Biology subjects

Cassidy, C.

Publications and source records attributed to Cassidy, C..

6 recordsLinked to original sources

bioRxiv2026

Developmental origins of thymic B-cell lymphomas

The thymus provides a specialized niche for lymphocyte differentiation, yet the developmental trajectories of its rare B-cell population and their relationship to thymic B-cell lymphomagenesis remain poorly understood. Here, we integrate single-cell multiomics and spatial profiling across human tissues to delineate a B-cell differentiation program selectively represented in the human thymus. This program links CCL17 and germinal center-like B-cell states along a trajectory distinct from canonical germinal center differentiation and can be recapitulated in vitro by signals operating in the thymic medulla. Extending this framework across human B-cell lymphomas, we identify an inherent malignant cell state in PMBCL that shares transcriptional and epigenetic features with CCL17 thymic B cells. This malignant state associates with early clonal positions in reconstructed B-cell receptor phylogenies and persists within tumor microenvironments distinct from the thymic niche. Together, these findings support a model in which thymus-specific B-cell differentiation programs are redeployed during thymic B-cell lymphomagenesis.

cancer biology↗

bioRxiv2026

Blunted fear-evoked striatal dopamine release in individuals with a family history of psychosis

While excess tonic dopamine signalling is a hallmark of schizophrenia and psychotic disorders, it has been difficult to reconcile with dopamine-dependent learning deficits seen in schizophrenia. Excess spontaneous activity of tonic dopamine neurons, coupled with reduced coordinated activity of phasic dopamine neurons, may explain the observed discrepancy between increased tonic signalling and impaired learning. Although intriguing, this chaotic dopamine hypothesis lacks empirical support. In the current study, Pavlovian fear conditioning is used to test this hypothesis in healthy individuals with and without a family history of psychosis using simultaneous [11C]raclopride PET/fMRI. In 16 healthy individuals without a family history of psychosis, we first show that fear conditioning releases dopamine and link this release to BOLD responses. We then report that in 12 first-degree relatives of individuals with psychotic disorders, this adaptive dopamine release in the posterior caudate is lacking, despite no differences in behavioural learning. Furthermore, reduced dopamine release is associated with increased self-reported paranoid thinking, but not with anhedonia. These findings provide novel in vivo evidence supporting the chaotic dopamine hypothesis, suggesting that an adaptive, stimulus-driven dopamine release is lacking in psychotic disorders and may contribute to positive symptoms like paranoia.

neuroscience↗

bioRxiv2025

Pleasure in groove is associated with neuromelanin levels in the substantia nigra of younger healthy individuals: A neuromelanin-sensitive MRI study

The pleasurable urge to move in response to music is called groove. Prior research has suggested a potential link between groove and dopamine function. However, no studies to date have directly investigated the relationship between the two. Here, we aimed to assess individual dopamine function in the substantia nigra of healthy individuals using neuromelanin-sensitive magnetic resonance imaging (NM-MRI), a non-invasive method associated with dopamine function, and to investigate the relationship between the individual dopamine proxy index and sensitivity to the groove experience. In this study, 15 younger (< 48 years) and 16 older ([greater double equals]48 years) healthy individuals participated. Participants listened to ten musical excerpts and rated the groove experience based on "pleasure" and "wanting to move." To assess whether the groove experience is related to NM levels, type of musical excerpts, and sex, we analyzed with linear mixed-effects regression models. The results showed that higher NM levels (p = 0.032) and male sex (p = 0.034) were associated with higher pleasure ratings in the younger group. For the "urge to move" ratings, type of musical excerpts was associated with ratings in both groups (ps < 0.001), where high-groove music (Janata et al., 2012) receiving higher ratings. Taken together, these results suggest that the "pleasure" aspect of the groove experience in younger individuals was related to dopamine levels in the substantia nigra, but may not be associated with the "urge to move." Thus, pleasure and the urge to move are likely to involve distinct dopaminergic pathways and mechanisms, warranting further investigation.

neuroscience↗

bioRxiv2024

Converging effects of cannabis and psychosis on the dopamine system: A longitudinal neuromelanin-sensitive MRI study in cannabis use disorder and first episode schizophrenia.

