Biology subjects

Bussey, T. J.

Publications and source records attributed to Bussey, T. J..

9 recordsLinked to original sources

bioRxiv2026

Myelin maturation failure and oligodendrocyte precursor loss underlie default mode network disruption in a humanized APP knock-in model of Alzheimers disease

Alzheimers disease disrupts large-scale brain networks before cognitive symptoms emerge, yet the mechanisms underlying this progression remain unclear. In humans, default mode network (DMN) connectivity follows a biphasic trajectory, with a transition from hypersynchrony to hyposynchrony associated with increasing amyloid burden and cognitive decline. Using a mouse model of amyloidopathy that recapitulates this trajectory, we show that amyloid-{beta} accumulation arrests normal age-dependent myelin maturation, followed by progressive myelin loss and oligodendroglial dysfunction. In healthy animals, regional myelin coverage predicts DMN strength, revealing a coupling that is disrupted by amyloidopathy. Notably, DMN hypersynchrony emerges before substantial amyloid accumulation or overt myelin loss, whereas subsequent oligodendroglial dysfunction and myelin loss coincide with DMN disintegration and cognitive deficits. These findings identify disruption of myelin-network coupling as a potential mechanism underlying the biphasic evolution of network dysfunction in Alzheimers disease and suggest that restoring oligodendroglial function may provide cognitive benefits beyond those of amyloid-targeting strategies.

neuroscience↗

bioRxiv2026

α-synuclein pathology drives multi-scale reorganization of fronto-limbic networks and cognitive flexibility in the common marmoset

Understanding how -synuclein misfolding and spreading affect brain systems is central to synucleinopathy research, yet evidence from primate models remains limited. Here, we combined histology, awake structural MRI, awake resting-state fMRI, regional homogeneity, actimetry and touchscreen behavioral testing to longitudinally track the consequences of striatal -synuclein seeding in the common marmoset. Phosphorylated -synuclein inclusions were detected from 2 months post-injection and spread progressively to distributed cortical and subcortical regions bilaterally, accompanied by regionally specific structural atrophy. Functional imaging revealed widespread disruption of large-scale networks, particularly within fronto-limbic circuits, alongside reductions in local functional coherence. Despite the absence of overt motor or sleep deficits, animals exhibited a selective impairment in cognitive flexibility, with preserved learning and task engagement. These findings indicate that striatal -synuclein seeding induces a multi-scale reorganization of brain networks preferentially affecting circuits supporting cognitive flexibility and limbic processing, establishing a primate platform for studying early stages of synucleinopathy.

animal behavior and cognition↗

bioRxiv2025

Cholinergic synaptic plasticity shapes resilience and vulnerability to tau

Synaptic dysfunction is a hallmark of Alzheimers disease (AD). Yet due to their plasticity, synapses may also adapt to early AD pathology. Here, we demonstrate that cholinergic neurons mount a presynaptic response to tau pathology in the living human brain. Using multi-tracer positron emission tomography in cognitively normal older adults at risk for AD, we observe that cholinergic neurons increase presynaptic vesicular acetylcholine transporter (VAChT) protein levels when colocalized to tau, but not amyloid. Notably, stronger VAChT responses were associated with cognitive resilience over a decade. Whole-brain single-nucleus RNA sequencing in human and mouse tissue reveal that cholinergic neurons are enriched for a plasticity gene-network anchored to the microtubule-associated protein tau (MAPT) gene. In mice, forebrain-specific deletion of VAChT impairs cortical plasticity and hippocampal structural integrity. Overall, our findings identify cholinergic synaptic plasticity, and its failure, as a fundamental mechanism of resilience and vulnerability to tau in presymptomatic AD.

neuroscience↗

bioRxiv2025

Prefrontal parvalbumin neurons as a target for enhancing cognition in non-pathological and 22q11.2 microdeletion syndrome mice

A failure of organized communication in the PFC is thought to contribute to the emergence of cognitive impairments in psychiatric diseases, with attentional deficits occurring as a fundamental symptom across various conditions. The 22q11.2 microdeletion syndrome is a rare genetic condition that confers a high risk for developing psychiatric and neurodevelopmental disorders, and mouse models have been shown to display attention impairments and PFC pathology that are relevant to clinical populations. Abnormalities in prefrontal parvalbumin-expressing neurons (PVNs) are part of the observed pathophysiology, and studies in rodents have shown that the direct manipulation of these cells can induce behavioral deficits that align with the cognitive symptoms observed in psychiatric diseases. In the present study, we expanded on the role of PVNs in supporting cognition by investigating their involvement in multiple aspects of attentional functions using a translationally relevant task of focused visual attention, in both non-pathological mice and a model of the 22q11.2 microdeletion syndrome. We observed that task-evoked prefrontal PVN activity was reduced in mice that exhibited poorer attention and in 22q11.2 mutant mice. While PVN activity was shaped across learning in non-pathological mice, mutant mice exhibited a lack of signal dynamics that coincided with attentional deficits. Importantly, we observed that task performance in both poor performing wild-types and 22q11.2 mutants could be alleviated by gamma frequency stimulation of PVNs. Thus, PVNs appear to be involved in the acquisition of task rules and execution of attention and continue to be a promising therapeutic target for cognitive dysfunction in disease.

