Biology subjects

Lazari, A.

Publications and source records attributed to Lazari, A..

10 recordsLinked to original sources

bioRxiv2026

A hippocampal neuroimaging signature of neurovascular insulin signalling links metabolism to mood

Depression is a leading cause of global disability and is increasingly linked to systemic metabolic dysfunctions, including insulin resistance. However, the biological pathways connecting metabolic state to affective symptoms are unresolved. A growing body of evidence indicates that insulin, beyond its role in systemic glucose homeostasis, supports brain metabolism, synaptic function and cognition, yet its contribution to mood regulation remains unclear. Here, we identify a human hippocampal metabolic signature associated with glycaemic variation in individuals with depression. Using multimodal neuroimaging, we show that hippocampal concentrations of GABA and lactate correlate with HbA1c and with mood severity, while functional connectivity between the hippocampus and the default mode network tracks affective symptoms independently of adiposity. To causally probe these relationships, we generated a mouse model of hippocampus-specific insulin receptor depletion. Unexpectedly, reducing insulin signalling at the blood brain barrier enhanced neuronal metabolism and attenuated anxiety-like behaviour. Notably, hippocampal lactate and GABA levels similarly tracked anxiety-related behaviour in mice, mirroring their association with symptom severity in humans. Together, these findings identify a conserved neurometabolic signature linking hippocampal insulin signalling to affective state, and reveal that brain insulin resistance exerts context- and cell-type-specific effects on behaviour. This work establishes a mechanistic basis for brain insulin resistance in depression and highlights the hippocampus as a critical hub for metabolic modulation of mood.

neuroscience↗

bioRxiv2023

Lasting dynamic effects of the psychedelic 2,5-dimethoxy-4-iodoamphetamine (+/-)-DOI) on cognitive flexibility

Psychedelic drugs can aid fast and lasting remission from various neuropsychiatric disorders, though the underlying mechanisms remain unclear. Preclinical studies suggest serotonergic psychedelics enhance neuronal plasticity, but whether neuroplastic changes can also be seen at cognitive and behavioural levels is unexplored. Here we show that a single dose of the psychedelic 2,5-dimethoxy-4-iodoamphetamine (({+/-})-DOI) affects structural brain plasticity and cognitive flexibility in young adult mice beyond the acute drug experience. Using ex vivo magnetic resonance imaging, we show increased volumes of several sensory and association areas one day after systemic administration of 2mgkg-1 ({+/-})-DOI. We then demonstrate lasting effects of ({+/-})-DOI on cognitive flexibility in a two-step probabilistic reversal learning task where 2mgkg-1 ({+/-})-DOI improved the rate of adaptation to a novel reversal in task structure occurring one-week post-treatment. Strikingly, ({+/-})-DOI-treated mice started learning from reward omissions, a unique strategy not typically seen in mice in this task, suggesting heightened sensitivity to previously overlooked cues. Crucially, further experiments revealed that ({+/-})-DOIs effects on cognitive flexibility were contingent on the timing between drug treatment and the novel reversal, as well as on the nature of the intervening experience. ({+/-})-DOIs facilitation of both cognitive adaptation and novel thinking strategies may contribute to the clinical benefits of psychedelic-assisted therapy, particularly in cases of perseverative behaviours and a resistance to change seen in depression, anxiety, or addiction. Furthermore, our findings highlight the crucial role of time-dependent neuroplasticity and the influence of experiential factors in shaping the therapeutic potential of psychedelic interventions for impaired cognitive flexibility.

animal behavior and cognition↗

bioRxiv2023

Ablation of oligodendrogenesis in adult mice alters brain microstructure and activity independently of behavioural deficits

Oligodendrocytes continue to differentiate from their precursor cells even in adulthood, a process that can be modulated by neuronal activity and experience. Yet, our understanding of the functional role of adult oligodendrogenesis remains limited. Previous work has indicated that conditional ablation of oligodendrogenesis in adult mice can lead to learning and memory deficits in a range of behavioural tasks. Our results, reported here, have replicated a key finding that learning to run on a complex wheel with unevenly spaced rungs is disrupted by ablation of oligodendrogenesis. However, using ex vivo MRI (MTR and DTI), we also found that ablating oligodendrogenesis by itself alters brain microstructure, independent of behavioural experience. Furthermore, in vivo EEG recording in behaviourally naive mice with ablated oligodendrogenesis revealed altered brain activity in the form of increased EEG power density across a broad frequency range. Together, our data indicate that disrupting the formation of new oligodendrocytes directly alters brain microstructure and activity. This suggests a role for adult oligodendrogenesis in the maintenance of brain function and indicates that task-independent changes to brain structure and function might contribute to the learning and memory deficits associated with oligodendrogenesis ablation.