ImportanceDespite evidence that individuals who use cannabis early in life are at elevated risk of psychosis and that the neurotransmitter dopamine has a role in both conditions, the mechanism linking the two conditions remains unclear. ObjectiveTo use neuromelanin-sensitive MRI (neuromelanin-MRI), a practical, proxy measure of dopamine function, to assess whether a common alteration in the dopamine system may be implicated in cannabis use and psychosis and whether this alteration can be observed in cannabis users whether or not they have a diagnosis of first-episode schizophrenia. Design, Setting, and ParticipantsThis longitudinal observational study recruited participants from 2019 to 2023 from an early intervention service for psychosis in London, Ontario, Canada. The sample consisted of 25 participants with cannabis use disorder (CUD) and 36 participants without CUD (nCUD), of which 28 had first-episode schizophrenia (FES). One-year follow-up was completed for 12 CUD and 25 nCUD participants. Main Outcomes and MeasuresNeuromelanin-MRI contrast within the substantia nigra (SN) and within a subregion previously linked to psychosis severity (a priori psychosis region of interest) and diagnoses of schizophrenia-spectrum disorder and cannabis use disorder derived from the Structured Clinical Interview for DSM-5. Linear mixed effects analyses were performed relating neuromelanin-MRI contrast to clinical measures. ResultsWe found that CUD was associated with elevated neuromelanin-MRI signal in a cluster of ventral SN voxels (387 of 2060 SN voxels, pcorrected=0.027, permutation test). Furthermore, CUD was associated with elevated neuromelanin-MRI signal in an SN subregion previously documented to have elevated signal in relation to untreated psychotic symptoms (t92 =2.12, p=0.037). In contrast, FES was not associated with a significant alteration in neuromelanin-MRI signal (241 SN voxels had elevated signal, pcorrected=0.094). Conclusions and RelevanceThese findings suggest that elevated dopamine function in a critical SN subregion may contribute to the risk of psychosis in people with CUD. Thus, cannabis affects the long-suspected final common pathway for the clinical expression of psychotic symptoms. Imaging the dopamine system with neuromelanin-MRI may index long-term dopamine turnover. Key PointsO_ST_ABSQuestionC_ST_ABSIs the same midbrain dopamine pathway impacted by cannabis as in psychosis? FindingsCannabis use disorder participants had elevated neuromelanin-MRI signal in a cluster of ventral substantia nigra voxels and in a subregion previously documented to have elevated signal in relation to untreated psychotic symptoms. MeaningIncreased dopamine functioning in the ventral substantia nigra may contribute to the risk of psychosis in people with cannabis use disorders.

neuroscience↗

bioRxiv2022

Normative values of neuromelanin-sensitive MRI signal in older adults obtained using a standard protocol for acquisition and analysis

BackgroundThe integrity and function of catecholamine neurotransmitter systems can be assessed using MRI sequences often referred to as neuromelanin-sensitive MRI (NM-MRI). The relevance of this method to neurodegenerative and psychiatric disorders is becoming increasingly evident, and it has potential as a clinical biomarker. To support such future applications, we report here the normative range of NM-MRI signal and volume metrics in cognitively normal older adults. Methods3 Tesla NM-MRI images and demographic and cognitive data were available from 152 cognitively normal older adults aged 53-86 years old at baseline; a subsample of 68 participants also had follow-up NM-MRI data collected around one-year later. NM-MRI images were processed to yield summary measures of volume and signal (contrast-to-noise ratio, CNR) for the substantia nigra (SN) and locus coeruleus (LC) using a recently developed software employing a fully automated algorithm. The extent of annual change in these metrics was quantified and tested for significance using 1-sample t-tests. ResultsBaseline SN signal (CNR) was 10.02% (left SN) and 10.28% (right) and baseline LC signal was 24.71% (left) and 20.42% (right). The only NM-MRI metric to show a significant annual change was a decrease in left SN volume. ConclusionWe report normative values for NM-MRI signal and volume in the SN and LC of cognitively normal older adults and normative values for their change over time. These values may help future efforts to use NM-MRI as a clinical biomarker for adults in this age range by facilitating identification of patients with extreme NM-MRI values.

neuroscience↗

bioRxiv2020

Optogenetic evaluation of the ability of different cutaneous C-fiber afferents to evoke aversive behaviors

Most cutaneous C-fibers, including both peptidergic and non-peptidergic subtypes are presumed to be nociceptors and respond to noxious input in a graded manner. However, mechanically sensitive, non-peptidergic C-fibers also respond to mechanical input in the innocuous range, and so the degree to which they contribute to nociception remains unclear. To address this gap, we investigated the function of non-peptidergic afferents using the MrgprdCre allele. In real time place aversion studies, we found that low frequency optogenetic activation of MrgrpdCre lineage neurons was not aversive in naive mice, but became aversive after spared nerve injury (SNI). To address the underlying mechanisms of this allodynia, we recorded from lamina I spinoparabrachial (SPB) neurons using the semi-intact ex vivo preparation. Following SNI, innocuous brushing of the skin gave rise to abnormal activity in lamina I SPB neurons, consisting of an increase in the proportion of recorded neurons that responded with excitatory post synaptic potentials or action potentials. This increase was likely due, at least in part, to an increase in the proportion of lamina I (LI) SPB neurons that received input upon optogenetic activation of MrgprdCre lineage neurons. Intriguingly, in SPB neurons there was a significant increase in the EPSC latency from MrgprdCre lineage input following SNI, consistent with the possibility that the greater activation post SNI could be due to the recruitment of a new polysynaptic circuit. Together, our findings suggest MrgprdCre lineage neurons can provide mechanical input to the dorsal horn that is non-noxious before injury but becomes noxious afterwards due the engagement of a previously silent polysynaptic circuit in the dorsal horn.

neuroscience↗