Biology subjects

Yassa, M. A.

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

At least 19 recordsLinked to original sources

bioRxiv2026

Anhedonia buffers the effects of early-life unpredictability on threat-reward decision-making.

Anhedonia - the diminished capacity to experience or anticipate pleasure - is among the most common consequences of early-life unpredictability, yet how these co-occurring conditions jointly shape real-world decision-making remains unknown. Here, we use a sequential foraging-under-threat task to probe motivational conflict decisions in 357 individuals varying in early-life unpredictability and anhedonia symptoms. We find that unpredictability and anhedonia exert opposing influences on choice: unpredictability shifts behavior away from the survival-optimal policy in a sex-dependent manner, while anhedonia promotes adherence to it, partly through heightened sensitivity to unexpected threatening outcomes. A mediation analysis reveals that anhedonia partially buffers the deleterious effects of unpredictability on decision quality. These results demonstrate that co-occurring conditions can mask one anothers behavioral signatures and suggest that the heterogeneous expression of transdiagnostic constructs like anhedonia may reflect context-dependent adaptations to distinct underlying etiologies.

neuroscience↗

bioRxiv2025

A compressed code for memory discrimination

The ability to discriminate similar visual stimuli has been used as an important index of memory function. This ability is widely thought to be supported by expanding the dimensionality of relevant neural codes, such that neural representations for the similar stimuli are maximally distinct, or "separated." An alternative hypothesis is that discrimination is supported by lossy compression of visual inputs, efficiently coding sensory information by discarding seemingly irrelevant details. A benefit of compression, relative to expansion, is that it allows the individual to efficiently retain fewer essential dimensions underlying stimulus variation--a process linked to higher-order visual processing--without hindering discrimination. Under the compression hypothesis, pattern separation is facilitated when more information from similar stimuli can be discarded, rather than preserving more information about distinct stimulus dimensions. We test the compression versus expansion hypotheses by predicting performance on the canonical mnemonic similarity task. First, we train neural networks to compress perceptual and semantic factors of stimuli, and measure lossiness of those representations using the mathematical framework underlying compression. Consistent with the compression hypothesis, and not the expansion hypothesis, we find that greater lossiness predicts the ease and performance of lure discrimination, particularly in later layers of convolutional neural networks shown to predict brain activity in the higher-order visual stream. We then empirically confirm these predictions across two sets of images, four behavioral datasets, and alternative metrics of lossiness. Finally, using task fMRI data, we identify signatures of lossy compression--neural dimensionality reduction and information loss--in the higher-order visual stream regions V4 and IT as well as hippocampal subregions dentate gyrus/CA3 and CA1 associated with lure discrimination performance. These results suggest lossy compression may support mnemonic discrimination behavior by discarding redundant and overlapping information.

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bioRxiv2025

A combined neuroanatomy, ex vivo imaging and immunohistochemistry defined MRI mask for the human paraventricular nucleus of the thalamus

The paraventricular nucleus of the thalamus (PVT) is an evolutionarily conserved midline thalamic structure known to contribute to arousal, interoceptive states, and motivated behaviors. Yet, a consensus anatomical definition of the human PVT across tissue-based and MRI-based approaches remains elusive, thereby limiting reliable translation between its cellular characteristics and in vivo functional connectivity. To address this challenge, we describe a histologically-informed PVT segmentation compatible with standard 3T MR imaging pipelines. We performed postmortem anatomical MRI scans on an intact whole brain and an excised thalamic block, manually segmented the PVT at high resolution using ex vivo calretinin staining and neuroanatomical landmarks, registered the resulting image-label pair to a commonly used MRI template space (Montreal Neurological Institutes MNI152), and performed a comparative reanalysis using this newly defined mask. This tissue-grounded PVT mask largely overlaps spatially with existing MRI-based PVT masks, with the exception of additional voxels posteriorly. Importantly, the functional connectivity patterns of this tissue-grounded mask are highly consistent with those previously reported. Collectively, this multimodal definition of the human PVT balances tissue-based ground truth with in vivo MRI features, providing a valuable resource for advancing translation between cellular level features identified by histology and in vivo functional connectivity at the meso/macro scale in the understudied human PVT. Key PointsO_LIAddresses conflict between histological and MRI-based borders of the human PVT. C_LIO_LIHistologically-defined PVT boundaries indicate additional posterior tail to the human PVT as compared to existing human MRI atlases. C_LIO_LIProvided MRI mask demonstrates functional connectivity patterns consistent with prior human and rodent studies. C_LI

