normal aged humans.

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