neuroscience↗

bioRxiv2022

Distributed and gradual microstructure changes track the emergence of behavioural benefit from memory reactivation

Memory traces develop gradually and link to neural plasticity. Memory reactivation during sleep is crucial for consolidation, but its precise impact on plasticity and contribution to long-term memory storage remains unclear. We used multimodal diffusion-weighted imaging to track the location and timescale of microstructural changes following Targeted Memory Reactivation (TMR) of a motor task. This showed continuous microstructure plasticity in precuneus across 10 days post-TMR, paralleling the gradual development of behavioural benefit. Both early (0 - 24 h post-TMR) and late (24 h - 10 days post-TMR) microstructural changes in striatum and sensorimotor cortex were associated with the emergence of behavioural effects of TMR at day 20. Furthermore, the baseline microstructural architecture of sensorimotor cortex predicted TMR susceptibility. These findings demonstrate that repeated reactivation of memory traces during sleep engenders microstructural plasticity which continues days after the stimulation night and is associated with the emergence of memory benefits at the behavioural level.

neuroscience↗

bioRxiv2022

Cueing motor memory reactivation during NREM sleep engenders learning-related changes in precuneus and sensorimotor structures

Memory reactivation during Non-Rapid Eye Movement (NREM) sleep is important for memory consolidation but it remains unclear exactly how such activity promotes the development of a stable memory representation. We used Targeted Memory Reactivation (TMR) in combination with longitudinal structural and functional MRI to track the evolution of a motor memory trace over 20 days. We show that repeated reactivation of motor memory during sleep leads to increased precuneus activation 24 h post-TMR. Interestingly, a decrease in precuneus activity over the next 10 days predicts longer-term cueing benefit. We also find both functional and structural changes in sensorimotor cortex in association with effects of TMR 20 days post-encoding. These findings demonstrate that TMR can engage precuneus in the short-term while also impacting on task-related structure and function over longer timescales.

neuroscience↗

bioRxiv2022

Hebbian activity-dependent plasticity in white matter

Synaptic plasticity is required for learning and follows Hebbs Rule, the com-putational principle underpinning associative learning. In recent years, a complementary type of brain plasticity has been identified in myelinated axons, which make up the majority of brains white matter. Like synaptic plasticity, myelin plasticity is required for learning, but it is unclear whether it is Hebbian or whether it follows different rules. Here, we provide evidence that white matter plasticity operates following Hebbs Rule in humans. Across two experiments, we find that co-stimulating cortical areas to induce Hebbian plasticity leads to relative increases in cortical excitability and associated increases in a myelin marker within the stimulated fiber bundle. We conclude that Hebbian plasticity extends beyond synaptic changes, and can be observed in human white matter fibers.

neuroscience↗

bioRxiv2020

Heterogeneous relationships between white matter and behaviour

Several studies have established specific relationships between White Matter (WM) and behaviour. However, these studies have typically focussed on fractional anisotropy (FA), a neuroimaging metric that is sensitive to multiple tissue properties, making it difficult to identify what biological aspects of WM may drive such relationships. Here, we carry out a pre-registered assessment of WM-behaviour relationships in 50 healthy individuals across multiple behavioural and anatomical domains, and complementing FA with myelin-sensitive quantitative MR modalities (MT, R1, R2*). Surprisingly, we only find support for predicted relationships between FA and behaviour in one of three pre-registered tests. For one behavioural domain, where we failed to detect an FA-behaviour correlation, we instead find evidence for a correlation between behaviour and R1. This hints that multimodal approaches are able to identify a wider range of WM-behaviour relationships than focusing on FA alone. To test whether a common biological substrate such as myelin underlies WM-behaviour relationships, we then ran joint multimodal analyses, combining across all MRI parameters considered. No significant multimodal signatures were found and power analyses suggested that sample sizes of 40 to 200 may be required to detect such joint multimodal effects, depending on the task being considered. These results demonstrate that FA-behaviour relationships from the literature can be replicated, but may not be easily generalisable across domains. Instead, multimodal microstructural imaging may be best placed to detect a wider range of WM-behaviour relationships, as different MRI modalities provide distinct biological sensitivities. Our findings highlight a broad heterogeneity in WMs relationship with behaviour, suggesting that variable biological effects may be shaping their interaction. HighlightsO_LIPre-registered testing of microstructural imaging across modalities (FA, MT, R1, R2*) to test WM-behaviour relationships. C_LIO_LIPartial support for FA-behaviour relationships hypothesised based on previous literature. C_LIO_LIMultimodal approaches can help detect WM-behaviour relationships that are not detected with FA alone. C_LIO_LISample sizes of 40 to 200 may be needed to detect myelin-behaviour relationships in joint multimodal analyses. C_LIO_LIVariable biological effects may be shaping WM-behaviour relationships. C_LI

neuroscience↗

bioRxiv2020

Can MRI measure myelin? Systematic review, qualitative assessment, and meta-analysis of studies validating microstructural imaging with myelin histology