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bioRxiv2025

Divergence of Functional Brain Network Configurations in Same and Other Race Face Recognition

The "Other-Race Effect" (ORE) refers to the enhanced memory individuals have for faces within their own racial group compared to other races. This effect is attributed to limited exposure to different races and social-motivational factors affecting face processing. While past research has explored this effect through neuroimaging methods, the precise neural mechanisms that underlie the ORE remain a subject of ongoing investigation. Previous studies have largely adopted a modular perspective, concentrating on the differential activation of face-processing regions when comparing same-race and other-race facial recognition behaviors. However, given the multifaceted nature of the ORE, an exclusive focus on specialized regions may miss the pivotal role played by non-face-preferential brain areas in modulating this phenomenon. In the present study, we take a broader data-driven perspective using graph-theoretical techniques to investigate whole-brain network disparities in same- and other-race facial recognition. Our findings reveal a substantial impact of race on functional connectivity during face memorization. While other-race face recognition benefitted from higher local efficiency during encoding, reduced local efficiency was advantageous for memorization of same-race faces. Notably, successful other-race recognition was disproportionately supported by locally efficient processing in regions among the ventral and dorsal attention networks.

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bioRxiv2024

Parallel neuroinflammatory pathways to cerebrovascular injury and amyloid-beta in Alzheimer's disease

ImportanceWhile the hallmark pathologies of amyloid-beta (A{beta}) and tau in Alzheimers disease (AD) are well documented and even part of the definition, upstream neuroinflammation is thought to play an important role but remains poorly understood. ObjectivesWe tested whether two distinct neuroinflammatory markers are associated with cerebrovascular injury and A{beta}, and whether these markers are associated with plasma phosphorylated tau (pTau) concentration, medial temporal lobe (MTL) cortical and hippocampal atrophy, and memory deficits. We examined neuroinflammatory markers plasma YKL-40 and GFAP, due to previous conflicting evidence relating YKL-40 and GFAP to AD pathogenic markers. DesignCross-sectional data from a community observational study (Biomarker Exploration in Aging, Cognition, and Neurodegeneration - BEACoN) were included. SettingAll participants were enrolled in a single site, at University of California, Irvine. Participants126 participants were included if they had at least one of the following measures available: neuropsychological data, MRI, A{beta}-PET, or plasma. ExposuresPlasma YKL-40 and plasma glial fibrillary acidic protein (GFAP) levels. Main outcomes and measuresWhite matter hyperintensity (WMH) volume, 18F-florbetapir (FBP) PET mean SUVR, plasma phosphorylated tau (pTau-217) concentration, MTL cortical thickness, hippocampal volume, and memory function assessed by Rey Auditory Verbal Learning Test. Using path analysis, we tested whether higher plasma YKL-40 and GFAP are associated with WMH and A{beta}, and whether these converge to downstream markers of tauopathy, MTL neurodegeneration, and memory deficits. ResultsIn older adults without dementia (N=126, age=70.60+6.29, 62% women), we found that higher plasma YKL-40 concentration was associated with greater WMH volume, while higher plasma GFAP concentration was related to increased FBP SUVR. Further, higher plasma GFAP, WMH and FBP SUVR were independently associated with increased pTau-217. In turn, plasma pTau-217 was associated with reduced MTL cortical thickness and hippocampal volume. Subsequently, only reduced hippocampal volume was related to lower memory function. Conclusions and RelevanceNeuroinflammatory markers contribute to parallel pathways of cerebrovascular injury and A{beta}, which converge to tau-associated neurodegeneration and memory deficits in older adults. These observations underscore the need for a more comprehensive approach to developing an AD framework and treatment strategies. KEY POINTSO_ST_ABSQuestionC_ST_ABSHow does neuroinflammation impact downstream features of cerebrovascular injury and amyloid-beta (A{beta}) in Alzheimers disease? FindingsIn this study of 126 older adults without dementia, we found evidence for two distinct neuroinflammatory pathways that lead to neurodegeneration and memory deficits. One path involves plasma YKL-40 and its impact on cerebrovascular injury, as measured by white matter hyperintensities (WMH) on MRI scans. The other involves plasma glial fibrillary acidic protein (GFAP) and its impact on A{beta} deposition measured via 18F-florbetapir (FBP) PET. Both pathways converged on tauopathy, measured by plasma pTau-217, which was associated with lower medial temporal lobe (MTL) cortical thickness and hippocampal volume, and consequently, memory deficits. MeaningInflammation acts on Alzheimers disease mechanisms via multiple distinct and parallel pathways which converge downstream onto neurodegeneration. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=110 SRC="FIGDIR/small/616579v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@2d3c39org.highwire.dtl.DTLVardef@1ccc453org.highwire.dtl.DTLVardef@6d40bdorg.highwire.dtl.DTLVardef@b543cb_HPS_FORMAT_FIGEXP M_FIG C_FIG Credit: BioRender was used to help create this graphical abstract.