neuroscience↗

bioRxiv2025

Characterisation of a touchscreen-based Go/No Go task for assessing cognitive judgement bias in mice: a new translational tool for affective state disorder drug screening.

A major obstacle in the pre-clinical study of mood-related disorders and novel affective state therapeutic evaluation is the lack of animal models that fully recapitulate human symptomatology. In this study, we developed a touchscreen-based Go/No Go cognitive judgement bias (CJB) task for mice. In this task, animals first learned to discriminate between two visual stimuli displayed on the touchscreen: one associated with a reward (S+) and one associated with a time-out and flashing house light (S-). Once mice learned to respond to the S+ and to withhold responding to the S- consistently, a set of four ambiguous stimuli ranging in visual similarity to the S+ and S- stimuli were randomly interspersed in the stimulus presentation sequence. Responses to these ambiguous stimuli were interpreted as a greater expectation of positive ( optimistic bias) or negative ( pessimistic bias) outcomes as a function of their similarity to the S+ or S- stimuli. The acute administration of the SSRIs fluoxetine and citalopram and the 5HT-2C receptor antagonist SB204048 did not produce any effects on CJB task performance. However, the noradrenaline/dopamine reuptake inhibitor, bupropion, increased responses to the ambiguous stimuli consistent with induction of an optimistic bias and the pro-depressant tetrabenazine yielded the opposite effect. This study underscores the capacity of mice to respond to visually ambiguous stimuli in an ambiguity-dependent manner, a phenomenon observed across various species, including humans. Furthermore, it establishes and validates an operant behavioural task to assess CJB in mice delivered using the touchscreen platform which has significant intrinsic cross-species translational potential.

animal behavior and cognition↗

bioRxiv2024

Dissociable patterns of dopamine dynamics and causal contributions to stimulus-response behaviors across striatal subregions.

Rationale: Midbrain dopamine (DA) neurons project principally towards the striatum, serving as key regulators of movement, motivation, and cognition. Different striatal dopaminergic (DA) pathways may regulate different aspects of cognition. Objectives: We investigated how different striatal DA pathways contribute to a known function of the striatum, visuomotor conditional learning. Methods: Using fiber photometry, we recorded DA transients in these regions as mice learned the touchscreen Visuo-Motor Conditional Learning task. Results: DA transients in all regions dynamically tracked task events, but differed in the timing of peak responses and ramp-like activity preceding a choice, indicating region-specific temporal dynamics across learning. Manipulations of reward probability revealed DA transients in all regions during reward delivery and omission that are consistent with an interpretation in terms of reward prediction error. Thus, DA dynamics in all regions could indicate involvement in visuomotor conditional learning. Therefore, to determine whether nigrostriatal or mesolimbic DA is necessary for learning, we chemogenetically inhibited DA striatal afferents, revealing that only DLS-projecting nigrostriatal DA, and not NAc-projecting mesolimbic striatal DA, was necessary for learning the task. Conclusion: These findings demonstrate functional heterogeneity of aspects of striatal DA signaling, and selective causal roles in the learning of visuomotor conditional learning.

animal behavior and cognition↗

bioRxiv2022

Presymptomatic neuroanatomical and cognitive biomarkers of alpha-synuclein propagation in a mouse model of synucleinopathy

