Biology subjects

Jordan, J. T.

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

5 recordsLinked to original sources

bioRxiv2023

Delayed formation of neural representations of space in aged mice

Aging is associated with cognitive deficits, with spatial memory being very susceptible to decline. The hippocampal dentate gyrus (DG) is important for processing spatial information in the brain and is particularly vulnerable to aging, yet its sparse activity has led to difficulties in assessing changes in this area. Using in vivo two-photon calcium imaging, we compared DG neuronal activity and representations of space in young and aged mice walking on an unfamiliar treadmill. We found that calcium activity was significantly higher and less tuned to location in aged mice, resulting in decreased spatial information encoded in the DG. However, with repeated exposure to the same treadmill, both spatial tuning and information levels in aged mice became similar to young mice, while activity remained elevated. Our results show that spatial representations of novel environments are impaired in the aged hippocampus and gradually improve with increased familiarity. Moreover, while the aged DG is hyperexcitable, this does not disrupt neural representations of familiar environments.

neuroscience↗

bioRxiv2022

Genomic patterns of malignant peripheral nerve sheath tumour (MPNST) evolution correlate with clinical outcome and are detectable in cell-free DNA

Malignant peripheral nerve sheath tumour (MPNST) is an aggressive soft-tissue sarcoma that arises in peripheral nerves. MPNST occurs either sporadically or in people with neurofibromatosis type 1 (NF1), a common cancer predisposition syndrome caused by germline pathogenic variants in NF1. Although MPNST is the most common cause of death and morbidity for individuals with NF1, the molecular underpinnings of MPNST pathogenesis remain unclear. Here, we report the analysis of whole-genome sequencing, multi-regional exome sequencing, transcriptomic and methylation profiling data for 95 MPNSTs and precursor lesions (64 NF1-related; 31 sporadic) from 77 individuals. Early events in tumour evolution include biallelic inactivation of NF1 followed by inactivation of CDKN2A and in some cases also TP53 and polycomb repressive complex 2 (PRC2) genes. Subsequently, both sporadic and NF1-related MPNSTs acquire a high burden of somatic copy number alterations (SCNAs). Our analysis revealed distinct pathways of tumour evolution and immune infiltration associated with inactivation of PRC2 genes and H3K27 trimethylation (H3K27me3) status. Tumours with loss of H3K27me3 evolve through extensive chromosomal losses with retention of chromosome 8 heterozygosity followed by whole genome doubling and chromosome 8 amplification. These tumours show lower levels of immune cell infiltration with low cytotoxic activity and low expression of immune checkpoints. In contrast, tumours with retention of H3K27me3 evolve through extensive genomic instability in the absence of recurrent alterations and exhibit an immune cell-rich phenotype. Specific SCNAs detected in both tumour samples and cell-free DNA (cfDNA) act as a surrogate for loss of H3K27me3 and immune infiltration, and predict prognosis. Our results suggest that SCNA profiling of tumour or cfDNA could serve as a biomarker for early diagnosis and to stratify patients into prognostic and treatment-related subgroups.

cancer biology↗

bioRxiv2021

Silencing of hippocampal synaptic transmission impairs spatial reward search on a head-fixed tactile treadmill task

Head-fixed linear treadmill tasks have been used to study hippocampal physiology in mice. Although some hippocampal neurons establish place fields along linear treadmills, it is not clear if the hippocampus is required for spatial memory on this task. Using a Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) approach, we found that silencing hippocampal output on rewarded treadmill tasks impaired search for rewards signaled by spatial cues but did not impair search for rewards signaled by local cues, recapitulating findings from other behavior tasks. These findings serve to contextualize data on hippocampal physiology from mice performing this task.

neuroscience↗

bioRxiv2017

Behavior state-dependent lateralization of dorsal dentate gyrus c-Fos expression in mice

Hemispheric lateralization is a fundamental organizing principle of nervous systems across taxonomic groups with bilateral symmetry. The mammalian hippocampus is lateralized anatomically, physiologically, and chemically; however, functional asymmetries are not yet well understood. Imaging studies in humans have implicated the left and right hippocampus in specialized processing. However, it is not clear if lateralized activity occurs in the rodent hippocampus. c-Fos imaging in animals provides a measure of neuronal activity with a resolution at the level of single cells. The aim of this study was to determine whether lateralized activity-dependent c-Fos expression occurs in the rodent hippocampus. To understand functional lateralization of hippocampal processing, we compared interhemispheric expression of c-Fos in the dentate gyrus (DG), a structure involved in encoding new experiences, in mice that ran on a wheel, encoded a novel object, or remained in home cages. We found that wheel running induced the greatest amount of DG c-Fos expression in both hemispheres, with no difference between hemispheres. Object exploration resulted in left-lateralized DG c-Fos expression, whereas control mice were not lateralized. We then sought to determine whether differential consideration of hemispheres might influence the conclusions of a study by simulating common cell quantification methods. We found that different approaches led to different conclusions. These data demonstrate lateralization of neuronal activity in the mouse DG corresponding to the experience of the animal and show that differentially considering hemisphere leads to alternative conclusions.

neuroscience↗

bioRxiv2017

Interhemispheric specialization in the rodent hippocampus: Implications for storage and retrieval of short- and long-term memories

The left and right rodent hippocampi exhibit striking lateralization in some of the very neural substrates considered to be critical for hippocampal cognitive function. Despite this, there is an overwhelming lack of consideration for hemispheric differences in studies of the rodent hippocampus. Asymmetries identified so far suggest that a bilateral model of the hippocampus will be essential for an understanding of this brain region, and perhaps of the brain more widely. Although hypotheses have been proposed to explain how the left and right hippocampi contribute to behavior and cognition, these hypotheses have either been refuted by more recent studies or have been limited in the scope of data they explain. Here, I will first review data on human and rodent hippocampal lateralization. The implications of these data suggest that considering the hippocampus as a bilateral structure with functional lateralization will be critical moving forward in understanding the function and mechanisms of this brain region. In exploring these implications, I will then propose a hypothesis of the hippocampus as a bilateral structure. This discrete-continuous (DC) hypothesis proposes that the left and right hippocampi contribute to spatial memory and navigation in a complementary manner. Specifically, the left hemisphere stores spatial information as discrete, salient locations and that the right hemisphere represents space continuously, contributing to route computation and flexible spatial navigation. Consideration of hippocampal lateralization in designing future studies may provide insight into the function of the hippocampus and resolve debates concerning its function.

neuroscience↗