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bioRxiv2024

Sex-specific effects of early life unpredictability on hippocampal and amygdala responses to novelty in adolescents

BackgroundUnpredictable childhood experiences are an understudied form of early life adversity that impacts neurodevelopment in a sex-specific manner. The neurobiological processes by which exposure to early-life unpredictability impacts development and vulnerability to psychopathology remain poorly understood. The present study investigates the sex-specific consequences of early-life unpredictability on the limbic network, focusing on the hippocampus and the amygdala. MethodsParticipants included 150 youth (54% female). Early life unpredictability was assessed using the Questionnaire of Unpredictability in Childhood (QUIC). Participants engaged in a task-fMRI scan between the ages of 8 and 17 (223 total observations) measuring BOLD responses to novel and familiar scenes. ResultsExposure to early-life unpredictability associated with BOLD contrast (novel vs. familiar) in a sex-specific manner. For males, but not females, higher QUIC scores were associated with lower BOLD activation in response to novel vs. familiar stimuli in the hippocampal head and amygdala. Secondary psychophysiological interaction (PPI) analyses revealed complementary sex-specific associations between QUIC and condition-specific functional connectivity between the right and left amygdala, as well as between the right amygdala and hippocampus bilaterally. ConclusionExposure to unpredictability in early life has persistent implications for the functional operations of limbic circuits. Importantly, consistent with emerging experimental animal and human studies, the consequences of early life unpredictability differ for males and females. Further, impacts of early-life unpredictability were independent of other risk factors including lower household income and negative life events, indicating distinct consequences of early-life unpredictability over and above more commonly studied types of early life adversity.

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bioRxiv2024

Amyloid-β deposition in basal frontotemporal cortex is associated with selective disruption of temporal mnemonic discrimination