There is significant evidence suggesting aggregated misfolded alpha-synuclein, a major component of Lewy bodies, propagates in a prion-like manner contributing to disease progression in Parkinsons disease (PD) and other synucleinopathies. Animal models are essential for understanding and developing treatments for these diseases. However, despite modelling human pathology, most endpoints studied in mice do not translate to humans. Furthermore, the progression by which alpha-synuclein misfolding affects human-relevant measures such as brain volume and underlying subtle, high-level cognitive deficits is poorly understood. Here we used a mouse model of synucleinopathy; hemizygous M83 human A53T alpha-synuclein transgenic mice inoculated with recombinant human alpha-synuclein preformed fibrils (PFF) injected in the right striatum to initiate alpha-synuclein misfolding and aggregation. We examined alpha-synuclein-induced atrophy at 90 days post-injection using ex vivo magnetic resonance imaging as well as high-level cognition and motor function, as biomarkers of alpha-synuclein toxicity. We observed widespread atrophy in bilateral regions that project to or receive input from the injection site, highlighting a network of regions that are consistent with structural changes observed in humans with PD. Moreover, we detected early deficits in reversal learning with touchscreen testing in PFF-injected mice prior to motor dysfunction, consistent with the pathology observed in cortical-striatal and thalamic loops. We show, using translational approaches in mice, that progression of prion-like spreading of alpha-synuclein causes selective atrophy via connected brain regions leading to high-level cognitive deficits. We propose that precise imaging and cognitive biomarkers can provide a more direct and human-relevant measurement of alpha-synuclein-induced toxicity in pre-clinical testing. Significance StatementThe work described in this manuscript showcases the utility of state-of-the-art methodologies (magnetic resonance imaging and touchscreen behavioural tasks) to examine endophenotypes, both in terms of symptomatology and neuroanatomy, of alpha-synuclein propagation in a mouse model of synucleinopathy. Our work further validates the M83-Hu-PFF mouse model of synucleinopathy-associated pathogenesis of neurodegenerative diseases while highlighting precise imaging and cognitive biomarkers of protein misfolding toxicity. Specifically, we identified rapid and translational biomarkers that can serve as a proxy for the direct examination of cellular levels for pathology. We anticipate that these biomarkers can measure progression of toxicity, specifically in the early phases, and may be more reliable than end stage pathology and more useful as endpoints in the examination of novel therapeutics.

neuroscience↗

bioRxiv2021

Activity in perirhinal and entorhinal cortex predicts observer-specific perceived visual similarities between objects

Vision neuroscience has made great strides in understanding the hierarchical organization of object representations along the ventral visual stream (VVS). How VVS representations capture fine-grained visual similarities between objects that observers subjectively perceive has received limited examination so far. In the current study, we addressed this question by focusing on perceived visual similarities among subordinate exemplars of real world-categories. We hypothesized that these perceived similarities are reflected with highest fidelity in neural activity patterns downstream from inferotemporal regions, namely in perirhinal and anterolateral entorhinal cortex in the medial temporal-lobe. To address this issue with fMRI, we administered a modified 1-Back task that required discrimination between category exemplars as well as categorization. Further, we obtained observer-specific ratings of perceived visual similarities, which predicted behavioural performance during scanning. As anticipated, we found that activity patterns in perirhinal and anterolateral entorhinal cortex predicted the structure of perceived visual similarity relationships among category exemplars, including its observer-specific component, with higher precision than any other VVS region. Our findings provide new evidence that subjective aspects of object perception that rely on fine-grained visual differentiation are reflected with highest fidelity in the medial temporal lobe.

neuroscience↗

bioRxiv2018

Basal forebrain and brainstem cholinergic neurons differentially impact amygdala circuits and learning-related behavior

The central cholinergic system and the amygdala are important for motivation and mnemonic processes. Different cholinergic populations innervate the amygdala but it is unclear how these projections impact amygdala processes. Using optogenetic circuit-mapping strategies in ChAT-cre mice we demonstrate that amygdala-projecting basal forebrain and brainstem ChAT-containing neurons can differentially affect amygdala circuits and behavior. Photo-activating ChAT terminals in vitro revealed the underlying synaptic impact of brainstem inputs to the central lateral division to be excitatory, mediated via the synergistic glutamatergic activation of AMPA and NMDA receptors. In contrast, stimulating basal forebrain inputs to the basal nucleus resulted in endogenous ACh release resulting in biphasic inhibition-excitation responses onto principal neurons. Such response profiles are physiological hallmarks of neural oscillations and could thus form the basis of acetylcholine-mediated rhythmicity in amygdala networks. Consistent with this, in vivo NBm activation strengthened amygdala basal nucleus theta and gamma frequency rhythmicity, both of which continued for seconds after stimulation and were dependent on local muscarinic or nicotinic receptor activation, respectively. Activation of brainstem ChAT-containing neurons however resulted in a transient increase in central lateral amygdala activity that was independent of cholinergic receptors. In addition, driving these respective inputs in behaving animals induced opposing appetitive and defensive learning-related behavioral changes. Since learning and memory is supported by both cellular and network-level processes in central cholinergic and amygdala networks, these results provide a route by which distinct cholinergic inputs can convey salient information to the amygdala and promote associative biophysical changes that underlie emotional memories.

neuroscience↗