Recent years have seen an increased understanding of the importance of myelination in healthy brain function and neuropsychiatric diseases. Non-invasive microstructural magnetic resonance imaging (MRI) holds the potential to expand and translate these insights to basic and clinical human research, but the sensitivity and specificity of different MR markers to myelination is a subject of debate. To consolidate current knowledge on the topic, we perform a systematic review and meta-analysis of studies that validate microstructural imaging by combining it with myelin histology. We find meta-analytic evidence for correlations between myelin histology and markers from different MRI modalities, including fractional anisotropy, radial diffusivity, macromolecular pool, magnetization transfer ratio, susceptibility and longitudinal relaxation rate, but not mean diffusivity. Meta-analytic correlation effect sizes range widely, between R2 = 0.26 and R2 = 0.82. However, formal comparisons between MRI-based myelin markers are limited by methodological variability, inconsistent reporting and potential for publication bias, thus preventing the establishment of a single most sensitive strategy to measure myelin with MRI. To facilitate further progress, we provide a detailed characterisation of the evaluated studies as an online resource. We also share a set of 12 recommendations for future studies validating putative MR-based myelin markers and deploying them in vivo in humans. HighlightsO_LISystematic review and meta-analysis of studies validating microstructural imaging with myelin histology C_LIO_LIWe find many MR markers are sensitive to myelin, including FA, RD, MP, MTR, Susceptibility, R1, but not MD C_LIO_LIFormal comparisons between MRI-based myelin markers are limited by methodological variability, inconsistent reporting and potential for publication bias C_LIO_LIResults emphasize the advantage of using multimodal imaging when testing hypotheses related to myelin in vivo in humans. C_LI

neuroscience↗

bioRxiv2020

Causal evidence of network communication in whole-brain dynamics through a multiplexed neural code

An important question in neuroscience is how local activity can be flexibly and selectively routed across the brain network. A proposed mechanism to flexibly route information is frequency division multiplexing: selective readout can be achieved by segregating the signal into non-overlapping frequency bands. Here, in wild-type mice and in a transgenic model (3xTgAD) of Alzheimers Disease (AD), we use optogenetic activation of the entorhinal cortex, concurrent whole-brain fMRI, and hidden Markov modeling. We demonstrate how inducing neuronal spiking with different theta frequencies causes spatially distinct states of brain network dynamics to emerge and to preferentially respond to one frequency, showing how selective information streams can arise from a single neuronal source of activity. This theta modulation mechanism, however, is impaired in the AD model. This work demonstrates that neuronal multiplexing is a sufficient mechanism to enable flexible brain network communication, and provides insight into the aberrant mechanisms underlying cognitive decline.

neuroscience↗

bioRxiv2019

Skill acquisition increases myelination and strengthens functional connectivity in the sensorimotor circuit of the adult rat

The effects of skill acquisition on whole-brain structure and functional networks have been extensively investigated in humans but have yet to be explored in rodents. Forelimb reaching training in rodents results in well-established focal functional and structural reorganization within the motor cortex (M1) and cerebellum, indicating distributed alterations in both structure and function. However, it is unclear how local alterations in structure and function relate to distributed learning-related changes across motor networks. Here we trained adult rats in skilled reaching and used multimodal whole-brain in vivo MRI to assess both structural and functional plasticity over time.\n\nWe detected increases in a myelin-related MRI metric in white matter, cortical areas, and to a lesser extent in the cerebellum, paralleled by strengthened functional connectivity between M1 and cerebellum, possibly reflecting a decrease in cerebellum inhibition over M1. Skill learning therefore leads to myelin increases in pathways that connect sensorimotor regions, and in functional connectivity increases between areas involved in motor learning, all of which correlate with performance. These findings closely mirror previous reports of network-level changes following motor learning in humans and underlines the correspondence between human and rodent brain circuits for motor learning, despite important differences in the anatomy of physiology of movement circuits between species.

neuroscience↗