Cerebral amyloid-beta (A{beta}) accumulation, a hallmark pathology of Alzheimers disease (AD), precedes clinical impairment by two to three decades. However, it is unclear whether A{beta} contributes to subtle memory deficits observed during the preclinical stage. The heterogenous emergence of A{beta} deposition may selectively impact certain memory domains, which rely on distinct underlying neural circuits. In this context, we tested whether specific domains of mnemonic discrimination, a neural computation essential for episodic memory, exhibit specific deficits related to early A{beta} deposition. We tested 108 cognitively unimpaired human older adults (66% female) who underwent 18F-florbetapir positron emission tomography (A{beta}-PET), and a control group of 35 young adults, on a suite of mnemonic discrimination tasks taxing object, spatial, and temporal domains. We hypothesized that A{beta} pathology would be selectively associated with temporal discrimination performance due to A{beta}s propensity to accumulate in the basal frontotemporal cortex, which supports temporal processing. Consistent with this hypothesis, we found a dissociation in which generalized age-related deficits were found for object and spatial mnemonic discrimination, while A{beta}-PET levels were selectively associated with deficits in temporal mnemonic discrimination. Further, we found that higher A{beta}-PET levels in medial orbitofrontal and inferior temporal cortex, regions supporting temporal processing, were associated with greater temporal mnemonic discrimination deficits, pointing to the selective vulnerability of circuits related to temporal processing early in AD progression. These results suggest that A{beta} accumulation within basal frontotemporal regions may disrupt temporal mnemonic discrimination in preclinical AD, and may serve as a sensitive behavioral biomarker of emerging AD progression.

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bioRxiv2024

Engagement in moderate-intensity physical activity supports overnight emotional memory retention in older adults

ImportancePreserving the ability to vividly recall emotionally rich experiences contributes to quality of life in older adulthood. While prior work suggests that moderate-intensity physical activity (MPA) may bolster memory, it is unclear whether this extends to emotionally salient memories consolidated during sleep. ObjectiveTo investigate associations between engagement in physical activity (PA) and overnight emotional memory retention and examine whether theoretically replacing 30-minutes of lower-intensity activity with MPA is associated with better consolidation. Design, Setting, and ParticipantsA cross-sectional study of 40 community-dwelling older adults free of neurological and psychiatric disorders. Data were collected from May 2018 to July 2022 and analyzed from January to July 2024. ExposuresParticipants completed an overnight polysomnography (PSG) with emotional memory tested before and after sleep and a self-report questionnaire assessing habitual PA. Main Outcome(s) and Measures(s)Emotional memory performance was assessed via recognition memory or mnemonic discrimination performance. Overnight memory retention was calculated by subtracting immediate test from delayed test performance for both recognition memory and mnemonic discrimination, with more negative scores indicating lower memory retention. Frequency and duration of MPA, light-intensity PA, non-exertive activity, and sedentary behavior were calculated from the Community Health Activities Model Program for Seniors (CHAMPS) Activities Questionnaire for Older Adults. Isotemporal substitution modelling evaluated whether statistically reallocating time spent in sedentary and lower-intensity activity to MPA was associated with better overnight memory retention. ResultsData from 40 participants were analyzed ({square}age=72.3{+/-}5.8, 26 female). Better overnight emotional recognition memory retention was associated with the frequency ({beta}=0.663, SE=0.212, p=0.003) and duration ({beta}=0.214, SE=0.101, p=0.042) of MPA. No relationships were found with mnemonic discrimination or neutral recognition memory. Statistically modelling the replacement of 30 minutes of lower-intensity activity with MPA was associated with better overnight retention of emotional memories ({beta}=0.108, SE=0.048, p=0.030), but not neutral ({beta}=-0.029, SE=0.069, p=0.679). Conclusions and RelevanceMPA may enhance sleep-dependent consolidation of emotional memories in older adults. Modest increases in MPA may yield significant benefits for sleep-dependent emotional memory retention. These findings may guide interventions to preserve memory function and inform public health recommendations by demonstrating that substituting even short durations of low-intensity activity for MPA could produce significant cognitive gains relevant for maintaining quality of life in older adulthood.

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bioRxiv2024

Age-related constraints on the spatial geometry of the brain

Age-related structural brain changes may be better captured by assessing complex spatial geometric differences rather than isolated changes to individual regions. We applied a novel analytic method to quantify age-related changes to the spatial anatomy of the brain by measuring expansion and compression of global brain shape and the distance between cross-hemisphere homologous regions. To test how global brain shape and regional distances are affected by aging, we analyzed 2,603 structural MRIs (range: 30-97 years). Increasing age was associated with global shape expansion across inferior-anterior gradients, global compression across superior-posterior gradients, and regional expansion between frontotemporal homologues. Specific patterns of global and regional expansion and compression were further associated with clinical impairment and distinctly related to deficits in various cognitive domains. These findings suggest that changes to the complex spatial anatomy and geometry of the aging brain may be associated with reduced efficiency and cognitive dysfunction in older adults.

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bioRxiv2024

Slow running benefits: Boosts in mood and facilitation of prefrontal cognition even at very light intensity

Although running upright has been reported to have positive effects on both physical and mental health, the minimum running intensity/speed that would benefit mood and prefrontal cognition is not yet clear. For this reason, we aimed to investigate the acute effect of very slow running, which is classified as a very light intensity exercise, on mood, executive function (EF), and their neural substrates in the prefrontal cortex (PFC). Twenty-four healthy participants completed a 10-minute very slow running session on a treadmill at 35% [Formula] and a resting control session in randomized order. EF was measured using the Stroop task and the mood state was measured using the Two-Dimensional Mood Scale (TDMS) before and after both sessions. Cortical hemodynamic changes while performing the task were monitored using functional near-infrared spectroscopy (fNIRS). The results show that ten minutes of very slow running significantly enhanced mood, reduced Stroop interference time (i.e., enhanced EF), and elicited left lateral PFC activation. Moreover, head acceleration, the magnitude of up-and-down oscillations, was measured during running, and a significant positive correlation with pleasant mood was found. Head acceleration is a remarkable characteristic of running and may be one of the factors related to a pleasant mood induced by very slow running. In conclusion, the current study reveals that a single bout of running, even at very slow speed, elicits a pleasant mood and improved executive function with enhancing activation in prefrontal subregions. This shed light on the slow running benefits to brain health.

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bioRxiv2024

Cerebrovascular pathology mediates associations between hypoxemia during rapid eye movement sleep and medial temporal lobe structure and function in older adults

Obstructive sleep apnea (OSA) is common in older adults and is associated with medial temporal lobe (MTL) degeneration and memory decline in aging and Alzheimers disease (AD). However, the underlying mechanisms linking OSA to MTL degeneration and impaired memory remains unclear. By combining magnetic resonance imaging (MRI) assessments of cerebrovascular pathology and MTL structure with clinical polysomnography and assessment of overnight emotional memory retention in older adults at risk for AD, cerebrovascular pathology in fronto-parietal brain regions was shown to statistically mediate the relationship between OSA-related hypoxemia, particularly during rapid eye movement (REM) sleep, and entorhinal cortical thickness. Reduced entorhinal cortical thickness was, in turn, associated with impaired overnight retention in mnemonic discrimination ability across emotional valences for high similarity lures. These findings identify cerebrovascular pathology as a contributing mechanism linking hypoxemia to MTL degeneration and impaired sleep-dependent memory in older adults.

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bioRxiv2023

Medial temporal lobe functional network architecture supports sleep-related emotional memory processing in older adults

Memory consolidation occurs via reactivation of a hippocampal index during non-rapid eye movement slow-wave sleep (NREM SWS) which binds attributes of an experience existing within cortical modules. For memories containing emotional content, hippocampal-amygdala dynamics facilitate consolidation over a sleep bout. This study tested if modularity and centrality--graph theoretical measures that index the level of segregation/integration in a system and the relative import of its nodes--map onto central tenets of memory consolidation theory and sleep-related processing. Findings indicate that greater network integration is tied to overnight emotional memory retention via NREM SWS expression. Greater hippocampal and amygdala influence over network organization supports emotional memory retention, and hippocampal or amygdala control over information flow are differentially associated with distinct stages of memory processing. These centrality measures are also tied to the local expression and coupling of key sleep oscillations tied to sleep-dependent memory consolidation. These findings suggest that measures of intrinsic network connectivity may predict the capacity of brain functional networks to acquire, consolidate, and retrieve emotional memories.

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bioRxiv2023

NODDI-derived measures of microstructural integrity in medial temporal lobe white matter pathways are associated with Alzheimer's disease pathology and cognitive outcomes

INTRODUCTIONDiffusion tensor imaging has been used to assess white matter (WM) changes in the early stages of Alzheimers disease (AD). However, the tensor model is necessarily limited by its assumptions. Neurite Orientation Dispersion and Density Imaging (NODDI) can offer insights into microstructural features of WM change. We assessed whether NODDI more sensitively detects AD-related changes in medial temporal lobe WM than traditional tensor metrics. METHODSStandard diffusion and NODDI metrics were calculated for medial temporal WM tracts from 199 older adults drawn from ADNI3 who also received PET to measure pathology and neuropsychological testing. RESULTSNODDI measures in medial temporal tracts were more strongly correlated to cognitive performance and pathology than standard measures. The combination of NODDI and standard metrics exhibited the strongest prediction of cognitive performance in random forest analyses. CONCLUSIONSNODDI metrics offer additional insights into contributions of WM degeneration to cognitive outcomes in the aging brain.

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bioRxiv2023

Theta mediated dynamics of human hippocampal-neocortical learning systems in memory formation and retrieval

Episodic memory arises as a function of dynamic interactions between the hippocampus and the neocortex, yet the mechanisms have remained elusive. Here, using human intracranial recordings during a mnemonic discrimination task, we report that 4-5 Hz (theta) power is differentially recruited during discrimination vs. overgeneralization, and its phase supports hippocampal-neocortical when memories are being formed and correctly retrieved. Interactions were largely bidirectional, with small but significant net directional biases; a hippocampus-to-neocortex bias during acquisition of new information that was subsequently correctly discriminated, and a neocortex-to-hippocampus bias during accurate discrimination of new stimuli from similar previously learned stimuli. The 4-5 Hz rhythm may facilitate the initial stages of information acquisition by neocortex during learning and the recall of stored information from cortex during retrieval. Future work should further probe these dynamics across different types of tasks and stimuli and computational models may need to be expanded accordingly to accommodate these findings.

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bioRxiv2023

Pathological brain states in Alzheimer's disease

Dynamic and rapid reconfigurations of neural activation patterns, known as brain states, support cognition. Recent analytic advances applied to functional magnetic resonance imaging now enable the quantification of brain states, which offers a substantial methodological improvement in characterizing spatiotemporal dynamics of activation over previous functional connectivity methods. Dysfunction to the persistence and temporal transitions between discrete brain states may be proximal factors reflecting neurophysiological disruptions in Alzheimers disease, although this has not yet been established. Here, we identified six distinct brain states, representing spatiotemporal trajectories of coactivation at single time points, in older adults across the Alzheimers disease continuum. Critically, we identified a pathological brain state that reflects coactivation within limbic regions. Higher persistence within and transitions to this limbic state, at the expense of other brain states, is associated with an increased likelihood of a clinically impaired diagnosis, worse cognitive performance, greater Alzheimers pathology, and neurodegeneration. Together, our results provide compelling evidence that neural activity settling into a pathological limbic state reflects the progression to Alzheimers disease. As brain states have recently been shown to be modifiable targets, this work may inform the development of novel neuromodulation techniques to reduce limbic state persistence. This application would be an innovative clinical approach to rescue cognitive decline in the early stages of Alzheimers disease.

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bioRxiv2022

Posterior white matter hyperintensities are associated with reduced medial temporal lobe subregional integrity and long-term memory in older adults

White matter hyperintensities are a marker of small vessel cerebrovascular disease that are strongly related to cognition in older adults. Similarly, medial temporal lobe atrophy is well-documented in aging and Alzheimers disease and is associated with memory decline. Here, we assessed the relationship between lobar white matter hyperintensities, medial temporal lobe subregional volumes, and hippocampal memory in older adults. We collected MRI scans in a sample of 139 older adults without dementia (88 females, mean age (SD) = 76.95 (10.61)). Participants were administered the Rey Auditory Verbal Learning Test (RAVLT). Regression analyses tested for associations among medial temporal lobe subregional volumes, regional white matter hyperintensities and memory, while adjusting for age, sex, and education and correcting for multiple comparisons. Increased occipital white matter hyperintensities were related to worse RAVLT delayed recall performance, and to reduced CA1, dentate gyrus, perirhinal cortex (Brodmann area 36), and parahippocampal cortex volumes. These medial temporal lobe subregional volumes were related to delayed recall performance. The association of occipital white matter hyperintensities with delayed recall performance was fully mediated statistically only by perirhinal cortex volume. These results suggest that white matter hyperintensities may be associated with memory decline through their impact on medial temporal lobe atrophy. These findings provide new insights into the role of vascular pathologies in memory loss in older adults and suggest that future studies should further examine the neural mechanisms of these relationships in longitudinal samples.

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bioRxiv2022

The Entorhinal-DG/CA3 Pathway in the Medial Temporal Lobe Retains Visual Working Memory of a Simple Surface Feature

Classic models consider working memory (WM) and long-term memory as distinct mental faculties that are supported by different neural mechanisms. Yet, there are significant parallels in the computation that both types of memory require. For instance, the representation of precise item-specific memory requires the separation of overlapping neural representations of similar information. This computation has been referred to as pattern separation, which can be mediated by the entorhinal-DG/CA3 pathway of the medial temporal lobe (MTL) in service of long-term episodic memory. However, although recent evidence has suggested that the MTL is involved in WM, the extent to which the entorhinal-DG/CA3 pathway supports precise item-specific WM has remained elusive. Here, we combine an established orientation WM task with high-resolution fMRI to test the hypothesis that the entorhinal-DG/CA3 pathway retains visual WM of a simple surface feature. Participants were retrospectively cued to retain one of the two studied orientation gratings during a brief delay period and then tried to reproduce the cued orientation as precisely as possible. By modeling the delay-period activity to reconstruct the retained WM content, we found that the anterior-lateral entorhinal cortex (aLEC) and the hippocampal DG/CA3 subfield both contain item-specific WM information that is associated with subsequent recall fidelity. Together, these results highlight the contribution of MTL circuitry to item-specific WM representation.

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bioRxiv2022

Signal Transformations and New Timing Rules of Hippocampal CA3 to CA1 Synapses

The synapse is the fundamental unit of communication in the nervous system. Determining how information is transferred across the synaptic interface is one of the most complex endeavors in neuroscience, owing to the large number of contributing factors and events. An approach to solving this problem involves collapsing across these complexities to derive concise mathematical formulas that fully capture the governing dynamics of synaptic transmission. We investigated the feasibility of deriving such a formula - an input-output transformation function for the CA3 to CA1 node of the hippocampus -- using the Volterra expansion technique for nonlinear system identification. The entirety of the field EPSP in the apical dendrites of mouse brain slices was described with >94% accuracy by a 2nd order equation that captured the linear and nonlinear influence of past inputs on current outputs. This function generalized to cases not included in its derivation and uncovered previously undetected timing rules. The basal dendrites expressed a substantially different transfer function and evidence was obtained that, unlike the apical system, a 3rd order system or higher will be needed for complete characterization. Collectively, these results describe a readily implemented and unusually sensitive means for evaluating the effects of pharmacological treatments and disease related conditions on synaptic dynamics. At scale, the approach will also provide information needed for the construction of biologically realistic models of brain networks.

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